Level of the SARS-CoV-2 receptor ACE2 activity is highly elevated in old-aged patients with aortic stenosis: implications for ACE2 as a biomarker for the severity of COVID-19

Abstract

Coronavirus disease 2019 (COVID-19) has a high mortality in elderly patients with pre-existing cardiovascular diseases. The cellular receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the angiotensin-converting enzyme 2 (ACE2), thereby implicating a link between cardiovascular diseases and SARS-CoV-2 susceptibility. Aortic stenosis (AS) represents a chronic inflammatory state with severe cardiovascular complications in the elderly, a prime condition for COVID-19 mortality. The circulating ACE2 levels were measured in 111 patients with severe AS and compared to patients with hypertension and healthy individuals. About 4 times higher circulating ACE2 activity was found in patients with severe AS than in hypertensives or healthy individuals (88.3 ± 61.6., n = 111, 20.6 ± 13.4, n = 540, and 16.1 ± 7.4 mU/L, n = 46, respectively). Patients with severe AS were older than patients with hypertension (80 ± 6 years vs. 60 ± 15 years, P < 0.05). Serum ACE2 activity correlated negatively with the left ventricular ejection fraction, aortic root area, TAPSE, and positively with the right ventricular systolic pressure, cardiac diameters in patients with AS. In contrast, circulating ACE2 activity was independent of the blood pressure, peak flow velocity at the aortic root, kidney function (GFR), and inflammatory state (CRP). We found no effect of RAAS inhibitory drugs on the serum ACE2 activity in this group of patients. Our results illustrate circulating ACE2 as a potential interface between chronic inflammation, cardiovascular disease, and COVID-19 susceptibility. Elderly patients with AS have markedly elevated ACE2 levels together with altered left and right ventricular functions, which may pose higher risks during COVID-19. Our clinical data do not support a role for RAAS inhibitors in regulating circulating ACE2 levels.

Alterations in ACE and ACE2 Activities and Cardiomyocyte Signaling Underlie Improved Myocardial Function in a Rat Model of Repeated Remote Ischemic Conditioning

“…This observation motivated us for the investigation of the signaling processes mobilized by rRIC. Interestingly, rRIC largely reduced tissue ACE and ACE2 activities in comparison to those in the MI group, and hence our data support direct links between the dysregulation of tissue ACE and ACE2 activities and myocardial remodeling as has been also illustrated by previous results of our group and others [21][22][23][24][25]. The mechanism by which rRIC lead to the downregulation of cardiac ACE and ACE2 activities was not aimed in this study.…”

Changes in the SARS-CoV-2 cellular receptor ACE2 levels in cardiovascular patients: a potential biomarker for the stratification of COVID-19 patients

“…Serum ACE2 levels in end-stage heart failure patients were about fourfold higher than those in hypertensive subjects and about twofold higher than those in heart failure patients of low NYHA classes [ 28 , 29 ]. Our previous studies revealed an inverse relationship between serum ACE2 activity and left ventricular ejection fraction in heart failure patients with reduced ejection fraction (HFrEF) and in patients with hypertension [ 28 , 29 , 39 ]. This proposed negative correlation between circulating ACE2 activity and left ventricular ejection function has been confirmed here, in a large cardiovascular patient population ranging from mild hypertensives to end-stage heart failure patients.…”

The SARS-CoV-2/Receptor Axis in Heart and Blood Vessels: A Crisp Update on COVID-19 Disease with Cardiovascular Complications

“…Since angiotensin II is elevated during the heart failure condition, the activity of ADAM-17 is internally promoted by angiotensin II that is reported in several cardiac diseases, as a feedback system to sustain the ratio of angiotensin II/ACE2 expression [ 39 ]. The cleaved and shed sACE2 circulates in the plasma of patients with heart failure [ 53 ], aortic stenosis [ 54 , 55 ] and coronary artery disease (CAD) [ 56 ] and positively correlates with worsening disease prognosis. Of note, plasma sACE2 has been accounted as a highly ranked and independent determinant for cardiovascular mortality compared to other established cardiovascular risk factors [ 57 ].…”