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Abstract

Although women account for a significant proportion of the growing heart failure epidemic, they have been poorly represented in clinical trials. As emerging epidemiologic data reveal a growing prevalence and burden of disease among women, it is increasingly important that treating physicians and researchers recognize sex-based differences. Despite the overall incidence of heart failure being lower in women compared with men, the magnitude of improvement in survival over the last several decades has been less apparent in women. Women with heart failure are more likely to be older, have preserved systolic function and nonischemic cardiomyopathy. While clinical trials have demonstrated improved outcomes among heart failure patients, they have predominantly included men, yielding results that are sometimes inadequately powered to detect a benefit for women. Without adequate representation of women in clinical trials, one cannot assume that the same level of therapeutic evidence also applies to women. Nonetheless, it appears that β-blockers and angiotensin-converting enzyme inhibitors provide the same survival benefits in women with systolic dysfunction as in men. In addition, some studies suggest that angiotensin-receptor blockers may lead to a better survival in women when compared with angiotensin-converting enzyme inhibitors. Focused research is needed to understand and guide the management of women with heart failure.

Keywords

epidemiology heart failure treatment women

Heart failure prevalence has been increasing steadily over the last decades, fueled in large part by an aging population and advancements in the treatment of coronary heart disease [1]. Over 5 million people currently have heart failure in the USA, with an equal number in Western Europe, and over 500,000 new cases are being diagnosed yearly on each side of the Atlantic ocean. Although women make up more than half of this heart failure population and account for the majority of the hospital admissions, they remain under-represented in clinical trials [1,2]. Recent data suggest that biological variability in response to risk factors may account for the differences in epidemiology, clinical characteristics and treatment response in women compared with their male counterparts. The present review will highlight some of these differences.

Epidemiology of heart failure

Large, population-based studies identify key sex-based differences in heart failure incidence and prevalence. The Framingham Heart Study demonstrated that while the heart failure incidence remained stable over the last 30 years in men, it increased by approximately 5% in women in the 1990s compared with the 1970s [3]. These findings were mirrored in the Olmsted County Study, which demonstrated no significant increase in heart failure incidence in men but a significant 10% increase in women since 1979 [4]. In a review of medical records from the Kaiser Permanente database, the overall incidence of heart failure increased by 14% between the early 1970s to the early 1990s, with a higher increase in women than in men [5]. Despite the fact that the overall incidence remains approximately 25% lower in women compared with men, women still account for 50–55% of the prevalent heart failure cases [3 –6]. One exception to these trends is represented by the Cardiovascular Health Study, in which the overall incidence was higher than in the Framingham and Olmsted cohorts (19 vs 4 and 5 per 1000 person-years, respectively); men had an 80% higher incidence of the disease than women, most likely reflecting the age range of this cohort (over 60% of participants were older than 75 years of age) with a higher prevalence of smoking, diabetes and coronary heart disease [7].

The steady rise in heart failure incidence over the last decades and the concomitant increase in the elderly population have resulted in a burgeoning prevalence of the disease, with a consequent rise in the number of hospital admissions for heart failure exacerbations. Intensive blood pressure control and advances in revascularization for acute and chronic coronary heart disease have allowed patients to live longer and, thus, have shifted the age profile of the disease ( Figure 1 ) [6]. The mean age at diagnosis rose from 63 years in the 1950s to 80 years in the 1990s, and women are more likely to be diagnosed at an older age [3,4]. As a result of the increasing prevalence, hospitalizations related to heart failure have also increased, particularly in women. In 1999, there were over 1 million hospitalizations, over half of which were women [8]. Overall, the hospitalizations with a primary diagnosis of heart failure increased by 39% for women and 29% for men; for women, the annual hospitalization rate increased from 1990 to 1999 in each age group, while the age-adjusted rates did not change in men [9].

Figure 1.

Age distribution of patients with heart failure in the 1981 and 1991 cohorts in Rochester, MN, USA.

