Introduction

There are both sex-based (biologic) and gender-related (sociocultural) differences in heart failure (HF). Differences in occurrence of HF between women and men may be partly due to variable prevalence and pathophysiologic influence of specific cardiovascular disease risk factors. Disparity in prognosis between woman and men with HF may be influenced by varying treatment efficacy and/or management strategy. It was not until 1991 that the National Institutes of Health (NIH) established a policy that all NIH-funded trials must include both women and men in studies of conditions that affect both sexes [1]. Most of the studies on women and cardiovascular disease including HF commenced following this mandate.

Heart Failure in Women

HF affects 5.1 million people in the United States, more than 40% of HF patients are women, and among the elderly the prevalence of HF is greater in women than in men [2]. In 2010, 32,847 deaths in women were due to HF, which accounted for more deaths in women than in men (58.2% versus 41.8%) [3]. The prevalence of HF increases with age, with more women than men having HF after 79 years of age. Although the lifetime risk for the development of HF in a 40-year-old individual is not different between both sexes (one in five), the lifetime risk for the development of HF in a 40-year-old individual without a preceding myocardial infarction is one in six for women versus one in nine for men [4, 5].

The risk factors associated with HF and its underlying pathophysiology differ to some extent by sex. Review of data from the Framingham Heart Study indicates that hypertension and diabetes mellitus impose a greater risk of HF in wom en than in men [6]. Women with HF have more hypertension, valvular heart disease, and thyroid disorders than men do but are less likely to have obstructive coronary artery disease (CAD) [7, 8]. Even though obstructive CAD is less frequent in women, it is a stronger risk factor than hypertension for the development of HF [9].

Unique circumstances for development of HF in women include cardiac toxicity from the chemotherapeutic drugs used for the treatment of breast cancer [10,11,12] and cardiomyopathy that occurs in the peripartum period [13,14,15]. Women with acute decompensated HF are twice as likely as men to have preserved left ventricular (LV) systolic function or HF with a preserved ejection fraction (HFpEF) [16]. Even women with an impaired left ventricular ejection fraction (LVEF) will have a higher LVEF than men do [16]. Notably, women with HF have a lower quality of life, lower functional capacity, more hospitalizations for HF, and more frequent depression [17]. Nonetheless, overall survival is better for women than for men with HF, except among HF patients with ischemic cardiomyopathy where prognosis is similar in both sexes.

Clinical Manifestations and Diagnosis of Heart Failure

The Studies of Left Ventricular Dysfunction (SOLVD) demonstrated that women with an impaired LVEF were more likely than men to have edema, elevated jugular venous pulsation, and an S3 gallop [18]. However, women (n = 54,674) in the Acute Decompensated Heart Failure National Registry (ADHERE) registry, comprising both impaired and preserved systolic function, did not differ from men (n = 50,713) with respect to the frequency of HF symptoms and signs. The difference in this study versus others may be related to how ADHERE was specifically examining manifestations of acute decompensated HF rather than chronic symptoms [8].

The level of natriuretic peptides such as brain natriuretic peptide (BNP) and N-terminal pro Atrial Natriuretic Peptide (NT-proANP) levels used to diagnose HF are higher in women than in men [19, 20]. Although elevated levels of BNP and NT-proANP were associated with a greater risk of HF, the association was similar in both women and men [21]. BNP higher than 500 pg/mL appears to be a stronger predictor of death in women with HF than in men [22]. The levels of biomarkers related to inflammation, including C-reactive protein and interleukin-6, were lower in women than in men [23]. In this study, mortality was also lower in women compared with men, independent of differences in clinical characteristics [23].

Breast Cancer Chemotherapy-Induced Cardiotoxicity

Cardiotoxic effects of chemotherapeutic agents is well known [10,11,12]. Briefly, in specific relevance to breast cancer treatment, adjuvant therapy with anthracyclines such as doxorubicin has demonstrable survival benefits but at a greater risk of early as well as late-onset myocardial dysfunction in a cumulative dose-dependent manner [24]. Anthracycline-induced cardiotoxicity is mediated by free radical production causing deoxyribonucleic acid (DNA) damage, apoptosis, cardiomyocyte death, and sarcopenia that may result in irreversible HF [12].

Recombinant monoclonal antibodies such as Trastuzumab used in the treatment of human epidermal growth factor receptor 2 (HER2) positive breast cancer also has proven beneficial effects but with a higher risk of severe HF, symptomatic HF, and decline in LVEF [25, 26]. This deleterious effect on the myocardium is thought to be due to inhibition of cardiomyocyte HER2 signaling and its ligand neuregulin-1 rather than because of induction of cell death and hence is potentially reversible [12, 27].

