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Heart failure in women
Lars H. Lund, MD, Donna Mancini, MD*
Columbia University College of Physicians and Surgeons, New York, NY, USA
Women exhibit distinct differences compared with men in regard to
epidemiology, risk factors, causes, mechanisms for disease development,
response to treatment, and outcomes in heart failure (HF). However,
because diagnostic criteria have been variable in large epidemiologic surveys
and because women have constituted a minority of enrollees in major HF
trials, many questions remain. Gender differences have been well elucidated
in the area of coronary artery disease (CAD) but less so in HF, even though
differences in HF are probably more distinct. The purpose of this review is
to describe known differences in HF between men and women.
Epidemiology
Improved management of hypertension (HTN), diabetes (DM), hyper-
cholesterolemia, and other risk factors for HF or CAD, as well as advances
in the treatment of acute coronary syndromes (eg, thrombolytics and
primary angioplasty) have had complex influences on the epidemiology of
HF. Improved management has allowed people to live longer with risk
factors and after acute coronary events, which has allowed time to developHF and, consequently, increased the incidence and prevalence of HF.
Conversely, improved management of risk factors has also prevented HF in
many people in whom it would otherwise have developed, with the opposite
effect on HF incidence and prevalence data. The aging of the population and
improved medical management of HF have also contributed to the
increasing prevalence. Finally, greater physician awareness and availability
of noninvasive imaging, leading to more frequent and accurate diagnoses,
may also have contributed to increasing incidence and prevalence.
* Corresponding author. Division of Cardiology, Department of Medicine, Columbia
University College of Physicians and Surgeons, 622 West 168th Street, New York, NY 10032.
E-mail address: [email protected] (D. Mancini).
0025-7125/04/$ - see front matter 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.mcna.2004.03.003
Med Clin N Am 88 (2004) 13211345
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Most available data come from government agencies or from large
population cohorts (Table 1) [110], such as the Framingham Study (9405
participants, 47% male subjects who have been followed since 1949)
[1,2,4,6,8]. These studies provide statistical power but should be interpreted
cautiously because clinical criteria [1,2,46,8] or medical records [3,7] are
used for diagnosis. Some studies use self-reported HF data [3,7]. Self-
reported HF is less common than HF established by clinical indices,
especially among women (Fig. 1A) [5,11]. Furthermore, the type of HF (eg,
systolic versus diastolic) is often not differentiated.The most recently available figures [10] indicate that HF in the United
States affects 4.9 million people (2.5 million women and 2.4 million men),
which is close to 2% of the total population, with an annual incidence of
550,000 cases. Although the absolute number of patients with HF is higher
among women than men, women live longer and develop HF later in life.
Thus, the age-adjusted percentage of prevalence is lower in women (1.5%
white women versus 2.3% in men and 3.1% black women versus 3.5% in
men) [10], with an age-adjusted annual incidence of 564 per 100,000 in men
and 327 per 100,000 in women [8].In absolute figures, prevalence and incidence of HF have increased over
the last 40 years, with the more dramatic increase in prevalence (Fig. 2A)
[2,6,10]. Age-adjusted incidence has actually decreased by 31% in women
and 7% in men between the 1950s and the 1990s (see Fig. 2B) [8].
Stratified by age, both the prevalence and incidence of HF increase
dramatically after age 65 (Fig. 1) [5,6,9,10]. In the Framingham Study, mean
age at diagnosis increased from 57 in the 1950s to 76 in the 1980s [11]. In the
past, HF was more prevalent in women than men at the extremes of age (see
Fig. 1A, B) [5,6]. This difference in prevalence may be partly explained bygender differences in the cause of the disease. Pregnancy and connective tissue
diseases in younger women account for the higher prevalence in the young age
group (Table 2) [12]. Higher prevalence of CAD among men 45 to 80 years of
age [10] raises prevalence in this group. More HTN (leading to progressive
damage) and longer life span among women generally increase female
representation in the oldest age group; however, more recent data suggest that
Table 1
Major epidemiologic surveys
Source [Ref. no.] Years HF criteriaFramingham [1,2,4,6,8] 19491999 Framingham Study criteria
National Center for
Health Statistics [3]
19701978 Coding on death certificates
and hospital discharges
National Health
Interview Survey [9]
Annual survey;
data from 1999
Self-reported
National Health and
Nutrition Examination
Survey I and III [5,7,10]
I: 19711975
I follow-up:
19821986
III: 19881994
Self-reported, clinical
criteria, and medical records
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rates are similar between the genders at the extremes of age and dramatically
higher among men than women in the middle age group (Fig. 1C, D) [9,10].
