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) coreceptor for cellular entry. The prevailing hypothesis is that SARS-CoV-2-ACE2 interactions lead to an imbalance of the RAS, favoring proinflammatory angiotensin II (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 33 patients with moderate and severe COVID-19 and physiologically matched COVID-19-negative controls to quantify the circulating RAS. Our enrollment strategy led to physiological matching of COVID-19-negative and COVID-19-positive moderate hypoxic respiratory failure cohorts, in contrast to the severe COVID-19 cohort, which had increased severity of illness, prolonged intensive care unit (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 with COVID-19-negative controls (2.2 ± 0.9 × 10 5 vs. 2.9 ± 0.8 × 10 5 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.
Keywords: ACE2; SARS-CoV-2; acute respiratory distress syndrome; angiotensin; critical care.
【저자키워드】 SARS-CoV-2, ACE2, Critical care, acute respiratory distress syndrome, angiotensin, 【초록키워드】 COVID-19, clinical trial, Critical care, severe COVID-19, hypoxic respiratory failure, Anti-inflammatory, severity, peptide, clinical trials, angiotensin-converting enzyme 2, RAS, ICU, renin-angiotensin system, outcomes, proinflammatory, Cohort, Patient, Control, pathway, Mild, cellular entry, Degradation, Critical, moderate, acute respiratory distress, Alternative pathway, Signaling, Interaction, Hypothesis, Concentration, ACE, physiological, Ex vivo, Enrollment, no significant difference, pilot study, cohorts, increased mortality, peptidase, circulating, component, Multiple, laboratory assays, controls, conducted, demonstrated, reduction in, were measured, ANG, patients with moderate, prolonged intensive care, severe COVID-19 cohort, the SARS-CoV-2 virus, 【제목키워드】 COVID-19, Respiratory failure, renin-angiotensin system, pilot study, circulating,