END0STAGERENAL FAILURE BENJAMINKANE*DUNDON · 2014. 6. 19. ·...

EVALUATION OF ALTERATIONS IN CARDIOVASCULAR

STRUCTURE AND FUNCTION IN

END-STAGE RENAL FAILURE

BENJAMIN KANE DUNDON

MBBS FRACP

DOCTOR OF PHILOSOPHY

DISCIPLINE OF MEDICINE

SCHOOL OF MEDICINE

UNIVERSITY OF ADELAIDE

ADELAIDE, SOUTH AUSTRALIA

AUSTRALIA

Submitted in the total fulfilment of the requirements

for the degree of Doctor of Philosophy

March 2013

ii

To Annabel, without whom

none of this would have been possible.

iii

TABLE OF CONTENTS

TABLE OF CONTENTS ..................................................................................................... III

FIGURE LEGEND: .............................................................................................................. IX

TABLE LEGEND.............................................................................................................. XIII

ABSTRACT........................................................................................................................XIV

Background:............................................................................................................................................................................xiv

Methods / Results:...............................................................................................................................................................xiv

Conclusions:............................................................................................................................................................................xvi

DECLARATION .............................................................................................................. XVII

ACKNOWLEDGMENTS ...............................................................................................XVIII

ABBREVIATIONS ............................................................................................................XXI

BACKGROUND.....................................................................................................................1

CHRONIC KIDNEY DISEASE................................................................................................................. 2

Glomerular Filtration Rate.......................................................................................................................2

Disease Burden ..............................................................................................................................................6

Financial Burden of CKD ...........................................................................................................................7

Aetiology...........................................................................................................................................................8

Co-Morbid Conventional Cardiovascular Risk Factors ............................................................. 10

Diabetes Mellitus ...................................................................................................................................................................11

Hypertension...........................................................................................................................................................................12

Smoking.....................................................................................................................................................................................12

Hyperlipidaemia ....................................................................................................................................................................13

Obesity .......................................................................................................................................................................................14

Disease-Specific Cardiovascular Risk Factors ............................................................................... 14

Anaemia.....................................................................................................................................................................................14

iv

Disordered Calcium / Phosphate Metabolism..........................................................................................................16

Uraemia .....................................................................................................................................................................................19

CARDIOVASCULAR SEQUELAE OF CKD.......................................................................................... 26

Left Ventricular Disease in CKD .......................................................................................................... 27

Congestive Cardiac Failure................................................................................................................................................32

Atrial Disease in CKD ............................................................................................................................... 36

Valvular Disease in CKD.......................................................................................................................... 38

Endothelial Dysfunction in CKD .......................................................................................................... 41

Pathobiology of Endothelial Dysfunction in CKD....................................................................................................42

Assessment of Endothelial Function.............................................................................................................................44

Endothelial Dysfunction and Cardiovascular Risk in CKD ..................................................................................44

Coronary Artery Disease in CKD.......................................................................................................... 46

Coronary Endothelial Function.......................................................................................................................................46

Coronary Atherosclerosis ..................................................................................................................................................52

Vascular Disease in Chronic Kidney Disease.................................................................................. 56

Arterial Function ...................................................................................................................................................................56

Atherosclerosis.......................................................................................................................................................................58

Arteriosclerosis......................................................................................................................................................................59

Vascular Calcification ..........................................................................................................................................................60

Non-‐invasive Evaluation of Arterial Stiffness ...........................................................................................................62

ARTERIO-‐VENOUS FISTULAE AND CARDIOVASCULAR STRUCTURE AND FUNCTION............... 69

Arterio-venous Fistula Creation .......................................................................................................... 69

Pulmonary Hypertension in Patients with Arterio-‐venous Fistulae...............................................................71

Arterio-Venous Fistula Ligation.......................................................................................................... 72

EFFECTS OF RENAL TRANSPLANTATION ON CARDIOVASCULAR STRUCTURE AND FUNCTION

............................................................................................................................................................. 73

EVALUATION OF CARDIOVASCULAR RISK PRIOR TO RENAL TRANSPLANTATION................... 76

Tachycardia Stress Methodologies ................................................................................................................................78

NON-‐INVASIVE IMAGING OF CARDIOVASCULAR STRUCTURE AND FUNCTION IN CKD........... 80

v

Trans-‐thoracic Echocardiography .................................................................................................................................81

Single Photon Emission Computed Tomography....................................................................................................83

Cardiovascular Computed Tomography .....................................................................................................................83

Cardiovascular Magnetic Resonance Imaging ..........................................................................................................84

AIMS OF THIS THESIS ....................................................................................................................... 88

METHODS .......................................................................................................................... 89

RESEARCH ETHICS CONSIDERATIONS............................................................................................ 90

STUDY 1: EVALUATION OF ALTERATIONS IN CARDIOVASCULAR STRUCTURE AND FUNCTION

FOLLOWING ELECTIVE ARTERIO-‐VENOUS FISTULA CREATION IN PRE-‐DIALYSIS END-‐STAGE

RENAL FAILURE ................................................................................................................................ 90

Subjects .......................................................................................................................................................... 90

Inclusion Criteria...................................................................................................................................................................90

Exclusion Criteria ..................................................................................................................................................................90

Study Investigations ................................................................................................................................. 91


FOLLOWING ELECTIVE ARTERIO-‐VENOUS FISTULA LIGATION FOLLOWING SUCCESSFUL,

STABLE RENAL TRANSPLANTATION.............................................................................................. 92

Subjects .......................................................................................................................................................... 92

Inclusion Criteria...................................................................................................................................................................92

Exclusion Criteria ..................................................................................................................................................................92

Study Investigations ................................................................................................................................. 93

Cardiovascular Magnetic Resonance Protocol – Studies 1 and 2......................................... 94

Cardiac Protocol.....................................................................................................................................................................94

Vascular Protocol ..................................................................................................................................................................97

Summary of CMR Investigations for Arterio-‐Venous Fistula Studies..........................................................101

STUDY 3: EVALUATION OF THE DIAGNOSTIC ACCURACY OF DOBUTAMINE-‐STRESS CARDIAC

MRI IN THE DETECTION OF ANGIOGRAPHICALLY-‐SIGNIFICANT CORONARY ARTERY DISEASE

PRIOR TO RENAL TRANSPLANTATION .........................................................................................103

vi

Subjects ........................................................................................................................................................103

Inclusion Criteria................................................................................................................................................................103

Exclusion Criteria ...............................................................................................................................................................103

Study Investigations ...............................................................................................................................104

Dobutamine Stress Cardiac MRI ..................................................................................................................................104

Invasive Coronary Angiography ..................................................................................................................................105

STUDY 4: EVALUATION OF DYNAMIC CORONARY ENDOTHELIAL FUNCTION IN END-‐STAGE

RENAL FAILURE ..............................................................................................................................107

Subjects ........................................................................................................................................................107

Inclusion Criteria................................................................................................................................................................107

Exclusion Criteria ...............................................................................................................................................................107

Study Investigations ...............................................................................................................................108

Coronary Endothelial Function....................................................................................................................................108

Quantitative Coronary Angiography..........................................................................................................................109

Coronary Blood Flow / Microvascular Function ..................................................................................................110

STATISTICAL METHODS.................................................................................................................111

RESULTS...........................................................................................................................113


FOLLOWING ELECTIVE ARTERIO-‐VENOUS FISTULA CREATION IN PRE-‐DIALYSIS END-‐STAGE

RENAL FAILURE ..............................................................................................................................114

Introduction ...............................................................................................................................................114

Methods........................................................................................................................................................117

Statistical Methods ............................................................................................................................................................117

Power Calculation ..............................................................................................................................................................117

Results...........................................................................................................................................................119

Clinical Results ....................................................................................................................................................................121

Cardiac Results ....................................................................................................................................................................121

Vascular Results: ................................................................................................................................................................125

Discussion....................................................................................................................................................130

vii

Conclusion...................................................................................................................................................140


FOLLOWING ELECTIVE ARTERIO-‐VENOUS FISTULA LIGATION FOLLOWING SUCCESSFUL

STABLE RENAL TRANSPLANTATION............................................................................................141

Introduction ...............................................................................................................................................141

Methods........................................................................................................................................................143

Statistical Methods ............................................................................................................................................................143


Results...........................................................................................................................................................145

Clinical Results ....................................................................................................................................................................146

Cardiac Results ....................................................................................................................................................................146

Vascular Results: ................................................................................................................................................................150

Discussion....................................................................................................................................................156

Conclusion...................................................................................................................................................161

STUDY 3: EVALUATION OF THE DIAGNOSTIC ACCURACY OF DOBUTAMINE-‐STRESS CARDIAC

MRI IN THE DETECTION OF ANGIOGRAPHICALLY-‐SIGNIFICANT CORONARY ARTERY DISEASE

PRIOR TO RENAL TRANSPLANTATION .........................................................................................163

Introduction ...............................................................................................................................................163

Methods........................................................................................................................................................166

Statistical Analysis .............................................................................................................................................................166

Results...........................................................................................................................................................167

Discussion....................................................................................................................................................172

Limitations ............................................................................................................................................................................180

Conclusion...................................................................................................................................................181

STUDY 4: EVALUATION OF DYNAMIC CORONARY ENDOTHELIAL FUNCTION IN END-‐STAGE

RENAL FAILURE ..............................................................................................................................183

Introduction ...............................................................................................................................................183

Methods........................................................................................................................................................185

viii

Statistical Analysis .............................................................................................................................................................187


Results...........................................................................................................................................................188

Discussion....................................................................................................................................................191

Limitations ............................................................................................................................................................................198

Conclusion...................................................................................................................................................201

CONCLUSION...................................................................................................................202

THESIS SUMMARY...........................................................................................................................203

FUTURE DIRECTIONS .....................................................................................................................206

BIBLIOGRAPHY..............................................................................................................209

ix

FIGURE LEGEND:

Figure 1: Prevalence of ESRF patients in Australia in 2005, with relative

contributions of dialysis (peritoneal and haemodialysis) and transplant renal

replacement therapies (adapted from ANZDATA Annual Report, 2006).14................... 6

Figure 2: Prevalence of End-Stage Kidney Disease (ESKD) in relation to the

Australian population between 1980 and 2004.15 .................................................................... 7

Figure 3: Trends in patient age at commencement of Renal Replacement Therapy

in Australia, 1981-2006.19.................................................................................................................... 9

Figure 4: Age-specific prevalence of Diabetes diagnosis, by gender, 2004-5.19......11

Figure 5: Active daily smokers, Australian population aged ≥14, 1985-2004.26 ..13

Figure 6: Age-standardised Rates of Death from Any Cause (Panel A),

Cardiovascular Events (Panel B) and Hospitalisation (Panel C) according to eGFR

among 1,120,295 ambulatory adults. (Reproduced from Go AS, et al, N Engl J Med,

2004 with permission. Copyright © [2004] Massachusetts Medical Society. All

rights reserved.) .....................................................................................................................................27

Figure 7: Probability of overall survival (A) and cardiovascular event-free

survival (B) amongst successful responders to the LVM reduction intervention, and

non-responders (response defined by a >10% change in LVM) (p<0.001 for both).

(Reproduced from London et al, J Am Soc Nephrol, 2001, with permission from the

American Society of Nephrology). ..................................................................................................32

x

Figure 8: Kaplan-Meier survival analysis for all cause mortality by NYHA

Classification for 1322 patients with ESRF. (Reproduced from Postorino M, et al,

Nephrol Dial Transplant., 2007, by permission of Oxford University Press)................35

Figure 9: Measurement of carotid-femoral PWV, utilising the foot-to-foot

method, where (∆t) represents the change in time, and (∆L) represents the distance

between waveform measurement sites. (Reproduced from Laurent S. et al. Eur

Heart J, 2006;27:2592, with permission from Oxford University Press ).......................64

Figure 10: Schematic representation of the method for determining arterial

distensibility by measuring changes in arterial lumen cross-sectional area across

the cardiac cycle (∆A = Maximal change in lumen area during cardiac cycle; D =

diameter), as they relate to local pulse pressure. (Reproduced from Laurent S. et al.

Eur Heart J, 2006;27:2593, with permission from Oxford University Press). ..............66

Figure 11: Representation of an illustrative central pressure waveform,

demonstrating identification of the Augmentation Pressure; determined as the

difference between the second (P1) and first (P2) systolic pressure peaks. AIx may

then be calculated by evaluation of the augmentation pressure in relation to the

pulse pressure. (Reproduced from Laurent S. et al. Eur Heart J, 2006;27:2595, with

permission from Oxford University Press). .................................................................................67

Figure 12: Representation of CMR methodology for the use of the long axis

reference images (horizontal long axis image shown on left) to enable acquisition

of sequential, parallel ventricular short-axis images from the atrio-ventricular

plane to the ventricular apices (end-diastolic images shown). .........................................95

xi

Figure 13: Sagittal oblique image of the aorta (left) with pictorial representation

of the reference levels used in the acquisition of cross-sectional aortic images at the

Ascending Aorta (AA), Proximal Descending Aorta (PDA) and Distal Descending

Aorta (DDA) (right). .............................................................................................................................98

Figure 14: Alterations in Left Ventricular Structure and Function following

successful AVF creation in ESRF...................................................................................................123

Figure 15: Alterations in Right Ventricular Structure and Function following

successful AVF creation in ESRF...................................................................................................124

Figure 16: Alterations in Left and Right Atrial Area following successful AVF

creation in ESRF. .................................................................................................................................125

Figure 17: Alterations in Aortic Distensibility following AVF creation in ESRF..126

Figure 18: Aortic Distensibility by Aortic Level Prior to (Pre-), and Following

(Post-) AVF creation in ESRF. ........................................................................................................127

Figure 19: Alterations in Peripheral Endothelial Function following successful

AVF creation in ESRF. .......................................................................................................................128

Figure 20: Alteration in CMR-assessed brachial artery blood-flow, ipsilateral and

contralateral to the newly created arterio-venous fistula. ..............................................129

Figure 21: Alterations in Left Ventricular Structure and Function following AVF-

ligation in the context of successful, stable renal transplantation. ..............................148


AVF-ligation in the context of successful, stable renal transplantation. ....................149

xii

Figure 23: Alterations in Left and Right Atrial Area following AVF-ligation in the

context of successful, stable renal transplantation. ............................................................150

Figure 24: Alterations in Aortic Distensibility following AVF-ligation in the

context of successful, stable renal transplantation. ............................................................151

Figure 25: Aortic Distensibility by Aortic Level Prior to (Pre-), and Following

(Post-) AVF ligation in the context of stable, successful renal transplantation. .....152

Figure 26: Average Aortic Distensibility in ESRF subjects following AVF-creation

compared to successful RTx recipients following AVF-ligation......................................153

Figure 27: Evaluation of Alterations in Endothelial Function following AVF

ligation in the context of stable, successful renal transplantation. ..............................154


contralateral to the ligated arterio-venous fistula in the context of stable,

successful renal transplantation..................................................................................................155

Figure 29: Comparison of CMR-derived vs. SPECT-derived evaluation of LVEF. 171

xiii

TABLE LEGEND

Table 1: Classification of Stages of Chronic Kidney Disease according to the

National Kidney Foundation Kidney Disease Outcome Quality Initiative (K/DOQI)

Advisory Board Findings.1.................................................................................................................... 2

Table 2: Prevalence of echocardiographic findings of abnormalities in left

ventricular structure and function at dialysis commencement (Reproduced from

Parfrey PS, et al. Nephrol Dial Transplant., 1996;11:1277-1285, with permission of

Oxford University Press). ....................................................................................................................28

Table 3: Subject Baseline Characteristics – Study 1 ........................................................120



Table 6: Diagnostic performance of DS-CMR and Stress-Perfusion SPECT in the

detection of angiographically significant coronary stenoses..........................................170

Table 7: Subject Baseline Characteristics – Study 4 ACEI = Angiotensin

Converting Enzyme Inhibitor; ARB = Angiotensin Receptor Blocker...........................188

xiv

ABSTRACT

Background:

Chronic renal dysfunction is associated with myriad alterations in cardiovascular

structure and function, resulting in markedly elevated rates of cardiac and

vascular morbidity and mortality. Utilising advances in cardiovascular magnetic

resonance imaging (CMR), we evaluated the cardiovascular sequelae of arterio-‐

venous fistula formation in advanced chronic kidney disease, and the impact of

elective arterio-‐venous fistula ligation following successful renal transplantation.

Furthermore, we undertook to evaluate the diagnostic accuracy of dobutamine-‐

stress CMR in the detection of haemodynamically-‐significant coronary artery

disease prior to renal transplantation. Finally, we invasively evaluated coronary

endothelial function in the presence of advanced renal dysfunction, and

compared this to subjects with preserved renal function.

Methods / Results:

Study 1: CMR was undertaken to evaluate cardiac structure and function,

brachial artery endothelial function (as assessed by flow-‐mediated dilatation)

and aortic distensibility in twenty-‐four subjects at baseline, and 6-‐months

following, clinically indicated arterio-‐venous fistula creation in preparation for

the commencement of haemodialysis for end-‐stage renal failure. Following

arterio-‐venous fistula creation, mean cardiac output increased by 25.0%

(p<0.0001), with substantial associated increases in left and right ventricular

volumes, left and right atrial area and left ventricular mass (12.7% increase,

xv

p<0.0001). Peripheral endothelial function was significantly impaired at follow-‐

up (9.0±9% vs. 3.0±6%, p=0.01). No significant change in aortic distensibility

was identified.

Study 2: Cardiac and vascular function were similarly assessed utilising CMR in

eighteen subjects prior to, and 6-‐months following, clinically indicated arterio-‐

venous fistula ligation in the context of successful, stable renal transplantation.

Following AVF-‐ligation, mean cardiac output fell by 15.6% (p=0.004), with

significant attendant decreases in atrial and ventricular chamber dimensions.

Notably, left ventricular mass fell by 9.7% (p=0.0001) at follow-‐up. Aortic

distensibility was unchanged following AVF-‐ligation, though endothelial function

improved significantly (2.5±6.5% vs. 8.0±5.9%, p=0.043).

Study 3: Dobutamine-‐stress CMR was performed in twenty-‐one subjects prior to

clinically-‐indicated invasive coronary angiography before potential renal

transplantation. Dobutamine-‐stress CMR demonstrated 100% sensitivity and

93% specificity for the detection of angiographically significant coronary disease

(≥70% stenosis severity). This compared favourably to results for the

institutional-‐standard (SPECT: sensitivity 67%, specificity 38%; p<0.0001

compared to CMR).

Study 4: At invasive coronary angiography, endothelium-‐dependent and

endothelium–independent coronary endothelial and microvascular function

were evaluated amongst eight pre-‐renal transplant subjects with only minimal

coronary artery disease (≤20% epicardial coronary stenoses). Utilising intra-‐

coronary infusions of acetylcholine (10-‐7M and 10-‐6M), adenosine (48mcg) and

glyceryl tri-‐nitrate (100mcg), results were compared to thirteen control subjects

with minimal coronary artery disease but comparatively preserved renal

xvi

function. There was no significant difference in endothelium-‐dependent or

endothelium–independent coronary endothelial function between the cohorts.

Microvascular function (as assessed by coronary flow reserve following

adenosine administration) was markedly impaired in subjects with advanced

renal impairment compared to controls (1.9±0.4 vs. 3.0±1.1, p=0.01).

Conclusions:

Chronic kidney disease is associated with substantial alterations in

cardiovascular structure and function. Arterio-‐venous fistulae, though necessary

for the performance of haemodialysis, appear to contribute significantly to the

high burden of cardiovascular maladaptation present in this condition. Recent

advances in CMR and stress-‐CMR may play a significant role in improving the

detection of sub-‐clinical cardiovascular disease in these high-‐risk patients.

xvii

DECLARATION

This body of work contains no material which has been accepted for the award of any

other degree or diploma in any university or tertiary institution and, to the best of my

knowledge and belief, contains no material previously published or written by another

person, except where due reference has been made in the text.

I give consent to this copy of my thesis, when deposited in the University Library,

being available for loan and photocopying.

Dr Benjamin Kane Dundon

Discipline of Medicine

School of Medicine

University of Adelaide

Adelaide

South Australia, 5000

AUSTRALIA

xviii

ACKNOWLEDGMENTS

It was with no small amount of trepidation that I initially committed to the

commencement of this PhD. Having never been exposed to meaningful research

during my under-graduate education or post-graduate clinical training, as an advanced

trainee in Cardiology the idea of removing myself from clinical medicine for three

years seemed a path both onerous and of little lasting professional value – merely a

hoop to be jumped through in order to “tick the research box”. It is with great

gratitude and humility that I commit this Thesis to the numerous colleagues who have

mentored, aided and supported me through an experience that has proven to be of

immense professional and personal value.

To Professor Stephen Worthley, never could it be said that you lack for optimism. I

am deeply indebted to you for your vision, support, mentorship and enthusiasm in

supporting my research undertakings and, more broadly, my professional career. Few

in number are the clinicians throughout medical education who truly shape with

lasting effect the future path of their trainees. I consider myself extremely fortunate to

have benefitted from your guidance and example as a clinician and a mentor.

Invaluable is a leader who, by example, engenders a pervasive culture of teamwork

and determination in the pursuit of excellence. Such has been my experience.

To Dr Matthew Worthley, for your boundless enthusiasm and limitless accessibility, I

sincerely thank you. The path from doctor to academic clinician is besieged by

obstacles, both small and large. I am extremely fortunate to have experienced in my

primary supervisor a mentor infectiously passionate in his commitment to medical

xix

research and ceaselessly patient in his support of the fledgling steps of an early career

researcher. Through humour, wisdom and enthusiasm, you form the heart of our

research team. I am deeply indebted to you for all of your support.

To Professor Randall Faull and Associate Professor Kym Bannister, I am extremely

grateful for your advice and support in the conduct of my research. I remain humbled

by your commitment to the welfare of your patients and exceedingly thankful for your

willingness to mentor a lowly Cardiologist within the realms of Renal and

Transplantation Medicine. Through efficient systems and outstanding personnel, the

cooperation of the Renal Unit was instrumental to the success of my research studies.

To Mr Kim Torpey, your contribution to the AV fistula research is peerless. I

sincerely thank you for your tireless support and enthusiasm for these Projects and for

your dedication to the success of our work together. My PhD has much to be grateful

to you for your hard work, outstanding patient rapport and ever-present good cheer.

To my many colleagues within the Cardiovascular Research Centre of the Royal

Adelaide Hospital, thank you for your immeasurable support. The two years of PhD

research and training in Cardiovascular Magnetic Resonance Imaging were a busy but

fulfilling period of my Cardiology career. Without the support and assistance of the

many members of the CRC team however, the numerous tasks necessary in the

completion of a PhD would surely have proven insurmountable. To Ms Kerry

Williams, thank you for your tireless assistance in the booking and performance of the

many CMR studies undertaken for my research. I am truly grateful for all of your

hard work. To Dr Rishi Puri, thank you for your assistance in the performance of the

xx

QCA measures for our invasive study. Your enthusiasm for research and your

unwavering curiosity for new discoveries enabled the completion of many productive

Projects together. To Mr Angelo Carbone, thank you for your commitment to the

team and your constant willingness to help others in the department, wherever

assistance was required. To Dr Adam Nelson, I remain truly humbled by your

capacity for productivity despite your numerous clinical, research and administrative

commitments. I look forward to watching and supporting your undoubtedly stellar

career in the years to come. Thank you for all your help.

I thank the Cardiac Society of Australia and New Zealand, the National Health and

Medical Research Council and the National Heart Foundation of Australia for their

support of my research career, and I thank the Board of the Cardiovascular Lipid

Research Grants for their support of my arterio-venous fistula ligation study. Without

such support, the undertaking of meaningful research is greatly hampered.

I would also like to thank Dr Leo Mahar, whose mentorship during my Cardiology

training I have valued above all others. I benefitted immensely from the example of

your dignity and strength of leadership within our Department and greatly value the

enormous library of highly educational (and often highly amusing) anecdotes you

shared in your commitment to my education on the path to becoming a Consultant

Physician. For your generosity and commitment to my career, I sincerely thank you.

But more than any other, I thank my wife, Annabel. For our wonderful boys James,

William and Thomas and for your love and unwavering support through all of the

challenges and hardships of this PhD, I thank you.

xxi

ABBREVIATIONS

Ach Acetylcholine

ACS Acute Coronary Syndrome

ADMA Asymmetrical dimethylarginine

AF Atrial Fibrillation

AGE Advanced Glycosylation End-‐products

AIx Augmentation Index

ANP Atrial Natriuretic Peptide

ANZDATA Australian and New Zealand Dialysis and Transplant Registry

APV Average Peak Velocity

ARVC Arrhythmogenic Right Ventricular Cardiomyopathy

ASCOT Anglo-‐Scandinavian Cardiac Outcomes Trial

AVF Arterio-‐Venous Fistula

BMI Body Mass Index

BNP Brain Natriuretic Peptide

CABG Coronary Artery Bypass Graft

CAD Coronary Artery Disease

CAFÉ Conduit Artery Function Evaluation

CBF Coronary Blood Flow

CCF Congestive Cardiac Failure

CFR Coronary Flow Reserve

CKD Chronic Kidney Disease

CMR Cardiovascular Magnetic Resonance Imaging

CO Cardiac Output

xxii

CrCL Creatinine Clearance

CT Computed Tomography

CV Cardiovascular

CVD Cardiovascular Disease

DBP Diastolic Blood Pressure

eGFR Estimated Glomerular Filtration Rate

eNOS Endothelial Nitric Oxide Synthase

EPO Erythropoietin

ESKD End Stage Kidney Disease

ESRF End-‐stage Renal Failure

ET-‐1 Endothelin-‐1

FAME Fractional Flow Reserve versus Angiography for Multivessel

Evaluation

FFR Fractional Flow Reserve

FISP Fast-‐imaging with Steady State Free Precession

FMD Flow-‐mediated Dilatation

FOV Field of View

GFR Glomerular Filtration Rate

GTN Glyceryl Tri-‐nitrate

Hb Haemoglobin

HDx Haemodialysis

HMG-‐CoA Hydroxyl-‐methylglutaryl coenzyme-‐A

HR Heart Rate

ICA Invasive Coronary Angiography

IHD Ischaemic Heart Disease

xxiii

IMR Index of Microvascular Resistance

IQR Inter-‐quartile Range

IVUS Intravascular Ultrasound

K/DOQI National Kidney Foundation Kidney Disease Outcome Quality

Initiative

LA Left Atrial

LAD Left Anterior Descending Artery

LDL Low Density Lipoprotein

LIFE Losartan Intervention for Endpoint Reduction in Hypertension

LV Left Ventricular

LVEDP Left Ventricular End-‐Diastolic Pressure

LVEF Left Ventricular Ejection Fraction

LVH Left Ventricular Hypertrophy

LVM Left Ventricular Mass

LVSV Left Ventricular Stroke Volume

MDRD Modification of Diet in Renal Disease Study Group

MI Myocardial Infarction

MOD Method of Discs

MPI Myocardial Perfusion Imaging

NO Nitric Oxide

NPV Negative Predictive Value

NSF Nephrogenic Systemic Fibrosis

NSTEMI Non-‐ST-‐segment Elevation Myocardial Infarction

NYHA New York Heart Association

oxLDL Oxidised Low Density Lipoprotein

xxiv

PAP Pulmonary Artery Pressure

PCI Percutaneous Coronary Intervention

PGI2 Prostacyclin (Prostaglandin I2)

PHT Pulmonary Hypertension

PP Pulse Pressure

PPV Positive Predictive value

PTCA Percutaneous Trans-‐luminal Coronary Angioplasty

PTH Parathyroid Hormone

PWV Pulse-‐wave Velocity

QALY’s Quality-‐Adjusted Life Years

QCA Quantitative Coronary Angiography

RA Right Atrial

RAAS Renin-‐Angiotensin-‐Aldosterone System

RRT Renal Replacement Therapy

RTx Renal Transplantation

RV Right Ventricular

SBP Systolic Blood Pressure

SPECT Single Photon Emission Computed Tomography

SSFP Steady-‐State Free Precession

STEMI ST-‐segment Elevation Myocardial Infarction

TIIDM Type II Diabetes mellitus

TE Echo Time

TR Repetition Time

TTE Trans-‐thoracic Echocardiography

TXA2 Thromboxane

xxv

UVB Ultraviolet B

25(OH)VitD3 25-‐hydroxyvitamin D3

1

BACKGROUND

� ��

��

��

�� !

��"� �� #�� $�� % ��

��

�&��'�� (�� )��!'��

�� )'�� '�� *�"(� �� %��

�� +$,�"��

�

'�� +$,� � ��

(� ≥�-.� #�� %�� %��

�� "�"�� "�

�� /.!0-� 1��

�%�� "�

� .!*-� 1�� "�

�

2� (*!�-� ' � � �� "��

�

*� 3(*� 4 �� "� �� !

�� )'��

��

�� !��

"�#�� $�%�!��&��'��

�

��

+$,� ��

5��6�� "�+$,��%��

� ��

3

serum creatinine will remain within most laboratories’ normal range until ≥50-‐

60% of total kidney function is lost.2 Importantly, GFR is a measure of glomerular

function, rather than renal tubular function, and as such, many of the homeostatic

functions of the kidney may remain relatively intact despite declining GFR.

Specifically, the tubular mechanisms maintaining water and sodium/potassium

homeostasis, as well as acid-‐base balance, remain robust, even unto severe renal

dysfunction. As such, many patients are unaware of the presence of significant

renal dysfunction (as assessed by GFR) due to an absence of apparent symptoms

or clinical signs (such as oedema due to reduced free water clearance). This

tubular compensation for glomerular impairment/loss gives rise to the potential

for the ‘silent’ advance of renal dysfunction, in the absence of surveillance

urinalysis or blood tests in at-‐risk individuals (e.g. diabetic and/or hypertensive

patients).

Numerous methods exist for the evaluation of GFR, with variable associated

diagnostic accuracy and prognostic value. The “gold standard” method for

evaluating GFR involves the administration of a chemical that maintains a steady

pharmacokinetic profile within the serum, with no extra-‐renal excretion, and is

freely filtered at the glomerulus, but undergoes neither reabsorption nor

secretion within the renal tubules. A fixed dose is administered intravenously,

with subsequent urine excretion quantified. Inulin is the classical agent used for

this purpose, although radiopharmaceuticals are also routinely used in clinical

practice.

Such ideal properties for assessing GFR are distinct from serum creatinine, which

although freely filtered at the glomerulus, is known to undergo active tubular

secretion, with substantial inter-‐ and intra-‐individual variability due to the

4

saturable nature of the tubular secretory process. Furthermore, tubular secretion

of creatinine may be impaired or blocked by various pharmaco-‐therapeutic

agents (e.g. trimethoprim and cimetidine), and hence measurement of serum

creatinine in patients receiving these agents may provide a spurious indication of

altered renal excretory function relative to previous measurements.3

Furthermore, as renal function declines, there is a rise in extra-‐renal degradation

of creatinine,4 potentially leading to under-‐estimation of the decline in renal

function due to attenuation of the rise in serum creatinine arising from decreased

renal clearance.5,6 Thus, serum creatinine, and derived creatinine clearance, may

over-‐ or under-‐estimate true GFR, depending on the stage of renal disease and

concomitant therapies. Confusingly, these terms (‘creatinine clearance’ and

‘glomerular filtration rate’) are often used interchangeably in clinical practice.

Currently, the most commonly used estimate of renal excretory function is the

‘estimated GFR’ (eGFR), which is now routinely reported as a component of

results from renal function serological assays. This measure was developed by

the Modification of Diet in Renal Disease Study Group [MDRD], and is most

commonly derived from four key variables: serum creatinine, age, gender and

race.7

For estimation of eGFR for creatinine values in µmol/L:

eGFR = 32,788 x [Serum Creatinine]-‐1.154 x [Age]-‐0.203 x [0.742 if female]

For individuals of African heritage, results from the above equation are then

multiplied by 1.210, due to the relatively greater mean muscle mass within this

racial group. Application of this equation to the Australian Aboriginal population

5

remains contentious and further work is required in this area – particularly in

light of the relatively high prevalence of CKD in the Australian Indigenous

population.8

The MDRD equations have been validated in a variety of CKD cohorts, however

these formulae (the common 4-‐variable eGFR, and the original 6-‐variable version

which also includes blood urea nitrogen and serum albumin) underestimate GFR

in healthy patients with GFR>60mL/min.9,10 As such, in clinical practice, values

greater than this are generally reported as “eGFR >60mL/min/1.73m2”.

Prior to the development of the MDRD eGFR, GFR was more commonly estimated

utilizing the Cockcroft-‐Gault formula. First published in 197611, this equation

estimates an individual’s “creatinine clearance” (eCrCL), as a measure of GFR.

(140-‐age) x Body weight x Constant

eCrCL =

Serum Creatinine (µmol/L)

Where the constant is 1.23 for men and 1.04 for women. As this equation utilises

serum creatinine, age, gender, and body mass (in kilograms) to estimate

creatinine production, as well as clearance, it is widely agreed that the derived

values provide a more individualised estimate of glomerular function than eGFR,

as the eGFR methodology underestimates true GFR in heavy people, and

overestimates glomerular function in underweight individuals. The requirement

for clinical details such as body weight inhibits the use of this equation in the

routine reporting of serum biochemistry however.

6

Disease Burden

Despite substantial advances in health care in recent decades, CKD accounts for a

significant and growing burden of morbidity and mortality in Australia.12

Approximately 50% of Australians aged 65 or over have significant renal

impairment and an increasing number are progressing to End Stage Renal Failure

(ESRF) requiring renal replacement therapy (RRT)(dialysis or transplantation).13

(Figure 1)

Figure 1: Prevalence of ESRF patients in Australia in 2005, with relative

contributions of dialysis (peritoneal and haemodialysis) and transplant

renal replacement therapies (adapted from ANZDATA Annual Report,

2006).14

In fact, while the Australian population has grown by approximately 40% over

the last 25 years, the number of Australians treated with dialysis or kidney

A NOTE:

This figure/table/image has been removed to comply with copyright regulations. It is included in the print copy of the thesis held by the University of Adelaide Library.

7

transplantation has grown by more than 400% over the same period (Figure 2).15

With the burgeoning epidemics of obesity and Type II Diabetes Mellitus (TIIDM),

the continuing impact of the glomerulonephritides and hypertension, and the

progressive aging of the Australian population, it is anticipated that CKD and

ESRF will continue to rise in prevalence for the foreseeable future.15

Figure 2: Prevalence of End-Stage Kidney Disease (ESKD) in relation to the

Australian population between 1980 and 2004.15

Financial Burden of CKD

The growing prevalence of CKD has significant attendant costs – most directly to

the individual patient and their family/carers, but also to the community.

Australian health care expenditure on CKD was $898.7 million in 2004-‐5, with

conservative estimates anticipating compounded rises in CKD expenditure of up

A NOTE:


8

to 27% per year – more than double the rate of growth in total health care

expenditure.16 The provision of RRT in the form of dialysis (both peritoneal and

haemodialysis) and renal transplantation programs is highly cost intensive, and

accounts for nearly 85% of the total CKD budget.16 Such expenditure is estimated

to provide Australian RRT patients an overall benefit of 60,000 life-‐years over a

period of 10-‐years from RRT commencement, or 30,000 quality-‐adjusted life

years (QALY’s).15

Although the aforementioned costs are substantial, these figures fail to include

the additional costs associated with the management of the frequent co-‐morbid

conditions endured by CKD patients, nor the indirect and non-‐health sector costs

associated with the condition.

Aetiology

In Australia and New Zealand, population details of ESKD are diligently recorded

by the participant renal medicine units of the Australia and New Zealand Dialysis

and Transplant Registry (ANZDATA). As a reflection of the universal commitment

of local Nephrologists to ANZDATA’s raison d’être -‐ to monitor treatment and

perform analyses to improve the quality of care for people with kidney failure -‐

100% of all Renal Medicine Units in Australia and New Zealand participate in the

data collection process. As such, ANZDATA provides an enviably comprehensive

overview of CKD and ESKD in the Australian and New Zealand context.

The most contemporary ANZDATA Annual Report (2010)17 states that there were

18,243 people receiving RRT in Australia as at 31st December, 2009. This figure

comprises 7,902 individuals with a functioning renal transplant (RTx), and

9

10,341 individuals undergoing dialysis treatment – either peritoneal or

haemodialysis. The provision of RRT occurred at a rate of 834 per million

population, with 2,337 people commencing RRT in Australia during 2009 – an

incidence of 107 per million population per year. The mean age at RRT

commencement was reported at 60.8 years (median 63.6 years), with a rising

tide of elderly Australians commencing RRT during the last three decades.18

(Figure 3)

Figure 3: Trends in patient age at commencement of Renal Replacement Therapy

in Australia, 1981-2006.19

Conventional cardiovascular risk factors such as hypertension, hyperlipidaemia

and TIIDM are recognized to be highly prevalent in the CKD cohort. Of the new

patients commencing RRT in 2007, diabetic nephropathy was the most common

A NOTE:


10

cause of ESKD, recorded as the primary cause in 31%. A further 25% attributed

glomerulonephritis as the primary cause of ESKD, and 16% hypertensive renal

disease.20 This finding is a relatively new phenomenon, with glomerulonephritis

consistently listed as the most common primary cause of ESKD in Australia prior

to 2005, when diabetic nephropathy became the most prevalent primary

underlying aetiology for the first time (30%, vs. 25% glomerulonephritis).21 This

growing emergence of diabetic nephropathy as the primary contributor to the

need for RRT therapies in Australia is anticipated to continue to rise for the

foreseeable future.20

Co-Morbid Conventional Cardiovascular Risk Factors

Despite substantial technical improvements in the management of CKD and ESRF

over the last 2-‐3 decades, minimal progress has been made on the impact of

cardiovascular disease in affected patients. As previously mentioned,

conventional CV risk factors are highly prevalent amongst CKD patients. The

burden of CVD however, is disproportionate to the conventional risk factor

burden.22

Notably, the prevalence of CKD and ESRF increase with advancing age, peaking in

the 65-‐74 year age group for ESRF. Furthermore, a significant proportion of

advanced CKD and RRT patients have pre-‐existing coronary artery, peripheral

artery and cerebrovascular disease. Such factors contribute significantly to the

risk of future cardiovascular events in these cohorts, independent of other

contributory risk factors such as diabetes and hypertension.

11

Diabetes Mellitus

TIIDM contributes substantially to the burden of pre-‐ESRF CKD in the Australian

community.12,23 It is well appreciated that the prevalence of TIIDM in Australia

has risen steadily over the last two decades, rising from <1.5% of the population

in 1989, to almost 3.5% by 2005.19 This growing burden of diabetes is over-‐

represented amongst older Australians, with a peak incidence in the 65-‐74 years

age group.19 This skewed prevalence ensures a rising tide of CKD and ESRF

amongst elderly Australians, with the greatest prevalence of diabetes diagnosis

coinciding with the greatest population burden of CKD also (Figure 4).19

Figure 4: Age-specific prevalence of diabetes diagnosis, by gender, 2004-5.19

A NOTE:


12

Hypertension

Hypertension is known to be a potent risk factor for the development of renal

disease and may hasten progression of renal dysfunction in early CKD.24 As

mentioned previously, hypertensive renal disease accounted for 16% of ESRF

cases in Australia in 2008, with rates steadily increasing over the last two

decades.20 Additionally, hypertension is a common consequence of advancing

CKD (if it is not already present), further contributing to the ‘pro-‐CVD milieu’ in

this condition. Hypertension contributes significantly to the burden of cardiac

and vascular disease of CKD and ESRF and will be discussed in greater detail

below.

Smoking

Smoking is known to be associated with an increased risk of renal impairment

and proteinuria.25 Although the prevalence of smoking in the Australian

community has steadily fallen in recent times (Figure 5)26, smoking prevalence

amongst individuals commencing RRT has remained remarkably stable since

2001, but at a relatively lower rate (12% of patients entering RRT during 2001-‐

2007 vs. 19.8% of the general Australian population aged ≥14 in 2007).19,20 This

persistence of smoking as a contributing risk factor to CVD disease progression in

a population already at markedly elevated risk of cardiovascular morbidity and

mortality remains a significant challenge to clinicians managing CKD and ESRF.

13

Figure 5: Active daily smokers, Australian population aged ≥14, 1985-2004.26

Hyperlipidaemia

Hyperlipidaemia is a common co-‐morbid condition in CKD patients, and appears

to increase in prevalence with increasing renal dysfunction.27 Although numerous

studies have demonstrated substantial prognostic benefits with low-‐density lipid

(LDL) lowering utilizing hydroxyl-‐methylglutaryl coenzyme-‐A (HMG-‐CoA)

reductase inhibitors (“statins”) in the general community and various higher-‐risk

cohorts28-‐33, there remains no convincing evidence of prognostic advantage to

these agents in the ESRF context34,35, despite similar LDL-‐lowering efficacy.34-‐39

Although substantial controversy persists regarding the use of statin therapy in

ESRF patients, and the generalizability of the AURORA34 study results in

particular, it is supposed that the causal relationship between LDL and the

generation of cardiovascular events is altered in dialysis patients.40 It is well

appreciated that, although vascular disease is common in ESRF, only one quarter

A NOTE:


14

of cardiac mortality in ESRF is attributable to acute myocardial infarction41, while

other common causes of death such as cardiac arrest, arrhythmia and heart

failure could not be expected to be affected by LDL-‐lowering. Notably, the larger

Study of Heart and Renal Protection (SHARP) involving combination therapy with

ezetimibe and simvastatin in the management of hyperlipidaemia in advanced

CKD recently demonstrated a significant reduction in major atherosclerotic

events.42 This study has provided greater confidence in the utility of lipid

lowering in the CKD context, although questions still remain regarding the patho-‐

biology of atherosclerosis in this condition.

Obesity

The prevalence of obesity in Australia has more than doubled over the last 20

years43, with significant corresponding increases in the prevalence of overweight

Australians during this period also. Obesity is a known risk factor for

cardiovascular disease and contributes to deleterious vascular remodelling and

hypertension.44-‐47 Although indices of malnutrition, such as low BMI, albumin and

total cholesterol, have previously been associated with increased mortality in

ESRF48,49, excess visceral adiposity and the associated metabolic syndrome

remain significant contributors to morbidity and mortality in CKD and ESRF.50

Disease-Specific Cardiovascular Risk Factors

Anaemia

Anaemia is a common complication of declining renal function, and is strongly

predictive of adverse cardiovascular prognosis in CKD and ESRF.51,52 As the

15

kidneys are responsible for the production of endogenous erythropoietin (EPO),

progressive destruction of the renal parenchyma inevitably leads to reduced red

cell haematopoiesis, and resultant anaemia due to EPO deficiency. This

underproduction of red blood cells is further complicated by reduced red cell

lifespan in advancing CKD, and dilutional anaemia associated with progressive

derangement of extracellular fluid homeostasis as renal function declines.53,54

Numerous observational studies support the role of exogenous EPO

supplementation in ESRF for the management of anaemia and the minimization

of deleterious cardiovascular remodelling and premature mortality.51,55-‐61

Despite this, normalisation of haemoglobin (Hb) levels has failed to demonstrate

convincing improvements in left ventricular geometry, or overall survival in

prospective studies.62-‐64 Furthermore, recent evidence disputes the use of EPO

supplementation to prevent cardiovascular events in pre-‐dialysis CKD65,66, with

evidence actually suggesting an increase in adverse outcomes if Hb>13.5g/dL is

targeted.67,68 Despite these conflicting findings, EPO administration remains a

mainstay of international guidelines regarding the management of anaemia in

CKD.60,69

Iron deficiency is also common in the CKD and ESRF populations, contributing

further to the development of anaemia. Due to the not-‐infrequent development of

relative EPO resistance in the uraemic context70, supra-‐normal ferritin levels are

often required to ensure sufficient red cell haematopoiesis. Substantial work has

focused on the optimal delivery and serum levels of iron in CKD, with evidence

strongly supporting the role of regular intravenous iron administration in

haemodialysis patients in particular.71 Evidence supporting a role for aggressive

iron supplementation in pre-‐dialysis CKD is less convincing however.71

16

Disordered Calcium / Phosphate Metabolism

Calcium and phosphate homeostasis relies upon a complex, tightly controlled

system of hormones and serum ions that influence calcium and phosphorus

regulation at the level of the kidney, intestine and bone.72 Derangement of the

renal contribution to this complex regulatory system leads to a number of

compensatory, but ultimately pathological responses.

Vitamin D / Parathyroid Hormone

Vitamin D is poorly named, as its synthesis and actions more closely represent

the behaviour of a hormone than a true vitamin, as with sufficient exposure to

sunlight, no dietary supplementation is necessary.73 Once bio-‐transformed to its

active metabolite (1,25-‐dihydroxyvitamin D3), Vitamin D influences homeostatic

mechanisms within the kidney, intestines, bone, and parathyroid glands, with

strong influence over calcium and phosphorus physiology. Vitamin D is initially

derived from 7-‐dehydrocholesterol (provitamin D3), transformed within the

epidermis following exposure to ultraviolet B radiation (UVB). Vitamin D3

continues to be produced for many hours after epidermal exposure to UVB (most

commonly from sunlight), and is then transported to the liver by vitamin D-‐

binding protein, where it is hydroxylated to the still-‐inactive 25-‐hydroxyvitamin

D3 [25(OH)VitD3]. 25(OH)VitD3 is then further hydroxylated by renal tubular

mitochondria to the active 1,25-‐dihydroxyvitamin D3. This activation is indirectly

enhanced by hypocalcaemia, which triggers increased production of parathyroid

hormone (PTH). PTH acts to restore serum calcium levels, and contributes to

17

increased 1,25-‐dihydroxyvitamin D3 synthesis within the renal tubular cells,

which in turn provides negative feedback to further PTH production. 1,25-‐

dihydroxyvitamin D3 assists PTH in increasing circulating calcium levels through

the enhancement of intestinal calcium and phosphate absorption, as well as

stimulation of increased bone turnover. Excess phosphate is normally deposited

in bone by osteoblasts (predominantly as hydroxyapatite), or excreted by the

renal tubules under the influence of PTH.72,73

Renal parenchymal destruction leads to relative 1,25-‐dihydroxyvitamin D3

deficiency, reduced gastro-‐intestinal calcium absorption, excess PTH secretion

and commonly, compensatory secondary hyperparathyroidism. This maladaptive

secondary hyperparathyroidism leads to progressive depletion of calcium stores

within the bone reservoir, leading to a condition known as renal osteodystrophy.

This derangement of calcium homeostasis is further complicated by the

progressive decline in renal phosphate excretion, leading to a state of chronic

hyperphosphataemia – an independent risk factor for vascular calcification and

subsequent arterial stiffness. Arterial stiffness leads to increased cardiac work

and reduced coronary blood flow, which, particularly in this renal failure cohort,

may contribute to excess CV mortality.74

Phosphate Restriction

Vitamin D supplementation has been routinely undertaken in advancing CKD, to

prevent hypocalcaemia and secondary hyperparathyroidism. Although the

enhancement of gastrointestinal calcium absorption mitigates the need for

increased PTH secretion and restricts the development of renal osteodystrophy,

as previously mentioned, Vitamin D (commonly administered in the form of oral

18

calcitriol) also leads to increased gastrointestinal phosphate absorption,

exacerbating the decline in renal excretion of this pro-‐calcific anion.

As the capacity for phosphate excretion falls, restriction of phosphate absorption

becomes an essential component of CKD management. Even following the

commencement of dialysis in ESRF, the removal of circulating phosphate often

fails to adequately compensate for dietary phosphate intake. The removal of

phosphate during dialysis is impaired by the complex interaction kinetics of

intracellular and extracellular phosphate within the human body, and by dialysis’

inability to remove large amounts of phosphate from the serum using

conventional dialysis methodologies (both peritoneal and haemodialysis).75

Historically, control of hyperphosphataemia was achieved through the

administration of oral aluminium-‐hydroxide at meal times to bind dietary

phosphates prior to absorption. Although effective, this led to progressive

aluminium intoxication in ESKD patients, most notably in the form of

osteomalacia and dementia.73 Calcium-‐based phosphate binders are used widely,

as they are inexpensive and effective, increasing gastro-‐intestinal phosphate

excretion through the intra-‐luminal formation of insoluble calcium-‐phosphate. In

combination with vitamin D supplementation however, it became apparent that

calcium-‐based phosphate binders may contribute to the excess vascular

calcification of CKD by inducing a strongly positive calcium balance.76 Non-‐

calcium-‐based phosphate binders have now been developed (e.g. sevelamer-‐

HCL), with evidence of reduced risk of hypercalcaemia and cardiovascular

calcification.77-‐79 There remains uncertainty, however, whether these newer

therapies lead to improved clinical outcomes in CKD and ESRF patients.80

19

As hyperphosphataemia and hyperparathyroidism have been independently

associated with cardiovascular morbidity and mortality, as well as all-‐cause,

cardiovascular and fracture-‐related hospitalisation in ESRF patients74, efforts to

control these entities remains an important goal for renal clinicians and

researchers.

Uraemia

As glomerular and tubular function progressively decline, there is a gradual

accumulation of numerous organic by-‐products of metabolism usually excreted

by the intact kidneys. This accumulation is associated with the development of

the clinical syndrome of “uraemia”, characterised by a complex constellation of

symptoms and signs, including fatigue, anorexia, nausea, pruritis, muscle cramps,

restless legs, reduced mental acuity, peripheral neuropathy and ultimately

seizures and coma.81 Additionally, uraemia is associated with the development of

a number of significant physiological derangements that contribute directly to

the promotion of CVD. These include insulin resistance, platelet dysfunction,

increased oxidative stress and the promotion of a pro-‐inflammatory milieu.81

Insulin Resistance

Insulin resistance is defined as the inadequate blood glucose response to

physiological levels of circulating insulin. Insulin resistance, and the associated

metabolic syndrome, have been strongly implicated in the development of CVD in

the general population, and contribute significantly to the burden of premature

mortality in the Australian community.19,82,83 Similarly, insulin resistance has also

20

been established as an independent predictor of cardiovascular mortality in non-‐

diabetic patients with ESRF.84 Significantly, uraemia per se is known to contribute

to the development of insulin resistance, through induction of tissue insensitivity

to insulin.85 This uraemia-‐associated insulin insensitivity is known to correlate

linearly with declining renal function, and has been demonstrated to manifest

early in the course of renal dysfunction.86,87 The resultant compensatory hyper-‐

insulinaemia has long been known to be associated with glucose intolerance and

dyslipidaemia88-‐90 – further potential contributors to CVD progression.

Furthermore, the hyper-‐insulinaemia of CKD is implicated in the development of

muscle wasting in advancing CKD and ESRF, potentially contributing to the

commonly described fatigue and exercise intolerance in uraemia patients.91,92

Although multi-‐factorial, this uraemia-‐induced sedentariness of advancing CKD

has also been implicated in the ‘pro-‐CVD milieu’ of this condition.93

Platelet Dysfunction

Uraemia is the most common systemic disorder associated with clinically

important platelet dysfunction.94 Moderate thrombocytopaenia is a common

finding in uraemia, with the mean platelet volume of remaining platelets often

reduced – a measure inversely proportional to bleeding time.95 Although reduced

in number, thrombocytopaenia sufficiently severe to cause bleeding is rare.

Despite this, numerous other factors are known to impair platelet function in

uraemia whether by impacting platelet granule composition96,97, platelet-‐platelet

interactions98-‐100 or platelet-‐vessel interactions.101-‐103 Moreover, the presence of

anaemia may further impair platelet function in uraemia.104-‐106 Within the

circulation, red blood cells increase platelet vessel wall contact by displacing

21

platelets away from the axial flow of blood towards the vessel wall.95 Red blood

cells further enhance platelet function through the release of ADP and

inactivation of PGI2.95,107 Additionally, Hb acts as a scavenger for nitric oxide

(NO), which along with PGI2 is increased in uraemia and are known to inhibit

platelet function.95,108 Dialysis is associated with improvement in platelet

function, through the removal of a variety of circulating factors associated with

platelet functional abnormalities.109-‐111 Despite this, haemodialysis may be

associated with an increase in bleeding risk, due to inappropriate platelet

activation induced by interaction of circulating platelets with the dialysis

membrane, as well as through the use of heparin anti-‐coagulation during dialysis.

Peritoneal dialysis has been demonstrated to be more effective in correcting

uraemic platelet dysfunction than haemodialysis112, though this RRT

methodology is not suitable for all patients. Finally, platelet function may be

further impaired by the administration of aspirin, a common therapy in CKD and

ESRF due to the high rate of CV morbidity and mortality in this condition. It is

recognised that aspirin may have a more significant impact on bleeding time in

uraemia than in non-‐uraemic patients, and may further be associated with

increased risk of gastro-‐intestinal ulceration and subsequent bleeding.113,114 The

management of the competing interests of CVD prevention and bleeding

minimisation provide an ongoing clinical quandary in the management of CKD

and ESRF patients, due to the paradoxical association of impaired haemostasis

and increased risk of atherothrombosis in uraemia.115

22

Oxidative Stress

Oxidative stress is a widely used term that describes the compensatory biological

response to noxious oxidative stimuli – a process that is most commonly self-‐

limiting. In CKD and a variety of other chronic inflammatory conditions however,

this oxidative stress exceeds biologically optimal levels, leading to

disadvantageous physiological sequelae.

Oxidative processes predominantly occur within the mitochondria, with the

mitochondrial cytochrome oxidase enzyme responsible for 90% of the oxygen

metabolised by human cells.116 This enzyme transfers four electrons to oxygen in

a direct redox reaction that creates two molecules of water in the process. This

reaction generally proceeds without any intervening steps, however a small

percentage of this reaction (<5%) proceeds via an intermediate step that results

in the formation of “free radicals”.116,117 To counteract the production of these

potentially injurious free radicals, numerous antioxidant responses have

developed to interact with these by-‐products of oxygen metabolism and render

them inert before they can cause oxidative damage to cellular components and

function.118

Phagocytes within the human immune system specifically utilise reactive oxygen

species in the host defence against pathogens. Four enzymes are predominantly

responsible for the creation of reactive oxidative products: NADPH oxidase,

superoxide dismutase, nitric oxide synthase and myeloperoxidase.116 These

enzymes produce superoxide anion, hydrogen peroxide, NO and hypochlorous

acid respectively, often utilised in the destruction of invading microorganisms.

Oxidative stress is achieved when the ongoing production of these free radicals

exceeds the available anti-‐oxidant capacity of surrounding tissue – leading to the

23

generation of a local chronic inflammatory state and perpetuating local tissue

injury.

Uraemia is associated with an increase in oxidative stress.118,119 This increased

oxidative burden leads to an increase in oxidative modification of proteins, lipids

and carbohydrates that progressively increases as renal function declines, along

with inactivation of the ‘vascular protective’ molecule nitric oxide and

subsequent formation of peroxynitrite.116 The effect of oxidative stress on

dynamic vascular function will be discussed later in this Background section.

Oxidative Stress in the Promotion of CVD

Atherosclerosis is now widely regarded as an immune / inflammatory response

to endothelial injury120,121, and that this injury is initiated by the accumulation of

sub-‐intimal lipid.122 Native lipoprotein particles (most notably LDL) freely enter

the intima under normal circumstances, and are utilised by vascular cells via

LDL-‐receptor mediated endocytosis without precipitating an immunological or

inflammatory response. These native LDL particles, thus, are not phagocytosed by

local macrophages and do not initiate atherosclerotic changes in the vessel

wall.120,122,123 Oxidative transformation of lipoproteins (LDL in particular),

however, markedly alters the biological activity of these particles. Furthermore,

smaller, denser LDL particles are particularly susceptible to oxidative

modification, leading to the recognition of this subtype of LDL as being

particularly atherogenic.124,125 Following oxidative transformation, the oxidised

LDL (oxLDL) particles become chemotactic for monocytes and T lymphocytes,

initiate a local pro-‐inflammatory response, induce phenotypic endothelial

alterations and trigger macrophage differentiation.120,126 Subsequently, these pro-‐

24

inflammatory molecules are avidly taken up by intimal macrophages utilising

scavenger receptors, rather than the traditional LDL-‐receptors present

ubiquitously on the surface of mammalian cells.120,127 This adaptive response to

potentially injurious oxLDL eventually overwhelms the macrophage’s capacity for

handling the intracellular lipid, leading to the formation of heavily cholesterol-‐

laden foam cells within the vessel wall – cells known to be critical components of

the ‘fatty streak’ and an initiating step in the atherosclerotic process. Critically,

the uptake of these modified LDL particles into differentiated macrophages is

also believed to initiate a chronic pro-‐inflammatory milieu within the vessel wall,

perpetuating the creation of local oxidative molecules and advancing the

atherosclerotic process further.127

Distinct from the oxidative process precipitated by conventional cardiovascular

risk factors such as smoking and obesity, and the hyper-‐atherogenic properties of

numerous chronic inflammatory conditions (e.g. rheumatoid arthritis), ESKD

further contributes to the promotion of CVD through the accumulation of

oxidative end-‐products – most notably aldehyde (carbonyl) species. Reactive

aldehydes may be formed by numerous oxidative reactions.128 Generally excreted

via renal clearance, many such oxidative end-‐products are present in uraemic

serum (and in the serum of haemodialysis patients in particular), at substantially

higher concentrations than are present in healthy individuals.129,130 These

aldehydes are implicated in the promotion of advanced glycosylation end-‐

products (AGE) – formed through the irreversible, non-‐enzymatic interaction of

reactive carbonyl compounds (i.e. aldehydes) and a variety of human proteins.131

These AGE’s are known to be potent promoters of the atherosclerotic process132,

have been recognised as contributors to the oxidisation of LDL133, and are

25

believed to contribute substantially to the excess cardiovascular morbidity and

mortality of CKD and ESKD.134

Immune System Dysregulation

After CVD, infectious disease is the second most common cause of death in ESKD

patients. This elevated risk of infection reflects a state of immune system

dysregulation, further demonstrated through a higher prevalence of autoimmune

disease and neoplasms, cutaneous anergy in delayed-‐type hypersensitivity

reactions to common antigens, and impaired response to vaccination.135 This

state of immunodeficiency predates the commencement of dialysis, but is

enhanced by haemodialysis in particular due to immune cell activation by serum

contact with dialysis membranes.135,136 The underlying causes behind this

immune system dysregulation have not yet been comprehensively characterised,

but are believed to originate from an imbalance between pro-‐inflammatory

cytokines and their inhibitors in the context of the uraemic milieu.135 Inter-‐

current infections, co-‐morbidities, dialysis-‐related triggers and even renal failure

itself have been implicated in the genesis of the pro-‐inflammatory state of

uraemia. Regardless of the myriad underlying causes, the chronic inflammatory

activation of CKD is known to further promote atherosclerotic progression,

endothelial dysfunction, haematopoietic resistance and cardiac failure – all

independent risk factors for reduced survival in this clinical context.137

26

Cardiovascular Sequelae of CKD

Cardiovascular disease (CVD) is the leading cause of death amongst ESRF

patients.20,138,139 Mortality rates amongst ESRF patients are widely accepted to be

15-‐ to 30-‐times that of the age-‐matched mortality in the general population.20,140

Strikingly, according to the US Renal Data System141 only 35% of haemodialysis

patients can expect to live for a five year period.93 Cardiovascular mortality rates

are similarly raised across all age groups, with CV mortality amongst the

youngest age groups (age 25 to 34 years) particularly excessive – up to 500 times

that of age-‐matched peers in the general community.142

This increased risk of CVD extends to less severe stages of renal dysfunction

also.139 Alan Go and colleagues presented striking data in the New England

Journal of Medicine in 2004, demonstrating the rising risk of CV death with

advancing renal dysfunction.143 This study of 1,120,295 ambulatory adults within

the San Francisco Bay area revealed a dramatic inverse association between

incremental risk of all-‐cause mortality, risk of CV events and risk of all-‐cause

hospitalisation with declining renal function, as measured by eGFR (Figure 6).

Furthermore, it has been shown to be more likely that patients with early CKD

will die of CVD, than develop ESRF.144 The explanation for this rising risk of

hospitalization, CV events and mortality with declining renal function most likely

finds its genesis in the myriad conventional and disease-‐specific CV risk factors

previously described. In particular, declining renal function is associated with

complicated neurohormonal and biochemical derangements that strongly

promote the development of hypertension, vascular stiffening, endothelial

dysfunction and various cardiac abnormalities. Although briefly alluded to above,

27

the cardiac and vascular manifestations of CKD and ESRF will be discussed

further below.

Figure 6: Age-standardised Rates of Death from Any Cause (Panel A),

Cardiovascular Events (Panel B) and Hospitalisation (Panel C)

according to eGFR among 1,120,295 ambulatory adults. (Reproduced

from Go AS, et al, N Engl J Med, 2004 with permission.143 Copyright ©

[2004] Massachusetts Medical Society. All rights reserved.)

Left Ventricular Disease in CKD

The prevalence of cardiac abnormalities in CKD is substantial. In a landmark

study, Parfrey and colleagues evaluated 432 ESKD patients with trans-‐thoracic

echocardiography at the initiation of dialysis therapy and demonstrated that less

than 16% of patients studied had normal left ventricular size and systolic

function.145 In this study, 41% of patients had concentric left ventricular

hypertrophy (LVH), 28% LV dilatation, and 16% demonstrated systolic

dysfunction. Significantly, these abnormalities appeared to be closely related to

patient prognosis, both with regards time from dialysis initiation to development

of heart failure, and overall survival from index echocardiogram (Table 2).145

28

Echocardiography

Findings

Prevalence of

Finding %

(n)

Time to

Development

of Heart

Failure

(median)

Significance

vs. Patients

with Normal

LV

Overall

Survival

(median)

Significance

vs. Patients

with Normal

LV

Normal LV Size

and Function 15.6% (64) n/a -‐ >66 months -‐

LV Dilatation 28.0% (117) 38 months p = 0.002 56 months p=NS

Concentric LVH 40.7% (168) 38 months p<0.001 48 months p=NS

LV Systolic

Impairment 15.6% (64) 19 months p<0.001 38 months p<0.001

Table 2: Prevalence of echocardiographic findings of abnormalities in left

ventricular structure and function at dialysis commencement

(Reproduced from Parfrey PS, et al. Nephrol Dial Transplant.,

1996;11:1277-1285, with permission of Oxford University Press).

In this Study, the relative risk of developing heart failure in patients with LV

abnormalities (independent of age, gender, diabetes and ischaemic heart disease

[IHD]) was 3.0 (p<0.001) for LVH, 2.74 (p=0.002) for LV dilatation, and 3.66

(p<0.001) for LV systolic impairment.145

Other authors have previously demonstrated LVH to be an independent predictor

of increased mortality in CKD.146 As suggested by the study by Go and

colleagues143, the cardiac and vascular abnormalities of CKD have been shown to

begin early in the course of the disease.147,148 Furthermore, the development of

29

LVH continues to have prognostic significance in ESRF, with reduced survival

noted amongst patients developing LVH following the commencement of

dialysis.149 In particular, it is a significant finding that routine dialysis does not

achieve stabilisation of the progressive increase in left ventricular mass (LVM),

indicating repeated imaging assessments may be useful to monitor this important

correlate of clinical outcomes periodically after dialysis commencement.150

Recent evidence suggests that more intensive haemodialysis programs may also

play a role in ameliorating the progression of LVH in dialysis-‐dependent ESRF.151

Left ventricular dilatation and hypertrophy are fundamental cardiac adaptive

responses to increases in volume and pressure loads. Increased LVM is frequently

seen in athletes (e.g. cyclists, long distance runners), during pregnancy and as a

physiological adaptation to growth from infancy to adulthood.152 In all of these

cases, the development of increased LVM is a normal physiological compensation

that is reversible with attenuation of the situational trigger.

The development of LVH in CKD appears to be multi-‐factorial, but the prevalence

of LVH appears to be directly related to the severity of renal dysfunction.153 As in

the general population, LV dilatation and hypertrophy are fundamentally

adaptive responses designed to maintain cardiac output and prevent excessive

increases in myocardial wall stress.154 In particular, increased LVM in CKD has

previously been demonstrated to be closely linked to increased cardiac stroke

work index154 – a factor of stroke volume and changes in left ventricular mean

systolic pressure – and exacerbated by other factors such as age, gender,

anaemia, oxidative stress, renin-‐angiotensin-‐aldosterone system (RAAS)

activation.154

30

In CKD however, LVH is not simply a factor of cardiomyocyte hypertrophy

compensating for increased physiological demand. Hypertensive and, in

particular, uraemic LVH is further characterised by significant expansion of the

supporting extracellular architecture of interstitial fibrous tissue.155 This increase

in extracellular matrix leads to a progressive increase in the relative proportion

of interstitial myocardial fibrosis to cardiac myocytes, causing progressive

ventricular stiffening and resultant abnormalities of diastolic filling. Additionally,

in experimental models, this fibrotic process has been coupled to a decline in

vascular capillary density, increasing the distance required for O2 diffusion to

contracting myocytes.156 Thus, even in the absence of obstructive epicardial

coronary artery disease, LVH may be associated with a relative cellular ischaemia

that may contribute further to ventricular diastolic and systolic impairment.

Significantly, this substantially altered myocardial architecture, in combination

with perpetuating neurohormonal and vascular triggers, ensures that the

capacity for meaningful regression of uraemic LVH is markedly reduced.

Given LVH has been determined to be probably the most powerful indicator of

mortality and CV events in patients with advanced CKD157, numerous studies

have evaluated the capacity for LVH regression utilising aggressive management

of associated triggers – most notably anaemia and hypertension.63,158-‐161 These

studies have demonstrated mixed results. Although the development of anaemia

has been strongly associated with findings of LVH in epidemiological studies of

CKD patients162, anaemia correction alone appears not to lead to significant

reductions in LVM.63,158,159 Such findings suggest that the relationship between

anaemia and development of LVH is likely not directly causal.158

31

Significantly however, in 2001, Gérard London’s prolific research group

published a landmark Study in the Journal of the American Society of Nephrology

evaluating whether a concerted interventional study specifically targeting LVM

reduction through dialysis optimisation and tight control of Hb and blood

pressure could impact on patient survival amongst 153 haemodialysis

patients.160 Blood pressure, trans-‐thoracic echocardiography and aortic pulse

wave velocity were performed at baseline and then again at follow-‐up (54±37

months). The intervention led to significant reductions in systolic and diastolic

blood pressure (DBP) and cardiac output across the cohort, and a significant

associated reduction in overall LVM of approximately 10% (290±80g vs.

264±86g, p<0.01).160 This striking demonstration of LVM regression through

targeted therapeutic optimisation was particularly significant, as Cox

proportional hazard analyses demonstrated a strong, independent association

between LVM reduction and overall survival (after correction for age, gender,

diabetes, history of CVD, and “all non-‐specific CV risk factors”)(Figure 7).160 This

study demonstrated that a 10% change in LVM was associated with a relative risk

of 0.78 (0.63-‐0.92, p=0.0012) for all cause mortality, and 0.72 (0.51-‐0.90,

p=0.0016) for CV event-‐free survival across the cohort. This relative risk

reduction was particularly notable amongst subjects with no prior history of CVD

(RR 0.69 [0.52-‐0.83, p=0.0182] for all cause mortality, and 0.52 [0.23-‐0.75,

p=0.0204] for CV event-‐free survival).160

32

Figure 7: Probability of overall survival (A) and cardiovascular event-free survival

(B) amongst successful responders to the LVM reduction intervention,

and non-responders (response defined by a >10% change in LVM)

(p<0.001 for both). (Reproduced from London et al, J Am Soc Nephrol,

2001, with permission from the American Society of Nephrology).

Although oft-‐debated, this Study’s results demonstrate the potential for

improvement in patient prognosis in ESRF associated with therapeutic efforts

that reduce LVM, and reflects the known association of worsened prognosis with

increases in LVM. These findings mirror Studies in the general population163-‐165,

but are particularly pertinent in the high-‐risk CKD context. Such observations

form an important basis for the Research Studies outlined herein.

Congestive Cardiac Failure

Congestive cardiac failure (CCF) is known to be portentous of increased

morbidity and mortality in the general population.166,167 Renal function however,

A NOTE:


33

is a potent risk factor for death and hospitalisation amongst patients with clinical

features of heart failure.168 In CKD, and in ESRF in particular, salt and water

retention due to failing renal excretory capacity or insufficient dialysis is often

indistinguishable from ‘true’ heart failure due to cardiac dysfunction. Myocardial

hypertrophy and fibrosis contributes substantially to diastolic left ventricular

impairment, and are important contributors to the development of heart failure

in CKD.150 Furthermore, excess volume loading, myocardial ischaemia and

uraemic cardiomyopathy are important predisposing factors in the development

of left ventricular dilatation and systolic myocardial dysfunction.169 Additionally,

arterio-‐venous fistulae (AVF) created for the purpose of haemodialysis place a

substantial increased volume load on the left ventricle in ESRF, necessitating

corresponding increases in baseline cardiac output to compensate.170 In the stiff,

hypertrophied ventricle, or the dilated ventricle with regional systolic

impairment, physiological reserve is rapidly overwhelmed by further increases in

cardiac demand, or acute insult to the ventricular myocardium.

Dialysis enables the periodic removal of excess extracellular fluid, and the

maintenance of an ideal, ‘dry-‐weight’, theoretically preventing fluid overload

contributing to CCF in ESRF. Despite this, within 6-‐months of commencing

dialysis, approximately one-‐third of patients will exhibit clinical features of

CCF.171 A further 7% of dialysis patients will develop CCF each year, promoted by

systolic impairment, anaemia, hypertension, hypoalbuminaemia and advancing

age.172 Thus, although dialysis may provide an effective method for the periodic

removal of excess fluid and solutes in ESRF, advancing CKD creates a “perfect

storm” for the development of CCF. It is therefore clear that a substantial burden

34

of the myocardial injury predisposing to the development of CCF is present prior

to dialysis commencement.

Heart failure is a common cause of death in CKD and ESRF, and is an independent

risk factor for mortality in affected patients.173 Dialysis patients hospitalised for

heart failure, features of fluid overload or pulmonary oedema have an abysmal 5-‐

year survival rate – 12.5%, 20.2% and 21.3% respectively.174 Even lesser forms of

CCF may have a dramatic impact on survival. Regardless of aetiology, New York

Heart Association (NYHA) classification of exertional dyspnoea severity has been

proven to be a potent measure of survival in ESRF (Figure 8).175 Cardiac

morphological features may further influence prognosis in this condition, with

increases in LVM, LV dilatation and echocardiographic evidence of LV systolic

impairment adding incremental risk prior to, and following, the clinical

manifestation of CCF.173 Therefore, the focus of preventative care in CKD and

ESRF has moved to the prevention of LVH and LV dilatation development.

Therapeutic options in this regard remain limited, however.

35

Figure 8: Kaplan-Meier survival analysis for all cause mortality by NYHA

Classification for 1322 patients with ESRF. (Reproduced from Postorino

M, et al, Nephrol Dial Transplant., 2007, by permission of Oxford

University Press).

It has been proposed that intermittent 3x/week haemodialysis may complicate,

rather than assist in, the management of ESRF patients with CCF. Haemodialysis-‐

induced myocardial dysfunction has recently received attention as an under-‐

appreciated clinical phenomenon that may have longer-‐term implications for

cardiac function.176 Specifically, haemodialysis has been associated with an acute

reduction in global and regional myocardial blood flow utilising positron

emission tomography (PET)177 and repetitive haemodialysis-‐induced myocardial

stunning may contribute to the development of longer term regional left

ventricular dysfunction, regardless of epicardial coronary artery patency.178

36

Peritoneal dialysis, rather than haemodialysis, has been proposed as a more

effective means of managing ESRF patients with CCF, allowing ‘continuous’

ambulatory dialysis that may more evenly manage fluid retention and the

associated neuro-‐hormonal activation in ESRF patients with impaired cardiac

function.179 The potential disadvantage of this periodic cardiac overload of

haemodialysis has been further supported by the finding that clinical features of

inter-‐dialysis session fluid retention are associated with a markedly elevated risk

of all-‐cause and cardiovascular death in affected patients.180

CCF poses a difficult management dilemma in the care of CKD patients, with

prevention through aggressive risk reduction appearing to offer the greatest

potential for therapeutic success. Further studies to identify contributors to

cardiac dysfunction in CKD and potential disease-‐specific therapeutic options in

this cohort are urgently needed.

Atrial Disease in CKD

Atrial fibrillation (AF) is the most common sustained arrhythmia in the general

population and is known to be associated with an increased risk of morbidity and

mortality.181 Recent studies have confirmed AF as a significant negative

prognostic factor in ESRF.182-‐184 The prevalence of AF is increased in ESRF

compared to the general community, and contributes disproportionately to

morbidity and mortality in affected patients.183,185 Although haemodialysis in

particular is a known risk factor for the development of AF182,186, it remains

unclear whether declining renal function contributes independently to this risk,

or whether the high prevalence of AF risk factors (e.g. advancing age,

37

hypertension, CCF, LVH, coronary artery disease and valvular heart disease)

amongst CKD patients is responsible for the high prevalence of this condition in

CKD.

It is increasingly appreciated that AF initiation and perpetuation relies upon the

interaction of arrhythmia triggers and supporting atrial substrate.187,188

Specifically, ectopic electrical activity within the pulmonary veins commonly

provides the initial trigger, with left (and right) atrial structural and electrical

remodelling providing the necessary substrate for longer-‐term persistence of the

arrhythmia.185,188

Left atrial (LA) volume is commonly increased in ESRF, in comparison to the

general community.189 Factors such as hypertension, myocardial ischaemia and

anaemia contribute substantially to the development of LVH and diastolic LV

impairment in CKD patients, resulting in a chronic increase in left ventricular

end-‐diastolic pressure (LVEDP). This increased LVEDP leads to chronic LA stretch

and compensatory LA (and often pulmonary vein) dilatation.190-‐192 Additionally,

LA dilatation is accompanied by the development of patchy interstitial fibrosis

within the LA myocardium, delaying local conduction velocities and providing

rich substrate for the perpetuation of multiple re-‐entrant circuits and subsequent

AF.187,188,193

CKD is known to be associated with an increase in cardiac volume and pressure

load, contributing to atrial, as well as ventricular, sequelae. It is unsurprising

therefore that LA and right atrial (RA) dilatation are common findings in CKD and

ESRF.189 LA dilatation, in particular, has been associated with increased

serological evidence of inflammation, and greater burden of atherosclerosis at

coronary angiography.194 Importantly, atrial dilatation has been identified as an

38

independent risk factor for the development of AF in ESRF and may contribute to

the poor CV prognosis of patients with CKD.183,195 Recent evidence confirms an

association between LA dilatation and increased mortality in ESRF patients with

LVH.196 Certainly, there is evidence supporting the prognostic benefits of LVH

regression in the general community197 and such regression has been associated

with reductions in risks relating to AF.198 As mentioned, it appears that at least

partial regression of LVH can be achieved in ESRF with aggressive targeting of the

relevant risk factors, such as HT, anaemia and markers of calcium/phosphate

balance.199 It remains to be seen whether the deleterious health outcomes

associated with atrial dilatation can be reversed in CKD and ESRF, however

regression of LVH and the associated chronic elevation of LVEDP may play an

important role in this relationship.

Valvular Disease in CKD

Valvular calcification is common in CKD.200 Valvular sclerosis and calcification of

the aortic valve (in particular) is common in the general population with

advancing age, affecting 20-‐30% of the population over the age of 65 years, with

clinically significant aortic stenosis in 2%.201-‐203 In ESRF, aortic valve calcification

occurs in 28-‐55% of patients, but occurs 10-‐20 years earlier than in the general

population.204-‐206 Mitral annular and valvular calcification is also common in

CKD207,208 and has been linked to the presence of coronary atherosclerosis and

reduced survival in affected patients209,210, although not all studies of this

association have been confirmatory.211 In comparison to aortic valvular

calcification however, mitral calcification is less commonly associated with

39

clinically relevant valvular dysfunction requiring surgical correction.204,206,212,213

Mitral regurgitation (rather than mitral stenosis) is the more common outcome of

mitral valvular and para-‐valvular calcification, with mitral incompetence

contributing further to left ventricular volume loading, and advancing the

development of CCF in this population.206,212

Although patient age remains a strong risk factor for the development of valvular

calcification in advancing CKD213,214, progression to clinically significant aortic

stenosis occurs more rapidly in ESRF, potentially evolving from mild, subclinical

disease to haemodynamically compromising valvular dysfunction within only a

few years.206,214,215 In fact, it has been demonstrated that the mean annual

decrease in aortic valve area amongst ESRF patients with calcific aortic stenosis is

more than four-‐fold greater than observed in non-‐uraemic patients (0.23cm2/yr

vs. 0.05cm2/yr).200,214

Prevention remains the mainstay of therapy. Although advancing age is a potent

contributor to valvular calcification in CKD, hypertension, vitamin D3 levels and

calcium / phosphate product are modifiable risk factors for this condition.204,214-‐

216 Recent evidence supports the use of aggressive phosphate restriction and the

use of the binding agents such as sevelamer in the attenuation of valvular

calcification in ESRF.78,217 Furthermore, although often difficult to control, the

high-‐output state of renal failure is believed to contribute substantially to

valvular deterioration, due to high trans-‐valvular flow rates, and the associated

promotion of injury-‐related valvular inflammation and calcification.200,218

Following the development of severe calcific aortic stenosis, conservative medical

management is associated with high mortality rates. Due to the rapid progression

of aortic stenosis in this condition, more frequent echocardiographic evaluation is

40

warranted in ESRF patients than is usual in the general population.

Haemodialysis may also be problematic in this condition, particularly where

significant fluid removal is necessary, as the combination of aortic stenosis and a

non-‐compliant, hypertrophied LV may precipitate an acute reduction in cardiac

output with aggressive ultrafiltration.200 Prompt and aggressive treatment of

arrhythmias such as AF, is also recommended to maintain cardiac output,

particularly in the context of compensatory LVH and associated diastolic

dysfunction necessitating preservation of the atrial contribution to LV filling.

Additionally, ESRF patients with valvular disease are at an increased risk for

endocarditis, and appropriate prophylactic measures should be considered

where clinically appropriate.200

Surgical aortic valve replacement is associated with higher procedural and post-‐

procedural mortality in ESRF than in the general population, but is similarly

associated with improvement in overall survival in symptomatic stenotic

disease.206,219,220 Mitral valve replacement is less common than aortic valve

surgery in ESRF221,222, and some groups promote mitral valvular repair in

congestive uraemic cardiomyopathy, despite the known risks of accelerated

calcification and delayed repair failure in ESRF.223 Surgical practice guidelines

have historically preferred the use of mechanical prosthetic valves over bio-‐

prostheses in ESRF, due to the greater presumed risk of bio-‐prosthetic

calcification and recurrent valvular dysfunction with biological xenografts.224

Retrospective research in this area disputes this contention however, and

promotes the use of bio-‐prostheses in ESRF, due to the reduced risk of

haemorrhage from anticoagulation, and the similar medium-‐term post-‐surgical

prognosis.221,222,225,226 In the absence of prospective studies, and with large

41

observational studies demonstrating high mortality rates for ESRF patients

following valve replacement regardless of prosthesis type, current guidelines

suggest bioprosthetic valves may be appropriate in many patients.227

Progressive valvular calcification and dysfunction are highly prevalent in CKD

and ESRF and represent a unique challenge to physicians treating affected

patients. In the context of an aging Australian population, and the provision of

dialysis to increasingly elderly patients, valvular calcification and dysfunction will

inevitably become more common in the management of Australian CKD patients.

Endothelial Dysfunction in CKD

It is widely acknowledged that endothelial dysfunction is an important initiating

factor in the development of atherosclerosis.228 Endothelial dysfunction

represents a failure of the balance between endothelial injury and the capacity

for repair and involves the fundamental alteration of vaso-‐protective

mechanisms into pro-‐atherosclerotic tendencies, with the hallmark change of

impaired NO bioavailability. Dysfunctional endothelium is characterised by a

reduction in vaso-‐dilatory molecules (most notably NO), and an increase in vaso-‐

constrictive factors.229 This imbalance is largely quantified by dynamic changes in

conduit vessel size, mediated by these endothelium-‐derived vasoactive

molecules, described as ‘endothelium-‐dependent’ vasodilatation.230 Additionally,

dysfunctional endothelium becomes pro-‐coagulant (promoting clinically relevant

athero-‐thrombotic events) and pro-‐inflammatory (releasing cytokines that are

chemo-‐attractant for chronic inflammatory cells).231 As previously mentioned,

the development of this local pro-‐inflammatory milieu leads to local tissue injury,

42

fibrotic / calcific repair and the development of atherosclerotic plaques. Thus,

endothelial dysfunction provides a unique marker of the systemic tendency

towards the development of future, clinically significant CV events.232

Pathobiology of Endothelial Dysfunction in CKD

Numerous vasodilatory and anti-‐aggregatory factors are released by the intact

endothelium. The principal smooth muscle cell relaxing factors are NO,

prostacyclin (PGI2) and endothelial derived hyperpolarising factor (EDHF) which

also exert anti-‐aggregatory effects on local platelets.233 Endothelin-‐1 (ET-‐1) and

thromboxane (TXA2) are prominent examples of endothelial-‐derived vaso-‐

constrictive factors that have been implicated in diseases of the vascular

endothelium.234 In the evaluation of endothelial function, substantial work has

focussed on NO as a critical factor, due to the experimental capacity for NO to

protect against atherosclerosis, and for NO inhibition to promote experimental

atheroma formation.235 Clinically, endothelial dysfunction is almost universally

characterised by reduced NO bioavailability, and NO bioavailability is known to

be reduced in CKD.235

NO is formed in vivo by transformation of the amino acid L-‐arginine through the

action of endothelial NO-‐synthase (eNOS). Once produced, NO is susceptible to

further transformation by local oxygen free radicals in situations of high

oxidative stress (such as CKD), with resultant loss of its vaso-‐protective activity.

Specifically, superoxide anion (O2-‐) scavenges NO, yielding peroxynitrite (ONOO-‐),

which may be further transformed to form nitrate and the highly reactive OH• -‐ a

potent contributor to local tissue injury.233,236,237

43

In addition to increased NO degradation, NO activity may be further affected by

reduced production in CKD.238,239 eNOS may be inhibited by a variety of

circulating factors, many of which accumulate with declining renal function and

have been proposed as pathogenic in CKD. Principal among the factors

implicated in the endothelial dysfunction of uraemia is asymmetrical

dimethylarginine (ADMA) – a member of a family of guanidine compounds

known to be present in uraemic serum in sufficient concentrations to inhibit

eNOS.240 The relationship between ADMA and the promotion of endothelial

dysfunction and CVD in CKD has been extensively investigated since the initial

proposal of causation in 1992.241,242 ADMA has been associated with impairment

in measures of endothelial function243, and has been found to be a strong

predictor of CV events and death in patients with early CKD, ESRF and in the

general population.241,244,245 Furthermore, as a small, water-‐soluble molecule,

ADMA is freely removed with dialysis246, and acute reduction in ADMA following

dialysis have been associated with acute improvements in endothelial function247,

although these findings are contentious.248-‐251

Thus, the combined effects of increased oxidative stress within the pro-‐

inflammatory milieu of CKD, and the endothelium-‐toxic effects of uraemic serum,

contribute to the inhibition of endothelial vaso-‐protective properties and the

promotion of the clinical phenotype of endothelial dysfunction of CKD. This

phenotype is believed to be predominantly responsible for the promotion of

atherosclerosis in advancing CKD241,252 – a process known to be profoundly

accelerated in this condition.253

44

Assessment of Endothelial Function

In the research and clinical settings, endothelial function may be measured

utilising a variety of different methodologies, and in a variety of vascular beds.

Numerous circulating biomarkers have been associated with endothelial

dysfunction, both in the general community and in CKD.254-‐256 Evaluation of flow-‐

mediated arterial dilatation (FMD) is the most commonly utilised approach for

the evaluation of regional endothelial function. This method relies upon the

normal endothelial cell response to increased mechanical shear-‐stress – the

release of endothelium-‐derived factors responsible for vascular smooth muscle

cell relaxation and subsequent vaso-‐dilatation.254 Utilising this principle, a

standardised method for evaluating conduit artery dilatation in response to

increased flow was developed.257 Evaluating the calibre of the brachial artery

(most commonly), FMD is measured in response to an increase in arterial flow,

typically induced by a period of distal circulatory bed ischaemia (e.g. forearm).254

Ultrasound methodologies are most commonly used, but suffer from the potential

for investigator-‐initiated inaccuracies – particularly in inexperienced hands.254,258

Newer imaging methodologies, such as computed tomography (CT) and

cardiovascular magnetic resonance imaging (CMR), are increasingly being

utilised to enhance diagnostic accuracy and reproducibility, and potentially

contribute additional functionality in this field (see below).259,260

Endothelial Dysfunction and Cardiovascular Risk in CKD

FMD is mediated, in part, by the release of NO from endothelial cells – a response

that is reduced in patients with CV risk factors or clinically significant

45

atherosclerosis (peripheral, cerebral and coronary).254,257,261 Evaluation of

endothelial dysfunction in the forearm (i.e. peripheral) is used as a surrogate for

endothelial function in clinically relevant arterial systems such as the coronary

circulation and hence has been used to provide a non-‐invasive method for

predicting the presence of coronary artery atherosclerosis, and future coronary

events in at-‐risk patients.262-‐266 Additionally, improvements in peripheral

endothelial function have been associated with therapeutic interventions that

improve cardiovascular risk.263,264

Almost all traditional and unconventional risk factors for atherosclerosis and CV

morbidity and mortality have been found to be associated with endothelial

dysfunction.230 The mechanisms by which smoking, hypertension, diabetes

mellitus and hypercholesterolaemia contribute to the development of endothelial

dysfunction are complex and heterogenous.267 CKD provides a particularly

complex precipitant for endothelial dysfunction, resulting from multiple

circulating factors injurious to the endothelium and promotional of the necessary

pro-‐inflammatory setting for endothelial dysfunction and accelerated

atherosclerosis.256 Endothelial dysfunction has been identified in pre-‐dialysis

CKD patients, haemodialysis and peritoneal dialysis patients and following renal

transplantation and has similarly been implicated in the promotion of

cardiovascular structural and functional alterations promoting CVD.268 Notably,

impairment in forearm endothelial function has been shown to be associated

with an increase in all-‐cause mortality in ESRF.265

46

Coronary Artery Disease in CKD

Coronary artery disease (CAD) is a leading cause of morbidity and mortality in

CKD patients.20,141 As with the systemic circulation, the coronary arteries may be

affected by a wide range of pathological processes, including endothelial

dysfunction, intimal / medial calcification, atherosclerosis, and athero-‐

thrombosis precipitating acute coronary syndrome (ACS). Disease within the

coronary arteries, however, plays a significantly greater role in CV morbidity and

mortality, and hence evaluating and understanding the patho-‐physiology of CAD

is of critical importance in attempts to ameliorate the risks of CVD in CKD

patients.

Coronary Endothelial Function

The coronary endothelium is responsible for the maintenance of blood flow

within the coronary circulation, and the regulation of inflammation, thrombosis

and platelet activation in this territory.254 Imbalance between local vaso-‐dilatory,

anti-‐inflammatory substances (such as NO) and vaso-‐constrictive, pro-‐

inflammatory mediators (such as ET-‐1) provides the basis for the development of

coronary endothelial dysfunction and clinically significant CAD. Significantly,

coronary endothelial dysfunction has been demonstrated to be predictive of

increased risk for subsequent cardiac events, even in the presence of only minor

coronary atherosclerosis.262,269

As previously mentioned, peripheral measures of endothelial function (i.e. FMD)

have been associated with invasively assessed coronary endothelial function,

although the absolute correlation was found to be modest.270 Peripheral arterial

47

applanation tonometry has also been utilised to estimate coronary vasomotor

function, though such indirect measures remain surrogates for actual coronary

endothelial function.254

“Gold standard” evaluation of coronary artery endothelial function involves the

introduction of a Doppler-‐based coronary flow wire into the coronary circulation,

and evaluating coronary flow and diameter characteristics in response to a range

of stimuli – both direct pharmacological agents and remote (e.g. cold pressor271)

stimuli. Classically, acetylcholine (Ach) is introduced into the coronary artery

utilising an intra-‐coronary infusion catheter during invasive coronary

angiography (ICA). The coronary flow wire is repositioned within the proximal to

mid-‐portion of the coronary artery avoiding nearby bifurcations, until a stable

Doppler signal is achieved. Coronary artery diameter (by quantitative coronary

angiography [QCA], or more recently by intravascular ultrasound [IVUS]272), is

assessed 5mm distal to the tip of the coronary flow wire. Alterations in coronary

blood flow (CBF) and coronary vascular resistance are observed in response to

infusion of previously validated doses of intra-‐coronary Ach.273,274

The response to Ach provides a marker for the local availability of NO, and hence

can evaluate both macrovascular and microvascular coronary endothelium-‐

dependent vasodilator function.254 In the presence of dysfunctional endothelium,

the normal vaso-‐dilatory stimulus of Ach can become vaso-‐constrictive, with

subsequent changes in macrovascular and microvascular function measured by

changes in coronary luminal diameter and CBF respectively. Endotheliium-‐

independent microvascular coronary vasomotor function is also assessed

utilising the administration of intracoronary adenosine boluses (18-‐48µg) to

48

achieve maximal hyperaemia, with endothelium-‐independent macrovascular

function measured in response to intra-‐coronary glyceryl-‐trinitrate (GTN).254

Coronary blood flow is calculated from the widely used formula:275

[π x 0.125 x (Coronary Diameter)2 x (Coronary Blood Flow APV)] x 60

where Diameter is measured in cm, Average Peak Velocity (APV) of coronary

blood flow is measured in cm/sec and CBF is measured in mL/min. .

A normal response is considered to have occurred if endothelial-‐dependent CBF

increases by more than 50% in response to Ach, and the coronary flow reserve

(CFR) – the ratio of maximal to baseline CBF -‐ is greater than 2.5 following

adenosine.276

Remarkably little work has focussed on the evaluation of coronary endothelial

function in CKD. Although the invasive nature of the procedure has inherent risks,

it is likely that the potential nephrotoxicity of angiographic contrast agents has

impeded assessment of pre-‐dialysis patients in particular. It is widely presumed

that the extensive literature demonstrating peripheral endothelial dysfunction in

CKD and ESRF applies similarly to the coronary circulation. A single study

evaluating non-‐endothelium-‐dependent coronary endothelial function amongst

diabetic patients (a cohort known to have a high prevalence of coronary

endothelial dysfunction) with ESRF but angiographically normal coronary

arteries was published in the American Heart Journal in 2004.277 This study

compared invasive coronary endothelial function indices in 11 diabetic patients

with preserved renal function (serum creatinine < 1.0mg/dL [88µmol/L]) and no

evidence of microvascular complications (i.e. retinopathy or neuropathy), with 21

49

patients with ESRF from diabetic nephropathy. A control group of 32 subjects

without diabetes or renal impairment was also evaluated. CFR was found to be

impaired (defined in this Study as CFR<2.0) in 9% of normal subjects and 18% of

diabetic, non-‐ESRF patients, compared to 57% of patients in the diabetic

nephropathy cohort (p<0.001). Interestingly, APV increased in all cohorts in

response to maximal hyperaemia (with intravenous adenosine 140µg/kg/min),

and peak APV was not significantly different between the 3 groups.277 The reason

for the reduced CFR amongst the ESRF cohort (1.6±0.5 vs. 2.7±0.7 for non-‐ESRF

diabetics vs. 2.8±0.8 for normal controls, p<0.001 for ESRF vs. other cohorts) was

an elevated basal APV in 67% of abnormal CFR cases.277 That is, ESRF appeared

to be associated with an elevation in basal coronary blood flow velocity, resulting

in a blunted response to hyperaemic stimulus (adenosine), rather than the

presence (solely) of microvascular disease which might be expected to cause

blunting of the hyperaemic response, rather than elevation of baseline APV.

This finding has recently been affirmed non-‐invasively utilising PET.278 Published

in 2009, this Study evaluated basal and hyperaemic (post-‐dipyridamole)

myocardial perfusion in twenty-‐two patients with moderate to severe CKD

(divided into three cohorts according to eGFR), and compared these results to ten

healthy control subjects with preserved renal function. Although this Study found

preserved CFR amongst the CKD patients (as distinct from the previously

discussed invasive study), basal myocardial blood flow was significantly elevated

amongst the CKD patients vs. controls (p<0.001), with a negative correlation

between eGFR and myocardial blood flow seen (Spearman correlation

coefficient=0.63, p=0.0001).278 An ultrasound-‐based FMD protocol was also

undertaken in this Study, with FMD (% change in brachial artery diameter)

50

significantly reduced amongst the CKD cohorts compared to controls (p<0.03).

The authors conclude that “coronary and peripheral vascular function are

disturbed by different mechanisms in patients with CKD”, although direct

comparison of the two methodologies utilised in this Study is questionable. FMD

is a measure of endothelium-‐dependent vasodilatation in response to an increase

in endothelial shear-‐stress (flow) resulting from induction of distal vascular bed

ischaemia.257,279 This evaluation of large-‐vessel endothelial-‐dependent function in

the brachial artery is distinct from the evaluation of coronary endothelium-‐

independent, microvascular function evaluated following the administration of

dipyridamole in this study. Although previous studies have demonstrated a link

between peripheral microvascular function (as assessed by ‘gold-‐standard’

venous occlusion plethysmography) and peripheral arterial FMD responses280,

the two are not equivalent and comparison of coronary microvascular responses

to dipyridamole with FMD as a surrogate marker of peripheral microvascular

function might perhaps be considered disingenuous.281

A further Study evaluated invasive CFR amongst 124 patients with

GFR<60mL/min/1.73m2, compared to 482 control subjects with

GFR>60mL/min/1.73m2, finding reduced GFR to be predictive of impaired CFR

by univariate, but not multivariate, analysis.282 Although the mean CFR was

reduced in subjects with mildly impaired renal function (compared to controls),

only increasing age, female gender, rising BMI and co-‐existent hypertension were

significantly associated with impairment of CFR by multivariate analysis.282 No

comment was made on differences in basal APV values between the two cohorts.

Although the non-‐invasive Study, in particular, has limitations, these three

studies highlight abnormalities in coronary microvascular homeostasis in

51

patients with declining renal function. Although uraemia per se may directly

influence microvascular function, coexistent factors such as diabetes mellitus,

hypertension and LVH may play a significant role in the genesis of elevated basal

CBF, and impairment in hyperaemic reserve in CKD patients. The metabolic

syndrome and hypertension (± associated myocardial diastolic dysfunction) have

been implicated in the genesis of CFR impairment in the general population.283-‐288

Numerous studies identifying impairment in coronary microvascular function in

LVH have also been published289-‐296, however only a few have demonstrated an

increase in basal CBF.291,293 Furthermore, LVM alone may not be responsible for

this impairment in CFR on a background of increased basal CBF, as previously

demonstrated by the differing CFR between athletes with compensatory LVH, and

hypertensive patients with secondary LVH.292

Numerous other factors associated with CKD have also been associated with

coronary microvascular dysfunction. Mitral annular and aortic valve calcification

– common findings in CKD -‐ have also been associated with findings of reduced

CFR in the general population.297,298 Furthermore, systemic inflammation in

patients with systemic lupus erythematosis and rheumatoid arthritis has

previously been identified as a potential contributor to coronary microvascular

dysfunction299, and this may have implications for the microvascular dysfunction

of the pro-‐inflammatory uraemic state of CKD also.

Anaemia, expansion of the extracellular fluid compartment and iatrogenic

arterio-‐venous fistulae (AVF) for the performance of haemodialysis may all

contribute substantially to the increase in systemic blood-‐flow of CKD and ESRF

patients. Combined with compensatory LVH and increased myocardial metabolic

demand caused by elevated systemic blood pressure, systolic myocardial wall

52

stress, diastolic LV pressure and myocardial mass, an increase in basal coronary

blood flow in this condition appears likely.295 Uraemic microvascular dysfunction

and obstructive coronary microvascular disease also appear potential

contributors to the blunted coronary microvascular response to dipyridamole

and adenosine in studies to date. Thus, in combination with an increase in basal

oxygen demand, CKD and ESRF patients likely suffer from an inability to

sufficiently increase myocardial oxygen delivery during periods of increased

metabolic demand (e.g. exercise / obstructive coronary disease), potentially

contributing substantially to the elevated rate of symptomatic CAD in this

condition.

Remarkably, endothelial-‐dependent coronary vasomotor function appears not to

have been evaluated in this condition. This observation forms the basis for the

invasive component of this PhD.

Coronary Atherosclerosis

CKD is associated with altered coronary plaque composition, including a higher

calcific burden and more diffuse atherosclerotic disease.253,300-‐302 These

differences in plaque morphology may play a significant role in the genesis of

clinically significant cardiac events. In particular, plaque calcification is more

extensive within coronary plaques of uraemic patients than amongst CAD

patients with preserved renal function.204,302 Strikingly, this calcification of

coronary plaques is evident in ESRF patients from a young age – much younger

than is usual within the general population.303 Furthermore, the process of

atherosclerotic plaque calcification appears to increase progressively with

53

declining renal function, greatest amongst ESRF patients requiring dialysis.204

This calcification has been demonstrated to be almost entirely calcium

phosphate, rather than calcium oxalate or other conjugates.302 This finding has

particular relevance in the context of the altered calcium / phosphate handling of

advancing CKD, and the control of calcium x phosphate product in ESRF patients

in particular, although this link remains contentious.304

Another striking finding regarding CAD in the context of declining renal function

is the propensity for progression, once initiated.305 Not only is the prevalence of

coronary atherosclerotic plaques amongst autopsy and angiographic studies of

ESRF patients high301,306,307 – approximately 30-‐40% of most series – but the

presence and severity of coronary atherosclerosis plays a significant role in

patient survival, particularly following dialysis commencement.308,309

The traditional assessment of CV disease severity based on symptoms and

evidence of end-‐organ damage may not adequately represent the true risk of CVD

in CKD patients.256 As previously stated, the inverse relationship between renal

function and CVD-‐risk implicates disease-‐specific mechanisms in the

development of the accelerated atherosclerosis, arteriosclerosis and myocardial

disease seen of CKD.143,310 Not only is the burden of coronary atherosclerotic

disease greater, but the propensity for clinically relevant coronary athero-‐

thrombotic events is increased further by the uraemic milieu.

Over the past three decades, enormous advances have been made in the

treatment of acute coronary syndrome (ACS). Invasive revascularisation and

adjunctive pharmacotherapy, in addition to standard anti-‐ischaemic therapy, has

led to marked reductions in CV mortality in the general population.19

Unfortunately, the prognosis for ESRF patients following ACS remains

54

unacceptably high however, and has not appreciably improved over the same

time period.311 Following acute myocardial infarction (MI), patients with ESRF

have been reported to have an inpatient mortality of 31.8%312 and longer term

mortality rates of 59.3% at 1 year, and 89.9% at 5 years.313 This abysmal

prognosis is not only confined to dialysis patients however, with a progressive

gradient of declining prognosis following MI in advancing CKD.312 In a recent

evaluation of 19,029 patients presenting to US hospitals with ST-‐segment

elevation myocardial infarction (STEMI), in-‐hospital survival amongst patients

with Stage 3a (eGFR=45-‐59mL/min/1.73m2), Stage 3b (eGFR=30-‐

44mL/min/1.73m2) and Stage 4 (eGFR=15-‐29mL/min/1.73m2) CKD was 8.8%,

17.9% and 27.3% respectively (p value for interaction<0.0001).312 This

compared to in-‐hospital mortality of 2.3% for patients with preserved renal

function.312

Although less profound, CKD patients also suffer a markedly increased risk of

death following hospitalisation for non-‐STEMI ACS.312,314,315 Amongst 30,462

patients presenting with non-‐ST-‐segment elevation myocardial infarction

(NSTEMI) to US hospitals in 2007, in-‐hospital mortality increased from 1.8% for

patients without renal dysfunction, to 13.4% and 12.4% for patients with Stage 4

and Stage 5 CKD respectively.312

The are numerous reasons for this increased risk. CKD patients have been

systematically excluded from the majority of clinical trials assessing new

therapies in CVD.316,317 Thus, concerns exist regarding the applicability of clinical

guidelines based on studies from non-‐CKD patients, to the CKD population.

Significantly, CKD patients presenting to hospital with ACS tend to be

‘undertreated’, with lower rates of ‘routine’ medication utilisation (e.g. aspirin,

55

clopidogrel, beta-‐blockers, statins) and lower rates of coronary

revascularisation.312,318,319 This discrepancy may result from considered omission

rather than neglect, given previous findings of equivocal benefit for statin therapy

in ESRF35, and concerns regarding the nephrotoxicity of an invasive management

strategy in pre-‐dialysis patients (Stages 3-‐4 ± 5). In fact, it appears that dialysis

patients may receive more aggressive interventional therapy than pre-‐dialysis

patients for this reason, with the Study by Fox et al312 demonstrating increased

utilisation of cardiac catheterisation, percutaneous coronary intervention (PCI)

and coronary artery bypass grafting (CABG) in Stage 5, versus Stage 4, CKD in

NSTEMI patients. In STEMI patients however, the utilisation of invasive

management strategies declined with increasing CKD severity.312 Despite the

increased overall mortality in Stage 5 CKD, bleeding rates are high in advancing

CKD, particularly in the context of the anti-‐thrombin and anti-‐platelet agents

commonly employed in the management of ACS. This excess risk of major

bleeding may stem from the intrinsic platelet dysfunction of uraemia, or from

inappropriate dosing in the context of reduced renal clearance.320-‐322

Furthermore, the high rate of pre-‐existing cardiac dysfunction (both diastolic and

systolic), and the reduced physiological reserve induced by advancing CKD

appear to contribute substantially to the poor prognosis of CKD patients

following hospitalisation with acute myocardial ischaemia.

Even with aggressive invasive management of CAD, historical 2-‐year survival

rates following CABG and PCI have been reported to be 56.4±1.4% and

48.4±2.0% respectively.323 This poor prognosis also highlights a potential

advantage of CABG over PCI for the revascularisation of ESRF patients, with the

relative benefit of CABG over PCI confirmed by other studies.324 This advantage

56

appears to stem from the very high re-‐stenosis rates in ESRF patients following

percutaneous trans-‐luminal coronary angioplasty (PTCA) and bare-‐metal stent

PCI, although differences in patient complexity have been blamed.325-‐327 Recent

results for PCI in the drug-‐eluting stent era have been more promising

however328, though renal insufficiency remains a potent predictor for increased

risk of late stent thrombosis.329

Vascular Disease in Chronic Kidney Disease

CKD is characterised by complex alterations in vascular structure and function.

Although atherosclerotic disease is highly prevalent in CKD and ESRF,

contributing substantially to the burden of cardiovascular morbidity and

mortality in this condition, non-‐atheromatous vascular remodelling, calcification

and stiffening play a major role in the evolution of CVD in this population.

Arterial Function

The systemic arterial bed has two distinct, inter-‐related functions: to deliver an

adequate blood-‐supply to peripheral tissues (conduit function) and to modulate

pressure variations arising from intermittent left ventricular ejection (cushioning

function).330 The conduit function relies on transmission of blood via large, low-‐

resistance central arteries, to smaller, less elastic peripheral arteries and

arterioles. In the absence of atherosclerotic obstruction, the conduit function can

accommodate significant changes in blood-‐flow, depending on distal tissue

requirements (e.g. skeletal muscle beds may receive up to 10-‐times resting blood-‐

flow during exertion).331 The arterial conduit adaptation to increased

57

physiological demand is mediated through acute changes in blood-‐flow velocity,

and by arterial diameter (resistance) changes – a process necessitating intact

endothelium-‐dependent vasomotor function.331

The arterial cushioning effect arises predominantly from the large, central elastic

arteries (such as the aorta and carotid arteries), and lessens progressively

towards the periphery, as arteries become more muscular.332 This arterial

elastance allows for the accommodation of up to 50% of ventricular stroke

volume within the larger central arteries, with elastic recoil in diastole ensuring

continuous tissue perfusion across the cardiac cycle.331 The capacity for the

arterial system to cushion the impact of ventricular systolic ejection depends on

the ‘visco-‐elastic’ properties of the arterial wall.331 The elasticity of the central

arteries is largely a function of the absolute and relative representation of elastin

and collagen within the vessel wall.331 The collagen to elastin ratio increases

progressively towards the periphery, contributing to progressively stiffer

“resistance” arteries distally. Additionally, turnover of extracellular matrix

proteins by metalloproteinases and other proteolytic enzymes contributes to

arterial stiffness over time.332 Finally, vascular calcification – as a function of

atherosclerosis, age and other disease states (such as CKD) – may also contribute

to larger artery stiffness.333

As arterial elasticity declines, the elastic recoil during ventricular diastole

progressively lessens, contributing to lower diastolic blood pressure.

Additionally, central arterial stiffness leads to an increased velocity of the

forward pressure wave (from left ventricle to the periphery). In an elastic arterial

system, this forward (incident) pressure wave is reflected from sites of structural

or functional inhomogeneity within the peripheral arterial tree, creating a

58

backward (reflected) pressure wave (from periphery towards ascending aorta)

that contributes to the maintenance of diastolic blood pressure.334,335 The

incident pressure wave and the reflected pressure waves interact, with timing

and amplitude of each wave contributing to the final arterial waveform for each

cardiac cycle.336 The appearance and amplitude of these waveforms also depend

entirely on the site of assessment as it relates to the sum of the component waves,

as pressure waveforms within the central arteries (distant from sites of

reflection) will be different to those of the peripheral arteries (closer to sites of

wave reflection).

Increased vascular stiffness is associated with increased incident wave velocity,

and hence earlier wave reflection from the periphery. Thus, the reflected waves

may eventually arrive within the ascending aorta during mid-‐systole, rather than

diastole, contributing substantially to left ventricular afterload, and detracting

from diastolic blood pressure. Thus, aging and disease states that increase

vascular stiffness contribute to an increase in central systolic blood pressure, a

decline in diastolic blood pressure, and a resultant elevation of pulse pressure

(PP) at the expense of coronary artery diastolic perfusion pressure.337-‐340

Atherosclerosis

In advancing CKD, atherosclerosis poses a significant threat to arterial conduit

function and tissue perfusion. Atherosclerosis is often well-‐advanced prior to the

commencement of dialysis in ESRF341-‐343, but appears to be accelerated in

haemodialysis patients in particular.253 Although CAD contributes substantially to

the burden of overall CVD in CKD patients, atherosclerosis within the peripheral,

59

cerebral and renal vascular beds plays a major role in overall patient morbidity

and mortality.22,344,345 As with the coronary system, atherosclerosis in CKD

patients exhibits a higher calcific burden, and less lipidic plaque as is usual in the

general population. Given the dearth of evaluable benefit for statins in ESRF34,35

(potentially related to the more advanced fibrotic/calcific nature of

atherosclerotic plaques in ESRF), atherosclerotic disease prevention benefits

greatest from earlier intervention in the course of CKD disease progression.

Arteriosclerosis

Significant arterial structural remodelling occurs in CKD. Many of the alterations

identified in CKD patients are similar to alterations known to occur with aging –

specifically dilatation, intimal-‐medial hypertrophy and stiffening of the aorta and

major arteries.346 In advancing CKD, anaemia, arterio-‐venous fistulae,

hypertension and fluid retention contribute to a perpetual state of “volume/flow

overload” that promotes compensatory systemic arterial remodelling.331 The

result of this remodelling, however, is highly disadvantageous to end-‐organ and

cardiac function.

CKD is characterised by a stepwise increase in vascular stiffening corresponding

to the stages of declining renal function.347 This progressive decline in aortic and

elastic artery distensibility is associated with progressive increases in incident

(and reflected) wave velocity and resultant patho-‐physiological complications.

Intima-‐media thickening and calcification, particularly within the larger elastic

arteries, contribute substantially to this increased vascular stiffening.346 The

resultant increases in systolic and pulse pressures, LV afterload and

60

compensatory LVH represent core components of the clinically relevant

cardiovascular pathology of CKD.

This combination of arterial and ventricular stiffening in CKD leads to a

progressive decline in cardiac reserve, as the reduced arterial compliance leads

to disadvantageous physiological responses to increased circulatory demand.

Exertion is generally associated with increases in heart rate (HR) and LV stroke

volume (LVSV) (unless diastolic dysfunction is severe, where LVSV may fall with

rising HR). In CKD, the increased arterial stiffness is associated with magnified

blood pressure and LV afterload changes with any increase in LV stroke volume,

due to the reduced arterial capacitance reserve.348 Significantly, coronary

perfusion may be markedly altered during these conditions, even in the absence

of obstructive coronary atherosclerosis.

Vascular Calcification

Vascular calcification primarily refers to the process of calcium phosphate

deposition within the intima and/or media of arteries and arterioles, and is a

common finding with advancing age and atherosclerosis.349 In CKD, vascular

calcification is a potent contributor to increased arterial stiffness. As previously

described, destruction of the renal parenchyma leads to a pro-‐calcific milieu that

enhances and promotes premature cardiac and vascular calcification,

contributing significantly to the excess burden of CV morbidity and mortality in

this condition.154 Vascular calcification may be intimal or medial, with differing

aetiologies and clinical implications. Intimal calcification is primarily associated

with atherosclerotic plaques, and is most commonly identified as diffuse,

61

punctate crystals that may progressively aggregate.349 It has been proposed that

atherosclerotic calcification develops initially within more metabolically active

plaques and may represent healing of previously disrupted plaques.350

Furthermore, intimal calcification may be promoted by vascular smooth muscle

and macrophage cell death, lipoproteins (particularly oxidised forms) and the

presence of increased extracellular calcium and phosphate concentrations.349

IVUS studies, however, indicate that vulnerable coronary plaques in the general

population are most commonly not calcified, and that increased calcification is

associated with more stable, fibrotic plaques.351-‐354 Thus, in the general

population, progressive calcification may represent an adaptive mechanism

stabilising atherosclerotic plaques at a later stage of their temporal

development.355 In CKD however, the presence of excessive vascular calcification,

may represent an acceleration of this adaptive response, in relation to a greater

burden of atherosclerosis and a more amenable systemic milieu.

Medial calcification however, occurs independently of atherosclerosis, most

commonly in the form of linear deposits along elastic lamellae and increases

progressively with age, contributing substantially to vascular stiffening.356 At it’s

most severe, it may form dense circumferential sheets within the media, bounded

by vascular smooth muscle cells on either side.349 Most commonly identified in

the peripheral vessels of elderly individuals as the appearance of vascular “rail-‐

tracking” on plain radiographs357, medial calcification is also prevalent in younger

patients with diabetes and CKD.349

As previously discussed, although the mechanisms behind the pro-‐calcific milieu

of CKD are numerous and remain to be definitively delineated, the patho-‐

physiological implications are widely appreciated. Vascular calcification is

62

associated with significant morbidity and mortality.333,358-‐363 Arterial calcification

contributes to significant vascular structural and functional alterations that are

subsequently associated with decreased DBP and increased PP364 -‐

haemodynamic indices closely linked with reduced survival in ESRF

patients.365,366 In ESRF, vascular calcification is strongly influenced by the

prescribed dose of calcium-‐based phosphate binders and the duration of

haemodialysis.364 Currently-‐available therapies to reduce the burden of vascular

calcification, once present, have failed to dramatically alter the poor prognosis of

ESRF patients however.40,367 Further work in this field is urgently required.

Non-‐invasive Evaluation of Arterial Stiffness

Pulse Wave Velocity

Vascular stiffening may be evaluated by various methodologies. Perhaps the

simplest and best-‐validated measure is pulse wave velocity (PWV) – the

assessment of the velocity of incident wave travel between two points in the

arterial system. Thus, to calculate PWV, the distance travelled between two

points is divided by the time taken by the incident wave to traverse the points

(PWV = Distance / Time). There is a linear correlation between the speed of

travel of the pulse wave and arterial stiffness over the distance traversed.348

Carotid-‐femoral PWV is considered the ‘gold standard’ for the evaluation of

central arterial stiffness.368 Widely used in epidemiological and interventional

studies in CKD, ESRF and a variety of other disease-‐states, carotid-‐femoral PWV

relies on an assumption of distance between the aortic arch and the site of

evaluation at the carotid artery, and on the course of the aorta (measured as a

63

straight line over the ventral thorax and abdomen) between the right carotid and

right femoral sites of evaluation.368 Although numerous methods have been

utilised to reduce the potential for inaccuracy based on inaccuracies in surface

distance measurement (e.g. related to factors such as abdominal obesity or

prominent female bust), or partial obstruction to flow induced by aortic or iliac

artery atherosclerosis.369 Generally, transit-‐time is measured from foot-‐to-‐foot of

the waves at the two measurement sites (Figure 9), and may be enhanced further

by electrocardiographic gating.368 Although differences in distance measurement

arising from body habitus or ectatic aortic degeneration (common in the elderly

and hypertensives) are less important in serial measurements (assuming the

same inaccuracies are made at each evaluation), establishment of normal

population values, or comparison of results between populations may be severely

impaired by such methodological inaccuracies.368

64

Figure 9: Measurement of carotid-femoral PWV, utilising the foot-to-foot method,

where (∆t) represents the change in time, and (∆L) represents the

distance between waveform measurement sites. (Reproduced from

Laurent S. et al. Eur Heart J, 2006;27:2592, with permission from Oxford

University Press ).

Regardless of the known limitations of the methodology, PWV is independently

predictive of future cardiovascular events, cardiovascular death and all-‐cause

mortality in a variety of patient cohorts370 – including ESRF371,372, pre-‐dialysis

CKD373,374, diabetes375, established CAD376-‐378, essential hypertension379-‐381,

healthy elderly382,383 and younger, normal populations.384,385 The simplicity,

reproducibility and prognostic significance of PWV ensures it will remain the

65

non-‐invasive gold standard for the evaluation of central arterial stiffness for the

foreseeable future.

Arterial Distensibility

Although PWV provides an “overall” assessment of central (aortic/carotid/iliac)

arterial stiffness, methods for the assessment of regional arterial stiffness may

provide alternative, or incremental information not provided by PWV (e.g.

specific evaluation of carotid artery stiffness in the assessment of

cerebrovascular risk). Distensibility of superficial arteries such as the carotid,

brachial, femoral, and more distal arteries have been evaluated utilising

ultrasound techniques (Figure 10). Such techniques require a higher level of

training, and are more time consuming than evaluation of PWV, and hence are

poorly suited to epidemiological studies and better suited to mechanistic /

interventional studies.368 Magnetic resonance imaging has more recently been

utilised to evaluate non-‐superficial arteries (such as the aorta) in a variety of

physiological and disease states259,386-‐393, and has been shown to correlate well

with traditional PWV.394 Very recently, CMR-‐derived aortic distensibility and

volumetric arterial strain have been found to be predictive of cardiovascular

clinical end-‐points and overall survival in ESRF on multivariate analysis.395

66

Figure 10: Schematic representation of the method for determining arterial

distensibility by measuring changes in arterial lumen cross-sectional

area across the cardiac cycle (∆A = Maximal change in lumen area

during cardiac cycle; D = diameter), as they relate to local pulse

pressure. (Reproduced from Laurent S. et al. Eur Heart J, 2006;27:2593,

with permission from Oxford University Press).