Morbidity and mortality
HF accounts for 1 million hospital discharge diagnoses annually (60%
women) and total mortality of over 260,000 [10]. HF is the leading cause of
hospitalization, accounting for at least 20% of all hospitalizations in the
patients over the age of 65 [13]. Among patients with reduced ejection
fraction (EF), women have more hospitalizations than men [14] and are
hospitalized longer [15], probably because they are older and more
frequently live alone [16]. Mortality rates are variable, reflecting differentcriteria for diagnosis and varying severity of HF. In longitudinal cohorts,
1-year survival in HF ranges from 55% to 90%, and 5-year survival ranges
from 20% to 55% [1,5,8,11,1719].
Generally, women have better survival, at least when results are adjusted
for age. In the Framingham Study, median survival after diagnosis was
3.2 years for women and 1.7 years for men, and 1-year survival was 57% for
men and 64% for women [11]. In Scotland, crude median survival and
survival rates were similar between the genders; however, the overall adjusted
hazards ratio for death was 0.87 for women compared with men (95%confidence interval (CI), 0.850.89) [18]. In the National Health and
Nutrition Examination Survey (NHANES) I, 10-year mortality was only
24% in women versus 54% in men [5]. In placebo-controlled trials, women
had a better prognosis than men in the Digitalis Investigation Group (DIG)
study [20], Survival and Ventricular Enlargement trial (SAVE) [21],
Metoprolol Extended-Release Randomized Intervention Trial in Heart
Failure (MERIT-HF) [22], and Cardiac Insufficiency Bisoprolol Study
(CIBIS) II [23] but a worse prognosis in the Cooperative New Scandinavian
Enalapril Survival Study (CONSENSUS) II [24], the Trandolapril CardiacEvaluation (TRACE) [25], Studies of Left Ventricular dysfunction (SOLVD)
[14], and the US carvedilol study (Table 3) [26]. In both men and women, the
prognosis is better in nonischemic disease causes (see Table 2) [12].
Despite improvements in therapy, the prognosis in population cohorts
only recently appears to be improving [13]. In the Framingham Study, there
was no change in age-adjusted survival over a period of 40 years [11]. This
probably reflects the fact that HF has become more severe. In Scotland,
crude median survival increased from 1.23 years to 1.64 years between 1986
and 1995. Adjusted for age and other factors, the improvements were moredramatic: 30-day mortality fell by 26% in men and 17% in women, and
longer term mortality fell by 18% in men and 15% in women [18]. In more
recent Framingham Study analysis, 1-year age-adjusted mortality fell from
30% to 28% in men and from 28% to 24% in women over 40 years (Fig. 3),
figures that correspond to a 12% relative improvement in survival per
decade [8].
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Fig. 1. Prevalence of HF by gender and age group in different time periods. (A) NHANES-I
(19711975) data show self-reported rates lower than clinical rates, especially those reported
among young women. (Data from Shocken DD, Pinsky JL, Kannel WB, Levy D. The
epidemiology of heart failure: the Framingham Study. J Am Coll Cardiol 1993;22(Suppl A):6A13A.) (B) In the Framingham Study (19491988) a higher prevalence is shown among
women than men in older age groups. (Data from Ho KKL, Anderson KM, Kannel WB,
Grossman W, Levy D. Survival after the onset of congestive heart failure in Framingham Heart
Study Subjects. Circulation 1993;88:10715.)
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Cause of death
The most common causes of death in HF are progressive HF and sudden
cardiac death (SCD), accounting for approximately 50% and 40% of deaths
Fig. 1 (continued) (C) Prevalence of HF by age and sex. More recent data in NHANES-III
(19881994) suggest a higher prevalence among men than among women, overall, and in all age
groups. (Data from American Heart Association. Heart disease and stroke statistics2003
update. Available at http://www.americanheart.org/presenter.jhtml?identifier=1928 and http://
www.americanheart.org/presenter.jhtml?identifier=2007. Accessed 2003.) (D) Self-reported data
in NHIS (1999) show that the prevalence of HF is higher in men at all ages. (From Ni H.
Prevalence of self-reported heart failure among US adults: Results from the 1999 National
Health Interview Survey. Am Heart J 2003;146(1):1218; with permission.)
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in HF, respectively [19,21,2729]. In HF, SCD occurs at a rate of six to ninetimes that of the general population [4,10]. In the total population, age-
adjusted SCD is 2- to 3-fold more common in men [30], and in the HF
population it is also more common in men [4]. Because SCD is much more
common in men than in women without documented heart disease, the
magnitude of the increase in relative risk (RR) for SCD in individuals with
HF compared with those without HF is higher for women than for men. In
Fig. 2. Absolute annual incidence and prevalence of HF in the United States in men and
women, reported over 4 decades. (A) Consolidation of data from large epidemiologic surveys.
(Data from Refs. [2,6,10].) Both absolute incidence and prevalence have increased over time.
