Heart Failure Subtypes and Cardiomyopathies in Women

Abstract

Heart failure affects over 2.6 million women and 3.4 million men in the United States with known sex differences in epidemiology, management, response to treatment and outcomes across a wide spectrum of cardiomyopathies that include peripartum cardiomyopathy, hypertrophic cardiomyopathy, stress cardiomyopathy, cardiac amyloidosis and sarcoidosis. Some of these sex-specific considerations are driven by the cellular effects of sex hormones on the renin-angiotensin-aldosterone system, endothelial response to injury, vascular aging, and left ventricular remodeling. Other sex differences are perpetuated by implicit bias leading to undertreatment and underrepresentation in clinical trials. The goal of this narrative review is to comprehensively examine the existing literature over the last decade regarding sex differences in various heart failure syndromes from pathophysiological insights to clinical practice.

Introduction

Heart failure (HF) affects over 2.6 million women and 3.4 million men in the United States (U.S.).¹ There are major sex differences in the prevalence of HF, response to treatment, and mortality across the spectrum of left ventricular ejection fraction (LVEF). Additionally, peripartum cardiomyopathy is a sex specific disease with unique considerations. Other conditions such as stress cardiomyopathy, hypertrophic cardiomyopathy, sarcoidosis, and amyloidosis have important but less well-recognized sex differences in prevalence, management, and outcomes. Some of these sex-specific considerations are driven by the cellular effects of sex hormones on the renin-angiotensin-aldosterone system, endothelial response to injury, vascular aging, and left ventricular remodeling. Others are a result of implicit bias leading to underdiagnosis, undertreatment, and underrepresentation in clinical trials. The objective of this narrative review is to discuss the sex differences with respect to pathophysiology, epidemiology, treatment and prognosis as well as limitations in the field including under-representation of women in HF studies, under-utilization of treatment, and selection bias for rare diseases.

Heart Failure with Reduced Ejection Fraction

Epidemiology

Heart failure with reduced ejection fraction (HFrEF) is usually defined as HF with LVEF <40%² although studies have included patients with LVEF <45%³ and LVEF <50%.⁴ The lifetime risk for HFrEF is lower in women compared to men (5.8% versus 10.6%) based on two large prospective cohort studies (Cardiovascular Health Study and the Multiethnic Study of Atherosclerosis [MESA]).³ HF incidence has declined over the years with a greater reduction in women than men with HFrEF according to a population study in Olmsted County, Minnesota.⁴ There are also sex differences in underlying disease with women more likely to have non-ischemic cardiomyopathy while men are more likely to have an ischemic cardiomyopathy.^5,6 Among hospitalized HFrEF patients, women compared to men are older, more likely to have hypertension and valvular disease, less likely to have coronary artery disease, peripheral vascular disease and tobacco usage, and have higher natriuretic peptides (Figure 1).⁷ Morbidity and mortality associated with HFrEF is significant with important sex differences. Based on two large HFrEF trials (PARADIGM-HF and ATMOSPHERE), women compared to men have worse quality of life despite lower mortality after adjusting for possible confounders (adjusted HR: 0.68, 95% CI 0.62–0.74; p < 0.001) and lower risk of HF hospitalization (HR 0.80, 95% CI 0.72–0.89; p < 0.001).⁸ Older studies have also found similar sex differences in prognosis.^5,6

Figure 1.

Sex Differences in the Pathophysiology and Treatment of Heart Failure with Reduced Ejection Fraction

Notable sex differences exist with respect to the epidemiology of heart failure with reduced ejection fraction. Additionally, trials have shown differential effect of neurohormonal blockade and device therapy in men and women.

ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; CRT = cardiac resynchronization therapy; HFrEF = heart failure with reduced ejection fraction; ICD = implantable cardioverter defibrillator; LVAD = left ventricular assist device

Medical Therapy

Medical therapy for HFrEF has been shown to reverse remodeling of the LV, improve quality of life, reduce HF hospitalizations, and reduce mortality.^9–11 Our understanding of sex differences in response to therapy is limited by retrospective and post-hoc subgroup analyses of landmark HF clinical trials that often had under-representation of women.^6,7 Despite these limitations, review of these studies suggest that not all HF medications benefit men and women equally (Table 1).^11–17 For instance, two large angiotensin converting enzyme inhibitors (ACEI) meta-analyses showed no definitive benefit of an ACEI in women^12,13 and a large observational HFrEF study in Canada with 10,223 women and 9,475 men was notable for women having better survival on angiotensin receptor blockers (ARB) than ACEI (adjusted HR 0.69, 95% CI 0.59–0.80; p <0.0001) with no difference in survival for men (adjusted HR 1.10, 95% CI 0.95–1.30, p=0.21).¹⁸ This analysis and the two large ACEI meta-analyses raise the importance of choosing optimal controls when performing clinical trials. For example, in the PARADIGM-HF trial which compared Angiotensin Receptor-Neprilysin Inhibitor (ARNI) to ACEI (enalapril) in symptomatic HFrEF patients, the combined endpoint (mortality and HF hospitalization) among the women taking ARNI was driven by a reduction in HF hospitalizations. Due to the choice of control (ACEI instead of valsartan), it remained unclear if the benefit of ARNI in women was due to the sacubitril-valsartan combination therapy versus valsartan alone since valsartan also was shown to reduce HF hospitalizations in women in Val-HeFT (Table 1).

Table 1.

Sex Differences in Risk of Mortality and/or Hospitalization in Heart Failure with Reduced Ejection Fraction

