gender (dis)advantages in cardiac remodelling lessons from mice and men female gender,myocardial...

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

Female gender,myocardial Female gender,myocardial remodellingremodelling

and cardiac functionand cardiac function

Antonio Abbate, MDAntonio Abbate, MDAssistant Professor of MedicineVirginia Commonwealth UniversityDepartment of Internal MedicineRichmond, VA, USA

FAVOURINGMEN

FAVOURINGWOMEN

HEART DISEASE IN WOMENHEART DISEASE IN WOMEN

FAVOURINGMEN

FAVOURINGWOMEN

DELAYED ONSET OF CORONARY

ATHEROSCLEROSIS


FAVOURINGMEN

FAVOURINGWOMEN

UNDERDIAGNOSIS OF HEART DISEASE

IN WOMEN


ATHEROSCLEROSIS


FAVOURINGMEN

FAVOURINGWOMEN


ATHEROSCLEROSIS

MORE FAVOURABLE

CARDIAC REMODELLING


IN WOMEN


FAVOURINGMEN

FAVOURINGWOMEN

LOWER INCIDENCE,

PREVALENCE, AND SEVERITY OF

HEART FAILURE


ATHEROSCLEROSIS

MORE FAVOURABLE

CARDIAC REMODELLING


IN WOMEN


Female gender,myocardial Female gender,myocardial remodellingremodelling

and cardiac functionand 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

AgeIschemiaOxidative stressPressure overloadVolume overload

Injury Remodelling

Favourable

Unfavourable

Changes in:-wall thickness-cavity volumes-contractility

ConcentricHypertrophy –preserved EF%

EccentricHypertrophy –reduced EF%

Modified from Biondi-Zoccai GGL et al. Ital Heart J 2004

Systolic Heart Failure

Remodelling Remodelling PatternsPatterns

Are there gender-related Are there gender-related differences in cardiac differences in cardiac

remodelling ?remodelling ?• OBSERVATIONAL CLINICAL

STUDIES

• POST-MORTEM STUDIES IN HUMANS

• ANIMAL STUDIES

• AGING

• PRESSURE OVERLOAD

• VOLUME OVERLOAD

• MYOCARDIAL INFARCTION

• HEART FAILURE

LV

wei

gh

t (g

)L

V w

eig

ht

(g)

RV

wei

gh

t (g

)R

V w

eig

ht

(g)

Gender differences in Gender differences in Remodelling:Remodelling:

Impact of AgingImpact of AgingL

V w

eig

ht

(g)

LV

wei

gh

t (g

)R

V w

eig

ht

(g)

RV

wei

gh

t (g

)

post-menopausal womenpost-menopausal women

Olivetti et al. J Am Coll Cardiol 1995Olivetti et al. J Am Coll Cardiol 1995

106 subjects selected at autopsy (53 women) 106 subjects selected at autopsy (53 women)

Myo

cyte

s (x

10M

yocy

tes

(x10

99 ))

RV

RV

LV

LV

Olivetti et al. J Am Coll Cardiol 1995Olivetti et al. J Am Coll Cardiol 1995

post-menopausal womenpost-menopausal women

Myo

cyte

s (x

10M

yocy

tes

(x10

99 ))

RV

RV

LV

LV


Impact of Aging (2)Impact of Aging (2)

Mallat et al. J Gerontol A Biol Sci 2001Mallat et al. J Gerontol A Biol Sci 2001

Non-cardiac cause of death

Men vs Women P<0.01

No correlation with aging


Impact of Aging (3)Impact of Aging (3)41 subjects selected at autopsy (19 women) 41 subjects selected at autopsy (19 women)

Zhang et al. J Mol Cell Cardiol 2007Zhang et al. J Mol Cell Cardiol 2007

P<0.01P<0.01


Impact of Aging (4)Impact of Aging (4)In a cohort of monkeys (Macaca fascicularis) In a cohort of monkeys (Macaca fascicularis)

% Apoptosis% Apoptosis


Impact of Aging (5)Impact of Aging (5)

Therefore there appears to be a greater Therefore there appears to be a greater myocyte lossmyocyte loss in men vs women in men vs women

associated, at least in part with agingassociated, at least in part with aging

Pressure overload Pressure overload cardiomyopathycardiomyopathy

Kostkiewics et al. Int J Cardiol 1999Kostkiewics et al. Int J Cardiol 1999

195 patients with severe aortic stenosis 195 patients with severe aortic stenosis studied at echocardiographystudied at echocardiography