Prevalence has increased more dramatically, consistent with an aging population and increased
longevity with HF. (B) Age-adjusted incidence has decreased over the last 40 years. (Data from
Levy D, Kenchaiah S, Larson MG, Benjamin EJ, Kupka MJ, Ho. KKL, et al. Long-term
trends in the incidence of and survival with heart failure. N Engl J Med 2002;347:1397402.)
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Rotterdam, the adjusted RR of SCD in HF was 6.6 in women and 3.7 in
men with HF [19], and in the Framingham Study the adjusted RR was 9.1
and 6.2, respectively [4].
Etiology
HF is multifactorial, and many risk factors have direct and indirect
(through an intermediary) influence on its development. CAD, HTN,
idiopathic dilated cardiomyopathy, and valvular heart disease are the mostcommon causes in both genders; however, the relative roles of these diseases
are different in men and women (Figs. 4 and 5). A combination of CAD and
HTN is present in many patients. The best data examining risk factors and
attempting to establish causality are found in the NHANES-I Epidemio-
logic Follow-up Study [7]. Causality is best estimated by population
attributable risk (PAR) which is defined as ([RR1] P)/([RR1]
P+1) 100% [7], where P = proportion of population with risk factor at
baseline or cumulative proportion exposed during follow-up, and RR = re-
lative risk in persons with versus persons without given risk factor (derivedfrom Cox proportional hazards models). PAR estimates the proportion of
cases that could be eliminated if the risk factor were eliminated from the
total population [7]. For example, HTN is more common than CAD in the
general population (see Fig. 4A) and approximately equal to CAD in the HF
population (see Fig. 4B, C). Because HTN is more common in the general
population, its PAR is lower (see Fig. 5A, B). In multivariate analysis of
Table 2
Underlying causes in HF initially considered idiopathic
Cause Women n (%) Men n (%) TotalAdjusted HRfor mortality
All Causesa 492 (100) 738 (100) 1230
Idiopathic 234 (47.6) 382 (51.8) 616 (50.1) 1.00
Myocarditis 46 (9.3) 65 (8.9) 111 (9.0) 1.05
Ischemic 21 (4.3) 70 (9.5) 91 (7.4) 1.52*
Infiltrative 19 (3.9) 40 (5.4) 59 (4.8) 4.40*
Peripartum 51 (10.4) 0 (0) 51 (4.1) 0.31*
HTN 21 (4.3) 28 (3.9) 49 (4.0) 0.74
HIV 8 (1.6) 37 (5.1) 45 (3.7) 5.86*
Connective tissue disease 27 (5.5) 12 (1.6) 39 (3.2) 1.75*
Substance abuse 7 (1.4) 30 (4.1) 37 (3.0) 1.41
Doxorubicin 13 (2.6) 2 (0.3) 15 (1.2) 3.46*
Other 48 (9.8) 69 (9.4) 117 (9.5) 1.30
Abbreviation: HR, hazard ratio.
Data from Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL,
et al. Underlying causes and long-term survival in patients with initially unexplained
cardiomyopathy. N Engl J Med 2003;342(15):107784.a May not equal 100% because of rounding.
* P\ 0.05.
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NHANES-I data, CAD, HTN, cigarette use, obesity, DM, and valvular
heart disease were all significant and independent risk factors for HF in both
genders, and male gender also was a significant risk factor. Inactivity was
a risk factor only in women [7]. HF increases dramatically with age, and age
itself is an important risk factor. Most risk factors are more common at
older ages and have a higher risk of causing HF in older ages, but HF ismore common in older ages even without a particular condition; therefore
the RR factor for each condition decreases with age [6]. Although from
different populations, this is illustrated by a RR factor for HF from DM of
8 and 4 in women and men, respectively, in ages less than 65 years old [6]
compared with an overall RR of HF from DM of less than 2 [7], even
though DM is more common in older ages.
Table 3
Mortality in clinical trials by men/women subgroups
All-cause mortality (%)
Trial n
Women
(%)
Follow-up
(mo) Subgroup Rx Placebo
RR, HR, OR, or
RRR (95% CI)
DIG [20] 6800 22 37 M 35.2 36.9 P = NS
W* 33.1 28.9 P\ 0.05
CONSENSUS II [24] 6090 26 6 M 9.0 8.8 P = NS
W 13.5 11.2 P = NS
SAVE [21] 2231 18 42 M 20.6 25.7 P\ 0.05; RRR,
22 (636)
Wa 19.9 20.1 P = NS; RRR,
2 (5737)
TRACE [25] 1749 28 2450 M 32.4 41.2 P\ 0.05; RR,
0.74 (0.620.89)
W 40.6 44.8 P = NS; RR,
0.90 (0.691.18)
ACE inhibitor
meta-analysis [84]
7105 NA 242 M 16.5 22.7 OR, 0.76
(0.650.88)
W 13.4 20.1 OR, 0.79
(0.591.06)
US Carvedilol [26] 1094 23 612 M 3.2 7.2 P\ 0.05; HR,0.41 (0.220.80)
W 3.1 9.6 P\ 0.05; HR,
0.23 (0.070.69)
MERIT-HF [22] 3991 22 12 M 7.4 11.8 P\ 0.05; HR, 0.61
Wa 6.9 7.4 P = NS; HR, 0.92
CIBIS II [22] 1647 31 16 M 12.9 18.2 P\ 0.05; HR, 0.71
W 7.0 13.6 P\ 0.05; HR, 0.52
Abbreviations: CI, confidence interval; HR, hazard ratio; NA, not available; OR, odds ratio;
RR, relative risk; RRR, relative risk reduction; Rx, treatment.a P for interaction between gender and treatment, NS (not significant).
