Women and Ischemic Heart Disease: A Changing Paradigm. Clinical CV Translational Research

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1 Women and Ischemic Heart Disease: A Changing Paradigm Noel Bairey Merz, M.D., F.A.C.C., F.A.H.A. Medical Director, Women s Heart Center and Preventive Cardiac Center The Women s Guild Chair in Women s Health Heart Institute Cedars-Sinai Medical Center 1615PC Bairey-Merz/Slide #1 Clinical 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. Observation 2. Mechanisms 3. Intervention 4. Translation 1615PC Bairey-Merz/Slide #2 Problem: Adverse Mortality Gap Resulting in a New Female Majority for CVD Current Strategies Not Working Optimally in Women 1615PC Bairey-Merz/Slide #3 1

2 Clinical Translational Research 1. Observation 2. Mechanisms 3. Intervention 4. Translation 1615PC Bairey-Merz/Slide #4 Observation: Women have a two-fold increase in normal coronary arteries in the setting of ACS, nonste and STE AMI Bugiardini and Bairey Merz JAMA 2005;293: PC Bairey-Merz/Slide #5 Observation: Phenotype - Microvascular Coronary Disease Exertional angina Abnormal SPECT No obstructive CAD Abnormal coronary flow reserve and elevated LVEDP Diffuse atherosclerosis by IVUS NCDR estimate 3 million women in the US a larger problem than breast cancer. Circulation. 1999;99: PC Bairey-Merz/Slide #6 2

3 Clinical Translational Research 1. Observation 2. Mechanisms 3. Intervention 4. Translation 1615PC Bairey-Merz/Slide #7 Hypothetical New Understanding of Ischemic Heart Disease in Women (Shaw and Bairey Merz) Autoimmune Diseases Symptomatic Manifestations E2 - Post-Menopause - Hypothalamic Hypoestrogenemic -PCOS HTN Obesity Lipids Inflammatory Milieu Normal Artery & CFR Vascular Dysfunction Abnormal coronary vasomotion Metabolic Δs, Perfusion Positive Remodeling Progenitor Cell Repair, Microvascular Disease, Fibrosis, Diastolic Dysfxn Normal Artery - CFR Subclinical Atherosclerosis Obstructive CAD Shaw et al, JACC 2009 Progressive Manifestations of Demand Ischemia Exposure Time of Mismatch in Myocardial Oxygen Supply / Demand Near Term 1615PC Prolonged Bairey-Merz/Slide #8 V PC Bairey-Merz/Slide #9 3

4 Women and Ischemic Heart Disease (Shaw, Bugiardini, Bairey Merz, JACC 2009) Systolic Dysfunction Repetitive / Progressive Manifestations of Ischemia Decreased Segmental Perfusion Diastolic Dysfunction Micro-Infarction/Myocardial Fibrosis Altered Metabolism/Abnormal ST segment response Decreased Subendocardial Perfusion Endothelial and Microvascular Dysfunction Regional Wall Motion Exposure Time of Mismatch in Myocardial Oxygen Supply / Demand Near Term Prolonged 1615PC Bairey-Merz/Slide #10 Coronary Reactivity Testing Vasoconstriction Of LAD Baseline Post ACH Post NTG 1615PC Bairey-Merz/Slide #11 Mechanisms: Abnormal Coronary Vasomotion To Acetylcholine Independently Predicts Cardiac Events In Women with No Obstructive CAD Proportion Without CV Event Dilation (N=56) No Dilation (N=67) Log-rank p= Multivariate p= Years Of Follow-up VON MERING et al, Circulation 2004;109: PC Bairey-Merz/Slide #12 4

5 MECHANISM: POLYMORPHISM AT POSITION 573 AT-1R GENE IS ASSOCIATED WITH AN ABNORMAL ENDOTHELIAL FUNCTION, INDEPENDENT OF CAD % CHANGE IN CORONARY ARTERY CROSS SECTIONAL AREA VON MERING, JACC 2001;37:SUPPL A;293A TT/TC n =120, Mean values SE p=0.008, Wilcoxon rank sum TT/TC vs CC CC NO CAD MILD CAD SIG CAD GENOTYPE 1615PC Bairey-Merz/Slide #13 Mechanisms: Beta1 Adrenergic Polymorphism* Predicts Adverse Outcome in Women with No Obstructive CAD (n=936) 100 Cumulative Survival (%) 90 A: Non-obstructive CAD, Arg389 homozygote 80 B: Non-obstructive CAD, Gly389 carrier 70 C: Obstructive CAD, Arg389 homozygote 60 Race-adjusted log-rank A vs. B P=0.015 D: Obstructive CAD, Gly389 carrier 50 C vs. D P= Pancanowski et al (submitted) Time to Event (months) *Adrenergic control of myocardial contractility, microvasculature and renin release 1615PC Bairey-Merz/Slide #14 Hypothetical Model of Female-Specific Vasculopathic Angina Sex-Specific Precursors PCOS, Hypoestrogenemia, Menopause Hormonal Alterations Coupled with: Pro-Atherogenic Factors HTN, IR, Inflammation Pro-Vasculopathy Accelerating Factors Early Menopause Risk Factor Clustering Nonobstructive Atheroma Reduced CFR Subendocardial or Epicardial Ischemia Vascular Dysfxn Symptoms Atypical Symptoms SOB Unusual Fatigue Frequency 1615PC Bairey-Merz/Slide #15 5