Study	Endpoint	Risk (95% CI)
		Women	Men
ACEI
ACEI meta-analysis12	Mortality	OR 0.79 (0.59–1.06)	OR 0.76 (0.65–0.88)
ACEI meta-analysis12	Mortality and HF Hospitalizations	OR 0.78 (0.59–1.04)	OR 0.63 (0.55–0.73)
ACEI meta-analysis13	Mortality	RR 0.92 (0.81–1.04)	RR 0.82 (0.74–0.90)
ARB
Val-HeFT†	Mortality	HR 0.93 (0.68–1.27)	HR 1.04 (0.90–1.19)
Val-HeFT†	HF Hospitalizations	HR 0.74 (0.55–0.98)	HR 0.73 (0.62–0.86)
CHARM- Trials†	CV Mortality or HF hospitalization	HR 0.81 (0.67–0.98)	HR 0.82 (0.73–0.91)
ELITE II158	Mortality	HR 1.14 (0.8–1.8)	HR 1.12 (0.9–1.4)
ARNI
PARADIGM-HF10	CV Mortality or HF Hospitalization	Not reported but p-value for interaction = 0.63	Not reported but p-value for interaction = 0.63
Aldosterone blockers
Meta-analysis159	CV Mortality or HF hospitalization	aHR0.73 (0.62–0.86)	aHR0.69 (0.62–0.77)
Nitrate + Hydralazine
A-HEFT22	Mortality	HR 0.33 (0.16–0.71)	HR 0.79 (0.46–1.35)
A-HEFT22	Mortality or HF hospitalization	HR 0.58(0.39– 0.86)	HR 0.67 (0.49–0.92)
B-blocker therapy
US Carvedilol HF160	Mortality	HR 0.23 (0.07–0.69)	HR 0.41 (0.22–0.80)
COPERNICUS161	Mortality	RR 0.63 (0.39–1.04)	RR 0.68 (0.54–0.86)
CIBIS II162	Mortality	RH 0.53 (0.42–0.67)	RH 0.37 (0.19–0.69)
MERIT-HF163	Mortality	RR 0.93 (0.58–1.49)	RR 0.63 (0.50–0.78)
Ivabradine
Ivabradine23	CV Mortality or HF hospitalization	HR 0.74 (0.60–0.91)	HR 0.84 (0.76–0.94)
Digitalis
Digitalis19	Mortality	aHR1.23 (1.02–1.47)	aHR0.93 (0.85–1.02)
Digitalis19	HF Hospitalizations	HR 0.87 (0.72–1.04)	HR 0.66 (0.60– 0.73)
SGLT2 inhibitors
DAPA-HF11	HF Hospitalization, IV therapy or CV Mortality	HR 0.79 (0.59–1.06)	HR 0.73 (0.63–0.85)
EMPEROR17	CV Mortality or HF hospitalization	HR 0.59 (0.44–0.80)	HR 0.80 (0.68–0.93)

^†Unpublished data provided by the principal investigators

Sex hormones may be responsible for some of these observed differences in HF medical therapies.²⁴ Plasma renin levels are lower in women compared to men (Figure 2). ACE activity, vascular response to angiotensin II, and aldosterone secretion are all decreased by estrogen and increased by androgens. Additionally, expression of the Angiotensin II type 2 (AT₂) receptor, which is on the X chromosome, increases much more in women than men in response to injury.²⁴ Therefore, in pathophysiological conditions such as heart failure, estrogen stimulates increased AT₂ receptor expression and activation. As a result, the inhibitory effect of ARB is more pronounced in women than men. This may explain the greater efficacy of ARBs, and subsequently ARNIs, relative to ACE inhibitors in women.

Figure 2.

Postulated Estrogen-Mediated Mechanisms in Heart Failure

Estrogen modulates a variety of pathophysiologic processes including endothelial response to injury, the renin-angiotensin-aldosterone system, and left ventricular remodeling. Additionally, estrogen has roles in maintaining diastolic function and in the coronary microvasculature. These may explain sex differences in heart failure pathophysiology at a mechanistic level.

Knowledge of sex differences in HF therapy is also necessary to prevent harm. Among the 1,519 women participants in the Digitalis Investigation Group (DIG) trial there was a higher risk of mortality with digitalis and no significant reduction in HF hospitalizations.¹⁹ An in-depth analysis attributed the higher mortality in women to higher serum digoxin levels despite similar doses. Digoxin was deemed safe when serum concentrations ranged from 0.5 to 0.9 ng/ml emphasizing the importance of recognizing the considerable sex differences in pharmacokinetics.^19,20

Under-representation of women in clinical trial has been another concern⁵ with some trials such as Vasodilator-Heart Failure Trial I (V-HeFT 1) not even including women when comparing prazosin, isosorbide and hydralazine to placebo in heart failure patients.²¹ In fact, isosorbide and hydralazine were studied only in women participating in the African American Heart Failure Trial (A-HEFT) but have not been studied among women with HFrEF of other races. In A-HEFT which included 420 women with moderately severe HF symptoms (New York Heart Association [NYHA] class III-IV) already on guideline medical therapy, the combination of isosorbide and hydralazine therapy reduced mortality and HF hospitalization.²² There was improvement in quality of life with treatment but it did not reach statistical significance in both sexes which may be due to relatively small number of patients in both subgroups.

Finally, newer therapies like ivabradine and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have limited sex specific data that are important to review. Ivabradine is recommended for symptomatic HFrEF patients in normal sinus rhythm with resting heart rate ≥ 70 beats per minute despite maximal β-blocker therapy. Based on the Systolic Heart Failure Treatment with the I_r Inhibitor Ivabradine Trial (SHIFT) that included 1,535 women, ivabradine reduced combined endpoint of cardiovascular death and HF hospitalization in women and had similar benefit in men.²³ SGLT2i are indicated in symptomatic HFrEF patients with or without diabetes mellitus type II. In the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced), empagliflozin reduced a combined endpoint of cardiovascular death or HF hospitalization among the 893 women participating.¹⁷ Dapagliflozin is another SGLT2i with limited sex-specific data, that showed among the 1,109 women with HFrEF a trend towards reduced combined endpoint of HF hospitalizations, intravenous outpatient therapy for HF or cardiovascular death in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial.¹¹ These studies show some benefit despite under-representation of women in HFrEF trials.

Sex Hormones and Heart Failure

Sex hormones have many effects on the vasculature and renin-angiotensin-aldosterone system as discussed earlier (Figure 2). Estrogen in the form of hormone replacement therapy (HRT) has also been shown to effect postmenopausal women with symptomatic HF.²⁵ In a secondary analysis of Beta-Blocker Evaluation of Survival Trial (BEST), which included patients with NYHA Class III or IV HF with an LVEF of 35% or less, there was a significant survival benefit for HRT users among the 237 nonischemic postmenopausal women even after adjustment for potential confounders (HR = 0.35, 95% CI 0.14–0.87).²⁵ Posited mechanisms included reduced activation of neurohormonal systems and suppression of sympathetic activity.²⁵

Implantable Cardioverter Defibrillators (ICD)