In addition to the evaluation of arterial stiffness through assessment of PWV and

arterial distensibility, evaluation of the central impact of peripheral wave

reflection may also be performed non-‐invasively.368 This may be performed

through the evaluation of the arterial waveform at the common carotid artery, or

peripherally (conventionally the radial artery) through the application of a

‘transfer function’.396-‐398 Both Millar strain gauge transducers, and arterial

applanation tonometry have been used for this purpose.396-‐400 Whether directly

evaluated (at the carotid), or derived from peripheral (radial) artery applanation

tonometry, the resultant central pressure waveform can be interrogated to

determine the augmentation index (AIx) – the difference between the second and

first systolic pressure peaks (P2 -‐ P1; Figure 11), expressed as a percentage of the

67

PP.368 Central arterial AIx has been demonstrated to provide independent

prognostic value in the prediction of all-‐cause mortality in ESRF patients401,402, as

well as the prediction of CV events in a variety of other disease states.403-‐405

Figure 11: Representation of an illustrative central pressure waveform,

demonstrating identification of the Augmentation Pressure; determined

as the difference between the second (P1) and first (P2) systolic pressure

peaks. AIx may then be calculated by evaluation of the augmentation

pressure in relation to the pulse pressure. (Reproduced from Laurent S.

et al. Eur Heart J, 2006;27:2595, with permission from Oxford University

Press).

68

Arterial Stiffness as a Modifiable Risk Factor

Arterial stiffness provides a clinically relevant measure of longitudinal vascular

injury and is predictive of future cardiovascular events independent of

conventional CV risk factors.372,375,379,380,382,383,406 Although risk factors such as

hypertension and hyperlipidaemia may be effectively reduced by pharmacologic

intervention, the vascular injury induced by such risk factors over time is not

immediately negated by such therapies. Thus arterial stiffness has been

postulated to provide a more relevant surrogate for future CV risk than

conventional risk factors.370 Until recently, however, this premise had received

little attention.

The Conduit Artery Function Evaluation (CAFÉ)404 sub-‐study drew on 2,073

patients from the larger Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)407

to assess this issue. CAFÉ demonstrated that despite similar reductions in

brachial systolic blood pressure (SBP) and PP, the combination of amlodopine +

perindopril was more efficacious in reducing central SBP and PP than the

atenolol + thiazide combination404, corresponding to the demonstration of

reduced cardiovascular events in the amlodopine + perindopril cohort.407

Similarly, losartan was shown to reduce arterial stiffness and central PP to a

greater degree than the comparator (atenolol) with an associated reduction in

stroke in the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE)

study.408 The differing impact of alternative anti-‐hypertensive agents on central

vascular stiffness has thus been proposed as a potential explanation for the

differential effects of these agents on CV events.404,409

Of particular relevance was the finding that the CV benefits of blood pressure

lowering in ESRF were attenuated in patients where PWV was not improved by

69

anti-‐hypertensive therapies.371 Thus, though the conventional risk factor was

moderated by standard therapies, the modifiability of the associated arterial

alterations was a more useful predictor of future CV prognosis.370

Such findings highlight the potential prognostic impact of therapeutic

interventions that improve central arterial structure and function, and provide

the basis for the vascular research studies described herein.

Arterio-Venous Fistulae and Cardiovascular Structure and

Function

Arterio-venous Fistula Creation

As CKD advances towards end-‐stage, patient co-‐morbidities and preference play a

significant role in determining the optimal mode of RRT. Although live-‐donor

renal transplantation has increased in prevalence and popularity in eligible

patients in recent years, in Australia most advanced CKD patients also undergo

surgical creation of a radial or brachial AVF (where surgically feasible). The

surgical anastomosis of the radial (or brachial) artery to an adjacent vein (e.g.

cephalic vein) creates a low-‐resistance iatrogenic channel, diverting arterial

pressure and flow directly into the systemic venous system. Once matured, such

fistulae provide a ‘fail-‐safe’ method for the performance of haemodialysis if/when

the metabolic derangements of decompensated ESRF intervene. The

haemodynamic consequences of AVF creation are not benign however.

Immediately following creation, AVF are associated with a 10-‐20% increase in

systemic cardiac output, achieved predominantly through a reduction in systemic

vascular resistance, increased myocardial contractility (through sympathetic

70

nervous system activation) and an increase in stroke volume and heart rate.410

Over the following week, circulating blood volume increases in conjunction with

increases in atrial natriuretic peptide (ANP) and brain natriuretic peptide

(BNP).411,412 These alterations are associated with early increases in LV filling

pressure, and associated increases in LA volume and LV end-‐diastolic volume

(LVEDV).411 AVF blood-‐flow increases progressively over the initial 6-‐12 weeks

following creation145, diverting a substantial burden of overall cardiac output to

service the AVF (commonly 0.5-‐2L/minute). To maintain sufficient systemic

cardiac output, LV CO must increase proportionately, resulting in longer-‐term

implications for cardiac and vascular structure and function.412,413 In fact, AVF

creation has been demonstrated to be associated with worsening of LVH in ESRF

patients, and echocardiographic features of diastolic dysfunction including left

atrial dilatation.411,414 In some patients, giant AVF may lead to progressive high-‐

output cardiac failure, despite preserved systolic LV function.415-‐417 Such cases

may require AVF banding or ligation to limit flow and reduce systemic cardiac

demand.418,419

Many of the earliest studies evaluating the cardiac effects of AVF creation were

performed prior to the institution of routine erythropoietin supplementation

when significant anaemia may have contributed to the haemodynamic effects

witnessed. Despite this, the increased cardiac demand associated with AVF

creation is undisputed, and is believed to be a significant contributor to the

excess burden of CV morbidity and mortality of ESRF.170 Specifically, AVF

creation has been discouraged in ESRF patients with significantly depressed

cardiac function (LVEF<30%), due to fears of reduced physiological reserve

precipitating fulminant cardiac decompensation.420,421 Patients with pre-‐existent

71

coronary stenoses may not have the coronary flow reserve to manage this

increase in cardiac work, with an associated deterioration in sub-‐endocardial

perfusion and worsened anginal symptoms.421 Furthermore, patients with prior

CABG utilising internal thoracic artery grafts may develop coronary steal

phenomena from ipsilateral AVF creation/haemodialysis.422,423 Given the

prognostic advantage of internal thoracic artery grafting in CABG424-‐426, such

findings may have deleterious implications for the management of CKD patients

requiring coronary revascularisation.

Despite these issues, AVF may still be created in elderly ESRF patients, following

appropriate selection to avoid cardiovascular complications.427 The alternative to

AVF creation for the performance of haemodialysis, is the insertion of a large-‐

bore a central venous catheter (e.g. Permacath). Such catheters have a substantial

morbidity and mortality, related to vascular complications (bleeding, thrombosis,

central venous stenosis) and infection.428 The use of AVF, despite the

disadvantageous cardiovascular adaptations, is associated with lesser

cardiovascular mortality than catheter-‐based haemodialysis.428

Pulmonary Hypertension in Patients with Arterio-‐venous Fistulae

Pulmonary hypertension (PHT) refers to an elevation of mean pulmonary artery

pressure (PAP) beyond normal levels (>25mmHg). PHT may be caused by

cardiac, pulmonary, vascular or systemic conditions, but regardless of aetiology,

the development of PHT portends increased morbidity and mortality, regardless

of the underlying condition.429-‐431

72

PHT is a common finding amongst haemodialysis patients with iatrogenic arterio-‐

venous access.432-‐434 The causes for this elevation are multi-‐factorial, with factors

such as local vascular tone, pulmonary vascular calcification, reduced left

ventricular diastolic compliance, increased left atrial pressure and elevated

pulmonary blood flow induced by AVF maturation considered contributory.433,435-‐

437 Significantly, this failure of the pulmonary circulation to compensate for the

increased right ventricular output is associated with reduced survival for affected

ESRF patients.435 Importantly though, the acute and chronic affects of AVF

creation and, furthermore, AVF-‐ligation on right atrial, right ventricular and

pulmonary arterial decompensation have not been systematically studied.

Arterio-Venous Fistula Ligation

Following successful RTx, AVF may persist indefinitely, despite the absence of

ongoing clinical necessity. The longer-‐term cardiac impact of AVF persistence

following successful RTx is not known, however there is mounting evidence that

AVF contribute significantly to persistence of LVH (and potentially, associated

diastolic left ventricular dysfunction) in post-‐transplant patients. The published

data in this field is contradictory however438-‐440, with some evidence that only

larger AVF are responsible for disadvantageous cardiac remodelling.441 A recent

study further suggests that the AVF, rather than the necessity for haemodialysis,

is the propagating factor in LVH, demonstrating a marked reduction in adverse

cardiac indices following failure of AVF, but ongoing intermittent haemodialysis

via a central venous catheter.442 In addition to the ongoing uncertainty regarding

the benefits of routine AVF ligation with regards left ventricular geometry and

73

function, the effect of AVF ligation on right ventricular and atrial structure and

function as well as central and peripheral vascular structure and function remain

uncertain.

Ongoing uncertainty in this arena forms the foundation for the Studies evaluating

alterations in cardiovascular structure and function with AVF creation and AVF

ligation within this PhD.

Effects of Renal Transplantation on Cardiovascular Structure and

Function

RTx is associated with dramatic alterations in QOL, morbidity and mortality for

ESRF patients.443-‐449 In fact, successful cadaveric RTx has been shown to more

than triple the life-‐expectancy of ESRF patients on dialysis, when compared to

patients remaining on the waiting list.445 A substantial component of this benefit

arises from a reduction in cardiovascular deaths. Despite this, CVD remains a

leading cause of death amongst RTx recipients.450,451 Significantly, despite

marked improvements in post-‐transplant care, longer-‐term survival amongst

successful RTx recipients has not appreciably improved in Australia over the last

1-‐2 decades.451,452 Furthermore, RTx recipients experience an incidence of CV

mortality that is many times that of the age-‐matched controls from the general

population.451,453 Thus renal transplantation is associated with substantial CV

benefits, but a significant burden of CVD persists in this vulnerable patient

cohort.

LV dilatation and hypertrophy are highly prevalent amongst RTx recipients.

Increased LVM has been shown to be present in 40-‐60% of new RTx recipients

74

and only the minority of RTx patients have normal left ventricular structure and

systolic function as measured by standard trans-‐thoracic echocardiography

(TTE).454 Despite this, RTx has been shown to be associated with significant

reductions in LVM and LV volumes following transplantation, though cardiac

structure and function do not universally normalise.454-‐463 Thus, despite

restoration of renal excretory function, RTx does not completely abrogate the

trigger to disadvantageous cardiac remodelling. As previously mentioned, the

role of AVF persistence in this context remains to be definitively elucidated.

Mounting evidence has demonstrated that the rigorous screening processes

involved in selecting ESRF patients suitable for RTx is relatively successful in

selecting patients at lower risk of ischaemic CV events. Amongst patients free of

major cardiac events 1 year following transplantation, the subsequent incidence

of a major ischaemic event has been reported to be 1.2-‐1.5% per year453,464,465 – a

rate similar to that experienced by the general community within the

Framingham Heart Study.465,466 Despite this, the rate of new CCF was found to be

3-‐4 times that seen in the general population467-‐469, with only ~30% of CCF

events in post-‐RTx patients appearing to be associated with an ischaemic

precipitant.465 Compared to RTx patients who remain free of new ischaemic

events or CCF, affected RTx patients have a 1.5-‐ to 2-‐fold higher rate of death,

independent of each other, patient age, gender or the presence of TIIDM.465

Unlike the more common association of IHD and CCF in the general community,

CCF following RTx appears to be aetiologically distinct from IHD, but is associated

with significant mortality risk.465 The role of pre-‐existing, sub-‐clinical LV

pathology, and the potential contributions of immunosuppressive therapies,

75

hypertension, anaemia, graft dysfunction and persistent AVF remain to be

determined.

Vascular structure and function appear also to be favourably influenced by RTx.

Endothelial dysfunction is a common finding in ESRF, contributing substantially

to the premature development of CVD in affected patients. Although generally

improved, endothelial dysfunction commonly persists following RTx.470-‐472 Many

of the immunosuppressive agents utilised following RTx contribute to this

persistent endothelial dysfunction, and may contribute further to overall CVD

risk through unfavourable effects on lipid profiles, blood pressure and glucose

intolerance.473 Thus, endothelial dysfunction post-‐RTx remains a potential trigger

to the development of clinically significant CVD, and hence remains a potential

target for therapeutic interventions, whether by improved blood pressure and

lipid control, smoking cessation or by other novel means.472

Large artery structure and compliance is also adversely affected by ESRF and

long-‐term dialysis474-‐476, with improvement but persistence of increased arterial

stiffness following transplantation.477-‐480 The calcineurin inhibitors have been

implicated in the promotion of arterial stiffness following RTx, although the

process is clearly multi-‐factorial.481-‐484 The role of ventriculo-‐arterial coupling in

the promotion of deleterious LV and arterial remodelling post-‐RTx remains to be

determined.348

Such observations contribute to the foundation underlying the Study evaluating

alterations in cardiovascular structure and function following elective AVF

ligation within this PhD.

76

Evaluation of Cardiovascular Risk Prior to Renal Transplantation

CVD is the leading cause of death in ESRF and RTx cohorts, however the risk of

CVD morbidity and mortality in ESRF patients is markedly reduced by RTx.443-‐449

RTx is an expensive and highly intensive intervention however, utilising a scarce

community resource (i.e. organs). Furthermore, RTx is not without risk, as it is

associated with an early increase in all-‐cause and cardiovascular mortality for

recipients.443,485,486 In fact, the survival advantage of RTx appears not to be

apparent until beyond 250 days post-‐transplantation486, making survival to this

point a necessary pre-‐condition to RTx benefit. Furthermore, according to a large

Scandinavian study, between the second and third years post-‐RTx, 41.4% of

failed transplants are lost due to chronic rejection, but 42% are lost due to

patient death with a functioning graft.450 A substantial burden of this early

mortality is due to CVD.468 To reduce peri-‐operative CV morbidity and mortality,

or early graft loss due to CVD, potential RTx recipients undergo rigorous

screening processes and these pre-‐RTx screening investigations need to consider

not only peri-‐operative risk, but also must be designed to provide information

regarding CV risk in the early years post-‐RTx to ensure recipients are most likely

to enjoy the mortality advantages associated with the RTx process.487 Although

there is widespread support for CV evaluation prior to RTx485,488-‐492, there is no

universally accepted screening process and hence each RTx centre may have

different routines depending on local experience and expertise.

Given that CVD is a leading cause of morbidity and mortality in CKD and ESRF

patients, and that conventional CV risk factors such as TIIDM and HT are highly

prevalent in this population, exclusion of coronary artery disease (CAD)

comprises a substantial component of CV screening in higher risk RTx candidates.

77

The presence or absence of exertional chest pain is a poor predictor of the

presence of significant CAD in CKD and ESRF patients.493 It has been shown that

angiographically severe CAD may be present in asymptomatic patients with CKD,

potentially related to the reduced exertional capacity of uraemia and the

potential for autonomic neuropathy related to both uraemia and TIIDM.494

Furthermore, up to 75% of HDx patients with CAD may not experience typical

angina495, with silent ischaemia three times more prevalent than in the

Framingham study population.496 Additionally, up to 50% of ESRF patients with

angina have been shown not to have significant CAD at coronary

angiography.301,497,498 Reasons postulated for this phenomenon include the

presence of anaemia, reduced coronary vasodilatory reserve, microvascular

disease and supply-‐demand mismatch associated with the presence of LVH -‐ a

common echocardiographic finding in this context (as previously discussed).487

Thus, the presence or absence of chest pain provides little clinical certainty in

distinguishing between the presence and absence of significant CAD in potential

RTx recipients.

There is substantial debate regarding the necessity to perform ICA to exclude

significant CAD prior to RTx. Numerous studies have been published

demonstrating the advantages and limitations of non-‐invasive investigations in

the ESRF context.494,499-‐513 In particular, in ESRF it appears that vasodilator stress

is inferior to tachycardic stress in the non-‐invasive detection of significant

CAD.513 This may result from the requirement for dipyridamole, adenosine and

the recently FDA-‐approved regadenoson (commonly utilised pharmacological

vasodilators in non-‐invasive ischaemia imaging) to achieve maximal myocardial

hyperaemia through coronary microvasculature vasodilatation.514-‐516 ESRF is

78

associated with significant endothelial dysfunction, and theoretically, the

coronary microvasculature of affected patients may not maximally vasodilate in

response to endothelium-‐dependent stimuli. Hence, stressors that require

detection of differential myocardial perfusion based on regional hyperaemia in

non-‐obstructed coronary territories, as compared to relatively under-‐perfused

territories unable to achieve maximal hyperaemia due to epicardial coronary

obstruction, may be less accurate in ESRF.

Tachycardia Stress Methodologies

Exercise-‐based stress testing is widely accepted as the preferred, and most

accurate, methodology for the non-‐invasive exclusion of coronary ischaemia.

Uraemia, however, is commonly associated with reduced exertional capacity,

frequently preventing ESRF patients from achieving the necessary level of

tachycardia required to minimise the occurrence of a false negative result.

Previous studies have demonstrated a higher risk of future CV events amongst

patients unable to complete exercise stress tests, regardless of the presence of a

negative result.517 Thus combinations of exercise and vasodilatory agents, or

dobutamine infusion have been utilised to optimise non-‐invasive imaging results.

Conventionally, exercise (+/-‐ dipyridamole or adenosine) or dobutamine single

photon emission computed tomography (SPECT) myocardial perfusion imaging

(MPI) have been the most commonly utilised investigation in the non-‐invasive

exclusion of ischaemia prior to RTx. Dobutamine stress echocardiography (DSE)

is a commonly utilised alternative, with some results indicating a higher

79

specificity attributable to this investigation, but similar overall accuracy in non-‐

renal failure patients.518-‐522

Results of a meta-‐analysis of eleven smaller studies in ESRF patients indicate that

a negative MPI or DSE study was associated with a 1.8% annualised risk of

cardiac death, compared to a 6.3% risk following a positive study.511 A positive

study of course, may be associated with more intensive, or invasive intervention

to minimise the risk of MI, so the relatively low rate of MI following a positive MPI

study is obviously not representative of an untreated group. Regardless, current

non-‐invasive imaging techniques have an enviable evidence base supporting their

prognostic value, and in particular the favourable prognosis associated with a

negative study in the non-‐CKD population.523-‐530

Despite such results in the general community, the presence of a negative study

does not entirely exclude the presence of haemodynamically significant coronary

artery disease, hence the preference within some RTx centres to rely solely upon

ICA for the evaluation of coronary risk in this context.501 Importantly, however, it

is now widely appreciated that ICA provides only a 2-‐dimensional “lumenogram”,

and provides only limited insight into the potential haemodynamic and clinical

significance of identified lesions in respect to therapeutic decision-‐making in the

general community.531,532 Invasive assessment of fractional flow reserve (FFR)

has become the new “gold standard” for the assessment of coronary lesion

haemodynamic significance, particularly in determining potential benefit with

regards coronary revascularisation, although ESRF patients have routinely been

excluded from studies of this technology.531,533-‐536 Invasive studies, however are

associated with procedural risk. The risk of nephrotoxicity related to iodinated

contrast administration during ICA remains a concern, however femoral artery /

80

retroperitoneal bleeding and coronary or cerebrovascular complications, albeit

uncommon, should be considered prior to performing these investigations as

routine screening tests, regardless of the high prevalence of CAD in this cohort.

Ideally, pre-‐RTX risk would be assessed non-‐invasively, but with a high degree of

accuracy and lower rate of false positives without compromising sensitivity.

Dobutamine stress CMR (DS-‐CMR) has recently been demonstrated to provide a

very high level of accuracy in the non-‐invasive detection of significant CAD, with

low procedural risk, and avoidance of nephrotoxic contrast agents.537-‐540

Additionally, longer-‐term prognostic data has begun to emerge demonstrating

very low rates of CV events following a negative DS-‐CMR study.541 Although

access to CMR units with experience in dobutamine stress imaging is an issue

preventing universal uptake, this highly accurate non-‐invasive imaging technique

has the potential to improve specificity and hence reduce unnecessary invasive

angiograms in pre-‐RTx candidates.

Non-invasive Imaging of Cardiovascular Structure and Function

in CKD

The evaluation of cardiac structure and function is the cornerstone of non-‐

invasive cardiac imaging. LV ejection fraction (LVEF), LV chamber dimensions

and LVM are all closely associated with future CV morbidity and mortality in the

general community and amongst CKD and ESRF patients. Additionally, measures

of left and right atrial size and right ventricular size and function are known to

provide incremental, clinically relevant information during cardiac imaging, with

81

recent evidence supporting an association between left atrial size and mortality

amongst ESRF patients referred for RTx.196

Numerous methodologies exist to evaluate cardiac structure and function, though

few are also capable of evaluating vascular structure and function

simultaneously. The available methodologies are briefly discussed.

Trans-‐thoracic Echocardiography

TTE provides a widely available, relatively inexpensive, portable and universally

safe method for evaluation of LV structure and function. Quantitative TTE

imaging requires the acquisition of parasternal and trans-‐apical images of the

heart via variable imaging windows in-‐between adjacent ribs. As a result, TTE is

highly operator and acoustic window dependent.542-‐544 Pulmonary parenchymal

over-‐expansion (such as in COPD), thoracic obesity (or profound cachexia where

insufficient tissue remains to allow optimal probe contact), and myriad

musculoskeletal and co-‐morbid medical conditions may impair image quality, and

hence the reliability of quantitative TTE results.

Utilising 2-‐dimensional TTE, LVEF is conventionally evaluated by a method

known as Simpson’s Bi-‐plane Method of Discs (MOD). Utilising the apical long-‐

axis images in the 4-‐chamber and 2-‐chamber projections, 3-‐dimensional volumes

are calculated based on geometric assumptions arising from the two long axis

areas outlined in diastole and systole. Unfortunately, the LV apex is frequently

foreshortened by echocardiography, and regional impairment of endocardial

definition (particularly affecting the anterior wall) contribute to the relatively

high-‐degree of intra-‐observer and inter-‐observer variability described when

82

measuring LVEF by TTE – often greater than 20%.545-‐548 TTE may also be used to

estimate LVM, with robust prognostic data published in this area in a variety of

patient subsets including CKD and post-‐RTx cohorts. TTE estimates of LVM have

been shown to vary significantly, with accuracy declining as distance from the

transducer increases.543 Thus, despite the numerous publications utilising TTE to

evaluate LVM, concerns remain regarding the accuracy of this

methodology.542,543,549,550

Distinct from LV assessment, TTE allows for the reproducible assessment of left

and right atrial chamber dimensions, with results comparable to 3-‐dimensional

TTE and CMR measures.551-‐553 Quantitative right ventricular assessment is

suboptimal by echocardiography however, owing to the non-‐uniform geometry of

the right ventricle and limited number of available imaging planes by TTE. There

is increasing recognition, however, of the importance of this chamber in the

development of exertional limitation in health and disease.554,555 Real-‐time 3-‐

dimensional TTE may provide superior accuracy in this field in the future.556

TTE does however provide valuable information regarding valvular structure and

function, and LV diastolic function that is superior to that provided by other

available methodologies. Furthermore, recent advances in real-‐time 3-‐

dimensional TTE have enhanced the capabilities and reproducibility of this

ubiquitous technology. Of course, TTE is limited to assessment of cardiac

structure and function only, with alternative ultrasound techniques necessary for

evaluation of peripheral artery structure and function. Acoustic window

limitations also prevent evaluation of central arteries (e.g. aorta) in the

determination of alterations in vascular structure and function in the CKD

context.

83

Single Photon Emission Computed Tomography

ECG-‐gated myocardial perfusion tomography has been validated in the

assessment of LV volumes and LVEF.557 As has previously been demonstrated

with TTE, SPECT has reasonable reliability in the normal heart, but accuracy

declines in the presence of LV impairment and prior myocardial infarction.558-‐562

SPECT also suffers from poor spatial and temporal resolution, and necessitates

exposure to ionising radiation (10-‐20mSv doses have been reported), lessening

its appeal as a routine screening investigation, particularly for serial studies.544

Cardiovascular Computed Tomography

Substantial advances have been made in the field of CV CT in recent years.563 The

availability of wider detector arrays (256-‐row and 320-‐row), able to image the

whole heart in a single (or partial) gantry rotation has markedly improved

cardiac image acquisition and speed. This further allows most studies to be

completed within a single heartbeat, and with retrospective gating, to acquire

both systolic and diastolic images for ventricular (and atrial) volume and LVEF

assessment. The information provided by such imaging is comparable to that

derived from CMR, and superior to standard TTE.564-‐570 CT however has

significantly inferior temporal resolution to TTE and CMR, and spatial resolution

during the systolic phases is frequently reduced to minimise radiation dose.566

CT is able, by widening the imaging field, to also image the aorta during cardiac

assessment. Due to the capacity for unlimited image reconstructions following CT

image acquisition, evaluation of aortic compliance is possible (with retrospective

84

gating) at any level within the field of imaging.571 Evaluation of peripheral arterial

structure and function is more difficult, however.

Despite its numerous imaging advantages, the most significant limitation to

imaging with CT is the escalating radiation exposure for repeated imaging

(routinely <2mSv per scan). Thoracic (and mammary) radiation exposure during

cardiac CT largely precludes use of this investigation for routine cardiovascular

imaging in research studies, or repeated serial studies, particularly in young

patients/subjects (especially women), where the potential for triggering delayed

malignancy is greatest.572-‐574

Cardiovascular Magnetic Resonance Imaging

Cardiac Structure and Function

CMR has been recognised as the modern non-‐invasive gold standard for the

evaluation of cardiac structure and function. It has numerous advantages over

TTE, SPECT and the emerging technology of ECG-‐gated multi-‐detector CT.

Without exposure to contrast or ionising radiation, CMR is able to provide high

quality epicardial and endocardial border definition for the left and right

ventricles, with the capacity to evaluate structure and function with unrestricted

imaging planes during image acquisition. Hence, CMR does not require any

geometric assumptions in determining volumetric assessments of cardiac

chambers.

LV and right ventricular function and mass can be measured with high degrees of

accuracy and reproducibility by CMR.568,575-‐578 In fact, TTE has less than 50% of

85

the precision of CMR in evaluation of LVM – a strong independent predictor of CV

events in ESRF and post-‐RTx patients.549,550

In this regard, CMR has demonstrated the lowest standard deviation in

differences between inter-‐study measurements for left ventricular volumetric

indices and LVEF.579 Such improvements in inter-‐study standard deviations

allows for a squared reduction in required sample sizes for research studies – i.e.

halving of the standard deviation allows for a quartering of the required sample

size. It has been determined that to undertake a study evaluating an intervention

aiming to achieve a 10% reduction in left ventricular mass (with 80% power, and

p=0.05), TTE would require a sample size of 505. For the demonstration of a

statistically significant reduction in LVM of 10%, CMR would require a sample

size of only 14.544,549

Right ventricular (RV) size and function is also readily assessable by CMR.578 CMR

has become the non-‐invasive gold-‐standard investigation for this purpose also,

providing markedly improved assessment of alterations in RV structure and

function in healthy subjects and a variety of disease states, including congenital

heart disease states, arrhythmogenic right ventricular cardiomyopathy (ARVC),

atrial septal defects and primary PHT.555,556,578,580-‐583 RV mass measurements are

also possible by CMR, with validation previously performed against ex vivo calf

hearts, with a high level of accuracy demonstrated.581 Although potentially more

technically challenging due to the highly trabeculated nature of the right

ventricle, such assessments may have clinical utility in disease states that

contribute to the development of PHT.

Atrial size and function can be readily assessed by CMR during a conventional

cardiac study. Both area and volumes may be calculated, with atrial function

86

assessable by atrial ejection fractions. In this regard, the atria may be

interrogated in the horizontal long axis, short axis or vertical long axis to derive a

true 3-‐dimensional volume in atrial diastole and systole, although horizontal long

axis imaging is most commonly utilised.584 Furthermore, left and right ventricular

diastolic function may also be estimated by mitral and tricuspid inflow

characteristics during phase-‐contrast CMR sequences, deriving waveforms

similar to that demonstrated by Doppler echocardiographic techniques.585-‐588

Even pulmonary vein flow characteristics may be assessable by CMR, in imitation

of echocardiographic assessments.589

Hence, CMR not only provides superior accuracy to other available imaging

techniques, but allows a more comprehensive assessment of cardiovascular

structure and function, and enables research into potentially beneficial

therapeutic interventions to be undertaken with more readily achievable subject

sample sizes.

Vascular Structure and Function

Unlike the aforementioned technologies, CMR is also able to evaluate dynamic

aortic, carotid and peripheral arterial structure and function in the same setting.

Measures of aortic flow and compliance have been widely published utilising

CMR techniques147,259,389-‐391,394,395, with growing evidence supporting a link

between declining aortic distensibility and increased morbidity and mortality in

ESRF patients.333,371,395,406 Furthermore, there is evidence that aortic distensibility

can be favourably modified by therapeutic interventions.590

Brachial artery FMD, as previously discussed, is a widely utilised and

prognostically relevant investigation257,266,591, most commonly performed using

87

ultrasound techniques.254,258 Impairment of endothelial function as measured by

FMD has also been associated with increased central vascular stiffness, providing

a link between functional and structural vascular changes in the initiation and

perpetuation of disease.259,592 Brachial artery FMD has been demonstrated to

improve following RTx, and thus provides a valuable, modifiable marker of

vascular structure and function in response to therapeutic interventions in ESRF

and post-‐RTx.470,593

FMD is able to be reliably assessed utilising CMR. CMR allows for assessment of

brachial artery area, with three-‐dimensional reconstructions allowing for a truly

perpendicular imaging plane – a factor that is difficult to reliably achieve with

ultrasound techniques.594 Furthermore, edge detection and image reproducibility

are critical to detecting small changes in vessel diameter by ultrasound. For

example, an 11.7% increase in brachial artery diameter from 3.65mm to 4.08mm

with hyperaemia requires the reliable detection of a 0.43mm change in vessel

diameter, unaffected by altered imaging plane or vessel deformation. CMR

provides for the non-‐invasive, reproducible evaluation of cross-‐sectional vessel

area, vessel compliance over the cardiac cycle and even quantification of brachial

artery flow, if desired. Although the prognostic value of brachial artery flow and

shear stress calculations remains to be determined, recent work suggests a

stronger association between vessel flow and CV risk factors than traditional

FMD measures.595 Such observations potentially open a new avenue of research

in this area.

Thus, CMR is able to provide accurate, reproducible and comprehensive

assessments of cardiac and vascular structure and function within a single

investigation. Such utility provides the basis for the Projects outlined in this PhD.

88

Aims of this Thesis

The aim of the Studies outlined within this Thesis is to provide insights into

alterations in CV structure and function in the context of routine therapeutic

interventions and investigations in ESRF and following RTx.

Specifically, the broad aims of the Studies outlined include:

1. To evaluate alterations in CV structure and function following elective

AVF-‐creation in pre-‐dialysis ESRF.

2. To evaluate alterations in CV structure and function following elective

AVF-‐ligation following stable, successful RTx.

3. To evaluate the diagnostic accuracy of DS-‐CMR in the detection of

haemodynamically significant CAD prior to RTx.

4. To evaluate the impact of ESRF on dynamic coronary endothelial function.

89

METHODS

90

Research Ethics Considerations

All patients involved in the research studies outlined herein provided written

informed consent following approval of the study protocols by the Research

Ethics Committee of the Royal Adelaide Hospital.

Study 1: Evaluation of Alterations in Cardiovascular Structure

and Function Following Elective Arterio-Venous Fistula Creation

in Pre-Dialysis End-Stage Renal Failure

Subjects

Inclusion Criteria

Patients aged over 18-‐years under the care of the Royal Adelaide Hospital Renal

Medicine Unit for advanced, progressive CKD were eligible for the study. Patients

were enrolled prior to undergoing clinically-‐driven, elective surgical AVF

formation in preparation for anticipated haemodialysis commencement in the

subsequent 6-‐12months, as clinically indicated.

Exclusion Criteria

Patients with acute, or rapidly deteriorating renal dysfunction anticipated to

require haemodialysis within the next 6months.

CKD, ESRF or post-‐RTx patients with a history of previous AVF creation.

Solid organ or haematological malignancy in previous five years.

Current or planned pregnancy (within next 9-‐months)

91

Presence of contraindications to CMR:

Cardiac Pacemaker / Defibrillator or retained pacemaker leads

Cerebral aneurysm clips

Implanted neuro-‐stimulators or electronic devices including Cochlear Implant

History of penetrating eye injury, or presence of ocular metallic fragments

Presence of shrapnel

Claustrophobia

Presence of Specific Contra-indications to the use of Glyceryl-trinitrate:

Hypertrophic obstructive cardiomyopathy

Haemodynamically significant aortic or mitral stenosis

Recent cerebral haemorrhage / head trauma

Concomitant sildenafil, tadalafil or vardenafil therapy

Study Investigations

Following enrolment and informed consent, all patients were scheduled for

elective surgical AVF-‐formation as per the clinical practice of the RAH Renal

Medicine and Vascular Surgery Units.

Clinical history and study CMR evaluation of baseline CV structure and function

were scheduled to occur two weeks prior to the elective surgical date (CMR

protocol detailed below [Page 94]).

At six-‐months following elective AVF-‐formation, repeat clinical history and

identical CMR study were performed to evaluate alterations in CV structure and

function related to AVF-‐formation and maturation in the context of declining

renal function. The CMR protocol is summarized below [Page 94].

92


and Function Following Elective Arterio-Venous Fistula Ligation

Following Successful, Stable Renal Transplantation

Subjects

Inclusion Criteria


Medicine Unit following stable, successful RTx, with a persistently functioning

AVF were considered for enrolment prior to clinically-‐indicated, surgical AVF

ligation.

Exclusion Criteria

Patients with unstable or deteriorating post-‐RTx renal function anticipated to

require reinstitution of haemodialysis within the subsequent 12-‐24months.

Solid organ or haematological malignancy in previous five years.

Current or planned pregnancy (within next 9-‐months)







Claustrophobia

93

Presence of Specific Contra-indications to the use of Glyceryl-trinitrate:




Concomitant sildenafil, tadalafil or vardenafil therapy


Following enrolment and informed consent, all patients were scheduled for

elective surgical AVF-‐ligation as per the clinical practice of the RAH Renal

Medicine and Vascular Surgery Units.

Clinical history and study CMR evaluation of baseline CV structure and function

were scheduled to occur two weeks prior to the elective surgical date (CMR

protocol detailed below).

At six-‐months following elective AVF-‐ligation, repeat clinical history and identical

CMR study were performed to evaluate alterations in CV structure and function

related to AVF-‐ligation in the context of continued stable renal function following

successful RTx.

94

Cardiovascular Magnetic Resonance Protocol – Studies 1 and 2

All CMR studies were performed utilising the Siemens Avanto 1.5 Tesla magnetic

resonance imaging scanner (Siemens Medical Imaging, Erlangen, Germany)

located within the Cardiovascular Investigation Unit of the Royal Adelaide

Hospital.

Cardiac Protocol

All CMR studies were performed with the subjects in a supine position, with a

phased-‐array surface coil positioned over the thorax. Initial long axis reference

views were performed to enable optimal placement of the 7 to 12 parallel short-‐

axis slices from the mitral annulus to beyond the left ventricular apex (Figure 12).

Horizontal and vertical long axis views were also taken of the left atrium and left

ventricle, as well as a long axis view of the left ventricular outflow tract. All

images were acquired during expiratory breath-‐hold (approximately 8-‐12

seconds) with retrospectively ECG-‐gated True-‐FISP (Fast Imaging with Steady

State Free Precession) sequences. Section thickness was 6mm with short-‐axis

intersection intervals of 4mm. Acquisition time was determined to include 90%

of the R-‐R interval, image matrix 256 x 150, Field of View (FOV) 380mm,

Repetition Time (TR) 52ms, Echo Time (TE) 1.74ms, flip angle 700 with 8-‐15

cardiac cycles required per image.

95

Figure 12: Representation of CMR methodology for the use of the long axis

reference images (horizontal long axis image shown on left) to enable

acquisition of sequential, parallel ventricular short-axis images from the

atrio-ventricular plane to the ventricular apices (end-diastolic images

shown).

Offline analysis was performed to determine LA, RA, LV and RV dimensions in

diastole and systole. Diastolic LVM was also concurrently determined. Image

analysis was performed utilising proprietary software (Argus software, Siemens

Medical Imaging, Erlangen, Germany). Ventricular short axis images were utilized

for ventricular assessment, with epicardial and endocardial LV contours and

endocardial RV contours manually traced at diastole (start of the ECG R-‐wave)

and at end-‐systole (determined by the timing of the smallest ventricular cavity

size). As per standard CMR protocol, myocardial trabeculations and unattached

papillary muscles were ascribed to the left ventricular cavity. The basal LV slice

was determined to be that slice where at least 50% of the cavity was surrounded

96

by ventricular myocardium, and the apical slice was defined as the most apical

slice still containing intra-‐cavity blood-‐pool.596,597 A similar assessment of basal

LV slice was then undertaken at end-‐systole, with the overall number of LV short-‐

axis images generally 1-‐2 slices less at end-‐systole, due to the well recognized

phenomenon of ventricular shortening associated with systolic contraction.544,598

If the aortic valve appeared in the basal slice at diastole or systole, only the intra-‐

cavity volume up to the level of the aortic valve was included as a component of

the ventricular volume, as per accepted protocol.597

For the right ventricle, intra-‐cavity volumes below the level of the pulmonary

valve were included in the analysis. For the RV inflow tract, intra-‐cavity volumes

were excluded if the surrounding myocardium was thin and not trabeculated,

indicative of presence within the RA cavity.596

By measurement of diastolic and end-‐systolic volumes for both left and right

ventricles, and tracing of the epicardial LV contour at end-‐diastole, left and right

ventricular end-‐diastolic volumes, end-‐systolic volumes, stroke volumes,

ejections fractions, cardiac output and LVM were all able to be derived.

Left and right atrial area were assessed in the horizontal long-‐axis in atrial end-‐

diastole (largest area) immediately prior to mitral valve opening.

Owing to the reduced accuracy in contour tracing by untrained, inexperienced

observers599, all study CMR images were evaluated by a single experienced

operator blinded to the name and date of the Study.

97

Vascular Protocol

Aortic Distensibility

Immediately following completion of the cardiac protocol, ECG-‐gated True-‐FISP

cine sequences were acquired of the ascending aorta, descending thoracic aorta

and proximal abdominal aorta in a sagittal oblique orientation. Utilising the level

of the right pulmonary artery as the reference level in each patient, a

perpendicular cross-‐sectional True-‐FISP cine image was then taken at the

ascending aorta and the proximal descending aorta. A final True-‐FISP cine image

was then acquired at the level of the distal descending aorta, 5-‐10cm distal to the

diaphragm (Figure 13), as previously described.394

Brachial artery blood pressure was taken concurrently using an MRI compatible

automated non-‐invasive sphygmomanometer, with the results of three

measurements averaged, and any outliers discarded and repeat blood pressure

taken as required.

98

Figure 13: Sagittal oblique image of the aorta (left) with pictorial representation of

the reference levels used in the acquisition of cross-sectional aortic

images at the Ascending Aorta (AA), Proximal Descending Aorta (PDA)

and Distal Descending Aorta (DDA) (right).

Aortic distensibility was then determined offline by manually tracing aortic cross-‐

sectional images at the level of the ascending aorta, proximal descending aorta

and distal descending aorta in end-‐diastole (minimum lumen area) and peak-‐

systole (maximum lumen area). Aortic distensibility was derived by the following

equation:

99

where pulse pressure was derived from the non-‐invasive brachial artery blood

pressure during image acquisition. Aortic area was measured in mm2 and pulse

pressure measured in mmHg, with the final unit of aortic distensibility

represented as mmHg-‐1, by standard convention. Measures of aortic distensibility

were recorded at each location individually, and then the three measurements

were averaged for an indicative average aortic distensibility for each subject. Our

research group has previously published robust intra-‐ and inter-‐individual

reproducibility for this technique (1% and 2% respectively).394

Brachial Artery Blood Flow – Arterio Venous Fistula Arm

Patients were then removed from the scanner briefly, to allow removal of the

thoracic phased-‐array surface coil and placement of a single four-‐channel

Machnet phased-‐array surface coil (Machnet, Netherlands) overlying the brachial

artery ipsilateral to the site of AVF surgery. Scout “time of flight” images were

acquired of the brachial artery to allow positioning of the cross-‐sectional plane of

brachial artery imaging, proximal to the brachial bifurcation. A single, velocity

encoded sequence was acquired during free-‐breathing, with sequence acquisition

individually optimized for peak brachial artery flow velocity.

Analysis of brachial artery flow was performed utilizing proprietary software

(Argus software, Siemens Medical Imaging, Erlangen, Germany), following

manual tracing of the brachial artery in each of twenty-‐five phases over the

cardiac cycle. Brachial artery flow was evaluated prior to AVF-‐surgery and at 6-‐

months post-‐surgery.

100

Brachial Artery Flow Mediated Dilatation

Patients were again briefly removed from the scanner, to allow repositioning of

the single four-‐channel Machnet phased-‐array surface coil (Machnet,

Netherlands) to overlay the brachial artery contralateral to the site of AVF

surgery. A manual sphygmomanometer cuff was then applied to the forearm

ipsilateral to the imaging coil prior to imaging. Scout “time of flight” images of the

brachial artery were then acquired to allow optimal positioning of the cross-‐

sectional plane of brachial artery imaging, proximal to the brachial bifurcation.

At baseline, the brachial artery cross-‐sectional area was evaluated utilising True-‐

FISP cine imaging at a single location at end-‐diastole. In a sub-‐group within each

study, baseline brachial artery flow was also evaluated utilising velocity-‐encoded

imaging. The forearm sphygmomanometer cuff was then inflated to 50mmHg

above systolic blood pressure and pressure maintained for 5-‐minutes, as per

validated protocol.254,258,594 One minute following release of the occlusive cuff,

brachial artery endothelium-‐dependent vascular function was assessed utilizing

repeat True-‐FISP cine imaging at the same location as the baseline image.

Ten minutes following release of the cuff pressure, repeat baseline cine imaging

was performed (again at the same cross-‐sectional location within the brachial

artery), prior to administration of 400mcg of sublingual GTN. Three minutes

following GTN administration, True-‐FISP cine sequences were repeated, for

evaluation of endothelium-‐independent vascular function.254

Offline analysis was performed using proprietary software (Argus software,

Siemens Medical Imaging, Erlangen, Germany), with manual tracing of the

brachial artery lumen area in each of the cine and velocity encoded acquisitions.

Endothelium-‐dependent responses were determined by percentage change in

101

vessel area following ischaemic stimulus, and endothelium-‐independent

responses were determine by percentage change in vessel area following GTN

administration.

Summary of CMR Investigations for Arterio-‐Venous Fistula Studies

The CMR protocol outlined was performed 1-‐2 weeks prior to planned elective

AVF surgery, and the identical protocol was repeated 6-‐months following surgery

for comparison with pre-‐surgical results.

A 6-‐month follow-‐up period was chosen for the AVF studies following evaluation

of the available literature in this field. Studies utilising relatively short follow-‐up

(<2-‐months) periods have demonstrated alterations in cardiac output, cardiac

chamber size, and neurohormonal measures following AVF creation.411,412 Such

studies were of insufficient follow-‐up duration to enable evaluation of adaptive

changes in LVM however.170 Longer follow-‐up studies following either

spontaneous or deliberate AVF closure have evaluated echocardiographic

alterations in cardiac structure and function at 6-‐months, 10-‐months and 21-‐

months with similar signals regarding the potential for advantageous CV

remodeling following AVF-‐ligation.438,439,462 Thus, a 6-‐month follow-‐up period

was chosen to ensure sufficient time to allow acute haemodynamic alterations to

induce any relevant adaptive cardiac remodeling, but for the follow-‐up duration

to not be so lengthy as to prevent completion of the Studies within the allotted

PhD period, or prior to the commencement of dialysis in the majority of subjects.

On the basis of the available literature, we believed 6-‐months to be an

appropriate duration to allow firm conclusions to be determined regarding the

102

potential longer-‐term impact of AVF creation / ligation on CV structure and

function, and to be of sufficient length to determine that where alterations were

not seen, such parameters, perhaps, were either less malleable, or could not be

influenced by the presence or absence of an AVF.

103

Study 3: Evaluation of the Diagnostic Accuracy of Dobutamine-

Stress Cardiac MRI in the Detection of Angiographically-

significant Coronary Artery Disease prior to Renal

Transplantation

Subjects

Inclusion Criteria


Medicine Unit being considered for acceptance onto the South Australian RTx

waiting list, for the treatment of advanced CKD / ESRF and who were clinically

deemed to be at high-‐risk of significant CAD by the RTx assessment team.

Exclusion Criteria

Standard, clinically driven contraindications to RTx







Claustrophobia

Presence of Specific Contra-indications to the use of Dobutamine:



104


Presence of Specific Contra-indications to Invasive Coronary Angiography:

Absence of suitable femoral arterial access to allow the performance of ICA

Allergy or other non-‐renal intolerance to iodinated contrast media


Dobutamine Stress Cardiac MRI

Patients will be required to refrain from anti-‐anginal medications including beta-‐

blockers, calcium channel antagonists and nitrate medications for a period of 48-‐

hours prior to the scheduled procedure. On the day of the procedure, subjects

were required to fast for 4-‐hours prior to the DS-‐CMR and blood sugar readings

were taken in diabetic subjects. A single 18-‐gauge intra-‐venous cannula was

inserted and body weight taken to determine the appropriate dobutamine dose.

All DS-‐CMR studies were performed with the subjects in a supine position, with a

phased-‐array surface coil positioned over the thorax. Initial long axis reference

views were performed to enable optimal placement of the three ventricular short

axis and three ventricular long axis views (horizontal long axis, vertical long axis

and longitudinal left ventricular outflow tract) evaluating all 17 American Heart

Association myocardial segments.600,601

Resting images were acquired during expiratory breath-‐hold (approximately 5-‐8

seconds) with retrospectively ECG-‐gated True-‐FISP sequences (25 phases per

cardiac cycle; TR 2.7ms, TE 1.4ms, flip angle 600). Typical in-‐plane spatial

resolution was 1.8 x 1.8mm with section thickness of 6mm, similar to previously

published work in this field.539

105

Dobutamine infusion was undertaken as per standard protocol – progressive 3-‐

minutely intravenous infusion of 10mcg/kg/min, 20mcg/kg/min, 30mcg/kg/min

and 40mcg/kg/min ± atropine up to 1.2mg (in 600mcg increments) until

achievement of ≥85% of maximal expected heart rate (220 – age [beats per

minute]). Standard termination criteria for dobutamine cessation were applied.

Regional wall motion was assessed at each dose increment, utilising the

aforementioned views, with segmental analysis of the cine scans performed on-‐

line throughout the procedure as a component of the procedural safety

monitoring. Offline analysis was subsequently performed for the purposes of

clinical and research reporting by consensus of two experienced observers

blinded to the results of the subsequent coronary angiography. A standard

segmental wall motion scoring system was utilised (1=normokinesis,

2=hypokinesis, 3=akinesis, 4=dyskinesis). For dobutamine studies, ischaemia was

defined as ≥1 segment showing inducible regional wall motion abnormality as

defined by deterioration in segmental wall motion score of ≥1 grade.539

Invasive Coronary Angiography

On a separate day following performance of the DS-‐CMR, patients were scheduled

to undergo ICA. On the day of the procedure, subjects were required to fast for 6-‐

hours prior to the procedure and blood sugar readings were assessed in diabetic

subjects. A single 18-‐gauge intra-‐venous cannula was inserted and intravenous

saline administered at a rate of 80mL/hour to a maximum of 500mL pre-‐

procedure in non-‐dialysis-‐dependent patients with significant residual urine

output.

106

Standard coronary angiography was performed via femoral arterial access.

Standard Judkins catheters were used to engage the left main and right coronary

arteries, with dedicated views taken of the left main, left anterior descending, left

circumflex and right coronary arteries and their branches utilizing iodinated

contrast (Iohexol-‐350).

Offline analysis of angiographic stenosis severity was performed by two

experienced observers, with clinical significance determined for coronary

stenoses of ≥70% in luminal diameter, by visual estimation.

Comparison of correlation of DS-‐CMR and invasive coronary angiographic

findings was determined following independent reporting of each investigation

by observers blinded to the results of the alternative investigation. Correlation of

significant inducible wall motion abnormalities during DS-‐CMR with territories

supplied by epicardial coronary arteries was based on individual coronary

dominance.

107

Study 4: Evaluation of Dynamic Coronary Endothelial Function in

End-Stage Renal Failure

Subjects

Inclusion Criteria

Subjects – Chronic Kidney Disease Study Cohort

Patients aged 18-‐75 years under the care of the Royal Adelaide Hospital Renal

Medicine Unit being considered for RTx for the treatment of advanced CKD /

ESRF and who are clinically deemed to require ICA prior to listing as a candidate

by the South Australian RTx assessment team.

Subjects –Non-Chronic Kidney Disease Study Cohort

Patients aged 18-‐75 years undergoing clinically indicated ICA at the Royal

Adelaide Hospital Cardiovascular Investigation Unit, and who are found to have

only minor epicardial coronary artery stenoses and CrCL≥60mL/min.

Exclusion Criteria

Presence of significant co-‐morbidity that, in the opinion of the treating

Cardiologist, may be expected to cause death or significant disability in the

following 12-‐months.

Presence of Specific Contra-indications to Invasive Coronary Angiography:

Absence of suitable femoral arterial access to allow the performance of ICA

Allergy or other non-‐renal intolerance to iodinated contrast media

108

Presence of Specific Contra-indications to Coronary Endothelial Function

Assessment:

Coronary anatomy unsuitable for Doppler Flo-‐wire instrumentation – e.g.

excessive coronary tortuosity or heavy calcification

Presence of epicardial coronary artery stenoses in the target vessel of >20%

luminal diameter

Haemodynamic instability as to prevent cardiac catheterisation.

Presence of Clinical Characteristics Unfavourable for Accurate Assessment of

Coronary Endothelial Function:

Presence of cardiomyopathy

Presence of diffuse atherosclerosis within the Study vessel as determined by

invasive angiography

Prior CABG


Coronary Endothelial Function

At the time of Coronary Angiography, a 0.014-‐inch Coronary Doppler Flo-‐wire

(Volcano Therapeutics, CA, USA) was advanced into the study vessel (the LAD

was chosen preferentially) via an intra-‐coronary infusion catheter, following the

administration of therapeutic heparin. The Flo-‐wire was positioned in the

proximal or mid-‐segment of the Study vessel so as to obtain stable Doppler flow

velocity signals. Resting coronary flow velocities were recorded and epicardial

coronary diameter was determined 5mm distal to the tip of the coronary

guidewire by QCA.

109

Protocol consisted of the following interventions:

-‐ 5% dextrose control infusion for 2-‐minutes (Control 1)

-‐ Acetylcholine (3-‐minute infusions of Ach 10-‐7M [1.6mcg/min], then 10-‐6M

[16mcg/min)


-‐ bolus dose of GTN (50mcg)

-‐ bolus dose of Adenosine (48mcg)

as per validated protocol.602,603 At the completion of each intra-‐coronary infusion,

a coronary angiogram was performed using 9mL of non-‐ionic contrast

(Omnipaque, GE Healthcare, Waukesha, USA) injected through a Medrad infusion

pump at 5mL/s, with images saved for offline analysis. Doppler indices,

haemodynamic data (systemic blood pressure and heart rate) and ECG rhythm

strip were recorded continuously throughout the study for off-‐line analysis.

Coronary endothelial function data were presented as response to Ach 10-‐6M for

CBF and vessel diameter. Values for Ach 10-‐7M used if severe epicardial

constriction response to 10-‐6M precluded data collection. Values for ESRF and

non-‐CKD cohorts were then compared for evaluation of coronary endothelial

dysfunction in ESRF vs. non-‐CKD control subjects.

Quantitative Coronary Angiography

Following acquisition of standardised coronary angiography during the Study

protocol, offline analysis was performed using proprietary edge-‐detection

software (QCA-‐CMSTM, Medis Medical Imaging Systems, Leiden, Netherlands).

Mean coronary diameter was assessed 5mm distal to the tip of the Doppler

110

guidewire over a 5mm segment. Changes in vessel diameter in response to Ach

and GTN were analysed as measures of epicardial endothelium-‐dependent and –

independent function. As previously described, subjects experiencing a >5%

reduction in vessel diameter in response to Ach 10-‐6M were designated as having

endothelium dysfunction.602

Coronary Blood Flow / Microvascular Function

Coronary velocity measurements were analysed by a technician blinded to the

results of the QCA analysis. Coronary blood flow (CBF) was then calculated from

the formula:275


where Diameter is measured in cm, Average Peak Velocity (APV) of coronary

blood flow is measured in cm/sec and CBF is measured in mL/min. Coronary flow

velocity reserve (CFR) is determined as a ratio of:

APV (post-‐adenosine) / APV (baseline)




adenosine.276

111

Statistical Methods

All measures were tested for normality using the Kolmogorov-‐Smirnov / Lilliefor

Test and Shapiro-‐Wilk W test. All normally distributed values are represented as

mean±standard deviation, with all column graphs represented as mean with

standard error bars. Parameters that were deemed not normally distributed were

reported as median and inter-‐quartile range (IQR). Paired parameters were

analysed by two-‐tailed paired Student T-‐test. Where normally distributed,

comparison of non-‐paired measures was performed by unpaired t-‐test (with

Welch’s correction for samples of unequal variance), or one-‐way ANOVA as

appropriate. Where parameters were not normally distributed, paired analyses

were performed utilising the Wilcoxon matched pairs test, and non-‐paired

analyses were performed using the Mann-‐Whitney U test. Correlation between

parameters was performed utilising Pearson’s correlation for normally

distributed samples, and Spearman’s correlation for non-‐parametric data.

In Study 1 and Study 2, comparison of binary test outcomes pre-‐ and post-‐surgery

was performed using Fisher’s exact test.

In Study 3, sensitivity, specificity, accuracy, predictive values (positive and

negative) and likelihood ratios were calculated according to standard definitions

and compared between groups (χ2 or Fisher’s exact test for small samples).

Diagnostic performance of DS-‐CMR vs. stress-‐SPECT was performed utilising an

identity binomial generalized estimating equation as per University Statistician

advice. Accuracy of SPECT assessment of LVEF compared to non-‐invasive gold-‐

112

standard CMR was performed utilising paired Student T-‐test and Bland-‐Altman

comparison.

In Study 4, comparison of haemodynamic and invasive coronary indices was

undertaken with an unpaired T-‐test (with Welch correction for samples with

different variances) where values were normally distributed and Mann-‐Whitney

U test where values were non-‐parametrically distributed. Comparison of within-‐

group haemodynamic measures was performed using one-‐way repeated-‐

measures ANOVA with Tukey post-‐hoc multiple comparison test.

Statistical significance was determined by 2-‐tailed tests, with statistical

significance determined at p=0.05.

Analyses were performed with Prism 5 for Mac OS X (GraphPad Software, Inc, CA,

USA). The identity binomial generalized estimating equation was performed

utilizing validated University software.

113

RESULTS

114


and Function following Elective Arterio-Venous Fistula Creation

in Pre-dialysis End-Stage Renal Failure

Introduction

End-‐stage renal failure (ESRF) necessitates provision of alternative excretory

capacity and pharmacological replacement of endogenous renal endocrine

function for the maintenance of life. Although peritoneal dialysis provides many

ESRF patients with a more flexible alternative, haemodialysis (HDx) remains at

the core of renal replacement therapies (RRT) for ESRF patients worldwide. It is

well appreciated that HDx performed via an implanted central venous catheter

(e.g. Permacath, Vascath, etc) is associated with a marked increase in morbidity

and mortality, predominantly related to vascular complications (bleeding,

thrombosis, central venous stenosis) and infection.428 Thus, HDx necessitates the

creation of an iatrogenic arterio-‐venous fistula (AVF) – most commonly involving

the radial or brachial arteries and an adjacent large vein – with the subsequent

low-‐resistance channel diverting arterial pressure and flow directly into the

systemic venous system. Once matured, such fistulae provide a ‘fail-‐safe’ method

for the performance of haemodialysis if/when the metabolic derangements of

decompensated ESRF intervene. The haemodynamic consequences of AVF

creation are not benign however.

Immediately following creation, AVF are associated with a 10-‐20% increase in

systemic cardiac output, achieved predominantly through a reduction in systemic

vascular resistance, increased myocardial contractility (through sympathetic

115

nervous system activation) and an increase in stroke volume and heart rate.410

Over the following week, circulating blood volume increases in conjunction with

increases in ANP and BNP.411,412 These alterations are associated with early

increases in LV filling pressure, and associated increases in LA volume and

LVEDV.411 AVF blood-‐flow increases progressively over the initial 6-‐12 weeks

following creation145, diverting a substantial burden of overall cardiac output to

service the AVF (commonly 0.5-‐2L/minute).