* P for interaction between gender and treatment\0.05.
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Ischemic heart disease
The incidence [10] and prevalence (see Fig. 4A) [7] of CAD and the
contribution of CAD to mortality in the population [31] are lower in women
than in men, but the decrease in cardiovascular mortality over the last
20 years is less significant in women [31]. Over the past 40 years, theprevalence of CAD among patients with HF has increased in both genders,
suggesting an increasing causative role of ischemic heart disease [32]. In HF
patients, CAD is less frequent in women than in men, ranging from 8% to
74% and 17% to 84%, respectively (see Fig. 4B) [6,9,33].
Previous incidents of myocardial infarction (MI) are less common among
women than men with HF [33]; however, women, and especially black
women, who sustain an MI, have a worse long-term prognosis. After MI,
22% of men and 46% of women will develop HF, and 25% of men and 38%
of women will die within 1 year [10]. Women are less likely to undergorevascularization than are men [34], but if they do, they have higher
incidence of subsequent HF [35] and mortality [36]. Women are less likely to
receive thrombolytics or aspirin, even when this likelihood is adjusted for
indications, but both are equally likely to receive b-blockers acutely, and are
slightly more likely to receive angiotensin-converting enzyme (ACE)
inhibitors [34]. Past inadequacies in the management of CAD in women
Fig. 3. Age-adjusted survival in men and women from 1970 to 1999. Survival data
(percentages) are shown for 30 days and 1 and 5 years. (Data from Levy D, Kenchaiah S,
Larson MG, Benjamin EJ, Kupka MJ, Ho KKL, et al. Long-term trends in the incidence of and
survival with heart failure. N Engl J Med 2002;347:1397402.)
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Fig. 4. (A) Overall (crude) prevalence data from NHANES-I in the total population (ie, with
and without HF) of listed conditions. (Data from He J, Ogden L, Bazzano LA, Vupputuri S,
Loria C, Whelton PK. Risk factors for congestive heart failure in US Men and Women. ArchIntern Med 2001;161:9961002.) (B) Prevalence of risk factors in the HF population in the
NHIS, Framingham, and SOLVD studies (additional studies are cited in the text). (Data from
Refs. [6,9,33].) (C) Comparison of relative risk of heart failure for subjects with and without
predisposing conditions. (Data from He J, Ogden L, Bazzano LA, Vupputuri S, Loria C,
Whelton PK. Risk factors for congestive heart failure in US men and women. Arch Intern Med
2001;161:9961002.)
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may have contributed to the high prevalence and incidence of HF among
older women today.
Hypertension
HTN affects 50 million Americans between the ages of 20 and 74 [10] and
is more common in men (26%30%) than women (21%27%) (see Fig. 4A)
[7,10]. In contrast, HTN is more common in HF (see Fig. 4B) and is a more
important risk factor for HF (see Figs. 4C, and 5A, B) in women than men.Systolic HTN predicts HF in women, whereas pulse pressure is more
predictive in men [4]. In the Framingham Study, the risk, adjusted for age
and other risk factors, of HF in HTN compared with those without HTN
was doubled in men and tripled in women [6,37]. The prevalence of HTN
with HF was 78% and 70% in women and men, respectively [6]; the PAR of
HF for HTN was 39% in men and 59% in women [37]. In NHANES-I, the
prevalence of HTN in the general population was 27% in women and 30%
in men, and the PAR of HF for HTN was 12% for women and 9% for men
[7]. In SOLVD, 55% of women and 39% of men had concomitant HTN[33], but HTN was considered to be primarily involved in only 7% [14].
These disparate numbers make sense if the respective populations are
examined. In the Framingham Study, diagnosis was clinical and broad and
included large numbers. In NHANES-I, only self-reported diagnoses were
included, yielding lower rates of HTN and, thus, a lower PAR of HTN. The
SOLVD study included only patients with depressed EF. Normal EF
Fig. 4 (continued)
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accounts for half of all HF [17,38], and HTN is the main cause of HF with
normal EF (HFNEF), whereas CAD is the main cause of HF with depressed
EF.
