Reply to: ‘Interaction between RAAS inhibitors and ACE2 in the context of COVID-19’

Abstract

1 , the crucial role of angiotensin-converting enzyme 2 (ACE2) in severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infection, which causes coronavirus disease 2019 (COVID-19), was highlighted. ACE2 is a membrane-bound aminopeptidase that cleaves angiotensin I and angiotensin II into the angiotensin-(1-9) and angiotensin-(1-7) peptides. Several studies support the existence of a cardiovascular-protective ACE2angiotensin-(1-7)-Mas receptor axis 2. ACE2 is overexpressed in heart failure, arterial hypertension and diabetes mellitus 3. Moreover, ACE2 has been identified as a functional receptor for the entry of corona viruses generally, and SARS-CoV-2 specifically, into host cells 4. Given that most of the severe forms of COVID-19 have occurred in elderly patients with cardiovascular comorbidities, Zheng and colleagues speculate about the influence of chronic treatment with blockers of the renin-angiotensin-aldosterone system (RAAS) on the severity of the infection, stating that "ACE2 levels can be increased by the use of renin-angiotensin-aldosterone system inhibitors" 1. Consequently, the authors suggest that "the safety and potential effects of antihypertension therapy with ACE inhibitors or angiotensin-receptor blockers in patients with COVID-19 should be carefully considered". We wish to clarify that different RAAS inhibitors have different effects on ACE2 levels. By acting at different levels of the system, RAAS inhibitors result in heterogeneous effects on the peptides and enzymes involved. Whereas angiotensin-receptor blockers and mineralocorticoid-receptor blockers have been shown to increase the levels of ACE2 expression and activity in various experimental and clinical models 5,6 , administration of ACE inhibitors increased cardiac Ace2 mRNA levels but had no effect on ACE2 activity in experimental models 7,8. In addition, in an animal model of diabetic nephropathy, the chronic administration of aliskiren (a direct inhibitor of renin) was associated with a reduction in ACE2 expression 9. For these reasons, we believe that chronic treatment

Redefining Cardiac Biomarkers in Predicting Mortality of Inpatients With COVID-19

“…These findings are consistent with earlier reports that cardiac injury biomarkers are associated with an increased risk of COVID-19 mortality. 7 , 10 Elevated levels of cardiac troponin I and NT-proBNP, CK-MB, and MYO are also associated with more severe symptoms and disease progression. 11 – 14 Our larger sample size helped to better define and to improve the performance characteristics of these biomarkers for COVID-19, which manifest with widely divergent outcomes from full recovery to rapid death.…”

“…Accordingly, patients with biomarker levels above each recalibrated cutoff were at a significantly higher risk of 28-day all-cause mortality of COVID-19, compared with those under the cutoff points ( Figure S3). After adjusted for age, sex, and comorbidities in the mixed-effects Cox model and treated hospital site as a random effect, patients with elevated myocardial biomarkers over the new cutoffs were at a significantly higher risk of mortality than those having biomarker levels under cutoff values with adjusted HR of 10 (Table S8).…”

Covid-19: the renin–angiotensin system imbalance hypothesis

“…Considering the role of ACE2 as the viral receptor and the implication of these interactions, several authors discussed the suspension or continuation of RAS inhibitors therapy after Covid-19 outbreak [12]. Indeed, the administration of angiotensin II receptor antagonists (ARAs) and ACE inhibitors (ACEi) might seem counter-intuitive, since experimental studies pointed to an increased expression of ACE2 after treatment of cardiovascular diseases with these medications in animal models [13], although the extrapolation of this finding to humans deserves further investigation. One might consider that increased expression of transmembrane ACE2, the SARS-CoV-2 receptor, could be interpreted as harmful, due to the possibility of favoring viral entrance [14].…”

COVID-19: molecular targets, drug repurposing and new avenues for drug discovery

“…(132,133) Recently, some researchers have debated over the administration of these drugs to patients with known or suspected COVID-19. (133,134,135,136) The main reason for this discussion is that RAAS inhibitors may induce ACE2 expression, which, in theory, could increase the severity of the infection. (133,136) Nonetheless, evidence suggests that these drugs may protect patients from lung injury by suppressing angiotensin II signaling mediated by angiotensin receptor 1 (AT1R).…”

“…(135,136,137) Further investigation is still required to determine whether ACE-i and ARB have a beneficial or deleterious role in COVID-19 treatment. (134) In order to become fusion-competent, SAR-CoVs S proteins must be cleaved by host proteases. In SARS-CoV-2, this process appears to be mediated primarily by TMPRSS2 in the plasma membrane.…”