To maintain sufficient systemic cardiac output, LV CO must increase

proportionately, resulting in longer-‐term implications for cardiac and vascular

structure and function.412,413 In fact, AVF creation has been demonstrated to be

associated with worsening of LVH in ESRF patients, and echocardiographic

features of diastolic dysfunction including LA dilatation.411,414 In some patients,

giant AVF may lead to progressive high-‐output cardiac failure, despite preserved

systolic LV function.415-‐417 Such cases may require AVF banding or ligation to limit

flow and reduce systemic cardiac demand.418,419

Many of the earliest studies evaluating the cardiac effects of AVF creation were

performed prior to the institution of routine erythropoietin supplementation

when significant anaemia may have contributed to the haemodynamic effects

witnessed. Despite this, the increased cardiac demand associated with AVF

creation is undisputed, and is believed to be a significant contributor to the

excess burden of CV morbidity and mortality of ESRF.170 Specifically, AVF

creation has been discouraged in ESRF patients with significantly depressed

cardiac function (LVEF<30%), due to fears of reduced physiological reserve

precipitating fulminant cardiac decompensation.420,421 Patients with pre-‐existent

coronary stenoses may suffer an unmanageable increase in cardiac work, with an

116

associated deterioration in sub-‐endocardial perfusion and worsened anginal

symptoms.421 Furthermore, patients with prior CABG utilising internal thoracic

artery grafts may develop coronary steal phenomenon from ipsilateral AVF

creation/haemodialysis.422,423 Given the prognostic advantage of internal thoracic

artery grafting in CABG424-‐426, such findings may have deleterious implications for

the management of CKD patients requiring coronary revascularisation. Despite

these issues, AVF may still be created in elderly ESRF patients, following

appropriate selection to avoid cardiovascular complications.427 Furthermore,

despite the numerous disadvantageous cardiovascular adaptations, HDx via an

AVF is associated with lesser cardiovascular mortality than catheter-‐based

haemodialysis.428

We sought to evaluate the effect of AVF creation on cardiovascular structure and

function in the modern era of ESRF management utilizing recent advances in non-‐

invasive CMR imaging.

117

Methods

Study Methods have been detailed previously (p90).

In brief, subjects with stable, progressive CKD were enrolled prior to clinically-‐

driven, elective surgical AVF formation in preparation of anticipated

haemodialysis commencement in the subsequent 6-‐12-‐months, as clinically

indicated. Standard exclusion criteria were applied.

Subjects were then evaluated utilizing combined Cardiac and Vascular magnetic

resonance protocols (protocol detailed previously, p94) at baseline, ideally 2-‐

weeks prior to the planned surgical date. An identical follow-‐up CMR protocol

was then performed at 6-‐months post-‐AVF creation to evaluate alterations in CV

parameters in response to AVF creation.

Statistical Methods

As previously described (Statistical Methods, p111).

Power Calculation

The proposed study is multi-‐factorial in nature and has not previously been

performed in the manner described. For the purposes of the power calculation

for this Pilot Study, in line with previously published data in echocardiographic

studies and our experience with CMR in other subject subsets, we set increase in

left ventricular end-‐diastolic volume as our primary end-‐point. We estimated that

we would need to complete baseline and follow-‐up studies in 18 subjects to

provide 80% power to detect a 20% difference in the primary end-‐point

assuming a standard deviation of 25% in the measured parameter, correlation

118

between baseline and follow-‐up measures of 0.5 (equivalent to an effect size [dz]

of 0.63) and alpha error of 0.05 (G*Power v3.0.10).

119

Results

Twenty-‐seven subjects (median age 60-‐years, 59.3% male) were enrolled in the

Study with initial CMR imaging undertaken approximately 2-‐weeks prior to

planned AVF surgery. Due to the elective nature of the surgery, surgical dates

were often cancelled by the Hospital in favour of more urgent cases, such that the

interval from scan to surgery often exceeded the 2-‐week time-‐frame (time from

scan to surgery 17±22 days). One subject was unable to undergo AVF creation at

the scheduled surgical date due to surgically unattractive anatomy not apparent

at pre-‐surgical assessment. One subject died following development of acute CVD

progression between the CMR scan and scheduled surgical date, with deferral of

AVF surgery and subsequent patient death. No clinical predictors of impending

CV decompensation were apparent at the initial Study CMR scan. These two

subjects were excluded from the Study analyses.

A complete CV protocol was possible in twenty-‐five (25) subjects, with two

subjects unable to undergo FMD protocol due to SBP>200mmHg at time of FMD

acquisition. A third subject was unable to complete the endothelium-‐independent

component of the FMD protocol due to back pain related to lying supine in the

CMR scanner.

Of the twenty-‐five (25) subjects who underwent successful AVF surgery (age

60±13 years, 60% male), one subject developed an occluded AVF within one

month of surgery, and following commencement of peritoneal dialysis, elected

not to have the AVF repaired. This subject had no follow-‐up CMR data and hence

was also excluded from the subsequent analysis. Twenty-‐four patients were thus

included in the follow-‐up study to evaluate alterations in cardiac and vascular

120

structure over time following successful AVF creation (age 59±12 years, 58%

male). Baseline characteristics are detailed in Table 3. All baseline and follow-‐up

scan parameters were normally distributed. The average time from surgery to

follow-‐up scan was 198±32 days. At follow-‐up, all subjects completed the cardiac

protocol, aortic distensibility and brachial artery blood flow protocols. One

subject was unable to undertake the FMD protocol due to back pain. A further

two subjects only undertook the endothelium-‐dependent component of the FMD

protocol, unable to tolerate the endothelium-‐independent component of the FMD

protocol due to back pain.

Characteristic n=24

Age (years) 59±12

Gender (male), % (n) 58 (14)

Hypertension, % (n) 88 (21)

Hyperlipidaemia, % (n) 54 (13)

Type II Diabetes Mellitus, % (n) 38 (9)

Smoking, % (n)

-‐ current

-‐ former

-‐ non-‐smoker

12 (3)

17 (4)

71 (17)

Prior Coronary Artery Disease, % (n) 21 (5)

Cerebrovascular Disease, % (n) 8 (2)

Chronic Pulmonary Disease. % (n) 21 (5)

Baseline Creatinine (μmol/L) 552±130

Table 3: Subject Baseline Characteristics – Study 1

121

Clinical Results

Clinical findings were predominantly unchanged following AVF-‐creation (weight:

80±19kg vs. 78±17kg, p=0.07; SBP: 146±19mmHg vs. 146±17mmHg, p=0.96; Hb:

115±12g/dL vs. 119±15g/dL, p=0.26). All subjects were undergoing treatment

with EPO-‐analogues at baseline and at follow-‐up. Notably, resting heart rate was

significantly increased at follow-‐up compared to baseline (HR: 71±12bpm vs.

76±11bpm, p=0.008). Furthermore, across the entire cohort, a small, non-‐

significant increase in serum creatinine was noted (serum creatinine:

552±127μmol/L vs. 620±163μmol/L, p=0.11). When the three subjects who had

commenced dialysis prior to follow-‐up imaging were excluded from the

creatinine analysis, the serum creatinine for the remaining subjects was noted to

have increased significantly 6-‐months following study enrolment, as would be

expected clinically in this condition (529±91μmol/L vs. 652±123μmol/L,

p=0.0006).

Cardiac Results

In the presence of advanced CKD / ESRF, baseline imaging revealed preserved

left ventricular systolic function (LVEF 72±7%; Normal range 58-‐76%)586 with

normal left ventricular size (LVEDV 149±31mL; Reference range: Males 115-‐

198mL; Females 88-‐168mL)586 and CO (7.5±1.5L/min; Reference range: Males

2.82-‐8.82L/min, Females 2.65-‐5.98L/min). Despite the high prevalence of HT,

LVM was within normal limits at baseline (132±33g; Reference ranges: Males

108-‐184g, Females 72-‐144g).586 LA area was mildly increased across the cohort,

122

with RA area at the upper limits of the normal range (LA Area 27±6cm2, RA Area

23±6cm2; Normal range <24cm2).551

At follow-‐up, significant alterations in cardiac structure and function were

identified. LVEF and RVEF were unchanged at follow-‐up however, confirming the

limited utility of this index for the evaluation of alterations in cardiac structure

and function despite its universal use in echocardiographic surveillance (LVEF

72±7% vs. 71±9%, p=0.60; RVEF 66±5% vs. 67±6%, p=0.45). Significant

increases were seen for the majority of measured or derived parameters for atrial

and ventricular structure and function however. Mean LVEDV increased by

17.2% (149±31mL vs. 175±43mL, p<0.0001), mean LVESV by 20.7% (43±16mL

vs. 52±24mL, p=0.014), mean LVSV by 15.9% (107±24mL vs. 124±29mL,

p<0.0001) and LV CO by 25.0% (7.5±1.5L/min vs. 9.4±2.2L/min, p<0.0001).

Significantly, mean LVM was increased by 12.7% (132±32g vs. 149±35g,

p<0.0001) 6-‐months following AVF-‐creation.

Similar results were seen for the increases in mean RVEDV (17.9% increase;

142±32mL vs. 167±42mL p<0.0001), RVESV (15.1% increase; 49±14mL vs.

56±18mL, p=0.0014) and RVSV (19.6% increase; 93±24mL vs. 112±27mL,

p<0.0001). Mean LA area was increased by 11.3% (27±6cm2vs. 30±6cm2,

p=0.0003) and mean RA area was increased by 8.9% (23±6cm2 vs. 25±6cm2,

p=0.0046).

Notably, 62.5% of subjects had CMR measures for LVEF, LVEDV, LVESV, LVSV and

LVMI within normal limits prior to AVF creation, however this had reduced to

41.7% of subjects 6-‐months following AVF creation (p=0.24). The results of

changes in cardiac structure and function are summarised graphically in figures

14-‐16.

123

Figure 14: Alterations in Left Ventricular Structure and Function following

successful AVF creation in ESRF.

124


successful AVF creation in ESRF.

125

Figure 16: Alterations in Left and Right Atrial Area following successful AVF

creation in ESRF.

Vascular Results:


Aortic distensibility was not significantly altered by the creation of a surgical AVF

at the 6-‐month follow-‐up scan (2.3±1.2mmHg-‐1 vs. 2.2±1.2mmHg-‐1, p=0.59).

Ascending aorta (AA), proximal descending aorta (PDA), distal descending aorta

(DDA) and average aortic distensibility ([AA+PDA+DDA]/3) were all numerically,

but not statistically significantly, lower following AVF creation (Figure 17).

126

Figure 17: Alterations in Aortic Distensibility following AVF creation in ESRF.

Prior to AVF creation, baseline aortic distensibility decreased progressively from

DDA to AA, consistent with an increase in aortic stiffness (reduced aortic

compliance) in the more proximal aortic segments (AA 1.41±1.0mmHg-‐1 vs. PDA

2.20±1.3mmHg-‐1, p=0.023; AA 1.41±1.0mmHg-‐1 vs. DDA 3.20±2.0mmHg-‐1,

p=0.0003; PDA 2.20±1.3mmHg-‐1 vs. DDA 3.20±2.0mmHg-‐1, p=0.046). These

finding remained similar following AVF creation, although the numerical

difference between aortic distensibility at PDA and DDA did not quite reach

127

statistical significance (AA 1.27±1.2mmHg-‐1 vs. PDA 2.11±1.3mmHg-‐1, p=0.024;

AA 1.27±1.2mmHg-‐1 vs. DDA 3.10±2.0mmHg-‐1, p=0.0004; PDA 2.11±1.3mmHg-‐1

vs. DDA 3.10±2.0mmHg-‐1, p=0.052) (Figure 18).

Figure 18: Aortic Distensibility by Aortic Level Prior to (Pre-), and Following (Post-)

AVF creation in ESRF.

Brachial Artery Flow-Mediated Dilatation

Twenty-‐one subjects completed the FMD protocol at both pre-‐AVF and follow-‐up

scanning. In these subjects, brachial artery endothelium-‐dependent

vasodilatation, as measured by flow-‐mediated dilatation was markedly reduced

at 6-‐month follow-‐up imaging following AVF-‐creation (9.0±9.2% vs. 3.0±5.7%,

p=0.012; Figure 19). Endothelium-‐independent vasodilatation was unaffected by

AVF-‐creation in the subjects evaluated (13.3±9.1% vs. 12.2±10.0%, p=0.74).

Notably, in a sub-‐population of 17-‐subjects where this sequence was performed,

there was no significant change in baseline brachial artery blood flow in the arm

128

contralateral to the AVF – a factor with the potential to contribute to any

measured alterations in endothelial function (0.054±0.030L/minute vs.

0.055±0.03L/minute, p=0.97) (Figure 20). Baseline brachial artery area was

unchanged across the study cohort between baseline and follow-‐up scans

(26.5±8mm2 vs. 27.7±7mm2, p=0.31). There was no significant correlation

between % change in FMD and % change in AVF flow (r=0.17, p=0.52), % change

in LV CO (r=-‐0.29, p=0.24) or % change in LVSV (r=-‐0.27, p=0.28).

Figure 19: Alterations in Peripheral Endothelial Function following successful AVF

creation in ESRF.

Brachial Artery Blood Flow – Arterio-Venous Fistula Arm

Brachial artery blood flow ipsilateral to the AVF increased substantially following

AVF creation (0.057±0.04L/minute vs. 1.158±0.44L/minute, p<0.0001)(Figure

20). This represents a more than 20-‐fold increase in mean ipsilateral brachial

artery blood-‐flow 6-‐months following AVF-‐creation. Notably, there was no

129

significant association between increases in AVF-‐arm brachial artery blood flow

and adaptive change in LV CO (r=0.09, p=0.71) or LVSV (r=0.13, p=0.59),

potentially implicating a more complex systemic circulatory adaptation to AVF

creation.


contralateral to the newly created arterio-venous fistula.

130

Discussion

Elective AVF creation is associated with substantial alterations in cardiac

structure and function, necessary to accommodate the increase in cardiac output

sufficient to service the fistula whilst maintaining homeostatic systemic supply.

These changes include bi-‐atrial and bi-‐ventricular dilatation, increased

ventricular stroke volume and cardiac output, as well as a clinically significant

increase in LVM – a measure closely associated with adverse outcomes in ESRF.

This adaptive cardiac remodelling, coupled with a >2000% increase in brachial

artery blood flow ipsilateral to the newly created AVF, was also associated with a

marked reduction in remote endothelial function and a consistent numerical, but

not statistically significant, increase in aortic stiffness. Although necessary for the

provision of HDx, it is striking that a planned medical intervention could cause

such widespread maladaptation within the CV system of already high-‐risk

individuals. That said, it is acknowledged that HDx performed via such conduits

results in a substantially lower burden of overall morbidity and mortality than

HDx via implanted catheters which may not contribute so significantly to CV

maladaptation.428

Previous TTE studies have demonstrated the potential for increased LVM and LV

dilatation following AVF creation.411,414 Since the first publication of efficacy for a

synthetic EPO in the treatment of ESRF anaemia in the New England Journal of

Medicine in January 1987604, substantial inroads have been made in the

management of anaemia, hypertension and salt/fluid imbalance in ESRF.

Downward revision of blood pressure targets, increased therapeutic options and

an increased recognition of the horrifying CV prognosis of patients with ESRF

131

have all contributed to improvements in care for affected patients. Despite such

advances, however, our Study demonstrates comprehensively the enduring CV

impact of AVF creation in these high-‐risk individuals.

Parfrey et al have previously demonstrated the negative prognostic implications

of concentric LVH, LV dilatation and LV dysfunction as measured by TTE in ESRF

patients commencing dialysis.145 Furthermore, London et al have previously

demonstrated an extraordinary prognostic advantage to therapeutic

interventions in ESRF that successfully reduce LVM by at least 10%.160 Such

measures were associated with a relative risk of 0.78 (0.63-‐0.92, p=0.0012) for

all-‐cause mortality, and 0.72 (0.51-‐0.90, p=0.0016) for CV-‐event-‐free survival

across the cohort. This relative risk reduction was particularly notable amongst

subjects with no prior history of CVD (RR 0.69 [0.52-‐0.83, p=0.0182] for all cause

mortality, and 0.52 [0.23-‐0.75, p=0.0204] for CV event-‐free survival).160

In the present Study, we demonstrated a 17.2% increase in mean LVEDV and a

12.7% increase in mean LVM 6-‐months following AVF-‐creation (p<0.0001 for

both). Although beyond the scope of this observational study, such cardiac

adaptations may thus be expected to be associated with a deleterious impact on

CV morbidity and mortality. Furthermore, recognition of the impact of a 25.0%

increase in mean CO 6-‐months following AVF creation (p<0.0001) may be an

important factor in the clinical management of pre-‐dialysis patients – particularly

as such measures are rarely reported using conventional cardiac imaging

modalities, where LVEF (unchanged in this Study despite the myriad other

structural and functional cardiac alterations) routinely forms the basis of a

clinician’s determination of significant functional cardiac impact.

132

RV structure and function have historically been neglected in the evaluation of

cardiac structure and function. TTE provides only a limited evaluation of RV size

and systolic function, although tissue Doppler indices of RV function have

recently been evaluated – particularly in the context of known pulmonary

hypertension. Substantial recent research has focussed on the importance of RV

structure and function in the maintenance of exercise capacity – both in healthy

athletes and diverse disease states.605-‐611 The role of RV remodelling in the

reduced exercise capacity common in ESRF remains to be determined, but it is

certain that CMR will be integral to future research in this area. Unlike previous

studies, CMR enabled more comprehensive RV evaluation in the present Study.

Accordingly, we demonstrated substantial alterations in RV structure and

function 6-‐months following AVF creation, with >15% increases seen in mean

RVEDV, RVESV and RVSV (p≤0.0003 for all). Although intuitive, such findings are

important to appreciate given the known association of AVF creation and the

development of clinically significant PHT in ESRF patients. The role of sub-‐clinical

RV remodelling and dysfunction in the exercise intolerance of ESRF remains to be

determined but the results from this Study provide an important link in this line

of enquiry.

LA size is more commonly increased in ESRF, in comparison to the general

community.189 Such atrial dilatation is known to be associated with the

development of patchy interstitial fibrosis within the LA myocardium, delaying

local atrial conduction velocities and providing rich substrate for the

perpetuation of multiple re-‐entrant circuits in the perpetuation of AF.187,188,193 In

fact, LA dilatation has previously been identified as an independent risk factor for

the development of AF in ESRF and may contribute to the poor CV prognosis of

133

patients with CKD.183,195 Furthermore, whether through the predisposition to AF

or as a marker of chronic LV diastolic impairment, recent evidence confirms an

association between LA dilatation and increased mortality in ESRF patients with

LVH.196

In the present Study, at 6-‐month follow-‐up imaging, AVF-‐creation was associated

with an 11.3% increase in mean LA area (p=0.0003) and an 8.9% increase in RA

area (p=0.0046). As previously mentioned, such alterations occurred in the

context of increases in LVEDV/RVEDV, LVSV/RVSV, and LVM. Thus, increased LA

and RA area may be expected to occur following AVF creation as a result of

increases in both ventricular volumes and filling pressures in the context of

increased myocardial mass and stretch. As such, the induced increase in atrial

stretch (LA in particular) provides a more conducive substrate for the

development of intra-‐atrial re-‐entrant arrhythmia, and AF more specifically.

Atrial fibrillation (AF) is the most common sustained arrhythmia in the general

population and recent studies have confirmed AF as a significant negative

prognostic factor in ESRF.182-‐184 AF is more highly prevalent in ESRF than the

general community, and contributes disproportionately to morbidity and

mortality in affected patients.183,185 Although haemodialysis in particular is a

known risk factor for the development of AF182,186, it remains unclear whether

declining renal function contributes independently to this risk, or whether the

high prevalence of AF risk factors (e.g. advancing age, hypertension, CCF, LVH,

coronary artery disease, valvular heart disease) amongst CKD patients is

responsible for the high prevalence of this condition in CKD. It would appear that

AVF creation might play a significant role in the promotion of atrial dilatation

within the ESRF milieu.

134

Thus, in the modern era of anaemia and uraemia management, this Study

demonstrates the significant role AVF creation has in the genesis and promotion

of atrial and ventricular structural and functional abnormalities. Although beyond

the scope of this observational study, the potential for disadvantageous

prognostic outcomes directly related to such alterations remains to be

determined. Of course, the absence of a feasible, lower risk alternative to the

provision of HDx remains a major stumbling block.


Arterial stiffness provides a clinically relevant measure of longitudinal vascular

injury and is predictive of future cardiovascular events independent of

conventional CV risk factors.372,375,379,380,382,383,406 Although risk factors such as

hypertension and hyperlipidaemia may be effectively reduced by pharmacologic

intervention, the vascular injury induced by such risk factors over time is not

immediately negated by such therapies. Thus arterial stiffness has been

postulated to provide a more relevant surrogate for future CV risk than

conventional risk factors.370

This theory was tested by the Conduit Artery Function Evaluation (CAFÉ)404 sub-‐

study which drew on 2,073 patients from the larger Anglo-Scandinavian Cardiac

Outcomes Trial (ASCOT)407 to assess this issue. CAFÉ demonstrated that despite

similar reductions in brachial systolic blood pressure (SBP) and PP, the

combination of amlodopine + perindopril was more efficacious in reducing

central SBP and PP than the atenolol + thiazide combination404, corresponding to

the demonstration of lesser cardiovascular events in the amlodopine +

perindopril cohort.407 Similarly, losartan was shown to reduce arterial stiffness

135

and central PP to a greater degree than the comparator (atenolol) with an

associated reduction in stroke in the Losartan Intervention for Endpoint Reduction

in Hypertension (LIFE) study.408 The differing impact of alternative anti-‐

hypertensive agents on central vascular stiffness has thus been proposed as a

potential explanation for the differential effects of these agents on CV

events.404,409

Of particular relevance was the finding that the CV benefits of blood pressure

lowering in ESRF were attenuated in patients where PWV was not improved by

anti-‐hypertensive therapies.371 Thus, though the conventional risk factor was

moderated by standard therapies, the modifiability of the associated arterial

alterations was a more useful predictor of future CV prognosis.612

Aortic distensibility provides a novel measure of central vascular compliance in

response to systemic pulse pressure. MRI has recently been utilised to evaluate

non-‐superficial arteries (such as the aorta) in a variety of physiological and

disease states259,386-‐393, and has been shown to correlate well with traditional

PWV.394 Specifically, CMR-‐derived aortic distensibility and volumetric arterial

strain have been found to be predictive of cardiovascular clinical end-‐points and

overall survival in ESRF on multivariate analysis.395

We evaluated aortic distensibility at baseline and 6-‐months following AVF-‐

creation utilising a validated CMR methodology. Notably, aortic distensibility was

not significantly altered at 6-‐month follow-‐up although a consistent numerical

fall in distensibility was noted at each of the aortic levels assessed. Such a finding

may of course be a chance observation, but provides substrate for the hypothesis

that 6-‐months is too short a follow-‐up period to identify chronic alterations in

central vascular stiffness in response to AVF-‐creation in the context of chronic

136

uraemia. Notably, the CAFÉ study evaluated vascular stiffness on repeated visits

for up to 4-‐years in their demonstration of significant differences between the

large treatment arms.

Of perhaps more significance is the finding that aortic stiffness increases

progressively from distal aorta to proximal. Our research team has previously

identified a significant difference between aortic distensibility at the distal

descending aorta as compared to the ascending aorta in healthy elderly subjects,

with a numerical, but not statistically significant trend for stepwise increasing

stiffness from distal to proximal segments.394 This finding was not replicated in

young healthy subjects in that study and had not previously been demonstrated

for measures of aortic distensibility. We proposed that this finding might relate to

regional differences in the aortic elastin:collagen ration, with the proportion of

elastin known to be greater in the proximal segments of the aorta compared to

the distal segments (almost three-‐fold relative difference).613 Elastin is thought to

be particularly susceptible to fragmentation and destruction in response to the

cyclical fatigue associated with repetitive systolic/diastolic pressure waves over

time. Hence the proximal aortic segments would be expected to be particularly

prone to deterioration in compliance with diminution of medial elastic

content.614,615 By contrast, the distal aorta may behave relatively more like

muscular conduit arteries that have been shown to have less elastin content and

exhibit little or no age-‐related alteration in distensibility or compliance compared

to more proximal arteries which have a higher elastin content.616-‐618 Such

findings have previously been inferred using PWV methodologies.619-‐621

Such an observation is particularly significant as an increase in proximal aortic

stiffness may be expected to play a prominent role in the generation of CVD. More

137

specifically, we hypothesised that increased proximal segmental stiffness may be

associated with an increase in ventricular afterload and loss of the usual

cushioning of the transmission of cyclical ventricular stroke volume to the

peripheries. Furthermore, we proposed that this derangement of ventriculo-‐

vascular coupling might play a significant role in the promotion of LVH and,

potentially, deterioration in diastolic coronary perfusion resulting from reduced

proximal aortic diastolic elastic recoil.394 Such a finding is particularly relevant in

the context of CKD, as deterioration in vascular elasticity has been proposed as a

metabolic consequence of chronic uraemia, with the addition of accelerated

vascular calcification (common within the proximal aorta) further contributing to

increased vascular stiffness in CKD.

The combination of increased arterial stiffening and reduced ventricular

compliance in the context of ventricular hypertrophy and dilatation in ESRF

contributes to a progressive decline in cardiac reserve, as the reduced arterial

compliance leads to disadvantageous physiological responses to increased

circulatory demand. Exertion is generally associated with increases in HR and

LVSV (unless diastolic dysfunction is severe, where LVSV may fall with rising HR).

In CKD, the increased arterial stiffness is associated with magnified blood

pressure and exaggerated LV afterload in response to any increase in LVSV, due

to the reduced arterial capacitance reserve.348 Significantly, coronary perfusion

may be markedly altered during these conditions, even in the absence of

obstructive coronary atherosclerosis. Such a combination may provide a potent

substrate for functional myocardial ischaemia during exertion and periods of

increased circulatory demand (e.g. infection, haemodialysis) and contribute

further to myocardial dysfunction and CV morbidity.

138

Endothelial Function

Endothelial dysfunction is known to be a critical precondition to the development

of atherosclerosis and subsequent CV sequelae.228 Significantly, the presence of

peripheral endothelial dysfunction has previously been correlated with

impairment in coronary endothelial function270, and hence has been used to

provide a non-‐invasive method for predicting the presence of coronary artery

atherosclerosis, and future coronary events in at-‐risk patients.262-‐266 Additionally,

improvements in peripheral endothelial function have been associated with

therapeutic interventions that improve cardiovascular risk.263,264

CKD provides a particularly complex precipitant for endothelial dysfunction,

resulting from multiple circulating factors injurious to the endothelium and

promotional of the necessary pro-‐inflammatory setting for endothelial

dysfunction and accelerated atherosclerosis.256 Notably, impairment in forearm

endothelial function has been shown to be associated with an increase in all-‐

cause mortality in ESRF.265

In this Study, we found a clinically significant reduction in endothelial function

(as measured by brachial artery FMD) 6-‐months following elective AVF creation.

Our results demonstrated a reduction in mean FMD response from 9.02±9.2% to

3.05±5.7% at 6-‐month follow-‐up (p=0.012). There was no deterioration in

endothelium-‐independent (GTN-‐mediated) brachial artery dilatation over the

follow-‐up period however, indicating a primarily functional rather than

structural contribution to this dysfunction. Such a finding strongly implicates a

mechanistic trigger to remote endothelial dysfunction from the increased blood

flow and vascular shear stress in the AVF arm and that induced by the

compensatory increase in systemic cardiac output required to service the fistula.

139

Furthermore, such findings occurred in the absence of detectable change in

baseline brachial artery blood flow in the FMD arm. Such findings implicate AVF

creation in the promotion of the complex pro-‐atherogenic milieu of CKD and

ESRF and such conduits may contribute significantly to the development of

accelerated CVD associated with this condition.

Limitations

Although similiarities exist between our Study design and that of other published

studies evaluating the cardiac effects of AVF creation411,414, the most significant

limitation of the current study is the absence of a comparable control group. In

this regard, due to clinical imperatives, there was no available cohort of stable

advanced CKD subjects with functioning AVF, but not yet receiving dialysis

therapy, at our institution. Comparison with a pre-‐dialysis, pre-‐AVF cohort may

have provided a beneficial comparison, despite the lesser severity of CKD such a

cohort would necessarily have experienced. Despite the absence of a control

group in this study, the results were highly consistent across the cohort, with a

high degree of biological plausibility.

Additionally, although values for the majority of clinically relevant parameters

evaluated remained stable between the Study investigations, the progressive

decline in renal function witnessed cannot be excluded as a potential contributor

to the CV alterations demonstrated. The magnitude of change detected across the

majority of evaluated parameters in this Study, however, are demonstrably out of

proportion to the decline in renal function seen, implicating an alternative

mechanism capable of relatively acute adaptive change. AVF creation provides

such a potential mechanism.

140

Furthermore, re-‐evaluation of the cohort at an additional, earlier time-‐point may

have provided valuable information regarding the time-‐course of these CV

adaptations. Whether many of these CV adaptations occur acutely, or whether

such alterations (other than LVM) occur progressively over months, remains to

be determined.

Conclusion

Elective AVF creation in pre-‐dialysis CKD is associated with significant increases

in bi-‐atrial and bi-‐ventricular chamber volumes and LVM commensurate with the

requirement for a 25% mean increase in cardiac output. Furthermore, AVF

creation is associated with deterioration in systemic endothelial function, and a

consistent small, but statistically non-‐significant trend towards increased aortic

stiffening at all levels. Such alterations in CV structure and function have been

strongly linked to poorer CV and all-‐cause mortality in previous epidemiological

and observational studies. The role of therapeutic strategies in ameliorating such

disadvantageous sequelae following creation of these necessary iatrogenic

conduits in high-‐risk ESRF patients requires further study.

141


and Function following Elective Arterio-Venous Fistula Ligation

following Successful Stable Renal Transplantation

Introduction

CVD is the leading cause of death in patients with ESRF and remains a leading

cause of morbidity and mortality amongst successful RTx recipients.451 Despite

substantial improvements in all-‐cause and CV mortality following RTx443,622,623,

transplant patients endure a significantly higher burden of CV and all-‐cause

mortality than similarly-‐aged members of the general population.444,451 Such

persistently elevated risk is multi-‐factorial and is influenced by the burden of

maladaptive CV alterations accumulated during the period of impaired renal

function, in addition to the contribution of post-‐transplant immunosuppressive

therapies to CV risk. As such, efforts to promote the reversal of ESRF-‐induced

maladaptive CV alteration may enhance the prognostic advantage of RTx for ESRF

patients.

Previous studies have demonstrated conflicting results with regards the

beneficial impact of RTx on CV structure and function.624-‐626 LVH is common in

ESRF and is an independent predictor of adverse outcomes in ESRF and post-‐

RTx.627,628 Furthermore, increased LA size has recently been linked with elevated

mortality in association with LVH in ESRF patients referred for renal

transplantation.196 Similarly, altered vascular function has been linked with

elevated CV mortality in ESRF395,629, however results of recent studies evaluating

142

improvements in vascular structure and function following RTx have been

mixed.630-‐633

Significantly, many successful RTx recipients have persistently functioning AVF,

despite the absence of ongoing clinical need. Although some AVF may

spontaneously occlude following RTx, such AVF place a persistently elevated

demand on cardiac function, and may contribute to the promotion of vascular

structural and functional derangement that precedes clinically significant CVD.

Previous small echocardiographic studies have demonstrated improvements in

LV size and LVM following elective surgical ligation of clinically large AVF post-‐

RTx.439,634 It remains unclear whether such improvements in cardiac structure

and function are limited to ligation of clinically large fistulae, or whether routine

AVF ligation may be associated with beneficial cardiac and vascular effects. We

sought to evaluate the effect of AVF ligation on cardiovascular structure and

function in the modern era of post-‐RTx management utilizing recent advances in

non-‐invasive CMR imaging.

143

Methods


In brief, subjects with were enrolled following stable, successful RTx in the

context of persistent AVF prior to clinically-‐driven, elective surgical AVF ligation.

Standard exclusion criteria were applied.

Subjects were then evaluated utilizing combined Cardiac and Vascular magnetic

resonance protocols (protocols detailed previously, p94) at baseline, ideally 2-‐

weeks prior to the planned surgical date. An identical follow-‐up CMR protocol

was then performed at 6-‐months post-‐surgery to evaluate alterations in CV

parameters in response to AVF ligation.

Statistical Methods

As previously described (Statistical Methods, p111).

Power Calculation

This Pilot study was multi-‐factorial in nature and had not previously been

performed in the manner described. For the purposes of the power calculation, in

line with previously published data in echocardiographic studies and our

experience with CMR in other subject subsets, we set a decrease in LVEDV as our

primary end-‐point. We estimated that we would need to complete baseline and

follow-‐up studies in 18 subjects to provide 80% power to detect a 20% difference

in the primary end-‐point assuming a standard deviation of 25% in the measured

parameter, correlation between baseline and follow-‐up measures of 0.5

144

(equivalent to an effect size [dz] of 0.63) and alpha error of 0.05 (G*Power

v3.0.10).

145

Results

Eighteen (18) subjects (median age 59-‐years [IQR 47-‐65 years], 77.8% male)

were enrolled in the study with initial CMR imaging undertaken approximately 2-‐

weeks prior to planned elective AVF surgery. Due to the elective nature of the

surgery, surgical dates were often cancelled by the Hospital in favour of more

urgent cases, such that the interval from scan to surgery often exceeded the 2-‐

week time-‐frame (time from scan to surgery 20.3±18 days). Baseline

characteristics are detailed in Table 4.

Characteristic n=18

Age (years) [IQR] 58.5 [47.0-‐64.5]

Gender (male), % (n) 78 (14)

Time from Transplant to Initial Scan (days) 1141 [884-‐1565]




Smoking, % (n)

-‐ current

-‐ former

-‐ non-‐smoker

6 (1)

50 (9)

44 (8)


Peripheral Vascular Disease, % (n) 0 (0)



A complete CV protocol was possible in sixteen (16) subjects, with two subjects

unable to undergo FMD protocol due to SBP>200mmHg at time of FMD

146

acquisition. A third subject was unable to complete the endothelium-‐independent

component of the FMD protocol due to back pain related to lying supine for the

long CMR protocol.

The median time from surgery to follow-‐up scan was 201 days (IQR 187-‐220

days). All subjects completed the cardiac protocol, aortic distensibility and

brachial artery blood flow protocols. One subject was unable to undertake the

FMD protocol due to back pain. A further one subject only undertook the

endothelium-‐dependent component of the FMD protocol, unable to tolerate the

additional duration in the scanner necessary to complete the endothelium-‐

independent component of the FMD protocol due to back pain.

Clinical Results

No significant changes were detected in clinical parameters between baseline and

follow-‐up imaging (weight: 81±16kg vs. 81±16kg, p=0.69; SBP: 144±17mmHg vs.

138±18mmHg, p=0.13; HR: 72±8bpm vs. 71±11bpm, p=0.73; Hb: 131±18g/dL vs.

134±15g/dL, p=0.26; serum creatinine: 125±63μmol/L vs. 130±65μmol/L,

p=0.60). No subjects required blood transfusion or dialysis during the study

period.

Cardiac Results

Eighteen subjects were included in the follow-‐up study and underwent initial

cardiac protocol. In the presence of successful, stable RTx, baseline imaging

revealed preserved mean left ventricular systolic function (LVEF 73% [67-‐80%];

Normal range 58%-‐76%)586 with mean LVEDV at the upper range of normal

147

(192±52mL; Reference range: Males 115-‐198mL; Females 88-‐168mL).586 Cardiac

output was increased in this cohort at baseline (9.6±2.9L/min; Reference range:

Males 2.82-‐8.82L/min, Females 2.65-‐5.98L/min). In the context of a high

prevalence of prior HT, LVM was at the upper limit of normal limits at baseline

(166±56g; Reference ranges: Males 108-‐184g, Females 72-‐144g).586 Left and

right atrial area were mildly increased across the cohort at baseline (LA Area

29±5cm2, RA Area 27±4cm2; Normal range <24cm2).551

At follow-‐up, significant alterations in cardiac structure and function were

identified. LVEF and RVEF were unchanged however, confirming the limited

utility of this index for the evaluation of alterations in cardiac structure and

function, despite its universal use in echocardiographic surveillance (mean LVEF

73% [67-‐80%] vs. 72% [68-‐78%], p=0.89; RVEF 65% [60-‐69%] vs. 64% [56-‐

68%], p=0.34). Significant alterations were seen for a number of other measured

or derived parameters for atrial and ventricular structure and function.

Mean LVEDV decreased by 13.1% (192±52mL vs. 167±52mL, p=0.013), mean

LVSV by 14.4% (135±43mL vs. 115±33mL, p=0.008) and mean LV CO by 15.6%

(9.6±2.9L/min vs. 8.1±2.3L/min, p=0.004). Significantly, mean LVM decreased by

9.7% (166±56g vs. 149±51g, p=0.0001) 6-‐months following AVF-‐ligation. Change

in LVESV (10.1% decrease; 57±31mL vs. 52±32mL, p=0.16) was not statistically

significant (Figures 21-‐23).

Similar results were seen for the decreases in mean RVEDV (12.1% decrease;

175±45mL vs. 153±43mL, p=0.006) and RVSV (14.8% decrease, 112±34mL vs.

95±29mL, p=0.003). Mean LA area was reduced by 10.1% (29±5cm2 vs. 26±5cm2,

p=0.016) and mean RA area decreased by 8.4% (27±4cm2 vs. 25±3cm2, p=0.016)

(Figures 21-‐23).

148

Figure 21: Alterations in Left Ventricular Structure and Function following AVF-

ligation in the context of successful, stable renal transplantation.

149

Figure 22: Alterations in Right Ventricular Structure and Function following AVF-

ligation in the context of successful, stable renal transplantation.

150

Figure 23: Alterations in Left and Right Atrial Area following AVF-ligation in the

context of successful, stable renal transplantation.

Vascular Results:


Aortic distensibility was not significantly altered by the surgical ligation the AVF

at the 6-‐month follow-‐up scan (2.6±1.4mmHg-‐1 vs. 2.6±1.2mmHg-‐1, p=0.84).

Ascending aorta (AA), proximal descending aorta (PDA), distal descending aorta

(DDA) and average aortic distensibility ([AA+PDA+DDA]/3) were all numerically

similar following AVF ligation (Figure 24).

151

Figure 24: Alterations in Aortic Distensibility following AVF-ligation in the context

of successful, stable renal transplantation.

Prior to AVF creation, baseline aortic distensibility decreased progressively from

DDA to AA, consistent with an increase in aortic stiffness in the more proximal

aortic segments, though only the comparison of AA with DDA distensibility

demonstrated a statistically significant difference (AA 1.74±1.5mmHg-‐1 vs. PDA

2.51±1.2mmHg-‐1, p=0.11; AA 1.74±1.5mmHg-‐1 vs. DDA 3.51±2.2mmHg-‐1, p=0.010;

PDA 2.51±1.2mmHg-‐1 vs. DDA 3.51±2.2mmHg-‐1, p=0.11). These finding remained

152

similar following AVF ligation (AA 1.78±1.3mmHg-‐1 vs. PDA 2.60±1.4mmHg-‐1,

p=0.08; AA 1.78±1.3mmHg-‐1 vs. DDA 3.49±1.8mmHg-‐1, p=0.002; PDA

2.60±1.4mmHg-‐1 vs. DDA 3.49±1.8mmHg-‐1, p=0.10) (Figure 25).

Figure 25: Aortic Distensibility by Aortic Level Prior to (Pre-), and Following (Post-)

AVF ligation in the context of stable, successful renal transplantation.

Although representative of significantly different clinical cohorts, there was no

significant difference detected in average aortic distensibility between Study 1

subjects with ESRF 6-‐months following AVF-‐creation, and stable post-‐RTx

patients 6-‐months following AVF ligation in this Study (2.16±1.3mmHg-‐1 vs.

2.62±1.2mmHg-‐1, p=0.23; Figure 26).

153

Figure 26: Average Aortic Distensibility in ESRF subjects following AVF-creation

compared to successful RTx recipients following AVF-ligation.

Flow-Mediated Brachial Artery Dilatation

Sixteen (16) subjects completed the FMD protocol at both pre-‐AVF and follow-‐up

scanning. In these subjects, brachial artery endothelium-‐dependent

vasodilatation, as measured by flow-‐mediated dilatation was significantly

improved at 6-‐month follow-‐up imaging following AVF-‐ligation (2.5±6.5% vs.

8.0±5.9%, p=0.0426; Figure 27). Endothelium-‐independent vasodilatation was

unaffected by AVF-‐ligation in the subjects evaluated (11.9±4.4% vs. 11.6±7.6%,

p=0.87). Importantly, no significant change was detected in baseline brachial

artery blood flow between initial and follow-‐up scans (0.08±0.04L/min vs.

0.09±0.05L/min, p=0.24) in a sub-‐population of 8-‐subjects where this sequence

was performed (Figure 28). Similarly, there was no significant change in baseline

brachial artery area detected across the study cohort between baseline and

follow-‐up scans (28.4±10mm2 vs. 27.4±10mm2, p=0.76). There was no

154

correlation between % change in FMD and % change in LV CO (r=0.24, p=0.56) or

LVSV (r=-‐0.08, p=0.84).

Figure 27: Evaluation of Alterations in Endothelial Function following AVF ligation

in the context of stable, successful renal transplantation.

Brachial Artery Blood Flow – Arterio-Venous Fistula Arm

Brachial artery blood flow ipsilateral to the AVF decreased substantially

following AVF creation (1.59±0.69L/minute vs. 0.083±0.05L/minute,

p<0.0001)(Figure 28). This represents an almost 95% reduction in mean

ipsilateral brachial artery blood-‐flow 6-‐months following AVF-‐ligation. Notably,

there was no significant association between % change in brachial artery blood

flow and % change in LV CO (r=0.22, p=0.41) or % change in LVSV (r=0.09,

p=0.74).

155


contralateral to the ligated arterio-venous fistula in the context of

stable, successful renal transplantation.

156

Discussion

Following successful, stable RTx, elective AVF ligation is associated with myriad

desirable alterations in cardiac structure and function. Most notably, AVF ligation

was associated with substantial regression of LV cavity dilatation and a clinically

significant reduction in LVM – increased at baseline in this post-‐RTx cohort.

Additionally, in the context of unchanged LVEF and RVEF, there were significant

reductions in measures of RV and bi-‐atrial dilatation. Such alterations were noted

in the context of a >15% reduction in mean CO 6-‐months following AVF ligation

and a 95% reduction in brachial artery blood-‐flow ipsilateral to the ligated AVF.

Notably, the improvement in contralateral brachial FMD closely mirrored the

deterioration in this parameter following AVF creation in Study 1. Such

alterations in cardiac structure and function were not mirrored by significant

alterations in vascular structure, as measured by CMR-‐derived aortic

distensibility however. Most importantly, the majority of the subjects studied had

undergone successful renal transplantation >3 years previously, with indefinite

persistence of clinically unnecessary AVF potentially providing a strong source of

maladaptive CV stress in affected patients.

AVF may persist indefinitely following successful RTX. Although some RTx

patients note spontaneous thrombosis of their AVF, routine post-‐RTx surgical

AVF-‐ligation following a meaningful period of clinically stability remains a focus

of ongoing research rather than routine clinical practice worldwide. The longer-‐

term cardiac impact of AVF persistence following successful RTx is not known,

however there is mounting evidence that AVF contribute significantly to

persistence of LVH (and potentially, associated diastolic left ventricular

dysfunction) in post-‐transplant patients. The published data in this field is

157

contradictory however438-‐440, with some evidence that only larger AVF are

responsible for disadvantageous cardiac remodelling.441 A recent study further

suggests that the AVF, rather than the necessity for haemodialysis, is the

propagating factor in LVH, demonstrating a marked reduction in adverse cardiac

indices following failure of AVF, but ongoing intermittent haemodialysis via a

central venous catheter.442 Moreover, the impact of AVF-‐ligation on right

ventricular and atrial structure and function as well as central and peripheral

vascular structure and function has not previously been determined. Our Study

demonstrates regression of bi-‐ventricular and bi-‐atrial dilatation, improvement

in LVM and a statistically significant improvement in remote endothelial function

as measured by FMD – all factors associated with lesser morbidity and mortality.

It is well appreciated that successful RTx is associated with a substantial

improvement in morbidity and mortality for ESRF patients.443-‐449 Despite this,

RTx recipients endure a persistently elevated risk of CV morbidity and mortality

compared to the general population, despite substantial improvements in post-‐

RTx care in the last two decades.451 Successful RTx has previously been shown to

be associated with significant reductions in LVM and LV volumes following

transplantation, though cardiac structure and function do not universally

normalise.454-‐463 Thus, the role for novel therapies to improve post-‐RTx care, and

CV morbidity and mortality in particular, deserves particular attention.

Endothelial dysfunction is a common finding in ESRF. Although generally

improved, endothelial dysfunction commonly persists following RTx.470-‐472 Many

of the immunosuppressive agents utilised following RTx contribute to this

persistent endothelial dysfunction, and may contribute further to overall CVD

risk through unfavourable effects on lipid profiles, blood pressure and glucose

158

intolerance.473 Thus, endothelial dysfunction post-‐RTx remains a potential trigger

to the development of clinically significant CVD, and hence remains a potential

target for therapeutic interventions, whether by improved blood pressure and

lipid control, smoking cessation or by other novel means.472 In our Study,

endothelium-‐dependent vasodilatation (as measured by FMD) demonstrated a

significant improvement in mean brachial artery dilatation 6-‐months following

AVF-‐ligation. Notably, endothelial function at baseline was particularly poor,

despite generally preserved RTx function. The finding of improved endothelium-‐

dependent vasodilatation is significant, as it infers a widespread benefit to

systemic endothelial function, related potentially to a combination of reduced

systemic blood flow and/or alteration of circulating triggers to endothelial

dysfunction. Importantly, our Study did not find any significant change in

baseline brachial artery blood flow in the FMD arm that may have contributed to

these findings. Moreover, that a peripheral arterial bed remote from the AVF

demonstrated improved endothelial function raises the possibility of

improvements in clinically more important vascular beds such as the coronary

and cerebral circulations. Previous studies in non-‐CKD cohorts have

demonstrated reduction in future CV events associated with improvements in

peripheral endothelial function.635 Such an hypothesis remains to be determined

in post-‐RTx, however the potential for the relatively minimally-‐invasive AVF

ligation procedure to induce a beneficial impact on clinical CV events through

improved systemic endothelial function deserves further investigation.

Anecdotally, the male subjects evaluated commented upon noticeable

improvements in erectile function following AVF-‐ligation. Although this factor

was not evaluated prospectively, it provides further basis for the hypothesis of

159

potential improvement in systemic endothelial function with AVF-‐ligation.

Regardless, it remains to be determined whether the FMD finding in this Study

would be replicated in other vascular beds, and whether such improvements in

systemic endothelial function may abrogate this potent trigger to atherosclerosis

and future CV events this high-‐risk cohort.

Large artery structure and compliance is also adversely affected by ESRF and

long-‐term dialysis474-‐476, with improvement but persistence of increased arterial

stiffness following transplantation.477-‐480 The calcineurin inhibitors have been

implicated in the promotion of arterial stiffness following RTx, although the

process is clearly multi-‐factorial.481-‐484 Persistence of LVH and diastolic LV

impairment are also believed to play a significant role in the continuation of large

artery dysfunction, with disadvantageous CV sequelae.348 In this Study, we have

demonstrated persistence of aortic stiffness despite marked reductions in CO and

LVM following elective AVF-‐ligation. Such a finding may relate to the relatively

less modifiable nature of aortic structure, or perhaps an insufficient duration

between surgical AVF ligation and the follow-‐up evaluation. Interestingly

however, this Study further demonstrates a stepwise increase in aortic stiffness

from distal to proximal aorta. As discussed in the previous Chapter, such a finding

may relate to intrinsic differences in the elastin:collagen ratio in proximal vs.

distal aortic segments. Regardless, we propose that an increase in proximal aortic

stiffening may contribute significantly to LV afterload, and have a particularly

deleterious impact on coronary artery perfusion resulting from reduced proximal

aortic diastolic elastic recoil.394

Despite persistence of aortic stiffness in this RTx cohort, there was no statistically

significant difference in aortic distensibility between ESRF patients 6-‐months

160

following AVF-‐creation and the successful RTx recipients evaluated 6-‐months

following AVF-‐ligation. This is despite the post-‐RTx subjects being generally

younger than the ESRF subjects evaluated in Study 1 (54.6±12years vs.

59.2±12years, p=0.22). Such a finding would suggest that previously published

improvements in reported exercise capacity following RTx may stem more from

improvements in cardiac, rather than vascular, structure enabling improved

cardiac reserve despite persistently elevated ventricular afterload. Such an

hypothesis remains to be investigated.

We have demonstrated significant improvements in CV structure and function

following elective AVF-‐ligation, utilising recent advances in cardiac and vascular

imaging through CMR. CMR provides for substantially greater accuracy and

reproducibility in the detection of cardiac abnormalities as compared to

traditional TTE or nuclear technologies.525,536-‐539 In fact, TTE has less than 50% of

the precision of CMR in evaluation of LVM – a strong independent predictor of CV

events in ESRF and post-‐RTx patients.509,510 As such, studies utilising CMR require

a substantially reduced sample size to detect significant differences in CV

structure and function following therapeutic intervention. In this regard, our

Study is unique, in that we have been able to address alterations in CV structure

and function following AVF-‐ligation more accurately and comprehensively than

previously possible, with our results highlighting this capacity.

Limitations

This Study represented a Pilot examination of the potential for advantageous CV

remodelling in response to elective AVF ligation in the context of successful,

stable RTx. Although prospectively conducted and similar in design to previously

161

published work evaluating alterations in cardiac structure and function as

assessed by TTE440, the absence of a control group provides a notable limitation

to the generalizability of the Study results. Ideally, a control group consisting of

successful RTx recipients with persistently functioning AVF, matched for time

from AVF creation, time from RTx and baseline characteristics such as age and

gender would have served to optimise the Study design. Using this Pilot study for

power calculations, such a study is currently being undertaken at our centre.

Despite this, the cohort evaluated in the present Study represented patients with

long-‐standing successful RTx, with stable renal function and best-‐practice co-‐

morbidity management. Clinical stability was an overriding clinical imperative

prior to referral for AVF ligation, reducing the chance of RTx management or

renal function to contribute to the alterations seen.

Furthermore, it remains to be determined whether a larger sample size may have

enabled the detection of significant alterations in aortic distensibility, or whether

such changes require a longer follow-‐up interval, given the more structural

nature of this parameter. Given the recent recognition of the prognostic

significance of this measure, further work in this area is certainly warranted.

Conclusion

Cardiac structure and function is significantly improved by elective AVF-‐ligation

in the context of stable successful RTx. Furthermore, AVF-‐ligation was associated

with significant improvement in systemic endothelial function, as evaluated by

FMD. Aortic distensibility was unaltered by AVF-‐ligation in this Study. Thus

despite a >15% reduction in overall CO and a ~95% reduction in brachial artery

162

blood flow ipsilateral to the ligated AVF, disadvantageous alterations in vascular

structure may be more entrenched than derangements in vascular function or

disadvantageous cardiac remodelling. Efforts to minimise the duration of

maladaptive triggers to vascular dysfunction require further attention in the

prevention of potentially irreversible deleterious vascular remodelling in ESRF

and following successful RTx. We propose elective AVF ligation be considered in

all successful RTx recipients following a suitable period of clinical stability.

163

Study 3: Evaluation of the Diagnostic Accuracy of Dobutamine-

Stress Cardiac MRI in the Detection of Angiographically-

Significant Coronary Artery Disease prior to Renal

Transplantation

Introduction

RTx is associated with significant improvements in QOL, morbidity and mortality

for successful recipients.443-‐449 In comparison to ESRF patients accepted for

transplantation but remaining on the waiting list, cadaveric RTx has been shown

to more than triple the life-‐expectancy of ESRF patients on dialysis.445 A

substantial proportion of this benefit relates to a reduction in CV death. Despite

this, CVD remains a leading cause of death amongst RTx recipients450,451 and RTx

recipients experience an incidence of CV mortality that is many times that of the

age-‐matched controls from the general population.451,453 Thus RTx is associated

with substantial CV benefits, but a significant burden of CVD persists in this

vulnerable, high-‐risk patient cohort.

Current pre-‐RTx screening processes are somewhat heterogeneous, but are

relatively successful in identifying patients at lower risk of ischaemic CV events.

Despite this, RTx is associated with an early increase in all-‐cause and

cardiovascular mortality for recipients.443,485,486 Notably, the survival advantage

of RTx appears not to be apparent until beyond 250-‐days post-‐transplantation486,

making survival to this point a necessary pre-‐condition to RTx benefit.

Furthermore, according to a large Scandinavian study, between the second and

164

third years post-‐RTx, 41.4% of failed grafts are lost due to chronic rejection, but

42% are lost due to patient death with a functioning graft.450 A substantial

burden of this early mortality is due to CVD.468

To reduce peri-‐operative CV morbidity and mortality, or early graft loss due to

CVD, potential RTx recipients undergo rigorous screening processes. These pre-‐

RTx screening investigations must consider not only peri-‐operative risk, but

should also be designed to provide information regarding CV risk into the early

years post-‐RTx to ensure recipients are most likely to enjoy the mortality

advantages associated with the RTx process.487 Although there is widespread

support for CV evaluation prior to RTx485,488-‐492, there is no universally accepted

screening process and hence each RTx centre may have different routines

depending on local experience and expertise. Much of this debate also centres

around the appropriateness of coronary revascularisation in often asymptomatic

subjects in whom ‘significant’ coronary artery disease has been detected.

There is substantial debate regarding the necessity to perform ICA to exclude

significant CAD prior to RTx. Numerous studies have been published

demonstrating the advantages and limitations of non-‐invasive investigations in

the ESRF context.499,501,505,636 In particular, in ESRF it appears that vasodilator

stress is inferior to tachycardia-‐stress in the non-‐invasive detection of significant

CAD.513 Exercise-‐capacity is often limited in ESRF however, limiting the capacity

for exercise-‐based stress imaging to provide a universally applicable non-‐

invasive methodology for the exclusion of significant coronary artery disease.

Nuclear-‐based technologies have been widely utilised for this purpose, though

suffer from technical limitations and a not-‐insignificant radiation dose,

particularly for younger patients requiring recurrent studies. The incidence of

165

malignancy is known to be increased following RTx, hence it would appear

reasonable to avoid unnecessary medical radiation in the pre-‐RTx evaluation. As

a result, many authors have favoured stress echocardiography for the evaluation

of pre-‐RTx subjects.493,505,512,637 This technique, however, is highly dependent on

imaging adequacy and interpreter expertise, and is confined to a limited range of

imaging windows.

DS-‐CMR is a relatively more recent addition to the non-‐invasive imaging

pantheon, but provides a high level of diagnostic accuracy in studies evaluating

non-‐CKD patients at intermediate-‐high clinical risk.638,639 Following a standard

dobutamine-‐stress protocol (as for dobutamine-‐stress echocardiography), DS-‐

CMR provides superior image quality and unlimited imaging planes, without the

administration of exogenous contrast agents or ionising radiation. The diagnostic

accuracy of this methodology is yet to be determined in the ESRF / pre-‐RTx

context however. Hence, we sought to evaluate the diagnostic accuracy of DS-‐

CMR in comparison to ICA, and to compare these results to the current

institutional standard – myocardial perfusion scintigraphy.

166

Methods


In brief, Subjects were enrolled following referral for exclusion of significant CAD,

prior to listing for RTx for the treatment of advanced CKD / ESRF by the South

Australia RTx Team. Standard exclusion criteria were applied. All subjects

underwent DS-‐CMR as per validated protocol. Offline analysis was subsequently

performed to exclude inducible wall motion abnormalities indicative of regional

ischaemia. On a separate day, all subjects then underwent ICA to determine the

presence and severity of epicardial coronary stenoses. Offline analysis of

angiographic stenosis severity was determined by two experienced observers,

with clinical significance determined for coronary stenoses of ≥70% in luminal

diameter by visual estimation.

Comparison of DS-‐CMR and invasive coronary angiographic findings was

determined following independent reporting of each investigation by observers

blinded to the results of the alternative investigation.

Statistical Analysis

As previously described (Statistical Methods, p111)

167

Results

Twenty-‐two subjects were evaluated with DS-‐CMR prior to ICA, as per the clinical

protocol of the Royal Adelaide Hospital Renal Medicine Department and South

Australian Renal Transplant Unit (Age 56.1±8.5years, 68.2% male). Baseline

characteristics are detailed in Table 5. Twenty subjects (90.9%) also underwent

SPECT perfusion imaging, as a component of the standard current clinical work-‐

up for higher-‐risk pre-‐transplant candidates at our institution. All subjects were

asymptomatic with regards myocardial ischaemia.

Characteristic Proportion

(n=22)

Age (years) 56.1±8.5

Gender (male), % (n) 68 (15)




Smoking, % (n)

-‐ current

-‐ former

-‐ non-‐smoker

5 (1)

18 (4)

77 (17)


Peripheral Vascular Disease, % (n) 9 (2)


Receiving Dialysis, % (n) 95 (21)


168

The median time-‐period between DS-‐CMR and ICA was 13 days (IQR 8-‐31 days).

