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Gender (dis)advantages in cardiac remodelling Lessons from mice and men

Gender (dis)advantages in cardiac remodelling Lessons from mice and men. Female gender,myocardial remodelling and cardiac function. Antonio Abbate, MD Assistant Professor of Medicine Virginia Commonwealth University Department of Internal Medicine Richmond, VA, USA. FAVOURING MEN .

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Gender (dis)advantages in cardiac remodelling Lessons from mice and men

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  1. Gender (dis)advantages in cardiac remodelling Lessons from mice and men Female gender,myocardial remodelling and cardiac function Antonio Abbate, MD Assistant Professor of Medicine Virginia Commonwealth University Department of Internal Medicine Richmond, VA, USA

  2. FAVOURING MEN FAVOURING WOMEN HEART DISEASE IN WOMEN

  3. HEART DISEASE IN WOMEN DELAYED ONSET OF CORONARY ATHEROSCLEROSIS FAVOURING MEN FAVOURING WOMEN

  4. HEART DISEASE IN WOMEN DELAYED ONSET OF CORONARY ATHEROSCLEROSIS UNDERDIAGNOSIS OF HEART DISEASE IN WOMEN FAVOURING MEN FAVOURING WOMEN

  5. HEART DISEASE IN WOMEN DELAYED ONSET OF CORONARY ATHEROSCLEROSIS UNDERDIAGNOSIS OF HEART DISEASE IN WOMEN MORE FAVOURABLE CARDIAC REMODELLING FAVOURING MEN FAVOURING WOMEN

  6. HEART DISEASE IN WOMEN DELAYED ONSET OF CORONARY ATHEROSCLEROSIS UNDERDIAGNOSIS OF HEART DISEASE IN WOMEN MORE FAVOURABLE CARDIAC REMODELLING LOWER INCIDENCE, PREVALENCE, AND SEVERITY OF HEART FAILURE FAVOURING MEN FAVOURING WOMEN

  7. Female gender,myocardial remodelling and cardiac function REMODELLING • defined as the molecular and cellular events following • an injury to the myocardium (i.e. ischemia, pressure- • overload, infection) • a process that involves the affected and unaffected • myocardium • leading to an initial favourable hemodynamic change • early after the insult (i.e. restoration of adequate • stroke volume) • but also eventually leading to unfavourable changes in • size, geometry and function

  8. Remodelling Patterns Favourable Concentric Hypertrophy – preserved EF% Remodelling Injury Age Ischemia Oxidative stress Pressure overload Volume overload • Changes in: • wall thickness • cavity volumes • contractility Eccentric Hypertrophy – reduced EF% Unfavourable Systolic Heart Failure Modified from Biondi-Zoccai GGL et al. Ital Heart J 2004

  9. Are there gender-related differences in cardiac remodelling ? • OBSERVATIONAL CLINICAL STUDIES • POST-MORTEM STUDIES • IN HUMANS • ANIMAL STUDIES • AGING • PRESSURE OVERLOAD • VOLUME OVERLOAD • MYOCARDIAL INFARCTION • HEART FAILURE

  10. LV weight (g) RV weight (g) Gender differences in Remodelling: Impact of Aging 106 subjects selected at autopsy (53 women) LV weight (g) post-menopausal women RV weight (g) Olivetti et al. J Am Coll Cardiol 1995

  11. LV Myocytes (x109) RV Gender differences in Remodelling: Impact of Aging (2) LV Myocytes (x109) post-menopausal women RV Olivetti et al. J Am Coll Cardiol 1995

  12. Gender differences in Remodelling: Impact of Aging (3) 41 subjects selected at autopsy (19 women) Non-cardiac cause of death Men vs Women P<0.01 No correlation with aging Mallat et al. J Gerontol A Biol Sci 2001

  13. Gender differences in Remodelling: Impact of Aging (4) In a cohort of monkeys (Macaca fascicularis) % Apoptosis P<0.01 Zhang et al. J Mol Cell Cardiol 2007