There are sex differences in the utilization, outcomes, and adverse events with ICDs, which are recommended to prevent sudden death for all HF patients NYHA class II-III with LVEF ≤ 35% (Class I indication) or those with NYHA class III-IV eligible for biventricular pacemaker (CRT).² Eligible women are less likely than men to have an ICD based on many studies,^26–31 with one large analysis showing no sex differences in ICD utilization among those who received counseling.²⁷ The benefit of an ICD to prevent sudden death in women remains controversial because the landmark primary ICD trials included few women. In one meta-analysis of five primary prevention ICD trials (DEFINITE, SCD-HeFT, DINAMIT, MUSTT, and MADIT-II) that included 934 women there was no survival benefit for women with an ICD (HR 1.01, 95% CI 0.76–1.33).³² In another meta-analysis that included 1,145 women, there was also no survival benefit among the women with an ICD (HR 0.78, 95% CI 0.57–1.05, p= 0.1). Women were also less likely to receive appropriate ICD therapies compared to men (HR 0.63, 95% CI 0.49–0.82, p=0.001).³³ In the EU-CERT-ICD project that included 957 women from 11 European countries, women with an ICD for primary prevention had fewer appropriate ICD shocks when compared to men (8% women vs 14% men) yet better survival even after adjusting for confounders such as age, biventricular pacemaker, and ischemic cardiomyopathy (adjusted HR 0.65, 95% CI 0.53–0.79; p<0.0001).³⁴ The sex differences in the benefit of ICDs for primary prevention may be attributed to sex differences in mode of death with one study showing a 32% lower risk of sudden death in women than men and no sex difference in pump failure.³⁵

The risk of complications with an ICD remains low but two large registries have reported a higher likelihood of women having adverse events. In the National Cardiovascular Data Registry that included Medicare patients with an ICD for primary prevention, women were more likely than men to have 30- and 90-day adverse events such as bleeding and mechanical complications (aOR:1.39, 95% CI 1.26–1.53; p <0.001) as well as hospital readmissions within 6 months (aOR: 1.32, 95% CI 1.23–1.42, p <0.001).³⁶ In the Ontario ICD Database with 1,106 women implanted with an ICD for primary and secondary prevention, women compared to men had a higher likelihood of major complications within 45 days including the risk of lead dislodgement (odds ratio, 1.78 [CI, 1.24 to 2.58]; p = 0.002).³⁷ The cause of sex differences in adverse events may be due to differences in vascular access with smaller vessels and body size in women compared to men.

Cardiac Resynchronization Therapy (CRT)

Similar underutilization in women compared to men has been seen with CRT despite greater benefit. CRT is recommended for symptomatic HF patients (NYHA II-IV) with LVEF ≤35%, sinus rhythm, and LBBB with QRS ≥150 ms (Class I indication) and may be helpful in those with LBBB with QRS 120–149ms, non-LBBB with QRS ≥ 150 ms, or those with significant pacemaker dependency regardless of underlying rhythm (Class IIa).² Eligible women with HFrEF are less likely than men to receive CRT and this sex disparity in utilization has increased over time in the U.S.^38–41 However, women are more likely than men to benefit from CRT with improved quality of life, ventricular remodeling, HF hospitalizations, and mortality. In the Management of Atrial Fibrillation Suppression in AF-HF Comorbidity Therapy (MASCOT) study that included 82 women with LVEF ≤ 35% and QRS ≥ 130 ms, women compared to men with CRT had more improvement in quality of life, greater reduction in left ventricular end-diastolic dimension (−8.27 +/− −11.14% vs −1.14 +/− 22.05%, p=0.02), and fewer HF hospitalizations (p = 0.045).⁴² In another study including 105 women, women compared to men had greater reduction in LV end-systolic dimension (0.85 +/−1.2 cm vs 0.34 +/− 0.91 cm, p<0.01) and greater increase in LVEF (12+/− 13% vs 0.89+/−9%).⁴³ A meta-analysis of three CRT studies (REVERSE, MADIT-CRT, RAFT) also demonstrated sex differences in the benefits of CRT with a narrower QRS. In this meta-analysis with HFrEF, LBBB, and QRS 130–149 ms, only women had reduced HF and mortality (HR 0.24, 95% CI 0.11–0.53, P < 0.001) and reduced mortality alone with CRT (HR 0.24, 95% CI, 0.06–0.89, P = 0.03).⁴⁴

Baroreflex Activation Therapy

Baroreflex activation therapy (BAT) with an electrode attached to the bifurcation of the carotid artery reduces sympathetic activity and increases parasympathetic activity resulting in reduction in blood pressure and improved venous and arterial compliance.^45,46 This therapy has been deemed safe and effective in HFrEF patients based on a multicenter study that showed improvements in quality of life and reduced HF hospitalizations with BAT, especially for patients without CRT therapy.⁴⁷ In the BeAT-HF (Baroreflex Activation Therapy for Heart Failure) that included 53 women randomized to BAT vs guideline directed medical therapy (GDMT) followed for 6 months, BAT was deemed safe and effective with women benefiting based on improvement in quality of life, improvement in 6 minute walk test (44 +/− 45 m BAT vs −32 +/− 118 m GDMT, p<0.01), improvement in NYHA functional class (70% BAT vs 27% GDMT, p <0.01) and NT-proBNP levels (−43% BAT vs 7% GDMT; p<0.01).⁴⁶ Sex differences in mortality or HF hospitalization have not been fully evaluated and will need a larger female cohort.

Transcatheter Mitral Valve Repair

There are similarly limited sex specific data on response to transcatheter edge-to-edge mitral valve repair (TMVr) for patients with functional mitral regurgitation. Among 614 patients in the COAPT trial, 221 (36.0%) were women. Women were more likely to have NYHA Class III or IV symptoms than men with lower baseline KCCQ scores and 6-min walk distances despite being younger with fewer comorbidities.⁴⁸ Although treatment with TMVr reduced HF hospitalization compared to treatment with GDMT alone, the effect was less in women than in men (P interaction = 0.002).⁴⁸ Even after adjusting for clinically relevant covariates, a significant interaction persisted between sex and treatment modality for outcome of HF hospitalization at 2 years (adjusted P interaction = 0.009).⁴⁸ In contrast to these findings a similar analysis from the real-world European Registry of Transcatheter Repair for Secondary Mitral Regurgitation found equal effectiveness in both sexes with similar all-cause mortality and durability of MR reduction.⁴⁹

