Cardiovascular Pharmacology in the Time of COVID-19: A Focus on Angiotensin-Converting Enzyme 2.

Coronavirus disease-2019 (COVID-19) has emerged as a pandemic affecting millions of adults. Severe acute respiratory syndrome coronavirus-2019 (SARS-CoV-2), the causative virus of COVID-19, infects host cells through angiotensin-converting enzyme 2 (ACE2). Preclinical models suggest that ACE2 upregulation confers protective effects in acute lung injury. In addition, renin-angiotensin aldosterone system inhibitors reduce adverse atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease outcomes, but may increase ACE2 levels. We review current knowledge of the role of ACE2 in cardiovascular physiology and SARS-CoV-2 virology, as well as clinical data to inform the management of patients with or at risk for COVID-19 who require renin-angiotensin-aldosterone system inhibitor therapy.

The severe acute respiratory syndrome-coronavirus-2 [SARS-CoV-2; previously known as novel coronavirus-2019 (nCoV-19)] causes coronavirus disease-2019 (COVID-19). At the time of publication (April 30, 2020), the COVID-19 pandemic has led to 3,090,445 cases and 217,769 deaths across 209 countries according to World Health Organization data.[1] Older patients with COVID-19, those with underlying pulmonary disease, and those with hypertension, diabetes, or established cardiovascular disease have a worse prognosis than their counterparts without these comorbidities.[2-8]

SARS-CoV-2 infects host cells by binding to human angiotensin-converting enzyme-2 (ACE2),[9-11] a membrane-bound enzyme expressed in the lungs, heart, and kidneys (among many other organs).[12,13] Within the heart, pericytes express the greatest levels of ACE2, although cardiomyocytes and endothelial cells also express ACE2.[14] ACE2 catalyzes the conversion of angiotensin-I and angiotensin-II to angiotensin-(1-9) and angiotensin-(1-7), respectively.[15] Angiotensin-II promotes increased sympathetic tone, sodium and water retention, fibrosis and inflammation through the angiotensin type 1 receptor, whereas angiotensin (1-7) counteracts these effects by binding to the Mas receptor (Fig. 1).[15]

FIGURE 1.

Interactions between the renin–angiotensin–aldosterone system and coronavirus Disease-2019. The complex RAAS regulates blood pressure, sodium and water retention and plays an important role in the pathogenesis of cardiovascular disease. Angiotensin-converting enzyme converts angiotensin-I to angiotensin-II, which mediates vasoconstriction, sodium and water retention and inflammation through the angiotensin type 1 receptor (red arrows). Angiotensin converting enzyme-2 (ACE2) counterbalances the angiotensin-II/angiotensin type 1 receptor pathway by converting angiotensin-II to angiotensin-(1-7), which binds the Mas receptor to mediate vasodilation and anti-inflammatory effects (yellow arrows). Importantly, the angiotensin-II/angiotensin type 1 receptor pathway leads to cleavage of membrane-bound ACE2 via ADAMS17 (green arrow). Severe acute respiratory coronavirus-2 (SARS-CoV-2) binds ACE2 and undergoes endocytosis to infect host cells. As a consequence, SARS-CoV-2 infection decreases membrane-bound ACE2 and impairs the beneficial effects of the angiotensin-(1-7)/Mas receptor axis.

It has been proposed that renin–angiotensin–aldosterone system (RAAS) inhibitors predispose to SARS-CoV-19 infection and worsen outcomes after COVID-19 by upregulating ACE2 expression.[16] Angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin receptor type 1 blockers (ARBs) and mineralocorticoid receptor antagonists increase heart, vascular, and kidney ACE2 expression and activity in animals.[17-21] Chronic treatment with an ACE inhibitor for 6 months was associated with increased plasma angiotensin-(1-7) level and angiotensin-II to angiotensin-(1-7) ratio, whereas no such association was observed in the immediate period after acute ACE inhibitor treatment.[22,23] Spironolactone treatment increased ACE2 activity and mRNA in human monocyte-derived macrophages from patients with heart failure.[21]

Yet others support the hypothesis that RAAS inhibitors and ACE2 counteract angiotensin-II-mediated pulmonary injury in respiratory viral illness.[24,25] These beneficial effects could be attributable to angiotensin-(1-7) binding to the Mas receptor, which promotes anti-inflammatory signaling.[15] In one study of acid aspiration and sepsis lung injury, ACE2 knockout mice and mice pretreated with recombinant human ACE2 had attenuated lung damage.[26] In the same models, treatment of ACE2 knockout mice with an angiotensin type 1 receptor blocker also protected against lung injury.[26] Administration of recombinant human ACE2 beginning one day before respiratory syncytial virus infection decreased pulmonary immune cell infiltration and attenuated histologic lung injury in mice.[27] Recombinant human ACE2 increased angiotensin-(1-7) and decreased angiotensin-II concentrations in patients with acute respiratory distress syndrome, but was stopped early for futility with no significant difference in the partial pressure of arterial oxygen to fraction of inspired oxygen ratio.[28] These data suggest that ACE2 modulation may protect against lung damage from acute respiratory distress syndrome, but do not address whether ACE2 modulation may salvage lung function after the initial lung insult. Moreover, it is unclear whether the hypothetical benefits of ACE2-mediated lung protection outweigh the theorized ACE2-mediated increase in SARS-CoV-2 entry.

