Clinical Outcomes in Women: Insights for Coronary Pathophysiology

1. Clinical Outcomes in Women: Insights for Coronary Pathophysiology Viola Vaccarino, MD, PhD Professor of Medicine Emory University School of Medicine

2. Ischemic Heart Disease in Women • Women develop IHD 10-20 years later than men • Women with IHD, compared with men: • Less severe coronary artery disease (CAD) • Smaller infarcts • More preserved systolic function • However: • More symptoms, lower function • More adverse outcomes after MI and cardiac procedures (if younger than 60)

3. Paradox of Incidence vs. Mortality of MI by Gender Bairey Merz et al, JACC 2006

4. Outcome Differences by Sex Depend on Age NRMI 1994-1998 N=384, 878 Sex-Age Interaction: P<0.001 Vaccarino et al., N Engl J Med 1999

5. 4 Adjusted OR, Women vs. Men 3 1 2 3 4 2 1 80+ <50 50-59 60-69 70-79 0 Hospital Death after CABG National Cardiovascular Network, N=51,187 1993-1999 Sex-Age Interaction: P<0.001 Men more multivessel disease Women more comorbidity Vaccarino et al, Circulation 2002

6. * * * ≤55 >55 ≤55 >55 Coronary Injury Bleeding Hospital Complications after PCI Emory University Hospital, N=4,768 Elective PCI 2001-2004 Men more multivessel disease and ostial lesions Women more comorbidity, ulcerated plaque and graft vessels Argulian et al, AJC 2006

7. Questions • Why are women protected against IHD but suffer more complications and death once they get it? • Do women have a different, more severe form of IHD?

8. Clues for Sex Differences in Pathophysiology: Conditions Unique to Women • Physiologic conditions: • Pregnancy • Menstrual cycle • Plasticity, regenerative capacity—should be protective • Risks: • Hypertensive disorders of pregnancy • Gestational diabetes • Polycystic ovarian syndrome • Other forms of hypoestrogenemia / ovarian insufficiency

9. Risk Conditions for Women • More Common in Women: • Clustering of risk factors • Higher level of risk factors • Age-related comorbidities • Higher CRP • Vasculitis, chronic inflammatory diseases (lupus, temporal arteritis, RA, asthma)

10. Nonobstructive CAD Rates in Acute Coronary Syndrome Trials Non-Obstructive CAD: <50% stenosis ACS UA MI Bugiardini & Bairey Merz, JAMA 2005

11. NIH-NHLBI-Sponsored WISE: 5-yr Rates of Functional Disability 5-Year Disability (DASI<4.7 METs) % • Similar rates of disability • Similar rate of typical angina Shaw et al., Circulation 2006; 114:894-904.

12. Hypotheses: Women Vs. Men • Positive remodeling (compensatory vessel enlargement) • Diffuse atherosclerosis (vs plaque) • Coronary endothelial dysfunction (vasoconstriction) • Microvascular disease (vsepicardialstenoses) More ischemic symptoms and adverse outcomes despite less obstructive angiographic CAD Bairey Merz et al, JACC 2006

13. Sex Differences in CAD and Endothelial Dysfunction by IVUS • No sex difference in arterial remodeling • Women as likely as men to undergo positive or negative remodeling • Women have less diffuse coronary endothelial dysfunction • Women have lower CFR, but largely explained by age and body size • Women do have lower plaque burden • Despite more risk factors • After taking into account vessel size and body size Nicholls et al., JACC 2007 Han AH et al., Eur Heart J 2008

14. Endothelial Dysfunction • Women have better endothelial function than men • Advantage declines with age • At all level of risk factors Framingham Heart Study, N=2,883 Benjamin EJ et al., Circulation 2004

15. Abnormal Coronary Vasomotion and Subsequent CVD in WomenThe WISE Study • N=163 women with suspected ischemia • 75% no significant obstructive CAD • Coronary reactivity assessment with coronary angiography • >50% had endothelial dysfunction Acetylcholine Nitroglycerine Von Mering GO et al., Circulation 2004

16. Is ischemia based on microvascular disease more important for women? • “Microvascular angina” proposed for women (Shaw LJ et al., JACC 2009) • Vascular smooth muscle diseases more common in women (Raynaud, migraine, coronary spasm) • Retinal microvascular abnormalities predict CVD in women but not in men (ARIC, Wong et al. JAMA 2002) • Evidence elusive • May be explained by older age and smaller body habitus (Han AH et al., Eur Heart J 2008) • May be true only in subset (WISE Study)

17. Noninvasive Metabolic Marker of Ischemia:[31] P Nuclear Magnetic Resonance (NMR) SpectroscopyPhosphocreatine:ATP ratio 35 women hospitalized for chest pain but no CAD 31P-NMR spectroscopy before and after isometric handgrip exercise 7 (20 %) had decrease in the phosphocreatine:ATP ratio during handgrip > 2 SD below the mean value of control subjects without chest pain Abnormal response Buchthal SD et al., NEJM 2000; 342:829-835

18. CVD Events in Women with abnormal NMR Spectroscopy and no CAD Difference driven by hospitalizations for angina and repeat angiography The WISE Study, Johnson BD et al., Circulation 2004

19. CVD Events in Women with abnormal NMR Spectroscopy and no CAD The WISE Study, Johnson BD et al., Circulation 2004

20. Additional Mechanisms • Vessel size • Vascular repair • Plaque morphology

21. Vessel Size • Women have smaller vessels independent of body size • Androgens may cause vessel enlargement (positive remodeling) • Female hearts transplanted to men  larger arteries • Genetic men deprived of androgens  smaller arteries • Small vessel size may be protective • Vessel enlargement associated with endothelial dysfunction and early atherosclerosis • Larger vessels associated with more CAD in women • But small diameter  more likely occlusion if CAD? Herity et al., JACC 2003 Herman SM et al., ATVB 1997 Holubkov R et al., Am Heart J 2002

22. Vascular Repair • Bone marrow-derived endothelial progenitor cells (EPCs) important in vascular repair • Depleted by aging and multiple risk factors • Women older and more risk factors  repair processes may be impaired • Estrogen increases EPCs • Younger women should be advantaged but have worse outcomes

23. Plaque Morphology Rupture Erosion • Younger women • Thrombus over a base rich in smooth muscle • Necrotic, lipid core often absent • Older women & Men • Thin fibrous cap • Large necrotic core • Infiltration with foamy macrophages Burke et al., Circulation 1998;97:2110-2116.

24. Summary and Future Directions • Women with IHD, particularly younger women, may have a “different” form of vascular disease • Less severe CAD • More vascular remodeling • Microvascular disease • Little objective evidence

25. Summary and Future Directions • Lack of studies linking such mechanisms to hard cardiac endpoints • Lack of studies comparing women and men to better define vascular processes that are unique to women

26. Unanswered Questions • Why are women protected from heart disease but fare worse when they get it? • Why is this paradox restricted to the coronary arteries? • What is different about the female coronary arteries?