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Transcript of 3 VASCULAR AGING PLAN 1.Introduction 2.Normal vascular anatomy and physiology 3.What is vascular...
MODULE 3 CHAPTER 1D
3
VASCULAR AGING
PLAN1. Introduction
2. Normal vascular anatomy and physiology
3. What is vascular aging ?
4. What causes it ?
5. How to diagnose it ?
6. How to treat and prevent it ?
7. Take away
Aging : What matters?
45 yr IT professionalArteries are 70 yr old
70 yr Athlete Arteries are 45 yr old
Chronological age is different from biological age
Atherothrombosis Significantly Shortens Life
Analysis of data from the Framingham Heart Study.Peeters A, et al. Eur Heart J. 2002;23:458-466.
Atherothrombosis reduces life expectancy by around 8-12 years in patients aged over 60 years1
Average Remaining Life Expectancy at Age 60 (Men)
0
4
8
12
16
20
Healthy
Yea
rs
History of AMI
-9.2 years
History of Cardiovascular Disease
-7.4 years
History of Stroke
-12 years
Vascular age
Vascular age is the apparent age of the blood vessels, particularly the arteries when compared to what is normal for the healthy population
Vascular age is affected by genetic predisposition, lifestyle choices and other factors
PLAN
1. Introduction
2. Normal vascular anatomy and physiology
3. What is vascular aging?
4. What causes it?
5. How to diagnose it?
6. How to treat and prevent it?
7. Takeaways
THE ARTERIAL SYSTEM These are the main conducting vessels
carrying blood away from the heart
Can be muscular or elastic. There is a gradual transition between these two types
Elastic Arteries Are characterised by a predominance of elastin in
the tunica media and little smooth muscle Are found just downstream from the heart Undergo expansion with each systole of the heart On relaxation of the heart the elastic recoil of the
wall helps propel blood through the blood vessels Include the aorta, pulmonary, common carotid and
other major vessels
Muscular Arteries These are medium sized to smaller arteries Are characterised by a predominance of smooth
muscle cells in the tunica media Make up the main distributing branches of the
arterial tree, eg. the femoral, radial, coronary and cerebral arteries
Remember, there is a gradual transition between elastic and muscular arteries.
AORTA
ARTERIESARTERIOLES
ELASTIC
MUSCULAR
Systole
Normal Arterial Pulsation
Diastole
Systole
Increases vascular afterload with a propensity to develop LVH Decreases coronary perfusion pressure Increases myocardial oxygen demand and subendocardial ischemia Increases flow turbulence, endothelial dysfunction and atherogenesis Increases in pulsatile strain and chance of plaque rupture All recognized by a wide brachial artery pulse pressure in the elderly
Young compliant arteries : Normal PW velocity (8 m/sec)
Elderly stiff arteries with ISH : Increased PW velocity (12 m/sec)
(1) Ventricular-Vascular coupling
(2) coronary blood flow
(1) Ventricular-vascular mismatch(2) The reflected wave increases or “augments” central SBP during late systole:
Cushion Conduit
Forwardwave
Reflected Wave
Pulsatile flow to Continuous flow- Cushion effect
Conduit function – Role of Endothelium
Tunica adventitia
Tunica media
Tunica intimaEndothelium
Subendothelial
connective tissue
Internal elastic
membrane
Smooth muscle cells
Elastic/collagen
fibers
External elastic
membrane
Normal Endothelium
Regulates vascular tone and produces
The endothelium is the gatekeeper of the vasculature and a major regulator of vascular tone and hemostasisIt Provides a smooth, non-thrombogenic surface and a selectively permeability barrier between the circulation and the vessel wall.
Adapted from Ormolgul and Dzau, J Vasc Med Biol., 1991, 282-301,Pepine, C., et. al., “Vascular Health as as Therapeutic Target in Cardiovascular Disease,” VBW , University of Florida, 1998Atomic force micrograph frpm Barbara et al, Am J Physiol [Heart Care Physiol.], 1995; 266: H1765-H1772
• Endogenous vasodilators and vasoconstrictors.
