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.
Developing new drugs that activate the protective arm of the renin–angiotensin system as a potential treatment for respiratory failure in COVID-19 patients
