Historically, women of childbearing potential had been excluded from all clinical trials, including those pertaining to HF, largely due to interpretation of US Food and Drug Administration (FDA) 1977 legislature, which was cancelled in 1993.1 Over the past 40 years, female participation in clinical trials has doubled, but women remain significantly under-represented.2 For example, in the case of heart failure (HF), women still account for just 29% of participants enrolled in clinical trials, despite population data indicating that women have a 2:1 incidence of HF with preserved ejection fraction (HFpEF) compared to men and a 4.2% incidental increase in HFpEF with every 5-year increment in age.1–4 Sex differences have also been detected in the penetrance of genetic cardiomyopathies, sex-specific conditions such as peripartum cardiomyopathy and risk factors such as breast cancer, which may be associated with cancer treatment-induced cardiomyopathy.5–7
The principal barriers to female participation in HF trials include low rates of referral, age-related exclusion criteria, a perception of increased risk of harm, childcare responsibilities, the sex/gender of recruiters and research chiefs and other socioeconomic barriers, such as travel burden.3
Sisk et al. improved diverse patient participation using a stepwise approach to increasing the enrolment of women, the elderly and racially/ethnically diverse populations in clinical trials by providing dedicated and appropriate resources to help with informed decision-making, remuneration for travel and childcare expenses, assistance and transport for elderly patients and the incorporation of language preferences.5 Future research should seek to incorporate this model in recruitment design to ensure gender enrolment is reflective of population registries.
The aim of this paper is to review the main sex differences in HF physiology and clinical exacerbation. Due to the nature of the review, we did not address sex differences in pharmacological management.
Sex Differences in Heart Failure with Reduced Ejection Fraction
According to European Society of Cardiology guidelines, patients diagnosed with HF with reduced ejection fraction (HFrEF) are those who present symptoms and signs of HF with a left ventricular ejection fraction (LVEF) of <40%.1 In this HF subtype, it is crucial to understand the epidemiological, diagnostic, prognostic and treatment differences between males and females. The prevalence of HFrEF is higher among men than women.1 This can be attributed, in part, to the predisposition of men to macrovascular coronary artery disease and MI, which are the primary causes of HFrEF. Men with HFrEF typically exhibit a higher prevalence of AF, ischaemic disease and stroke than women with HFrEF.8–11 Rates of alcohol consumption and smoking are also higher among men than women with HFrEF. Conversely, women with HFrEF are older and more likely to have a history of hypertension, obesity, valve disease, chronic kidney disease and depression.9–10
Although there are no major differences in terms of the presentation in cases of HFrEF, certain sex-related differences should be noted (Figure 1). Women with HFrEF tend to exhibit more symptoms, more congestion and higher N-terminal pro B-type natriuretic peptide concentrations than men.9,11 In addition, women with HFrEF exhibit lower exercise tolerance, poorer pulmonary function and lower kidney function than men.11 It has also been reported that LVEF is mildly better in women than men with HFrEF.10
Women have superior survival rates than men with HFrEF, with a lower risk of sudden death. Stolfo et al. reported that the risks of hospitalisation due to cardiovascular causes and HF were lower in women than men; no sex-related differences were observed in the risk of hospitalisation for non-cardiovascular causes.9 Prognostic predictors that differ between the two sexes include diabetes and New York Heart Association (NYHA) class, which are associated with a higher risk of mortality in men than in women.9 It has also been reported that the quality of life of female patients with HFrEF is impacted to a greater extent, both physically and psychologically, than that of men.10–12
