Soluble ACE2 and Angiotensin II levels Modulated in Hypertensive COVID-19 Patients treated with different Antihypertension Drugs

Abstract

Hypertension is a major risk factor and common comorbidity among severe Coronavirus Disease 2019 (COVID-19) patients. Prominent antihypertensive drugs, such as angiotensin-converting-enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) can modulate the expression of angiotensin-converting enzyme 2 (ACE2) and may influence COVID-19 prognosis. Other classes of antihypertensive drugs, such as beta-blockers (BB) and calcium channel blockers (CCB) are associated with reduced mortality. Still, their effect on the circulating levels of ACE2 and angiotensin II, as well as the severity of COVID-19, are less characterized. Two hundred hypertensive COVID-19 patients on four different classes of antihypertensive medication (ACEi, ARB, BB, and CCB), with different COVID-19 severities (mild, moderate, and severe) were recruited, and clinical data were assessed. Sera-circulating ACE2 and angiotensin II levels were measured using standard ELISA kits. Linear regression models were used to assess the effect of antihypertensive medications on circulating levels of ACE2 and angiotensin II in relation to disease severity and other clinical indices. Included patients were on ACEi (n=57), ARB (n=68), BB (n=15), or CCB (n=30), with mild (n=76), moderate (n=76), or severe (n=52) COVID-19. ACE2 levels were higher in patients with severe COVID-19 than those with mild (p=0.04) and moderate (p=0.007) disease. ACE2 levels correlated positively with the length of hospital stay (r=0.3, p=0.003), while angiotensin II levels decreased with disease severity (p=0.04). Higher ACE2 levels were associated with elevated CRP and D-dimer, while higher angiotensin II levels were associated with lower levels of CRP, D-dimer, and troponin. Among the four treated groups, patients on ARB exhibited elevation in ACE2 levels with increased disease severity (p=0.01), whereas patients on ACEi showed lower angiotensin II levels with increased disease severity. Patients on BB showed the lowest disease severity compared to other treated groups. Our data show increased COVID-19 severity with elevated levels of circulating ACE2 and lower levels of angiotensin II and suggest a protective effect of BB treatment against disease severity in hypertensive patients, independently of ACE2 and angiotensin II levels.