RAAS Blockade and COVID‐19: Mechanistic Modeling of Mas and AT1 Receptor Occupancy as Indicators of Pro‐Inflammatory and Anti‐Inflammatory Balance

Melissa Hallow, Karen; Dave, Ishaan

ACE inhibitors (ACEis) and angiotensin receptor blockers (ARBs) are standard‐of‐care treatments for hypertension and diabetes, common comorbidities among hospitalized patients with coronavirus disease 2019 (COVID‐19). Their use in the setting of COVID‐19 has been heavily debated due to potential interactions with ACE2, an enzyme that links the pro‐inflammatory and anti‐inflammatory arms of the renin angiotensin system, but also the entryway by which severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) invades cells. ACE2 expression is altered by age, hypertension, diabetes, and the virus itself. This study integrated available information about the renin angiotensin aldosterone system (RAAS) and effects of SARS‐CoV‐2 and its comorbidities on ACE2 into a mechanistic mathematical model and aimed to quantitatively predict effects of ACEi/ARBs on the RAAS pro‐inflammatory/anti‐inflammatory balance. RAAS blockade prior to SARS‐CoV‐2 infection is predicted to increase the mas‐AT1 receptor occupancy ratio up to 20‐fold, indicating that in patients already taking an ACEi/ARB before infection, the anti‐inflammatory arm is already elevated while the pro‐inflammatory arm is suppressed. Predicted pro‐inflammatory shifts in the mas‐AT1 ratio due to ACE2 downregulation by SARS‐CoV‐2 were small relative to anti‐inflammatory shifts induced by ACEi/ARB. Predicted effects of changes in ACE2 expression with comorbidities of diabetes, hypertension, or aging on mas‐AT1 occupancy ratio were also relatively small. Last, predicted changes in the angiotensin (Ang(1‐7)) production rate with ACEi/ARB therapy, comorbidities, or infection were all small relative to exogenous Ang(1‐7) infusion rates shown experimentally to protect against acute lung injury, suggesting that any changes in the ACE2‐Ang(1‐7)‐mas arm may not be large enough to play a major role in COVID‐19 pathophysiology.