Aims The current pandemic coronavirus SARS-CoV-2 infects a wide age group but predominantly elderly individuals, especially men and those with cardiovascular disease. Recent reports suggest an association with use of renin–angiotensin–aldosterone system (RAAS) inhibitors. Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for coronaviruses. Higher ACE2 concentrations might lead to increased vulnerability to SARS-CoV-2 in patients on RAAS inhibitors. Methods and results We measured ACE2 concentrations in 1485 men and 537 women with heart failure (index cohort). Results were validated in 1123 men and 575 women (validation cohort). The median age was 69 years for men and 75 years for women. The strongest predictor of elevated concentrations of ACE2 in both cohorts was male sex (estimate = 0.26, P < 0.001; and 0.19, P < 0.001, respectively). In the index cohort, use of ACE inhibitors, angiotensin receptor blockers (ARBs), or mineralocorticoid receptor antagonists (MRAs) was not an independent predictor of plasma ACE2. In the validation cohort, ACE inhibitor (estimate = –0.17, P = 0.002) and ARB use (estimate = –0.15, P = 0.03) were independent predictors of lower plasma ACE2, while use of an MRA (estimate = 0.11, P = 0.04) was an independent predictor of higher plasma ACE2 concentrations. Conclusion In two independent cohorts of patients with heart failure, plasma concentrations of ACE2 were higher in men than in women, but use of neither an ACE inhibitor nor an ARB was associated with higher plasma ACE2 concentrations. These data might explain the higher incidence and fatality rate of COVID-19 in men, but do not support previous reports suggesting that ACE inhibitors or ARBs increase the vulnerability for COVID-19 through increased plasma ACE2 concentrations.

The overall lifetime risk of heart failure (HF) is similar between men and women, however, there are marked sex differences in the landscape of this condition that are both important and under-recognized. Men are predisposed to HF with reduced ejection fraction (HFrEF), whereas women predominate in HF with preserved ejection fraction (HFpEF). Sex differences are also notable in the penetrance of genetic cardiomyopathies, risk factors, e.g. breast cancer which may be associated with cancer treatment-induced cardiomyopathy, as well as sex-specific conditions such as peripartum cardiomyopathy (PPCM). This review outlines the key sex differences with respect to clinical characteristics, pathophysiology, and therapeutic responses to HF treatments. Finally, we address important differences in the prognosis of HF. A central hypothesis is that the higher risk of HFrEF in men compared to women may be attributable to their predisposition to macrovascular coronary artery disease and myocardial infarction, whereas coronary microvascular dysfunction/endothelial inflammation has been postulated to play a key role in HFpEF and maybe the common link among HF syndromes that women are predisposed to Takotsubo cardiomyopathy, PPCM, and breast cancer radiotherapy-induced cardiomyopathy. Under-pinning current sex disparities in HF, there is a paucity of women recruited to HF clinical trials (20–25% of cohorts) and thus treatment guidelines are predominantly based on male-derived data. Large gaps in knowledge exist in sex-specific mechanisms, optimal drug doses for women and sex-specific criteria for device therapy.

Background: Guideline-recommended doses of angiotensin-converting-enzyme (ACE) inhibitors/angiotensin-receptor blockers (ARBs) and beta-blockers are similar for men and women with heart failure with reduced ejection fraction (HFrEF), even though there are known sex differences in pharmacokinetics of these drugs. We hypothesized that there may be sex differences in the optimal dose of ACE-inhibitors/ARBs and beta-blockers in patients with HFrEF. Methods: We performed a post-hoc-analysis of BIOSTAT-CHF, a prospective study of HF patients in whom initiation and up-titration of ACE-inhibitors/ARBs and beta-blockers was encouraged by protocol. Findings were validated in an independent cohort (ASIAN-HF) of 3,539 men and 961 women with HFrEF. Findings: Among 1,308 men and 402 women with HFrEF from BIOSTAT-CHF, women were older (74 vs. 70 years, p<0•001), and had lower body weight (72 vs. 85 kg, p<0•001) and height (162 vs. 174 cm, p<0•001) than men, although body mass index did not differ significantly. A similar % of men and women reached guideline-recommended target doses of ACE-inhibitors/ARBs (25 vs. 23%; p=0•61) and beta-blockers (14 vs. 13%; p=0•54). In men, the lowest hazards of death and/or HFhospitalization occurred at 100% of the recommended dose of ACE-inhibitors/ARBs and betablockers, but women showed a ~30% lower risk at only 50% of the recommended doses, with no further decrease in risk at higher dose levels. These sex differences were still present after adjusting for clinical covariates including age and body surface area. In the ASIAN-HF registry, similar patterns were observed for both ACE-inhibitors/ARBs and beta-blockers, with women having a ~30% lower risk at 50% of the recommended doses, with no further benefit at higher dose levels. Interpretation: This study suggests that women with HFrEF may need lower doses of ACEinhibitors/ARBs and beta-blockers as compared with men, and brings into question what true 'optimal medical therapy' is for women versus men.

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