Heart failure (HF) mortality is greater among women than men at all ages in US (1). In 2018, HF was the implicated cause of 83,616 deaths (38,487 males and 45,129 females) (1). Approximately 300,000 HF patients in the US currently have advanced HF (AHF), and an additional 5% will progress to advanced disease each year (2). Estimates of the prevalence of AHF varies from 5 to 25% between studies (2), and the exact proportion of women of reproductive age who have AHF is unknown. AHF is associated with high morbidity and mortality, and huge healthcare-related costs, especially in the last year of life (3, 4). The 1-year mortality estimated by HF survival models is >20%−25% (4). In crude analyses, the heart transplantation (HT) rate for women and men were 0.789/100,000 and 2.33/100,000 respectively each year (5). Using data from the United Network for Organ Sharing and Centers for Disease Control and Prevention the HT to HF mortality ratio was 0.263 for women and 0.424 for men, supporting reports that irrespective of disease severity, less women than men receive a HT (5).

AHF is defined as the presence of progressive and/or persistent severe signs and symptoms of HF despite optimized medical, surgical, and device therapy (3, 6). While sex-related differences in epidemiology, risk factors, pathophysiology, response to therapies and outcomes in HF have been reported (7, 8), the unique characteristic of AHF in women and the influence of sex hormones has not been extensively described. Additionally, there is minimal data on female sex-specific cardiovascular risk factors in the evidence that directs current HF practice guidelines (9). When considering HF subtypes, women have a higher prevalence of HF with preserved ejection fraction (HFpEF) than men, which is rarely an indication for HT or left ventricular assist device implantation (LVAD) implantation (10). Among those with AHF and recurrent hospital admissions, women have a similar prevalence of HFpEF and HF with reduced ejection fraction (HFrEF), while most men with recurrent hospital admissions have HFrEF (5). Age-adjusted case fatality rates from the Atherosclerosis Risk in Communities study showed that HFrEF contributes to more mortality than HFpEF in women (11).

The management of AHF in women is complicated because detection by patients, their families and providers is often delayed (3). Recognizing AHF in women requires a thorough clinical assessment and risk stratification (4). Little is known about the impact of sex on HT allocation or the potential effect of gender bias on the decision-making process for other AHF therapies (12). Data from the organ procurement and transplantation network shows less women than men on the HT waiting list or receiving a HT, and this proportion further declines with age (Table 1). Younger women (<50 years) comprised only 9.6% of the total number of patients on the waitlist and 10.17% of total number who received a HT. The purpose of this review is to discuss the role of sex hormones on the pathophysiology of AHF, describe the clinical presentation, diagnostic evaluation and definitive therapies of AHF in women with specific attention to pregnancy, lactation, contraception and menopause, while considering barriers to treatment.

The pathophysiological mechanisms underlying HF involve the activation of structural, neurohumoral, cellular, and molecular pathways in response to myocardial injury in an attempt to maintain homeostasis (13). Sex hormones including estrogen, progesterone and testosterone modify some of the pathophysiological processes that promote HF progression in women (Figure 1). Estrogen modulates the expression of proteins that regulate vascular tone and response to myocardial injury, and influences ventricular contractile function, endothelial calcium metabolism, coronary calcification, coagulation and fibrinolysis, insulin resistance, inflammation and lipid oxidation (14). Through these actions, it limits cardiac remodeling and attenuates myocardial hypertrophy (15). Progesterone affects vascular tone by modulating calcium channel activity, inhibiting vascular smooth muscle proliferation and migration, and worsening the response to vascular injury (16, 17).

Androgen excess is associated with greater risk of heart disease in women, due to its adverse effects on the vasculature, lipoprotein levels and adiposity (16, 18, 19). Low androgen levels are also associated with atherosclerosis and coronary artery disease (19). Elevated testosterone promotes cardiac remodeling by causing myocardial hypertrophy, modulating the autonomic nervous system and regulating excitation contraction coupling through its effects on intracellular calcium levels (16). Physiological levels of testosterone improves endothelial function, peripheral vascular resistance and vasomotor tone, and its effects on the cardiovascular system depends on circulating estrogen levels and the peripheral conversion of testosterone to estradiol (19).

The effects of female sex hormones on HF pathophysiology is a continuum, that persists with progression to advanced disease, such that AHF is not an end-state but a dynamic condition where numerous mechanical, molecular, immunologic, ischemic, proarrhythmic, vascular, and musculoskeletal forces contribute to symptoms and continuing deterioration (20). There is increasing inability to meet the metabolic demands of end-organs and skeletal muscle, renal and hepatic dysfunction, and reduction in exercise capacity, cachexia, and fatigue (3). Estrogen, progesterone and testosterone receptors continue to activate cellular mechanistic cascades that modulate inflammation, apoptosis, vascular abnormalities and myocardial remodeling in response to worsening pathologic conditions in AHF (16).

There is no specific event that marks the progression to AHF, instead a pattern of clinical findings may be the optimal indicator (3). AHF is characterized by recurrent hospitalizations, escalation of diuretics, intolerance or dose-reduction of guideline directed medical therapies, development of end-organ dysfunction, cardiac cachexia, and refractory arrhythmias with or without device shocks (3). Recurrent hospitalization is a strong indicator of progressive decompensation as HF approaches its late stages (4). Failure to respond to conventional therapies, another manifestation of disease progression, presents with persistent functional impairment which can be nonspecific in elderly patients (3) and women. The absence of a sex-oriented assessment of disease severity could make the identification of AHF among women a persistent challenge for clinicians (21). However, the use of gender-specific risk prediction models did not improve the accuracy of predicting mortality risk in decompensated HF (22).