  14. Gender differences in Remodelling: Impact of Aging (5) Therefore there appears to be a greater myocyte loss in men vs women associated, at least in part with aging

  15. Pressure overload cardiomyopathy 195 patients with severe aortic stenosis studied at echocardiography • When compared to men, women had: • similar transvalvular gradient and estimated area • smaller end-diastolic and end-systolic dimensions • greater LV fractional shortening and ejection • fraction • greater LV relative wall thickness Kostkiewics et al. Int J Cardiol 1999

  16. Pressure overload cardiomyopathy (2) • Spontaneously hypertensive rats (SHR) • SHR are rats with genetically determined hypertension • Male and female SHRs had similar systolic BP values • When compared to male SHRs, female SHRs had: • - greater ejection fraction and cardiac index • - smaller end-diastolic and end-systolic volumes • Female SHRs (6-18 mo) had completely normal heart • dimensions and function Pfeffer JM et al. Am J Physiol HCP 1982

  17. female control male control female LVH male LVH FEMALES MALES Pressure overload cardiomyopathy (3) Banding of the ascending aorta in rats (isolated hearts) Assessment of LV contractile reserve in the isolated heart (LVDevP in response to Ca++) Female controls developed higher pressures (contractile force) than male controls Female LVH had preserved contractile reserved, whereas male LVH had depressed contractile reserve Weinberg et al. J Am Coll Cardiol 1999

  18. Pressure overload cardiomyopathy (4) Therefore, in response to pressure overload, female gender appears to be associated with preserved function whereas male gender is not

  19. Volume overload cardiomyopathy 33 patients with pure severe aortic regurgitation (9 women) Despite similar degree of aortic regurgitation, women had: - smaller EDVi (98 ml/m2 vs 127 ml/m2, P<0.05) - smaller ESVi (46 ml/m2 vs 62 ml/m2, P<0.05) - similar LEVF, and wall thickness Rohde et al. Am J Card Fail 1997

  20. P<0.001 Volume overload cardiomyopathy (2) Rats with volume overload due to infrarenal aorto-caval fistula Males had 10-fold higher mortality despite similar increase in CO, and this was associated with greater LV dilatation in males Gardner et al. J Card Fail 2002

  21. Volume overload cardiomyopathy (3) Therefore, in response to volume overload, compared to male gender, female gender appears to be protected from cardiac enlargement and death

  22. Ischemic Heart Disease • 21 subjects with recent AMI studied at autopsy (8 women – all post-menopausal) • Apoptosis was correlated with LV dilatation • Women had significantly higher apoptotic rates Biondi-Zoccai, Abbate, et al. Heart 2005

  23. FEMALES MALES Ischemic Heart Disease (2) Post-MI remodelling in the mouse model Mortality (%) Males had 3-times higher mortality despite similar infarct size Shortening fraction (SF) was 1.5-times higher in females Cavasin et al. Life Sci 2004

  24. MALES MALES FEMALES FEMALES Ischemic Heart Disease (3) Post-MI remodelling in the mouse model Cavasin et al. Life Sci 2004

  25. Ischemic Heart Disease (4) Therefore, after an acute myocardial infarction, female gender appears to be associated with less myocyte loss and preserved function

  26. Heart Failure 27 hearts explanted from subjects with end-stage CHF (9 women – all post-menopausal) Men with CHF had twice the number of apoptotic cells vs women (P<0.001) Guerra et al. Circ Res 1999

  27. Heart Failure (2) 7599 patients with CHF (2400 women) There were 44 significant differences in the baseline characteristics !!!! Men and women are different!!!! Women were less likely to have ischemic heart disease (51% vs 67%, P<0.001) Women tended to have higher LVEF (43% vs 37%, P<0.001) and only 9% of women had LVEF<25% (vs 15% among men, P<0.001) O’Meara et al. Circ 2007 – CHARM study

