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) 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 × 10⁵ vs. 2.9 ± 0.8 × 10⁵ 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.

Figure 1.

Results from each participant are shown for COVID-19-negative patients with moderate AHRF, COVID-19-positive patients with moderate AHRF, and COVID-19-positive patients with severe AHRF. Bars represent the mean and SD values for plasma levels of angiotensin II (ANG II) (A), angiotensin-(1–7) [ANG-(1–7)] (B), prolyloligopeptidase (POP) (C), angiotensin-converting enzyme (ACE) (D), and angiotensin-converting enzyme 2 (ACE2) (E). AHRF, acute hypoxic respiratory failure.

Figure 2.

Results from each partcipant are shown for peptide levels grouped by COVID-19-negative patients with moderate AHRF and combined moderate and severe COVID-19-positive patients with AHRF. Bars represent the mean and SD values for plasma levels of angiotensin II (ANG II) (A), angiotensin-(1–7) [ANG-(1–7)] (B), ANG-(1–7):ANG II ratio (C), angiotensin-converting enzyme (ACE) (D), angiotensin-converting enzyme 2 (ACE2) (E), and prolyloligopeptidase (POP) (F). AHRF, acute hypoxic respiratory failure.

Figure 3.

Correlation between “direct” and “surrogate” ACE2 or POP activity. Results from each participant are shown and represent the direct serum ACE2 activity (A) and POP activity (B) plotted against “surrogate” enzymatic activities using the corresponding plasma ANG-(1–7):ANG II peptide ratio. Each dot represents the paired corresponding enzymatic activity and peptide ratio for an individual patient. ACE2, angiotensin-converting enzyme 2; ANG, angiotensin; POP, prolyloligopeptidase.