Heart failure: normal ejection fraction
HFNEF, frequently termed diastolic HF, is mainly a disease of elderly
women, most of whom have HTN [39]. HFNEF is becoming increasinglyrecognized as a cause of HF [17,38,40]. When echocardiograms were
obtained on 73 Framingham Study subjects with HF, 51% had normal
EF. Sixty-five percent of those with normal EF were women, whereas
only 25% of those with reduced EF were women [17]. The prevalence of
HFNEF increases with age [40]. Prognosis in HFNEF is poor, although it is
better than in systolic dysfunction. The Framingham Study and the
Fig. 5. Approximate population-attributable risk for men (A) and women (B). The population-
attributable risk is the closest estimation of direct and primary causation (see text). The
cumulative population-attributable risk of all risk factors slightly exceeds 100%. Values in these
pie charts are approximate but proportional. (Data from He J, Ogden L, Bazzano LA,
Vupputuri S, Loria C, Whelton PK. Risk factors for congestive heart failure in US men and
women. Arch Intern Med 2001;161:9961002.)
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Cardiovascular Health Study revealed annual mortality of 15% to 19% in
systolic HF, 8% to 9% in HFNEF, and 1% to 4% in matched controls
without HF [17,41]. HFNEF accounts for more deaths than systolicdysfunction in the elderly because it is more common in this age group [41].
The differential effects of sex hormones on the myocardial hypertrophic
response may account for the greater incidence of HFNEF in women [42,43].
In normal subjects, left ventricular (LV) mass and chamber size are lower in
women compared with men, even when normalized for body surface area
[44]. HTN is more predictive of HF in women than men (see Figs. 4C, and
5A, B) [6,7,37]. LV mass increases with age in women but decreases in men
[44]. Women have a more dramatic hypertrophic response to increased
myocardial work load and injury [45]. In response to renovascularhypertension in an animal model, myocardial mass was increased in female
rats by 46% compared with 14% in male rats [43]. Both male and female rats
exhibit hypertrophy in response to aortic banding, but only males develop
impaired contractility [46]. In a transgenic tumor necrosis factor-a mouse
model, both genders progress to HF, but female mice exhibit wall thickening
without dilation and preserved fractional shortening, whereas male mice
exhibit marked dilation and loss of fractional shortening [47].
Effects of sex hormones on cardiac function
Androgen and estrogen receptors have been detected in blood vessels and
atrial and ventricular tissue in both genders [42,48,46]. Distinct cardiovas-
cular effects result from these sex hormones (Table 4) [42,4951]. Estrogen
protects against HTN partly by decreasing renin activity, whereas
testosterone promotes HTN partly by increasing renin activity [49]. Estrogen
inhibits vascular remodeling, vasoconstriction, and smooth muscle cell
growth [49], and replacement therapy promotes vasodilation in postmeno-
pausal women [48]. The rate of collagen deposition in the myocardiumis decreased by estrogen whereas deposition is increased by the presence
of androgens. Estrogen also inhibits cardiac fibroblast and myocyte
Table 4
Differential effects of sex hormones
Site Androgens Estrogens
Cardiac
Contractility " $
LV mass" #
Fibrosis " #
Vascular Vasoconstriction Vasodilation
Skeletal muscle " #
Renal
Glomerulosclerosis " #
Renin " #
Data from Refs. [42,4951].
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growth [42,49]. Gonadectomy decreases contractile performance among both
male and female rats, with a greater decline among males, and decreases heart
weight in males only [50]. Testosterone replacement increases cardiac andskeletal muscle mass and improves ventricular performance in rats in both
genders [51]. Oral contraceptive use protects against the development of
idiopathic dilated cardiomyopathy [52], and hormone replacement improves
survival in women with systolic HF [53], although as we are learning from the
Womens Health Initiative and Heart and Estrogen/progestin Replacement
Study [55], hormone replacement therapy is not beneficial and may be
harmful when used for primary [54] or secondary [55] prevention of CAD.
Diabetes mellitus, obesity, inactivity, and the metabolic syndrome
DM affects 8 million men and nearly 9 million women in the United
States [10]. Among whites it is more common in men, whereas the opposite
is true among blacks [10]. DM is an independent predictor of LV mass and
wall thickness in women but not men [56] and is independently associated
with increased LV mass and wall thickness, reduced LV systolic function,
and increased arterial stiffness [57]. Small-vessel disease, interstitial fibrosis,
and autonomic dysfunction are believed to contribute to diabetic cardio-
myopathy [58]. Thus, DM predisposes to HF in both genders but moreso in women (see Figs. 4C, and 5A, B) [6,7], and especially in younger
women [6]. The risk of HF is independent of CAD, HTN, age, and lipid
status [6,7] and is higher with older age, insulin use [59], and poor glycemic
control [60]. In early Framingham Study analysis, DM was present in 26%
of women and 14% of men with HF and associated with a 5- and 2.4-fold
increased risk of HF in women and men [1]. In later Framingham Study
data, the incidence of HF was 8- and 4-fold higher, respectively, in diabetic
women and men [6]. These risks were even greater when CAD was
eliminated, suggesting that DM has a distinct role in HF, even in theabsence of its indirect role as a cause of ischemic heart disease [61]. DM also
increases mortality in established HF [62].