Advanced Heart Failure

Advanced HF refers to patients with severe HF despite optimal medical guideline therapy and compliance with diet and fluid restrictions. Therapeutic options are limited to mechanical circulatory support (MCS) and heart transplantation with known sex differences in utilization and outcomes. A recent hospital study to assess disparities in temporary mechanical support for cardiogenic shock due to heart failure using the National Inpatient Sample (N=57,742, 40% women) was notable for women less likely to receive these devices than men (aOR 0.72, p<0.0167). Women with cardiogenic shock due to HF also had a higher mortality than men (aOR 1.17, p< 0.05) even after adjusting for race, insurance, income, age, comorbidities, hospital characteristics and type of temporary MCS.⁵⁰ Among patients waiting for heart transplantation in the U.S., fewer women than men were supported with durable continuous flow left ventricular assist devices (LVAD) and were less likely to undergo transplantation. Waitlist mortality was also higher among women compared to men with LVAD even after adjusting for device type (HR 1.51; p<0.001).⁵¹ Sex differences in adverse events with durable LVADs have recently been demonstrated with a contemporary international database that included 2,066 women with continuous flow-LVADs. In this analysis, women had a higher risk of mortality during the first 4 months after LVAD implantation compared to men (aHR 1.74; p <0.0001) with the cause of death mainly due to neurologic complications (aHR 2.62, 95% CI 1.80–3.81;p= 0.006).⁵²

Heart Failure with Preserved Ejection Fraction

Epidemiology

There are more women than men with HF and preserved ejection fraction (HFpEF). In the EPidemiologia da Insuficiência Cardiaca e Aprendizagem —Epidemiology of Heart Failure and Learning (EPICA) study in Portugal,⁵³ the prevalence of HFpEF was higher in women (2.42%; 95% CI 1.86–2.98%) compared to men (0.88%; 95% CI, 0.57–1.20%) at any given age. As for incidence of HFpEF, the age- and sex-adjusted incidence of HF in Olmsted County, Minnesota from 2000 to 2010 declined from 3.2 to 2.2 cases per 1000 person years, corresponding to a 37.5% decline over the decade-long study period. The reduction was more pronounced in women (43%) than in men (29%), and smaller for HFpEF (LVEF EF ≥50%; 28% reduction in incidence) than for HFrEF (45% reduction in incidence).⁴ Overall, HFpEF constituted an increasing proportion of both prevalent and incident HF cases over time.^4,54–56

Risk Factors and Comorbidities

While population-based longitudinal studies have established the well-known clinical risk factors for incident HF, few have taken into account different HF types and sex differences in comorbidities. In the Framingham Heart Study (FHS),⁵⁷ risk factors specific to HFpEF included higher body mass index, smoking, and a history of atrial fibrillation. Older age was also associated with a higher risk of HFpEF than HFrEF.⁵⁷ In a larger analysis pooling individual level data from FHS, Prevention of Renal and Vascular End-stage Disease (PREVEND) and Cardiovascular Health Study (CHS),⁵⁸ independent predictors of incident HFpEF included older age, higher systolic blood pressure, increased body mass index, antihypertensive treatment, and previous myocardial infarction. Older age was more strongly associated with HFpEF than HFrEF. Female sex was not a predictor of HFpEF suggesting that the predominance of women is strongly related to aging.

One important risk factor with sex differential associations with HFpEF is obesity. In a sex-pooled analysis of FHS, CHS, PREVEND and MESA,⁵⁹ each one standard deviation increase in body mass index (BMI) was associated with 34% increase in incident HFpEF (vs 18% for HFrEF). Sex stratified analyses revealed that the differential association between BMI and HFpEF versus HFrEF was more apparent in women than men. Similarly, waist circumference was associated with HFpEF but not HFrEF in women and with both HF subtypes in men. This is consistent with findings from the Women’s Health Initiative showing that the population attributable risk of obesity was larger for HFpEF compared to HFrEF in this population of exclusively women.⁶⁰ An inflammatory-metabolic hypothesis has been proposed, wherein an expanded epicardial adipose tissue mass, microvascular endothelial dysfunction, and (possibly) altered activity of adipocyte-associated inflammatory mediators, may predispose women to greater risk of HFpEF in the presence of systemic inflammatory conditions such as obesity, diabetes and the metabolic syndrome.⁶¹

Atrial fibrillation (AF) is another comorbidity that often exists in conjunction with heart failure and is associated with higher morbidity and mortality in women compared with men. Women with AF and HF have a significantly higher risk of mortality compared to men with both conditions. Additionally, women with new-onset AF without HF had a 9-fold risk of developing HF.⁶² Women also remain less likely to receive anticoagulation with DOACs for AF than men at all levels of CHADS-VASc score.⁶³ Additionally, women are less likely to be treated with rhythm control and ablation which may explain the higher symptom burden reported in women. Sex specific data regarding left atrial appendage closure is limited with the Watchman trial only included 30% women. Nonetheless, population analyses have showed that women compared to men had higher rates of in-hospital adverse outcomes, including bleeding, vascular, cardiac complications, post-procedure stroke and acute kidney injury after left atrial appendage closure.⁶⁴

Differences in cardiac aging and changes in LV remodeling

Sex differences in cardiac aging underscore the relative protection against the development of HFrEF in women as compared with men. Coupled with the lower incidence of obstructive coronary artery disease, women exhibit lower rates of myocardial apoptosis and necrosis in response to myocardial infarction (MI), and lower rates of adverse cardiac remodeling in response to MI and aging.^65,66

Conversely, cardiac aging in women serves as fertile ground for the development of HFpEF. Women have higher systolic and diastolic elastance which increases to a greater extent with aging than men. This is alongside greater arterial elastance, higher pulse pressure, smaller arterial caliber, and earlier wave reflection than men.⁶⁷ Furthermore, women exhibit greater concentric remodeling and heightened load-induced impairment of left ventricular relaxation.^68,69 Dysfunction of the coronary microvasculature also plays a central role in HFpEF pathophysiology,⁷⁰ and is seen to a greater extent in cardiac aging in women than men.⁷¹

Intrinsic differences in remodeling and reactivity of the pulmonary vasculature may also affect HFpEF development and severity. Women have higher rates of pulmonary arterial hypertension,⁷² and women are overrepresented amongst HFpEF patients with combined precapillary-postcapillary pulmonary hypertension,⁷³ suggestive of underling sex differences in the pulmonary circulation.