Comorbidities & risk factors

Multiple studies demonstrate that women diagnosed with heart failure are more likely to be older, hypertensive and have preserved systolic function, and have less coronary artery disease, when compared with their male counterparts (Tables 1–3) [4,10 –15]. Moreover, coronary artery disease and hypertension appear to have different etiologic-risk profiles for heart failure in men and women. Hypertension increases the risk of developing heart failure by threefold in women, compared with approximately twofold in men [14]. Owing to its high prevalence, hypertension has the greatest population-attributable risk percentage in both sexes, which is associated with 59% of the incident heart failure cases in women and 39% in men [16]. Similarly, the population-attributable risk percentage for myocardial infarction is 13% in women and 34% in men [16]. Clinical trials, which have typically included only patients with reduced ejection fraction, also demonstrate the prominent role of nonischemic etiology among women with heart failure. In a pooled analysis of five large clinical trials, 60% of the women enrolled had nonischemic cardiomyopathy, compared with only 43% of enrolled men [17]. Despite the lower proportion of women with heart failure and coronary artery disease, a prior myocardial infarction is associated with a higher risk of developing heart failure in women than in men. In addition, the risk of death in patients who developed postmyocardial infarction heart failure is higher in women compared with men [18].

Table 1.

Mean age at the time of heart failure diagnosis.

Study	Mean age (years)			Ref.
		Women	Men	p-value
Ho et al. (1993)	72	68	< 0.001	[10]
Rathore et al. (2005)	81	78	< 0.001	[11]
Roger et al. (2004)	79	73	< 0.001	[4]
McCullough et al. (2002)	74	69	< 0.001	[12]

Table 2.

Prevalence of coronary artery disease and hypertension in men and women with heart failure.

Study	Hypertension (%)			Coronary artery disease (%)			Ref.
	Women	Men	p-value	Women	Men	p-value
Roger et al. (2004)	72	61	0.02	24	32	0.08	[4]
Rathore et al. (2005)	66	57	< 0.001	52	66	< 0.001	[11]
Gottdiener et al. (2000)	75	70	N/A	27	39	N/A	[7]

Table 3.

Characteristics of patients with heart failure and reduced versus preserved ejection fraction.

Study	Women (%)			Hypertension (%)			Mean age (years)			Ref.
	SHF	DHF	p-value	SHF	DHF	p-value	SHF	DHF	p-value
Vasan et al. (1999)	25	65	N/A	71	75	N/A	74	72	N/A	[28]
Masoudi et al. (2003)	49	71	< 0.001	61	69	< 0.001	78	80	< 0.001	[13]
Yancy et al. (2006)	40	62	< 0.001	69	77	< 0.001	70	74	< 0.001	[29]

DHF: Preserved ejection fraction; SHF: Reduced ejection fraction.

Data on the prevalence of diabetes mellitus in women with heart failure are conflicting. In the Olmsted County Study, the prevalence of diabetes was 10% lower in women than in men [4]. A pooled analysis of five clinical trials in patients with heart failure and reduced ejection fraction demonstrated that the prevalence of diabetes was approximately 10% higher in women with ischemic etiology, while there was no difference in prevalence among those with nonischemic heart failure when compared with men [17]. However, other studies have found no gender differences in the prevalence of diabetes, regardless of the heart failure etiology; the prevalence varied between 10 and 35%, with higher percentages recorded in the studies enrolling patients with worse heart failure status [19,20]. The first National Health and Nutrition Examination Survey (NHANES I) found that diabetes increased the risk of developing heart failure by approximately 80% in both genders [21]. Data from the Framingham Heart Study showed similar trends with respect to men, but found that the risk of heart failure was over threefold higher in diabetic women compared with nondiabetics [16]. Likewise, the Heart and Estrogen–Progestin Replacement Study (HERS), which included only women with coronary artery disease, demonstrated that the risk of heart failure in women with diabetes was three-times higher than those with coronary artery disease alone [22].

Even in the absence of diabetes, obesity is a risk factor for heart failure. In the Framingham Heart Study, a BMI greater than 30 doubled the risk of incident heart failure in both genders. Owing to the high prevalence of overweight and obesity, the population-attributable risk percentage of heart failure due to overweight was 14% in women and 9% in men, while the corresponding percentages due to obesity were 14% in women and 11% in men [23].