When compared to men, women had:When compared to men, women had:

• similar transvalvular gradient and estimated areasimilar transvalvular gradient and estimated area

• smaller end-diastolic and end-systolic dimensionssmaller end-diastolic and end-systolic dimensions

• greater LV fractional shortening and ejection greater LV fractional shortening and ejection fractionfraction

• greater LV relative wall thicknessgreater LV relative wall thickness

Pfeffer JM et al. Am J Physiol HCP 1982Pfeffer JM et al. Am J Physiol HCP 1982

Spontaneously hypertensive rats (SHR)Spontaneously hypertensive rats (SHR)

• SHR are rats with genetically determined hypertensionSHR are rats with genetically determined hypertension

• Male and female SHRs had similar systolic BP valuesMale and female SHRs had similar systolic BP values

• When compared to male SHRs, female SHRs hadWhen compared to male SHRs, female SHRs had::

- greater ejection fraction and cardiac index- greater ejection fraction and cardiac index- smaller end-diastolic and end-systolic volumessmaller 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 functiondimensions and function

Pressure overload Pressure overload cardiomyopathy (2)cardiomyopathy (2)

Weinberg et al. J Am Coll Cardiol 1999Weinberg et al. J Am Coll Cardiol 1999

Banding of the ascending aorta in ratsBanding of the ascending aorta in rats(isolated hearts)(isolated hearts)

Assessment of LV contractile Assessment of LV contractile reserve in the isolated heartreserve in the isolated heart(LVDevP in response to Ca++)(LVDevP in response to Ca++)

Female controls developed Female controls developed higher pressures (contractile higher pressures (contractile force) than male controlsforce) than male controls

Female LVH had preserved Female LVH had preserved contractile reserved, whereas contractile reserved, whereas male LVH had depressed male LVH had depressed contractile reserve contractile reserve


femalefemalecontrolcontrol

malemalecontrolcontrol

femalefemaleLVHLVH

malemaleLVHLVH

MALESMALES

FEMALESFEMALES


Therefore, in response to pressure Therefore, in response to pressure overload, overload, female gender appears to be female gender appears to be

associated with preserved functionassociated with preserved function whereas male gender is notwhereas male gender is not

Volume overload Volume overload cardiomyopathycardiomyopathy

33 patients with pure severe aortic regurgitation 33 patients with pure severe aortic regurgitation (9 women)(9 women)

Rohde et al. Am J Card Fail 1997Rohde et al. Am J Card Fail 1997

Despite similar degree of aortic regurgitation,Despite similar degree of aortic regurgitation,women had:women had:

- smaller EDVi (98 ml/m- smaller EDVi (98 ml/m2 2 vs 127 ml/mvs 127 ml/m22, P<0.05), P<0.05)

- smaller ESVi (46 ml/m2 vs 62 ml/m2, P<0.05)- smaller ESVi (46 ml/m2 vs 62 ml/m2, P<0.05)

- similar LEVF, and wall thickness - similar LEVF, and wall thickness

Rats with volume overload due to Rats with volume overload due to infrarenal aorto-caval fistulainfrarenal aorto-caval fistula

P<0.001P<0.001

Gardner et al. J Card Fail 2002Gardner et al. J Card Fail 2002

Males had 10-fold higher mortality despite similar increase in CO, Males had 10-fold higher mortality despite similar increase in CO, and this was associated with and this was associated with greater LV dilatationgreater LV dilatation in males in males

Volume overload Volume overload cardiomyopathy (2)cardiomyopathy (2)

Volume overload Volume overload cardiomyopathy (3)cardiomyopathy (3)

Therefore, in response to volume Therefore, in response to volume overload, compared to male gender, overload, compared to male gender,

female gender appears to be protected female gender appears to be protected from cardiac enlargement and deathfrom cardiac enlargement and death

Ischemic Heart DiseaseIschemic Heart Disease

Biondi-Zoccai, Abbate, et al. Heart 2005Biondi-Zoccai, Abbate, et al. Heart 2005

21 subjects with recent AMI studied at autopsy 21 subjects with recent AMI studied at autopsy (8 women – all post-menopausal)(8 women – all post-menopausal)

• Apoptosis was correlated with LV dilatationApoptosis was correlated with LV dilatation

• Women had significantly higher apoptotic ratesWomen had significantly higher apoptotic rates

Cavasin et al. Life Sci 2004Cavasin et al. Life Sci 2004

Post-MI remodelling in the mouse modelPost-MI remodelling in the mouse model

Males had 3-times higher mortality Males had 3-times higher mortality despite similar infarct sizedespite similar infarct size