The role of sex hormones in cardiac ageing may also contribute to the development of HFpEF; whilst estrogen has an overwhelmingly protective effect on the cardiovascular system, the sudden loss of these effects with menopause could potentially contribute to HFpEF development.⁷⁴ Loss of ovarian estrogens has been linked to activation of the renin-angiotensin-aldosterone system.⁷⁵ Estrogen both induces the production of nitric oxide via non-nuclear estrogen receptor alpha signaling, and prolongs the half-life of cyclic guanosine monophosphate. Both pathways are central to HFpEF pathophysiology with effects on coronary vasodilation, and inhibition of inflammation and cardiomyocyte proliferation.⁷⁶ Accordingly, mouse models of pressure overload have demonstrated that estrogen protects against the development of cardiac hypertrophy, and response to phosphodiesterase 5 (PDE5) inhibition is dependent on estrogen receptor signaling, supporting a role for estrogen in the development of HFpEF in postmenopausal women and dictating response to PDE5 inhibition. Loss of estrogen with menopause may also contribute to the development of coronary microvascular dysfunction due its pro-angiogenic properties, with implications for HFpEF development given the strong association between HFpEF and microvascular dysfunction.⁷⁷ Additionally, women have a higher age-adjusted incidence of LV diastolic dysfunction than men. Parameters of diastolic dysfunction in postmenopausal women are attenuated by the use of hormone replacement therapy, highlighting the important role of estrogen in maintaining normal diastolic function.⁷⁴

Sex Differences in Aortic Stenosis

Similar sex differences in LV remodeling are seen in the context of aortic stenosis. Studies using cardiac magnetic resonance show greater concentric remodeling in men resulting in greater LV volumes and LV mass. Comparatively, women have less concentric remodeling with lower LV volumes. As a result, women likely develop higher wall stress and filling pressures which leads to more advanced symptoms.⁷⁸ Even when adjusted for body area, women have less aortic valve calcification with no difference in aortic valve areas. Perhaps due to lower levels of myocardial fibrosis, studies have also shown greater LV mass regression after TAVR in women compared to men.⁷⁸

Sex Differences in Exercise Hemodynamics

Several studies have investigated sex differences in the hemodynamic response of HFpEF patients to exercise. Two have identified attenuated cardiac output reserve with exercise, along with greater rises in pulmonary capillary wedge pressure indexed to cardiac output and workload in women compared to men.^79,80 Poorer pulmonary and systemic arterial compliance were also seen⁷⁹ which may reflect greater ventricular-vascular stiffening in women.⁶⁷ Both poorer diastolic reserve and adverse pulmonary vascular remodeling have been associated with HFpEF symptom severity^81,82 and may contribute to the poorer quality of life observed amongst women compared to men.⁸³

Conversely, males with HFpEF have higher mortality⁸⁴ which may parallel right ventricular (RV) dysfunction.⁸⁵ An invasive cardiopulmonary exercise testing study of patients with HFpEF identified adverse RV-pulmonary arterial (RV-PA) coupling in men as compared to women at peak exercise.⁸⁶ This RV-PA uncoupling was attributable to greater increases in RV afterload in conjunction with poorer contractile reserve and was associated with poorer peak exercise aerobic capacity. This mirrors findings of poorer resting RV systolic function in males,⁸⁷ which appears to be independent of the degree of RV afterload.⁸⁸ These studies highlight differing hemodynamic phenotypes between the sexes and may point to differences in underlying mechanisms of HFpEF (Figure 3).

Figure 3.

Sex Differences in the Pathophysiology and Treatment of Heart Failure with Preserved Ejection Fraction

Sex differences also exist in the epidemiology of heart failure with preserved ejection fraction. Differences in vascular aging, concomitant comorbidities, and therapeutic response have all been demonstrated in the literature.

ARNI =angiotensin receptor neprilysin inhibitor; HFpEF = heart failure with preserved ejection fraction; RV = right ventricle; PCWP = pulmonary capillary wedge pressure

Sex Interactions in Medical Therapy

While trials of pharmacologic treatment for HFpEF have been largely neutral, there are notable sex differences.⁸⁹ An exploratory, post hoc, non-pre-specified analysis of the Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function (TOPCAT) trial evaluated sex differences in outcomes and responses to spironolactone in patients with HFpEF.⁹⁰ Of the 1,757 participants, 882 (49.9%) were women and were older with fewer comorbidities compared to the male participants. There were no sex differences in the primary outcome of a composite of cardiovascular mortality, aborted cardiac arrest, or HF hospitalization. However, there was a significant reduction in all-cause mortality associated with spironolactone in women (HR: 0.66, 95% CI: 0.48–0.90, p = 0.01) but not in men with a significant sex-treatment interaction (P_interaction = 0.024).⁹⁰

As we have seen in trials of neurohormonal blockade in women with HFrEF, there was also a sex treatment interaction observed with angiotensin-neprilysin inhibitors (ARNIs). In PARAGON-HF, ARNIs showed a reduction in the primary outcome in women but not in men, independent of baseline differences.⁹¹ The effect was mainly driven by reduction in HF hospitalization rather than mortality and was significant in women with an ejection fraction (EF) of 45–60%. This may indicate that the women who responded had a mildly reduced, rather than preserved, EF given women’s higher EFs than men.⁹² Alternative explanations include a relative natriuretic peptide deficit in women, translating to a greater benefit from ARNIs⁹¹ or more transthyretin amyloidosis among men with HFpEF associated with poorer response to neurohormonal blockade.⁹³

SGLT2 inhibitors are a new therapy for both men and women with HFpEF. The Empaglifozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) evaluated the effects of SGLT2i with empaglifozin on major HF outcomes in HFpEF patients. Among 5,988 patients with HFpEF (LVEF >40%) and New York Heart Association functional class II-IV followed for a median of 26.2 months, empaglifozin 10 mg per day reduced the combined risk of cardiovascular death or hospitalization (HR: 0.79, 95% CI 0.69–0.90, p<0.001). In a pre-specified sub-group analysis, 162 of 1,338 women receiving empagliflozin experienced a composite of cardiovascular death or hospitalization for heart failure compared to 214 of 1,338 women in the placebo group (HR 0.75, 95% CI 0.61–0.92). This landmark trial demonstrates a new therapeutic option for women with HFpEF.⁹⁴

Remote Hemodynamic Monitoring Systems

Therapy guided by remote monitoring of pulmonary artery (PA) pressures using the CardioMEMS PA pressure sensor has been demonstrated to reduce hospitalization rates in HF patients but many clinical subgroups including women were underrepresented in the CHAMPION trial.^95,96 The CardioMEMS Post-Approval Study, a multi-center, prospective, open-label, single-arm trial evaluating the use of CardioMEMS pressure-guided therapy in routine clinical practice subsequently enrolled 452 women of 1,200 adults (38% of total).⁹⁷ Both men and women demonstrated similar reductions in pulmonary artery pressures, significant decreases in HF hospitalizations over 12 months compared with the year before the study (interaction p = 0.13), and improved quality of life.⁹⁷ In the more recent GUIDE-HF, there were 37.5% women. The primary outcome was a composite of all-cause mortality, HF hospitalizations, and urgent HF visits. The hazard ratio for women was 0.65 (95% CI 0.47–0.87) compared to 1.05 (95% CI 0.84–1.31) in men with interaction p-value of 0.01.⁹⁸

Specific Cardiomyopathies

There are many cardiomyopathies worthy of separate discussion because they are unique to women (peripartum cardiomyopathy), reversible (takosubo cardiomyopathy) or cross the spectrum of HFpEF and HFrEF (hypertrophic cardiomyopathy and amyloidosis). Data in some of these cardiomyopathies is ample (peripartum cardiomyopathy) while others is sparse (sarcoidosis). Below is a summary of the literature with a focus on sex differences.

