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; Viktor Bánhegyi; Katalin Úri; Attila Enyedi; Erzsébet Lizanecz; Ivetta Siket Mányiné; Lilla Mártha; Gábor Áron Fülöp; Tamás Radovits; Miklós Pólos; Béla Merkely; Árpád Kovács; Zoltán Szilvássy; Zoltán Ungvári; István Édes; Zoltán Csanádi; Judit Boczán; István Takács; Gábor Szabó; József Balla; György Balla; Petar Seferovic; Zoltán Papp; Attila Tóth

doi:10.1007/s11357-021-00467-2

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

Geroscience. 2021 Oct;43(5):2289-2304. doi: 10.1007/s11357-021-00467-2. Epub 2021 Oct 21.

Authors

Miklós Fagyas^#^{1

2}, Viktor Bánhegyi^#^{1

3

4}, Katalin Úri¹, Attila Enyedi⁵, Erzsébet Lizanecz^{1

2}, Ivetta Siket Mányiné¹, Lilla Mártha¹, Gábor Áron Fülöp^{1

3

6}, Tamás Radovits⁶, Miklós Pólos⁶, Béla Merkely⁶, Árpád Kovács^{1

2}, Zoltán Szilvássy⁷, Zoltán Ungvári^{8

9}, István Édes², Zoltán Csanádi², Judit Boczán¹⁰, István Takács⁵, Gábor Szabó⁴, József Balla^{11

12}, György Balla^{12

13}, Petar Seferovic¹⁴, Zoltán Papp^#^{1

12}, Attila Tóth^{15

16}

Affiliations

¹ Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, 22 Móricz Zsigmond street, Debrecen, 4032, Hungary.
² Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
³ Doctoral School of Kálmán Laki, University of Debrecen, Debrecen, Hungary.
⁴ Department of Cardiac Surgery, University of Halle, Halle (Saale), Germany.
⁵ Department of Surgery, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
⁶ Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
⁷ Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
⁸ Vascular Cognitive Impairment and Neurodegeneration Program, Oklahoma Center for Geroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁹ International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary.
¹⁰ Department of Neurology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
¹¹ Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
¹² HAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, Budapest, Hungary.
¹³ Department of Pediatrics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
¹⁴ Heart Failure Center, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
¹⁵ Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, 22 Móricz Zsigmond street, Debrecen, 4032, Hungary. atitoth@med.unideb.hu.
¹⁶ HAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, Budapest, Hungary. atitoth@med.unideb.hu.

^# Contributed equally.

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.

Keywords: Angiotensin converting enzyme 2 (ACE2); Cardiovascular disease; Heart failure; Hypertension; RAAS inhibitors; Renin-angiotensin-aldosterone system (RAAS); SARS-CoV-2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Angiotensin-Converting Enzyme 2
Biomarkers
COVID-19*
Female
Humans
Male
Renin-Angiotensin System
SARS-CoV-2*
Stroke Volume
Ventricular Function, Left

Substances

Biomarkers
ACE2 protein, human
Angiotensin-Converting Enzyme 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding