Abstract
AimsMembrane‐bound angiotensin‐converting enzyme (ACE)2 is the main cellular access point for SARS‐CoV‐2, but its expression and the effect of ACE inhibition have not been assessed quantitatively in patients with heart failure. The aim of this study was to characterize membrane‐bound ACE2 expression in the myocardium and myocardial vasculature in patients undergoing heart transplantation and to assess the effect of pharmacological ACE inhibition.Methods and resultsLeft ventricular (LV) tissue was obtained from 36 explanted human hearts from patients undergoing heart transplantation. Immunohistochemical staining with antibodies directed against ACE2 co‐registered with cardiac troponin T (cTnT) and α‐smooth muscle cell actin (SMA) was performed across the entire cohort. ACE2 receptor expression was quantitatively assessed throughout the myocardium and vasculature. ACE2 was consistently expressed throughout the LV myocardium (28.3% ± 22.2% of cardiomyocytes). ACE2 expression was also detected in small calibre blood vessels (range, 2–9 μm), albeit at quantitatively much lower levels (5% ± 9% of blood vessels). There was no significant difference in ACE2 expression between patients receiving ACE inhibitors prior to transplantation and ACE inhibitor‐negative controls (P > 0.05). ACE2 expression did not differ significantly between the different diagnostic groups as the underlying reason for heart transplantation (ANOVA > 0.05). N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) (R 2 = 0.37, P = 0.0006) and pulmonary capillary wedge pressure (PCWP) (R 2 = 0.13, P = 0.043) assessed by right heart catheterization were significantly correlated with greater ACE2 expression in cardiomyocytes.ConclusionsThese data provide a comprehensive characterization of membrane‐bound cardiac ACE2 expression in patients with heart failure with no demonstrable effect exerted by ACE inhibitors.
Highlights
Angiotensin-converting enzyme 2 (ACE2) serves as a key counter-regulator of the renin–angiotensin aldosterone system (RAAS)
Cases were classified as dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), ischaemic cardiomyopathy (ICM) or arrhythmogenic cardiomyopathy (ACM) and were categorized into angiotensin-converting enzyme (ACE) inhibitor administration present or absent based on the history
Left ventricular (LV) tissue sections were stained with antibodies directed against ACE2 and cardiac troponin T (cTnT) as well as ACE2 and smooth muscle cell actin (SMA) and were subsequently quantified and correlated with clinical baseline characteristics
Summary
Angiotensin-converting enzyme 2 (ACE2) serves as a key counter-regulator of the renin–angiotensin aldosterone system (RAAS). Decreased levels of ACE2 increase susceptibility to heart failure driven by the fibrotic, oxidative and pro-inflammatory effects of the Ang II/AT1R axis, whereas increased ACE2 levels counterbalance these effects via the conversion of Ang II to Ang 1–7, imparting protection against heart failure.[1] At the same time, membrane-bound ACE2 and its accessory protease TMPRSS2 serve as the main cellular entry points for SARS-CoV-2, making them key determinants of disease susceptibility.[2,3]. In the wake of the first global COVID-19 wave, concerns were raised as to the safety of ACE inhibitors and angiotensin receptor blockers (ARBs), because preclinical data demonstrated that these drugs result in increased ACE2 expression.[4,5,6] clinical studies have since shown that their use is safe in patients with COVID-19 and does not result in increased disease susceptibility.[7,8,9,10] ACE inhibitors and ARBs may exert protective effects as ACE2 is reduced in COVID-19, resulting in unopposed detrimental action of AngII on the lungs.[11]
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