Angiotensin-converting enzyme 2: a double-edged sword in COVID-19 patients with an increased risk of heart failure

Abstract

The coronavirus disease (COVID-19) pandemic is a global health priority. Given that cardiovascular diseases (CVD) are the leading cause of morbidity around the world and that several trials have reported severe cardiovascular damage in patients infected with SARS-CoV-2, a substantial number of COVID-19 patients with underlying cardiovascular diseases need to continue their medications in order to improve myocardial contractility and to prevent the onset of major adverse cardiovascular events (MACEs), including heart failure. Some of the current life-saving medications may actually simultaneously expose patients to a higher risk of severe COVID-19. Angiotensinconverting enzyme 2 (ACE2), a key counter regulator of the renin-angiotensin system (RAS), is the main entry gate of SARS-CoV-2 into human host cells and an established drug target to prevent heart failure. In fact, ACE inhibitors, angiotensin II receptor blockers, and mineralocorticoid antagonists may augment ACE2 levels to protect organs from angiotensin II overload. Elevated ACE2 expression on the host cell surface might facilitate viral entrance, at the same time sudden nonadherence to these medications triggers MACEs. Hence, safety issues in the use of RAS inhibitors in COVID-19 patients with cardiac dysfunction remain an unsolved dilemma and need paramount attention. Although ACE2 generally plays an adaptive role in both healthy subjects and patients with systolic and/or diastolic dysfunction, we conducted a literature appraisal on its maladaptive role. Understanding the exact role of ACE2 in COVID-19 patients at risk of heart failure is needed to safely manage RAS inhibitors in frail and non-frail critically ill patients.

miR-98 Regulates TMPRSS2 Expression in Human Endothelial Cells: Key Implications for COVID-19

“…It is important to note that several potential therapeutic strategies targeting ACE2 have been already proposed to tackle COVID-19; however, mainly owing to the critical metabolic and hemodynamic roles of ACE2, including the regulation of glucose homeostasis [56][57][58][59] as well as the cleavage of Angiotensin I and Angiotensin II [60,61], these approaches could lead to major issues in the clinical scenario [57,62,63]. Therefore, TMPRSS2 could represent a valid alternative target in COVID-19 [64][65][66].…”

Dysregulated Bradykinin: Mystery in the Pathogenesis of COVID-19

“…Another important inflammatory response of bradykinin through B2 receptor is pain and fever [ 3 ]. It also counterbalances the deleterious effects of Ang-II in normal conditions [ 25 ]. Bradykinin triggers cough reflex, induces bronchoconstriction, and increases airway resistance partly through B2 receptor activation.…”

DNA aptamers masking angiotensin converting enzyme 2 as an innovative way to treat SARS-CoV-2 pandemic

“…The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped, non-segmented, positive sense RNA virus that causes COVID-19, a highly contagious zoonosis mostly transmitted through airborne droplets and characterized by a wide spectrum of damages on different vital organs including the lungs, heart, blood vessels, central nervous system and intestine [1] , even if detection of infectious SARS-CoV-2 in the bloodstream remains controversial [2] , [3] , [4] . The COVID-19 case fatality rate in the worldwide population is 2.2% (https://ourworldindata.org/mortality-risk-covid?country=~OWID_WRL), although the likelihood increases with age and the presence of co-morbidities, reaching a value of 64% for elderly patients with 3 or more co-morbidities [5] , [6] . The molecular interaction between the receptor binding domain (RBD) of the activated S1 subunit of its S protein and the membrane bound ACE2 [7] , [8] , which leads to rapid endocytic entry of the virus into the host cell [9] plays crucial role in the widespread diffusion of SARS-CoV-2.…”