Peripartum Cardiomyopathy

Peripartum cardiomyopathy (PPCM) is a pregnancy-associated, idiopathic cardiomyopathy presenting with HF due to left ventricular systolic dysfunction, typically early after delivery but also during pregnancy or up to a few months after the delivery.^99,100 PPCM is the leading cause of HF in pregnancy and the post-partum period and an important cause of non-obstetrical maternal mortality.¹⁰¹ The incidence of PPCM varies widely, between approximately 1:100 live births in Nigeria and 1:20,000 in Japan. In the U.S., the incidence is approximately 1:3,000 live births and is increasing due to advancing maternal age, increased rate of multifetal pregnancies, and an increased recognition of the disease.⁹⁹

There is a strong association between PPCM and older maternal age, pregnancy-associated hypertension, preeclampsia, multifetal pregnancies, African American race, and possibly diabetes mellitus and anemia. Familial clustering has been reported and recent studies have shown that some women with PPCM share a genetic profile with familial non-ischemic dilated cardiomyopathy (NICM).¹⁰²

The diagnosis of PPCM is often missed or delayed because many of the signs and symptoms of normal pregnancy can mimic those of HF, resulting in preventable complications¹⁰³ such as severe HF, cardiogenic shock, thromboembolic complications, arrythmias and death.⁹⁹ The incidence of intra-cardiac thrombi is higher compared to other forms of NICM, emphasizing the importance of cardiac imaging. The rate of recovery of cardiac function is variable. In the U.S., it is higher than 50% and recovery mostly occurs within 2 to 6 months after diagnosis although later recovery is possible.¹⁰⁴ Recovery of myocardial function greatly depends on the degree of the initial myocardial insult reflected by low LVEF (<30%), enlarged LV diastolic dimension (>6.0 cm), RV dysfunction, high levels of natriuretic peptides, and troponin elevation.^99,104,105 In addition, late diagnosis and African American ethnicity adversely affect recovery. The rate of LV recovery is significantly lower and the timing longer in African American patients compared with non- African American women.¹⁰⁶ Reports of rate of recovery in other countries are variable with high recovery rates in Germany Japan, China, Pakistan and low recovery rates in Africa, Turkey, and Haiti.⁹⁹

Goals of therapy are symptomatic improvement, recovery of cardiac function, prevention of thromboembolic complications and sudden death (Figure 4).⁹⁹ Management of PPCM is similar to other forms of NICM and includes early use of guideline-directed medical therapy, considering fetal safety during pregnancy and lactation.⁹⁹ The prolactin inhibitor, bromocriptine, has been shown in animal studies to prevent the development of a pregnancy associated cardiomyopathy. In a small clinical trial in African women bromocriptine improved the rate of recovery and outcome of patients with PPCM and has received a IIb recommendation for use in women with PPCM by the European society of cardiology guidelines.¹⁰⁷ No information is available about the safety and efficacy of the drug in North America. A National Institute of Health supported randomized, double-blind study for the evaluation of the effect of bromocriptine in women with PPCM (The REBIRTH study) is about to start soon in the U.S. and Canada. Because of the increased incidence of thromboembolic complications, the use of prophylactic anticoagulation may be useful in women with PPCM receiving bromocriptine.¹⁰⁸ Similarly, anticoagulation is recommended during pregnancy and for 6 weeks postpartum for women with severe left ventricular dysfunction (LVEF <35%). Data are lacking regarding stopping HF medications after normalization of LV function in this population. It may be possible to extrapolate from the TRED-HF trial, which included patients with dilated cardiomyopathy who had recovered LVEF from <40% to 50% or greater. Within 6 months of withdrawal of medications, 44% relapsed.¹⁰⁹ Therefore, in patients with PPCM, discontinuation of medications should only be done gradually with close monitoring of LV function followed by annual assessment of LV function for early detection of recurrent cardiomyopathy.⁹⁹

Figure 4.

Approach to Peripartum Cardiomyopathy

Peripartum cardiomyopathy is the leading cause of HF in pregnancy. Risk factors, presentation, treatment, prognosis, and the role of transplantation are depicted here. GDMT = guideline-directed medical therapy; LV = left ventricular; LVEF = left ventricular ejection fraction; MCS = mechanical circulatory support; PPCM = peripartum cardiomyopathy

Mortality is caused by sudden death in 30% of cases and most deaths occur within the first 6 months after diagnosis and in women with LVEF < 30%. Criteria for ICD and CRT-D are similar to other causes of HF, but given the high risk of sudden cardiac death, may warrant usage of wearable external defibrillators in patients with severe LV dysfunction as a bridge to recovery or permanent ICD.¹¹⁰ In women with persistent LV dysfunction, ICD placement is recommended.

MCS devices and heart transplantation have been used successfully in patients with cardiogenic shock not responding to medical therapy including vasoactive medications.^111,112 Because the rate of recovery in patients with PPCM is higher than in those with other forms of NICM, temporary devices should be considered as a bridge to recovery before referral for cardiac transplantation. Review of the UNOS registry of patients receiving heart transplantation between 1987 and 2019 identified 666 with PPCM. These patients were younger and 48% were African American. They had fewer days on the wait list and demonstrated a greater incidence of pre-transplant panel reactive antibodies. The overall post-transplant survival was slightly lower in the PPCM group than other etiologies.¹¹³

Subsequent pregnancy in women with a history of PPCM can lead to deterioration of LV function and symptoms.¹¹⁴ The risk of relapse is higher in women with persistent LV dysfunction compared to those with recovered function and can be associated with significant decline in LVEF, clinical deterioration and death. Approximately 20% of women with recovered systolic function also have a decline in LVEF with the subsequent pregnancy. The change is usually mild but persists in about half of the patients. Isolated cases of severe deterioration of LV function and life-threatening arrythmias have been described; fortunately there have been no reported deaths.¹¹⁴

Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a genetic cardiomyopathy with a prevalence that is estimated between 1:500 and 1:200.¹¹⁵ Various cohort studies have suggested a slight male predominance (55–65%) both globally and in the U.S.^116–118