Age-adjusted prevalence of obesity (defined as body mass index over 30)
has increased from 16% to 34% of women and from 11% to 28% of men
between 1960 and 2000 [10]. Among Americans over age 20, 26 million men
and 35 million women are obese [10]. Obesity is independently associated with
HF in both genders, but it is more predictive in women [7,63]. Obesity may be
an underlying cause in women who have HFNEF [64]. In the Framingham
Study, each incremental point in body mass index was associated with a 5%and 7% increased risk of HF in men and women, respectively [63]. Despite the
strong associations, whether obesity is an independent risk factor for HF or
even CAD is still controversial. Obesity increased risk of HF independently of
its intermediaries (HTN, DM, CAD, and LV hypertrophy). Obesity and the
metabolic syndrome, however, are associated not only with each other and
with elevated blood pressure, dyslipidemia, and insulin resistance but also
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with elevated C-reactive protein levels, activation of the central nervous
system, and increased thrombosis, all of which may be the true culprits when
obesity has been implicated in HF [65].Thirty-eight percent of American adults report no leisure time physical
activity [10]. Inactivity is more common in women of all ages than in men
(see Fig. 4A) and is associated with an increased risk of CAD and HTN [10].
Inactivity predisposes to HF primarily through intermediate risk factors,
although in NHANES-I, inactivity independently increased the risk of HF,
significantly in women (RR 1.31, P = 0.002) and nonsignificantly in men
(RR 1.14, P = 0.19) (see Figs. 4C, and 5B) [7].
Alcohol
Observational studies suggest that light to moderate alcohol use reduces
the risk of CAD [66]. In NHANES-I, regular alcohol consumption was
associated with a decreased risk of developing HF in women (RR = 0.70,
P = 0.03) but not in men [7]; however, it has long been recognized that
chronic consumption of large amounts of alcohol is a risk factor for
cardiomyopathy. In one study, the prevalence of alcoholic women with
dilated cardiomyopathy (DCM) was similar to that of men, but women
required a lower lifetime dose of alcohol to develop DCM [67].
Idiopathic dilated cardiomyopathy
Because idiopathic dilated cardiomyopathy is often a diagnosis of
exclusion, and diagnostic approaches vary between studies, the epidemiol-
ogy of idiopathic dilated cardiomyopathy is difficult to establish. In
Olmstead County, the annual incidence was 7.6 per 100,000 men and 2.5
per 100,000 women [68]. In other studies, men account for approximately
80% of DCM cases [69,70], but in the Framingham Study, unknown causes
accounted for only 7% of all HF in men and women [32]. Underlying
conditions are not always obvious. In a group of 1230 patients (40% female)
with initially unexplained cardiomyopathy, further evaluation revealed that
half had specific causes (see Table 2) [12]. Underlying causes varied greatly
by gender and correlated strongly with prognosis (see Table 2). In this study
[12], male gender was independently associated with mortality (adjusted
hazard ratio 1.26, 95% CI 1.001.60). Peripartum cardiomyopathy was
significantly associated with better survival, whereas ischemic, infiltrative,
and HIV were significantly associated with higher mortality [12].
Signs and symptoms, clinical presentation, and diagnosis
The diagnosis of HF is generally based on clinical data in population-
based cohorts and on LV function in clinical trials. The most frequently
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used criteria are the Framingham Study criteria [1], which do not reliably
distinguish between systolic and diastolic dysfunction. Women with HF
have a poorer quality of life and more symptoms than men, especially indecreased exercise tolerance [33,70]. Women have more signs of HF (edema,
S3 gallop, jugular venous distension) than men [33]. Although they are
fewer, women who do have systolic dysfunction have more LV dilation then
men [70]. Women are less likely to be referred to the hospital, managed by
cardiologist, or have cardiac diagnostic testing [15]. The reason for these
discrepancies are not known but may relate to older age at presentation,
causes of HF, or bias similar to that observed in CAD.