• Growth promoting and growth inhibiting factors.
• Anticoagulants and Procoagulants.
Retards platelet and leucocyte adhesion
Inhibits VSMC migration & proliferation
Barrier to LDL, degrade VLDL & chylotriglyceride
Normal Arterial Function
Cushion function – mainly by Aorta; prevents transmission of systolic pressure to the periphery , slows systolic velocity and maintains continuous flow in distributing arteries and arterioles
Conduit function – Mainly by arteries and their endothelium ; prevents atheroma, plaque, thrombus formation to provide continuous and uninterrupted blood flow to the organs
PLAN1.Introduction
2.Normal vascular anatomy and physiology
3.What is the mechanism of vascular aging ?
4.What causes it ?
5.How to diagnose it ?
6.How to treat and prevent it ?
7.Takeaways
Mechanism
Loss or reduction of Cushion and Conduit functions of the blood vessels
NORMAL SIZENORMAL RELAXATION
YOUNG OLD
DILATEDSTIFF
Systole
Aortic Stiffening and Early Wave Reflection
Diastole
Systole
Young compliant arteries : Normal PW velocity (8 m/sec)
Elderly stiff arteries with ISH : Increased PW velocity (12 m/sec)
(1) Ventricular-Vascular coupling
(2) coronary blood flow
(1) Ventricular-vascular mismatch(2) The reflected wave increases or “augments” central SBP during late systole:
LV systolic,diastolic dysfunction
Abnormal cushion function
Abnormal Conduit FunctionAbnormal Endothelium
Dysfunction
LDL-C Hypertension Diabetes Smoking
Oxidative stress
Angiotensin II Homocysteine
Oestrogen deficiency
Endothelial dysfunction sets the
stage for atherosclerosis
Formation of superoxide anion with inactivation of NO & stimulation
of vascular oxidase system
platelet and leucocyte adhesion
VSMC migration & proliferation
LDL deposition lipid clearance
Adapted from Ormolgul and Dzau, J Vasc Med Biol., 1991, 282-301Griendling, K. et.al., “Oxidative Stress and Cardiovascular Disease,”Circulation, 1007; 96: 3264-3265.
Atomic force micrograph frpm Barbara et al, Am J Physiol [Heart Care Physiol.], 1995; 266: H1765-H1772
The Evolution of AtherosclerosisThe Evolution of Atherosclerosis
FoamCells
FattyStreak
IntermediateLesion Atheroma
FibrousPlaque
ComplicatedLesion/Rupture
Endothelial DysfunctionEndothelial Dysfunction
From 1st DecadeFrom 1st Decade From 3rd DecadeFrom 3rd Decade From 4th DecadeFrom 4th Decade
Growth Mainly by Lipid AccumulationGrowth Mainly by Lipid Accumulation Smooth Muscle& Collagen
Smooth Muscle& Collagen
Thrombosis,Hematoma
Thrombosis,Hematoma
Adapted From Stary HC et al. Circulation. 1995;92:1355-1374Adapted From Stary HC et al. Circulation. 1995;92:1355-1374