The lifetime risk of developing heart failure is one in five for both men and women, remaining constant regardless of baseline age (40–80 years of age), which illustrates the markedly higher incidence in older age groups despite the shorter remaining lifespan [24]. Likewise, the Rotterdam Study, using more sensitive but less specific diagnostic criteria for heart failure, has described lifetime risks for heart failure of approximately 30% for men and women, with similar remaining lifetime risks across the age spectrum [25].

Morbidity & mortality in women with heart failure

Prognosis after the onset of heart failure remains grim, with an annual mortality of 21% in men and 17% in women [4]. Most epidemiological studies have found that women have better survival after the onset of heart failure, with a mortality risk approximately 15–20% less than that of men ( Table 4 ).

Table 4.

Age-adjusted mortality rates after the diagnosis of heart failure.

Study	Time period	30-day mortality (%)		12-month mortality (%)		5-year mortality (%)		Ref.
		Women	Men	Women	Men	Women	Men
Roger et al. (2004)	1996–2000	4	6	17	21	46	50	[4]
Barker et al. (2006)	1990–1994	9	10	28	33	65	69	[5]
Levy et al. (2002)	1990–1999	10	11	24	28	45	59	[3]

In patients with heart failure and reduced ejection fraction, the etiology of heart failure contributes differently to mortality risk in the two sexes. The ß-Blocker Evaluation of Survival Trial (BEST) demonstrated that nonischemic etiology confers a lesser mortality risk among women when compared with ischemic etiology. Moreover, among nonischemic patients, women had a better survival than men [19]. These findings were confirmed in a pooled analysis of five clinical trials of patients with heart failure and reduced ejection fraction, where time to death was longer for women than men among patients with both ischemic and nonischemic etiologies, but the difference between men and women was greater in the nonischemic group [17]. While the majority of clinical trials included only patients with reduced ejection fraction, the Framingham Heart Study evaluated prognosis in all participants with incident heart failure and confirmed that female gender was associated with a survival benefit; the etiology of heart failure in women was not associated with outcome in this cohort [10].

The relationship between diabetes and mortality in heart failure patients is less clear. In the Framingham Heart Study, while the mortality risk was 70% higher in women with diabetes and heart failure compared with women with heart failure alone, there was no significant increase in mortality risk for diabetic men with heart failure [10]. Analysis of the Digitalis Investigation Group (DIG) study also demonstrated a significant gender–diabetes interaction, with increased mortality in women with concomitant diabetes and heart failure, particularly over the age of 65 years [26]. When examining only patients with reduced ejection fraction enrolled in a clinical trial, diabetes did not appear to be associated with higher mortality in women [19].

The apparent lower mortality in women with heart failure may be related to the relatively preserved left ventricular function, which is more common in women than in men. In the Cardiovascular Health Study, the 6-year mortality among patients with reduced ejection fraction was almost double that of those with preserved systolic function, findings confirmed by the Framingham Heart Study [27,28]. Two other studies, examining outcomes of heart failure patients following a hospital admission, also demonstrated that patients with preserved systolic function had a lower subsequent mortality and fewer readmissions for heart failure than those with depressed systolic function [29,30].

While most data support an overall improved survival in women with heart failure, the survival trends between genders over time are less consistent across cohorts. In the Framingham Heart Study cohort, the 5-year survival improved by approximately 30% between 1950 and 2000, a significant trend that was similar for both genders, with most of the improvement after 1990 [3]. While the Olmsted County participants also showed improved survival over time, the 5-year survival for women improved to a lesser degree than for men (10 vs 25% decrease in mortality in the 1996–2000 time period compared with 1979–1984 in women and men, respectively) [4]. Data from the Kaiser Permanente registry mimic the Olmsted cohort, with a 14% improvement in 1- and 5-year mortality rates for men between 1970 and 1994, but stable mortality rates for women [5].