Exercise capacity
Peak oxygen consumption (VO2) is an important predictor of survival
and is frequently used to guide selection for transplantation [71]. It is less
accurate in women, however, for whom the predicted peak VO2 percentage
may be a better prognostic marker [72]. In HF, as in normal subjects, peak
VO2 is lower in women than men [70]. This is attributed to the lower
hemoglobin and reduced skeletal muscle mass, which in turn are the result
of sex hormones. Healthy men but not women increase their EF in response
to exercise [73] but in HF neither do. Stroke volume increases to a similardegree in both genders, but in women a 30% increase in end-diastolic
volume occurs. Thus, men appear to rely on contractility and women on the
FrankStarling mechanism to increase cardiac output [42].
Therapy
Numerous therapies that decrease morbidity or mortality in HF are now
available. Women have generally been under-represented in HF trials, withparticipation rates ranging from 0% to 32% (see Table 3) [16]. Selection
bias, age, and the likelihood that women are more likely to decline
participation are possible reasons, but a proportionately lower incidence of
systolic dysfunction in women is a significant reason. In the Losartan
Intervention for Endpoint (LIFE) trial, in which criteria were HTN and
LVH but not depressed EF, 60% of the participants were women [74]. In
many trials, outcomes are not reported separately for women and men. In
some trials, the point estimate of the benefit is similar in both genders, but
the 95% CI crosses 1 in women. In other studies, no benefit is seen at all inwomen. Outcomes in trials quantifying gender subgroup analyses are listed
in Table 3.
Women receive proven therapies less often than their male counterparts.
Rates of ACE inhibitor use ranged from 34% to 51% in women and 45% to
71% in men, in studies explicitly comparing genders [75,76]. The low rate of
use in women was attributed to contraindications and older age [75],
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although more frequent HF with normal EF and, consequently, less
established benefit in women is also likely to be responsible. Elderly patients
have been included in the major ACE inhibitor trials and benefit similarly toyounger people, yet they are less likely to receive this treatment [77]. The fact
that elderly patients are more likely to be women may be the basis for under-
prescribing HF agents to women. In contrast, women tend to be more
compliant with prescribed HF therapy than men [78].
Digoxin
In a gender-specific analysis of DIG, women but not men experienced
higher adjusted mortality with digoxin use than with placebo (hazard ratio
[HR] 1.23, 95% CI 1.021.47) [20]. Mortality in men correlated with serum
digoxin levels. Women in the DIG had higher short-term serum concen-
trations than men. Whether higher levels explain the increased mortality in
women has not yet been analyzed. Overall, mortality was lower among
women than men in both treatment and placebo groups (see Table 2).
Hospitalization rates were lower in women on digoxin versus placebo.
Hydralazine and nitrates
Experience with hydralazine and nitrates is based primarily on the
Veterans Heart Failure Trials [79], which included only men and revealed
more benefits when compared with placebo but less benefits than with ACE
inhibitor. Use of hydralazine and nitrates is recommended for patients who
are intolerant to ACE inhibitors and angiotensin receptor blockers.
Although there appears to be no reason to believe this regimen has different
effects in men and women, there is no clinical evidence that it is effective in
women.
Angiotensin-converting enzyme inhibitors
In systolic HF, ACE inhibitors reduce hospitalization and prolong
survival [21,27,28,80], and in high-risk patients they prevent the de-
velopment of HF [81]. It is probable but not definite that ACE inhibitors
benefit women. In the Cooperative North Scandinavian Enalapril Survival
Study (CONSENSUS-I; severe HF), men had a significant 51% RRreduction for mortality at 6 months, but for women it was only 6% and
insignificant [82]. In SOLVD (treatment and prevention), enalapril reduced
mortality and hospitalization in both women and men, but the decrease was
less in women [83]. In the SAVE and TRACE (HF post-MI) trials, there was
only a 2% and 10% RR reduction (P = nonsignificant in both) for
mortality in women, compared with 22% and 26% in men, respectively
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[21,25]. In the Acute Infarction Ramipril Efficacy (AIRE) trial (signs of
post-MI HF), ramipril decreased mortality in both women and men and
actually more so in women [84]. In a meta-analysis of 7105 patients in 32trials, the odds ratio for total mortality was 0.76 (95% CI 0.650.88) for
men and 0.79 (0.591.06) for women [85]. In a later meta-analysis of 12,763
patients in five trials (SAVE, AIRE, TRACE, and two SOLVD trials), the
odds ratio for death was 0.79 (0.720.87) for men and 0.85 (0.711.02) for
women [86].
Thus, there is a less convincing benefit of ACE inhibitors for women than
for men; however, there are important caveats. Many women with HF do
not have systolic dysfunction, a requirement for most ACE inhibitor trials,
and in SOLVD, women had more coughing and withdrew more frequently[87]. One can speculate why the benefits of ACE inhibition appear to be
diminished in women. African Americans respond less to ACE inhibitors,
possibly because of less of a renin component in the pathophysiology of
HTN and HF [88]; similarly, women may respond less because estrogen
decreases and testosterone increases renin activity [49]. Furthermore,
women have not been analyzed prospectively and separately. Thus, if a trial
reveals overall benefit, it is not appropriate to conclude that women do not
benefit because this subgroup result may be the result of a smaller sample
size. In the larger meta-analysis and in SAVE, the P values for theinteraction (heterogeneity) of gender and treatment were nonsignificant
(Table 3) [86,89]. In SAVE, a proportional hazards model revealed the
benefits of captopril to be independent of many variables, including gender,
and after adjustment for gender, the benefits remained significant [89].