Abnormal cushionfunction
Abnormal conduitfunction
VASCULARAGING
PLAN
1. Introduction
2. Normal vascular anatomy and physiology
3. What is the mechanism of vascular aging ?
4. What causes it ?
5. How to diagnose it ?
6. How to treat and prevent it ?
7. Takeaways
INTERHEART: THE EFFECT OF MODIFIABLE FACTORS ON RISK FOR MI
Midsegment obesity FAMILY HISTORY
LARGE ARTERIES
HYPERGLYCEMIA,OTHER RF
A G E S
PROTEIN GLYCATIONIN VESSEL WALL
LESS DISTENSIBLE COLLAGEN
LOSS OF ARTERIALCOMPLIANCE
HIGH SYSTOLIC BP
LOW DIASTOLIC BP
HIGH PULSE PRESSURE
ATHEROMA
Factors contributing to Abnormal conduit function
PAI-1
Endothelial dysfunction
Proteolysis
NO + Local mediators + Tissue ACE, Angiotensin II
VCAM, ICAM, Cytokines- NF-kB
Endothelin Growth factors, matrix
LDL-C Hypertension Diabetes Smoking
Oxidative stress
Angiotensin II Homocysteine
Thrombosis Plaque rupture
Inflammation Vasoconstriction Vascular lesion and remodelling
Clinical Sequelae
Gibbons GH, Dzau VJ, New England J Med,1994; 330: 1431-1438
ATHERO- ARTERIO- SCLEROSIS SCLEROSIS
(Increased vascular stiffness Decreased vascular compliance)
Focal, Occlusive Intimal disease Inflammatory Endothelial
dysfunction Related to LDL
cholesterol oxidation “Inside-out” Sensitive to A II and
other substances
Diffuse, Dilatory Medial disease Fibrotic (elastin
breakdown, collagen increase)
Adventitial and medial hypertrophy
Related to age and BP “Outside-in” Sensitive to A II and
other substances
PLAN
1.Introduction
2.Normal vascular anatomy and physiology
3.What is the mechanism of vascular aging ?
4.What causes it ?
5.How to diagnose it ?
6.How to treat and prevent it ?
7.Takeaways
(CUSHION) (CONDUIT)
PULSE WAVE FORM ANALYSIS- TONOMETRY
MAP
TONOMETRY-PULSE WAVE FORM ANALYSIS
NORMAL CUSHION EFFECT
Normal systolic,diastolicAnd pulse pressure
ABNORMAL CUSHION EFFECT
High systolic,lowDiastolic and highPulse pressure
Identification of Arterial Aging
CAD Death Rate per 10,000 Person-years
100+ 90-99 80-89 75-79 70-74 <70<120
120-139140-159160+
Diastolic BP (mmHg)
Systolic BP (mmHg)
20.610.3 11.8 8.8 8.5 9.2
11.812.612.813.9
24.6 25.3 25.2 24.9
16.923.8
31.025.8
34.743.8
38.1
80.6
37.4
48.3
Neaton et al. Arch Intern Med 1992; 152:56-64.
Effect of SBP and DBP onAge-Adjusted CAD Mortality: MRFIT
High systolic and low diastolic pressure is dangerous
PULSE WAVE VELOCITY
What is Central Aortic Pressure ? Blood pressure in the aorta, closer to the vital organs
Central aorticpressure
Peripheral brachialpressure
RISK FACTORS AND MARKERS
RISK FACTORS PREDICT DISEASE DM,DUR. LIPIDS HBP SMOKING MET SYN MENTAL STRESS FAMILY HISTORY
RISK MARKERS INDICATE PRESENCE MICROALB.,ED,CKD,
FMD CIMT, AB INDEX,PW
VELOCITY MSCT, STRESS TEST Hs CRP ECHO – DD,E/E’
INDIVIDUAL ASSESSMENT FOR EARLY VASCULAR AGING (EVA)? AT 30 YRS
RISK FACTOR AND RISK MARKER ASSESSMENT
RISK FACTORS +RISK MARKERS +
ALREADY EVA +
RISK FACTORS +RISK MARKERS --
LIKELY TO DEVELOP EVA
RISK FACTORS –RISK MARKERS --
PREVENT EVA
PLAN
1.Introduction
2.Normal vascular anatomy and physiology
3.What is the mechanism of vascular aging ?
4.What causes it ?
5.How to diagnose it ?
6.How to treat and prevent it ?