Men and women experience comparable benefits from therapies for reduced HF, including renin–angiotensin system inhibitors, angiotensin receptor–neprilysin inhibitors, β-blockers, mineralocorticoid receptor antagonists and sodium–glucose cotransporter 2 inhibitors.13 Women are more likely to be prescribed β-blockers and digoxin, and there is a lower usage of diuretics and anticoagulants among women.9,10 Moreover, the ideal medication dosages for HF therapy may vary between the sexes, with women potentially benefiting from lower doses compared with guideline recommendations.1 Women experience adverse events from HF medications at a rate up to twice that of men.11 The use of digoxin is associated with a higher risk of mortality in women, likely due to higher plasma concentrations with the same dosage.7
Women have longer rate-corrected QT intervals, and the use of antiarrhythmic drugs, such as amiodarone, to prevent sudden death is associated with a higher incidence of QT prolongation and Torsades de pointes in women than in men.11
There are also notable differences in device therapy. Women are undertreated with devices and have a higher rate of implantation-related complications.11,14 Although they seem to derive less benefit from ICD implantation, likely due to predominant non-ischaemic aetiologies, women respond more favourably to resynchronisation therapy.1 The reasons for this better response are still being debated, but are possibly attributable to anatomical rather than biological factors.7 Finally, women are less likely to be enrolled in a rehabilitation program or prescribed an exercise regimen.10,15 Despite these sex differences in HFrEF therapies, current guidelines do not make any distinctions between treatments and this should be taken into consideration.1
Sex Differences in Heart Failure With Preserved Ejection Fraction
There are a number of comorbidities associated with HFpEF, including hyperlipidaemia, obesity, hypertension, AF, coronary artery disease, anaemia, diabetes, chronic kidney disease and sleep apnoea.4 It is often found that sex differences in these conditions interplay with sex differences in HFpEF. Non-modifiable risk factors may have different weights for male and female patients, whereas modifiable risk factors may have different prevalences and different weights in contributing to the risk of developing HF.6
For example, it has been found that obesity is a stronger risk factor for developing HFpEF than HFrEF in general, but also that it’s weighted more strongly in contributing to HFpEF in women than in men.15,16 Thus, not only is obesity more prevalent in women than in men, but obese women are also more likely to develop HFpEF than obese men. This example demonstrates how one risk factor can underlie sex differences in HFpEF and how it interplays with other potential differentiators, such as insulin resistance.16
Risk Factors Specific to Women
Sex-specific risk factors for HFpEF include menopause, reproductive factors and adverse pregnancy outcomes. It seems that although oestrogen itself has a protective role against the development of cardiovascular disease, supplemental oestrogen is a risk factor in cardiovascular disease.17,18 Lim et al. analysed menopause as a potential inflection point in HFpEF sex characteristics based on their understanding of the trophic effect of gender hormones and established a chronology of haemodynamic echocardiographic characteristics of left ventricular (LV) diastolic dysfunction across both sexes, with women in particular having a larger LVEF over the age of 50 years with left-sided structural changes not seen in men.18
Inflammation and Microvascular Dysfunction
Women have a greater propensity for endothelial inflammation and coronary microvasculature dysfunction.19 On a cellular level, altered nitric oxide signalling characterises endothelial inflammation. It has been found that endothelial dysfunction of the systemic and pulmonary vasculature is involved in the pathophysiology of HFpEF.19 Furthermore, sex differences in immune responses have been found, with higher concentrations of proinflammatory cytokines, greater activation of inflammatory T cells and, in general, heightened inflammation and higher levels of inflammatory markers in women than in men.18 Specifically, there is greater upregulation of proinflammatory gene expression in women than in men.19
The Dallas Heart Study proved that, in the general population, women have a higher LVEF than men because they have a higher stroke volume per end-diastolic volume.19 Anatomical variation in how the LV is built and functions affects remodelling, and therefore pathophysiological processes, causing different HF phenotypes.20 For example, LV remodelling is more concentric and diastolic dysfunction is more severe with impaired LV relaxation in women than in men.