At DS-‐CMR, target HR was achieved in 19 subjects (86.4%), with one subject

reaching 93% of predicted target heart rate at a Dobutamine dose of

40mcg/kg/minute and supplemental Atropine (1.2mg). One subject’s DS-‐CMR

protocol was ceased prematurely due to the development of clinically significant

regional myocardial dysfunction, indicative of a large territory of inducible

myocardial ischaemia at sub-‐maximal dobutamine stress. One subject failed to

reach target HR at maximal dobutamine dose, with evidence of widespread, non-‐

viable myocardial infarction noted (deemed a positive study for CAD, hence

atropine not administered). There were no other haemodynamic or clinically

relevant complications related to Dobutamine-‐infusion in the subjects evaluated.

Mean LVEF was preserved overall (61±15%) with six subjects having LVEF

<55%. LVM was significantly increased within this cohort, indexed to body-‐

surface area (113g/m2; Reference range: 45-‐81g/m2 for men, 31-‐79g/m2 for

women).

The median time-‐period between SPECT and ICA was 108 days (IQR 49-‐231

days). This is substantially longer than that for the DS-‐CMR, as the SPECT imaging

was performed as a clinically-‐referred test, with subsequent referral for coronary

angiography proceeding after assessment of the results within the clinical

practice of the SA Renal Transplant and RAH Cardiology Units. Of the SPECT

studies, 11 (55%) utilised Dobutamine as the stressor, 7 (35%) utilised exercise

stress and two studies (10%) utilised dipyridamole – a vasodilator stress

previously associated with reduced diagnostic accuracy in the context of ESRF.513

Notably, one dipyridamole-‐SPECT study result was a true negative for ischaemia

and the other a false negative for ischaemia.

169

Diagnostic Accuracy:

At ICA, seven subjects (31.8%) had coronary artery stenoses of ≥70% severity

within the major epicardial coronary arteries. DS-‐CMR correctly identified the

presence of significant coronary artery disease in all seven subjects (Sensitivity =

100%; 95% CI 54-‐100%). Of the fifteen subjects without significant coronary

artery disease, DS-‐CMR was negative in 14 (Specificity = 93%, 95% CI 68-‐100%).

A single subject was deemed to have a positive DS-‐CMR study with no

haemodynamically significant coronary artery disease identified at ICA. Positive

predictive value (PPV) of DS-‐CMR was 88% (95% CI 47-‐100%) and negative

predictive value (NPV) was 100% (95% CI 77-‐100%). (Table 6)

SPECT imaging correctly identified the presence of significant coronary stenoses

in four of the seven subjects with stenoses ≥70% severity (Sensitivity = 57%,

95% CI 18-‐90%). SPECT falsely identified the presence of myocardial ischaemia

related to epicardial coronary artery disease in eight of thirteen subjects without

significant stenoses at ICA (Specificity = 38%, 95% CI 14-‐68%). PPV of SPECT in

this cohort was 33% (95% CI 10-‐65%) and NPV was 63% (95% CI 25-‐91%).

(Table 6)

170

DS-CMR SPECT

Sensitivity 100% 57%

Specificity 93% 38%

Positive Predictive Value 88% 33%

Negative Predictive Value 100% 63%

Accuracy 95% 42%

Likelihood Ratio 15.00 0.93

Table 6: Diagnostic performance of DS-CMR and Stress-Perfusion SPECT in the

detection of angiographically significant coronary stenoses.

Utilising an identity binomial generalised estimating equation, the diagnostic

performance of DS-‐CMR was significantly superior to SPECT imaging for the

detection of significant coronary stenoses ≥70% at ICA (p<0.0001).

Assessment of Left Ventricular Ejection Fraction

Assessment of cardiac structure and function was performed for all DS-‐CMR

studies. SPECT-‐based assessment was reported quantitatively for 18 of the 19

SPECT studies. No other structural or functional information was available from

the SPECT studies. In those subjects undergoing both studies, mean LVEF by CMR

was 60.6±15%, but mean LVEF by SPECT was only 50.2±13%. This represents a

statistically and clinically significant 10.4±4% mean underestimation by SPECT

compared to the internationally-‐recognised gold-‐standard assessment of LVEF by

CMR (p<0.001) (Figure 29).

171

Figure 29: Comparison of CMR-derived vs. SPECT-derived evaluation of LVEF.

172

Discussion

To our knowledge, the diagnostic performance of DS-‐CMR has not previously

been evaluated in the detection of significant coronary artery disease in ESRF

patients prior to RTx. In this pilot study, we have demonstrated a very high level

of diagnostic accuracy for this technique, with highly reassuring NPV and strong

PPV. Furthermore, DS-‐CMR clearly outperformed the institutional standard

(SPECT) on all fronts, with SPECT concerningly misdiagnosing three patients as

having no significant CAD despite stenoses ≥70% at ICA. The procedure was safe

and well tolerated by all subjects and CMR is additionally able to provide gold-‐

standard evaluation of left and right ventricular structure and function, LVM, as

well as measures of atrial volumes, valvular function and thoracic aorta

dimensions and compliance. Other than LVEF, SPECT is unable to reliably

evaluate any of these cardiac parameters, with SPECT-‐based evaluation of gated

LVEF proving systematically unreliable in this Study. Given the importance of this

measure in prognostic evaluation of ESRF patients, such a clinically significant

discrepancy is highly concerning, and illustrates the unreliability of SPECT

imaging in correctly excluding significant coronary artery disease or accurately

quantifying LVEF.

Death with a functioning transplant remains a leading cause of long-‐term graft

failure and CVD remains a leading cause of post-‐transplant mortality. As such, CV

evaluation prior to RTx remains an important component of determining

eligibility for RTx. Although resting abnormalities of LV structure and function

have been shown to regress following successful RTx, in the absence of

myocardial ischaemia640,641, the presence of myocardial ischaemia on myocardial

perfusion scintigraphy or stress echocardiography has been shown to be

173

associated with a markedly poorer prognosis.511,637,642 Previous authors have

suggested that all potential RTx recipients undergo ICA for the exclusion of

significant CAD, with some studies demonstrating ICA to provide superior

prognostic value over non-‐invasive investigations.500 The optimal form of pre-‐

RTx evaluation remains to be determined definitively however.

DS-‐CMR is a relatively new addition to the non-‐invasive armoury for the

exclusion of significant coronary artery disease in patients at intermediate-‐high

risk. Despite this, the technique has been evaluated in a variety of non-‐ESRF

cohorts, demonstrating a high level of diagnostic accuracy with sensitivity and

specificity generally ≥80-‐85% for each.638,639 This compares very favourably to

studies evaluating other non-‐invasive functional cardiac imaging tests. In the

context of this high level of diagnostic accuracy, DS-‐CMR has also recently

demonstrated strong prognostic value in predicting future CV events.540,541,643,644

Reassuringly, a negative DS-‐CMR has been shown to predict a low rate of cardiac

events in subsequent years with previous large studies in this field having

consistently demonstrated a cardiac event rate of ~1% per year in the 2-‐4 years

following a negative DS-‐CMR study.540,541,645 This is similar to the widely

published event rates for CV event-‐free survival following negative myocardial

perfusion imaging646 and stress echocardiography.647 Additionally, DS-‐CMR

benefits from a high spatial resolution and hence a low rate of inter-‐observer

variability with regards reporting of inducible ischaemia.648 Such attributes are

highly desirable in a non-‐invasive investigation, particularly in the screening

evaluation of a generally asymptomatic cohort at high risk of future CV events.

Although previously demonstrated to be of prognostic value in the pre-‐operative

assessment of patients undergoing non-‐cardiac surgery, but unsuitable for stress

174

echocardiography643, to our knowledge, DS-‐CMR has not previously been

assessed in the evaluation of ESRF patients prior to RTx. This population

provides unique challenges in the use of DS-‐CMR, potentially adversely

influencing diagnostic accuracy. Non-‐ischaemic resting wall motion abnormalities

related to uraemic cardiomyopathy have the potential to influence the detection

of myocardial ischaemia through the false attribution of inducible ischaemia to

such wall motion defects, or the concealment of true adjacent ischaemia.

Furthermore, the high prevalence of LVH in the ESRF cohort may influence the

prognostic value of DS-‐CMR, even in the presence of a negative scan.649,650 Despite

these limitations, all non-‐invasive imaging modalities suffer from limitations in

respect of their accuracy in various cohorts. More specifically, SPECT is known to

suffer from attenuation artefacts related to the diaphragm and body habitus and

stress echocardiography suffers from impaired image quality in the presence of

obesity, cachexia and obstructive pulmonary disease. Though CMR is able to

overcome most limitations related to body habitus, the detection of inducible

regional wall motion defects at very high heart rates provides some technical

challenges for CMR. The temporal resolution of CMR is generally lower than that

for echocardiography, and SSFP imaging generally requires 8-‐12 cardiac cycles to

generate a composite cine image. This may be problematic in the context of

irregular cardiac rhythms such as AF or frequent ventricular ectopy, causing the

endocardial margins on the composite cine to become indistinct. Such issues can

usually be overcome by converting to a prospectively-‐gated acquisition and

altering the triggering delay time to avoid incorporation of cardiac cycles with

shorter R-‐R intervals. During dobutamine-‐stress imaging, tachycardia is the

prime objective of the study protocol as a surrogate marker of the achievement of

175

peak pharmacological stress. The rate of cardiac contraction and relaxation

during peak tachycardia may be associated with loss of image quality due to

insufficient temporal resolution. Such an issue sometimes necessitates the

combination of standard ECG-‐triggered, retrospectively-‐gated SSFP imaging with

real-‐time, non-‐triggered True-‐FISP imaging – a sequence that provides a

marginally lower level of spatial resolution in favour of increased temporal

resolution during peak stress imaging. We have found the combination to be

advantageous in the clinical reporting of DS-‐CMR scans.

Despite its high-‐level of diagnostic accuracy, DS-‐CMR is not the most commonly

utilised stress-‐CMR modality at our institution or internationally. Adenosine-‐

stress perfusion CMR has received significantly greater attention for the

detection of significant CAD in at-‐risk individuals. This technology utilises a

gradient-‐echo sequence, imaging during first-‐pass myocardial perfusion

following intravenous administration of a gadolinium-‐based contrast agent. The

spatial resolution of this technique is marginally lower than that used for SSFP

wall-‐motion imaging (~2.3-‐2.8mm in-‐plane resolution for perfusion imaging

sequences vs. 1.8-‐2.0mm in-‐plane resolution for SSFP), however this level of

resolution allows for the assessment of 5-‐8 radial myocardial image pixels in the

presence of normal myocardial thickness. This compares to 1-‐2 pixels for

conventional SPECT imaging. Thus, the detection of sub-‐endocardial myocardial

ischaemia during vasodilator stress is greatly enhanced over standard nuclear

imaging techniques.651-‐654 Furthermore, the gadolinium-‐based contrast agent

used is biologically inert in its chelate form, excreted efficiently via renal

clearance within 24-‐48 hours in the presence of preserved renal function and is

176

not associated with the not-‐insignificant burden of iatrogenic ionising radiation

associated with SPECT imaging.

Adenosine-‐stress perfusion CMR additionally provides the capacity to evaluate

the myocardium for evidence of fibrosis indicative of prior myocardial infarction

or non-‐ischaemic fibrotic replacement.655-‐657 At our institution, a conventional

adenosine-‐stress cardiac perfusion scan with standard evaluation of cardiac

structure and function, stress and rest perfusion imaging and delayed contrast-‐

enhancement imaging is generally completed within 40-‐45minutes of scan

commencement. Thus, a wealth of information was available from a relatively

short scan time, elegantly combining many of the technically superior aspects of

CMR imaging into a single study. Unfortunately, however, the administration of

gadolinium-‐based contrast agents in the presence of CKD has been associated

with the development of a potentially fatal condition termed Nephrogenic

Systemic Fibrosis (NSF). Such a condition is believed to develop following the

dissociation of gadolinium from its chelate in the presence of reduced/absent

renal excretion and hence more prolonged circulation time. As such, the

disassociated gadolinium may deposit in the dermis and solid organs such as the

liver, causing an inflammatory reaction that may lead to local cell death and

fibrosis.658 As such, regulatory agencies have advised against the use of

gadolinium-‐based contrast agents in the absence of extreme clinical need, largely

preventing the use of this imaging technique in patients with ESRF, particularly

within the confines of a research study. CMR clinicians therefore continue to

await a safe, approved contrast agent capable of providing comparable diagnostic

accuracy without the associated risk of gadolinium-‐based chelates in individuals

177

with CKD. The capacity for higher Tesla MRI scanners to detect alterations in

regional myocardial oxygen consumption also offers future promise.

Despite these issues, a recent head-‐to-‐head study evaluating the diagnostic

performance of adenosine-‐stress perfusion and dobutamine-‐stress CMR in a non-‐

ESRF population demonstrated almost identical results on a per patient and per

segment basis.659 Previous studies have suggested a marginal advantage for DS-‐

CMR in terms of specificity however, when compared to anatomical assessment

of coronary patency at ICA, leading to the recommendation of DS-‐CMR as the

“method of choice for current state-‐of-‐the-‐art treatment regimens to detect

ischemia in patients with suspected or known coronary artery disease but no

history of prior myocardial infarction”.539 In this regard, although small, our

Study has demonstrated that DS-‐CMR is highly accurate in the detection of

angiographically significant coronary artery disease in ESRF, despite a high

prevalence of LVH and conventional CV risk factors in the Study cohort at

baseline.

DS-‐CMR has previously been demonstrated to be a safe Study for the detection of

CAD.660 During our Study, there were no clinically-‐significant arrhythmias or

haemodynamic complications. A single subject experienced a significant

reduction in blood pressure during dobutamine stress, related to the

development of a large burden of segmental myocardial dysfunction due to

inducible myocardial ischaemia, and the test was promptly terminated. Such a

result represents a strongly positive study (confirmed at ICA) rather than an

adverse outcome per se, with no other clinical sequelae noted during prolonged

post-‐scan monitoring. Previous studies of dobutamine stress echocardiography

have demonstrated a high level of safety with this technique, though serious

178

complications may occur.661-‐663 This risk profile does not appear exaggerated in

ESRF and although small, this Study confirms the safety of Dobutamine stress

imaging in ESRF prior to RTx.

At ICA, we prospectively determined coronary stenosis severity ≥70% to be

haemodynamically significant. This cut-‐off was determined based on usual

clinical practices, both at our institution and more generally amongst the

international cardiology community. Such a cut-‐off is routinely used in

determining, angiographically, suitability for coronary revascularisation in the

absence of alternative justifications (e.g. classical exertional symptoms in the

presence of convincing non-‐invasive evidence of inducible ischaemia in the

territory supplied by a 50-‐69% stenosis). All anatomical cut-‐offs for

haemodynamic significance are based on the false presumption of the infallibility

of ICA, and the neglect of the numerous other lesion characteristics important in

the induction of downstream myocardial ischaemia. The Fractional Flow Reserve

versus Angiography for Multivessel Evaluation (FAME) Study recently

demonstrated the superiority of functional over purely anatomical evaluation of

coronary ischaemia in improving outcomes in patients with significant

multivessel CAD.531 Furthermore, the evaluation of fractional flow reserve (FFR)

revealed striking findings regarding the diagnostic accuracy of ICA in determining

lesion significance. In this landmark study, 80% of lesions of 70-‐89% stenotic

severity were haemodynamically significant as determined by FFR, and 96% of

lesions ≥90% stenosis. Of stenoses 50-‐69% severity, 35% were deemed

functionally significant, despite conventional practices deeming such lesions

angiographically “moderate” rather than “severe”, and generally undeserving of

coronary revascularisation.532 Thus, although a cut-‐off of 70% stenosis provides a

179

high level of diagnostic accuracy, comparison of a functional study (such as DS-‐

CMR) evaluating the development of stress-‐induced regional ischaemia with an

anatomical but ultimately imperfect “gold-‐standard” such as ICA, may result in

anatomical “false positive” and/or “false negative” results that may, in fact, be

correctly identifying the presence/absence of myocardial ischaemia in the

context of a wide range of non-‐critical epicardial coronary lesions. Arguably, the

FAME study provides the strongest available evidence for the angiographic

determination of the functional significance of coronary stenotic severity and the

prognostic relevance of revascularisation in the presence of multivessel coronary

disease. Furthermore, although inferior to FFR, this study utilised subjective

evaluation of coronary stenosis severity, rather than QCA to determine lesion

severity (in keeping with universal clinical practice), we elected to utilise a

visually-‐determined cut-‐off of 70% stenosis for our Study. No such data exists

comparing QCA favourably to gold-‐standard coronary FFR to refute such an

approach.

As an aside, adenosine-‐stress perfusion CMR has been validated against invasive

FFR in a number of studies, with sensitivity and specificity approaching or

exceeding 90% in most studies – values that are generally superior to that

reported for diagnostic accuracy based on anatomical coronary stenotic severity

alone.664-‐668 SPECT, however, has demonstrated poor concordance with invasive

FFR determination of myocardial ischaemia due to epicardial coronary disease.533

At this stage, DS-‐CMR has not been evaluated against the invasive gold-‐standard,

though this work is proceeding currently.

It is important to note also, that there may be a significant difference between the

determination of haemodynamic significance of single or multiple coronary

180

stenoses, and the clinical significance the presence of even mild-‐moderate

epicardial coronary atherosclerotic disease may signify. In this regard, the 2-‐year

FAME study follow-‐up demonstrated a risk of myocardial infarction of only 0.2%

for lesions where revascularisation was deferred based on an FFR>0.80

(haemodynamically non-‐significant).534 Furthermore, such deferred lesions were

associated with disease progression necessitating revascularisation in 3.2% at 2-‐

years. Whether such results may be applied to the dissimilar pathobiology of

coronary atherosclerosis in the ESRF and post-‐RTX cohorts remains to be

determined however.

Limitations

Our Study suffers from a relatively small sample size, potentially leading to over-‐

estimation of the diagnostic accuracy of DS-‐CMR. Alternative manuscripts

evaluating stress-‐echocardiography and stress-‐SPECT in similar patient cohorts

were based on the evaluation of 40-‐50 subjects each, necessitating (as planned)

continued recruitment prior to publication.505,513,669 Despite this, the current

study provides the first opportunity to assess the utility of DS-‐CMR in this high-‐

risk patient subset, with results demonstrating a high level of accuracy and no

safety concerns. The results for the institutional standard (SPECT) are highly

disappointing, regardless of the Study sample size, and raise significant concerns

regarding the appropriateness of continued use of this modality at our institution.

A further limitation of our Study is the absence of an invasive functional gold-‐

standard such as FFR to compare the results of the non-‐invasive functional study.

As highlighted, the comparison of anatomical coronary stenotic severity with the

181

results of a functional study evaluating the development of myocardial ischaemia

in response to dobutamine stress may be compromised by the imperfect nature

of ICA lesion characterisation. Studies evaluating DS-‐CMR against per-‐vessel FFR

are ongoing.

Ideally, to allow for optimal comparison of the stress methodologies studied, all

subjects would have undergone both DS-‐CMR and SPECT prior to ICA. In our

Study, two subjects did not undergo SPECT imaging, but were referred directly to

ICA as a component of the clinical pathway, due to the perception of very-‐high

pre-‐test risk. Interestingly, neither of these subjects had ischaemia detected at

DS-‐CMR, nor significant CAD detected at ICA. It is uncertain whether performance

of SPECT in these subjects would have led to an improved measure of specificity

for SPECT, in light of the poor specificity demonstrated in the subjects evaluated.

Although relatively small, DS-‐CMR demonstrated an unequivocal statistical and

clinical superiority in the subjects evaluated in this Study, though further

research is required to ensure our initial results remain robust in a larger, less

highly selected ESRF patient cohort.

Conclusion

In this pilot study, we have demonstrated a high level of diagnostic accuracy for

DS-‐CMR in the detection of angiographically significant CAD in ESRF subjects

undergoing CV risk assessment prior to RTx. Furthermore, DS-‐CMR significantly

out-‐performed the institutional standard – SPECT myocardial perfusion imaging.

In this high-‐risk cohort, DS-‐CMR was safe, highly accurate and provided a wealth

of prognostically significant structural and functional cardiac data to the referring

182

clinician. Although further work in this area is necessary, we propose DS-‐CMR as

a new standard of care in ESRF patients undergoing evaluation prior to RTx.

183

Study 4: Evaluation of Dynamic Coronary Endothelial Function in

End-Stage Renal Failure

Introduction

CVD is a leading cause of morbidity and mortality in ESRF and following

successful RTx. A significant component of this burden relates to the end-‐organ

injury resulting from impaired oxygen delivery due to atherosclerotic stenotic

disease in subtending vessels. Atherosclerosis represents a final common

pathway resulting from myriad causes of endothelial injury and subsequent

endothelial dysfunction. Systemic endothelial dysfunction is highly prevalent in

the presence of CKD, with numerous studies demonstrating a strong link between

systemic endothelial dysfunction and future CV events. In fact, a substantial body

of literature has focused on the evaluation of systemic endothelial function in

ESRF, with numerous methodologies claiming superiority in predicting future

coronary and cerebrovascular events. Remarkably, little (if any) work has

focused on the evaluation of coronary endothelial function in this condition

however.

Coronary endothelial dysfunction has previously been associated with a

significantly increased burden of future cardiac events.262,670 Research evaluating

the link between coronary and peripheral endothelial function has revealed

varying results however, suggesting that coronary endothelial function may not

be directly predicted by evaluating peripheral artery function.270,671-‐674 We sought

to invasively evaluate coronary endothelial function in the presence of advanced

CKD in subjects undergoing clinically-‐indicated ICA prior to potential RTx.

184

Furthermore, we sought to compare indices of coronary macrovascular and

microvascular function in RTx candidates with values for coronary vascular

function for subjects with normal renal function and minimal CAD.

185

Methods


In brief, CKD subjects were enrolled following referral for ICA prior to listing for

RTx for the treatment of advanced CKD / ESRF by the South Australia RTx Team.

Non-‐CKD subjects were enrolled from patients with eGFR>60mL/min/1.73m2

undergoing clinically-‐driven ICA for exclusion of significant CAD. Subjects from

both cohorts were excluded if significant CAD was identified within the epicardial

coronary arteries at ICA. Standard exclusion criteria for the performance of

coronary endothelial function assessment were applied.

At ICA, if coronary anatomy was suitable, coronary endothelial function was

evaluated utilizing a 0.014-‐inch coronary Doppler Flo-‐wire (Volcano

Therapeutics, CA, USA) advanced into the Study vessel via an infusion catheter.

Following achievement of stable Doppler Flow velocity signals, resting coronary

flow velocities were determined, with determination of epicardial coronary

diameter by standardized quantitative angiography with offline analysis.

Coronary endothelial function was then evaluated by validated protocol602,603,

consisting of the following interventions:


-‐ Acetylcholine (3-‐minute infusions of Ach 10-‐7M [1.6mcg/min], then 10-‐6M

[16mcg/min)


-‐ bolus dose of GTN (50mcg)

-‐ bolus dose of Adenosine (48mcg)

186

At the completion of each infusion, a coronary angiogram was performed using

9mL of non-‐ionic contrast (Omnipaque, GE Healthcare, Waukesha, USA) injected

through a Medrad infusion pump at 5mL/s, with images saved for offline analysis.

Doppler indices, haemodynamic data (systemic blood pressure and heart rate)

and ECG rhythm strip were recorded continuously throughout the study for off-‐

line analysis.

Quantitative Coronary Angiography

Following acquisition of standardised coronary angiography during the Study

protocol, offline analysis was performed using proprietary edge-‐detection

software (QCA-‐CMSTM, Medis Medical Imaging Systems, Leiden, Netherlands).

Mean coronary diameter was assessed 5mm distal to the tip of the Doppler

guidewire over a 5mm segment.

Coronary Blood Flow

Coronary velocity measurements were analysed by a technician blinded to the

results of the QCA analysis. Coronary blood flow (CBF) was then calculated by

validated formula.275


Coronary flow velocity reserve (CFR) was then determined as a ratio of:

APV (post-‐adenosine) / APV (baseline)




adenosine.275

187

Statistical Analysis

As previously described (Statistical Methods, p111)

Power Calculation

The outlined Study was a Pilot Study performed to evaluate the scope of coronary

endothelial dysfunction in the presence of advanced CKD, as compared to a non-‐

CKD cohort. As such, a formal Power calculation was not performed.

188

Results

Following determination of coronary artery suitability at ICA, coronary

endothelial function was invasively evaluated in eight (8) pre-‐RTx subjects and

thirteen (13) non-‐CKD subjects. Baseline characteristics are described in Table 7.

Characteristic CKD

(n=8)

Controls

(n=13)

p

Age (years) 52.5±10 53.9±14 0.72

Gender (male) 63% 62% p=0.69

Hypertension 100% 45% p=0.006

Hyperlipidaemia 63% 36% p=0.17

Type II Diabetes Mellitus 63% 18% p=0.04

Smoking

-‐ current

-‐ former

-‐ non-‐smoker

13%

25%

62%

18%

22%

60%

p=0.86

Prior Coronary Artery Disease 13% 54% p=0.07

Receiving Dialysis 88% 0% p<0.0001

Baseline Creatinine (μmol/L) 709±140 68±21 p=0.0002

Baseline Haemoglobin (g/dL) 108±10 138±13 p=0.0004

Medications

-‐ Aspirin

-‐ Statin

-‐ Beta-‐blocker

-‐ ACEI / ARB

-‐ Diuretic

-‐ Calcium Channel Blocker

-‐ Insulin

25%

63%

75%

88%

0%

63%

13%

45%

36%

36%

27%

18%

18%

9%

p=0.87

p=0.17

p=0.06

p=0.006

p=0.37

p=0.04

p=0.50


ACEI = Angiotensin Converting Enzyme Inhibitor; ARB = Angiotensin Receptor Blocker

189

There was no difference in the mean age of the subjects within the two cohorts

(52.5±10 vs. 53.9±14, p=0.72). All subjects had only minor coronary artery

disease within the study vessel (≤20% epicardial coronary stenoses)[LAD=100%]

and subjects with diffuse atherosclerosis were specifically excluded. Constant

haemodynamic monitoring was performed throughout the Study. Baseline SBP,

DBP and HR were not statistically dissimilar between the cohorts (SBP:

142±24mmHg vs. 125±24mmHg, p=0.13; DBP: 82±14mmHg vs. 80±10mmHg,

p=0.76; HR: 79±23bpm vs. 67±14bpm, p=0.26). There was no statistically

significant alteration in HR or blood pressure detected during endothelial

function assessment within the cohorts.

Endothelium-Dependent Coronary Function

There was no difference between the CKD and normal cohorts with respect to the

maximum change in CBF following Ach 10-‐6M administration (81.0±68% vs.

89.8±71%, p=0.79). Notably, study vessel diameter at the site of assessment was

greater in the non-‐CKD cohort at baseline (2.7±0.5mm vs. 3.6±1.0mm, p=0.02),

with this difference persisting during high-‐dose Ach infusion (2.8±0.7mm vs.

3.6±1.0mm, p=0.048). Despite this, there was no statistically significant

difference in either baseline (48.4±20mL/min vs. 64.7±23mL/min, p=0.12), or

peak (88.2±46mL/min vs. 113.8±35mL/min, p=0.17) CBF between the cohorts,

although the CKD cohorts CBF was numerically lower at both time-‐points (in the

presence of significantly smaller Study vessels). Change in CBF following Ach was

also not significantly different between the cohorts (81.0±68% vs. 89.8±71%,

p=0.97). There was no significant difference between the cohorts in the change in

vessel diameter in response to high-‐dose Ach (2.2±10.3% vs. 1.2±5.7%, p=0.80).

190

No subject in either cohort had a significant epicardial coronary constriction

response to Ach 10-‐6M (defined as a >50% reduction in cross-‐sectional area as

derived from QCA).276

Endothelium-Independent Macrovascular Coronary Function

There was no statistically significant difference between the CKD and non-‐CKD

cohorts with respect to endothelium-‐independent conduit vessel vasodilatation

in response to intracoronary GTN (Vessel QCA: 10.9±12% vs. 9.7±21%, p=0.73).

Endothelium-Independent Microvascular Function

There was a highly significant difference in microvascular function between the

CKD and non-‐CKD cohorts, as measured by CFR. CFR was significantly reduced in

the CKD cohort, but preserved in the non-‐CKD cohort (1.9±0.4 vs. 3.0±1.1,

p=0.01). Despite the potentially greater prevalence of anaemia and LVH in the

CKD cohort, there was no significant difference in baseline APV between the

cohorts (27.0±5.4cm/s vs. 24.1±11.5cm/s, p=0.44) to explain the differences in

CFR, as has been proposed by other authors.277

191

Discussion

We have found a significant difference in coronary flow reserve (CFR) following

adenosine administration between subjects with advanced CKD and those with

preserved renal function, in the presence of only minor epicardial coronary

disease at ICA. This finding is striking, in that adenosine is an endothelium-‐

independent vasodilator675, acting directly via activation of the A2 receptors on

vascular smooth muscle of resistance vessels ≤100μm in diameter.676

Preservation of microvascular function has previously been defined as a CFR>2.5

in response to adenosine administration.276 The results of our Study demonstrate

impaired augmentation of coronary microvascular dilatation in response to a

potent microvascular dilatory stimulus in the CKD cohort, strongly implicating

coronary microvascular dysfunction in the presence of CKD.

Previous studies in this area have demonstrated conflicting results. In 2004,

Ragosta et al published a Study evaluating invasive CFR amongst subjects with

TIIDM evaluating differences in the presence and absence of associated ESRF. In

their Study, the presence of advanced CKD was associated with a reduction in

CFR, predominantly mediated via an increase in basal coronary average peak

velocity (APV), rather than a failure of APV augmentation in response to

intravenous adenosine.277 The authors hypothesised this impairment in CFR in

CKD to potentially result from the greater prevalence of LVH in that cohort and

the possible presence of otherwise unidentified circulating vasodilatory humoral

factors specific to renal failure directly mediating the elevated baseline APV.

Furthermore, they refute the potential contribution of anaemia to the elevated

baseline APV in their CKD cohort due to the absence of statistically significant

192

difference in haematocrit between subjects with normal vs. abnormal CFR. Of

course, the absence of a statistically significant difference in this sub-‐analysis may

simply reflect Type II statistical error, rather than the true absence of an

association.

This finding of elevated basal CBF has recently been affirmed non-‐invasively

utilising PET.278 Published in Circulation in 2009, the Study by Koivuviita et al

evaluated basal and hyperaemic (post-‐dipyridamole) myocardial perfusion in

twenty-‐two patients with moderate to severe CKD (divided into three cohorts

according to eGFR), and compared these results to ten healthy control subjects

with preserved renal function. Although this Study found preserved CFR amongst

the CKD patients (as distinct from the previously discussed invasive study and

our own results), basal myocardial blood flow was significantly elevated amongst

the CKD patients vs. the non-‐CKD controls (p<0.001), with a negative correlation

between eGFR and myocardial blood flow seen (Spearman correlation

coefficient=0.63, p=0.0001).278 An ultrasound-‐based FMD protocol was also

undertaken in this Study, with FMD (% change in brachial artery diameter)

significantly reduced amongst the CKD cohorts compared to controls (p<0.03).

The authors conclude that “coronary and peripheral vascular function are

disturbed by different mechanisms in patients with CKD”, although direct

comparison of the two methodologies utilised in this Study is questionable. The

evaluation of large-‐vessel endothelial-‐dependent function in the brachial artery is

distinct from the evaluation of coronary endothelium-‐independent,

microvascular function evaluated by the administration of intravenous

dipyridamole in this study. Although previous studies have demonstrated a link

between peripheral microvascular function (as assessed by ‘gold-‐standard’

193

venous occlusion plethysmography) and peripheral arterial FMD responses280,

the two are not equivalent and comparison of coronary microvascular responses

to dipyridamole with FMD as a surrogate marker of peripheral microvascular

function is somewhat disingenuous.281

A further Study by Chade et al published in 2006 evaluated invasive CFR amongst

124 patients with milder renal dysfunction (GFR<60mL/min/1.73m2), compared

to 482 control subjects with preserved renal function (GFR>60mL/min/1.73m2),

finding reduced GFR to be predictive of impaired CFR by univariate, but not

multivariate, analysis.282 Although the mean CFR was reduced in subjects with

mildly impaired renal function (compared to controls), only increasing age,

female gender, rising BMI and co-‐existent hypertension were significantly

associated with impairment of CFR by multivariate analysis.282 No comment was

made on differences in basal APV values between the two cohorts in this Study.

In our Study, the baseline APV was not significantly different between the cohorts

and coronary angiography failed to demonstrate the presence of diffuse

atherosclerosis as a contributor to a falsely impaired CFR. The difference

between cohorts derived almost entirely from the failure of vasodilatory

augmentation of coronary flow velocity, strongly implicating microvascular

dysfunction as the primary aetiology. This finding is significant, as no previous

Study has demonstrated such a finding in ESRF, although the phenomenon has

been strongly suspected by clinicians. Importantly, the demonstration of

microvascular dysfunction in advanced CKD provides a sound biological basis for

published work demonstrating angina to occur in the absence of obstructive

epicardial coronary disease in up to 50% of ESRF patients undergoing ICA.456-‐458

In this regard, a recent publication by Sicari et al in a non-‐CKD cohort

194

demonstrated a significant prognostic disadvantage for patients presenting with

chest pain, but in whom ICA revealed normal or near-‐normal coronary arteries.

In this Study, patients with a CFR<3.0 (as assessed by echocardiography) had a

markedly lower infarct-‐free survival out to 4-‐years follow-‐up (55% vs. 96%,

p<0.0001). In our Study, the finding of reduced CFR may be impacted by the

presence of factors such as anaemia and supply-‐demand mismatch in the context

of LVH487, the presence of microvascular disease must certainly be considered a

significant component of the milieu in CKD, and may contribute to the adverse CV

outcomes seen in CKD patients.

The documentation of impaired CFR in CKD is particularly significant in

considering the non-‐invasive evaluation of possible myocardial ischaemia

affecting CKD and ESRF patients in clinical practice. Vasodilator stress imaging

(particularly SPECT-‐based imaging) provides a cornerstone for the non-‐invasive

evaluation of possible myocardial ischaemia in most developed nations. Whether

in the evaluation of CV risk prior to possible RTx, or in the assessment of

clinically suggestive symptoms in CKD/ESRF patients, vasodilator stress imaging

predominantly depends upon the demonstration of differential regional blood

flow induced by maximal hyperaemia following vasodilator (e.g. adenosine)

administration. Myocardial territories subtended by epicardial coronary vessels

with haemodynamically significant stenoses already have maximal or near-‐

maximal microvascular vasodilatation as a component of the intrinsic auto-‐

regulatory mechanisms within the coronary microcirculation.677 Thus, at rest, in

the absence of active ischaemia, microvascular auto-‐regulation maintains

sufficient (relatively homogenous) blood flow to the myocardium, even within

territories supplied by epicardial coronary stenoses. During vasodilator

195

administration, the microvasculature subtended by normal or minimally diseased

epicardial arteries undergoes substantial vasodilatation leading to a 3-‐5-‐fold

increase in regional blood flow. Due to the near-‐maximal microvascular dilatation

at rest in stenosed territories, further microvascular dilatation may not be

possible, leading to the development of a relative hypoperfusion of the

“ischaemic” territory. In the presence of global coronary microvascular

dysfunction, as may be seen in CKD/ESRF, the augmentation of blood flow into

“non-‐ischaemic” territories appears to be blunted, potentially reducing the

capacity for relative hyper-‐perfusion to these myocardial segments. Thus, the

capacity to detect perfusion inhomogeneity during vasodilator administration in

the presence of significant epicardial coronary disease is impaired, potentially

reducing the sensitivity of the non-‐invasive imaging study.678 Furthermore, the

capacity of the CKD/ESRF microvasculature subtended by stenosed coronary

arteries to maximally vasodilate may also be blunted, potentially leading to

myocardial ischaemia in the presence of less severe epicardial disease.

This theory concurs with the available body of literature evaluating vasodilator

stress imaging against ICA in ESRF.669,679 Marwick et al reported an exceedingly

low sensitivity for dipyridamole SPECT in their prospective Study – 29% for the

detection of coronary stenoses ≥70% at ICA.669 Although numerically superior to

that published by Marwick et al, the results from Vandenberg’s retrospective

Study in Transplantation revealed a sensitivity of only 62% -‐ a result that fails to

inspire confidence in the technique for the accurate exclusion of significant CAD

in this high-‐risk condition.679 Boudreau et al published more reassuring results in

1990680, however concerns remain regarding the use of this technique in clinical

practice. In light of the biological theory regarding the prevalence of

196

microvascular dysfunction in CKD, previous authors have proposed tachycardia

stress as a more appropriate stress-‐modality in this condition, whether utilising

echocardiographic or SPECT imaging.505,513 Published results for tachycardia

stress in this condition appear to provide a greater level of diagnostic accuracy,

though head-‐to-‐head studies are lacking.513 The inherent limitations of the

imaging technology may also play a significant role in determining diagnostic

accuracy, as demonstrated by the poor results achieved for tachycardia-‐stress

SPECT reported in the previous Chapter of this Thesis.

Endothelium-dependent Coronary Function

Perhaps surprisingly, our Study failed to demonstrate a significant difference in

endothelium-‐dependent epicardial coronary vasodilatation between the cohorts

in response to intra-‐coronary Ach infusion. While the standard deviations around

the cohort means were wide, the numerical difference between the cohorts was

small, suggesting the absence of a clinically significant difference that was simply

underestimated due to the small sample sizes. Both cohorts demonstrated a

>50% increase in CBF in response to Ach, indicating preservation of

endothelium-‐dependent coronary vascular function, even in the presence of

advanced CKD in this Study.276 Despite this, it is also notable that the non-‐CKD

cohort failed to demonstrate a significant increase in epicardial coronary

diameter in response to the endothelium-‐dependent vasodilator Ach and the

resultant increase in CBF detected. One subject in the non-‐CKD cohort and two

subjects in the CKD cohort demonstrated a >5% reduction in vessel diameter in

response to Ach 10-‐6M, however there was no other evidence of significant

endothelial dysfunction detected during Ach administration.

197

Such findings run counter to the commonly held belief that CKD must be

associated with significant epicardial coronary endothelial dysfunction, as an

extension of the numerous studies demonstrating impairment of endothelial

function in the peripheral circulation. The absence of significant endothelial

dysfunction in this pre-‐RTx cohort is also notable as the increased burden of

peripheral endothelial dysfunction has commonly been used to infer a similar

pattern of dysfunction in the coronary beds, predisposing to the accelerated

coronary atherosclerosis commonly encountered in this condition. The

explanation for our findings may lay in the highly selective nature of the

population studied, rather than truly reflecting the absence of coronary

endothelial dysfunction as a component of CVD in ESRF and/or a small sample

size. In this regard, the CKD subjects studied represented a group, albeit with

coronary risk factors, at lower risk than standard dialysis patients who are not

considered ‘potential’ renal transplant candidates. ESRF patients on dialysis who

are not being considered for RTx generally represent the CKD cohort at greatest

risk of CV morbidity and mortality.451 Mortality for this group is exceedingly high,

relating often to the presence of prior CVD and/or advanced age. Such patients

were not considered for this Study, and the study population was further sub-‐

selected by excluding pre-‐RTx patients with anything more than minor

angiographically apparent coronary disease. It might therefore be hypothesised

that the subjects enrolled and evaluated in this Study were specifically enrolled

on the basis of an absence of indirect markers of coronary endothelial

dysfunction, by virtue of the absence of significant resultant end-‐organ vascular

disease. Whether such coronary endothelial findings are truly representative of

the wider ESRF population remains to be determined.

198

Endothelium-Independent Macrovascular Coronary Function

There was no significant difference between the cohorts in vessel diameter by

QCA following administration of intracoronary GTN in this Study. Such a finding

confirms the presence of intact epicardial endothelium-‐independent

vasodilatation in the two cohorts, consistent with the absence of fixed epicardial

coronary disease preventing vascular smooth muscle dilatation in response to

GTN. Although ESRF may be associated with a significant burden of both intimal

and medial vascular calcification, the CKD cohort in this Study was specifically

selected based on the absence of significant angiographically-‐apparent coronary

disease. Hence, given the less severely diseased ESRF cohort studied, it is not

surprising that the response to GTN was similar between the cohorts.

Limitations

There are a number of important limitations of the current Study. The sample

size of the two cohorts was small, potentially affecting our statistical power in the

detection of a significant difference between the groups studied for endothelium-‐

dependent function. In this regard, the Study was powered to detect a statistically

significant difference with 80% power for an effect size (d) of 1.22. The effect size

of the current study was only 0.14, potentially necessitating a substantially

greater sample size to detect any statistically significant difference. Despite this,

our Study failed to demonstrate a numerical trend towards endothelial

dysfunction (%change in CBF <50%) in the CKD cohort as would indicate the

presence of a clinically significant difference in coronary endothelial function

between the CKD and non-‐CKD cohorts.

199

Subjects were specifically selected based on the absence of angiographically

significant coronary atherosclerosis within the epicardial coronary vessels,

however in the absence of IVUS, diffuse epicardial atherosclerosis cannot be

entirely excluded. Moreover the presence of diffuse microvascular

atherosclerosis was unable to be excluded by the Study protocol. The presence of

such disease could certainly have led to diminution of both basal and peak APV in

response to adenosine, resulting in the findings described. Every effort was made

to exclude this potential confounder, and all of the CKD subjects studied were

asymptomatic with regards clinical features of haemodynamically significant

CAD. Furthermore, each of the CKD subjects studied had participated in the

previously reported Study of DS-‐CMR, with all those included in this Study having

no inducible ischaemia detected using this highly sensitive and accurate modality.

With regards the accuracy of our results, microvascular function was assessed in

this Study utilising CFR as assessed by the Volcano Flow-‐wire system (Volcano

Therapeutics, CA, USA). It is recognised that CFR may be influenced by the

concurrent haemodynamic state, with elevation of HR and increased contractile

state potentially influencing CFR measurements.681 More recently, the index of

microvascular resistance (IMR) has been proposed as a more specific and

reproducible measure of microvascular function.681-‐685 IMR is derived by

determination of the distal coronary pressure (derived from the pressure wire)

divided by coronary blood flow during maximal hyperaemia. CBF in this instance

is derived by a thermodilution method for evaluating coronary transit time

utilising a thermistor at the distal end of an alternative commercially available

pressure wire system. Importantly, IMR has been demonstrated to be less

affected by epicardial coronary stenosis or haemodynamic state of the patient.681

200

In this regard, IMR may provide a more specific evaluation of microvascular

function than CFR, although to date the Doppler flo-‐wire derived CBF assessment

remains the ‘gold-‐standard’ and most widely published invasive evaluation of

coronary blood flow.

Selection bias may have played a role in the results of this Study, in light of the

markedly different indications for ICA between the two cohorts. Although the

CKD cohort was evaluated to exclude asymptomatic CAD prior to RTx, the non-‐

CKD cohort were referred for ICA following suggestive symptoms or

demonstration of myocardial ischaemia by non-‐invasive evaluation. Previous

studies have demonstrated reduced endothelial function in patents presenting

with chest-‐pain syndromes, even in the absence of significant epicardial coronary

disease at ICA. Despite such differences in clinical indication for ICA, the CFR of

the non-‐CKD cohort was within the normal range, largely excluding diffuse

microvascular disease as a consistent finding in this cohort.

Finally, we administered adenosine via an intracoronary route, in line with

recommended protocols for invasive assessment of coronary vascular function.254

It remains to be determined whether 48mcg of adenosine is sub-‐maximal in the

context of advanced CKD, but regardless, such findings indicate the presence of

objective microvascular dysfunction. Moreover, whether alternative findings

would have been obtained with intravenous adenosine administration, or the use

of other vasodilatory agents (e.g. substance P), remains to be determined.

201

Conclusion

In this Study, we have documented the presence of significant coronary

microvascular dysfunction in the presence of advanced CKD, as compared to

subjects with minimal coronary artery disease and preserved renal function. This

finding related to the blunting of microvascular dilatation in response to intra-‐

coronary adenosine, rather than elevation of basal APV as had previously been

reported. We found no significant difference in endothelium-‐dependent or –

independent epicardial coronary function in response to Ach and GTN

respectively. Although surprising, such a finding occurred in the context of a

highly selected CKD population, with minimal epicardial coronary

atherosclerosis. Our findings are particularly significant in regards the potential

implications for the investigation and management of CKD patients where

microvascular dilatation in expected following administration of adenosine

analogues. Vasodilator-‐stress SPECT may be particularly inappropriate for the

exclusion of significant CAD in this cohort, and alternative stress modalities

should be considered in the presence of significant renal dysfunction to avoid an

unacceptable prevalence of false negative studies that may result from the

reduced sensitivity implied by our results.

202

CONCLUSION

203

Thesis Summary

The primary aims of this Thesis were directed to the evaluation of alterations in

CV structure and function in ESRF, and more specifically to the evaluation of: the

CV impact of AVF creation prior to dialysis commencement; the CV impact of

elective AVF ligation following successful, stable RTx; the diagnostic performance

of DS-‐CMR in excluding significant CAD prior to RTx, and; coronary endothelial

and microvascular function in advanced CKD/ESRF.

As detailed in the Background section of this Thesis, the prevalence of CKD is

rising progressively in developed countries, in tandem with the rising incidence

of obesity and TIIDM. The CV sequelae of advancing CKD are significant, and

ultimately lead to a markedly elevated incidence of CV morbidity and mortality,

with associated increases in personal and societal health care costs. Despite

substantial advances in the care of CV disease in the general community over the

last three decades, CKD and ESRF continue to confer a markedly shortened

lifespan on affected individuals, regardless of age. Significant markers for

particularly elevated risk included increases in LVH, increased atrial and

ventricular dimensions, the presence of peripheral endothelial dysfunction and

increased vascular stiffness. In light of the appallingly high mortality rates of

ESRF, greater efforts are clearly required to better identify and direct specific

care to the prevention and management of CVD in this condition.

In Study 1, we demonstrated the utility of CMR in the evaluation of CV structure

and function in ESRF, and further demonstrated the significant cardiac and

vascular alterations associated with the elective formation of an iatrogenic AVF

prior to the commencement of dialysis. Although prognostically superior to large-‐

204

bore central venous catheters, the creation of AVF was associated with

substantial alterations in CV structure and function including substantial

increases in CO, atrial and ventricular chamber dimensions, and LVM at 6-‐month

follow-‐up imaging. Furthermore, we identified a significant reduction in

endothelium-‐dependent brachial artery vasodilatation contralateral to the AVF at

follow-‐up, occurring in the absence of any alteration in baseline brachial artery

blood-‐flow. Notably, there was no detectable change in aortic distensibility

during the Study period, potentially indicating this parameter to be a less acutely

adaptable component of the vascular system. This Study demonstrated the

medium-‐term impact on prognostically significant structural and functional CV

parameters, and the need to consider therapeutic options that may help to offset

such disadvantageous CV adaptation to AVF formation.

In Study 2, we demonstrated the utility of CMR in the evaluation of CV structure

and function following successful RTx. CMR again demonstrated a high level of

spatial and temporal resolution, in the absence of ionizing radiation or exogenous

contrast agents, and provided for the detection of significant alterations in CV

structure and function with a high level of statistical significance despite modest

sample sizes. This Study demonstrated the potential for dramatic alterations in

prognostically-‐sensitive CV structural and functional parameters associated with

the elective ligation of clinically unnecessary, but persistent AVF following RTx.

Remarkably, despite the disparate clinical characteristics of the cohorts, the

response to AVF ligation closely mirrored those findings demonstrated in Study

1, with Study 2 demonstrating a “reversal” of many of the disadvantageous

alterations identified in the subjects evaluated in Study 1.

205

Study 3 focused on the evaluation of DS-‐CMR in the detection of

haemodynamically significant CAD in a cohort of advanced CKD / ESRF subjects

referred for coronary angiography prior to consideration of RTx. Many of these

subjects had also been investigated utilising the institutional standard, SPECT-‐

imaging – as a component of the routine clinical pathway evaluating potential

RTx recipients. This Study demonstrated a dramatic improvement in diagnostic

accuracy associated with DS-‐CMR imaging, as compared to SPECT, with 100%

sensitivity and diagnostic accuracy approaching 100% for the CMR technique.

Furthermore, it was demonstrated that SPECT imaging performed poorly in the

accurate quantification of LVEF in this condition, as compared to the “gold

standard” evaluation provided by CMR. Such results demonstrated the diagnostic

superiority of DS-‐CMR in the routine evaluation of ESRF patients with suspected

CAD, potentially opening an avenue for prognostic assessment of high-‐risk ESRF

patients in alternative clinical scenarios.

In Study 4, we undertook to invasively assess coronary endothelial function in

advanced CKD/ESRF and compare these findings with findings of coronary

endothelial function within a non-‐CKD cohort. The most striking finding of this

Study was the failure of microcirculatory vasodilatation in response to adenosine

in the CKD cohort, and the inference of significant microvascular dysfunction in

this condition. This finding was particularly notable in the absence of any

detectable dysfunction of coronary endothelium-‐dependent function as might

have been expected to be present in an ESRF cohort. Such findings of

microvascular dysfunction support a physiological basis for previous research

demonstrating impaired diagnostic accuracy associated with vasodilator-‐

dependent stress-‐imaging techniques (notably SPECT). The absence of significant

206

endothelial dysfunction in this ESRF cohort was somewhat surprising, but may be

more reflective of the highly selected Study population, than of the true absence

of significant endothelial dysfunction in ESRF more generally. Further work is

clearly necessary in this area.

Future Directions

The demonstration of diagnostic utility provided by CMR in the Studies outlined

opens a plethora of potential research avenues. The high diagnostic

reproducibility of CMR has previously been shown to allow for the detection of

highly significant alterations in cardiac and vascular structure without the

requirement for large sample populations. Hence CMR provides a potentially

superior imaging modality for future studies evaluating the CV impact of

alternative therapeutic interventions in this condition. More specifically, CMR

provides an outstanding opportunity to accurately detect potential CV benefits

associated with lifestyle (e.g. exercise) and pharmaco-‐therapeutic interventions

(e.g. alternative phosphate binders) in CKD, ESRF and following RTx.

Following the results of the AVF-‐ligation Study, we are progressing with a larger

randomised Study of systematic AVF ligation following successful RTx. Such a

Study would focus on the evaluation of the prognostic benefits that might be

expected to arise from the advantageous structural and functional alterations

seen in this initial Study.

The documentation of superior diagnostic accuracy associated with the use of DS-‐

CMR in the exclusion of significant CAD in a relatively healthy ESRF cohort being

assessed for suitability prior to RTx provides the basis for extending the use of

207

this imaging modality further in ESRF. Specifically, in light of the markedly

elevated risk of MI in ESRF, and the abysmal prognosis of affected patients,

prevention of such events is of paramount importance. It remains to be

determined whether a diagnostic technique of high accuracy may be able to

provide prognostic information regarding the future likelihood of coronary

events in this condition. By direct extension, such a modality may then allow for

the identification of ESRF patients at particularly high-‐risk who may benefit from

“prophylactic” revascularisation prior to a fatal cardiac event. Such a premise

remains to be proven however, despite the therapeutic attractiveness of such a

concept.

Finally, the demonstration of intact coronary endothelial function in a small

group of pre-‐RTx patients, where endothelial dysfunction might reasonably have

been expected, raises the potential for research aimed at the identification of

specific clinical / genetic characteristics that may provide relative protection to

the endothelium despite the presence a uraemic milieu. We are progressing with

this study to increase our numbers, and hence certainty that endothelial

dependent vasodilation is truly unaffected in our pre-‐renal transplantation

cohort. Further studies however evaluating coronary endothelial function in a

variety of higher-‐risk ESRF subjects may better illustrate the burden of coronary

endothelial function and dysfunction in this condition, although the presence of

significant CAD will remain a technical limitation to the use of the invasive

techniques described herein.

Renal dysfunction is associated with myriad alterations to CV structure and

function, many of which may not be recognised utilising standard clinical

investigations. CMR provides a novel avenue for the more comprehensive clinical

208

and investigational assessment of ESRF patients in the detection of sub-‐clinical

cardiac and vascular disease and the impact of therapeutic interventions in this

condition. Although limited by cost and availability, the increased penetration of

CMR into routine clinical practice more generally, and in ESRF more specifically,

provides an exciting opportunity to advance our understanding of the CV

sequelae of this condition, and to progress towards more effective preventive CV

care for these high-‐risk patients.

209

BIBLIOGRAPHY

210

1. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation,

classification, and stratification. Am J Kidney Dis 2002;39:S1-‐266.

2. Silkensen JR, Kasiske BL. Laboratory assessment of renal disease: clearance,

urinalysis, and renal biopsy. In: Brenner BM, ed. Brenner and Rector's The

Kidney, 7th ed. Philadelphia: Saunders, 2004:1107-‐1150.

3. Brenner BM. Brenner & Rector's The Kidney: Saunders Elsevier, 2006.

4. Mitch WE, Collier VU, Walser M. Creatinine metabolism in chronic renal failure.

Clin Sci (Lond) 1980;58:327-‐35.

5. Levey AS, Berg RL, Gassman JJ, Hall PM, Walker WG. Creatinine filtration,

secretion and excretion during progressive renal disease. Modification of Diet in

Renal Disease (MDRD) Study Group. Kidney Int Suppl 1989;27:S73-‐80.

6. Shemesh O, Golbetz H, Kriss JP, Myers BD. Limitations of creatinine as a

filtration marker in glomerulopathic patients. Kidney Int 1985;28:830-‐8.

7. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate

method to estimate glomerular filtration rate from serum creatinine: a new

prediction equation. Modification of Diet in Renal Disease Study Group. Ann

Intern Med 1999;130:461-‐70.

8. McDonald S, Excell L, Jose M. End-‐Stage Kidney Disease Among Indigenous

Peoples of Australia and New Zealand. ANZDATA Registry Report 2011;12.

9. Rule AD, Larson TS, Bergstralh EJ, Slezak JM, Jacobsen SJ, Cosio FG. Using serum

creatinine to estimate glomerular filtration rate: accuracy in good health and in

chronic kidney disease. Ann Intern Med 2004;141:929-‐37.

10. Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, Kusek JW,

Van Lente F. Using standardized serum creatinine values in the modification of

211

diet in renal disease study equation for estimating glomerular filtration rate. Ann

Intern Med 2006;145:247-‐54.

11. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum

creatinine. Nephron 1976;16:31-‐41.

12. Chadban SJ, Briganti EM, Kerr PG, Dunstan DW, Welborn TA, Zimmet PZ,

Atkins RC. Prevalence of kidney damage in Australian adults: The AusDiab kidney

study. J Am Soc Nephrol 2003;14:S131-‐8.

13. AIHW. Chronic Kidney Disease in Australia, 2005. In: AIHW, ed. Canberra:

Australian Institute of Health and Welfare, 2005:AIHW Cat.No.PHE 68.

14. McDonald S, Chang S, Excell L. ANZDATA Registry Report Australia and New

Zealand Dialysis and Transplant Registry. Adelaide, South Australia: Australia and

New Zealand Dialysis and Transplant Registry, 2006.

15. Cass A, Chadban S, Craig J, Howard H, McDonald S, Salkeld G, White S. The

Economic Impact of End-‐Stage Kidney Disease in Australia. Melbourne: Kidney

Health Australia, 2006.

16. AIHW. Health care expenditure on chronic kidney disease in Australia. In:

AIHW, ed. Canberra: Australian Institute of Health and Welfare, 2009:AIHW

Cat.No.PHE 117.

17. McDonald S, Excell L, Jose M. ANZDATA Registry Report Australia and New

Zealand Dialysis and Transplant Registry. Adelaide, South Australia: Australia and

New Zealand Dialysis and Transplant Registry, 2010.

18. Grace B, Excell L, Dent H, McDonald S. New Patients Commencing Treatment

in 2009 ANZDATA Registry Report. Adelaide, South Australia: Australia and New

Zealand Dialysis and Transplant Registry, 2010.

212

19. AIHW. Australia's Health, 2008. In: AIHW, ed. Canberra: Australian Institute

of Health and Welfare, 2008:Cat. No. AUS 99.

20. McDonald S, Excell L, Livingston B. ANZDATA Registry Report Australia and

New Zealand Dialysis and Transplant Registry. Adelaide, South Australia:

Australia and New Zealand Dialysis and Transplant Registry, 2008.

21. McDonald S, Excell L. ANZDATA Registry Report Australia and New Zealand

Dialysis and Transplant Registry. Adelaide, South Australia: Australia and New

Zealand Dialysis and Transplant Registry, 2005.

22. Cheung AK, Sarnak MJ, Yan G, Dwyer JT, Heyka RJ, Rocco MV, Teehan BP,

Levey AS. Atherosclerotic cardiovascular disease risks in chronic hemodialysis

patients. Kidney Int 2000;58:353-‐62.

23. Tapp RJ, Shaw JE, Zimmet PZ, Balkau B, Chadban SJ, Tonkin AM, Welborn TA,

Atkins RC. Albuminuria is evident in the early stages of diabetes onset: results

from the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). Am J Kidney

Dis 2004;44:792-‐8.

24. O'Seaghdha CM, Perkovic V, Lam TH, McGinn S, Barzi F, Gu DF, Cass A, Suh I,

Muntner P, Giles GG, Ueshima H, Woodward M, Huxley R. Blood pressure is a

major risk factor for renal death: an analysis of 560 352 participants from the

Asia-‐Pacific region. Hypertension 2009;54:509-‐15.