Mo

rtal

ity

(%)

Mo

rtal

ity

(%)

Shortening fraction (SF) was Shortening fraction (SF) was 1.5-times higher in females1.5-times higher in females

Ischemic Heart Disease (2)Ischemic Heart Disease (2)

FEMALESFEMALES

MALESMALES

Cavasin et al. Life Sci 2004Cavasin et al. Life Sci 2004

Post-MI remodelling in the mouse modelPost-MI remodelling in the mouse model


FEMALESFEMALES

FEMALESFEMALES

MALESMALES

MALESMALES


Therefore, after an acute myocardial Therefore, after an acute myocardial infarction, infarction, female gender appears to be female gender appears to be associated with less myocyte loss and associated with less myocyte loss and

preserved functionpreserved function

Heart FailureHeart Failure

Guerra et al. Circ Res 1999Guerra et al. Circ Res 1999

27 hearts explanted from subjects with end-27 hearts explanted from subjects with end-stage CHF (9 women – all post-menopausal)stage CHF (9 women – all post-menopausal)

Men with CHF had Men with CHF had twice the number of twice the number of apoptotic cells vs apoptotic cells vs women (P<0.001)women (P<0.001)

O’Meara et al. Circ 2007 – CHARM studyO’Meara et al. Circ 2007 – CHARM study

7599 patients with CHF (2400 women) 7599 patients with CHF (2400 women)

There were There were 4444 significant significant differences in the differences in the baseline baseline characteristics !!!!characteristics !!!!

Men and Men and women are women are different!!!!different!!!!

Women were less likely to have ischemic Women were less likely to have ischemic heart disease (51% vs 67%, P<0.001)heart disease (51% vs 67%, P<0.001)

Women tended to have higher LVEF (43% vs Women tended to have higher LVEF (43% vs 37%, P<0.001) and only 9% of women had 37%, P<0.001) and only 9% of women had LVEF<25% (vs 15% among men, P<0.001)LVEF<25% (vs 15% among men, P<0.001)

Heart Failure (2)Heart Failure (2)

O’Meara et al. Circ 2007O’Meara et al. Circ 2007

After adjustment for all 44 variables: After adjustment for all 44 variables:

• Women had 22% less mortalityWomen had 22% less mortality

• The reduction in mortality was The reduction in mortality was independent of age and menopause independent of age and menopause statusstatus


7599 patients with CHF (2400 women) 7599 patients with CHF (2400 women)

Regitz-Zagrosek et al. Progr Cardiovasc Dis 2007Regitz-Zagrosek et al. Progr Cardiovasc Dis 2007

Heart failure with preserved LVEF (HFpresEF)Heart failure with preserved LVEF (HFpresEF)

Are any downsides to concentric vs eccentric Are any downsides to concentric vs eccentric LV remodelling?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 characteristicsclinical characteristics


Regitz-Zagrosek et al. Progr Cardiovasc Dis 2007Regitz-Zagrosek et al. Progr Cardiovasc Dis 2007

Volume-pressure loopsVolume-pressure loopsin controls (top) andin controls (top) andHFpresEF (bottow) in HFpresEF (bottow) in women (left) and men women (left) and men (right(right

Compared to men, Compared to men, women with HFpresEF women with HFpresEF have:have:-higher LVEDPhigher LVEDP-lower LVEDVlower LVEDV-smaller stroke volumessmaller stroke volumes


Heart failure with preserved LVEF (HFpresEF)Heart failure with preserved LVEF (HFpresEF)

Pathophysiology Pathophysiology

Leri et al. Heart Dis 2000; Leri et al. Heart Dis 2000;

IGF-1?IGF-1?1) IGF-1 and IGF-1R are reduced with aging 1) IGF-1 and IGF-1R are reduced with aging

2) The lower the IGF-1 levels the greater the fibrosis2) The lower the IGF-1 levels the greater the fibrosis

3) Female mice had significantly higher IGF-1 levels3) Female mice had significantly higher IGF-1 levels

Akt?Akt?1) IGF-1 (as well as estradiol) induce Akt activation which 1) IGF-1 (as well as estradiol) induce Akt activation which

triggers cell survivaltriggers cell survival

Camper-Kirby et al. Circ Res 2001;Camper-Kirby et al. Circ Res 2001; Sugden and Clerk, Circ Res 2001Sugden and Clerk, Circ Res 2001

AktAkt

Cell survivalCell survival

Pathophysiology (2)Pathophysiology (2)

Grohe’ et al. J Endocrinol 1998, Cardiovasc Res 2004; Pelzer et al. BioBioResComm 2000Grohe’ et al. J Endocrinol 1998, Cardiovasc Res 2004; Pelzer et al. BioBioResComm 2000

MYOCARDIAL PRODUCTION OF ESTROGENS?MYOCARDIAL PRODUCTION OF ESTROGENS?

