Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin–angiotensin–aldosterone inhibitors

Abstract

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.

Plasma angiotensin-converting enzyme 2: novel biomarker in heart failure with implications for COVID-19

“…[10][11][12][13] In heart failure, elevated plasma ACE2 activity is associated with worsened prognosis and is higher in the acute setting compared with ambulatory heart failure patients. 10,11 In the current study, male sex was the strongest predictor of elevated plasma ACE2 concentrations in both cohorts, 9 which complements previous studies showing that men displayed higher ACE2 levels, and is consistent with a worse prognosis in men with heart failure. 12,13 Since Ace2 is an X-linked gene, this highlights an avenue of interest requiring further exploration with regards to sex-specific differences in the control of Ace2 expression and ACE2 processing and shedding into plasma.…”

“…In this issue of the European Heart Journal, Sama et al utilized existing cooperative Biobank samples to measure ACE2 concentrations in 1485 men and 537 women with heart failure (index cohort) and repeated this analysis in a validation cohort consisting of 1123 men and 575 women. 9 Using a high-throughput multiplex immunoassay, relative ACE2 levels were determined and correlated with demographic and clinical variables and the use of RAS inhibitors. In the index cohort, patients with higher concentrations of ACE2 were more often men, had atrial fibrillation, higher heart rate, and lower systolic blood pressure, which was largely confirmed in the validation cohort.…”

“…Importantly, the authors examined the impact of RAS inhibitors and the impact on plasma ACE2 levels. 9 In the validation cohort, ACE inhibitor and ARB use were independent ACE2 converts Ang I and Ang II into Ang 1-9 and Ang 1-7, respectively, thereby negatively regulating the renin-angiotensin system (A). ACE2 serving as the receptor for the SARS-CoV-2 and activation of ADAM-17 by Ang II and SARS-CoV-2 binding leading to a loss of membrane-bound ACE2 attenuates a key homeostatic mechanism limiting Ang II effects in tissues, culminating in cardiovascular, renal, and lung diseases, key components of the heart failure syndrome (B).…”

“…ACE2 serving as the receptor for the SARS-CoV-2 and activation of ADAM-17 by Ang II and SARS-CoV-2 binding leading to a loss of membrane-bound ACE2 attenuates a key homeostatic mechanism limiting Ang II effects in tissues, culminating in cardiovascular, renal, and lung diseases, key components of the heart failure syndrome (B). Higher plasma ACE2 levels were associated with male sex, history of atrial fibrillation, and coronary artery bypass graft, higher NYHA class, and heart rate; reduced ACE2 levels were associated with a history of chronic obstructive pulmonary diease, and higher left ventricular ejection fraction and systolic blood pressure (Sama et al 9 ). The dotted line indicates a putative role for ACE.…”

COVID‐19 and heart failure: from infection to inflammation and angiotensin II stimulation. Searching for evidence from a new disease

“…[75][76][77][78][79][80] This has been shown in experimental models, 75,77 tissue samples from the myocardium of patients with end-stage HF, 76,79 and using assays of ACE2 plasma levels. 78,80 A first study where circulating levels of ACE2 were measured in a large population of 1485 European men and 537 women with HF and results were validated in another, independent cohort, has been recently published. 80 Plasma levels of ACE2 were increased in patients with HF and, interestingly, their strongest predictor was male sex in both cohorts, consistently with the increased prevalence and severity of COVID-19 in males.…”