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

Miklós Fagyas,Zoltán Csanádi,Gábor Szabó,Viktor Bánhegyi,Miklós Pólos,Attila Tóth,Béla Merkely,Tamás Radovits,Ivetta Siket Mányiné,Erzsébet Lizanecz,Zoltán Szilvássy,József Balla,Zoltán Ungvári,György Balla,Judit Boczán,Zoltán Papp,Lilla Mártha,Katalin Úri,Ildikó Takács ,Árṕad Kov́acs ,István Èdes ,Petar Seferović ,Gábor Fülöp ,Ágnes Enyedi

doi:10.1007/s11357-021-00467-2

Abstract

Angiotensin-converting enzyme 2 (ACE2) is essential for SARS-CoV-2 cellular entry. Here we studied the effects of common comorbidities in severe COVID-19 on ACE2 expression. ACE2 levels (by enzyme activity and ELISA measurements) were determined in human serum, heart and lung samples from patients with hypertension (n = 540), heart transplantation (289) and thoracic surgery (n = 49). Healthy individuals (n = 46) represented the controls. Serum ACE2 activity was increased in hypertensive subjects (132%) and substantially elevated in end-stage heart failure patients (689%) and showed a strong negative correlation with the left ventricular ejection fraction. Serum ACE2 activity was higher in male (147%), overweight (122%), obese (126%) and elderly (115%) hypertensive patients. Primary lung cancer resulted in higher circulating ACE2 activity, without affecting ACE2 levels in the surrounding lung tissue. Male sex resulted in elevated serum ACE2 activities in patients with heart transplantation or thoracic surgery (146% and 150%, respectively). Left ventricular (tissular) ACE2 activity was unaffected by sex and was lower in overweight (67%), obese (62%) and older (73%) patients with end-stage heart failure. There was no correlation between serum and tissular (left ventricular or lung) ACE2 activities. Neither serum nor tissue (left ventricle or lung) ACE2 levels were affected by RAS inhibitory medications. Abandoning of ACEi treatment (non-compliance) resulted in elevated blood pressure without effects on circulating ACE2 activities. ACE2 levels associate with the severity of cardiovascular diseases, suggestive for a role of ACE2 in the pathomechanisms of cardiovascular diseases and providing a potential explanation for the higher mortality of COVID-19 among cardiovascular patients. Abandoning RAS inhibitory medication worsens the cardiovascular status without affecting circulating or tissue ACE2 levels.

Highlights

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) resulted in a global health crisis
Circulating angiotensinconverting enzyme 2 (ACE2) activity strongly correlated with the left ventricular ejection fraction (EF, Spearman’s rho = −0.7576, P < 0.05, n = 750, Fig. 1B), suggesting an almost linear correlation
It was suggested that the ACE2 locus was located in a quantitative trait locus for blood pressure and it was confirmed that ACE2 levels are higher in spontaneously hypertensive rats [37]

Summary

Introduction

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) resulted in a global health crisis. The mechanisms by which hypertension promotes increased COVID-19 mortality are complex and likely involve the interaction between hypertension, ageing and underlying cardiovascular comorbidities [5,6,7]. Evolution of SARS-CoV-2 targets the ACE2 binding site, as mutations in the ACE2 binding (spike) region of SARS-CoV-2 increased its virulence dramatically, resulting in the third wave of the pandemic [13]. Recent studies demonstrate that seriously ill COVID-19 patients exhibit significant increases in circulating ACE2 activity, suggesting that circulating ACE2 may predict disease severity [14, 15]

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Results

Conclusion