Women and Ischemic Heart Disease: A Changing … 1615PC Bairey-Merz/Slide #1 Women and Ischemic...

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1615PC Bairey-Merz/Slide #1

Women and Ischemic Heart Disease:Women and Ischemic Heart Disease:A Changing ParadigmA Changing Paradigm

Noel Bairey Merz, M.D., F.A.C.C., F.A.H.A.Medical Director, Women’s Heart Center

and Preventive Cardiac CenterThe Women’s Guild Chair in Women’s Health

Heart InstituteCedars-Sinai Medical Center


Clinical CV Translational ResearchClinical CV Translational Research

1. A systematic approach to an identified problem

2. T1 (bench bed), T2 (bed clinic), T3 (clinic community)

3. Four key steps –1. Observation2. Mechanisms3. Intervention4. Translation


Problem: Adverse Mortality Gap Resultingin a New Female Majority for CVD

Current Strategies Not Working Optimally in Women

2


Clinical Translational ResearchClinical Translational Research

1. Observation

2. Mechanisms

3. Intervention

4. Translation


Bugiardini and Bairey Merz JAMA 2005;293:477-84

Observation: Women have a two-fold increase in “normal”coronary arteries in the setting of ACS, nonSTE and STE AMI


Observation:Phenotype -MicrovascularCoronary DiseaseExertional angina

Abnormal SPECT

No obstructive CAD

Abnormal coronary flow reserve and elevated LVEDP

Diffuse atherosclerosisby IVUS

NCDR estimate 3 million women in the US – a largerproblem than breast cancer.

Circulation. 1999;99:1774

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1. Observation

2. Mechanisms

3. Intervention

4. Translation


Inflammatory MilieuE2

- Post-Menopause- Hypothalamic Hypoestrogenemic- PCOS

HTN

Obesity

↑ Lipids

Vascular Dysfunction

Positive Remodeling

Progressive Manifestations of Demand Ischemia

Symptomatic Manifestations

Abnormal coronary vasomotionMetabolic Δs, Perfusion

Exposure Time of Mismatch in Myocardial Oxygen Supply / DemandNear Term Prolonged

SubclinicalSubclinicalAtherosclerosisAtherosclerosis

Obstructive Obstructive CADCAD

Progenitor Cell Repair, Microvascular Disease, Fibrosis, Diastolic Dysfxn

NormalNormalArteryArtery-- ↓↓CFRCFR

NormalNormalArteryArtery& CFR& CFR

Autoimmune Diseases

Hypothetical New Understanding of IschemicHeart Disease in Women (Shaw and Bairey Merz)

Shaw et al, JACC 2009


V3005V3005

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Women and Ischemic Heart Disease (Shaw, Bugiardini, Bairey Merz, JACC 2009)

Exposure Time of Mismatch in Myocardial Oxygen Supply / DemandNear Term Prolonged

Rep

etiti

ve /

Prog

ress

ive

Man

ifest

atio

ns o

f Isc

hem

ia

Micro-Infarction/Myocardial Fibrosis

Diastolic Dysfunction

Decreased Segmental Perfusion

Regional Wall Motion

Decreased Subendocardial Perfusion

Systolic Dysfunction

Endothelial and MicrovascularDysfunction

Altered Metabolism/Abnormal ST segment response


Coronary Reactivity Testing

Post ACHBaseline Post NTG

VasoconstrictionOf LAD


Pro

port

ion

With

out C

V E

vent

No Dilation (N=67)

Dilation (N=56)

Log-rank p=0.0037

Multivariate p=0.001

Years Of Follow-up0 1 2 3 4 5 6

0.0

0.2

0.4

0.6

0.8

1.0

Mechanisms: Abnormal Coronary Vasomotion To Acetylcholine Independently Predicts Cardiac Events

In Women with No Obstructive CAD

Mechanisms: Abnormal Coronary Vasomotion To Acetylcholine Independently Predicts Cardiac Events

In Women with No Obstructive CAD

VON MERING et al, Circulation 2004;109:722-125

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MECHANISM: POLYMORPHISM AT POSITION 573 AT-1R GENE IS ASSOCIATED WITH AN ABNORMAL ENDOTHELIAL FUNCTION, INDEPENDENT OF CAD

-40.00

-30.00

-20.00

-10.00

0.00

10.00

20.00

30.00

TT/TC CC

GENOTYPE

% C

HA

NG

E IN

CO

RO

NA

RY

AR

TE

RY

CR

OS

S S

EC

TIO

NA

L A

RE

A NO CAD

MILD CAD

SIG CAD

n =120, Mean values SE p=0.008, Wilcoxon rank sum TT/TC vs CC

VON MERING, JACC 2001;37:SUPPL A;293A


Mechanisms: Beta1 Adrenergic Polymorphism* Predicts Adverse Outcome in Women with No Obstructive CAD (n=936)

Pancanowski et al (submitted)

Time to Event (months)

96847260483624120

Cum

ulat

ive

Surv

ival

(%

)

