DECLARATION OF CONFLICT OF INTEREST

Transcription

1 DECLARATION OF CONFLICT OF INTEREST

2 Microvascular Coronary Dysfunction in Women with and Ischemic Heart Disease: Lessons from the NHLBI-WISE Study Noel Bairey Merz, M.D., F.A.C.C., F.A.H.A., F.E.S.C. Medical Director, Women s Heart Center and Preventive Cardiac Center Women s Guild Chair in Women s Health Cedars-Sinai Heart Institute merz@cshs.org 1615PC Bairey-Merz/Slide # 2

3 Presenter Disclosure Information Microvascular Coronary Dysfunction in Women C. Noel Bairey Merz MD, FACC, FAHA, FESC Heart Institute, Cedars-Sinai Medical Center DISCLOSURE INFORMATION: The following relationships exist related to this presentation: Bairey Merz grant support Gilead

4 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 # 4

5 Problem: Adverse Mortality Gap Resulting in a New Female Majority for CVD Current Strategies Not Working Optimally in Women 1615PC Bairey-Merz/Slide # 5

6 Clinical Translational Research 1. Observation 2. Mechanisms 3. Intervention 4. Translation 1615PC Bairey-Merz/Slide # 6

7 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 # 7

8 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 # 8

9 Clinical Translational Research 1. Observation 2. Mechanisms 3. Intervention 4. Translation 1615PC Bairey-Merz/Slide # 9

10 Hypothetical New Understanding of Ischemic Heart Disease Mechanisms in Women (Shaw and Bairey Merz) Autoimmune Diseases Symptomatic Manifestations E2 HTN Obesity Inflammatory Milieu Vascular Dysfunction Abnormal coronary vasomotion Metabolic Δs, Perfusion - Post-Menopause - Hypothalamic Hypoestrogenemic - PCOS Lipids Normal Artery & CFR 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 Prolonged 1615PC Bairey-Merz/Slide # 10

11 V PC Bairey-Merz/Slide # 11

12 OBESE, HYPERTENSIVE, NIDDM, BLACK, 57 yo, FEMALE with HYSTERECTOMY at AGE 21 ADENOSINE ACETHYLCHOLINE NITROGLYCERIN 1615PC Bairey-Merz/Slide # 12

13 Proportion Without CV Event Mechanisms: Abnormal Coronary Vasomotion To Acetylcholine Independently Predicts Cardiac Events In Women with No Obstructive CAD 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 # 13

14 Mechanisms: Abnormal Non-endothelial Function to Adenosine Strongest Predictor of Cardiac Events In Women with No Obstructive CAD % With M ajo r Event A ll Wo men, N =190, p(trend)=0.03 N o C A D, N =153, p(trend)= < <2.70 _ > 2.70 Pepine JACC 2010 CFR 1615PC Bairey-Merz/Slide # 14

15 Hypothetical Model of Female-Specific Microvascular 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

16 Cardiac Magnetic Resonance Imaging <60 min evaluation Cardiac structure and function Stress and rest cardiac perfusion Scar imaging Zero radiation Adenosine stress Gadolinium contrast Cardiac Team 4 Specialist MRI technologists 4 Cardiac nurse practitioners Cardiac imaging radiologist and cardiologists (CMRI) 1615PC Bairey-Merz/Slide # 16

17 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

18 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 # 18

19 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 # 19

20 Clinical Translational Research 1. Observation 2. Mechanisms 3. Intervention 4. Translation 1615PC Bairey-Merz/Slide # 20

21 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, AHJ in press 1615PC Bairey-Merz/Slide # 21

22 Intervention: Patients with ischemia and no obstructive CAD randomized to low dose hormone (estrogen-progestin) therapy did not improve ischemia measured by metabolic MRI 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 PC Bairey-Merz/Slide # 22

23 MERLIN-TIMI 36: Efficacy results in major subgroups Subgroup n Primary endpoint 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 # 23

24 WISE-ISCHEMIA Pilot Data: Ranolazine Improves Seattle Angina Questionnaire (SAQ) Angina in WISE Women with MCD SAQ Scores Ranolazine Median (min, max) Placebo Median (min, max) Treatment effect (p-value) Physical Functioning 84.8 (70.4,99.5) 80.3 (63.9, 98.6) Angina Stability 75 (50, 100) 50 (25, 75) Angina Frequency Treatment Satisfaction 80 (50, 100) 75 (60, 87.5) (75, 100) 93.8 (75, 100) Quality of Life 75 (60.4, 83.3) 66.7 (58.3, 75) Mehta et al JACC Imaging June PC Bairey-Merz/Slide # 24

25 Scan 2 4/14/08 MPRI 1.2 (abnormal) Example of Adenosine CMRI Quantitative Analysis Scan 1 3/3/08 MPRI 2.5 (normal) Mehta et al JACC Imaging June PC Bairey-Merz/Slide # 25

26 Clinical Translational Research 1. Observation 2. Mechanisms 3. Intervention 4. Translation 1615PC Bairey-Merz/Slide # 26

27 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 # 27

28 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 # 28 Novak et al Am J Medicine 2008;121:602.

29 Problem: Adverse Mortality Gap Resulting in a New Female CVD Majority Current Strategies Not Working Optimally in Women 520 Deaths in Thousands Years NHLBI WISE study And Awareness and Guidelines Campaigns Males Females 1615PC Bairey-Merz/Slide # 29

30 Problem: Adverse Mortality Gap Resulting in a New Female CVD Majority Solution: Clinical Translational Research and Guidelines 520 Deaths in Thousands Years NHLBI WISE study And Awareness and Guidelines Campaigns Males Females 1615PC Bairey-Merz/Slide # 30

31 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 # 31

32 Conclusions and Next Steps 1. Sex differences in ischemic heart disease mechanisms, including microvascular coronary dysfunction, impact appropriate diagnosis and treatment, contributing to adverse outcomes in women. 2. Microvascular coronary dysfunction can be detected using a variety of techniques; CMRI may be an ideal noninvasive modality. 3. Ongoing research is further exploring detection, evaluation and treatments of ischemic heart disease in women. Contact us at merz@cshs.org or for information or referral. 1615PC Bairey-Merz/Slide # 32