One cohort study investigating sex differences among 969 patients with HCM in Italy and the U.S. found that women compared to men were older at diagnosis and initial evaluation.¹¹⁶ In this cohort, men were more likely to be diagnosed in the setting of routine medical examinations while women were more likely to be diagnosed after clinical manifestations.¹¹⁶ Women also were more likely than men to have exertional dyspnea, chest pain and syncope with higher outflow gradients and more likely to functionally decline or experience death from HF or stroke.¹¹⁶ There were no sex differences in the rate of ICD implantation, myectomy or alcohol septal ablation. There were similar findings in a Mayo Clinic study including 3,673 patients with HCM (45% women). In this study women compared to men underwent more frequent alcohol septal ablation with similar frequency of myectomy yet had significantly higher mortality at 5- and 10-years even when adjusted for age, NYHA Class III-IV symptoms, and comorbidities (aHR 1.13[1.03–1.22], p = 0.01).¹¹⁸ Given the sex differences in mortality in both cohorts despite similar therapy, there remain concerns that sex differences in outcome are due to sex differences in disease phenotype or progression at time of diagnosis and therapy (Figure 5).

Figure 5.

Sex Differences in Other Cardiomyopathies

Although overall less data are available in women, infiltrative and restrictive cardiomyopathies as well as stress cardiomyopathy have unique sex differences. In cardiac amyloidosis, it is unclear to what extent the male predominance of the disease is due to ascertainment bias and the potential role for sex-specific diagnostic criteria. Similarly, women with HCM are typically more symptomatic at first evaluation which may be due to the use of similar wall thickness cutoffs for both sexes.

The diagnostic criterion of LV wall thickness of at least 15 mm for HCM does not account for body surface area which may be why disease severity is underestimated in women.^115,119 Among patients referred for myectomy with MYH7 or MYBPC3 mutations, women were, on average, 7 years older than men with more advanced diastolic dysfunction.¹¹⁹ On a cellular level, women also had a greater amount of fibrosis compared with male patients.

Takotsubo Cardiomyopathy

Stress cardiomyopathy, also referred to as Takotsubo cardiomyopathy, refers to a transient and usually reversible form of cardiomyopathy typically instigated by a physical or emotional stress. Studies suggest a strong female predominance (female to male ratio of 9:1).¹²⁰ Diagnostic criteria include the Mayo Clinic Criteria as well as the International Expert Consensus Document on Takotsubo Syndrome, both of which include female sex as a risk factor.^121,122 Additionally, the majority of cases occur in postmenopausal women with mean age of 67 years old. Hypotheses include estrogen deficiency and a heightened autonomic nervous system leading to increased sympathetic stimulation.¹²³ In one case-control study of women with self-reported reproductive histories, a history of irregular menses, number of pregnancies, and use of post-menopausal hormone replacement therapy were associated with the development of Takotsubo cardiomyopathy.¹²⁴

Other studies have noted sex differences in risk factors and outcome. In Japanese studies, emotional stress was a more common trigger for women while prior physical stress was more common in men. Men were younger than women and were more likely to have severe pump failure or require mechanical circulatory support. In multivariable analysis, male sex was an independent predictor of adverse cardiac events including cardiovascular death, severe pump failure and ventricular arrhythmias (adjusted OR: 4.32 (1.41–13.6), p = 0.011).¹²⁵ Similar sex differences in outcomes have also been shown in other cohorts.¹²⁶

Cardiac Amyloidosis

Light-chain amyloidosis (AL) and Transthyretin amyloid cardiomyopathy (ATTR-CM) represent the two most common types of cardiac amyloidosis, an infiltrative myocardial disease caused by the deposition of misfolded amyloid fibrils within the heart muscle.^127–129 Light-chain amyloidosis arises from secretion and overproduction of immunoglobin light chains. Cardiac involvement has been observed in 50–75% of AL amyloid cases.^130,131 There is a slight male predominance of AL cardiac amyloidosis, and the disease generally presents from the fifth to seventh decade.¹³⁰ There is sparse data regarding the treatment responsiveness and prognosis of AL amyloid in women versus men. There is also limited data on the sex differences in cardiac transplantation for cardiac amyloidosis, however, single-center studies suggest similar post-transplantation outcomes in ATTR, AL, and non-amyloid cardiomyopathy.¹³²

ATTR-CM has shifted from a rare disease entity to an increasingly recognized cardiomyopathy with sex differences in the presentation, natural history, and, more recently, enrollment in clinical studies.^{129,132–134} Sex differences in ATTR-CM are most marked within wild-type ATTR-CM (ATTRwt) with 80–90% of patients men.^135–137 In an autopsy study of patients with an ante-mortem diagnosis of HFpEF without known amyloidosis, 17% had ATTRwt deposition with 5% having at least moderate deposition to suggest causative etiology.^135,138 Males had nearly a 3 times higher risk of having amyloid deposition post-mortem. However, in a prospective screening study of patients over 60 years of age admitted with HFpEF and left ventricular wall thickness (LVWT) >12 mm, there was an equal proportion of women and men identified as having ATTR-CM by scintigraphy, suggesting ascertainment bias in longitudinal cohorts reporting sex differences.¹³⁹ Furthermore, in a prospective endomyocardial biopsy study of 108 patients with HFpEF (61% women) 40% of the ATTR-CM patients were women.¹³⁶

There is some evidence for increased male prevalence among familial ATTR-CM (ATTRv) amyloidosis with selected mutations associated with ATTR-CM including Leu111Met, Ileu68Leu, Thr60Ala, and Val122Ile where only 30% of cases were observed in women.¹⁴⁰ A recent analysis from the Transthyretin Amyloidosis Outcomes Survey (THAOS) registry posited that given the higher prevalence of ATTRv in men compared to women with cardiac phenotypes and transthyretin mutations, female sex could be protective against the degree of myocardial involvement in ATTRv amyloidosis. Notably, women presented with higher LVEF, lower interventricular septal thickness, posterior wall thickness, and were less likely to have an abnormal electrocardiogram. They note that the proportion of men with ATTRv increased progressively with severity of disease based on quartiles utilizing natriuretic peptide levels (NT-proBNP), LVEF, mean left-ventricular wall thickness divided by height, and LV mass index divided by height.¹⁴¹ The THAOS study authors acknowledged that using LV wall thickness > 12 mm to define ATTRv cardiomyopathy may partially account for the lower proportion of women (27.8%) in the THAOS registry, given women may require a longer deposition period to reach this pre-specified wall thickness measurement. LV wall thickness is typically not indexed to height for registry and trial purposes and therefore does not account for baseline sex differences in this parameter. However, the investigators reasonably contend this measurement bias does not fully explain increasing prevalence of males in higher risk cardiac phenotypes.