7.Takeaways
To reverse and prevent vascular aging
Life style modification – Diet/ Exercise /
Good habits / Mental relaxation
Block Renin- Angiotensin system
Control Blood pressure
Reduce Lipids
Control Blood sugar
YYYYY Y Y Y
ACE
ACE
Angiotensin II LDL
endothelialdamage oxLDL/eLDL
lumen
subintima
+ +
ACEMacrophages
+
Ang II media
Foam-cells
smooth muscle cells + Growth factorsCytokines
Local Angiotensin System in Macrophages
and Role in Atherosclerosis
Ang II
oxidative stress
differentiation(activation)
Mod. from Diaz et al., N Engl J Med 337 (1997)
ACE
adhesion-molecules infiltration
fatty streak, plaque
endothelium
circulatingmonocytes
ACE
ACE I OR ARB?WHICH ACEI,ARB?
Surrogate vascular structure & function trials (SECURE) NIL
Post MI patients (AIRE,TRACE,SAVE) (OPTIMAAL)
High risk without LVF (HOPE/MICRO HOPE) NIL
Stroke (HOPE, PROGRESS) (SCOPE)
Preventing Heart failure (HOPE) NIL
Heart failure ?(CONSENSUS, SOLVD,HOPE) (ELITE II,Val-HeFT)
Diabetes & hypertension (CAPP,ABCD, FACET) (LIFE)
Renal disease (LEWIS II) (IDNT,RENAAL,IRMA2)
Evidence base in diabetic subjectsEvidence base in diabetic subjects
ACEIs ARBs
LIFE
Charm
TELMISARTAN
Distribution of ACE:
Renin-Angiotensin Systems (III)
Mod. from Dzau V, Arch Intern Med 153 (1993)
R A S
local (tissue)
10% 90%
Acute and short-term effectscardiovascular/
renal homeostasis
Long-term effectslocal "organ adaptation"
renal-independent activation
circulating (plasma)
VSMC-Contraction VSMC-Growth VSMC-Migration Platelet aggregation PAI-1 t-PA
Putative role of 10 mg ramipril:
Potential Pharmacological Actions of ACE Inhibitors in Atherosclerosis
RAS(Plasma-ACE)
RAS(Plaque-ACE)
Metalloproteinases(fibrous cap of plaque)
Plaque rupture
Ramipril
adapt. from Dzau et al., Drugs 47 (1994)
VSMC = vascular smooth muscle cells
Angiotensin II Bradykinin NO
Matrix-Stability
Blood pressurein hypertension
Collagen Elastin etc.
Other targets?(CUSHION)
(CONDUIT)
ACE I
Total CV events and procedures
Number at riskAmlodipine perindopril 9639 9277 8957 8646 8353 7207Atenolol thiazide 9618 9210 8848 8465 8121 6977
0.0 1.0 2.0 3.0 4.0 5.0 Years0.0
2.0
4.0
6.0
8.0
10.0
12.0
14.0
16.0
18.0
Amlodipine perindopril(No. of events 1362)
Atenolol thiazide(No. of events 1602)
HR = 0.84 (0.78 0.90)p < 0.0001
55
Effects of Statins and ACE Inhibitors
Agostino Faggiotto et al,Hypertension. 1999;34[part 2]:987-996.
State-of-the-art therapy
(incl. ASA, Amlo, Statins)
Deactivated Plaque
Activated Plaque
ACE activityin plaques
ACE activityin plaques
Antiatherosclerotic Effect of ACE Inhibitors in the Vasculature (HOPE)
Scheme of "plaque deactivation":
ACE activityin plaques
State-of-the-art therapy+ACE
inhibitor(e.g. 10 mg Ramipril)
So, to reverse and prevent Vascular Aging
Life style modification Block RAS-ACEI (Ramipril, Perindopril-Max.
tolerated dose) Control BP- Calcium blockers Amlodepin Control lipids- Statins Control sugar – emerging drugsDPP4
inhibitors Logical combination of above
PLAN
1. Introduction
2. Normal vascular anatomy and physiology
3. What is the mechanism of vascular aging?
4. What causes it?
5. How to diagnose it?
6. How to treat and prevent it?
7. Takeaways
Vascular Age - Approach
ReverseVascular aging
KEEPING THE ARTERIES YOUNGER
END OF MODULE 3 CHAPTER 1D