Peripartum Cardiomyopathy

Peripartum cardiomyopathy causes impaired LVEF in the last month of pregnancy or within 5 months postpartum, with no preexisting cardiac disease and no identifiable cause. Its incidence is estimated to be 1 in 4000 pregnancies, and it is associated with risk factors such as advanced maternal age, African descent, high parity, twin pregnancy, use of tocolytics, and poverty [28]. After the diagnosis, LVEF recovers in approximately half of the patients within 6 months, but 20% of patients deteriorate and either die or require heart transplantation. Recovery appears to be related to a less severe decline in LVEF [4]. The risk during subsequent pregnancies is not entirely clear.

Management of Heart Failure

Although women have been included in clinical trials in greater numbers than minorities, they have still been significantly underrepresented. This underrepresentation and the more prevalent HFpEF in women limit our overall understanding of HF management in women. Nonetheless, treatment guidelines for HF therapy provide similar recommendations for women and men [4]. In several major clinical trials including the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program, women were more likely to have preserved LV function than men (50% versus 35%) [29]. Overall, evidence-based HF therapies are underused in both sexes, and although women are less likely than men to receive them, this disparity did not translate into a higher rate of hospitalizations for HF or mortality. Women are less likely to receive vasoactive agents, but women and men have equal lengths of hospitalization and age-adjusted in-hospital HF mortality rates.

Beta-Blockers

Carvedilol , metoprolol succinate and bisoprolol are proven in multicenter, prospective, randomized trials to reduce mortality and morbidity in HF patients with reduced LV systolic function. In the Carvedilol Prospective Randomized Cumulative Survival Study (COPERNICUS), carvedilol reduced the combined end point of death or hospital stay in the 469 women studied with LVEF ≤25% and severe symptomatic HF [30, 31]. In the European Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), bisoprolol improved survival in the 515 women studied, with New York Heart Association (NYHA) functional class III or IV and LVEF ≤35% (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.19 to 0.69) [32]. In the Metoprolol Extended-Release Randomized Intervention Trial in Heart Failure (MERIT-HF) trial, although metoprolol succinate did not confer survival benefit for women (6.9% versus 7.5%, p = not significant) it reduced HF hospital stay by 42% (p = 0.021) in the 898 women studied with LVEF ≤40% who were NYHA functional class II to IV [33]. Meta-analyses of six major β-blocker trials including 2134 women and 7885 men, showed that women and men with symptomatic HF have similar mortality benefit when treated with beta-blockers (Table 4.1) [34].

Table 4.1 Effect of beta-blockers on mortality in men and women with heart failurea

To date, the use of β-blockers throughout pregnancy has not been associated with teratogenicity. A meta-analysis to determine teratogenicity of β-blockers in early pregnancy was conducted by Yakoob et al. [35]. They found that first-trimester oral β-blocker use showed no increased odds of all or major congenital anomalies (odds ratio [OR], 1.00; 95% CI, 0.91 to 1.10; 5 studies). However, in analyses examining organ-specific malformations, increased odds of cardiovascular defects, cleft lip/palate, and neural tube defects were observed. While they concluded that the strength and causality of this association is di fficult to interpret, it has also been suggested that β-blockers be prescribed cautiously later in pregnancy. β-Blockers have been studied most extensively for treatment of non-severe hypertension in pregnancy, and there has been no significant effect on the incidence of small-for-gestatio nal-age infants [36].

Angiotensin Converting Enzyme Inhibitors

Angiotensin Converting Enzyme (ACE) inhibitor s are among the most well-studied medications in HF therapy. ACE inhibitors reduce morbidity and mortality in HF with reduced ejection fraction (HFrEF) . Randomized controlled trials clearly establish the benefits of ACE inhibition in patients with mild, moderate, or severe symptoms of HF and in patients with or without coronary artery disease [37,38,39,40,41,42]. However, this benefit may not be similar for women and men. A combined analysis of more than 30 trials demonstrated a 37% decrease in mortality for men, with only a 22% decrease in women [43]. Another pooled analysis has confirmed the finding that there is a tendency toward less benefit for women treated with ACE inhibitors (Table 4.2) [34].

