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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
HEART DISEASE IN WOMEN
FAVOURING
MEN
FAVOURING
WOMEN
HEART DISEASE IN WOMEN
DELAYED ONSET OF
CORONARY
ATHEROSCLEROSIS
FAVOURING
MEN
FAVOURING
WOMEN
HEART DISEASE IN WOMEN
UNDERDIAGNOSIS
OF HEART DISEASE
IN WOMEN
FAVOURING
MEN
DELAYED ONSET OF
CORONARY
ATHEROSCLEROSIS
FAVOURING
WOMEN
HEART DISEASE IN WOMEN
UNDERDIAGNOSIS
OF HEART DISEASE
IN WOMEN
DELAYED ONSET OF
CORONARY
ATHEROSCLEROSIS
MORE
FAVOURABLE
CARDIAC
REMODELLING
FAVOURING
MEN
FAVOURING
WOMEN
HEART DISEASE IN WOMEN
UNDERDIAGNOSIS
OF HEART DISEASE
IN WOMEN
DELAYED ONSET OF
CORONARY
ATHEROSCLEROSIS
MORE
FAVOURABLE
CARDIAC
REMODELLING
FAVOURING
MEN
LOWER
INCIDENCE,
PREVALENCE, AND
SEVERITY OF
HEART FAILURE
FAVOURING
WOMEN
Female gender,myocardial remodelling
and cardiac function
REMODELLING
• defined as the molecular and cellular events following
an injury to the myocardium (i.e. ischemia, pressureoverload, 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
Patterns
Favourable
Concentric
Hypertrophy –
preserved EF%
Injury
Age
Ischemia
Oxidative stress
Pressure overload
Volume overload
Remodelling
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
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
Gender differences in Remodelling:
Impact of Aging
LV weight (g)
LV weight (g)
106 subjects selected at autopsy (53 women)
RV weight (g)
RV weight (g)
post-menopausal women
Olivetti et al. J Am Coll Cardiol 1995
LV
Myocytes (x109)
post-menopausal women
RV
RV
Myocytes (x109)
LV
Gender differences in Remodelling:
Impact of Aging (2)
Olivetti et al. J Am Coll Cardiol 1995
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
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
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
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
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
Pressure overload cardiomyopathy (3)
Banding of the ascending aorta in rats
(isolated hearts)
female
control
female
LVH
male
control
male
LVH
FEMALES
MALES
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
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)
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
Volume overload cardiomyopathy (2)
Rats with volume overload due to
infrarenal aorto-caval fistula
P<0.001
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
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
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
Ischemic Heart Disease (2)
Mortality (%)
Post-MI remodelling in the mouse model
FEMALES
MALES
Males had 3-times higher mortality
despite similar infarct size
Cavasin et al. Life Sci 2004
Shortening fraction (SF) was
1.5-times higher in females
Ischemic Heart Disease (3)
Post-MI remodelling in the mouse model
MALES
MALES
FEMALES
FEMALES
Cavasin et al. Life Sci 2004
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
27 hearts explanted from subjects with endstage 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
Heart Failure (2)
7599 patients with CHF (2400 women)
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
There were 44
significant
differences in the
baseline
characteristics !!!!
Men and
women are
different!!!!
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
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
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
Pathophysiology
IGF-1?
1) IGF-1 and IGF-1R are reduced with aging
2) The lower the IGF-1 levels the greater the fibrosis
Akt
3) Female mice had significantly higher IGF-1 levels
Akt?
1) IGF-1 (as well as estradiol) induce Akt activation which
triggers cell survival
Cell survival
Leri et al. Heart Dis 2000;
Camper-Kirby et al. Circ Res 2001; Sugden and Clerk, Circ Res 2001
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 genderbased 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
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
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
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
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
HEART DISEASE IN WOMEN
UNDERDIAGNOSIS
OF HEART DISEASE
IN WOMEN
DELAYED ONSET OF
CORONARY
ATHEROSCLEROSIS
MORE
FAVOURABLE
CARDIAC
REMODELLING
FAVOURING
MEN
LOWER
INCIDENCE,
PREVALENCE, AND
SEVERITY OF
HEART FAILURE
FAVOURING
WOMEN
Volume overload cardiomyopathy
Effects of ovariectomy
Brower et al. Mol Cell Biochem 2003
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