Women with AHF experience higher symptom burden, poor coping strategies, and greater prevalence of depression and social isolation than their male counterparts (23). As the disease progresses, its impact on functional status and quality of life is more debilitating among women, not just from HF alone, but the greater burden of comorbidities and older age of female HF patients (21). Frailty and cachexia, common features of AHF (4, 24), are more frequently seen in women (24). Physical frailty is characterized by worse symptom characteristics in women, and worse body composition characteristics in men (25). However, current frailty assessment tools are not sex-specific, and future research is needed to identify the ideal index for frailty assessment in women, and sex differences in reversibility of frailty with HF therapies (25). Women are also admitted less frequently than men for acute decompensated HF (1) which may lead to delayed recognition of advanced disease. Consequently, the gender distribution of patients referred for AHF therapies likely does not represent the actual proportions of patients with AHF.

The initial evaluation of AHF should be focused on excluding reversible causes and ensuring adequate treatment with maximally tolerated guideline directed medical therapies (26). For women with persisting features of hemodynamic instability or systemic hypoperfusion, with or without end-organ dysfunction, the evaluation process becomes more structured to establish candidacy for advanced therapies by identifying contraindications to heart transplantation (HT) or left ventricular assist device (LVAD) implantation (27). The evaluation process is both comprehensive and center-specific (26) and eligibility determined after review by a multidisciplinary selection committee.

Cardiopulmonary exercise testing provides objective information about cardiovascular reserve and prognosis (6). In women, a peak oxygen consumption ≤ 50% of expected is a recommended parameter for consideration for advanced therapies (28), since women exhibit better survival than men for any given peak oxygen consumption value (29). Invasive hemodynamics obtained from right heart catheterization provides information that guides specific pharmacotherapy and durable therapies by enabling precise assessment of filling pressures, pulmonary hypertension, cardiac output, and right ventricular performance (26). Sex differences in hemodynamics have not been systematically explored. However, in the SHOCK registry, cardiac power index, a strong predictor of mortality was significantly lower in women (30). Consequently, physiological differences between men and women must be acknowledged when interpreting functional testing. In the REVIVAL study, the 6-min walk test distance was significantly shorter in women than men by almost 40 m despite similar age and functional class (31). Cardiac biomarkers further improve risk stratification and selection for advanced therapies. Women with decompensated HF have higher natriuretic peptide levels than men for any given LV ejection fraction (32, 33), and natriuretic peptides are stronger predictors of HF-related mortality in women (34). Natriuretic peptides are influenced by adiposity, menopause and sex hormones, such that women have lower levels after the onset of menopause (35). It is unclear if sex-specific cut-offs in biomarker levels should be adopted for AHF prognostication (33).

Gender disparities persist in the utilization of AHF therapies (36). In a multicenter retrospective analysis, 73.4% of referrals evaluating candidacy for advanced therapies were men (37). Women are allocated to less than a third of HT and LVAD in the US (38) and are under-represented in HF clinical trials (5, 7, 10).

The reproductive continuum spans contraception use, pregnancy, lactation and the menopausal transition, resulting in sex hormonal changes that affect HF development and progression (Figure 2). Irrespective of their life stage, similar considerations should be applied when evaluating women for AHF therapies.

Barriers to AHF care prevail at the individual, provider and organizational levels (77) with well recognized gender differences (78) (Figure 3). Social determinants of health, including lack of health insurance, low income, and inadequate social support, are more prevalent among women, and contribute to physician bias in decision making, which promotes worse outcomes, delayed referrals and decreased access to advanced therapies for women (2). Self-care, an integral component of HF management is greatly affected by self-efficacy and functional status in women (79). Depression also negatively impacts self-care and is present in as many as 35% of HF patients (80). Depression, social isolation and poor support systems are recognized barriers to HF self-care in women (78). A woman's caregiving responsibilities may hinder her from seeking care due to conflicting priorities (38). Actual or perceived inadequacy in social support is an important barrier to equitable allocation of advanced therapies in women (10). African American women may be appraised more harshly (10), and are often perceived as having more financial and social challenges when compared to White patients and men (38). Strategies targeting barriers to advanced therapies in women must also be implemented at the individual, provider and organizational levels (Figure 3). Organizational policies especially those guiding the implementation of an integrated AHF program can influence individual and provider factors that affect candidacy for AHF therapies.

HF progression is influenced by sex-specific risk factors which should be considered when evaluating women for advanced therapies. The management of AHF in women is highly complex and requires effective integration of conventional treatments, advanced therapies and palliative care to achieve optimal outcomes. There are persisting inequities in allocation of advanced therapies, and women are less likely to be referred for a HT or LVAD evaluation despite facing a higher risk of AHF-related mortality. Future studies should address areas of equipoise in the management of AHF among women (Table 2). Women should be given equal opportunities as men for inclusion in clinical trials on AHF.

IE proposed the study. IE, ED, EAH, VR, MK, AB, MB, MM, RR, AH, and CG contributed to design of the study and drafting the initial manuscript. IE, ED, EAH, VR, FB, TD, and SH contributed to editing and revising of the manuscript for intellectual content. EMH, FB, TD, and SH provided critical feedback. All authors approved the final version of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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