25. Briganti EM, Branley P, Chadban SJ, Shaw JE, McNeil JJ, Welborn TA, Atkins

RC. Smoking is associated with renal impairment and proteinuria in the normal

population: the AusDiab kidney study. Australian Diabetes, Obesity and Lifestyle

Study. Am J Kidney Dis 2002;40:704-‐12.

26. AIHW. Australia's Health, 2006. In: AIHW, ed. Canberra: Australian Institute

of Health and Welfare, 2006:Cat. No. AUS 73.

213

27. Wanner C. Importance of hyperlipidaemia and therapy in renal patients.

Nephrol Dial Transplant 2000;15 Suppl 5:92-‐6.

28. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop

JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with

hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl

J Med 1995;333:1301-‐7.

29. Randomised trial of cholesterol lowering in 4444 patients with coronary

heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet

1994;344:1383-‐9.

30. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher

A, Chaitman BR, Leslie S, Stern T. Effects of atorvastatin on early recurrent

ischemic events in acute coronary syndromes: the MIRACL study: a randomized

controlled trial. JAMA 2001;285:1711-‐8.

31. Waters DD, Guyton JR, Herrington DM, McGowan MP, Wenger NK, Shear C.

Treating to New Targets (TNT) Study: does lowering low-‐density lipoprotein

cholesterol levels below currently recommended guidelines yield incremental

clinical benefit? Am J Cardiol 2004;93:154-‐8.

32. Deedwania P, Barter P, Carmena R, Fruchart JC, Grundy SM, Haffner S,

Kastelein JJ, LaRosa JC, Schachner H, Shepherd J, Waters DD. Reduction of low-‐

density lipoprotein cholesterol in patients with coronary heart disease and

metabolic syndrome: analysis of the Treating to New Targets study. Lancet

2006;368:919-‐28.

33. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Jr., Kastelein JJ,

Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J,

214

Willerson JT, Glynn RJ. Rosuvastatin to prevent vascular events in men and

women with elevated C-‐reactive protein. N Engl J Med 2008;359:2195-‐207.

34. Fellstrom BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K, Beutler J,

Chae DW, Chevaile A, Cobbe SM, Gronhagen-‐Riska C, De Lima JJ, Lins R, Mayer G,

McMahon AW, Parving HH, Remuzzi G, Samuelsson O, Sonkodi S, Sci D,

Suleymanlar G, Tsakiris D, Tesar V, Todorov V, Wiecek A, Wuthrich RP, Gottlow

M, Johnsson E, Zannad F. Rosuvastatin and cardiovascular events in patients

undergoing hemodialysis. N Engl J Med 2009;360:1395-‐407.

35. Wanner C, Krane V, Marz W, Olschewski M, Mann JF, Ruf G, Ritz E.

Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N

Engl J Med 2005;353:238-‐48.

36. Baigent C, Landray M, Leaper C, Altmann P, Armitage J, Baxter A, Cairns HS,

Collins R, Foley RN, Frighi V, Kourellias K, Ratcliffe PJ, Rogerson M, Scoble JE,

Tomson CR, Warwick G, Wheeler DC. First United Kingdom Heart and Renal

Protection (UK-‐HARP-‐I) study: biochemical efficacy and safety of simvastatin and

safety of low-‐dose aspirin in chronic kidney disease. Am J Kidney Dis

2005;45:473-‐84.

37. van den Akker JM, Bredie SJ, Diepenveen SH, van Tits LJ, Stalenhoef AF, van

Leusen R. Atorvastatin and simvastatin in patients on hemodialysis: effects on

lipoproteins, C-‐reactive protein and in vivo oxidized LDL. J Nephrol 2003;16:238-‐

44.

38. Wanner C, Horl WH, Luley CH, Wieland H. Effects of HMG-‐CoA reductase

inhibitors in hypercholesterolemic patients on hemodialysis. Kidney Int

1991;39:754-‐60.

215

39. Saltissi D, Morgan C, Rigby RJ, Westhuyzen J. Safety and efficacy of

simvastatin in hypercholesterolemic patients undergoing chronic renal dialysis.

Am J Kidney Dis 2002;39:283-‐90.

40. Navaneethan SD, Palmer SC, Craig JC, Elder GJ, Strippoli GF. Benefits and

harms of phosphate binders in CKD: a systematic review of randomized

controlled trials. Am J Kidney Dis 2009;54:619-‐37.

41. Baigent C, Burbury K, Wheeler D. Premature cardiovascular disease in

chronic renal failure. Lancet 2000;356:147-‐52.

42. Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, Wanner C,

Krane V, Cass A, Craig J, Neal B, Jiang L, Hooi LS, Levin A, Agodoa L, Gaziano M,

Kasiske B, Walker R, Massy ZA, Feldt-‐Rasmussen B, Krairittichai U,

Ophascharoensuk V, Fellstrom B, Holdaas H, Tesar V, Wiecek A, Grobbee D, de

Zeeuw D, Gronhagen-‐Riska C, Dasgupta T, Lewis D, Herrington W, Mafham M,

Majoni W, Wallendszus K, Grimm R, Pedersen T, Tobert J, Armitage J, Baxter A,

Bray C, Chen Y, Chen Z, Hill M, Knott C, Parish S, Simpson D, Sleight P, Young A,

Collins R. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe

in patients with chronic kidney disease (Study of Heart and Renal Protection): a

randomised placebo-‐controlled trial. Lancet 2011;377:2181-‐92.

43. Cameron AJ, Welborn TA, Zimmet PZ, Dunstan DW, Owen N, Salmon J, Dalton

M, Jolley D, Shaw JE. Overweight and obesity in Australia: the 1999-‐2000

Australian Diabetes, Obesity and Lifestyle Study (AusDiab). Med J Aust

2003;178:427-‐32.

44. Barbosa JA, Rodrigues AB, Mota CC, Barbosa MM, Simoes e Silva AC.

Cardiovascular dysfunction in obesity and new diagnostic imaging techniques:

the role of noninvasive image methods. Vasc Health Risk Manag 2011;7:287-‐95.

216

45. Reisin E, Jack AV. Obesity and hypertension: mechanisms, cardio-‐renal

consequences, and therapeutic approaches. Med Clin North Am 2009;93:733-‐51.

46. Bogaert YE, Linas S. The role of obesity in the pathogenesis of hypertension.

Nat Clin Pract Nephrol 2009;5:101-‐11.

47. Burke GL, Bertoni AG, Shea S, Tracy R, Watson KE, Blumenthal RS, Chung H,

Carnethon MR. The impact of obesity on cardiovascular disease risk factors and

subclinical vascular disease: the Multi-‐Ethnic Study of Atherosclerosis. Arch

Intern Med 2008;168:928-‐35.

48. Lowrie EG, Lew NL. Death risk in hemodialysis patients: the predictive value

of commonly measured variables and an evaluation of death rate differences

between facilities. Am J Kidney Dis 1990;15:458-‐82.

49. Goldwasser P, Mittman N, Antignani A, Burrell D, Michel MA, Collier J, Avram

MM. Predictors of mortality in hemodialysis patients. J Am Soc Nephrol

1993;3:1613-‐22.

50. Postorino M, Marino C, Tripepi G, Zoccali C. Abdominal obesity and all-‐cause

and cardiovascular mortality in end-‐stage renal disease. J Am Coll Cardiol

2009;53:1265-‐72.

51. Weiner DE, Tighiouart H, Vlagopoulos PT, Griffith JL, Salem DN, Levey AS,

Sarnak MJ. Effects of anemia and left ventricular hypertrophy on cardiovascular

disease in patients with chronic kidney disease. J Am Soc Nephrol 2005;16:1803-‐

10.

52. Regidor DL, Kopple JD, Kovesdy CP, Kilpatrick RD, McAllister CJ, Aronovitz J,

Greenland S, Kalantar-‐Zadeh K. Associations between changes in hemoglobin and

administered erythropoiesis-‐stimulating agent and survival in hemodialysis

patients. J Am Soc Nephrol 2006;17:1181-‐91.

217

53. Marsden PA. Treatment of anemia in chronic kidney disease-‐-‐strategies based

on evidence. N Engl J Med 2009;361:2089-‐90.

54. KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for

anemia in chronic kidney disease: 2007 update of hemoglobin target. Am J Kidney

Dis 2007;50:471-‐530.

55. Ma JZ, Ebben J, Xia H, Collins AJ. Hematocrit level and associated mortality in

hemodialysis patients. J Am Soc Nephrol 1999;10:610-‐9.

56. Madore F, Lowrie EG, Brugnara C, Lew NL, Lazarus JM, Bridges K, Owen WF.

Anemia in hemodialysis patients: variables affecting this outcome predictor. J Am

Soc Nephrol 1997;8:1921-‐9.

57. Collins AJ. Anaemia management prior to dialysis: cardiovascular and cost-‐

benefit observations. Nephrol Dial Transplant 2003;18 Suppl 2:ii2-‐6.

58. Ofsthun N, Labrecque J, Lacson E, Keen M, Lazarus JM. The effects of higher

hemoglobin levels on mortality and hospitalization in hemodialysis patients.

Kidney Int 2003;63:1908-‐14.

59. Mocks J. Cardiovascular mortality in haemodialysis patients treated with

epoetin beta -‐ a retrospective study. Nephron 2000;86:455-‐62.

60. Locatelli F, Aljama P, Barany P, Canaud B, Carrera F, Eckardt KU, Horl WH,

Macdougal IC, Macleod A, Wiecek A, Cameron S. Revised European best practice

guidelines for the management of anaemia in patients with chronic renal failure.

Nephrol Dial Transplant 2004;19 Suppl 2:ii1-‐47.

61. Pisoni RL, Bragg-‐Gresham JL, Young EW, Akizawa T, Asano Y, Locatelli F,

Bommer J, Cruz JM, Kerr PG, Mendelssohn DC, Held PJ, Port FK. Anemia

management and outcomes from 12 countries in the Dialysis Outcomes and

Practice Patterns Study (DOPPS). Am J Kidney Dis 2004;44:94-‐111.

218

62. Foley RN, Parfrey PS, Morgan J, Barre PE, Campbell P, Cartier P, Coyle D, Fine

A, Handa P, Kingma I, Lau CY, Levin A, Mendelssohn D, Muirhead N, Murphy B,

Plante RK, Posen G, Wells GA. Effect of hemoglobin levels in hemodialysis patients

with asymptomatic cardiomyopathy. Kidney Int 2000;58:1325-‐35.

63. Parfrey PS, Foley RN, Wittreich BH, Sullivan DJ, Zagari MJ, Frei D. Double-‐

blind comparison of full and partial anemia correction in incident hemodialysis

patients without symptomatic heart disease. J Am Soc Nephrol 2005;16:2180-‐9.

64. Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM,

Schwab SJ, Goodkin DA. The effects of normal as compared with low hematocrit

values in patients with cardiac disease who are receiving hemodialysis and

epoetin. N Engl J Med 1998;339:584-‐90.

65. Drueke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger

HU, Scherhag A. Normalization of hemoglobin level in patients with chronic

kidney disease and anemia. N Engl J Med 2006;355:2071-‐84.

66. Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU,

Feyzi JM, Ivanovich P, Kewalramani R, Levey AS, Lewis EF, McGill JB, McMurray JJ,

Parfrey P, Parving HH, Remuzzi G, Singh AK, Solomon SD, Toto R. A Trial of

Darbepoetin Alfa in Type 2 Diabetes and Chronic Kidney Disease. N Engl J Med

2009.

67. Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Reddan D.

Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med

2006;355:2085-‐98.

68. Clement FM, Klarenbach S, Tonelli M, Johnson JA, Manns BJ. The impact of

selecting a high hemoglobin target level on health-‐related quality of life for

219

patients with chronic kidney disease: a systematic review and meta-‐analysis.

Arch Intern Med 2009;169:1104-‐12.

69. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations

for Anemia in Chronic Kidney Disease. Am J Kidney Dis 2006;47:S11-‐145.

70. Elliott J, Mishler D, Agarwal R. Hyporesponsiveness to erythropoietin: causes

and management. Adv Chronic Kidney Dis 2009;16:94-‐100.

71. Rozen-‐Zvi B, Gafter-‐Gvili A, Paul M, Leibovici L, Shpilberg O, Gafter U.

Intravenous versus oral iron supplementation for the treatment of anemia in

CKD: systematic review and meta-‐analysis. Am J Kidney Dis 2008;52:897-‐906.

72. Taylor JG, Bushinsky DA. Calcium and phosphorus homeostasis. Blood Purif

2009;27:387-‐94.

73. Holick MF, Krane SM. Endocrinology and Metabolism. In: Braunwald E, Fauci

AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, eds. Harrison's Principles of

Internal Medicine. Sydney: McGraw-‐Hill, 2001:2192-‐2205.

74. Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM. Mineral

metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc

Nephrol 2004;15:2208-‐18.

75. Messa P, Cerutti R, Brezzi B, Alfieri C, Cozzolino M. Calcium and phosphate

control by dialysis treatments. Blood Purif 2009;27:360-‐8.

76. Spasovski G, Massy Z, Vanholder R. Phosphate metabolism in chronic kidney

disease: from pathophysiology to clinical management. Semin Dial 2009;22:357-‐

62.

77. Chertow GM, Burke SK, Raggi P. Sevelamer attenuates the progression of

coronary and aortic calcification in hemodialysis patients. Kidney Int

2002;62:245-‐52.

220

78. Raggi P, Bommer J, Chertow GM. Valvular calcification in hemodialysis

patients randomized to calcium-‐based phosphorus binders or sevelamer. J Heart

Valve Dis 2004;13:134-‐41.

79. Block GA, Spiegel DM, Ehrlich J, Mehta R, Lindbergh J, Dreisbach A, Raggi P.

Effects of sevelamer and calcium on coronary artery calcification in patients new

to hemodialysis. Kidney Int 2005;68:1815-‐24.

80. Tonelli M, Wiebe N, Culleton B, Lee H, Klarenbach S, Shrive F, Manns B.

Systematic review of the clinical efficacy and safety of sevelamer in dialysis

patients. Nephrol Dial Transplant 2007;22:2856-‐66.

81. Meyer TW, Hostetter TH. Uremia. N Engl J Med 2007;357:1316-‐25.

82. Tziomalos K, Athyros VG, Karagiannis A, Mikhailidis DP. Endothelial

dysfunction in metabolic syndrome: prevalence, pathogenesis and management.

Nutr Metab Cardiovasc Dis 2010;20:140-‐6.

83. Hu G, Qiao Q, Tuomilehto J. The metabolic syndrome and cardiovascular risk.

Curr Diabetes Rev 2005;1:137-‐43.

84. Shinohara K, Shoji T, Emoto M, Tahara H, Koyama H, Ishimura E, Miki T,

Tabata T, Nishizawa Y. Insulin resistance as an independent predictor of

cardiovascular mortality in patients with end-‐stage renal disease. J Am Soc

Nephrol 2002;13:1894-‐900.

85. DeFronzo RA, Alvestrand A, Smith D, Hendler R, Hendler E, Wahren J. Insulin

resistance in uremia. J Clin Invest 1981;67:563-‐8.

86. Kobayashi S, Maesato K, Moriya H, Ohtake T, Ikeda T. Insulin resistance in

patients with chronic kidney disease. Am J Kidney Dis 2005;45:275-‐80.

221

87. Fliser D, Pacini G, Engelleiter R, Kautzky-‐Willer A, Prager R, Franek E, Ritz E.

Insulin resistance and hyperinsulinemia are already present in patients with

incipient renal disease. Kidney Int 1998;53:1343-‐7.

88. Westervelt FB. Insulin effect in uremia. J Lab Clin Med 1969;74:79-‐84.

89. Hager SR. Insulin resistance of uremia. Am J Kidney Dis 1989;14:272-‐6.

90. Mak RH, DeFronzo RA. Glucose and insulin metabolism in uremia. Nephron

1992;61:377-‐82.

91. Lee SW, Park GH, Song JH, Hong KC, Kim MJ. Insulin resistance and muscle

wasting in non-‐diabetic end-‐stage renal disease patients. Nephrol Dial Transplant

2007;22:2554-‐62.

92. Siew ED, Pupim LB, Majchrzak KM, Shintani A, Flakoll PJ, Ikizler TA. Insulin

resistance is associated with skeletal muscle protein breakdown in non-‐diabetic

chronic hemodialysis patients. Kidney Int 2007;71:146-‐52.

93. Cheema BS. Review article: Tackling the survival issue in end-‐stage renal

disease: time to get physical on haemodialysis. Nephrology (Carlton)

2008;13:560-‐9.

94. Hassan AA, Kroll MH. Acquired disorders of platelet function. Hematology Am

Soc Hematol Educ Program 2005:403-‐8.

95. Galbusera M, Remuzzi G, Boccardo P. Treatment of bleeding in dialysis

patients. Semin Dial 2009;22:279-‐86.

96. Di Minno G, Martinez J, McKean ML, De La Rosa J, Burke JF, Murphy S. Platelet

dysfunction in uremia. Multifaceted defect partially corrected by dialysis. Am J

Med 1985;79:552-‐9.

222

97. Herbelin A, Nguyen AT, Zingraff J, Urena P, Descamps-‐Latscha B. Influence of

uremia and hemodialysis on circulating interleukin-‐1 and tumor necrosis factor

alpha. Kidney Int 1990;37:116-‐25.

98. Smith MC, Dunn MJ. Impaired platelet thromboxane production in renal

failure. Nephron 1981;29:133-‐7.

99. Remuzzi G, Benigni A, Dodesini P, Schieppati A, Livio M, De Gaetano G, Day SS,

Smith WL, Pinca E, Patrignani P, Patrono C. Reduced platelet thromboxane

formation in uremia. Evidence for a functional cyclooxygenase defect. J Clin Invest

1983;71:762-‐8.

100. Macconi D, Vigano G, Bisogno G, Galbusera M, Orisio S, Remuzzi G, Livio M.

Defective platelet aggregation in response to platelet-‐activating factor in uremia

associated with low platelet thromboxane A2 generation. Am J Kidney Dis

1992;19:318-‐25.

101. Castillo R, Lozano T, Escolar G, Revert L, Lopez J, Ordinas A. Defective

platelet adhesion on vessel subendothelium in uremic patients. Blood

1986;68:337-‐42.

102. Zwaginga JJ, Ijsseldijk MJ, Beeser-‐Visser N, de Groot PG, Vos J, Sixma JJ. High

von Willebrand factor concentration compensates a relative adhesion defect in

uremic blood. Blood 1990;75:1498-‐508.

103. Escolar G, Cases A, Bastida E, Garrido M, Lopez J, Revert L, Castillo R, Ordinas

A. Uremic platelets have a functional defect affecting the interaction of von

Willebrand factor with glycoprotein IIb-‐IIIa. Blood 1990;76:1336-‐40.

104. Livio M, Gotti E, Marchesi D, Mecca G, Remuzzi G, de Gaetano G. Uraemic

bleeding: role of anaemia and beneficial effect of red cell transfusions. Lancet

1982;2:1013-‐5.

223

105. Moia M, Mannucci PM, Vizzotto L, Casati S, Cattaneo M, Ponticelli C.

Improvement in the haemostatic defect of uraemia after treatment with

recombinant human erythropoietin. Lancet 1987;2:1227-‐9.

106. Vigano G, Benigni A, Mendogni D, Mingardi G, Mecca G, Remuzzi G.

Recombinant human erythropoietin to correct uremic bleeding. Am J Kidney Dis

1991;18:44-‐9.

107. Gaarder A, Jonsen J, Laland S, Hellem A, Owren PA. Adenosine diphosphate

in red cells as a factor in the adhesiveness of human blood platelets. Nature

1961;192:531-‐2.

108. Noris M, Remuzzi G. Uremic bleeding: closing the circle after 30 years of

controversies? Blood 1999;94:2569-‐74.

109. Rabiner SF, Molinas F. The role of phenol and phenolic acids on the

thrombocytopathy and defective platelet aggregation of patients with renal

failure. Am J Med 1970;49:346-‐51.

110. Horowitz HI, Stein IM, Cohen BD, White JG. Further studies on the platelet-‐

inhibitory effect of guanidinosuccinic acid and its role in uremic bleeding. Am J

Med 1970;49:336-‐45.

111. Remuzzi G, Livio M, Marchiaro G, Mecca G, de Gaetano G. Bleeding in renal

failure: altered platelet function in chronic uraemia only partially corrected by

haemodialysis. Nephron 1978;22:347-‐53.

112. Nenci GG, Berrettini M, Agnelli G, Parise P, Buoncristiani U, Ballatori E. Effect

of peritoneal dialysis, haemodialysis and kidney transplantation on blood platelet

function. I. Platelet aggregation by ADP and epinephrine. Nephron 1979;23:287-‐

92.

224

113. Gaspari F, Vigano G, Orisio S, Bonati M, Livio M, Remuzzi G. Aspirin prolongs

bleeding time in uremia by a mechanism distinct from platelet cyclooxygenase

inhibition. J Clin Invest 1987;79:1788-‐97.

114. Boyle JM, Johnston B. Acute upper gastrointestinal hemorrhage in patients

with chronic renal disease. Am J Med 1983;75:409-‐12.

115. Escolar G, Diaz-‐Ricart M, Cases A. Uremic platelet dysfunction: past and

present. Curr Hematol Rep 2005;4:359-‐67.

116. Himmelfarb J, Stenvinkel P, Ikizler TA, Hakim RM. The elephant in uremia:

oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney

Int 2002;62:1524-‐38.

117. Papa S, Skulachev VP. Reactive oxygen species, mitochondria, apoptosis and

aging. Mol Cell Biochem 1997;174:305-‐19.

118. Rigatto C, Singal PK. Oxidative Stress in Uremia: Impact on Cardiac Disease

in Dialysis Patients. Seminars in Dialysis 1999;12:91-‐96.

119. Massy ZA, Stenvinkel P, Drueke TB. The role of oxidative stress in chronic

kidney disease. Semin Dial 2009;22:405-‐8.

120. Siegel-‐Axel D, Daub K, Seizer P, Lindemann S, Gawaz M. Platelet lipoprotein

interplay: trigger of foam cell formation and driver of atherosclerosis. Cardiovasc

Res 2008;78:8-‐17.

121. Ross R. Atherosclerosis-‐-‐an inflammatory disease. N Engl J Med

1999;340:115-‐26.

122. Lusis AJ. Atherosclerosis. Nature 2000;407:233-‐41.

123. Torzewski M, Lackner KJ. Initiation and progression of atherosclerosis-‐-‐

enzymatic or oxidative modification of low-‐density lipoprotein? Clin Chem Lab

Med 2006;44:1389-‐94.

225

124. Verhoye E, Langlois MR. Circulating oxidized low-‐density lipoprotein: a

biomarker of atherosclerosis and cardiovascular risk? Clin Chem Lab Med

2009;47:128-‐37.

125. Berneis KK, Krauss RM. Metabolic origins and clinical significance of LDL

heterogeneity. J Lipid Res 2002;43:1363-‐79.

126. Matsuura E, Kobayashi K, Tabuchi M, Lopez LR. Oxidative modification of

low-‐density lipoprotein and immune regulation of atherosclerosis. Prog Lipid Res

2006;45:466-‐86.

127. Moore KJ, Freeman MW. Scavenger receptors in atherosclerosis: beyond

lipid uptake. Arterioscler Thromb Vasc Biol 2006;26:1702-‐11.

128. Uchida K. Role of reactive aldehyde in cardiovascular diseases. Free Radic

Biol Med 2000;28:1685-‐96.

129. Weiss MF, Erhard P, Kader-‐Attia FA, Wu YC, Deoreo PB, Araki A, Glomb MA,

Monnier VM. Mechanisms for the formation of glycoxidation products in end-‐

stage renal disease. Kidney Int 2000;57:2571-‐85.

130. Miyata T, van Ypersele de Strihou C, Kurokawa K, Baynes JW. Alterations in

nonenzymatic biochemistry in uremia: origin and significance of "carbonyl

stress" in long-‐term uremic complications. Kidney Int 1999;55:389-‐99.

131. Miyata T, Sugiyama S, Saito A, Kurokawa K. Reactive carbonyl compounds

related uremic toxicity ("carbonyl stress"). Kidney Int Suppl 2001;78:S25-‐31.

132. Sakata N, Imanaga Y, Meng J, Tachikawa Y, Takebayashi S, Nagai R, Horiuchi

S. Increased advanced glycation end products in atherosclerotic lesions of

patients with end-‐stage renal disease. Atherosclerosis 1999;142:67-‐77.

226

133. Berliner JA, Navab M, Fogelman AM, Frank JS, Demer LL, Edwards PA,

Watson AD, Lusis AJ. Atherosclerosis: basic mechanisms. Oxidation, inflammation,

and genetics. Circulation 1995;91:2488-‐96.

134. Wang Y, Marshall SM, Thompson MG, Hoenich NA. Cardiovascular risk in

patients with end-‐stage renal disease: a potential role for advanced glycation end

products. Contrib Nephrol 2005;149:168-‐74.

135. Descamps-‐Latscha B, Jungers P, Witko-‐Sarsat V. Immune system

dysregulation in uremia: role of oxidative stress. Blood Purif 2002;20:481-‐4.

136. Horl WH. Hemodialysis membranes: interleukins, biocompatibility, and

middle molecules. J Am Soc Nephrol 2002;13 Suppl 1:S62-‐71.

137. Chawla LS, Krishnan M. Causes and consequences of inflammation on

anemia management in hemodialysis patients. Hemodial Int 2009;13:222-‐34.

138. Foley RN, Parfrey PS, Sarnak MJ. Epidemiology of cardiovascular disease in

chronic renal disease. J Am Soc Nephrol 1998;9:S16-‐23.

139. Tonelli M, Wiebe N, Culleton B, House A, Rabbat C, Fok M, McAlister F, Garg

AX. Chronic kidney disease and mortality risk: a systematic review. J Am Soc

Nephrol 2006;17:2034-‐47.

140. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular

disease in chronic renal disease. Am J Kidney Dis 1998;32:S112-‐9.

141. US Renal Data System, USRDS 2007 Annual Data Report: Atlas of Chronic

Kidney Disease and End-Stage Renal Disease in the United States, National

Institutes of Health, National Institute of Diabetes and Digestive and Kidney

Diseases Bethesda, MD, 2007.

142. Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL,

McCullough PA, Kasiske BL, Kelepouris E, Klag MJ, Parfrey P, Pfeffer M, Raij L,

227

Spinosa DJ, Wilson PW. Kidney disease as a risk factor for development of

cardiovascular disease: a statement from the American Heart Association

Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research,

Clinical Cardiology, and Epidemiology and Prevention. Hypertension

2003;42:1050-‐65.

143. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease

and the risks of death, cardiovascular events, and hospitalization. N Engl J Med

2004;351:1296-‐305.

144. Foley RN, Murray AM, Li S, Herzog CA, McBean AM, Eggers PW, Collins AJ.

Chronic kidney disease and the risk for cardiovascular disease, renal

replacement, and death in the United States Medicare population, 1998 to 1999. J

Am Soc Nephrol 2005;16:489-‐95.

145. Parfrey PS, Foley RN, Harnett JD, Kent GM, Murray DC, Barre PE. Outcome

and risk factors for left ventricular disorders in chronic uraemia. Nephrol Dial

Transplant 1996;11:1277-‐85.

146. Silberberg JS, Barre PE, Prichard SS, Sniderman AD. Impact of left

ventricular hypertrophy on survival in end-‐stage renal disease. Kidney Int

1989;36:286-‐90.

147. Edwards NC, Ferro CJ, Townend JN, Steeds RP. Aortic distensibility and

arterial-‐ventricular coupling in early chronic kidney disease: a pattern

resembling heart failure with preserved ejection fraction. Heart 2008;94:1038-‐

43.

148. Paoletti E, Bellino D, Cassottana P, Rolla D, Cannella G. Left ventricular

hypertrophy in nondiabetic predialysis CKD. Am J Kidney Dis 2005;46:320-‐7.

228

149. Zoccali C, Benedetto FA, Mallamaci F, Tripepi G, Giacone G, Stancanelli B,

Cataliotti A, Malatino LS. Left ventricular mass monitoring in the follow-‐up of

dialysis patients: prognostic value of left ventricular hypertrophy progression.

Kidney Int 2004;65:1492-‐8.

150. Foley RN, Parfrey PS, Kent GM, Harnett JD, Murray DC, Barre PE. Serial

change in echocardiographic parameters and cardiac failure in end-‐stage renal

disease. J Am Soc Nephrol 2000;11:912-‐6.

151. Chan CT, Greene T, Chertow GM, Kliger AS, Stokes JB, Beck GJ, Daugirdas JT,

Kotanko P, Larive B, Levin NW, Mehta RL, Rocco M, Sanz J, Schiller BM, Yang PC,

Rajagopalan S. Determinants of left ventricular mass in patients on hemodialysis:

Frequent Hemodialysis Network (FHN) Trials. Circ Cardiovasc Imaging

2012;5:251-‐61.

152. London GM. Left ventricular hypertrophy: why does it happen? Nephrol Dial

Transplant 2003;18 Suppl 8:viii2-‐6.

153. Levin A, Thompson CR, Ethier J, Carlisle EJ, Tobe S, Mendelssohn D, Burgess

E, Jindal K, Barrett B, Singer J, Djurdjev O. Left ventricular mass index increase in

early renal disease: impact of decline in hemoglobin. Am J Kidney Dis

1999;34:125-‐34.

154. London GM. Cardiovascular disease in chronic renal failure:

pathophysiologic aspects. Semin Dial 2003;16:85-‐94.

155. Cuspidi C, Ciulla M, Zanchetti A. Hypertensive myocardial fibrosis. Nephrol

Dial Transplant 2006;21:20-‐3.

156. Amann K, Wiest G, Zimmer G, Gretz N, Ritz E, Mall G. Reduced capillary

density in the myocardium of uremic rats-‐-‐a stereological study. Kidney Int

1992;42:1079-‐85.

229

157. Middleton RJ, Parfrey PS, Foley RN. Left ventricular hypertrophy in the renal

patient. J Am Soc Nephrol 2001;12:1079-‐84.

158. Levin A, Djurdjev O, Thompson C, Barrett B, Ethier J, Carlisle E, Barre P,

Magner P, Muirhead N, Tobe S, Tam P, Wadgymar JA, Kappel J, Holland D, Pichette

V, Shoker A, Soltys G, Verrelli M, Singer J. Canadian randomized trial of

hemoglobin maintenance to prevent or delay left ventricular mass growth in

patients with CKD. Am J Kidney Dis 2005;46:799-‐811.

159. Cianciaruso B, Ravani P, Barrett BJ, Levin A. Italian randomized trial of

hemoglobin maintenance to prevent or delay left ventricular hypertrophy in

chronic kidney disease. J Nephrol 2008;21:861-‐70.

160. London GM, Pannier B, Guerin AP, Blacher J, Marchais SJ, Darne B, Metivier

F, Adda H, Safar ME. Alterations of left ventricular hypertrophy in and survival of

patients receiving hemodialysis: follow-‐up of an interventional study. J Am Soc

Nephrol 2001;12:2759-‐67.

161. Bossola M, Tazza L, Vulpio C, Luciani G. Is regression of left ventricular

hypertrophy in maintenance hemodialysis patients possible? Semin Dial

2008;21:422-‐30.

162. Levin A. The role of anaemia in the genesis of cardiac abnormalities in

patients with chronic kidney disease. Nephrol Dial Transplant 2002;17:207-‐10.

163. Levy D, Salomon M, D'Agostino RB, Belanger AJ, Kannel WB. Prognostic

implications of baseline electrocardiographic features and their serial changes in

subjects with left ventricular hypertrophy. Circulation 1994;90:1786-‐93.

164. Zhang R, Crump J, Reisin E. Regression of left ventricular hypertrophy is a

key goal of hypertension management. Curr Hypertens Rep 2003;5:301-‐8.

230

165. Verdecchia P, Schillaci G, Borgioni C, Ciucci A, Gattobigio R, Zampi I, Reboldi

G, Porcellati C. Prognostic significance of serial changes in left ventricular mass in

essential hypertension. Circulation 1998;97:48-‐54.

166. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup

M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson

LW, Yancy CW, Antman EM, Smith SC, Jr., Adams CD, Anderson JL, Faxon DP,

Fuster V, Halperin JL, Hiratzka LF, Jacobs AK, Nishimura R, Ornato JP, Page RL,

Riegel B. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of

Chronic Heart Failure in the Adult: a report of the American College of

Cardiology/American Heart Association Task Force on Practice Guidelines

(Writing Committee to Update the 2001 Guidelines for the Evaluation and

Management of Heart Failure): developed in collaboration with the American

College of Chest Physicians and the International Society for Heart and Lung

Transplantation: endorsed by the Heart Rhythm Society. Circulation

2005;112:e154-‐235.

167. Remme WJ, Swedberg K. Comprehensive guidelines for the diagnosis and

treatment of chronic heart failure. Task force for the diagnosis and treatment of

chronic heart failure of the European Society of Cardiology. Eur J Heart Fail

2002;4:11-‐22.

168. Hillege HL, Nitsch D, Pfeffer MA, Swedberg K, McMurray JJ, Yusuf S, Granger

CB, Michelson EL, Ostergren J, Cornel JH, de Zeeuw D, Pocock S, van Veldhuisen

DJ. Renal function as a predictor of outcome in a broad spectrum of patients with

heart failure. Circulation 2006;113:671-‐8.

231

169. Parfrey PS. Cardiac disease in dialysis patients: diagnosis, burden of disease,

prognosis, risk factors and management. Nephrol Dial Transplant 2000;15 Suppl

5:58-‐68.

170. MacRae JM, Levin A, Belenkie I. The cardiovascular effects of arteriovenous

fistulas in chronic kidney disease: a cause for concern? Semin Dial 2006;19:349-‐

52.

171. Kunz K, Dimitrov Y, Muller S, Chantrel F, Hannedouche T. Uraemic

cardiomyopathy. Nephrol Dial Transplant 1998;13 Suppl 4:39-‐43.

172. Harnett JD, Foley RN, Kent GM, Barre PE, Murray D, Parfrey PS. Congestive

heart failure in dialysis patients: prevalence, incidence, prognosis and risk

factors. Kidney Int 1995;47:884-‐90.

173. Parfrey PS, Griffiths SM, Harnett JD, Taylor R, King A, Hand J, Barre PE.

Outcome of congestive heart failure, dilated cardiomyopathy, hypertrophic

hyperkinetic disease, and ischemic heart disease in dialysis patients. Am J Nephrol

1990;10:213-‐21.

174. Banerjee D, Ma JZ, Collins AJ, Herzog CA. Long-‐term survival of incident

hemodialysis patients who are hospitalized for congestive heart failure,

pulmonary edema, or fluid overload. Clin J Am Soc Nephrol 2007;2:1186-‐90.

175. Postorino M, Marino C, Tripepi G, Zoccali C. Prognostic value of the New

York Heart Association classification in end-‐stage renal disease. Nephrol Dial

Transplant 2007;22:1377-‐82.

176. Burton JO, Jefferies HJ, Selby NM, McIntyre CW. Hemodialysis-‐induced

cardiac injury: determinants and associated outcomes. Clin J Am Soc Nephrol

2009;4:914-‐20.

232

177. McIntyre CW, Burton JO, Selby NM, Leccisotti L, Korsheed S, Baker CS,

Camici PG. Hemodialysis-‐induced cardiac dysfunction is associated with an acute

reduction in global and segmental myocardial blood flow. Clin J Am Soc Nephrol

2008;3:19-‐26.

178. Burton JO, Jefferies HJ, Selby NM, McIntyre CW. Hemodialysis-‐induced

repetitive myocardial injury results in global and segmental reduction in systolic

cardiac function. Clin J Am Soc Nephrol 2009;4:1925-‐31.

179. Gotloib L, Fudin R. The impact of peritoneal dialysis upon quality of life and

mortality of patients with end-‐stage congestive heart failure. Contrib Nephrol

2006;150:247-‐53.

180. Kalantar-‐Zadeh K, Regidor DL, Kovesdy CP, Van Wyck D, Bunnapradist S,

Horwich TB, Fonarow GC. Fluid retention is associated with cardiovascular

mortality in patients undergoing long-‐term hemodialysis. Circulation

2009;119:671-‐9.

181. Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA,

Halperin JL, Le Heuzey JY, Kay GN, Lowe JE, Olsson SB, Prystowsky EN, Tamargo

JL, Wann S, Smith SC, Jr., Jacobs AK, Adams CD, Anderson JL, Antman EM, Hunt SA,

Nishimura R, Ornato JP, Page RL, Riegel B, Priori SG, Blanc JJ, Budaj A, Camm AJ,

Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M,

Morais J, Osterspey A, Zamorano JL. ACC/AHA/ESC 2006 Guidelines for the

Management of Patients with Atrial Fibrillation: a report of the American College

of Cardiology/American Heart Association Task Force on Practice Guidelines and

the European Society of Cardiology Committee for Practice Guidelines (Writing

Committee to Revise the 2001 Guidelines for the Management of Patients With

233

Atrial Fibrillation): developed in collaboration with the European Heart Rhythm

Association and the Heart Rhythm Society. Circulation 2006;114:e257-‐354.

182. Abbott KC, Trespalacios FC, Taylor AJ, Agodoa LY. Atrial fibrillation in

chronic dialysis patients in the United States: risk factors for hospitalization and

mortality. BMC Nephrol 2003;4:1.

183. Genovesi S, Vincenti A, Rossi E, Pogliani D, Acquistapace I, Stella A, Valsecchi

MG. Atrial fibrillation and morbidity and mortality in a cohort of long-‐term

hemodialysis patients. Am J Kidney Dis 2008;51:255-‐62.

184. Vazquez E, Sanchez-‐Perales C, Garcia-‐Garcia F, Castellano P, Garcia-‐Cortes

MJ, Liebana A, Lozano C. Atrial fibrillation in incident dialysis patients. Kidney Int

2009;76:324-‐30.

185. Korantzopoulos P, Kokkoris S, Liu T, Protopsaltis I, Li G, Goudevenos JA.

Atrial fibrillation in end-‐stage renal disease. Pacing Clin Electrophysiol

2007;30:1391-‐7.

186. Genovesi S, Pogliani D, Faini A, Valsecchi MG, Riva A, Stefani F, Acquistapace

I, Stella A, Bonforte G, DeVecchi A, DeCristofaro V, Buccianti G, Vincenti A.

Prevalence of atrial fibrillation and associated factors in a population of long-‐

term hemodialysis patients. Am J Kidney Dis 2005;46:897-‐902.

187. Liu T, Li GP. Potential mechanisms between atrial dilatation and atrial

fibrillation. Am Heart J 2006;151:e1; author reply e3.

188. Shiroshita-‐Takeshita A, Brundel BJ, Nattel S. Atrial fibrillation: basic

mechanisms, remodeling and triggers. J Interv Card Electrophysiol 2005;13:181-‐

93.

234

189. Tripepi G, Benedetto FA, Mallamaci F, Tripepi R, Malatino L, Zoccali C. Left

atrial volume in end-‐stage renal disease: a prospective cohort study. J Hypertens

2006;24:1173-‐80.

190. Liu T, Li G. Pulmonary vein dilatation: another possible crosslink between

left atrial enlargement and atrial fibrillation? Int J Cardiol 2008;123:193-‐4.

191. Knackstedt C, Visser L, Plisiene J, Zarse M, Waldmann M, Mischke K, Koch

KC, Hoffmann R, Franke A, Hanrath P, Schauerte P. Dilatation of the pulmonary

veins in atrial fibrillation: a transesophageal echocardiographic evaluation.

Pacing Clin Electrophysiol 2003;26:1371-‐8.

192. Yamane T, Shah DC, Jais P, Hocini M, Peng JT, Deisenhofer I, Clementy J,

Haissaguerre M. Dilatation as a marker of pulmonary veins initiating atrial

fibrillation. J Interv Card Electrophysiol 2002;6:245-‐9.

193. Mathew ST, Patel J, Joseph S. Atrial fibrillation: mechanistic insights and

treatment options. Eur J Intern Med 2009;20:672-‐81.

194. Rao AK, Djamali A, Korcarz CE, Aeschlimann SE, Wolff MR, Stein JH. Left

atrial volume is associated with inflammation and atherosclerosis in patients

with kidney disease. Echocardiography 2008;25:264-‐9.

195. Atar I, Konas D, Acikel S, Kulah E, Atar A, Bozbas H, Gulmez O, Sezer S,

Yildirir A, Ozdemir N, Muderrisoglu H, Ozin B. Frequency of atrial fibrillation and

factors related to its development in dialysis patients. Int J Cardiol 2006;106:47-‐

51.

196. Patel RK, Jardine AG, Mark PB, Cunningham AF, Steedman T, Powell JR,

McQuarrie EP, Stevens KK, Dargie HJ. Association of left atrial volume with

mortality among ESRD patients with left ventricular hypertrophy referred for

kidney transplantation. Am J Kidney Dis 2010;55:1088-‐96.

235

197. Artham SM, Lavie CJ, Milani RV, Patel DA, Verma A, Ventura HO. Clinical

impact of left ventricular hypertrophy and implications for regression. Prog

Cardiovasc Dis 2009;52:153-‐67.

198. Okin PM, Wachtell K, Devereux RB, Harris KE, Jern S, Kjeldsen SE, Julius S,

Lindholm LH, Nieminen MS, Edelman JM, Hille DA, Dahlof B. Regression of

electrocardiographic left ventricular hypertrophy and decreased incidence of

new-‐onset atrial fibrillation in patients with hypertension. JAMA 2006;296:1242-‐

8.

199. Covic A, Mardare NG, Ardeleanu S, Prisada O, Gusbeth-‐Tatomir P, Goldsmith

DJ. Serial echocardiographic changes in patients on hemodialysis: an evaluation

of guideline implementation. J Nephrol 2006;19:783-‐93.

200. London GM, Pannier B, Marchais SJ, Guerin AP. Calcification of the aortic

valve in the dialyzed patient. J Am Soc Nephrol 2000;11:778-‐83.

201. Otto CM, Lind BK, Kitzman DW, Gersh BJ, Siscovick DS. Association of aortic-‐

valve sclerosis with cardiovascular mortality and morbidity in the elderly. N Engl

J Med 1999;341:142-‐7.

202. Stewart BF, Siscovick D, Lind BK, Gardin JM, Gottdiener JS, Smith VE,

Kitzman DW, Otto CM. Clinical factors associated with calcific aortic valve disease.

Cardiovascular Health Study. J Am Coll Cardiol 1997;29:630-‐4.

203. Lindroos M, Kupari M, Heikkila J, Tilvis R. Prevalence of aortic valve

abnormalities in the elderly: an echocardiographic study of a random population

sample. J Am Coll Cardiol 1993;21:1220-‐5.

204. Braun J, Oldendorf M, Moshage W, Heidler R, Zeitler E, Luft FC. Electron

beam computed tomography in the evaluation of cardiac calcification in chronic

dialysis patients. Am J Kidney Dis 1996;27:394-‐401.

236

205. Maher ER, Pazianas M, Curtis JR. Calcific aortic stenosis: a complication of

chronic uraemia. Nephron 1987;47:119-‐22.

206. Baglin A, Hanslik T, Vaillant JN, Boulard JC, Moulonguet-‐Doleris L, Prinseau J.

Severe valvular heart disease in patients on chronic dialysis. A five-‐year

multicenter French survey. Ann Med Interne (Paris) 1997;148:521-‐6.

207. Fox CS, Larson MG, Vasan RS, Guo CY, Parise H, Levy D, Leip EP, O'Donnell C

J, D'Agostino RB, Sr., Benjamin EJ. Cross-‐sectional association of kidney function

with valvular and annular calcification: the Framingham heart study. J Am Soc

Nephrol 2006;17:521-‐7.

208. Asselbergs FW, Mozaffarian D, Katz R, Kestenbaum B, Fried LF, Gottdiener

JS, Shlipak MG, Siscovick DS. Association of renal function with cardiac

calcifications in older adults: the cardiovascular health study. Nephrol Dial

Transplant 2009;24:834-‐40.

209. Sharma R, Pellerin D, Gaze DC, Mehta RL, Gregson H, Streather CP, Collinson

PO, Brecker SJ. Mitral annular calcification predicts mortality and coronary artery

disease in end stage renal disease. Atherosclerosis 2007;191:348-‐54.

210. Wang AY, Ho SS, Wang M, Liu EK, Ho S, Li PK, Lui SF, Sanderson JE. Cardiac

valvular calcification as a marker of atherosclerosis and arterial calcification in

end-‐stage renal disease. Arch Intern Med 2005;165:327-‐32.

211. Al-‐Absi AI, Wall BM, Aslam N, Mangold TA, Lamar KD, Wan JY, D'Cruz IA.

Predictors of mortality in end-‐stage renal disease patients with mitral annulus

calcification. Am J Med Sci 2006;331:124-‐30.

212. Huting J. Predictive value of mitral and aortic valve sclerosis for survival in

end-‐stage renal disease on continuous ambulatory peritoneal dialysis. Nephron

1993;64:63-‐8.

237

213. Mazzaferro S, Coen G, Bandini S, Borgatti PP, Ciaccheri M, Diacinti D,

Ferranti E, Lusenti T, Mancini G, Monducci I, et al. Role of ageing, chronic renal

failure and dialysis in the calcification of mitral annulus. Nephrol Dial Transplant

1993;8:335-‐40.

214. Urena P, Malergue MC, Goldfarb B, Prieur P, Guedon-‐Rapoud C, Petrover M.

Evolutive aortic stenosis in hemodialysis patients: analysis of risk factors.

Nephrologie 1999;20:217-‐25.

215. Rufino M, Garcia S, Jimenez A, Alvarez A, Miquel R, Delgado P, Marrero D,

Torres A, Hernandez D, Lorenzo V. Heart valve calcification and calcium x

phosphorus product in hemodialysis patients: analysis of optimum values for its

prevention. Kidney Int Suppl 2003:S115-‐8.

216. Lezaic V, Tirmenstajn-‐Jankovic B, Bukvic D, Vujisic B, Perovic M, Novakovic

N, Dopsaj V, Maric I, Djukanovic L. Efficacy of hyperphosphatemia control in the

progression of chronic renal failure and the prevalence of cardiovascular

calcification. Clin Nephrol 2009;71:21-‐9.

217. Ribeiro S, Ramos A, Brandao A, Rebelo JR, Guerra A, Resina C, Vila-‐Lobos A,

Carvalho F, Remedio F, Ribeiro F. Cardiac valve calcification in haemodialysis

patients: role of calcium-‐phosphate metabolism. Nephrol Dial Transplant

1998;13:2037-‐40.

218. Kajbaf S, Veinot JP, Ha A, Zimmerman D. Comparison of surgically removed

cardiac valves of patients with ESRD with those of the general population. Am J

Kidney Dis 2005;46:86-‐93.

219. Gultekin B, Ozkan S, Uguz E, Atalay H, Akay T, Arslan A, Sezgin A, Ozdemir N,

Tasdelen A, Aslamaci S. Valve replacement surgery in patients with end-‐stage

renal disease: long-‐term results. Artif Organs 2005;29:972-‐5.

238

220. Deleuze PH, Mazzucotelli JP, Maillet JM, Le Besnerais P, Mourtada A, Hillion

ML, Loisance DY, Cachera JP. [Cardiac surgery in chronic hemodialysed patients:

immediate and long-‐term results]. Arch Mal Coeur Vaiss 1995;88:43-‐8. In: London

GM, Pannier B, Marchais SJ, Guerin AP. Calcification of the aortic valve in the

dialyzed patient. J Am Soc Nephrol 2000;11(4):778-‐83.

221. Kaplon RJ, Cosgrove DM, 3rd, Gillinov AM, Lytle BW, Blackstone EH, Smedira

NG. Cardiac valve replacement in patients on dialysis: influence of prosthesis on

survival. Ann Thorac Surg 2000;70:438-‐41.

222. Herzog CA, Ma JZ, Collins AJ. Long-‐term survival of dialysis patients in the

United States with prosthetic heart valves: should ACC/AHA practice guidelines

on valve selection be modified? Circulation 2002;105:1336-‐41.

223. Chang JP, Kao CL. Mitral valve repair in uremic congestive cardiomyopathy.

Ann Thorac Surg 2003;76:694-‐7.

224. Bonow RO, Carabello B, de Leon AC, Jr., Edmunds LH, Jr., Fedderly BJ, Freed

MD, Gaasch WH, McKay CR, Nishimura RA, O'Gara PT, O'Rourke RA, Rahimtoola

SH, Ritchie JL, Cheitlin MD, Eagle KA, Gardner TJ, Garson A, Jr., Gibbons RJ, Russell

RO, Ryan TJ, Smith SC, Jr. Guidelines for the management of patients with valvular

heart disease: executive summary. A report of the American College of

Cardiology/American Heart Association Task Force on Practice Guidelines

(Committee on Management of Patients with Valvular Heart Disease). Circulation

1998;98:1949-‐84.

225. Brinkman WT, Williams WH, Guyton RA, Jones EL, Craver JM. Valve

replacement in patients on chronic renal dialysis: implications for valve

prosthesis selection. Ann Thorac Surg 2002;74:37-‐42; discussion 42.

239

226. Sharma A, Gilbertson DT, Herzog CA. Survival of kidney transplantation

patients in the United States after cardiac valve replacement. Circulation

2010;121:2733-‐9.

227. Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baron-‐Esquivias G,

Baumgartner H, Borger MA, Carrel TP, De Bonis M, Evangelista A, Falk V, Iung B,

Lancellotti P, Pierard L, Price S, Schafers HJ, Schuler G, Stepinska J, Swedberg K,

Takkenberg J, Von Oppell UO, Windecker S, Zamorano JL, Zembala M, Bax JJ,

Ceconi C, Dean V, Deaton C, Fagard R, Funck-‐Brentano C, Hasdai D, Hoes A,

Kirchhof P, Knuuti J, Kolh P, McDonagh T, Moulin C, Popescu BA, Reiner Z,

Sechtem U, Sirnes PA, Tendera M, Torbicki A, Von Segesser L, Badano LP, Bunc M,

Claeys MJ, Drinkovic N, Filippatos G, Habib G, Kappetein AP, Kassab R, Lip GY,

Moat N, Nickenig G, Otto CM, Pepper J, Piazza N, Pieper PG, Rosenhek R, Shuka N,

Schwammenthal E, Schwitter J, Mas PT, Trindade PT, Walther T. Guidelines on the

management of valvular heart disease (version 2012): The Joint Task Force on

the Management of Valvular Heart Disease of the European Society of Cardiology

(ESC) and the European Association for Cardio-‐Thoracic Surgery (EACTS). Eur

Heart J 2012.

228. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s.

Nature 1993;362:801-‐9.

229. Lerman A, Burnett JC, Jr. Intact and altered endothelium in regulation of

vasomotion. Circulation 1992;86:III12-‐19.

230. Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker of

atherosclerotic risk. Arterioscler Thromb Vasc Biol 2003;23:168-‐75.

231. Gossl M, Lerman LO, Lerman A. Frontiers in nephrology: early

atherosclerosis-‐-‐a view beyond the lumen. J Am Soc Nephrol 2007;18:2836-‐42.

240

232. Lerman A, Zeiher AM. Endothelial function: cardiac events. Circulation

2005;111:363-‐8.

233. Galle J, Quaschning T, Seibold S, Wanner C. Endothelial dysfunction and

inflammation: what is the link? Kidney Int Suppl 2003:S45-‐9.

234. Schiffrin EL. A critical review of the role of endothelial factors in the

pathogenesis of hypertension. J Cardiovasc Pharmacol 2001;38 Suppl 2:S3-‐6.

235. Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis.

Circulation 2004;109:III27-‐32.

236. Halliwell B, Zhao K, Whiteman M. Nitric oxide and peroxynitrite. The ugly,

the uglier and the not so good: a personal view of recent controversies. Free Radic

Res 1999;31:651-‐69.

237. Babior BM. Phagocytes and oxidative stress. Am J Med 2000;109:33-‐44.

238. Schmidt RJ, Yokota S, Tracy TS, Sorkin MI, Baylis C. Nitric oxide production

is low in end-‐stage renal disease patients on peritoneal dialysis. Am J Physiol

1999;276:F794-‐7.

239. Schmidt RJ, Baylis C. Total nitric oxide production is low in patients with

chronic renal disease. Kidney Int 2000;58:1261-‐6.

240. Cross J. Endothelial dysfunction in uraemia. Blood Purif 2002;20:459-‐61.

241. Kielstein JT, Zoccali C. Asymmetric dimethylarginine: a cardiovascular risk

factor and a uremic toxin coming of age? Am J Kidney Dis 2005;46:186-‐202.

242. Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an

endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet

1992;339:572-‐5.

243. Juonala M, Viikari JS, Alfthan G, Marniemi J, Kahonen M, Taittonen L, Laitinen

T, Raitakari OT. Brachial artery flow-‐mediated dilation and asymmetrical

241

dimethylarginine in the cardiovascular risk in young Finns study. Circulation

2007;116:1367-‐73.

244. Meinitzer A, Seelhorst U, Wellnitz B, Halwachs-‐Baumann G, Boehm BO,

Winkelmann BR, Marz W. Asymmetrical dimethylarginine independently predicts

total and cardiovascular mortality in individuals with angiographic coronary

artery disease (the Ludwigshafen Risk and Cardiovascular Health study). Clin

Chem 2007;53:273-‐83.

245. Zoccali C, Bode-‐Boger S, Mallamaci F, Benedetto F, Tripepi G, Malatino L,

Cataliotti A, Bellanuova I, Fermo I, Frolich J, Boger R. Plasma concentration of

asymmetrical dimethylarginine and mortality in patients with end-‐stage renal

disease: a prospective study. Lancet 2001;358:2113-‐7.

246. Kielstein JT, Bode-‐Boger SM, Frolich JC, Haller H, Boger RH. Relationship of

asymmetric dimethylarginine to dialysis treatment and atherosclerotic disease.

Kidney Int Suppl 2001;78:S9-‐13.

247. Cross JM, Donald A, Vallance PJ, Deanfield JE, Woolfson RG, MacAllister RJ.

Dialysis improves endothelial function in humans. Nephrol Dial Transplant

2001;16:1823-‐9.

248. Covic A, Goldsmith DJ, Gusbeth-‐Tatomir P, Covic M. Haemodialysis acutely

improves endothelium-‐independent vasomotor function without significantly

influencing the endothelium-‐mediated abnormal response to a beta 2-‐agonist.

Nephrol Dial Transplant 2004;19:637-‐43.

249. Kosch M, Levers A, Fobker M, Barenbrock M, Schaefer RM, Rahn KH,

Hausberg M. Dialysis filter type determines the acute effect of haemodialysis on

endothelial function and oxidative stress. Nephrol Dial Transplant 2003;18:1370-‐

5.

242

250. Lilien MR, Koomans HA, Schroder CH. Hemodialysis acutely impairs

endothelial function in children. Pediatr Nephrol 2005;20:200-‐4.

251. Meyer C, Heiss C, Drexhage C, Kehmeier ES, Balzer J, Muhlfeld A, Merx MW,

Lauer T, Kuhl H, Floege J, Kelm M, Rassaf T. Hemodialysis-‐Induced Release of

Hemoglobin Limits Nitric Oxide Bioavailability and Impairs Vascular Function. J

Am Coll Cardiol 2010;55:454-‐459.

252. Fliser D, Kielstein JT, Haller H, Bode-‐Boger SM. Asymmetric

dimethylarginine: a cardiovascular risk factor in renal disease? Kidney Int Suppl

2003:S37-‐40.

253. Lindner A, Charra B, Sherrard DJ, Scribner BH. Accelerated atherosclerosis

in prolonged maintenance hemodialysis. N Engl J Med 1974;290:697-‐701.

254. Deanfield J, Donald A, Ferri C, Giannattasio C, Halcox J, Halligan S, Lerman A,

Mancia G, Oliver JJ, Pessina AC, Rizzoni D, Rossi GP, Salvetti A, Schiffrin EL, Taddei

S, Webb DJ. Endothelial function and dysfunction. Part I: Methodological issues

for assessment in the different vascular beds: a statement by the Working Group

on Endothelin and Endothelial Factors of the European Society of Hypertension. J

Hypertens 2005;23:7-‐17.

255. Mallamaci F, Tripepi G, Cutrupi S, Malatino LS, Zoccali C. Prognostic value of

combined use of biomarkers of inflammation, endothelial dysfunction, and

myocardiopathy in patients with ESRD. Kidney Int 2005;67:2330-‐7.

256. Stenvinkel P, Pecoits-‐Filho R, Lindholm B. Coronary artery disease in end-‐

stage renal disease: no longer a simple plumbing problem. J Am Soc Nephrol

2003;14:1927-‐39.

243

257. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan

ID, Lloyd JK, Deanfield JE. Non-‐invasive detection of endothelial dysfunction in

children and adults at risk of atherosclerosis. Lancet 1992;340:1111-‐5.

258. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F,

Creager MA, Deanfield J, Drexler H, Gerhard-‐Herman M, Herrington D, Vallance P,

Vita J, Vogel R. Guidelines for the ultrasound assessment of endothelial-‐

dependent flow-‐mediated vasodilation of the brachial artery: a report of the

International Brachial Artery Reactivity Task Force. J Am Coll Cardiol

2002;39:257-‐65.

259. Wiesmann F, Petersen SE, Leeson PM, Francis JM, Robson MD, Wang Q,

Choudhury R, Channon KM, Neubauer S. Global impairment of brachial, carotid,

and aortic vascular function in young smokers: direct quantification by high-‐

resolution magnetic resonance imaging. J Am Coll Cardiol 2004;44:2056-‐64.