Table 4.2 Effect of ACE inhibitors on mortality in men and women with heart failure

Angiotensin Receptor Blockers

Patients intolerant to ACE inhibitors because of cough or angioedema should be started on ARBs; patients already tolerating ARBs for other indications may be continued on ARBs if they subsequently develop HF [44]. Sex-specific data for ARBs are limited. Pooled data from the CHARM-Alternative and the CHARM-Added trials that included 1188 women with NYHA functional class II-IV HF and LVEF ≤40% showed that candesartan reduced the combined endpoint of cardiovascular death or HF hospitalization in women [45]. In the CHARM-Overall population, reduction in the combined endpoint was similar for women and men [45]. In the Valsartan Heart Failure Trial (Val-HeFT), Valsartan failed to demonstrate mortality benefit in 1003 women with NYHA f unctional class II to IV and LVEF ≤40% when compared with a placebo, however, it reduced HF hospital stay (HR, 0.74; 95% CI, 0.55 to 0.98) and first morbid event (HR, 0.79; 95% CI, 0.63 to 0.99) [(4, 46)].

Aldosterone Receptor Antagonists

Subgroup analysis of the Randomized Aldactone Evaluation Study (RALES) with spironolactone and the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) with eplerenone revealed similar mortality benefits for women and men with systolic HF [34, 47]. The RALES trial included 446 women and studied the effects of spironolactone in ischemic and nonischemic cardiomyopathy patients with NYHA functional class III to IV and LVEF <35% [47]. The EPHESUS trial included 1918 women participants and studied the effects of eplerenone after an acute myocardial infarction in patients with LVEF ≤40% [48].

Angiotensin II-Receptor Blocker and Neprilysin Inhibitor

Angiotensin II-Receptor Blocker and Neprilysin Inhibitor (ARNI) is an ARB combined with an inhibitor of neprilysin, an enzyme that degrades natriuretic peptides, bradykinin, adrenomedullin, and other vasoactive peptides [44, 49]. In a randomized clinical trial that compared valsartan/sacubitril, with enalapril in symptomatic patients with HFrEF tolerating an adequate dose of either ACE inhibitor or ARB, the ARNI reduced the composite endpoint of cardiovascular death or HF hospitalization significantly, by 20% [49]. The benefit was seen to a similar extent for both death and HF hospitalization and was consistent across subgroups. The use of ARNI is associated with the risk of hypotension and renal insufficiency and may lead to angioedema, as well. Drugs that inhibit the RAAS can cause h arm to the fetus, and therefore, as with other ACE inhibito rs and ARBs, valsartan/sacubitril should not be administered to pregnant women [50].

Hydralazine and Isosorbide Dinitrate

The combination of hydralazine and isosorbide dinitrate is commonly used in the treatment of HF patients who are intolerant to ACEI or ARB. The original data supporting this practice was from Veterans Administration HF trials and was limited to men [51, 52]. There is still no data available for women using hydralazine and isosorbide dinitrate as a substitute for an ACEI or ARB. In the African-American Heart Failure Trial (A-HeFT), combination hydralazine/isosorbide dinitrate was added to ACE inhibitor/ARB and β-blocker therapy in 1050 self-identified African Americans with NYHA functional class III-IV HF (420 women). The trial was prematurely stopped because of the significant survival benefits that were noted for both women (HR, 0.33; 95% CI, 0.16 to 0.71; p = 0.003) and men (HR, 0.79; 95% CI, 0.46 to 1.35; p = 0.385) in addition to fewer hospital stays, with no significant treat ment interaction by sex [7].

Digoxin

Digoxin reduces HF hospital stay but has no beneficial effect on survival [53]. A post hoc subgroup analysis of the Digitalis Investigation Group (DIG) trial was concerning for increased mortality in women with reduced systolic function when treated with digoxin compared with placebo (adjusted HR, 1.23; 95% CI, 1.02 to 1.47), whereas in men digoxin had no effect on mortality (adjusted HR, 0.93; 95% CI, 0.85 to 1.02) [53, 54]. The increased mortality was presumed to be due to digoxin toxicity, because the risk of death increased at higher serum drug levels, and a subsequent analysis of the DIG trial data showed that digoxin at serum level of 0.5 to 0.9 ng/mL was safe and effective for both women and men [55].

