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

FAVOURING MEN FAVOURING WOMEN HEART DISEASE IN WOMEN

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

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

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

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

Female gender,myocardial remodelling and cardiac function and cardiac function 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 REMODELLING

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

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

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

Myocytes (x10 9 ) RV LV Olivetti et al. J Am Coll Cardiol 1995 post-menopausal women Myocytes (x10 9 ) RV LV Gender differences in Remodelling: Impact of Aging (2)

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

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

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

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

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

Weinberg et al. J Am Coll Cardiol 1999 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 Pressure overload cardiomyopathy (3) femalecontrolmalecontrol femaleLVHmaleLVH MALES FEMALES

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

Volume overload cardiomyopathy 33 patients with pure severe aortic regurgitation (9 women) Rohde et al. Am J Card Fail 1997 Despite similar degree of aortic regurgitation, women had: - smaller EDVi (98 ml/m 2 vs 127 ml/m 2, P<0.05) - smaller ESVi (46 ml/m2 vs 62 ml/m2, P<0.05) - similar LEVF, and wall thickness

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

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

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

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

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

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

Heart Failure Guerra et al. Circ Res 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)

O’Meara et al. Circ 2007 – CHARM study 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) Heart Failure (2)

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

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

Regitz-Zagrosek et al. Progr Cardiovasc Dis 2007 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 Heart Failure (5) Heart failure with preserved LVEF (HFpresEF)

Pathophysiology Leri et al. Heart Dis 2000; 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 triggers cell survival Camper-Kirby et al. Circ Res 2001;Sugden and Clerk, Circ Res 2001 Camper-Kirby et al. Circ Res 2001; Sugden and Clerk, Circ Res 2001 Akt Cell survival

Pathophysiology (2) Grohe’ et al. J Endocrinol 1998, Cardiovasc Res 2004; Pelzer et al. BioBioResComm 2000 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 based fashion 3) Estradiol prevents apoptosis and induces ANF in cardiac hypertrophy cardiac hypertrophyPTH-rP? 1) PTHrP is expressed in the heart (female>male) after ischemia ischemia Babiker et al. Circ 2004, Arterioscl Thromb Vasc Biol 2006

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

Conclusions Following cardiac injury, females tend to have a more favourable remodelling pattern characterized by: 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 Preservation of myocardial mass appears to be mediated by reduced apoptosis with greater preservation of the number of cardiomyocytes

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 Conclusions (2) Gender-related differences are independent of the inciting stimulus

Differences are independent of menopause per se, although some changes may be mediated by (locally produced) estrogens 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 Differences in the cell response to stress may favour cell survival in women Conclusions (3) 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 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

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

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

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