Angiotensin II receptor blockers
In general, angiotensin receptor blockers have similar benefits to ACE
inhibitors and are a good alternative when ACE inhibitors are not tolerated.In a head-to-head comparison of captopril and losartan for HF, the former
was associated with a nonsignificantly lower mortality in both men and
women [90]. In the Valsartan Heart Failure Trial (Val-HeFT) [91] (valsartan
in addition to existing therapy, often including an ACE inhibitor), women
were analyzed separately and had benefits similar to those in men but
without reaching statistical significance.
b-Blockers
The US carvedilol trial was terminated early after a dramatic decrease in
mortality in both men and women and more so in women, with HR of
mortality of 0.41 and 0.23 in men and women, respectively [26]. A meta-
analysis of CIBIS and CIBIS-II revealed a larger mortality benefit in women
than men with a RR compared with placebo of 0.61 in women and 0.71 in
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men (P\ 0.05 for both) [92]. In contrast, the MERIT-HF failed to reach
significant benefit for women, although overall the mortality reduction was
large and highly significant (absolute risk reduction [ARR] 3.8%, RR 0.66[95% CI 0.530.81]) [29]. Finally, the Carvedilol Prospective Randomized
Cumulative Survival (COPERNICUS) [93] trial showed a dramatic benefit
in both men and women with severe HF (symptoms at rest or with minimal
exertion) for both total mortality and for the combination of mortality and
hospitalization, although the overall mortality for women failed to reach
statistical significance. In a pooled analysis of the MERIT-HF, COPERNI-
CUS, and CIBIS II, the RR for mortality was 0.69 in women and 0.66 in
men [22]. How proposed mechanisms ofb-blockers might differ between the
genders is poorly understood.
Aldosterone antagonists
Aldosterone antagonists decrease mortality, hospitalization, and symp-
toms in HF. In the Randomized Aldactone Evaluation Study (RALES) [94],
overall mortality at 2 years was 35% in the spironolactone group and 46%
in the placebo group (RR 0.70, 95% CI 0.600.82), with a similar and
significant reduction in both men and women. Gynecomastia and breast
pain were reported in 10% of men but not reported in women. The
Eplerenone Postacute Myocardial Infarction Heart Failure Efficacy and
Survival Study (EPHESUS) [95] reported decreased overall mortality (RR
0.85, 95% CI 0.750.96) with eplerenone compared with placebo for
patients with acute MI complicated by HF. In subgroup analysis this benefit
was actually larger in women and failed to reach statistical significance in
men, but the P value for gender/treatment interaction was insignificant.
Mechanisms of benefit probably include inhibition of the negative effects of
aldosterone on the heart and possibly elevation of serum potassium; little is
known about how these effects may differ between genders, but again, thedifferent responses to pressure overload and MI probably play a role.
Cardiac transplantation
Orthotopic heart transplantation is associated with significant improve-
ment in survival and quality of life for patients with severe refractory HF.
Of the 2500 transplants performed annually in the United States, almost
80% are performed in men [96]. Women appear to be referred at equal levelsof severity of disease, based on clinical and hemodynamic parameters.
However, there is a higher acceptance of candidates with ischemic causes,
regardless of gender [97], which increases the proportion of men who
undergo transplantation. Once referred, women are as likely as men to be
found acceptable candidates [97], but they are less likely to accept [98].
Following transplantation, women tend to have more rejection and are less
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likely to tolerate a steroid-free regimen [99]. In some analyses, women have
been reported to have worse survival after orthotopic heart transplantation
[100], but a majority of studies report comparable survival [96], which is now85%90% at 1 year.
Summary
Distinct differences in sex hormones and their effects and differences in
response to injury, pressure overload, and aging account for many of the
differences between women and men with HF. The typical woman with HF
is more likely to have HTN, diastolic dysfunction, DM, obesity, and
inactivity and is less likely to have CAD or a previous MI or systolicdysfunction. Women are more symptomatic and are perhaps less likely to
benefit from established treatments; however, survival is better for women if
controlled for age. As the therapeutic options for HF increase, sex-based
differences in treatment may need to be considered. Future studies directed
exclusively at women may be warranted to confirm or establish benefits of
existing and future treatments.
Acknowledgments
We thank Graham Barr, MD, DrPH, for statistical assistance.
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