A pilot study to assess the circulating renin-angiotensin system in COVID-19 acute respiratory failure

Abstract

The renin-angiotensin system (RAS) is fundamental to COVID-19 pathobiology, due to the interaction between the SARS-CoV-2 virus and the angiotensin-converting enzyme-2 (ACE2) co-receptor for cellular entry. The prevailing hypothesis is that SARS-CoV-2-ACE2 interactions lead to an imbalance of the RAS, favoring pro-inflammatory Ang II related signaling at the expense of the anti-inflammatory Ang-(1-7) mediated alternative pathway. Indeed, multiple clinical trials targeting this pathway in COVID-19 are underway. Therefore, precise measurement of circulating RAS components is critical to understand the interplay of the RAS on COVID-19 outcomes. Multiple challenges exist in measuring the RAS in COVID-19 including improper patient controls, ex-vivo degradation and low concentrations of angiotensins, and unvalidated laboratory assays. Here, we conducted a prospective pilot study to enroll thirty-three moderate and severe COVID-19 patients and physiologically matched COVID-19 negative controls to quantify the circulating RAS. Our enrollment strategy led to physiologic matching of COVID-19 negative and positive moderate hypoxic respiratory failure cohorts, in contrast to the severe COVID-19 cohort which had increased severity of illness, prolonged ICU stay and increased mortality. Circulating Ang II and Ang-(1-7) levels were measured in the low picomolar (pM) range. We found no significant differences in circulating RAS peptides or peptidases between these three cohorts. The combined moderate and severe COVID-19 positive cohorts demonstrated a mild reduction in ACE activity compared to COVID-19 negative controls (2.2±0.9x105 vs. 2.9±0.8x105 RFU/mL, p=0.03). These methods may be useful in designing larger studies to physiologically match patients and quantify the RAS in COVID-19 RAS augmenting clinical trials.

Quantifying Renin-Angiotensin-System Alterations in COVID-19

“…This hypothesis is supported by the observation that, in the circulation and in the lungs, the conversion of AngII to Ang-( 1-7) is much more POP-dependent than ACE2-dependent [95]. Note, however, that in a recent investigation [93] no difference was observed between POP activity in COVID-19 patients and controls.…”

“…We review here recent data about measurements of RAS components in COVID-19. For that purpose, we manually collected and screened a series of clinical and experimental results from [79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94], listed in Supplementary Table S1. The individuals enrolled in these studies were classified into two or three classes: COVID-19 patients or severe and moderate COVID-19 patients, and controls or asymptomatic patients.…”

The Renin–Angiotensin–Aldosterone System in COVID-19–related and Non–COVID-19–related Acute Respiratory Distress Syndrome: Not So Different after All?

“…10 Previous pilot studies using this technique reported circulating levels of Ang II in the 20 pM range (20 pg/mL) amongst COVID-19 negative and positive patients with moderate and severe respiratory failure. 8 In contrast, Gerard et al found Ang II undetectable (<0.3 pg/mL) in the majority of their serum samples for both control and COVID19 groups, perhaps reflecting ex-vivo metabolism of Ang II in the serum samples.…”

“…These findings may be counterintuitive to the presumed pathophysiology related to ACE2-induced endocytosis as a result of SARS-CoV-2 binding and relative imbalance favoring AngII activity relative to Ang(1-7). 8 This imbalance has been suspected of being pro-inflammatory and vasoconstrictive, perpetuating acute lung injury in patients hospitalized with SARS-CoV-2 infection. Further, while this has been thought to be unique to COVID-19 related ARDS, findings by Gerard suggest this may be ubiquitous to ARDS regardless of etiology.…”

COVID-19: Target Selection

“…For example, it is known about the important role of the reninangiotensin-aldosterone system (RAAS), which is an integral part of the complex of blood pressure regulation and blood redistribution [28]. Currently, many researchers are considering changes in this system in patients with COVID-19 pneumonia resulting from viral aggression and are trying to find an effective correction of these deviations [29][30][31][32][33][34][35].…”