Although women tend to be more symptomatic at presentation with heart failure (e.g., more dyspnea, leg edema and pulmonary rales) [17], they tend to fare slightly better than men with respect to hospitalizations. A follow-up investigation of the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) study demonstrated that women were less likely to experience a cardiovascular hospitalization compared with men over a median follow-up of 3 years. Interestingly, while the rate of hospitalizations for heart failure was similar between the genders, it was actually higher in women with preserved ejection fraction, and lower in those with reduced ejection fraction compared with men [19,20,31]. In addition, there appears to be an interaction between gender and etiology with regard to hospitalizations; while the rate of hospitalizations was not different in nonischemic cardiomyopathy, women with ischemic cardiomyopathy and reduced ejection fraction had a higher risk of heart failure hospitalizations compared with men [19,20,31]. Analysis of the National Hospital Discharge Survey demonstrated that the hospitalizations with a primary diagnosis of heart failure almost doubled between 1979 and 2004, with a bimodal age–gender distribution. While in a group of patients younger than 64 years of age men had a higher increase in hospitalization rates, women over the age of 65 years had a larger increase than men, accounting for most of the Medicare expenditure for this diagnosis [9]. This larger increase in hospitalization rates could be explained by the proportional increase in risk factors (i.e., coronary heart disease, atrial fibrillation, hypertension and diabetes) in women with heart failure with increasing age compared with men; this risk profile may also account, in part, for the differential response to heart failure therapies in the two genders [25,32].

Sex-based biological differences in the failing myocardium

There is a growing body of evidence to suggest that the female myocardium has distinct adaptive mechanisms when subjected to stress, which may, in part, account for the observed clinical differences. Regardless of the animal models used to mimic heart failure conditions (including aortic banding, aldosterone infusions and a high-salt diet in sensitive animals), males had earlier progression to heart failure, suggesting a more robust adaptive response in females.

In a study using aortic banding to mimic pressure overload, male and female rats had similar increases in left ventricular wall thickness and mass after 6 weeks, with preserved systolic function. However, at 20 weeks, male rats had increased left ventricular cavity dilation, wall stress and evidence of systolic dysfunction; female rats had continued increase in the left ventricular mass, without cavity dilation, indicative of continued remodeling [33]. Podesser et al. induced hypertension and ventricular hypertrophy using a high-salt diet in salt-sensitive rats. After 4 weeks, female rats had increased cardiac mass with notable septal hypertrophy, whereas males had diffuse wall hypertrophy. Female hypertensive hearts had smaller cavity size for a given end diastolic pressure and a leftward shift in the pressure–volume relationship. When normalized for cardiac mass, female hearts developed higher pressures than males, suggesting superior contractility in the face of hypertensive heart disease [34]. Together, these data suggest a more rapid transition to heart failure in the male hearts when compared with the female hearts.

Sex-based disparities in cardiac remodeling extend beyond animal studies; clinical investigations have also illustrated key differences. For example, women with aortic stenosis develop concentric hypertrophy, lower wall stress and better systolic function compared with men [35]. An echocardiographic study comparing pre- and post-menopausal hypertensive women with age-matched male controls demonstrated that premenopausal women had smaller left ventricular cavity size with better function than men; these differences tended to disappear when comparing men with postmenopausal women [36]. These changes may suggest that the ejection fraction cut-off of 45–50% for systolic dysfunction used in men may not be appropriate in women, since the remodeling process may occur much earlier; in effect, an ejection fraction of 55% may be more appropriate as the lower limit of normal in women.

Physiologic differences between pre- and postmenopausal women add complexity to the adaptive response and call into question the role of estrogen in cardiac remodeling. Treatment with 17β-estradiol (a nonspecific estrogen-receptor agonist and the major circulating estrogenic hormone) in ovariectomized rats with heart failure induced by aortic banding, led to an attenuation of hypertrophy in response to pressure overload [37]. Another study in ovariectomized spontaneously hypertensive rats demonstrated that those who received the estrogen receptor α-specific agonist had smaller end systolic volumes and better left ventricular function compared with those treated with a nonspecific estrogen-receptor agonist or controls [38]. Conversely, a study inducing pressure overload by aortic banding in estrogen receptor α- and β-knockout mice found that the estrogen receptor-β was more important in mitigating the hypertrophic response to increased afterload, particularly in females [39].