6 Diastolic Relaxation Failure Increases Oxygen Consumption 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 #16 Mechanisms: Reduced perfusion in patients with normal coronary angiography - MR can measure the subendocardium 51/100 female Journal of the American College of Cardiology Volume 47, Issue 8, 18 April 2006, Pages PC Bairey-Merz/Slide #17 30 Mechanisms: Metabolic PCr/ATP (Magnetic Resonance [MR] 1.5 Tesla) ischemia is prevalent in patients with normal angiography Change in PCr/ATP during stress, percent sd NEJM 2001 Reference Population Women with Chest Pain but normal Angio >70% Stenosis p < 0.025, compared to normals 1615PC Bairey-Merz/Slide # 6

7 Stress Perfusion Rest Perfusion Patient 1 RV LV Subendocardial hypoperfusion Cine diastolic frame Papillary muscles Delayed enhancement 1615PC Bairey-Merz/Slide # PC Bairey-Merz/Slide #20 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. 1615PC Bairey-Merz/Slide #21 7

8 Interventional No Reflow: 21% MI and 2% elective PCI-stenting Circulation 2008;117; PC Bairey-Merz/Slide #22 Clinical Translational Research 1. Observation 2. Mechanisms 3. Intervention 4. Translation 1615PC Bairey-Merz/Slide #23 COURAGE Primary EP: Survival Free of Death or MI Randomization to PCI + OMT vs. OMT Intensive, Guideline-Driven Medical Therapy & Lifestyle Intervention In Both Groups Optimal Medical Therapy (OMT) PCI + OMT Hazard ratio: % CI ( ) P = Years 7 Source: Boden et al. N Engl J Med. 2007; 356: PC Bairey-Merz/Slide #24 8

9 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) Placebo ACE-I CFR Change Baseline CFR Pepine CJ et al, Circ in press 1615PC Bairey-Merz/Slide #25 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). Figure 10. Mean Number of Chest Pain or Symptom Episodes in the Prior Month by Eplerenone Vs. Placebo Treatment Group Chest Pain Episodes / Month Placebo Drug 0 Baseline Visit2 Visit3 Visit4 E-WISE unpublished data 1615PC Bairey-Merz/Slide #26 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) 10 PCr/ATP MRS 0 Ratio (%) Entry Exit p=0.17 compared to placebo placebo 1/10 NE/EE Bairey Merz CN et al Am Heart J (in press) 1615PC Bairey-Merz/Slide #27 9

10 MERLIN-TIMI 36: Efficacy results in major subgroups Primary endpoint Subgroup n Favors ranolazine Favors placebo P interaction Gender Men Women Age <75 years 75 years Diabetes No DM DM TIMI Risk Index event UA NSTEMI STD 1 mm No Yes Overall 6560 STD = ST-segment depression HR (95% CI) Morrow DA et al. JAMA. 2007;297: PC Bairey-Merz/Slide #28 Randomized, cross-over trial of ranolazine po bid vs placebo in women with signs and symptoms of ischemia and no obstructive coronary artery disease: Analysis in progress Scan 1 3/3/08 MPRI 2.5 Scan 2 4/14/08 MPRI PC Bairey-Merz/Slide #29 Clinical Translational Research 1. Observation 2. Mechanisms 3. Intervention 4. Translation 1615PC Bairey-Merz/Slide #30 10

11 Clinical Practice Guidelines (T3) This slide set was adapted from the following 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 and ACC=American College of Cardiology, AHA=American Heart Association 1615PC Bairey-Merz/Slide #31 Impact of AHA Get With The Guidelines-CAD Program on Quality of Care Baseline Q1 Q2 Q3 Q4 * p< 0.05 compared to baseline * * * 83 * * * * * * * * * * 57 * Aspirin Beta Blocker ACE Inhibitor Lipid Rx Smoking Cessation GWTG-CAD: 123 US Hospitals n=27,825 Labresh, Fonarow et al. Circulation 2003;108:IV PC Bairey-Merz/Slide #32 Guideline Implementation and ACS and the Sex Survival Gap Following guideline implementation, mortality for women improves and the sex gap narrows (RED) Persistent sex gap (BLUE) suggests more work Still needed to understand sexspecific pathophysiology to improve outcomes for women and men PC Bairey-Merz/Slide #33 Novak et al Am J Medicine 2008;121:

12 Problem: Adverse Mortality Gap Resulting in a New Female CVD Majority Current Strategies Not Working Optimally in Women Deaths in Thousands Years NHLBI WISE study And Awareness and Guidelines Campaigns Males Females Cardiovascular disease mortality trends for males and females (United States: ). Source: NCHS and NHLBI 1615PC Bairey-Merz/Slide #34 Problem: Adverse Mortality Gap Resulting in a New Female CVD Majority Solution: Clinical Translational Research and Guidelines Deaths in Thousands Years NHLBI WISE study And Awareness and Guidelines Campaigns Males Females Cardiovascular disease mortality trends for males and females (United States: ). Source: NCHS and NHLBI 1615PC Bairey-Merz/Slide #35 INVESTIGATORS 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 1615PC Bairey-Merz/Slide #36 12

13 Ischemic Heart Disease in Women: Changing Paradigm Conclusions and Next Steps 1. 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 merz@cshs.org or for information or referral. 1615PC Bairey-Merz/Slide #37 13