260. Bisoendial RJ, Hovingh GK, de Groot E, Kastelein JJ, Lansberg PJ, Stroes ES.

Measurement of subclinical atherosclerosis: beyond risk factor assessment. Curr

Opin Lipidol 2002;13:595-‐603.

261. Joannides R, Haefeli WE, Linder L, Richard V, Bakkali EH, Thuillez C, Luscher

TF. Nitric oxide is responsible for flow-‐dependent dilatation of human peripheral

conduit arteries in vivo. Circulation 1995;91:1314-‐9.

262. Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR, Jr., Lerman A.

Long-‐term follow-‐up of patients with mild coronary artery disease and

endothelial dysfunction. Circulation 2000;101:948-‐54.

263. Widlansky ME, Gokce N, Keaney JF, Jr., Vita JA. The clinical implications of

endothelial dysfunction. J Am Coll Cardiol 2003;42:1149-‐60.

244

264. Schindler TH, Cadenas J, Facta AD, Li Y, Olschewski M, Sayre J, Goldin J,

Schelbert HR. Improvement in coronary endothelial function is independently

associated with a slowed progression of coronary artery calcification in type 2

diabetes mellitus. Eur Heart J 2009;30:3064-‐73.

265. London GM, Pannier B, Agharazii M, Guerin AP, Verbeke FH, Marchais SJ.

Forearm reactive hyperemia and mortality in end-‐stage renal disease. Kidney Int

2004;65:700-‐4.

266. Kuvin JT, Patel AR, Sliney KA, Pandian NG, Rand WM, Udelson JE, Karas RH.

Peripheral vascular endothelial function testing as a noninvasive indicator of

coronary artery disease. J Am Coll Cardiol 2001;38:1843-‐9.

267. Brunner H, Cockcroft JR, Deanfield J, Donald A, Ferrannini E, Halcox J,

Kiowski W, Luscher TF, Mancia G, Natali A, Oliver JJ, Pessina AC, Rizzoni D, Rossi

GP, Salvetti A, Spieker LE, Taddei S, Webb DJ. Endothelial function and

dysfunction. Part II: Association with cardiovascular risk factors and diseases. A

statement by the Working Group on Endothelins and Endothelial Factors of the

European Society of Hypertension. J Hypertens 2005;23:233-‐46.

268. Pannier B, Guerin AP, Marchais SJ, Metivier F, Safar ME, London GM.

Postischemic vasodilation, endothelial activation, and cardiovascular remodeling

in end-‐stage renal disease. Kidney Int 2000;57:1091-‐9.

269. Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA,

Nour KR, Quyyumi AA. Prognostic value of coronary vascular endothelial

dysfunction. Circulation 2002;106:653-‐8.

270. Anderson TJ, Uehata A, Gerhard MD, Meredith IT, Knab S, Delagrange D,

Lieberman EH, Ganz P, Creager MA, Yeung AC, et al. Close relation of endothelial

245

function in the human coronary and peripheral circulations. J Am Coll Cardiol

1995;26:1235-‐41.

271. Nabel EG, Ganz P, Gordon JB, Alexander RW, Selwyn AP. Dilation of normal

and constriction of atherosclerotic coronary arteries caused by the cold pressor

test. Circulation 1988;77:43-‐52.

272. Puri R, Liew GY, Nicholls SJ, Nelson AJ, Leong DP, Carbone A, Copus B, Wong

DT, Beltrame JF, Worthley SG, Worthley MI. Intracoronary Salbutamol, Segmental

Plaque Burden and Focal Coronary Endothelial Function: Novel Mechanistic

Insights from an In Vivo Intravacular Ultrasound Study. . J Am Coll Cardiol

2011;57:410-‐08.

273. Ludmer PL, Selwyn AP, Shook TL, Wayne RR, Mudge GH, Alexander RW,

Ganz P. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic

coronary arteries. N Engl J Med 1986;315:1046-‐51.

274. Yeung AC, Vekshtein VI, Krantz DS, Vita JA, Ryan TJ, Jr., Ganz P, Selwyn AP.

The effect of atherosclerosis on the vasomotor response of coronary arteries to

mental stress. N Engl J Med 1991;325:1551-‐6.

275. Doucette JW, Corl PD, Payne HM, Flynn AE, Goto M, Nassi M, Segal J.

Validation of a Doppler guide wire for intravascular measurement of coronary

artery flow velocity. Circulation 1992;85:1899-‐911.

276. Hasdai D, Lerman A. The assessment of endothelial function in the cardiac

catheterization laboratory in patients with risk factors for atherosclerotic

coronary artery disease. Herz 1999;24:544-‐7.

277. Ragosta M, Samady H, Isaacs RB, Gimple LW, Sarembock IJ, Powers ER.

Coronary flow reserve abnormalities in patients with diabetes mellitus who have

246

end-‐stage renal disease and normal epicardial coronary arteries. Am Heart J

2004;147:1017-‐23.

278. Koivuviita N, Tertti R, Jarvisalo M, Pietila M, Hannukainen J, Sundell J,

Nuutila P, Knuuti J, Metsarinne K. Increased basal myocardial perfusion in

patients with chronic kidney disease without symptomatic coronary artery

disease. Nephrol Dial Transplant 2009;24:2773-‐9.

279. Sorensen KE, Celermajer DS, Spiegelhalter DJ, Georgakopoulos D, Robinson J,

Thomas O, Deanfield JE. Non-‐invasive measurement of human endothelium

dependent arterial responses: accuracy and reproducibility. Br Heart J

1995;74:247-‐53.

280. Wu HD, Katz SD, Beniaminovitz A, Khan T, DiTullio MR, Homma S.

Assessment of endothelium-‐mediated vasodilation of the peripheral circulation

by transcutaneous ultrasonography and venous occlusion plethysmography.

Heart Vessels 1999;14:143-‐8.

281. Bottcher M, Madsen MM, Refsgaard J, Buus NH, Dorup I, Nielsen TT,

Sorensen K. Peripheral flow response to transient arterial forearm occlusion does

not reflect myocardial perfusion reserve. Circulation 2001;103:1109-‐14.

282. Chade AR, Brosh D, Higano ST, Lennon RJ, Lerman LO, Lerman A. Mild renal

insufficiency is associated with reduced coronary flow in patients with non-‐

obstructive coronary artery disease. Kidney Int 2006;69:266-‐71.

283. Erdogan D, Yildirim I, Ciftci O, Ozer I, Caliskan M, Gullu H, Muderrisoglu H.

Effects of normal blood pressure, prehypertension, and hypertension on coronary

microvascular function. Circulation 2007;115:593-‐9.

284. Galderisi M, Capaldo B, Sidiropulos M, D'Errico A, Ferrara L, Turco A, Guarini

P, Riccardi G, de Divitiis O. Determinants of reduction of coronary flow reserve in

247

patients with type 2 diabetes mellitus or arterial hypertension without

angiographically determined epicardial coronary stenosis. Am J Hypertens

2007;20:1283-‐90.

285. Galderisi M, Cicala S, Caso P, De Simone L, D'Errico A, Petrocelli A, de Divitiis

O. Coronary flow reserve and myocardial diastolic dysfunction in arterial

hypertension. Am J Cardiol 2002;90:860-‐4.

286. Le Feuvre C, Raoux F, Beygui F, Helft G, Mogenet A, Dubois-‐Laforgue D,

Timsit J, Metzger JP. Cumulative adverse effects of diabetes mellitus and

hypertension on coronary flow velocity reserve. Arch Mal Coeur Vaiss

2004;97:849-‐54.

287. Pirat B, Bozbas H, Simsek V, Yildirir A, Sade LE, Gursoy Y, Altin C, Atar I,

Muderrisoglu H. Impaired coronary flow reserve in patients with metabolic

syndrome. Atherosclerosis 2008;201:112-‐6.

288. Vogt M, Motz W, Schwartzkopff B, Strauer BE. Coronary microangiopathy

and cardiac hypertrophy. Eur Heart J 1990;11 Suppl B:133-‐8.

289. Palombo C, Kozakova M, Magagna A, Bigalli G, Morizzo C, Ghiadoni L, Virdis

A, Emdin M, Taddei S, L'Abbate A, Salvetti A. Early impairment of coronary flow

reserve and increase in minimum coronary resistance in borderline hypertensive

patients. J Hypertens 2000;18:453-‐9.

290. Laine H, Raitakari OT, Niinikoski H, Pitkanen OP, Iida H, Viikari J, Nuutila P,

Knuuti J. Early impairment of coronary flow reserve in young men with

borderline hypertension. J Am Coll Cardiol 1998;32:147-‐53.

291. Kozakova M, Palombo C, Pratali L, Pittella G, Galetta F, L'Abbate A.

Mechanisms of coronary flow reserve impairment in human hypertension. An

248

integrated approach by transthoracic and transesophageal echocardiography.

Hypertension 1997;29:551-‐9.

292. Kozakova M, Galetta F, Gregorini L, Bigalli G, Franzoni F, Giusti C, Palombo C.

Coronary vasodilator capacity and epicardial vessel remodeling in physiological

and hypertensive hypertrophy. Hypertension 2000;36:343-‐9.

293. Choudhury L, Rosen SD, Patel D, Nihoyannopoulos P, Camici PG. Coronary

vasodilator reserve in primary and secondary left ventricular hypertrophy. A

study with positron emission tomography. Eur Heart J 1997;18:108-‐16.

294. Hamasaki S, Al Suwaidi J, Higano ST, Miyauchi K, Holmes DR, Jr., Lerman A.

Attenuated coronary flow reserve and vascular remodeling in patients with

hypertension and left ventricular hypertrophy. J Am Coll Cardiol 2000;35:1654-‐

60.

295. Anderson HV, Stokes MJ, Leon M, Abu-‐Halawa SA, Stuart Y, Kirkeeide RL.

Coronary artery flow velocity is related to lumen area and regional left

ventricular mass. Circulation 2000;102:48-‐54.

296. Houghton JL, Carr AA, Prisant LM, Rogers WB, von Dohlen TW, Flowers NC,

Frank MJ. Morphologic, hemodynamic and coronary perfusion characteristics in

severe left ventricular hypertrophy secondary to systemic hypertension and

evidence for nonatherosclerotic myocardial ischemia. Am J Cardiol 1992;69:219-‐

24.

297. Bozbas H, Pirat B, Yildirir A, Simsek V, Sade E, Eroglu S, Atar I, Altin C,

Demirtas S, Ozin B, Muderrisoglu H. Coronary flow reserve is impaired in patients

with aortic valve calcification. Atherosclerosis 2008;197:846-‐52.

249

298. Bozbas H, Pirat B, Yildirir A, Simsek V, Sade E, Altin C, Muderrisoglu H. Mitral

annular calcification associated with impaired coronary microvascular function.

Atherosclerosis 2008;198:115-‐21.

299. Recio-‐Mayoral A, Mason JC, Kaski JC, Rubens MB, Harari OA, Camici PG.

Chronic inflammation and coronary microvascular dysfunction in patients

without risk factors for coronary artery disease. Eur Heart J 2009;30:1837-‐43.

300. Ansari A, Kaupke CJ, Vaziri ND, Miller R, Barbari A. Cardiac pathology in

patients with end-‐stage renal disease maintained on hemodialysis. Int J Artif

Organs 1993;16:31-‐6.

301. Rostand SG, Kirk KA, Rutsky EA. Dialysis-‐associated ischemic heart disease:

insights from coronary angiography. Kidney Int 1984;25:653-‐9.

302. Schwarz U, Buzello M, Ritz E, Stein G, Raabe G, Wiest G, Mall G, Amann K.

Morphology of coronary atherosclerotic lesions in patients with end-‐stage renal

failure. Nephrol Dial Transplant 2000;15:218-‐23.

303. Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, Wang Y, Chung J,

Emerick A, Greaser L, Elashoff RM, Salusky IB. Coronary-‐artery calcification in

young adults with end-‐stage renal disease who are undergoing dialysis. N Engl J

Med 2000;342:1478-‐83.

304. McCullough PA, Sandberg KR, Dumler F, Yanez JE. Determinants of coronary

vascular calcification in patients with chronic kidney disease and end-‐stage renal

disease: a systematic review. J Nephrol 2004;17:205-‐15.

305. Gradaus F, Ivens K, Peters AJ, Heering P, Schoebel FC, Grabensee B, Strauer

BE. Angiographic progression of coronary artery disease in patients with end-‐

stage renal disease. Nephrol Dial Transplant 2001;16:1198-‐202.

250

306. Clyne N, Lins LE, Pehrsson SK. Occurrence and significance of heart disease

in uraemia. An autopsy study. Scand J Urol Nephrol 1986;20:307-‐11.

307. Ikram H, Lynn KL, Bailey RR, Little PJ. Cardiovascular changes in chronic

hemodialysis patients. Kidney Int 1983;24:371-‐6.

308. Joki N, Hase H, Takahashi Y, Ishikawa H, Nakamura R, Imamura Y, Tanaka Y,

Saijyo T, Fukazawa M, Inishi Y, Nakamura M, Yamaguchi T. Angiographical

severity of coronary atherosclerosis predicts death in the first year of

hemodialysis. Int Urol Nephrol 2003;35:289-‐97.

309. Stack AG, Bloembergen WE. Prevalence and clinical correlates of coronary

artery disease among new dialysis patients in the United States: a cross-‐sectional

study. J Am Soc Nephrol 2001;12:1516-‐23.

310. Fox CS, Larson MG, Keyes MJ, Levy D, Clouse ME, Culleton B, O'Donnell CJ.

Kidney function is inversely associated with coronary artery calcification in men

and women free of cardiovascular disease: the Framingham Heart Study. Kidney

Int 2004;66:2017-‐21.

311. Herzog CA. Sudden cardiac death and acute myocardial infarction in dialysis

patients: perspectives of a cardiologist. Semin Nephrol 2005;25:363-‐6.

312. Fox CS, Muntner P, Chen AY, Alexander KP, Roe MT, Cannon CP, Saucedo JF,

Kontos MC, Wiviott SD. Use of evidence-‐based therapies in short-‐term outcomes

of ST-‐segment elevation myocardial infarction and non-‐ST-‐segment elevation

myocardial infarction in patients with chronic kidney disease: a report from the

National Cardiovascular Data Acute Coronary Treatment and Intervention

Outcomes Network registry. Circulation 2010;121:357-‐65.

313. Herzog CA, Ma JZ, Collins AJ. Poor long-‐term survival after acute myocardial

infarction among patients on long-‐term dialysis. N Engl J Med 1998;339:799-‐805.

251

314. Gibson CM, Dumaine RL, Gelfand EV, Murphy SA, Morrow DA, Wiviott SD,

Giugliano RP, Cannon CP, Antman EM, Braunwald E. Association of glomerular

filtration rate on presentation with subsequent mortality in non-‐ST-‐segment

elevation acute coronary syndrome; observations in 13,307 patients in five TIMI

trials. Eur Heart J 2004;25:1998-‐2005.

315. Santopinto JJ, Fox KA, Goldberg RJ, Budaj A, Pinero G, Avezum A, Gulba D,

Esteban J, Gore JM, Johnson J, Gurfinkel EP. Creatinine clearance and adverse

hospital outcomes in patients with acute coronary syndromes: findings from the

global registry of acute coronary events (GRACE). Heart 2003;89:1003-‐8.

316. Himmelfarb J. Chronic kidney disease and the public health: gaps in

evidence from interventional trials. JAMA 2007;297:2630-‐3.

317. Coca SG, Krumholz HM, Garg AX, Parikh CR. Underrepresentation of renal

disease in randomized controlled trials of cardiovascular disease. JAMA

2006;296:1377-‐84.

318. Charytan D, Mauri L, Agarwal A, Servoss S, Scirica B, Kuntz RE. The use of

invasive cardiac procedures after acute myocardial infarction in long-‐term

dialysis patients. Am Heart J 2006;152:558-‐64.

319. Keough-‐Ryan TM, Kiberd BA, Dipchand CS, Cox JL, Rose CL, Thompson KJ,

Clase CM. Outcomes of acute coronary syndrome in a large Canadian cohort:

impact of chronic renal insufficiency, cardiac interventions, and anemia. Am J

Kidney Dis 2005;46:845-‐55.

320. Fox KA, Bassand JP, Mehta SR, Wallentin L, Theroux P, Piegas LS, Valentin V,

Moccetti T, Chrolavicius S, Afzal R, Yusuf S. Influence of renal function on the

efficacy and safety of fondaparinux relative to enoxaparin in non ST-‐segment

elevation acute coronary syndromes. Ann Intern Med 2007;147:304-‐10.

252

321. Collet JP, Montalescot G, Agnelli G, Van de Werf F, Gurfinkel EP, Lopez-‐

Sendon J, Laufenberg CV, Klutman M, Gowda N, Gulba D. Non-‐ST-‐segment

elevation acute coronary syndrome in patients with renal dysfunction: benefit of

low-‐molecular-‐weight heparin alone or with glycoprotein IIb/IIIa inhibitors on

outcomes. The Global Registry of Acute Coronary Events. Eur Heart J

2005;26:2285-‐93.

322. Alexander KP, Chen AY, Roe MT, Newby LK, Gibson CM, Allen-‐LaPointe NM,

Pollack C, Gibler WB, Ohman EM, Peterson ED. Excess dosing of antiplatelet and

antithrombin agents in the treatment of non-‐ST-‐segment elevation acute

coronary syndromes. JAMA 2005;294:3108-‐16.

323. Herzog CA, Ma JZ, Collins AJ. Comparative survival of dialysis patients in the

United States after coronary angioplasty, coronary artery stenting, and coronary

artery bypass surgery and impact of diabetes. Circulation 2002;106:2207-‐11.

324. Szczech LA, Reddan DN, Owen WF, Califf R, Racz M, Jones RH, Hannan EL.

Differential survival after coronary revascularization procedures among patients

with renal insufficiency. Kidney Int 2001;60:292-‐9.

325. Kahn JK, Rutherford BD, McConahay DR, Johnson WL, Giorgi LV, Hartzler GO.

Short-‐ and long-‐term outcome of percutaneous transluminal coronary

angioplasty in chronic dialysis patients. Am Heart J 1990;119:484-‐9.

326. Malanuk RM, Nielsen CD, Theis P, Assey ME, Usher BW, Leman RB.

Treatment of coronary artery disease in hemodialysis patients: PTCA vs. stent.

Catheter Cardiovasc Interv 2001;54:459-‐63.

327. Azar RR, Prpic R, Ho KK, Kiernan FJ, Shubrooks SJ, Jr., Baim DS, Popma JJ,

Kuntz RE, Cohen DJ. Impact of end-‐stage renal disease on clinical and

angiographic outcomes after coronary stenting. Am J Cardiol 2000;86:485-‐9.

253

328. Appleby CE, Ivanov J, Lavi S, Mackie K, Horlick EM, Ing D, Overgaard CB,

Seidelin PH, von Harsdorf R, Dzavik V. The adverse long-‐term impact of renal

impairment in patients undergoing percutaneous coronary intervention in the

drug-‐eluting stent era. Circ Cardiovasc Interv 2009;2:309-‐16.

329. Naidu SS, Krucoff MW, Rutledge DR, Mao VW, Zhao W, Zheng Q, Wilburn O,

Sudhir K, Simonton C, Hermiller JB. Contemporary incidence and predictors of

stent thrombosis and other major adverse cardiac events in the year after XIENCE

V implantation: results from the 8,061-‐patient XIENCE V United States study.

JACC Cardiovasc Interv 2012;5:626-‐35.

330. Guerin AP, Marchais SJ, Metivier F, London GM. Arterial structural and

functional alterations in uraemia. Eur J Clin Invest 2005;35 Suppl 3:85-‐8.

331. Guerin AP, Pannier B, Marchais SJ, London GM. Arterial structure and

function in end-‐stage renal disease. Curr Hypertens Rep 2008;10:107-‐11.

332. Vlachopoulos C, Aznaouridis K, Stefanadis C. Clinical appraisal of arterial

stiffness: the Argonauts in front of the Golden Fleece. Heart 2006;92:1544-‐50.

333. Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM. Arterial

calcifications, arterial stiffness, and cardiovascular risk in end-‐stage renal disease.


334. O'Rourke MF, Kelly RP. Wave reflection in the systemic circulation and its

implications in ventricular function. J Hypertens 1993;11:327-‐37.

335. Latham RD, Westerhof N, Sipkema P, Rubal BJ, Reuderink P, Murgo JP.

Regional wave travel and reflections along the human aorta: a study with six

simultaneous micromanometric pressures. Circulation 1985;72:1257-‐69.

254

336. London G, Guerin A, Pannier B, Marchais S, Benetos A, Safar M. Increased

systolic pressure in chronic uremia. Role of arterial wave reflections.


337. Watanabe H, Ohtsuka S, Kakihana M, Sugishita Y. Coronary circulation in

dogs with an experimental decrease in aortic compliance. J Am Coll Cardiol

1993;21:1497-‐506.

338. Ohtsuka S, Kakihana M, Watanabe H, Sugishita Y. Chronically decreased

aortic distensibility causes deterioration of coronary perfusion during increased

left ventricular contraction. J Am Coll Cardiol 1994;24:1406-‐14.

339. Watanabe H, Ohtsuka S, Kakihana M, Sugishita Y. Decreased aortic

compliance aggravates subendocardial ischaemia in dogs with stenosed coronary

artery. Cardiovasc Res 1992;26:1212-‐8.

340. Buckberg GD, Towers B, Paglia DE, Mulder DG, Maloney JV. Subendocardial

ischemia after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1972;64:669-‐

84. In: Guerin AP, Pannier B, Marchais SJ, London GM. Arterial structure and

function in end-‐stage renal disease. Curr Hypertens Rep 2008;10:107-‐11.

341. Hojs R, Hojs-‐Fabjan T, Balon BP. Atherosclerosis in patients with end-‐stage

renal failure prior to initiation of hemodialysis. Ren Fail 2003;25:247-‐54.

342. Shoji T, Emoto M, Tabata T, Kimoto E, Shinohara K, Maekawa K, Kawagishi T,

Tahara H, Ishimura E, Nishizawa Y. Advanced atherosclerosis in predialysis

patients with chronic renal failure. Kidney Int 2002;61:2187-‐92.

343. Joki N, Hase H, Nakamura R, Yamaguchi T. Onset of coronary artery disease

prior to initiation of haemodialysis in patients with end-‐stage renal disease.


255

344. Liu J, Huang Z, Gilbertson DT, Foley RN, Collins AJ. An improved comorbidity

index for outcome analyses among dialysis patients. Kidney Int 2010;77:141-‐51.

345. Toyoda K, Fujii K, Fujimi S, Kumai Y, Tsuchimochi H, Ibayashi S, Iida M.

Stroke in patients on maintenance hemodialysis: a 22-‐year single-‐center study.

Am J Kidney Dis 2005;45:1058-‐66.

346. London GM, Guerin AP, Marchais SJ, Pannier B, Safar ME, Day M, Metivier F.

Cardiac and arterial interactions in end-‐stage renal disease. Kidney Int

1996;50:600-‐8.

347. Wang MC, Tsai WC, Chen JY, Huang JJ. Stepwise increase in arterial stiffness

corresponding with the stages of chronic kidney disease. Am J Kidney Dis

2005;45:494-‐501.

348. Antonini-‐Canterin F, Carerj S, Di Bello V, Di Salvo G, La Carrubba S, Vriz O,

Pavan D, Balbarini A, Nicolosi GL. Arterial stiffness and ventricular stiffness: a

couple of diseases or a coupling disease? A review from the cardiologist's point of

view. Eur J Echocardiogr 2009;10:36-‐43.

349. Proudfoot D, Shanahan CM. Biology of calcification in vascular cells: intima

versus media. Herz 2001;26:245-‐51.

350. Burke AP, Weber DK, Kolodgie FD, Farb A, Taylor AJ, Virmani R.

Pathophysiology of calcium deposition in coronary arteries. Herz 2001;26:239-‐

44.

351. Schoenhagen P, Ziada KM, Kapadia SR, Crowe TD, Nissen SE, Tuzcu EM.

Extent and direction of arterial remodeling in stable versus unstable coronary

syndromes : an intravascular ultrasound study. Circulation 2000;101:598-‐603.

256

352. Smits PC, Pasterkamp G, de Jaegere PP, de Feyter PJ, Borst C. Angioscopic

complex lesions are predominantly compensatory enlarged: an angioscopy and

intracoronary ultrasound study. Cardiovasc Res 1999;41:458-‐64.

353. Gussenhoven EJ, Essed CE, Lancee CT, Mastik F, Frietman P, van Egmond FC,

Reiber J, Bosch H, van Urk H, Roelandt J, et al. Arterial wall characteristics

determined by intravascular ultrasound imaging: an in vitro study. J Am Coll

Cardiol 1989;14:947-‐52.

354. Hodgson JM, Reddy KG, Suneja R, Nair RN, Lesnefsky EJ, Sheehan HM.

Intracoronary ultrasound imaging: correlation of plaque morphology with

angiography, clinical syndrome and procedural results in patients undergoing

coronary angioplasty. J Am Coll Cardiol 1993;21:35-‐44.

355. Schoenhagen P, Tuzcu EM. Coronary artery calcification and end-‐stage renal

disease: vascular biology and clinical implications. Cleve Clin J Med 2002;69 Suppl

3:S12-‐20.

356. Elliott RJ, McGrath LT. Calcification of the human thoracic aorta during

aging. Calcif Tissue Int 1994;54:268-‐73.

357. Lindbom A. Arteriosclerosis and arterial thrombosis in the lower limb; a

roentgenological study. Acta Radiol Suppl 1950;80:1-‐80. In: Proudfoot D,

Shanahan CM. Biology of calcification in vascular cells: intima versus media. Herz

2001;26:245-‐51.

358. Witteman JC, Kok FJ, van Saase JL, Valkenburg HA. Aortic calcification as a

predictor of cardiovascular mortality. Lancet 1986;2:1120-‐2.

359. Wilson PW, Kauppila LI, O'Donnell CJ, Kiel DP, Hannan M, Polak JM, Cupples

LA. Abdominal aortic calcific deposits are an important predictor of vascular

morbidity and mortality. Circulation 2001;103:1529-‐34.

257

360. Abbott RD, Ueshima H, Masaki KH, Willcox BJ, Rodriguez BL, Ikeda A, Yano

K, White LR, Curb JD. Coronary artery calcification and total mortality in elderly

men. J Am Geriatr Soc 2007;55:1948-‐54.

361. Wade AN, Reilly MP. Coronary calcification in chronic kidney disease:

morphology, mechanisms and mortality. Clin J Am Soc Nephrol 2009;4:1883-‐5.

362. Thompson GR, Partridge J. Coronary calcification score: the coronary-‐risk

impact factor. Lancet 2004;363:557-‐9.

363. He ZX, Hedrick TD, Pratt CM, Verani MS, Aquino V, Roberts R, Mahmarian JJ.

Severity of coronary artery calcification by electron beam computed tomography

predicts silent myocardial ischemia. Circulation 2000;101:244-‐51.

364. Guerin AP, London GM, Marchais SJ, Metivier F. Arterial stiffening and

vascular calcifications in end-‐stage renal disease. Nephrol Dial Transplant

2000;15:1014-‐21.

365. Iseki K, Miyasato F, Tokuyama K, Nishime K, Uehara H, Shiohira Y, Sunagawa

H, Yoshihara K, Yoshi S, Toma S, Kowatari T, Wake T, Oura T, Fukiyama K. Low

diastolic blood pressure, hypoalbuminemia, and risk of death in a cohort of

chronic hemodialysis patients. Kidney Int 1997;51:1212-‐7.

366. Klassen PS, Lowrie EG, Reddan DN, DeLong ER, Coladonato JA, Szczech LA,

Lazarus JM, Owen WF, Jr. Association between pulse pressure and mortality in

patients undergoing maintenance hemodialysis. JAMA 2002;287:1548-‐55.

367. Raggi P, Vukicevic S, Moyses RM, Wesseling K, Spiegel DM. Ten-‐year

experience with sevelamer and calcium salts as phosphate binders. Clin J Am Soc

Nephrol 2010;5 Suppl 1:S31-‐40.

368. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D,

Pannier B, Vlachopoulos C, Wilkinson I, Struijker-‐Boudier H. Expert consensus

258

document on arterial stiffness: methodological issues and clinical applications.

Eur Heart J 2006;27:2588-‐605.

369. Van Bortel LM, Duprez D, Starmans-‐Kool MJ, Safar ME, Giannattasio C,

Cockcroft J, Kaiser DR, Thuillez C. Clinical applications of arterial stiffness, Task

Force III: recommendations for user procedures. Am J Hypertens 2002;15:445-‐52.

370. Laurent S, Boutouyrie P. Arterial stiffness: a new surrogate end point for

cardiovascular disease? J Nephrol 2007;20 Suppl 12:S45-‐50.

371. Guerin AP, Blacher J, Pannier B, Marchais SJ, Safar ME, London GM. Impact of

aortic stiffness attenuation on survival of patients in end-‐stage renal failure.

Circulation 2001;103:987-‐92.

372. Shoji T, Emoto M, Shinohara K, Kakiya R, Tsujimoto Y, Kishimoto H, Ishimura

E, Tabata T, Nishizawa Y. Diabetes mellitus, aortic stiffness, and cardiovascular

mortality in end-‐stage renal disease. J Am Soc Nephrol 2001;12:2117-‐24.

373. Lemos MM, Jancikic AD, Sanches FM, Christofalo DM, Ajzen SA, Miname MH,

Santos RD, Fachini FC, Carvalho AB, Draibe SA, Canziani ME. Pulse wave velocity-‐-‐

a useful tool for cardiovascular surveillance in pre-‐dialysis patients. Nephrol Dial

Transplant 2007;22:3527-‐32.

374. Upadhyay A, Hwang SJ, Mitchell GF, Vasan RS, Vita JA, Stantchev PI, Meigs JB,

Larson MG, Levy D, Benjamin EJ, Fox CS. Arterial stiffness in mild-‐to-‐moderate

CKD. J Am Soc Nephrol 2009;20:2044-‐53.

375. Cruickshank K, Riste L, Anderson SG, Wright JS, Dunn G, Gosling RG. Aortic

pulse-‐wave velocity and its relationship to mortality in diabetes and glucose

intolerance: an integrated index of vascular function? Circulation 2002;106:2085-‐

90.

259

376. Kingwell BA, Waddell TK, Medley TL, Cameron JD, Dart AM. Large artery

stiffness predicts ischemic threshold in patients with coronary artery disease. J

Am Coll Cardiol 2002;40:773-‐9.

377. Stefanadis C, Dernellis J, Tsiamis E, Stratos C, Diamantopoulos L, Michaelides

A, Toutouzas P. Aortic stiffness as a risk factor for recurrent acute coronary

events in patients with ischaemic heart disease. Eur Heart J 2000;21:390-‐6.

378. Chirinos JA, Zambrano JP, Chakko S, Veerani A, Schob A, Willens HJ, Perez G,

Mendez AJ. Aortic pressure augmentation predicts adverse cardiovascular events

in patients with established coronary artery disease. Hypertension 2005;45:980-‐

5.

379. Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux B, Guize L, Ducimetiere

P, Benetos A. Aortic stiffness is an independent predictor of all-‐cause and

cardiovascular mortality in hypertensive patients. Hypertension 2001;37:1236-‐

41.

380. Boutouyrie P, Tropeano AI, Asmar R, Gautier I, Benetos A, Lacolley P,

Laurent S. Aortic stiffness is an independent predictor of primary coronary

events in hypertensive patients: a longitudinal study. Hypertension 2002;39:10-‐5.

381. Laurent S, Katsahian S, Fassot C, Tropeano AI, Gautier I, Laloux B,

Boutouyrie P. Aortic stiffness is an independent predictor of fatal stroke in

essential hypertension. Stroke 2003;34:1203-‐6.

382. Meaume S, Benetos A, Henry OF, Rudnichi A, Safar ME. Aortic pulse wave

velocity predicts cardiovascular mortality in subjects >70 years of age.

Arterioscler Thromb Vasc Biol 2001;21:2046-‐50.

383. Sutton-‐Tyrrell K, Najjar SS, Boudreau RM, Venkitachalam L, Kupelian V,

Simonsick EM, Havlik R, Lakatta EG, Spurgeon H, Kritchevsky S, Pahor M, Bauer D,

260

Newman A. Elevated aortic pulse wave velocity, a marker of arterial stiffness,

predicts cardiovascular events in well-‐functioning older adults. Circulation

2005;111:3384-‐90.

384. Song BG, Park JB, Cho SJ, Lee SY, Kim JH, Choi SM, Park JH, Park YH, Choi JO,

Lee SC, Park SW. Pulse wave velocity is more closely associated with

cardiovascular risk than augmentation index in the relatively low-‐risk population.

Heart Vessels 2009;24:413-‐8.

385. Mitchell GF, Hwang SJ, Vasan RS, Larson MG, Pencina MJ, Hamburg NM, Vita

JA, Levy D, Benjamin EJ. Arterial stiffness and cardiovascular events: the

framingham heart study. Circulation 2010;121:505-‐11.

386. Mohiaddin RH, Underwood SR, Bogren HG, Firmin DN, Klipstein RH, Rees

RS, Longmore DB. Regional aortic compliance studied by magnetic resonance

imaging: the effects of age, training, and coronary artery disease. Br Heart J

1989;62:90-‐6.

387. Hundley WG, Kitzman DW, Morgan TM, Hamilton CA, Darty SN, Stewart KP,

Herrington DM, Link KM, Little WC. Cardiac cycle-‐dependent changes in aortic

area and distensibility are reduced in older patients with isolated diastolic heart

failure and correlate with exercise intolerance. J Am Coll Cardiol 2001;38:796-‐

802.

388. Savolainen A, Keto P, Hekali P, Nisula L, Kaitila I, Viitasalo M, Poutanen VP,

Standertskjold-‐Nordenstam CG, Kupari M. Aortic distensibility in children with

the Marfan syndrome. Am J Cardiol 1992;70:691-‐3.

389. Adams JN, Brooks M, Redpath TW, Smith FW, Dean J, Gray J, Walton S, Trent

RJ. Aortic distensibility and stiffness index measured by magnetic resonance

imaging in patients with Marfan's syndrome. Br Heart J 1995;73:265-‐9.

261

390. Groenink M, de Roos A, Mulder BJ, Spaan JA, van der Wall EE. Changes in

aortic distensibility and pulse wave velocity assessed with magnetic resonance

imaging following beta-‐blocker therapy in the Marfan syndrome. Am J Cardiol

1998;82:203-‐8.

391. Fattori R, Bacchi Reggiani L, Pepe G, Napoli G, Bna C, Celletti F, Lovato L,

Gavelli G. Magnetic resonance imaging evaluation of aortic elastic properties as

early expression of Marfan syndrome. J Cardiovasc Magn Reson 2000;2:251-‐6.

392. Murai S, Hamada S, Ueguchi T, Khankan AA, Sumikawa H, Inoue A,

Tsubamoto M, Honda O, Tomiyama N, Johkoh T, Nakamura H. Aortic compliance

in patients with aortic regurgitation: evaluation with magnetic resonance

imaging. Radiat Med 2005;23:236-‐41.

393. Kupari M, Hekali P, Keto P, Poutanen VP, Tikkanen MJ, Standerstkjold-‐

Nordenstam CG. Relation of aortic stiffness to factors modifying the risk of

atherosclerosis in healthy people. Arterioscler Thromb 1994;14:386-‐94.

394. Nelson AJ, Worthley SG, Cameron JD, Willoughby SR, Piantadosi C, Carbone

A, Dundon BK, Leung MC, Hope SA, Meredith IT, Worthley MI. Cardiovascular

magnetic resonance-‐derived aortic distensibility: validation and observed

regional differences in the elderly. J Hypertens 2009;27:535-‐42.

395. Mark PB, Doyle A, Blyth KG, Patel RK, Weir RA, Steedman T, Foster JE, Dargie

HJ, Jardine AG. Vascular function assessed with cardiovascular magnetic

resonance predicts survival in patients with advanced chronic kidney disease. J

Cardiovasc Magn Reson 2008;10:39.

396. Chen CH, Ting CT, Nussbacher A, Nevo E, Kass DA, Pak P, Wang SP, Chang

MS, Yin FC. Validation of carotid artery tonometry as a means of estimating

augmentation index of ascending aortic pressure. Hypertension 1996;27:168-‐75.

262

397. Chen CH, Nevo E, Fetics B, Pak PH, Yin FC, Maughan WL, Kass DA. Estimation

of central aortic pressure waveform by mathematical transformation of radial

tonometry pressure. Validation of generalized transfer function. Circulation

1997;95:1827-‐36.

398. Pauca AL, O'Rourke MF, Kon ND. Prospective evaluation of a method for

estimating ascending aortic pressure from the radial artery pressure waveform.


399. Adji A, O'Rourke MF. Determination of central aortic systolic and pulse

pressure from the radial artery pressure waveform. Blood Press Monit

2004;9:115-‐21.

400. Fetics B, Nevo E, Chen CH, Kass DA. Parametric model derivation of transfer

function for noninvasive estimation of aortic pressure by radial tonometry. IEEE

Trans Biomed Eng 1999;46:698-‐706.

401. Safar ME, Blacher J, Pannier B, Guerin AP, Marchais SJ, Guyonvarc'h PM,

London GM. Central pulse pressure and mortality in end-‐stage renal disease.


402. London GM, Blacher J, Pannier B, Guerin AP, Marchais SJ, Safar ME. Arterial

wave reflections and survival in end-‐stage renal failure. Hypertension

2001;38:434-‐8.

403. Weber T, Auer J, O'Rourke M F, Kvas E, Lassnig E, Lamm G, Stark N, Rammer

M, Eber B. Increased arterial wave reflections predict severe cardiovascular

events in patients undergoing percutaneous coronary interventions. Eur Heart J

2005;26:2657-‐63.

404. Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, Hughes

AD, Thurston H, O'Rourke M. Differential impact of blood pressure-‐lowering

263

drugs on central aortic pressure and clinical outcomes: principal results of the

Conduit Artery Function Evaluation (CAFE) study. Circulation 2006;113:1213-‐25.

405. Weber T, Auer J, O'Rourke MF, Kvas E, Lassnig E, Berent R, Eber B. Arterial

stiffness, wave reflections, and the risk of coronary artery disease. Circulation

2004;109:184-‐9.

406. Blacher J, Guerin AP, Pannier B, Marchais SJ, Safar ME, London GM. Impact of

aortic stiffness on survival in end-‐stage renal disease. Circulation 1999;99:2434-‐

9.

407. Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, Collins R,

Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E,

Ostergren J. Prevention of cardiovascular events with an antihypertensive

regimen of amlodipine adding perindopril as required versus atenolol adding

bendroflumethiazide as required, in the Anglo-‐Scandinavian Cardiac Outcomes

Trial-‐Blood Pressure Lowering Arm (ASCOT-‐BPLA): a multicentre randomised

controlled trial. Lancet 2005;366:895-‐906.

408. Devereux RB, Dahlof B. Potential mechanisms of stroke benefit favoring

losartan in the Losartan Intervention For Endpoint reduction in hypertension

(LIFE) study. Curr Med Res Opin 2007;23:443-‐57.

409. de Champlain J. Do angiotensin II antagonists provide benefits beyond blood

pressure reduction? Adv Ther 2005;22:117-‐36.

410. Guyton AC, Sagawa K. Compensations of cardiac output and other

circulatory functions in areflex dogs with large A-‐V fistulas. Am J Physiol

1961;200:1157-‐63. In: MacRae JM, Levin A, Belenkie I. The cardiovascular effects

of arteriovenous fistulas in chronic kidney disease: a cause for concern? Semin

Dial 2006;19:349-‐52.

264

411. Iwashima Y, Horio T, Takami Y, Inenaga T, Nishikimi T, Takishita S, Kawano

Y. Effects of the creation of arteriovenous fistula for hemodialysis on cardiac

function and natriuretic peptide levels in CRF. Am J Kidney Dis 2002;40:974-‐82.

412. Ori Y, Korzets A, Katz M, Perek Y, Zahavi I, Gafter U. Haemodialysis

arteriovenous access-‐-‐a prospective haemodynamic evaluation. Nephrol Dial

Transplant 1996;11:94-‐7.

413. Basile C, Lomonte C, Vernaglione L, Casucci F, Antonelli M, Losurdo N. The

relationship between the flow of arteriovenous fistula and cardiac output in

haemodialysis patients. Nephrol Dial Transplant 2008;23:282-‐7.

414. Ori Y, Korzets A, Katz M, Erman A, Weinstein T, Malachi T, Gafter U. The

contribution of an arteriovenous access for hemodialysis to left ventricular

hypertrophy. Am J Kidney Dis 2002;40:745-‐52.

415. Anderson CB, Codd JR, Graff RA, Groce MA, Harter HR, Newton WT. Cardiac

failure and upper extremity arteriovenous dialysis fistulas. Case reports and a

review of the literature. Arch Intern Med 1976;136:292-‐7.

416. Ahearn DJ, Maher JF. Heart failure as a complication of hemodialysis

arteriovenous fistula. Ann Intern Med 1972;77:201-‐4.

417. MacRae JM, Pandeya S, Humen DP, Krivitski N, Lindsay RM. Arteriovenous

fistula-‐associated high-‐output cardiac failure: a review of mechanisms. Am J

Kidney Dis 2004;43:e17-‐22.

418. Murray BM, Rajczak S, Herman A, Leary D. Effect of surgical banding of a

high-‐flow fistula on access flow and cardiac output: intraoperative and long-‐term

measurements. Am J Kidney Dis 2004;44:1090-‐6.

265

419. Bajraktari G, Rexhepaj N, Bakalli A, Shaqiri G, Osmani E, Vokrri L, Elezi S.

Remission of high-‐output heart failure after surgical repair of 30-‐month

arteriovenous femoral fistula: case report. Heart Surg Forum 2005;8:E118-‐20.

420. Abbott KC, Trespalacios FC, Agodoa LY. Arteriovenous fistula use and heart

disease in long-‐term elderly hemodialysis patients: analysis of United States

Renal Data System Dialysis Morbidity and Mortality Wave II. J Nephrol

2003;16:822-‐30.

421. Savage MT, Ferro CJ, Sassano A, Tomson CR. The impact of arteriovenous

fistula formation on central hemodynamic pressures in chronic renal failure

patients: a prospective study. Am J Kidney Dis 2002;40:753-‐9.

422. Crowley SD, Butterly DW, Peter RH, Schwab SJ. Coronary steal from a left

internal mammary artery coronary bypass graft by a left upper extremity

arteriovenous hemodialysis fistula. Am J Kidney Dis 2002;40:852-‐5.

423. Gaudino M, Serricchio M, Luciani N, Giungi S, Salica A, Pola R, Pola P, Luciani

G, Possati G. Risks of using internal thoracic artery grafts in patients in chronic

hemodialysis via upper extremity arteriovenous fistula. Circulation

2003;107:2653-‐5.

424. Rizzoli G, Schiavon L, Bellini P. Does the use of bilateral internal mammary

artery (IMA) grafts provide incremental benefit relative to the use of a single IMA

graft? A meta-‐analysis approach. Eur J Cardiothorac Surg 2002;22:781-‐6.

425. Chloroyiannis IA. Total arterial myocardial revascularization. Angiology

2008;59:80S-‐2S.

426. Lytle BW. Prolonging patency-‐-‐choosing coronary bypass grafts. N Engl J

Med 2004;351:2262-‐4.

266

427. Lok CE, Oliver MJ, Su J, Bhola C, Hannigan N, Jassal SV. Arteriovenous fistula

outcomes in the era of the elderly dialysis population. Kidney Int 2005;67:2462-‐9.

428. Wasse H, Speckman RA, McClellan WM. Arteriovenous fistula use is

associated with lower cardiovascular mortality compared with catheter use

among ESRD patients. Semin Dial 2008;21:483-‐9.

429. Damy T, Goode KM, Kallvikbacka-‐Bennett A, Lewinter C, Hobkirk J, Nikitin

NP, Dubois-‐Rande JL, Hittinger L, Clark AL, Cleland JG. Determinants and

prognostic value of pulmonary arterial pressure in patients with chronic heart

failure. Eur Heart J 2010.

430. Lang IM, Klepetko W. Chronic thromboembolic pulmonary hypertension: an

updated review. Curr Opin Cardiol 2008;23:555-‐9.

431. D'Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM,

Fishman AP, Goldring RM, Groves BM, Kernis JT, et al. Survival in patients with

primary pulmonary hypertension. Results from a national prospective registry.

Ann Intern Med 1991;115:343-‐9.

432. Yigla M, Nakhoul F, Sabag A, Tov N, Gorevich B, Abassi Z, Reisner SA.

Pulmonary hypertension in patients with end-‐stage renal disease. Chest

2003;123:1577-‐82.

433. Nakhoul F, Yigla M, Gilman R, Reisner SA, Abassi Z. The pathogenesis of

pulmonary hypertension in haemodialysis patients via arterio-‐venous access.


434. Beigi AA, Sadeghi AM, Khosravi AR, Karami M, Masoudpour H. Effects of the

arteriovenous fistula on pulmonary artery pressure and cardiac output in

patients with chronic renal failure. J Vasc Access 2009;10:160-‐6.

267

435. Abassi Z, Nakhoul F, Khankin E, Reisner SA, Yigla M. Pulmonary

hypertension in chronic dialysis patients with arteriovenous fistula: pathogenesis

and therapeutic prospective. Curr Opin Nephrol Hypertens 2006;15:353-‐60.

436. Abdelwhab S, Elshinnawy S. Pulmonary hypertension in chronic renal

failure patients. Am J Nephrol 2008;28:990-‐7.

437. Acarturk G, Albayrak R, Melek M, Yuksel S, Uslan I, Atli H, Colbay M, Unlu M,

Fidan F, Asci Z, Cander S, Karaman O, Acar M. The relationship between

arteriovenous fistula blood flow rate and pulmonary artery pressure in

hemodialysis patients. Int Urol Nephrol 2008;40:509-‐13.

438. Sheashaa H, Hassan N, Osman Y, Sabry A, Sobh M. Effect of spontaneous

closure of arteriovenous fistula access on cardiac structure and function in renal

transplant patients. Am J Nephrol 2004;24:432-‐7.

439. Unger P, Velez-‐Roa S, Wissing KM, Hoang AD, van de Borne P. Regression of

left ventricular hypertrophy after arteriovenous fistula closure in renal

transplant recipients: a long-‐term follow-‐up. Am J Transplant 2004;4:2038-‐44.

440. van Duijnhoven EC, Cheriex EC, Tordoir JH, Kooman JP, van Hooff JP. Effect

of closure of the arteriovenous fistula on left ventricular dimensions in renal

transplant patients. Nephrol Dial Transplant 2001;16:368-‐72.

441. Cridlig J, Selton-‐Suty C, Alla F, Chodek A, Pruna A, Kessler M, Frimat L.

Cardiac impact of the arteriovenous fistula after kidney transplantation: a case-‐

controlled, match-‐paired study. Transpl Int 2008;21:948-‐54.

442. Movilli E, Viola BF, Brunori G, Gaggia P, Camerini C, Zubani R, Berlinghieri N,

Cancarini G. Long-‐term effects of arteriovenous fistula closure on

echocardiographic functional and structural findings in hemodialysis patients: a

prospective study. Am J Kidney Dis 2010;55:682-‐9.

268

443. Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, Held PJ,

Port FK. Comparison of mortality in all patients on dialysis, patients on dialysis

awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J

Med 1999;341:1725-‐30.

444. Aakhus S, Dahl K, Wideroe TE. Cardiovascular morbidity and risk factors in

renal transplant patients. Nephrol Dial Transplant 1999;14:648-‐54.

445. Oniscu GC, Brown H, Forsythe JL. Impact of cadaveric renal transplantation

on survival in patients listed for transplantation. J Am Soc Nephrol 2005;16:1859-‐

65.

446. Rabbat CG, Thorpe KE, Russell JD, Churchill DN. Comparison of mortality

risk for dialysis patients and cadaveric first renal transplant recipients in Ontario,

Canada. J Am Soc Nephrol 2000;11:917-‐22.

447. Schnuelle P, Lorenz D, Trede M, Van Der Woude FJ. Impact of renal cadaveric

transplantation on survival in end-‐stage renal failure: evidence for reduced

mortality risk compared with hemodialysis during long-‐term follow-‐up. J Am Soc

Nephrol 1998;9:2135-‐41.

448. Shrestha A, Basarab-‐Horwath C, McKane W, Shrestha B, Raftery A. Quality of

life following live donor renal transplantation: A single centre experience. Ann

Transplant 2010;15:5-‐10.

449. Tomasz W, Piotr S. A trial of objective comparison of quality of life between

chronic renal failure patients treated with hemodialysis and renal

transplantation. Ann Transplant 2003;8:47-‐53.

450. Lindholm A, Albrechtsen D, Frodin L, Tufveson G, Persson NH, Lundgren G.

Ischemic heart disease-‐-‐major cause of death and graft loss after renal

transplantation in Scandinavia. Transplantation 1995;60:451-‐7.

269

451. McDonald S, Excell L, Livingston B. ANZDATA Registry Report Australia and

New Zealand Dialysis and Transplant Registry. Adelaide, South Australia:

Australia and New Zealand Dialysis and Transplant Registry, 2009.

452. Disney APS, Russ GR, Walker R, Collins J, Herbert K, Kerr P. ANZDATA

Registry Report 1998 Australia and New Zealand Dialysis and Transplant

Registry. Adelaide, South Australia: Australia and New Zealand Dialysis and

Transplant Registry, 1998.

453. Kasiske BL. Risk factors for accelerated atherosclerosis in renal transplant

recipients. Am J Med 1988;84:985-‐92.

454. Parfrey PS, Harnett JD, Foley RN, Kent GM, Murray DC, Barre PE, Guttmann

RD. Impact of renal transplantation on uremic cardiomyopathy. Transplantation

1995;60:908-‐14.

455. De Lima JJ, Vieira ML, Viviani LF, Medeiros CJ, Ianhez LE, Kopel L, de

Andrade JL, Krieger EM, Lage SG. Long-‐term impact of renal transplantation on

carotid artery properties and on ventricular hypertrophy in end-‐stage renal

failure patients. Nephrol Dial Transplant 2002;17:645-‐51.

456. Deligiannis A, Paschalidou E, Sakellariou G, Vargemezis V, Geleris P,

Kontopoulos A, Papadimitriou M. Changes in left ventricular anatomy during

haemodialysis, continuous ambulatory peritoneal dialysis and after renal

transplantation. Proc Eur Dial Transplant Assoc Eur Ren Assoc 1985;21:185-‐9.

457. Himelman RB, Landzberg JS, Simonson JS, Amend W, Bouchard A, Merz R,

Schiller NB. Cardiac consequences of renal transplantation: changes in left

ventricular morphology and function. J Am Coll Cardiol 1988;12:915-‐23.

458. Huting J. Course of left ventricular hypertrophy and function in end-‐stage

renal disease after renal transplantation. Am J Cardiol 1992;70:1481-‐4.

270

459. Huting J. Diastolic left ventricular function after renal transplantation in

patients with normal and hypertrophied myocardium. Clin Cardiol 1992;15:845-‐

50.

460. Lai KN, Barnden L, Mathew TH. Effect of renal transplantation on left

ventricular function in hemodialysis patients. Clin Nephrol 1982;18:74-‐8.

461. Larsson O, Attman PO, Beckman-‐Suurkula M, Wallentin I, Wikstrand J. Left

ventricular function before and after kidney transplantation. A prospective study

in patients with juvenile-‐onset diabetes mellitus. Eur Heart J 1986;7:779-‐91.

462. Peteiro J, Alvarez N, Calvino R, Penas M, Ribera F, Castro Beiras A. Changes

in left ventricular mass and filling after renal transplantation are related to

changes in blood pressure: an echocardiographic and pulsed Doppler study.

Cardiology 1994;85:273-‐83.

463. Rigatto C, Foley RN, Kent GM, Guttmann R, Parfrey PS. Long-‐term changes in

left ventricular hypertrophy after renal transplantation. Transplantation

2000;70:570-‐5.

464. Kasiske BL, Guijarro C, Massy ZA, Wiederkehr MR, Ma JZ. Cardiovascular

disease after renal transplantation. J Am Soc Nephrol 1996;7:158-‐65.

465. Rigatto C. Clinical epidemiology of cardiac disease in renal transplant

recipients. Semin Dial 2003;16:106-‐10.

466. Culleton BF, Larson MG, Wilson PW, Evans JC, Parfrey PS, Levy D.

Cardiovascular disease and mortality in a community-‐based cohort with mild

renal insufficiency. Kidney Int 1999;56:2214-‐9.

467. Senni M, Tribouilloy CM, Rodeheffer RJ, Jacobsen SJ, Evans JM, Bailey KR,

Redfield MM. Congestive heart failure in the community: trends in incidence and

survival in a 10-‐year period. Arch Intern Med 1999;159:29-‐34.

271

468. Ritz E, Schwenger V, Wiesel M, Zeier M. Atherosclerotic complications after

renal transplantation. Transpl Int 2000;13 Suppl 1:S14-‐9.

469. Roger VL, Weston SA, Redfield MM, Hellermann-‐Homan JP, Killian J, Yawn

BP, Jacobsen SJ. Trends in heart failure incidence and survival in a community-‐

based population. JAMA 2004;292:344-‐50.

470. Oflaz H, Turkmen A, Turgut F, Pamukcu B, Umman S, Ucar A, Akyol Y, Uzun

S, Kazancioglu R, Kurt R, Sever MS. Changes in endothelial function before and

after renal transplantation. Transpl Int 2006;19:333-‐7.

471. Kocak H, Ceken K, Yavuz A, Yucel S, Gurkan A, Erdogan O, Ersoy F,

Yakupoglu G, Demirbas A, Tuncer M. Effect of renal transplantation on

endothelial function in haemodialysis patients. Nephrol Dial Transplant

2006;21:203-‐7.

472. Mark PB, Murphy K, Mohammed AS, Morris ST, Jardine AG. Endothelial

dysfunction in renal transplant recipients. Transplant Proc 2005;37:3805-‐7.

473. Boots JM, Christiaans MH, van Hooff JP. Effect of immunosuppressive agents

on long-‐term survival of renal transplant recipients: focus on the cardiovascular

risk. Drugs 2004;64:2047-‐73.

474. Covic A, Haydar AA, Bhamra-‐Ariza P, Gusbeth-‐Tatomir P, Goldsmith DJ.

Aortic pulse wave velocity and arterial wave reflections predict the extent and

severity of coronary artery disease in chronic kidney disease patients. J Nephrol

2005;18:388-‐96.

475. Covic A, Goldsmith DJ, Florea L, Gusbeth-‐Tatomir P, Covic M. The influence

of dialytic modality on arterial stiffness, pulse wave reflections, and vasomotor

function. Perit Dial Int 2004;24:365-‐72.

272

476. Barenbrock M, Spieker C, Laske V, Baumgart P, Hoeks AP, Zidek W, Rahn KH.

Effect of long-‐term hemodialysis on arterial compliance in end-‐stage renal failure.

Nephron 1993;65:249-‐53.

477. Yildiz A, Fazlioglu M, Ersoy A, Gullulu M, Gullulu S, Yurtkuran M. Arterial

elasticity measurement in renal transplant recipients. Transplant Proc

2007;39:1455-‐7.

478. Posadzy-‐Malaczynska A, Kosch M, Hausberg M, Rahn KH, Stanisic G,

Malaczynski P, Gluszek J, Tykarski A. Arterial distensibility, intima media

thickness and pulse wave velocity after renal transplantation and in dialysis

normotensive patients. Int Angiol 2005;24:89-‐94.

479. Zoungas S, Kerr PG, Chadban S, Muske C, Ristevski S, Atkins RC, McNeil JJ,

McGrath BP. Arterial function after successful renal transplantation. Kidney Int

2004;65:1882-‐9.

480. Cohen DL, Warburton KM, Warren G, Bloom RD, Townsend RR. Pulse wave

analysis to assess vascular compliance changes in stable renal transplant

recipients. Am J Hypertens 2004;17:209-‐12.

481. Wystrychowski G, Chudek J, Zukowska-‐Szczechowska E, Wiecek A,

Grzeszczak W. Associations between calcineurin inhibitors and arterial

compliance in kidney transplant recipients. J Nephrol 2008;21:81-‐92.

482. Strozecki P, Adamowicz A, Wlodarczyk Z, Manitius J. The influence of

calcineurin inhibitors on pulse wave velocity in renal transplant recipients. Ren

Fail 2007;29:679-‐84.

483. Covic A, Mardare N, Gusbeth-‐Tatomir P, Buhaescu I, Goldsmith DJ. Acute

effect of CyA A (Neoral) on large artery hemodynamics in renal transplant

patients. Kidney Int 2005;67:732-‐7.

273

484. Kosch M, Hausberg M, Suwelack B. Studies on effects of calcineurin inhibitor

withdrawal on arterial distensibility and endothelial function in renal transplant

recipients. Transplantation 2003;76:1516-‐9.

485. Gill JS, Ma I, Landsberg D, Johnson N, Levin A. Cardiovascular events and

investigation in patients who are awaiting cadaveric kidney transplantation. J Am

Soc Nephrol 2005;16:808-‐16.

486. Ojo AO, Hanson JA, Meier-‐Kriesche H, Okechukwu CN, Wolfe RA, Leichtman

AB, Agodoa LY, Kaplan B, Port FK. Survival in recipients of marginal cadaveric

donor kidneys compared with other recipients and wait-‐listed transplant

candidates. J Am Soc Nephrol 2001;12:589-‐97.