Gender differences in myocardial calcium handling owing to estrogens or androgens are likely to cause gender differences in systolic and diastolic function [40,41]. In addition, increased availability of nitric oxide increases diastolic function in animal models and the human heart [42]. Nitric oxide leads to an earlier onset of relaxation and increases diastolic distensibility via effects on matrix metalloproteinase and cyclic guanosine monophosphate [42]. Estrogens affect the expression and activity of endothelial, neuronal and inducible nitric oxide synthase at different levels, leading to higher levels of nitric oxide in premenopausal women compared with men [42]. Polymorphisms in the nitric oxide system have greater effects in women than in men. Thus, differences in the nitric oxide synthesis represent the second candidate for improving the understanding of gender differences and differences between pre- and post-menopausal women in cardiac relaxation [42,43]. Endogenous brain natriuretic peptide acts similarly to nitric oxide to preserve diastolic function in congestive heart failure in dogs. Brain natriuretic peptide modulates cyclic guanosine monophosphate in the same direction as cyclic guanosine monophosphate. Interestingly, brain natriuretic peptide regulation is higher in women and exhibits less of an increase in heart failure than in men [43]. Ventricular stiffness depends largely on fibrillar collagen and cross-linking and estrogen reduces cardiac fibroblast proliferation and collagen synthesis at several levels: it decreases collagen I, and increases collagen III and matrix metalloproteinase gene expression [44]. Thus, reduction of matrix turnover by estrogens represents a third candidate to explain gender differences in diastolic function. The activity of the renin–angiotensin system and adrenergic receptor systems also contribute to gender-specific effects in relaxation. Endogenous, but not exogenous, estrogen inhibits angiotensinogen synthesis in the liver, inhibits the expression of the angiotensin receptor-1 receptors in the myocardium and increases the expression of the supposedly protective angiotensin receptor-2 receptor in the aging myocardium. Estrogen also upregulates renal angiotensin receptor-2 receptors. Modulation of the activity of angiotensin receptors and other components of the renin–angiotensin system is a major determinant of cardiac fibrosis. Therefore, downregulation of the renin–angiotensin system by endogenous estrogens is also a candidate to explain better diastolic function in premenopausal women [43,44].

Hormone-replacement therapy in women with heart failure

Early termination of the Women's Health Initiative (WHI) hormone-replacement therapy trials and data from HERS have drawn much attention to the relationship between estrogen and cardiovascular health [45 –47]. Clinical data are equivocal with regard to estrogen and heart failure. In a subgroup analysis of the BEST trial, which included patients with ejection fraction less than 35%, postmenopausal women taking hormone-replacement therapy had improved survival compared with those who were not. Interestingly, this benefit was most prominent in patients with nonischemic heart failure [48]. A subgroup analysis from the Vesnarinone Trials (VEST), which included patients with ejection fraction less than 30%, also found a significant mortality benefit for estrogen users. However, in contrast to the BEST study, the survival benefit with hormone-replacement therapy in the VEST study was apparent regardless of ischemic etiology [49]. Neither the VEST nor BEST studies randomized patients to hormone replacement, and, therefore, the observation must be interpreted with caution since residual confounding could explain the association between hormone-replacement use and improved outcomes. The HERS trial retrospectively examined women with heart failure taking estrogen–progestin and found no mortality benefit with hormone replacement among women with heart failure. It is noteworthy that this study included only patients with coronary artery disease and had a substantial number of patients with preserved ejection fraction [50]. These contradictory and limited findings highlight the need for further understanding of estrogen's role in the failing myocardium. An ongoing analysis of the data from the WHI hormone-replacement trials will hopefully provide more data in this regard.

Therapy in women with heart failure

Over the last decade, clinical trials in heart failure patients have yielded remarkable reductions in morbidity and mortality from different pharmacologic therapies. However, the majority of participants have been men, with women representing less than 20% of the patients enrolled in these trials [2]. In many cases, the smaller numbers have led to a lack of statistical significance when subgroup analyses were restricted to women; thus, it is unclear whether the true effects of the interventions differ by gender or whether the results are merely a statistical power issue.

Among the different pharmacological therapies tested, β-blockers have the most data to support their use in women with heart failure and reduced ejection fraction. In a subgroup analysis of the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) trial, investigators found that metoprolol succinate significantly decreased the risk of hospitalizations and mortality in women; however, their mortality alone was not significantly different, irrespective of the use of metoprolol succinate [51]. Pooled data from the MERIT-HF trial [52], the second Cardiac Insufficiency Bisoprolol Study (CIBIS-II) [53] and the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial [54], yielded a mortality benefit with β-blockers in women similar to that recorded in men. The relative risk of death was decreased by 31% in women compared with 34% in men, which are both significant findings ( Table 5 ) [51].

