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?:abstract
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ACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs) are standard-of-care treatments for hypertension and diabetes, common comorbidities among hospitalized COVID-19 patients. Their use in the setting of COVID-19 has been heavily debated due to potential interactions with ACE2, an enzyme that links the pro- and anti-inflammatory arms of the in the renin angiotensin system, but also the entryway by which SARS-CoV-2 invades cells. ACE2 expression is altered by age, hypertension, diabetes, and the virus itself. This study integrated available information about the RAAS system 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-/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. Lastly, predicted changes in the 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.
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