Implantable Cardioverter-Defibrillator

Guideline recommendations for implantable cardioverter-defibrillator (ICD) implantation to prevent sudden death are based on many multicenter studies, but women have been underrepresented and few studies have provided adequate sex-specific data [56, 57]. Unfortunately, the limited post hoc analyses available for women with an ICD do not clearly demonstrate a mortality benefit [56,57,58]. In the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), which included 382 women (190 randomized to an ICD and 192 to a placebo) with NYHA class II-III HF and LVEF ≤35% (ischemic and nonischemic cardiomyopathy), the benefits of an ICD were not clear, although the trial was not powered t o detect sex differences (HR, 0.96; 95% CI, 0.58 to 1.61 in women) [59]. In the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II), which included 192 women (119 randomized to an ICD) with ischemic cardiomyopathy and an LVEF ≤30%, ICD use was associated with a nonsignificant trend toward lower mortality in women (adjusted HR, 0.57; 95% CI, 0.28 to 1.18; p = 0.132) [60].

ICDs are underused in both sexes, particularly so in women. Eligible women, especially black women, are less likely than men to receive an ICD (26.5% versus 42.4%, p < 0.0001). ICD use increased over time , and the racial disparities disappeared by 2009, but the sex disparities have persisted [61]. None of the randomized trials for ICDs enrolled sufficient numbers of women to permit analysis of sex differences, current data are insufficient to support differential use of ICDs by sex.

Cardiac Resynchronization Therapy

Cardiac resynchronization therapy (CRT) is of benefit in both women and men with HF and a wide QRS complex, however, there is some evidence that women may derive greater benefit from CRT compared with men. In the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) study, which included 493 women, women who underwent CRT had a significant reduction in the combined endpoint of total mortality or hospital stay for any cause than did women receiving just medical therapy, and there was no interaction by sex [57]. In the MADIT-CRT trial, which randomized 1367 men and 453 women with an LVEF ≤30% and NYHA class II HF to CRT plus ICD versus ICD alone, CRT was associated with better outcomes and greater degree of reverse remodeling in women compared with men [62]. Although few studies have reported any sex-specific data, these same findings have been confirmed in a retrospective analysis of the Cardiac Resynchronization–Heart Failure (CARE-HF) study that included 215 women [63].

Left Ventricular Assist Devices

Implantable LV assist devices (LVADs) are being placed more frequently for the management of end-stage refractory HF as a bridge to transplant or a destination therapy [64]. Although there are no sex-related differences in the surgical techniques for implanting LVADs, small women had limited options with early devices as they require a minimum body size to fit properly [65]. However, more recent devices including HeartMate II, HeartMate III and the HeartWare, are smaller and more women have been enrolled in clinical trials with similar survival rates compared with men [66, 67]. A review from the Cleveland Clinic concluded that there were no significant sex-based differences in mortality, time to first infection, bleeding, or device malfunction with either pulsatile- or continuous-flow LVADs. However, women had an increased risk of first neurological event [68]. In a recent study comparing outcomes of continuous flow LVAD implantation between 24 women and 24 men as a bridge to transplantation, women had a longer duration of inotropic support and higher requirement for postoperative mechanical right ventricular support, but similar survival rates compared with men [69].

Cardiac Transplantation

Based on data from the International Society of Heart and Lung Transplantation registry, women received 23.7% of the 17,868 heart transplants performed from January 2006 to June 2011 [70], representing significant increases from 22.3% and 19.3% in the prior 5- and 10-year periods. Overall survival rates are now similar in women and men, although female recipients of a male donor heart may be at higher risk of 1-year mortality than male recipients from a male donor [70].

Heart transplantation occurs fa r less frequently in women than in men [71] with only 28% of heart transplants in the United States in 2011 occurring in women [70]. Reasons for lower rates of transplantation in women are not clear; this may be partly explained by higher levels of panel reactive antibody in parous women, which makes identifying suitable donors more challenging [72]. There is also a higher acceptance of patients for transplantation with an ischemic cause of cardiomyopathy, regardless of sex, which increases the proportion of men who undergo transplantation compared to women [73]. Women also tend to be older, possibly decreasing candidacy f or transplantation [72].

Conclusions

HF remains an important healthcare concern for women in the United States. Generally, HF affects women at a more advanced age with better global LV systolic function, compared with men. Women are more likely to have hypertension, diabetes mellitus and valvular disease as the etiology and less likely to have coronary artery disease. Most large HF trials have under-represented women in their enrollment numbers, and this has narrowed our knowledge of sex-related differences in HF pathophysiology, diagnosis, and treatment.

In general, survival seems to be better for women than for men with HF, with the likely exception of HF patients with ischemic heart disease where prognosis is similar in both sexes. Current treatment guidelines are not sex-specific because sufficient data is not available, however, as the therapeutic options for HF expand, sex-based modifications to HF management may be considered in future revisions.