Table 5.

Mortality in women and men with heart failure in pooled analyses of the major β-blocker trials.

Trial	Randomized (n)		Deaths (n)		Odds ratio (95% CI)
	Placebo	β-blockers	Placebo	β-blockers

CIBIS II
Women	258	257	35	18	0.52 (0.32–0.9)
Men	1062	1070	193	138	0.71 (0.61–0.9)
All	1320	1327	228	156	0.67 (0.42–0.8)
MERIT-HF
Women	447	451	33	31	0.91 (0.65–1.6)
Men	1554	1539	184	114	0.65 (0.55–0.8)
All	2001	1990	217	145	0.66 (0.53–0.8)
COPERNICUS
Women	227	243	N/A	N/A	0.65 (0.41–1.1)
Men	906	913	N/A	N/A	0.65 (0.51–0.8)
All	1133	1156	190	130	0.65 (0.52–0.8)
All three studies
Women	932	951	N/A	N/A	0.65 (0.51–0.9)
Men	3522	3522	N/A	N/A	0.64 (0.62–0.8)
All	4454	4473	635	431	0.64 (0.61–0.8)

CIBIS II: Cardiac Insufficiency Bisoprolol Study; COPERNICUS: Carvedilol Prospective Randomized Cumulative Survival; MERIT-HF: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure.

Adapted from [51].

Angiotensin-converting enzyme (ACE) inhibitors have also been shown to confer survival benefit to patients with heart failure and reduced ejection fraction, but, again, in these trials women were substantially under-represented. The treatment arm of the Studies of Left Ventricular Dysfunction (SOLVD) randomized patients with chronic heart failure and ejection fraction less than 35% to enalapril or placebo. The enalapril group had a 16% relative-risk reduction in mortality, but only 20% of the participants were women [55]. A 12-year follow-up of the same trial analyzed results by gender and found a nonsignificant survival benefit for women who were randomized to enalapril [56]. Finally, a pooled analysis of five ACE-inhibitor trials (including 2396 women) demonstrated a nonsignificant 15% reduction in mortality with ACE-inhibitor treatment in women (95% CI: 0.71–1.02) [57].

Angiotensin II receptor blockers (ARBs) have been studied more recently in large trials that include patients with preserved ejection fraction. Candesartan was equally beneficial in the prevention of cardiovascular death or hospitalization, regardless of gender [31,58]. However, more interesting data come from comparison of ARBs to ACE inhibitors. Head-to-head comparisons of losartan and captopril in elderly patients with ejection fraction less than 40% found no benefit of losartan over captopril, an effect that was similar in both genders [59,60]. A population-based study, including over 17,000 patients (50% women), found that ARBs compared with ACE inhibitors conferred a significant 31% survival benefit in women (95% CI: 0.59–0.80), but not in men (95% CI: 0.95–1.3) [61]. While this investigation was observational, it highlights the need for randomized clinical trials that are specific to women.

While the main DIG trial (including 22% women) demonstrated that digoxin had no effect on mortality and decreased hospitalizations for heart failure [62], a subgroup analysis in women showed a significantly increased risk for all-cause mortality and a trend toward more hospital admissions in women treated with digoxin [63]. Separate post hoc analyses of the data demonstrated that women had a higher serum digoxin concentration, raising the hypothesis that this may contribute to the increased mortality among women [64].

Discrepancies in heart failure management for women are apparent not only in randomized trials, but also in clinical practice. β-blockers, which have supportive data for men and women, are used less frequently in women with heart failure. In a European population-based study, women with heart failure and reduced ejection fraction were 25% less likely to receive β-blockers than men [65]. The CHARM study confirmed these findings, with women being 17% less likely than men to receive β-blockers [31]. Clinical practice also appears to vary in a gender-based fashion for ACE inhibitors. A British study found that women were 24% less likely to receive ACE inhibitors than men [65], while the National Heart Failure Project and the Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting (IMPROVE HF) trial found that older women with heart failure were less likely to receive guideline-recommended treatments compared with men [11,66].