100

90

80

70

60

50

B: Non-obstructive CAD, Gly389 carrier

D: Obstructive CAD, Gly389 carrier

C: Obstructive CAD, Arg389 homozygote

Race-adjusted log-rank A vs. B P=0.015 C vs. D P=0.799

A: Non-obstructive CAD, Arg389 homozygote

*Adrenergic control of myocardial contractility, microvasculature and renin release


Reduced CFR

NonobstructiveAtheroma

Pro-Atherogenic FactorsHTN, IR,

Inflammation…

Vascular Dysfxn SymptomsAtypical Symptoms

SOBUnusual Fatigue↑ Frequency

Pro-Vasculopathy

Sex-Specific PrecursorsPCOS, Hypoestrogenemia,Menopause

Accelerating FactorsEarly Menopause

Risk Factor Clustering

Hormonal Alterations Coupled with:

Hypothetical Model of Female-Specific Vasculopathic Angina

Subendocardial or Epicardial Ischemia

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Diastolic Relaxation Failure Increases Oxygen Diastolic Relaxation Failure Increases Oxygen Consumption and Reduces Oxygen SupplyConsumption and Reduces Oxygen Supply

Sustained contraction of ischemic tissue during diastole:

– Consumes energy, increasing myocardial oxygen consumption

– Causes intramural compression of small vessels, reducing myocardial blood flow and oxygen supply

– (Most blood flow to the heart occurs during diastole)

– Worsens ischemia and angina

1615PC Bairey-Merz/Slide #17Journal of the American College of CardiologyVolume 47, Issue 8 , 18 April 2006, Pages 1630-1638

Mechanisms: Reduced perfusion in patients with normal coronary angiography - MR can measure the subendocardium

51/100 female

1615PC Bairey-Merz/Slide #

Ch

ang

e in

PC

r/A

TP

du

rin

g s

tres

s, p

erce

nt

-50

-40

-30

-20

-10

0

10

20

30

>70% S ten o sisW o m en w ith

C h est P a inb u t n o rm a l A n g io

R efe ren ceP o p u la tio n

p < 0 .025 ,com pared to n o rm a ls

2 sd

Mechanisms: Metabolic PCr/ATP (Magnetic Resonance [MR] 1.5 Tesla) ischemia is prevalent in patients with normal angiography

NEJM 2001

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Patient 1

Stress Perfusion Rest Perfusion

RV LV

Papillary muscles

Subendocardial hypoperfusion

Cine –diastolic frame Delayed enhancement



Abnormal adenosine stress first pass perfusion demonstrating regional first pass hypoperfusion in the septum and apex in a patient with very recent LAD stent for acute MI. The patient has microvascular obstruction.

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Interventional No Reflow: Interventional No Reflow: 21% MI and 2% elective PCI21% MI and 2% elective PCI--stentingstenting

Circulation 2008;117;3152-3156



1. Observation

2. Mechanisms

3. Intervention

4. Translation


COURAGE Primary EP:COURAGE Primary EP:Survival Free of Death or MISurvival Free of Death or MI

Years0 1 2 3 4 5 6

0.0

0.5

0.6

0.7

0.8

0.9

1.0

PCI + OMT

Optimal Medical Therapy (OMT)

Hazard ratio: 1.0595% CI (0.87-1.27)P = 0.62

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• Randomization to PCI +

OMT vs. OMT

• Intensive, Guideline-Driven

Medical Therapy & Lifestyle

Intervention In Both Groups

Source: Boden et al. N Engl J Med. 2007; 356:1503-16.

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-0.2

0

0.2

0.4

0.6

0.8

1

≤2.0 2.1-2.2 2.3-2.4 2.5-2.6 2.7-2.8 2.9-3.0

Baseline CFR

CF

R C

ha

ng

e

Placebo

ACE-I

Intervention T2: Patients with ischemia and no obstructive CAD randomized to the ACE-I quinipril have improved microvascular coronary function measured by CFR (n=67)

Pepine CJ et al, Circ in press


Figure 10. Mean Number of Chest Pain or Symptom Episodes in the Prior Month by Eplerenone Vs. Placebo Treatment Group

0

5

10

15

20

25

30

35

40

45

50

Baseline Visit2 Visit3 Visit4

Ches

t Pai

n E

pis

odes

/ M

onth

Placebo

Drug

E-WISE unpublished data

Intervention T2: Patients with ischemia and no obstructive CAD randomized to the aldosterone blocker eplenerone have improved symptoms related to microvascular dysfunction (preliminary data)(n=43).


-40

-30

-20

-10

0

10

Entry

Exit

placebo1/10 NE/EE

(%)

PCr/ATP MRSRatio p=0.17

comparedto placebo

Intervention: Patients with ischemia and no obstructive CAD randomized to low dose hormone (estrogen-progestin) therapy did not improve ischemia measured by metabolic MR (preliminary data)

Bairey Merz CN et al Am Heart J (in press)

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MERLINMERLIN--TIMI 36: Efficacy results TIMI 36: Efficacy results in major subgroupsin major subgroups

Morrow DA et al. JAMA. 2007;297:1775-83.