1) Estradiol and its receptor alpha are synthetized in 1) Estradiol and its receptor alpha are synthetized in myocytes (female>male)myocytes (female>male)

2) iNOS expression is influenced by estrogen in a gender-2) iNOS expression is influenced by estrogen in a gender- based fashionbased fashion

3) Estradiol prevents apoptosis and induces ANF in 3) Estradiol prevents apoptosis and induces ANF in cardiac hypertrophy cardiac hypertrophy

PTH-rP?PTH-rP?

1) PTHrP is expressed in the heart (female>male) after 1) PTHrP is expressed in the heart (female>male) after ischemiaischemia

Babiker et al. Circ 2004, Arterioscl Thromb Vasc Biol 2006Babiker et al. Circ 2004, Arterioscl Thromb Vasc Biol 2006

Zhao and Eghbali-Webb, Endocrine 2002Zhao and Eghbali-Webb, Endocrine 2002

SURVIVAL PATHWAYS?SURVIVAL PATHWAYS?

1) Cells derived from female animals examined in vitro 1) Cells derived from female animals examined in vitro display different activation pathways than cells derived display different activation pathways than cells derived

from male animalsfrom male animals

2) Cardiac fibroblasts derived from female animals are 2) Cardiac fibroblasts derived from female animals are more resistant to in vitro hypoxia more resistant to in vitro hypoxia

Pathophysiology (3)Pathophysiology (3)

ConclusionsConclusions

Following cardiac injury, females tend to have a Following cardiac injury, females tend to have a

more favourable remodelling pattern characterized more favourable remodelling pattern characterized

by:by:

- concentric hypertrophy- concentric hypertrophy

- preserved systolic functionpreserved systolic function

Preservation of myocardial mass appears to be Preservation of myocardial mass appears to be

mediated by reduced apoptosis with greater mediated by reduced apoptosis with greater

preservation of the number of cardiomyocytespreservation of the number of cardiomyocytes

The differences in remodelling pattern may be The differences in remodelling pattern may be

associated with increased LV stiffness in womenassociated with increased LV stiffness in women

A better understanding of the process(es) leading A better understanding of the process(es) leading

to differences in remodelling in women will most to differences in remodelling in women will most

likely open the way to novel treatment modalities likely open the way to novel treatment modalities

and ultimately benefit patients of both gendersand ultimately benefit patients of both genders

Conclusions (2)Conclusions (2)

Gender-related differences are independent of the Gender-related differences are independent of the

inciting stimulusinciting stimulus

Differences are independent of menopause per Differences are independent of menopause per

se, although some changes may be mediated by se, although some changes may be mediated by

(locally produced) estrogens(locally produced) estrogens

Differences in the cell response to stress may Differences in the cell response to stress may

favour cell survival in womenfavour cell survival in women

Conclusions (3)Conclusions (3)

Although there appears to be a more favourable Although there appears to be a more favourable

remodelling in women, cardiac disease is still remodelling in women, cardiac disease is still

the number one killer in women, and lower the number one killer in women, and lower

awareness of such entity is a public enemyawareness of such entity is a public enemy

FAVOURINGMEN

FAVOURINGWOMEN

LOWER INCIDENCE,

PREVALENCE, AND SEVERITY OF

HEART FAILURE


ATHEROSCLEROSIS

MORE FAVOURABLE

CARDIAC REMODELLING


IN WOMEN


Volume overload Volume overload cardiomyopathycardiomyopathy

Brower et al. Mol Cell Biochem 2003Brower et al. Mol Cell Biochem 2003

Effects of ovariectomyEffects of ovariectomy

For further slides on these topics please feel free to visit the

metcardio.org website:

http://www.metcardio.org/slides.html

http://www.metcardio.org/slides.html

gender (dis)advantages in cardiac remodelling lessons from mice and men female gender,myocardial...

Documents

women heart disease

function remodelling

favouring men

cardiac remodelling

myocardial remodelling

usa slide

women lower incidence

ital heart j