Moreover, fewer women had measurement of ejection fraction than men [11,65], and women were three-times less likely than men to receive an implantable cardioverter-defibrillator [67]. In reviewing data from over 13,000 discharges after a heart failure hospitalization in patients with an ejection fraction less than 30%, women were 40% less likely to receive or have plans upon discharge to receive an implantable cardioverter-defibrillator compared with men [68]. This disparity may be partially due to the unclear benefits of implantable cardioverter-defibrillator in women with heart failure [69] or to the increased implant-related procedural risk that women experience in comparison with men [70].

Finally, surgical therapies for women with advanced heart failure and systolic dysfunction, such as high-risk coronary artery bypass surgery, mitral valve repair, left ventricular assist device placement and cardiac transplantation, are far less likely to be used in women than men [71 –73].

Conclusion & future perspective

Heart failure is a growing epidemic in the USA and a substantial and increasing number of patients are women, especially in those older than 65 years of age. At present, clinical trials have recruited only small numbers of female participants, resulting in studies that are inadequately powered to demonstrate a benefit for women. Results from existing trials are nonetheless applied to female patients in clinical practice, despite the lack of strong supporting evidence. Considering the gender-based differences in risk factors for heart failure, as well as particularities in myocardial remodeling and hormone effects, one should not assume that the same therapies have the same effects in men and women. Further investigations into myocardial remodeling, the role of estrogen and progesterone, as well as trials dedicated to women with heart failure, are needed to effectively treat this large, and largely neglected, patient population.

Executive summary

Epidemiology

Women have a lower incidence of heart failure than men, although the incidence may be increasing over time.

Since women have a greater life expectancy than men, but the same lifetime risk for developing heart failure, they represent a growing proportion of the heart failure epidemic. At present, women account for 50–55% of prevalent heart failure cases.

Comorbidities & risk factors

Hypertension is the most significant risk factor for heart failure in women, whereas ischemic heart disease is the most significant risk factor for heart failure in men.

Obesity and diabetes are also significant risk factors for heart failure in women.

Morbidity & mortality

Overall, women have a better survival rate than men (irrespective of heart failure etiology), but improvements in survival over time show a higher benefit in men.

Women tend to have higher heart failure hospitalization rates than men.

Sex-based differences in the failing myocardium

Animal studies and observational human data suggest that the female heart may have superior adaptation to increased afterload, resulting in preserved function.

The effect of estrogen and progesterone replacement in women with heart failure remain unclear and appear to vary based on heart failure etiology, as well as left ventricular function.

Therapy

Women represent less than 20% of patients included in clinical trials; as a result, some studies were not powered to detect effects of specific therapy in women.

In a pooled analysis, β-blockers had a significant survival benefit in women, while angiotensin-converting enzyme inhibitors showed a nonsignificant trend toward survival benefit.

Although clinical trials in patients with heart failure and systolic dysfunction have found similar mortality benefit of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers, a cohort study found that women may have a better survival with angiotensin-receptor blockers.

Digoxin use in women may increase mortality when serum drug levels are elevated.

Women with heart failure and decreased systolic function are less likely to receive implantable cardiac defibrillators for primary prevention, although more sex-specific research in the epidemiology and pathophysiology of sudden death in women with heart failure is needed.

Future perspective

Women older than 65 years of age will become the largest proportion of patients with heart failure and, in order to decrease the substantial costs associated with hospitalizations, future clinical trials need to enroll more women.

Future research needs to address treatments for heart failure with preserved systolic function, an entity more prevalent in women than men.

Research directed at understanding the interaction between individual genotypes, cardiac estrogen and β-adrenergic receptors will open new avenues for more personalized treatments of heart failure in women.

Footnotes

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Heart Failure in Women: Epidemiology,Biology and Treatment

Abstract

Keywords

Epidemiology of heart failure

Comorbidities & risk factors

Morbidity & mortality in women with heart failure

Sex-based biological differences in the failing myocardium

Hormone-replacement therapy in women with heart failure

Therapy in women with heart failure

Conclusion & future perspective

Footnotes

References