487. Karthikeyan V, Ananthasubramaniam K. Coronary risk assessment and

management options in chronic kidney disease patients prior to kidney

transplantation. Curr Cardiol Rev 2009;5:177-‐86.

488. Kasiske BL, Ramos EL, Gaston RS, Bia MJ, Danovitch GM, Bowen PA, Lundin

PA, Murphy KJ. The evaluation of renal transplant candidates: clinical practice

guidelines. Patient Care and Education Committee of the American Society of

Transplant Physicians. J Am Soc Nephrol 1995;6:1-‐34.

489. Gaston RS, Basadonna G, Cosio FG, Davis CL, Kasiske BL, Larsen J, Leichtman

AB, Delmonico FL. Transplantation in the diabetic patient with advanced chronic

kidney disease: a task force report. Am J Kidney Dis 2004;44:529-‐42.

490. Danovitch GM, Hariharan S, Pirsch JD, Rush D, Roth D, Ramos E, Starling RC,

Cangro C, Weir MR. Management of the waiting list for cadaveric kidney

transplants: report of a survey and recommendations by the Clinical Practice

Guidelines Committee of the American Society of Transplantation. J Am Soc

Nephrol 2002;13:528-‐35.

274

491. Knoll G, Cockfield S, Blydt-‐Hansen T, Baran D, Kiberd B, Landsberg D, Rush

D, Cole E. Canadian Society of Transplantation: consensus guidelines on eligibility

for kidney transplantation. CMAJ 2005;173:S1-‐25.

492. Pilmore H. Cardiac assessment for renal transplantation. Am J Transplant

2006;6:659-‐65.

493. Sharma R, Pellerin D, Gaze DC, Gregson H, Streather CP, Collinson PO,

Brecker SJ. Dobutamine stress echocardiography and the resting but not exercise

electrocardiograph predict severe coronary artery disease in renal transplant

candidates. Nephrol Dial Transplant 2005;20:2207-‐14.

494. Sharma R, Pellerin D, Gaze DC, Shah JS, Streather CP, Collinson PO, Brecker

SJ. Dobutamine stress echocardiography and cardiac troponin T for the detection

of significant coronary artery disease and predicting outcome in renal transplant

candidates. Eur J Echocardiogr 2005;6:327-‐35.

495. Braun WE, Phillips DF, Vidt DG, Novick AC, Nakamoto S, Popowniak KL,

Paganini E, Magnusson M, Pohl M, Steinmuller DR, et al. Coronary artery disease

in 100 diabetics with end-‐stage renal failure. Transplant Proc 1984;16:603-‐7. In:

Karthikeyan V, Ananthasubramaniam K. Coronary risk assessment and



496. Margolis JR, Kannel WS, Feinleib M, Dawber TR, McNamara PM. Clinical

features of unrecognized myocardial infarction-‐-‐silent and symptomatic.

Eighteen year follow-‐up: the Framingham study. Am J Cardiol 1973;32:1-‐7. In:

Karthikeyan V, Ananthasubramaniam K. Coronary risk assessment and



275

497. Roig E, Betriu A, Castaner A, Magrina J, Sanz G, Navarro-‐Lopez F. Disabling

angina pectoris with normal coronary arteries in patients undergoing long-‐term

hemodialysis. Am J Med 1981;71:431-‐4.

498. Rostand SG, Kirk KA, Rutsky EA. The epidemiology of coronary artery

disease in patients on maintenance hemodialysis: implications for management.

Contrib Nephrol 1986;52:34-‐41. In: Karthikeyan V, Ananthasubramaniam K.

Coronary risk assessment and management options in chronic kidney disease

patients prior to kidney transplantation. Curr Cardiol Rev 2009;5:177-‐86.

499. Bart BA, Cen YY, Hendel RC, Lee R, Marwick TH, Missov ED, Bachour FA,

Herzog CA. Comparison of dobutamine stress echocardiography, dobutamine

SPECT, and adenosine SPECT myocardial perfusion imaging in patients with end-‐

stage renal disease. J Nucl Cardiol 2009;16:507-‐15.

500. De Lima JJ, Sabbaga E, Vieira ML, de Paula FJ, Ianhez LE, Krieger EM, Ramires

JA. Coronary angiography is the best predictor of events in renal transplant

candidates compared with noninvasive testing. Hypertension 2003;42:263-‐8.

501. Enkiri SA, Taylor AM, Keeley EC, Lipson LC, Gimple LW, Ragosta M. Coronary

angiography is a better predictor of mortality than non-‐invasive testing in

patients evaluated for renal transplantation. Catheter Cardiovasc Interv 2010.

502. Feringa HH, Bax JJ, Schouten O, Poldermans D. Ischemic heart disease in

renal transplant candidates: towards non-‐invasive approaches for preoperative

risk stratification. Eur J Echocardiogr 2005;6:313-‐6.

503. Gang S, Dabhi M, Rajapurkar MM. Ischaemia imaging in type 2 diabetic

kidney transplant candidates-‐-‐is coronary angiography essential? Nephrol Dial

Transplant 2007;22:2334-‐8.

276

504. Gowdak LH, de Paula FJ, Cesar LA, Martinez Filho EE, Ianhez LE, Krieger EM,

Ramires JA, de Lima JJ. Screening for significant coronary artery disease in high-‐

risk renal transplant candidates. Coron Artery Dis 2007;18:553-‐8.

505. Herzog CA, Marwick TH, Pheley AM, White CW, Rao VK, Dick CD.

Dobutamine stress echocardiography for the detection of significant coronary

artery disease in renal transplant candidates. Am J Kidney Dis 1999;33:1080-‐90.

506. Le A, Wilson R, Douek K, Pulliam L, Tolzman D, Norman D, Barry J, Bennett

W. Prospective risk stratification in renal transplant candidates for cardiac death.

Am J Kidney Dis 1994;24:65-‐71.

507. Lewis MS, Wilson RA, Walker KW, Wilson DJ, Norman DJ, Barry JM, Bennett

WM. Validation of an algorithm for predicting cardiac events in renal transplant

candidates. Am J Cardiol 2002;89:847-‐50.

508. Lin K, Stewart D, Cooper S, Davis CL. Pre-‐transplant cardiac testing for

kidney-‐pancreas transplant candidates and association with cardiac outcomes.

Clin Transplant 2001;15:269-‐75.

509. Patel AD, Abo-‐Auda WS, Davis JM, Zoghbi GJ, Deierhoi MH, Heo J, Iskandrian

AE. Prognostic value of myocardial perfusion imaging in predicting outcome after

renal transplantation. Am J Cardiol 2003;92:146-‐51.

510. Penfornis A, Zimmermann C, Boumal D, Sabbah A, Meneveau N, Gaultier-‐

Bourgeois S, Bassand JP, Bernard Y. Use of dobutamine stress echocardiography

in detecting silent myocardial ischaemia in asymptomatic diabetic patients: a

comparison with thallium scintigraphy and exercise testing. Diabet Med

2001;18:900-‐5.

511. Rabbat CG, Treleaven DJ, Russell JD, Ludwin D, Cook DJ. Prognostic value of

myocardial perfusion studies in patients with end-‐stage renal disease assessed

277

for kidney or kidney-‐pancreas transplantation: a meta-‐analysis. J Am Soc Nephrol

2003;14:431-‐9.

512. West JC, Napoliello DA, Costello JM, Nassef LA, Butcher RJ, Hartle JE,

McConnell TR, Finley JW, Kelley SE, Chao S, Latsha R. Preoperative dobutamine

stress echocardiography versus cardiac arteriography for risk assessment prior

to renal transplantation. Transpl Int 2000;13 Suppl 1:S27-‐30.

513. Worthley MI, Unger SA, Mathew TH, Russ GR, Horowitz JD. Usefulness of

tachycardic-‐stress perfusion imaging to predict coronary artery disease in high-‐

risk patients with chronic renal failure. Am J Cardiol 2003;92:1318-‐20.

514. Al Jaroudi W, Iskandrian AE. Regadenoson: a new myocardial stress agent. J

Am Coll Cardiol 2009;54:1123-‐30.

515. Rossen JD, Quillen JE, Lopez AG, Stenberg RG, Talman CL, Winniford MD.

Comparison of coronary vasodilation with intravenous dipyridamole and

adenosine. J Am Coll Cardiol 1991;18:485-‐91.

516. Wilson RF, Wyche K, Christensen BV, Zimmer S, Laxson DD. Effects of

adenosine on human coronary arterial circulation. Circulation 1990;82:1595-‐606.

517. Navare SM, Mather JF, Shaw LJ, Fowler MS, Heller GV. Comparison of risk

stratification with pharmacologic and exercise stress myocardial perfusion

imaging: a meta-‐analysis. J Nucl Cardiol 2004;11:551-‐61.

518. Fleischmann KE, Hunink MG, Kuntz KM, Douglas PS. Exercise

echocardiography or exercise SPECT imaging? A meta-‐analysis of diagnostic test

performance. JAMA 1998;280:913-‐20.

519. Imran MB, Palinkas A, Picano E. Head-‐to-‐head comparison of dipyridamole

echocardiography and stress perfusion scintigraphy for the detection of coronary

278

artery disease: a meta-‐analysis. Comparison between stress echo and

scintigraphy. Int J Cardiovasc Imaging 2003;19:23-‐8.

520. Kim C, Kwok YS, Heagerty P, Redberg R. Pharmacologic stress testing for

coronary disease diagnosis: A meta-‐analysis. Am Heart J 2001;142:934-‐44.

521. Mahajan N, Polavaram L, Vankayala H, Ference B, Wang Y, Ager J, Kovach J,

Afonso L. Diagnostic accuracy of myocardial perfusion imaging and stress

echocardiography for the diagnosis of left main and triple vessel coronary artery

disease: a comparative meta-‐analysis. Heart 2010;96:956-‐66.

522. Picano E, Molinaro S, Pasanisi E. The diagnostic accuracy of pharmacological

stress echocardiography for the assessment of coronary artery disease: a meta-‐

analysis. Cardiovasc Ultrasound 2008;6:30.

523. De Lorenzo A, Hachamovitch R, Kang X, Gransar H, Sciammarella MG, Hayes

SW, Friedman JD, Cohen I, Germano G, Berman DS. Prognostic value of myocardial

perfusion SPECT versus exercise electrocardiography in patients with ST-‐

segment depression on resting electrocardiography. J Nucl Cardiol 2005;12:655-‐

61.

524. Hachamovitch R, Berman DS, Kiat H, Cohen I, Friedman JD, Shaw LJ. Value of

stress myocardial perfusion single photon emission computed tomography in

patients with normal resting electrocardiograms: an evaluation of incremental

prognostic value and cost-‐effectiveness. Circulation 2002;105:823-‐9.

525. Hachamovitch R, Kang X, Amanullah AM, Abidov A, Hayes SW, Friedman JD,

Cohen I, Thomson LE, Germano G, Berman DS. Prognostic implications of

myocardial perfusion single-‐photon emission computed tomography in the

elderly. Circulation 2009;120:2197-‐206.

279

526. Kang X, Berman DS, Lewin HC, Cohen I, Friedman JD, Germano G,

Hachamovitch R, Shaw LJ. Incremental prognostic value of myocardial perfusion

single photon emission computed tomography in patients with diabetes mellitus.

Am Heart J 1999;138:1025-‐32.

527. Krivokapich J, Child JS, Walter DO, Garfinkel A. Prognostic value of

dobutamine stress echocardiography in predicting cardiac events in patients with

known or suspected coronary artery disease. J Am Coll Cardiol 1999;33:708-‐16.

528. Poldermans D, Fioretti PM, Boersma E, Cornel JH, Borst F, Vermeulen EG,

Arnese M, el-‐Hendy A, Roelandt JR. Dobutamine-‐atropine stress

echocardiography and clinical data for predicting late cardiac events in patients

with suspected coronary artery disease. Am J Med 1994;97:119-‐25.

529. Steinberg EH, Madmon L, Patel CP, Sedlis SP, Kronzon I, Cohen JL. Long-‐term

prognostic significance of dobutamine echocardiography in patients with

suspected coronary artery disease: results of a 5-‐year follow-‐up study. J Am Coll

Cardiol 1997;29:969-‐73.

530. Zellweger MJ, Hachamovitch R, Kang X, Hayes SW, Friedman JD, Germano G,

Berman DS. Threshold, incidence, and predictors of prognostically high-‐risk silent

ischemia in asymptomatic patients without prior diagnosis of coronary artery

disease. J Nucl Cardiol 2009;16:193-‐200.

531. Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van' t Veer M, Klauss V,

Manoharan G, Engstrom T, Oldroyd KG, Ver Lee PN, MacCarthy PA, Fearon WF.

Fractional flow reserve versus angiography for guiding percutaneous coronary

intervention. N Engl J Med 2009;360:213-‐24.

532. Tonino PA, Fearon WF, De Bruyne B, Oldroyd KG, Leesar MA, Ver Lee PN,

Maccarthy PA, Van't Veer M, Pijls NH. Angiographic versus functional severity of

280

coronary artery stenoses in the FAME study fractional flow reserve versus

angiography in multivessel evaluation. J Am Coll Cardiol 2010;55:2816-‐21.

533. Melikian N, De Bondt P, Tonino P, De Winter O, Wyffels E, Bartunek J,

Heyndrickx GR, Fearon WF, Pijls NH, Wijns W, De Bruyne B. Fractional flow

reserve and myocardial perfusion imaging in patients with angiographic

multivessel coronary artery disease. JACC Cardiovasc Interv 2010;3:307-‐14.

534. Pijls NH, Fearon WF, Tonino PA, Siebert U, Ikeno F, Bornschein B, van't Veer

M, Klauss V, Manoharan G, Engstrom T, Oldroyd KG, Ver Lee PN, MacCarthy PA,

De Bruyne B. Fractional flow reserve versus angiography for guiding

percutaneous coronary intervention in patients with multivessel coronary artery

disease: 2-‐year follow-‐up of the FAME (Fractional Flow Reserve Versus

Angiography for Multivessel Evaluation) study. J Am Coll Cardiol 2010;56:177-‐84.

535. Pijls NH, van Schaardenburgh P, Manoharan G, Boersma E, Bech JW, van't

Veer M, Bar F, Hoorntje J, Koolen J, Wijns W, de Bruyne B. Percutaneous coronary

intervention of functionally nonsignificant stenosis: 5-‐year follow-‐up of the

DEFER Study. J Am Coll Cardiol 2007;49:2105-‐11.

536. Ragosta M, Bishop AH, Lipson LC, Watson DD, Gimple LW, Sarembock IJ,

Powers ER. Comparison between angiography and fractional flow reserve versus

single-‐photon emission computed tomographic myocardial perfusion imaging for

determining lesion significance in patients with multivessel coronary disease. Am

J Cardiol 2007;99:896-‐902.

537. Gebker R, Jahnke C, Hucko T, Manka R, Mirelis JG, Hamdan A, Schnackenburg

B, Fleck E, Paetsch I. Dobutamine stress magnetic resonance imaging for the

detection of coronary artery disease in women. Heart 2010;96:616-‐20.

281

538. Kelle S, Egnell C, Vierecke J, Chiribiri A, Vogel S, Fleck E, Nagel E. Prognostic

value of negative dobutamine-‐stress cardiac magnetic resonance imaging. Med Sci

Monit 2009;15:MT131-‐136.

539. Paetsch I, Jahnke C, Wahl A, Gebker R, Neuss M, Fleck E, Nagel E. Comparison

of dobutamine stress magnetic resonance, adenosine stress magnetic resonance,

and adenosine stress magnetic resonance perfusion. Circulation 2004;110:835-‐

42.

540. Wallace EL, Morgan TM, Walsh TF, Dall'Armellina E, Ntim W, Hamilton CA,

Hundley WG. Dobutamine cardiac magnetic resonance results predict cardiac

prognosis in women with known or suspected ischemic heart disease. JACC

Cardiovasc Imaging 2009;2:299-‐307.

541. Jahnke C, Nagel E, Gebker R, Kokocinski T, Kelle S, Manka R, Fleck E, Paetsch

I. Prognostic value of cardiac magnetic resonance stress tests: adenosine stress

perfusion and dobutamine stress wall motion imaging. Circulation

2007;115:1769-‐76.

542. Allison JD, Flickinger FW, Wright JC, Falls DG, 3rd, Prisant LM, VonDohlen

TW, Frank MJ. Measurement of left ventricular mass in hypertrophic

cardiomyopathy using MRI: comparison with echocardiography. Magn Reson

Imaging 1993;11:329-‐34.

543. Devlin AM, Moore NR, Ostman-‐Smith I. A comparison of MRI and

echocardiography in hypertrophic cardiomyopathy. Br J Radiol 1999;72:258-‐64.

544. Keenan NG, Pennell DJ. CMR of ventricular function. Echocardiography

2007;24:185-‐93.

545. Hundley WG, Kizilbash AM, Afridi I, Franco F, Peshock RM, Grayburn PA.

Administration of an intravenous perfluorocarbon contrast agent improves

282

echocardiographic determination of left ventricular volumes and ejection

fraction: comparison with cine magnetic resonance imaging. J Am Coll Cardiol

1998;32:1426-‐32.

546. Malm S, Frigstad S, Sagberg E, Larsson H, Skjaerpe T. Accurate and

reproducible measurement of left ventricular volume and ejection fraction by

contrast echocardiography: a comparison with magnetic resonance imaging. J Am

Coll Cardiol 2004;44:1030-‐5.

547. Nayyar S, Magalski A, Khumri TM, Idupulapati M, Stoner CN, Kusnetzky LL,

Coggins TR, Morris BA, Main ML. Contrast administration reduces interobserver

variability in determination of left ventricular ejection fraction in patients with

left ventricular dysfunction and good baseline endocardial border delineation.

Am J Cardiol 2006;98:1110-‐4.

548. Thomson HL, Basmadjian AJ, Rainbird AJ, Razavi M, Avierinos JF, Pellikka

PA, Bailey KR, Breen JF, Enriquez-‐Sarano M. Contrast echocardiography improves

the accuracy and reproducibility of left ventricular remodeling measurements: a

prospective, randomly assigned, blinded study. J Am Coll Cardiol 2001;38:867-‐75.

549. Bottini PB, Carr AA, Prisant LM, Flickinger FW, Allison JD, Gottdiener JS.

Magnetic resonance imaging compared to echocardiography to assess left

ventricular mass in the hypertensive patient. Am J Hypertens 1995;8:221-‐8.

550. Myerson SG, Montgomery HE, World MJ, Pennell DJ. Left ventricular mass:

reliability of M-‐mode and 2-‐dimensional echocardiographic formulas.


551. Anderson JL, Horne BD, Pennell DJ. Atrial dimensions in health and left

ventricular disease using cardiovascular magnetic resonance. J Cardiovasc Magn

Reson 2005;7:671-‐5.

283

552. Artang R, Migrino RQ, Harmann L, Bowers M, Woods TD. Left atrial volume

measurement with automated border detection by 3-‐dimensional

echocardiography: comparison with Magnetic Resonance Imaging. Cardiovasc

Ultrasound 2009;7:16.

553. Jenkins C, Bricknell K, Marwick TH. Use of real-‐time three-‐dimensional

echocardiography to measure left atrial volume: comparison with other

echocardiographic techniques. J Am Soc Echocardiogr 2005;18:991-‐7.

554. Aaron CP, Tandri H, Barr RG, Johnson WC, Bagiella E, Chahal H, Jain A, Kizer

JR, Bertoni AG, Lima JA, Bluemke DA, Kawut SM. Physical Activity and Right

Ventricular Structure and Function: The MESA-‐Right Ventricle Study. Am J Respir

Crit Care Med 2010.

555. Kaufmann MR, Barr RG, Bluemke DM, Jain A, Lima JAC, Tandri H, Kawut SM.

Right Ventricular Structure And Function Predict The Onset Of Dyspnea: The

MESA-‐Right Ventricle Study. Am J Respir Crit Care Med 2010;181:A3403.

556. Shimada YJ, Shiota M, Siegel RJ, Shiota T. Accuracy of right ventricular

volumes and function determined by three-‐dimensional echocardiography in

comparison with magnetic resonance imaging: a meta-‐analysis study. J Am Soc

Echocardiogr 2010;23:943-‐53.

557. Iskandrian AE, Germano G, VanDecker W, Ogilby JD, Wolf N, Mintz R,

Berman DS. Validation of left ventricular volume measurements by gated SPECT

99mTc-‐labeled sestamibi imaging. J Nucl Cardiol 1998;5:574-‐8.

558. Anagnostopoulos C, Gunning MG, Pennell DJ, Laney R, Proukakis H,

Underwood SR. Regional myocardial motion and thickening assessed at rest by

ECG-‐gated 99mTc-‐MIBI emission tomography and by magnetic resonance

imaging. Eur J Nucl Med 1996;23:909-‐16.

284

559. Johnson LL, Verdesca SA, Aude WY, Xavier RC, Nott LT, Campanella MW,

Germano G. Postischemic stunning can affect left ventricular ejection fraction and

regional wall motion on post-‐stress gated sestamibi tomograms. J Am Coll Cardiol

1997;30:1641-‐8.

560. Lee DS, Ahn JY, Kim SK, Oh BH, Seo JD, Chung JK, Lee MC. Limited

performance of quantitative assessment of myocardial function by thallium-‐201

gated myocardial single-‐photon emission tomography. Eur J Nucl Med

2000;27:185-‐91.

561. Sharir T, Germano G, Kavanagh PB, Lai S, Cohen I, Lewin HC, Friedman JD,

Zellweger MJ, Berman DS. Incremental prognostic value of post-‐stress left

ventricular ejection fraction and volume by gated myocardial perfusion single

photon emission computed tomography. Circulation 1999;100:1035-‐42.

562. Wang F, Zhang J, Fang W, Zhao SH, Lu MJ, He ZX. Evaluation of left

ventricular volumes and ejection fraction by gated SPECT and cardiac MRI in

patients with dilated cardiomyopathy. Eur J Nucl Med Mol Imaging 2009;36:1611-‐

21.

563. de Graaf FR, Schuijf JD, Delgado V, van Velzen JE, Kroft LJ, de Roos A, Jukema

JW, van der Wall EE, Bax JJ. Clinical application of CT coronary angiography: state

of the art. Heart Lung Circ 2010;19:107-‐16.

564. Kim SS, Ko SM, Song MG, Kim JS. Assessment of global function of left

ventricle with dual-‐source CT in patients with severe arrhythmia: a comparison

with the use of two-‐dimensional transthoracic echocardiography. Int J Cardiovasc

Imaging 2010.

565. Koch K, Oellig F, Kunz P, Bender P, Oberholzer K, Mildenberger P, Hake U,

Kreitner KF, Thelen M. [Assessment of global and regional left ventricular

285

function with a 16-‐slice spiral-‐CT using two different software tools for

quantitative functional analysis and qualitative evaluation of wall motion changes

in comparison with magnetic resonance imaging]. Rofo 2004;176:1786-‐93. In:

Keenan NG, Pennell DJ. CMR of ventricular function. Echocardiography

2007;24:185-‐93.

566. Nikolaou K, Flohr T, Knez A, Rist C, Wintersperger B, Johnson T, Reiser MF,

Becker CR. Advances in cardiac CT imaging: 64-‐slice scanner. Int J Cardiovasc

Imaging 2004;20:535-‐40.

567. Palumbo A, Maffei E, Martini C, Messalli G, Seitun S, Malago R, Aldrovandi A,

Emiliano E, Cuttone A, Weustink A, Mollet N, Cademartiri F. Functional

parameters of the left ventricle: comparison of cardiac MRI and cardiac CT in a

large population. Radiol Med 2010;115:702-‐13.

568. Salm LP, Schuijf JD, de Roos A, Lamb HJ, Vliegen HW, Jukema JW, Joemai R,

van der Wall EE, Bax JJ. Global and regional left ventricular function assessment

with 16-‐detector row CT: comparison with echocardiography and cardiovascular

magnetic resonance. Eur J Echocardiogr 2006;7:308-‐14.

569. Seneviratne SK, Truong QA, Bamberg F, Rogers IS, Shapiro MD, Schlett CL,

Chae CU, Cury R, Abbara S, Brady TJ, Nagurney JT, Hoffmann U. Incremental

diagnostic value of regional left ventricular function over coronary assessment by

cardiac computed tomography for the detection of acute coronary syndrome in

patients with acute chest pain: from the ROMICAT trial. Circ Cardiovasc Imaging

2010;3:375-‐83.

570. Wen Z, Zhang Z, Yu W, Fan Z, Du J, Lv B. Assessing the left atrial phasic

volume and function with dual-‐source CT: comparison with 3T MRI. Int J

Cardiovasc Imaging 2010;26 Suppl 1:83-‐92.

286

571. Ganten M, Krautter U, Hosch W, Hansmann J, von Tengg-‐Kobligk H, Delorme

S, Kauczor HU, Kauffmann GW, Bock M. Age related changes of human aortic

distensibility: evaluation with ECG-‐gated CT. Eur Radiol 2007;17:701-‐8.

572. Einstein AJ, Henzlova MJ, Rajagopalan S. Estimating risk of cancer associated

with radiation exposure from 64-‐slice computed tomography coronary

angiography. JAMA 2007;298:317-‐23.

573. Faletra FF, D'Angeli I, Klersy C, Averaimo M, Klimusina J, Pasotti E,

Pedrazzini GB, Curti M, Carraro C, Diliberto R, Moccetti T, Auricchio A. Estimates

of lifetime attributable risk of cancer after a single radiation exposure from 64-‐

slice computed tomographic coronary angiography. Heart 2010;96:927-‐32.

574. Huang B, Li J, Law MW, Zhang J, Shen Y, Khong PL. Radiation dose and

cancer risk in retrospectively and prospectively ECG-‐gated coronary angiography

using 64-‐slice multidetector CT. Br J Radiol 2010;83:152-‐8.

575. Bloomgarden DC, Fayad ZA, Ferrari VA, Chin B, Sutton MG, Axel L. Global

cardiac function using fast breath-‐hold MRI: validation of new acquisition and

analysis techniques. Magn Reson Med 1997;37:683-‐92.

576. Jarvinen VM, Kupari MM, Poutanen VP, Hekali PE. A simplified method for

the determination of left atrial size and function using cine magnetic resonance

imaging. Magn Reson Imaging 1996;14:215-‐26.

577. Myerson SG, Bellenger NG, Pennell DJ. Assessment of left ventricular mass

by cardiovascular magnetic resonance. Hypertension 2002;39:750-‐5.

578. Sechtem U, Pflugfelder PW, Gould RG, Cassidy MM, Higgins CB.

Measurement of right and left ventricular volumes in healthy individuals with

cine MR imaging. Radiology 1987;163:697-‐702.

287

579. Grothues F, Smith GC, Moon JC, Bellenger NG, Collins P, Klein HU, Pennell DJ.

Comparison of interstudy reproducibility of cardiovascular magnetic resonance

with two-‐dimensional echocardiography in normal subjects and in patients with

heart failure or left ventricular hypertrophy. Am J Cardiol 2002;90:29-‐34.

580. Carpenter JP, Alpendurada F, Deac M, Maceira A, Garbowski M, Kirk P,

Walker JM, Porter JB, Shah F, Banya W, He T, Smith GC, Pennell DJ. Right

ventricular volumes and function in thalassemia major patients in the absence of

myocardial iron overload. J Cardiovasc Magn Reson 2010;12:24.

581. Katz J, Whang J, Boxt LM, Barst RJ. Estimation of right ventricular mass in

normal subjects and in patients with primary pulmonary hypertension by nuclear

magnetic resonance imaging. J Am Coll Cardiol 1993;21:1475-‐81.

582. Marcus F, Basso C, Gear K, Sorrell VL. Pitfalls in the diagnosis of

arrhythmogenic right ventricular cardiomyopathy/dysplasia. Am J Cardiol

2010;105:1036-‐9.

583. Teo KS, Dundon BK, Molaee P, Williams KF, Carbone A, Brown MA, Worthley

MI, Disney PJ, Sanders P, Worthley SG. Percutaneous closure of atrial septal

defects leads to normalisation of atrial and ventricular volumes. J Cardiovasc

Magn Reson 2008;10:55.

584. Maceira AM, Cosin-‐Sales J, Roughton M, Prasad SK, Pennell DJ. Reference left

atrial dimensions and volumes by steady state free precession cardiovascular

magnetic resonance. J Cardiovasc Magn Reson 2010;12:65.

585. Daneshvar D, Wei J, Tolstrup K, Thomson LE, Shufelt C, Merz CN. Diastolic

dysfunction: Improved understanding using emerging imaging techniques. Am

Heart J 2010;160:394-‐404.

288

586. Maceira AM, Prasad SK, Khan M, Pennell DJ. Normalized left ventricular

systolic and diastolic function by steady state free precession cardiovascular

magnetic resonance. J Cardiovasc Magn Reson 2006;8:417-‐26.

587. Rathi VK, Doyle M, Yamrozik J, Williams RB, Caruppannan K, Truman C, Vido

D, Biederman RW. Routine evaluation of left ventricular diastolic function by

cardiovascular magnetic resonance: a practical approach. J Cardiovasc Magn

Reson 2008;10:36.

588. Rubinshtein R, Glockner JF, Feng D, Araoz PA, Kirsch J, Syed IS, Oh JK.

Comparison of magnetic resonance imaging versus Doppler echocardiography for

the evaluation of left ventricular diastolic function in patients with cardiac

amyloidosis. Am J Cardiol 2009;103:718-‐23.

589. Valsangiacomo ER, Barrea C, Macgowan CK, Smallhorn JF, Coles JG, Yoo SJ.

Phase-‐contrast MR assessment of pulmonary venous blood flow in children with

surgically repaired pulmonary veins. Pediatr Radiol 2003;33:607-‐13.

590. Negrou K, Burns J, Gupta S, Plein S, Radjenovic A, Greenwood JP. Assessment

of change in aortic distensibility in patients with left ventricular hypertrophy

(LVH), before and after therapy, using Cardiac Magnetic Resonance (CMR)

imaging. J Cardiovasc Magn Reson. 2009;11:P142.

591. Foster MC, Keyes MJ, Larson MG, Vita JA, Mitchell GF, Meigs JB, Vasan RS,

Benjamin EJ, Fox CS. Relations of measures of endothelial function and kidney

disease: the Framingham Heart Study. Am J Kidney Dis 2008;52:859-‐67.

592. Malik AR, Kondragunta V, Kullo IJ. Forearm vascular reactivity and arterial

stiffness in asymptomatic adults from the community. Hypertension

2008;51:1512-‐8.

289

593. Covic A, Goldsmith DJ, Gusbeth-‐Tatomir P, Buhaescu I, Covic M. Successful

renal transplantation decreases aortic stiffness and increases vascular reactivity

in dialysis patients. Transplantation 2003;76:1573-‐7.

594. Barac A, Campia U, Panza JA. Methods for evaluating endothelial function in

humans. Hypertension 2007;49:748-‐60.

595. Philpott AC, Lonn E, Title LM, Verma S, Buithieu J, Charbonneau F, Anderson

TJ. Comparison of new measures of vascular function to flow mediated dilatation

as a measure of cardiovascular risk factors. Am J Cardiol 2009;103:1610-‐5.

596. Hudsmith LE, Petersen SE, Francis JM, Robson MD, Neubauer S. Normal

human left and right ventricular and left atrial dimensions using steady state free

precession magnetic resonance imaging. J Cardiovasc Magn Reson 2005;7:775-‐82.

597. Alfakih K, Plein S, Thiele H, Jones T, Ridgway JP, Sivananthan MU. Normal

human left and right ventricular dimensions for MRI as assessed by turbo

gradient echo and steady-‐state free precession imaging sequences. J Magn Reson

Imaging 2003;17:323-‐9.

598. Pennell DJ. Ventricular volume and mass by CMR. J Cardiovasc Magn Reson

2002;4:507-‐13.

599. Karamitsos TD, Hudsmith LE, Selvanayagam JB, Neubauer S, Francis JM.

Operator induced variability in left ventricular measurements with

cardiovascular magnetic resonance is improved after training. J Cardiovasc Magn

Reson 2007;9:777-‐83.

600. Fieno DS, Thomson LE, Slomka PJ, Abidov A, Nishina H, Chien D, Hayes SW,

Saouaf R, Germano G, Friedman JD, Berman DS. Rapid assessment of left

ventricular segmental wall motion, ejection fraction, and volumes with single

290

breath-‐hold, multi-‐slice TrueFISP MR imaging. J Cardiovasc Magn Reson

2006;8:435-‐44.

601. Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK,

Pennell DJ, Rumberger JA, Ryan T, Verani MS. Standardized myocardial

segmentation and nomenclature for tomographic imaging of the heart: a

statement for healthcare professionals from the Cardiac Imaging Committee of

the Council on Clinical Cardiology of the American Heart Association. Circulation

2002;105:539-‐42.

602. Anderson TJ, Worthley MI, Goodhart DM, Curtis MJ. Relation of Basal

coronary nitric oxide activity to the burden of atherosclerosis. Am J Cardiol

2005;95:1170-‐4.

603. Farouque HM, Worthley SG, Meredith IT, Skyrme-‐Jones RA, Zhang MJ. Effect

of ATP-‐sensitive potassium channel inhibition on resting coronary vascular

responses in humans. Circ Res 2002;90:231-‐6.

604. Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW. Correction of

the anemia of end-‐stage renal disease with recombinant human erythropoietin.

Results of a combined phase I and II clinical trial. N Engl J Med 1987;316:73-‐8.

605. Aaron CP, Tandri H, Barr RG, Johnson WC, Bagiella E, Chahal H, Jain A, Kizer

JR, Bertoni AG, Lima JA, Bluemke DA, Kawut SM. Physical activity and right

ventricular structure and function: the MESA-‐right ventricle study. Am J Respir

Crit Care Med 2011;183:396-‐404.

606. La Gerche A, Heidbuchel H, Burns AT, Mooney DJ, Taylor AJ, Pfluger HB,

Inder WJ, Macisaac AI, Prior DL. Disproportionate Exercise Load and Remodeling

of the Athlete's Right Ventricle. Med Sci Sports Exerc 2010.

291

607. Scott JM, Esch BT, Haykowsky MJ, Paterson I, Warburton DE, Chow K, Cheng

Baron J, Lopaschuk GD, Thompson RB. Effects of high intensity exercise on

biventricular function assessed by cardiac magnetic resonance imaging in

endurance trained and normally active individuals. Am J Cardiol 2010;106:278-‐

83.

608. Grosse-‐Wortmann L, Roche SL, Yoo SJ, Seed M, Kantor P. Early changes in

right ventricular function and their clinical consequences in childhood and

adolescent dilated cardiomyopathy. Cardiol Young 2010;20:418-‐25.

609. Banks L, Sasson Z, Busato M, Goodman JM. Impaired left and right

ventricular function following prolonged exercise in young athletes: influence of

exercise intensity and responses to dobutamine stress. J Appl Physiol

2010;108:112-‐9.

610. Stevens GR, Lala A, Sanz J, Garcia MJ, Fuster V, Pinney S. Exercise

performance in patients with pulmonary hypertension linked to cardiac magnetic

resonance measures. J Heart Lung Transplant 2009;28:899-‐905.

611. Moller T, Peersen K, Pettersen E, Thaulow E, Holmstrom H, Fredriksen PM.

Non-‐invasive measurement of the response of right ventricular pressure to

exercise, and its relation to aerobic capacity. Cardiol Young 2009;19:465-‐73.

612. Laurent S, Boutouyrie P. Recent advances in arterial stiffness and wave

reflection in human hypertension. Hypertension 2007;49:1202-‐6.

613. Apter JT. Correlation of visco-‐elastic properties with microscopic structure

of large arteries. IV. Thermal responses of collagen, elastin, smooth muscle, and

intact arteries. Circ Res 1967;21:901-‐18.

614. Virmani R, Avolio AP, Mergner WJ, Robinowitz M, Herderick EE, Cornhill JF,

Guo SY, Liu TH, Ou DY, O'Rourke M. Effect of aging on aortic morphology in

292

populations with high and low prevalence of hypertension and atherosclerosis.

Comparison between occidental and Chinese communities. Am J Pathol

1991;139:1119-‐29.

615. Safar ME, Levy BI, Struijker-‐Boudier H. Current perspectives on arterial

stiffness and pulse pressure in hypertension and cardiovascular diseases.

Circulation 2003;107:2864-‐9.

616. Benetos A, Laurent S, Hoeks AP, Boutouyrie PH, Safar ME. Arterial

alterations with aging and high blood pressure. A noninvasive study of carotid

and femoral arteries. Arterioscler Thromb 1993;13:90-‐7.

617. Boutouyrie P, Laurent S, Benetos A, Girerd XJ, Hoeks AP, Safar ME. Opposing

effects of ageing on distal and proximal large arteries in hypertensives. J

Hypertens Suppl 1992;10:S87-‐91.

618. van der Heijden-‐Spek JJ, Staessen JA, Fagard RH, Hoeks AP, Boudier HA, van

Bortel LM. Effect of age on brachial artery wall properties differs from the aorta

and is gender dependent: a population study. Hypertension 2000;35:637-‐42.

619. Kimoto E, Shoji T, Shinohara K, Inaba M, Okuno Y, Miki T, Koyama H, Emoto

M, Nishizawa Y. Preferential stiffening of central over peripheral arteries in type

2 diabetes. Diabetes 2003;52:448-‐52.

620. Hatsuda S, Shoji T, Shinohara K, Kimoto E, Mori K, Fukumoto S, Koyama H,

Emoto M, Nishizawa Y. Regional arterial stiffness associated with ischemic heart

disease in type 2 diabetes mellitus. J Atheroscler Thromb 2006;13:114-‐21.

621. Kimoto E, Shoji T, Shinohara K, Hatsuda S, Mori K, Fukumoto S, Koyama H,

Emoto M, Okuno Y, Nishizawa Y. Regional arterial stiffness in patients with type 2

diabetes and chronic kidney disease. J Am Soc Nephrol 2006;17:2245-‐52.

293

622. Bonal J, Cleries M, Vela E. Transplantation versus haemodialysis in elderly

patients. Renal Registry Committee. Nephrol Dial Transplant 1997;12:261-‐4.

623. Controlling the epidemic of cardiovascular disease in chronic renal disease:

What do we know? What do we need to know? Where do we go from here?

Special report from the National Kidney Foundation Task Force on

Cardiovascular Disease. Am J Kidney Dis 1998;32:S1-‐199.

624. Chammas E, El-‐Khoury J, Barbari A, Kamel G, Karam A, Tarcha W, Ghanem G,

Stephan A. Early and late effects of renal transplantation on cardiac functions.

Transplant Proc 2001;33:2680-‐2.

625. De Lima JJ, Vieira ML, Molnar LJ, Medeiros CJ, Ianhez LE, Krieger EM. Cardiac

effects of persistent hemodialysis arteriovenous access in recipients of renal

allograft. Cardiology 1999;92:236-‐9.

626. Ferreira SR, Moises VA, Tavares A, Pacheco-‐Silva A. Cardiovascular effects of

successful renal transplantation: a 1-‐year sequential study of left ventricular

morphology and function, and 24-‐hour blood pressure profile. Transplantation

2002;74:1580-‐7.

627. Arnol M, Knap B, Oblak M, Buturovic-‐Ponikvar J, Bren AF, Kandus A.

Subclinical left ventricular echocardiographic abnormalities 1 year after kidney

transplantation are associated with graft function and future cardiovascular

events. Transplant Proc 2010;42:4064-‐8.

628. McGregor E, Jardine AG, Murray LS, Dargie HJ, Rodger RS, Junor BJ, McMillan

MA, Briggs JD. Pre-‐operative echocardiographic abnormalities and adverse

outcome following renal transplantation. Nephrol Dial Transplant 1998;13:1499-‐

505.

294

629. Zimmerli LU, Mark PB, Steedman T, Foster JE, Berg GA, Dargie HJ, Jardine

AG, Delles C, Dominiczak AF. Vascular function in patients with end-‐stage renal

disease and/or coronary artery disease: a cardiac magnetic resonance imaging

study. Kidney Int 2007;71:68-‐73.

630. Recio-‐Mayoral A, Banerjee D, Streather C, Kaski JC. Endothelial dysfunction,

inflammation and atherosclerosis in chronic kidney disease -‐ a cross-‐sectional

study of predialysis, dialysis and kidney-‐transplantation patients. Atherosclerosis

2011.

631. Stadler M, Theuer E, Anderwald C, Hanusch-‐Enserer U, Auinger M,

Bieglmayer C, Quehenberger P, Bischof M, Kastenbauer T, Wolzt M, Wagner O,

Prager R. Persistent arterial stiffness and endothelial dysfunction following

successful pancreas-‐kidney transplantation in Type 1 diabetes. Diabet Med

2009;26:1010-‐8.

632. Asberg A, Midtvedt K, Voytovich MH, Line PD, Narverud J, Reisaeter AV,

Morkrid L, Jenssen T, Hartmann A. Calcineurin inhibitor effects on glucose

metabolism and endothelial function following renal transplantation. Clin

Transplant 2009;23:511-‐8.

633. Nishioka T, Akiyama T, Nose K, Koike H. Arterial stiffness after successful

renal transplantation. Transplant Proc 2008;40:2405-‐8.

634. Unger P, Wissing KM, de Pauw L, Neubauer J, van de Borne P. Reduction of

left ventricular diameter and mass after surgical arteriovenous fistula closure in

renal transplant recipients. Transplantation 2002;74:73-‐9.

635. Suessenbacher A, Frick M, Alber HF, Barbieri V, Pachinger O, Weidinger F.

Association of improvement of brachial artery flow-‐mediated vasodilation with

cardiovascular events. Vasc Med 2006;11:239-‐44.

295

636. Bergeron S, Hillis GS, Haugen EN, Oh JK, Bailey KR, Pellikka PA. Prognostic

value of dobutamine stress echocardiography in patients with chronic kidney

disease. Am Heart J 2007;153:385-‐91.

637. Tita C, Karthikeyan V, Stroe A, Jacobsen G, Ananthasubramaniam K. Stress

echocardiography for risk stratification in patients with end-‐stage renal disease

undergoing renal transplantation. J Am Soc Echocardiogr 2008;21:321-‐6.

638. Nandalur KR, Dwamena BA, Choudhri AF, Nandalur MR, Carlos RC.

Diagnostic performance of stress cardiac magnetic resonance imaging in the

detection of coronary artery disease: a meta-‐analysis. J Am Coll Cardiol

2007;50:1343-‐53.

639. Nagel E, Lehmkuhl HB, Bocksch W, Klein C, Vogel U, Frantz E, Ellmer A,

Dreysse S, Fleck E. Noninvasive diagnosis of ischemia-‐induced wall motion

abnormalities with the use of high-‐dose dobutamine stress MRI: comparison with

dobutamine stress echocardiography. Circulation 1999;99:763-‐70.

640. Rakhit DJ, Zhang XH, Leano R, Armstrong KA, Isbel NM, Marwick TH.

Prognostic role of subclinical left ventricular abnormalities and impact of

transplantation in chronic kidney disease. Am Heart J 2007;153:656-‐64.

641. Sahagun-‐Sanchez G, Espinola-‐Zavaleta N, Lafragua-‐Contreras M, Chavez PY,

Gomez-‐Nunez N, Keirns C, Romero-‐Cardenas A, Perez-‐Grovas H, Acosta JH,

Vargas-‐Barron J. The effect of kidney transplant on cardiac function: an

echocardiographic perspective. Echocardiography 2001;18:457-‐62.

642. Reis G, Marcovitz PA, Leichtman AB, Merion RM, Fay WP, Werns SW,

Armstrong WF. Usefulness of dobutamine stress echocardiography in detecting

coronary artery disease in end-‐stage renal disease. Am J Cardiol 1995;75:707-‐10.

296

643. Rerkpattanapipat P, Morgan TM, Neagle CM, Link KM, Hamilton CA, Hundley

WG. Assessment of preoperative cardiac risk with magnetic resonance imaging.

Am J Cardiol 2002;90:416-‐9.

644. Hundley WG, Morgan TM, Neagle CM, Hamilton CA, Rerkpattanapipat P, Link

KM. Magnetic resonance imaging determination of cardiac prognosis. Circulation

2002;106:2328-‐33.

645. Kelle S, Chiribiri A, Vierecke J, Egnell C, Hamdan A, Jahnke C, Paetsch I,

Wellnhofer E, Fleck E, Klein C, Gebker R. Long-‐term prognostic value of

dobutamine stress CMR. JACC Cardiovasc Imaging 2011;4:161-‐72.

646. Geleijnse ML, Elhendy A, Fioretti PM, Roelandt JR. Dobutamine stress

myocardial perfusion imaging. J Am Coll Cardiol 2000;36:2017-‐27.

647. Sicari R, Nihoyannopoulos P, Evangelista A, Kasprzak J, Lancellotti P,

Poldermans D, Voigt JU, Zamorano JL. Stress Echocardiography Expert Consensus

Statement-‐-‐Executive Summary: European Association of Echocardiography

(EAE) (a registered branch of the ESC). Eur Heart J 2009;30:278-‐89.

648. Paetsch I, Jahnke C, Ferrari VA, Rademakers FE, Pellikka PA, Hundley WG,

Poldermans D, Bax JJ, Wegscheider K, Fleck E, Nagel E. Determination of

interobserver variability for identifying inducible left ventricular wall motion

abnormalities during dobutamine stress magnetic resonance imaging. Eur Heart J

2006;27:1459-‐64.

649. Walsh TF, Dall'Armellina E, Chughtai H, Morgan TM, Ntim W, Link KM,

Hamilton CA, Kitzman DW, Hundley WG. Adverse effect of increased left

ventricular wall thickness on five year outcomes of patients with negative

dobutamine stress. J Cardiovasc Magn Reson 2009;11:25.

297

650. Charoenpanichkit C, Morgan TM, Hamilton CA, Wallace EL, Robinson K, Ntim

WO, Hundley WG. Left ventricular hypertrophy influences cardiac prognosis in

patients undergoing dobutamine cardiac stress testing. Circ Cardiovasc Imaging

2010;3:392-‐7.

651. Chung SY, Lee KY, Chun EJ, Lee WW, Park EK, Chang HJ, Choi SI. Comparison

of stress perfusion MRI and SPECT for detection of myocardial ischemia in

patients with angiographically proven three-‐vessel coronary artery disease. AJR

Am J Roentgenol 2010;195:356-‐62.

652. Schwitter J, Wacker CM, van Rossum AC, Lombardi M, Al-‐Saadi N, Ahlstrom

H, Dill T, Larsson HB, Flamm SD, Marquardt M, Johansson L. MR-‐IMPACT:

comparison of perfusion-‐cardiac magnetic resonance with single-‐photon

emission computed tomography for the detection of coronary artery disease in a

multicentre, multivendor, randomized trial. Eur Heart J 2008;29:480-‐9.

653. Sakuma H, Suzawa N, Ichikawa Y, Makino K, Hirano T, Kitagawa K, Takeda K.

Diagnostic accuracy of stress first-‐pass contrast-‐enhanced myocardial perfusion

MRI compared with stress myocardial perfusion scintigraphy. AJR Am J

Roentgenol 2005;185:95-‐102.

654. Lee DC, Simonetti OP, Harris KR, Holly TA, Judd RM, Wu E, Klocke FJ.

Magnetic resonance versus radionuclide pharmacological stress perfusion

imaging for flow-‐limiting stenoses of varying severity. Circulation 2004;110:58-‐

65.

655. Kim RJ, Wu E, Rafael A, Chen EL, Parker MA, Simonetti O, Klocke FJ, Bonow

RO, Judd RM. The use of contrast-‐enhanced magnetic resonance imaging to

identify reversible myocardial dysfunction. N Engl J Med 2000;343:1445-‐53.

298

656. Kim RJ, Fieno DS, Parrish TB, Harris K, Chen EL, Simonetti O, Bundy J, Finn

JP, Klocke FJ, Judd RM. Relationship of MRI delayed contrast enhancement to

irreversible injury, infarct age, and contractile function. Circulation

1999;100:1992-‐2002.

657. McCrohon JA, Moon JC, Prasad SK, McKenna WJ, Lorenz CH, Coats AJ, Pennell

DJ. Differentiation of heart failure related to dilated cardiomyopathy and

coronary artery disease using gadolinium-‐enhanced cardiovascular magnetic

resonance. Circulation 2003;108:54-‐9.

658. Cowper SE. Nephrogenic Fibrosing Dermopathy [ICNSFR Website], 2001-‐

2009.

659. Manka R, Jahnke C, Gebker R, Schnackenburg B, Paetsch I. Head-‐to-‐head

comparison of first-‐pass MR perfusion imaging during adenosine and high-‐dose

dobutamine/atropine stress. Int J Cardiovasc Imaging 2010.

660. Wahl A, Paetsch I, Gollesch A, Roethemeyer S, Foell D, Gebker R, Langreck H,

Klein C, Fleck E, Nagel E. Safety and feasibility of high-‐dose dobutamine-‐atropine

stress cardiovascular magnetic resonance for diagnosis of myocardial ischaemia:

experience in 1000 consecutive cases. Eur Heart J 2004;25:1230-‐6.

661. Varga A, Garcia MA, Picano E. Safety of stress echocardiography (from the

International Stress Echo Complication Registry). Am J Cardiol 2006;98:541-‐3.

662. Lattanzi F, Picano E, Adamo E, Varga A. Dobutamine stress

echocardiography: safety in diagnosing coronary artery disease. Drug Saf

2000;22:251-‐62.

663. Kane GC, Hepinstall MJ, Kidd GM, Kuehl CA, Murphy AT, Nelson JM,

Schneider L, Stussy VL, Warmsbecker JA, Miller FA, Jr., Pellikka PA, McCully RB.

299

Safety of stress echocardiography supervised by registered nurses: results of a 2-‐

year audit of 15,404 patients. J Am Soc Echocardiogr 2008;21:337-‐41.

664. Lockie T, Ishida M, Perera D, Chiribiri A, De Silva K, Kozerke S, Marber M,

Nagel E, Rezavi R, Redwood S, Plein S. High-‐resolution magnetic resonance

myocardial perfusion imaging at 3.0-‐Tesla to detect hemodynamically significant

coronary stenoses as determined by fractional flow reserve. J Am Coll Cardiol

2011;57:70-‐5.

665. Watkins S, McGeoch R, Lyne J, Steedman T, Good R, McLaughlin MJ,

Cunningham T, Bezlyak V, Ford I, Dargie HJ, Oldroyd KG. Validation of magnetic

resonance myocardial perfusion imaging with fractional flow reserve for the

detection of significant coronary heart disease. Circulation 2009;120:2207-‐13.

666. Kurita T, Sakuma H, Onishi K, Ishida M, Kitagawa K, Yamanaka T, Tanigawa

T, Kitamura T, Takeda K, Ito M. Regional myocardial perfusion reserve

determined using myocardial perfusion magnetic resonance imaging showed a

direct correlation with coronary flow velocity reserve by Doppler flow wire. Eur

Heart J 2009;30:444-‐52.

667. Costa MA, Shoemaker S, Futamatsu H, Klassen C, Angiolillo DJ, Nguyen M,

Siuciak A, Gilmore P, Zenni MM, Guzman L, Bass TA, Wilke N. Quantitative

magnetic resonance perfusion imaging detects anatomic and physiologic

coronary artery disease as measured by coronary angiography and fractional

flow reserve. J Am Coll Cardiol 2007;50:514-‐22.

668. Rieber J, Huber A, Erhard I, Mueller S, Schweyer M, Koenig A, Schiele TM,

Theisen K, Siebert U, Schoenberg SO, Reiser M, Klauss V. Cardiac magnetic

resonance perfusion imaging for the functional assessment of coronary artery

300

disease: a comparison with coronary angiography and fractional flow reserve.

Eur Heart J 2006;27:1465-‐71.

669. Marwick TH, Steinmuller DR, Underwood DA, Hobbs RE, Go RT, Swift C,

Braun WE. Ineffectiveness of dipyridamole SPECT thallium imaging as a

screening technique for coronary artery disease in patients with end-‐stage renal

failure. Transplantation 1990;49:100-‐3.

670. Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary

vasodilator dysfunction on adverse long-‐term outcome of coronary heart disease.

Circulation 2000;101:1899-‐906.

671. Teragawa H, Ueda K, Matsuda K, Kimura M, Higashi Y, Oshima T, Yoshizumi

M, Chayama K. Relationship between endothelial function in the coronary and

brachial arteries. Clin Cardiol 2005;28:460-‐6.

672. Takase B, Hamabe A, Satomura K, Akima T, Uehata A, Ohsuzu F, Ishihara M,

Kurita A. Close relationship between the vasodilator response to acetylcholine in

the brachial and coronary artery in suspected coronary artery disease. Int J

Cardiol 2005;105:58-‐66.

673. Takiuchi S, Fujii H, Kamide K, Horio T, Nakatani S, Hiuge A, Rakugi H,

Ogihara T, Kawano Y. Plasma asymmetric dimethylarginine and coronary and

peripheral endothelial dysfunction in hypertensive patients. Am J Hypertens

2004;17:802-‐8.

674. Matsuo S, Matsumoto T, Takashima H, Ohira N, Yamane T, Yasuda Y,

Tarutani Y, Horie M. The relationship between flow-‐mediated brachial artery

vasodilation and coronary vasomotor responses to bradykinin: comparison with

those to acetylcholine. J Cardiovasc Pharmacol 2004;44:164-‐70.

301

675. Sato A, Terata K, Miura H, Toyama K, Loberiza FR, Jr., Hatoum OA, Saito T,

Sakuma I, Gutterman DD. Mechanism of vasodilation to adenosine in coronary

arterioles from patients with heart disease. Am J Physiol Heart Circ Physiol

2005;288:H1633-‐40.

676. Canty JM, Jr. Coronary Blood Flow and Myocardial Ischemia In: Braunwald E,

Bonow RO, eds. Braunwald's Heart Disease : A Textbook of Cardiovascular

Medicine. Philadelphia: Saunders, 2011:p.1049-‐1075.

677. Kern MJ, Lerman A, Bech JW, De Bruyne B, Eeckhout E, Fearon WF, Higano

ST, Lim MJ, Meuwissen M, Piek JJ, Pijls NH, Siebes M, Spaan JA. Physiological

assessment of coronary artery disease in the cardiac catheterization laboratory: a

scientific statement from the American Heart Association Committee on

Diagnostic and Interventional Cardiac Catheterization, Council on Clinical

Cardiology. Circulation 2006;114:1321-‐41.

678. Herzog CA. Is there something special about ischemic heart disease in

patients undergoing dialysis? Am Heart J 2004;147:942-‐4.

679. Vandenberg BF, Rossen JD, Grover-‐McKay M, Shammas NW, Burns TL, Rezai

K. Evaluation of diabetic patients for renal and pancreas transplantation:

noninvasive screening for coronary artery disease using radionuclide methods.

Transplantation 1996;62:1230-‐5.

680. Boudreau RJ, Strony JT, duCret RP, Kuni CC, Wang Y, Wilson RF, Schwartz JS,

Castaneda-‐Zuniga WR. Perfusion thallium imaging of type I diabetes patients with

end stage renal disease: comparison of oral and intravenous dipyridamole

administration. Radiology 1990;175:103-‐5.

681. Ng MK, Yeung AC, Fearon WF. Invasive assessment of the coronary

microcirculation: superior reproducibility and less hemodynamic dependence of

302

index of microcirculatory resistance compared with coronary flow reserve.

Circulation 2006;113:2054-‐61.

682. Aarnoudse W, van den Berg P, van de Vosse F, Geven M, Rutten M, Van

Turnhout M, Fearon W, de Bruyne B, Pijls N. Myocardial resistance assessed by

guidewire-‐based pressure-‐temperature measurement: in vitro validation.

Catheter Cardiovasc Interv 2004;62:56-‐63.

683. Fearon WF, Aarnoudse W, Pijls NH, De Bruyne B, Balsam LB, Cooke DT,

Robbins RC, Fitzgerald PJ, Yeung AC, Yock PG. Microvascular resistance is not

influenced by epicardial coronary artery stenosis severity: experimental

validation. Circulation 2004;109:2269-‐72.

684. Melikian N, Vercauteren S, Fearon WF, Cuisset T, MacCarthy PA,

Davidavicius G, Aarnoudse W, Bartunek J, Vanderheyden M, Wyffels E, Wijns W,

Heyndrickx GR, Pijls NH, de Bruyne B. Quantitative assessment of coronary

microvascular function in patients with and without epicardial atherosclerosis.

EuroIntervention 2010;5:939-‐45.

685. Layland J, Burns AT, Somaratne J, Whitbourn R. Looks can be deceiving:

dissociation between angiographic severity and hemodynamic significance of a

lesion. The importance of microvascular resistance. Cardiovasc Revasc Med 2010.

END0STAGERENAL FAILURE BENJAMINKANE*DUNDON · 2014. 6. 19. ·...

Documents

Transcript of END0STAGERENAL FAILURE BENJAMINKANE*DUNDON · 2014. 6. 19. ·...

END0STAGE*RENAL FAILURE BENJAMIN*KANE*DUNDON · 2014. 6. 19. ·...

Documents

Transcript of END0STAGE*RENAL FAILURE BENJAMIN*KANE*DUNDON · 2014. 6. 19. ·...

END0STAGERENAL FAILURE BENJAMINKANE*DUNDON · 2014. 6. 19. ·...

Transcript of END0STAGERENAL FAILURE BENJAMINKANE*DUNDON · 2014. 6. 19. ·...