Other genetic studies have raised similar concerns regarding sex differences. A study of patients with ATTR V30M found that women with type A fibrils had significantly lower median septal and posterior wall thicknesses and lower median LV mass compared to men, suggesting lower rates of cardiac infiltration.¹⁴² In another study involving Val122Ile patients , there were no sex differences in HF severity markers including NYHA class, cardiac troponin, and mortality despite women being older than men (76 vs. 69 years of age)¹⁴³ , also suggesting slower disease progression in women compared to men. However, there may have been referral bias given that the proportion of women diagnosed with Val122Ile cardiac amyloid increased from 22% early in the longitudinal study (2007–2012) to 50% from 2013–2018.¹⁴³

While sex-specific screening guidelines may have biologic justification and have already been proposed by amyloidosis experts,¹²⁸ ascertainment biases and ATTR-CM definitions that do not account for known sex differences may alter our perception regarding ATTR-CM. Based on the existing data, it remains unknown whether ATTR-CM occurs predominantly in men or whether we have failed to ascertain the true prevalence of the disease.

Cardiac Sarcoidosis (CS)

Cardiac sarcoid has had an evolving definition that typically involves either histologic diagnosis on endomyocardial biopsy or a combination of clinical cardiac manifestations in the presence of biopsy-confirmed extra-cardiac sarcoid.^144,145 Sarcoidosis tends to be more common in African-Americans, particularly women, and tends to effect residents of northern latitudes more commonly.^144,146,147 The prevalence of CS has increased partly because of new imaging modalities for diagnosis and better disease understanding and recognition of CS over time.^144,148,149 Prospective screening of patients with unexplained conduction abnormalities with fluorodeoxyglucose-positron emission tomography (FDG-PET) found that 34% of patients with atrioventricular block (AVB) had CS. Though this study had relatively small number of CS patients (n=11) there was no significant difference in the sex of those with CS vs. idiopathic AVB.¹⁵⁰

In the longitudinal Myocardial Inflammatory Diseases in Finland (MIDFIN) study CS prevalence has risen more than 20-fold from 1988–2012.¹⁴⁹ Of 110 patients with CS in this cohort, 71 had isolated CS, while 39 patients had CS with extra-cardiac disease. Those with isolated CS were more often women and had a higher frequency of LV dysfunction and septal wall motion abnormalities. Despite sex differences in the constellation of organ involvement in patients with CS, sex was not an independent predictor of outcomes in the Finnish cohort.¹⁴⁹

The incidence of supraventricular tachycardia was comparable between men and women in a cohort in patients with CS and known cardiac involvement¹⁵¹, however U.S. national survey data showed that women, who constituted the significant majority of patients with documented sarcoidosis (n=200,241, 67% women), had lower rates of ICD, CRT-D and endomyocardial biopsy compared to males.¹⁵² Interestingly, women had higher rates of atrial arrhythmia, lower rates of ventricular arrhythmia, and had significantly higher in-hospital mortality compared to men (64% vs. 36%, p<.0001).¹⁵²

Patients with CS have worse prognosis (i.e. sudden death and heart failure death) compared to sarcoid patients without cardiac involvement. In patients with clinical CS, LV dysfunction is the strongest predictor of survival.¹⁵³ Although sex differences in outcome for CS remain limited, the underutilization of devices (ICD, CRT-D) in CS women compared to men may contribute to poor cardiac outcomes.¹⁵² Cardiac transplantation for CS in the U.S. increased from 0.1% in the mid 1990’s to 0.5% in the mid 2000’s.¹⁵⁴ There is limited data on comparative outcomes between women and men post-transplantation with most transplant centers using more immunotherapy for CS patients compared to other transplant patients to prevent reoccurrence of disease. Potential toxicities during pregnancy and lactation should be considered, especially with steroid sparing therapeutic regimens.^155,156

Conclusions

Women and men have different phenotypes of HF with unique risk factors, epidemiology, prognosis, and response to interventions. Women continue to be undertreated with guideline-directed medical therapy and device therapy. Exploratory analyses suggest that sex specific criteria may be helpful given the benefit of biventricular pacing at lower QRS in women compared to men. Additionally, existing data in the areas of hypertrophic cardiomyopathy and cardiac amyloidosis may suggest benefit of sex differential diagnostic criteria, to avoid first identifying women at a later and more advanced stage of disease. Despite the data that currently exist, there remain gaps in knowledge regarding factors driving the underuse of medical and device therapies in clinical practice and how we can mitigate these disparities. Additionally, we need increased representation of women in heart failure clinical trials. Potential strategies to achieve this goal include minimizing the burden of study visits via telehealth given sex differences in responses to in-person clinical trials and increasing female representation in clinical trials by including more women leaders.¹⁵⁷ Furthermore, national and international guidelines should account for differential responses to treatment and outcomes by sex.

Table 2.

Sex Differences in Risk of Mortality and/or Hospitalization in Heart Failure with Preserved Ejection Fraction

Study	Endpoint	Risk (95% CI)
		Women	Men
ARNI
PARAGON-HF91	CV Mortality or HF Hospitalization	RR 0.73 (0.59–0.90)	RR 1.03 (0.85–1.25)
Aldosterone blockers
TOPCAT90	CV Mortality or HF hospitalization	aHR 0.81 (0.63–1.05)	aHR 0.85(0.67–1.08)
SGLT2 inhibitors
EMPEROR-Preserved94	CV Mortality or HF hospitalization	HR 0.75 (0.61–0.92)	HR 0.81 (0.69–0.96)

Abbreviations

ACEI

angiotensin converting enzyme inhibitors

AL

light chain amyloidosis

ARB

angiotensin receptor blockers

ARNI

angiotensin receptor neprilysin inhibitor

ATTR-CM

Transthyretin amyloid cardiomyopathy

ATTRv

familial ATTR-CM

BAT

baroreflex activation therapy

CRT

Cardiac Resynchronization Therapy

CS

cardiac sarcoidosis

LVEF

left ventricular ejection fraction

HF

heart failure

HFpEF

heart failure with preserved ejection fraction

HFrEF

heart failure with reduced ejection fraction

ICD

implantable cardioverter defibrillator

LVAD

left ventricular assist device

MCS

mechanical circulatory support

NT-proBNP

N-terminal pro-brain natriuretic peptide

NYHA

New York Heart Association

PA

pulmonary artery

PPCM

peripartum cardiomyopathy

RV

right ventricle

SGLT2i

Sodium glucose cotransporter 2 inhibitors