Preclinical Heart Failure
Accurate and timely diagnosis of HF is important in the preclinical stage and there are certain distinct early indices for both men and women, as demonstrated with phenotyping.1 Older patients with lower kidney function and worse diastolic function may represent a subset of preclinical HF with LVEF >40% that deserves more efforts to prevent clinical HF.21 According to Koepp et al., the H2FPEF score can identify individuals with preclinical HFpEF.22 An increased H2FPEF score was shown to be associated with greater left atrial dilation, LV hypertrophy and more severe diastolic dysfunction, and patients with an increased H2FPEF score had higher pulmonary artery pressures, higher left heart filling pressures, a lower cardiac index and more severely impaired aerobic capacity during exercise.22
Sex Differences in Cardiomyopathies
There is increasing attention in cardiovascular medicine of the marked sex differences in cardiomyopathies between men and women. According to the European Society of Cardiology, cardiomyopathies are classified into five groups: dilated, hypertrophic, restrictive, arrhythmogenic right ventricular and ‘unclassified’.6,14,15,23
Stress-induced Cardiomyopathy: Takotsubo
Takotsubo cardiomyopathy (TTC), also known as stress-induced cardiomyopathy and ‘broken-heart syndrome’, is a form of non-ischaemic cardiomyopathy. The term ‘takotsubo’ in Japanese means ‘octopus trap’, similar to the shape of the systolic apical ballooning of the LV that is seen in TTC.24 TTC is characterised by transient regional systolic dysfunction, inducing angina symptoms with ECG changes and cardiac enzyme elevation consistent with acute coronary syndrome presentation.25
TTC is rare and predominantly affects postmenopausal women.26 This may be linked to the influence of decreasing oestrogen levels on the pathogenesis of TTC.26 TTC is often preceded by severe acute emotional or physical stress in women and men, respectively.26 However, the underlying mechanism remains unclear. Hypotheses include a sudden overdrive of the sympathetic nervous system with increased catecholamine release, inflammation and microcirculatory dysfunction.27
TTC is often transient and requires supportive treatment. Patients with TTC usually recover well, but the rate of complications is similar to that of acute MI, with a reported mortality of up to 8%; thus, patients need to be closely monitored. Approximately 10–20% of males have TTC and it has been reported that males have a higher rate of severe in-hospital complications and mortality rate compared to women.26
Reports on sex differences in the pathogenesis and manifestation of TTC are insufficient because it is rare and because of female predominance. However, it appears that sex differences do exist in TCC. Further research and trials could help identify sex differences in TTC, contribute to a better understanding of disease manifestation and target therapy as a result.
Dilated Cardiomyopathy
Dilated cardiomyopathy (DCM) can be classified into primary and secondary DCM. Many cases are primary DCM due to idiopathic aetiology, without an identifiable cause. There may be a familial or genetic predisposition with or without a combination of secondary myocardial insults. There may be an interplay among these factors, influencing differences in the development and pathogenesis of DCM, clinical presentation, management and prognosis between men and women.6
Research indicates that DCM is inherited in approximately 20–50% of all cases, with more than 30 genes implicated in its development and progression.26 Several studies have shown that DCM is more prevalent in men than in women, at a ratio of 3:1.23,28
Recent studies have demonstrated that, compared with women, men with DCM have a higher chance of myocardial fibrosis contributing to the pathogenesis of DCM.23,28,29 This seems to support the hypothesis that oestrogen influences cardiac genes to play a reparative and remodelling role in the heart, improving cardiac function. However, the role of oestrogen on cardiac function is not fully understood.
Overall, there is a lack of studies addressing the interaction between biological, genetic and environmental factors that influence sex differences in DCM pathogenesis. In addition, often fewer women were recruited to DCM trials.25,29 This could lead to under-representation and a lack of evidence for effective management of DCM in women. Although there has been increased insight into the importance of sex differences in the pathogenesis and outcomes of DCM, evidence is lacking. Recent advances in genetic testing and genotypic–phenotypic studies, along with further sex-based trials, could aid our understanding of the differences in DCM to allow clinicians to treat DCM effectively in both men and women.