  28. Heart Failure (3) 7599 patients with CHF (2400 women) • After adjustment for all 44 variables: • Women had 22% less mortality • The reduction in mortality was • independent of age and menopause • status O’Meara et al. Circ 2007

  29. Heart Failure (3) Heart failure with preserved LVEF (HFpresEF) • Are any downsides to concentric vs eccentric LV remodelling? • Women are more likely to present with • congestive symptoms regardless of LVEF% • Women with HFpresEF have reduced left • ventricular compliance vs men with similar • clinical characteristics Regitz-Zagrosek et al. Progr Cardiovasc Dis 2007

  30. Heart Failure (5) Heart failure with preserved LVEF (HFpresEF) • Volume-pressure loops • in controls (top) and • HFpresEF (bottow) in • women (left) and men (right • Compared to men, women with HFpresEF have: • higher LVEDP • lower LVEDV • smaller stroke volumes Regitz-Zagrosek et al. Progr Cardiovasc Dis 2007

  31. Akt Cell survival Pathophysiology IGF-1? 1) IGF-1 and IGF-1R are reduced with aging 2) The lower the IGF-1 levels the greater the fibrosis 3) Female mice had significantly higher IGF-1 levels Akt? 1) IGF-1 (as well as estradiol) induce Akt activation which triggers cell survival Leri et al. Heart Dis 2000; Camper-Kirby et al. Circ Res 2001;Sugden and Clerk, Circ Res 2001

  32. Pathophysiology (2) MYOCARDIAL PRODUCTION OF ESTROGENS? 1) Estradiol and its receptor alpha are synthetized in myocytes (female>male) 2) iNOS expression is influenced by estrogen in a gender- based fashion 3) Estradiol prevents apoptosis and induces ANF in cardiac hypertrophy PTH-rP? 1) PTHrP is expressed in the heart (female>male) after ischemia Grohe’ et al. J Endocrinol 1998, Cardiovasc Res 2004; Pelzer et al. BioBioResComm 2000 Babiker et al. Circ 2004, Arterioscl Thromb Vasc Biol 2006

  33. Pathophysiology (3) SURVIVAL PATHWAYS? 1) Cells derived from female animals examined in vitro display different activation pathways than cells derived from male animals 2) Cardiac fibroblasts derived from female animals are more resistant to in vitro hypoxia Zhao and Eghbali-Webb, Endocrine 2002

  34. Conclusions • Following cardiac injury, females tend to have a more favourable remodelling pattern characterized by: • - concentric hypertrophy • - preserved systolic function Preservation of myocardial mass appears to be mediated by reduced apoptosis with greater preservation of the number of cardiomyocytes

  35. Conclusions (2) Gender-related differences are independent of the inciting stimulus The differences in remodelling pattern may be associated with increased LV stiffness in women A better understanding of the process(es) leading to differences in remodelling in women will most likely open the way to novel treatment modalities and ultimately benefit patients of both genders

  36. Conclusions (3) Differences are independent of menopause per se, although some changes may be mediated by (locally produced) estrogens Differences in the cell response to stress may favour cell survival in women Although there appears to be a more favourable remodelling in women, cardiac disease is still the number one killer in women, and lower awareness of such entity is a public enemy

  37. HEART DISEASE IN WOMEN DELAYED ONSET OF CORONARY ATHEROSCLEROSIS UNDERDIAGNOSIS OF HEART DISEASE IN WOMEN MORE FAVOURABLE CARDIAC REMODELLING LOWER INCIDENCE, PREVALENCE, AND SEVERITY OF HEART FAILURE FAVOURING MEN FAVOURING WOMEN

  38. Volume overload cardiomyopathy Effects of ovariectomy Brower et al. Mol Cell Biochem 2003

  39. For further slides on these topics please feel free to visit the metcardio.org website:http://www.metcardio.org/slides.html

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