0.6 0.8 1.41.2 1.6

Favors ranolazine Favors placebo

Gender MenWomen

Age <75 years

≥75 years

Diabetes No DMDM

SubgroupPrimary endpoint

n

TIMI Risk 0-34-7

STD ≥1 mm NoYes

Overall 6560

42692291

5406

1154

43402220

36012959

42552304

Pinteraction

0.12

0.80

0.39

0.16

0.23

Index event UANSTEMI

30673342

0.85

HR (95% CI)

STD = ST-segment depression


Scan 2 4/14/08

MPRI 1.2

Scan 1 3/3/08

MPRI 2.5

Randomized, cross-over trial of ranolazine 500-1000 po bid vs placebo in women with signs and symptoms of ischemia and no obstructive coronary artery disease: Analysis in progress



1. Observation

2. Mechanisms

3. Intervention

4. Translation

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This slide set was adapted from the following 2004-6 ACC/AHA guidelines:

Cardiovascular Disease Prevention in Women 2004

Management of Patients With ST-Elevation Myocardial Infarction

Management of Patients with Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction

Preventing Heart Attack and Death in Patients with Atherosclerotic Cardiovascular Disease

Management of Patients with Chronic Stable Angina

Update for Coronary Artery Bypass Graft Surgery

Evaluation and Management of Chronic Heart Failure in the Adult

The full-text guidelines and executive summaries are also available on the

ACC and AHA websites at www.acc.org and www.americanheart.org

Clinical Practice Guidelines (T3)Clinical Practice Guidelines (T3)

ACC=American College of Cardiology, AHA=American Heart Association


Impact of AHA Get With The GuidelinesImpact of AHA Get With The Guidelines--CAD CAD Program on Quality of CareProgram on Quality of Care

93

79

64 6757

95

83

6570 70

9787

6573 76

9687

6775 75

9791

6874

82

0102030405060708090

100

Aspirin Beta Blocker ACE Inhibitor Lipid Rx SmokingCessation

Baseline Q1 Q2 Q3 Q4

* ***

* p< 0.05 compared to baseline

* *

***

*

**

GWTG-CAD: 123 US Hospitals n=27,825Labresh, Fonarow et al. Circulation 2003;108:IV-722

**


GuidelineImplementation andACS and the Sex Survival Gap

Following guidelineimplementation, mortality for womenimproves andthe sex gap narrows(RED)

Persistent sex gap (BLUE)suggests more workStill neededto understand sex-specific pathophysiologyto improve outcomesfor women and men

Novak et al Am J Medicine 2008;121:602.

+

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Cardiovascular disease mortality trends for males and females Cardiovascular disease mortality trends for males and females (United States: 1979United States: 1979--2004).2004). Source: NCHS and NHLBI

380

400

420

440

460

480

500

520

79 80 85 90 95 00 04

Years

Dea

ths

in T

ho

usa

nd

s

Males Females

0

Problem: Adverse Mortality Gap Resulting in a New Female CVD MajorityCurrent Strategies Not Working Optimally in Women

NHLBI WISE study And Awareness and Guidelines Campaigns


Cardiovascular disease mortality trends for males and females Cardiovascular disease mortality trends for males and females (United States: 1979United States: 1979--2004).2004). Source: NCHS and NHLBI

380

400

420

440

460

480

500

520

79 80 85 90 95 00 04

Years

Dea

ths

in T

ho

usa

nd

s

Males Females

0

Problem: Adverse Mortality Gap Resulting in a New Female CVD Majority

Solution: Clinical Translational Research and Guidelines

NHLBI WISE study And Awareness and Guidelines Campaigns


NOEL BAIREY MERZ, MD SAIBAL KAR, MD

LESLEE SHAW, PhD STEVE NISSEN, MD

CARL J. PEPINE, MD RENU VIRMANI, MD

JULIE JOHNSON, PHARM D, PhD LOUISE THOMSON, MD

WILLIAMS ROGERS, MD DAN BERMAN, MD

VERA BITTNER, MD CHRISANDRA SHUFELT, MD

STEVE REIS, MD POITR SLOMKA, MD

RICARDO AZZIZ, MD EDUARDO MARBAN, MD, PhD

SHERYL F. KELSEY PhD SUPURNA CHOWDHURY PhD

DELIA JOHNSON, PhD RAJ MAKKAR, MD

GERALD POHOST, MD PK SHAH, MD

ARSHED QUYYUMI, MD CALVIN HOBEL, MD

AMIR LERMAN, MD CHANDER AROURA, PhD

BARRY SHARAF, MD GLENN BRAUNSTEIN, MD

GEORGE SOPKO, MD ANITA PHAN, MD

INVESTIGATORS

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Ischemic Heart Disease in Women: Ischemic Heart Disease in Women: Changing ParadigmChanging Paradigm

Conclusions and Next StepsConclusions and Next Steps1. Sex differences in ischemic heart disease

mechanisms impact appropriate diagnosis and treatment, contributing to adverse outcomes in women.

2. Microvascular coronary dysfunction can be evaluated using a variety of imaging techniques; CMRI may be an ideal noninvasive modality.

3. Ongoing research is further exploring noninvasive evaluation strategies. Contact us at [email protected] or 310 423 9680 for information or referral.

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