Hypertrophic Cardiomyopathy
Familial hypertrophic cardiomyopathy (HCM) is the most common type of inherited cardiomyopathy caused by genetic mutations of a sarcomere gene. HCM is characterised by LV hypertrophy often affecting the interventricular septum.23 According to several sex studies, HCM has male preponderance. A large study in 969 HCM patients showed a 3:2 male preponderance (59%), with other studies reporting similar sex ratios.23,30
It has been reported that men are more frequently diagnosed with HCM during routine medical consultations than women.30,31 It has also been reported that HCM diagnosis or referral occurs at an older age in women than in men, with most women remaining asymptomatic until the fifth decade.31 However, at presentation, women are more symptomatic with severe disease progression, often associated with LV outflow obstruction, progression to advanced heart failure NYHA Class III/IV, stroke or related death.29–31 Overall, women with HCM have a worse prognosis and survival than men with HCM.32
It is possible that the late onset of symptoms in women with HCM results in delayed diagnosis, or that the presence of underlying diagnostic bias with a lack of physician suspicion of the disease is resulting in low investigation rates. In addition, most younger athletes who undergo cardiovascular screening are male.33
Several studies have shown that loss of oestrogen at menopause may be linked to increased myocardial hypertrophy, fibrosis and defective ventricular relaxation.33 As evidenced by recent studies, women seem to require greater hypertrophy to reach the diagnostic threshold of HCM than men, presenting at an advanced age with severe progression at the time of diagnosis.29,30
There are significant sex differences in HCM in terms of its aetiology, clinical manifestation, diagnosis and therapeutic approaches. Although this is possibly related to genetic, phenotypic sex differences, endocrine or other social factors, further sex-specific evidence is required for effective medical management. In view of women presenting late, they require more surveillance and attention to allow for the early identification, diagnosis and active management of the disease.31–33
Heart Transplant/Assist Devices Patients
Overall, men present more with ischaemic cardiomyopathy and DCM than women.34 Men are frequently diabetic, hypertensive and smokers. Women have more pre-heart transplant malignancies, and their clinical status at transplant is worse due to renal function and mechanical ventilation. Survival and most of the mortality-related variables are similar in men and women. Following heart transplantation, death occurs more frequently in women due to rejection and primary failure, and in men due to malignancies.34
Recent data derived from INTERMACS reveal that women constitute approximately 21.4–22.7% of total LV assist device implantations.34 However, the MOMENTUM 3 trial did not observe a significant interaction between males and females in their prespecified subgroup analysis.35 In addition, MOMENTUM 3 reported that women faced a higher risk of mortality, a reduced likelihood of heart transplantation and an increased rate of adverse events following LV assist device implantation.36
Future Implications
Currently, there are large gaps in the literature regarding mechanisms by which HF occurs in men versus women, optimal drug therapy and the development of sex-specific criteria for device implantation.7 Women with HF have a greater risk of drug-related adverse reactions than men.7 Genetic mechanisms relating to polymorphisms that modify drug responses may be affected by sex-specific hormones, menstruation, age and associated comorbidities, but the specific underlying causes for the differences in drug responses remain unknown.
Taking into consideration sex differences will help clinicians personalise management and avoid the rehospitalisation of patients with HF, reducing healthcare costs. Furthermore, the more that sex differences in HF are acknowledged, the more the gap between the two sexes will be closed and women will be equally represented in HF clinical trials. This under-representation of women in HF clinical trials may have contributed to a lesser understanding of disease behaviour in female than in male patients. Understanding the evidence regarding sex differences in the pathophysiology and disease progression of HFpEF could help with providing individualised care according to a patient’s sex. Future research should elucidate the underlying HF pathophysiology and aim to identify the need for sex-specific drug dosages and the possible need for sex-specific device implantation criteria.
Conclusion
As a take-home message, across the spectrum of HF, there are important sex differences that need to be taken into account for the accurate diagnosis and management of patients.
Changes in the design of clinical studies to promote the participation of women are challenging due to variations in disease prevalence, prognostic indices and indications for intervention, as well as difficulties with patient enrolment. Proposals for revised study designs have included a mandate for reporting sex-specific findings, eliminating sex-based outcome measurements and promoting trials to detect significant sex differences in safety and efficacy endpoints.