Several questions about the relationship between SARS-CoV-2, ACE2, and RAAS inhibitors must be answered before drawing conclusions about RAAS inhibitors and COVID-19 and to inform the design of future studies. First, there are no data to support an increase in ACE2 expression on alveolar epithelial cells during RAAS inhibition in animal models. Plasma ACE2 activity may not represent enzymatic activity at the tissue level, because angiotensin-II infusion into mice decreases myocardial ACE2 protein level and activity, but increases plasma ACE2 activity.[29] Furthermore, increased plasma ACE2 levels are associated with an adverse cardiovascular prognosis.[30]

There may be relevant differences between ACE inhibitors and ARBs, and differences within each class, with respect to their effects on circulating and tissue ACE2. In a cross-sectional analysis of adults taking various antihypertensive agents, on-treatment urinary ACE2 concentrations were increased in patients taking olmesartan, but not ACE inhibitors or other ARBs.[31] Conversely, 2 studies demonstrated higher on-treatment circulating levels of angiotensin (1-7) in patients receiving an ACE inhibitor than an ARB.[32,33] In spontaneously hypertensive rats, sacubitril-valsartan restored cardiac ACE2 mRNA expression, whereas valsartan did not.[34] Circulating angiotensin-(1-7) may not reflect ACE2 activity in patients receiving sacubitril-valsartan because neprilysin converts angiotensin-(1-9) and angiotensin-I to angiotensin-(1-7).

ACE2-independent factors also influence SARS-CoV-2 infection and COVID-19 severity. For example, SARS-CoV-2 entry seems to require TMPRSS2, a serine protease expressed on ACE2-expressing cells.[11] Host genetics and comorbidities likely play a role in susceptibility to SARS-CoV-2 infection and outcome, as suggested by the high prevalence of advanced age, and cardiac and pulmonary comorbidities among patients with COVID-19.

Randomized clinical trials provide the only opportunity to answer to questions in a rigorous manner. Two ongoing trials will compare losartan, an ARB, against placebo or an active comparator in hospitalized patients and outpatients with COVID-19 (clinicaltrials.gov NCT04311177, NCT04312009 and NCT04328012). Another clinical trial will compare continuing ACE inhibitor or ARB therapy and switching to an alternative agent in patients with hypertension, but without COVID-19 (NCT04329195). Epidemiologic studies should be performed to estimate the association of RAAS inhibitor use to risk of COVID-19 in patients with hypertension, heart failure or chronic kidney disease.

Withdrawal of RAAS inhibition increases the risk of decompensation in patients with heart failure and adverse physiological changes occur shortly after RAAS inhibitor withdrawal. Plasma angiotensin II, aldosterone, cortisol, and norepinephrine levels increase to pretreatment levels within 4-days of ACE inhibitor cessation in patients with heart failure and New York Heart Association functional class III or IV symptoms.[35] After a mean 15 days without ACE inhibitor therapy, left ventricular end-diastolic and end-systolic volumes return to pretreatment values in patients with heart failure with reduced ejection fraction.[36] Worsening symptoms and decreased exercise tolerance occurs within 4–6 weeks of ACE inhibitor withdrawal.[37] Even among patients with recovery of left ventricular function and reversal of left ventricular remodeling, withdrawal of neurohormonal blockade increases the risk of clinical relapse or subclinical adverse left ventricular remodeling.[38] Discontinuing ACE inhibitor or ARB therapy in patients with progression of chronic kidney disease was associated with an increased risk of cardiovascular disease over a 5-year period.[39]

In March 2020, the American College of Cardiology, American Heart Association, Heart Failure Society of America and European Society of Cardiology issued recommendations against discontinuing RAAS inhibitors during the COVID-19 pandemic.[40,41] Clinicians should consider the risk of COVID-19 exposure when caring for patients with hypertension, heart failure, acute myocardial infarction, and diabetic nephropathy. Clinicians should reinforce preventative measures for those patients who must leave their homes to provide blood samples for electrolyte and renal function monitoring with RAAS inhibitors.[42]

In summary, we have limited preclinical and clinical evidence of the effects of RAAS inhibitors on COVID-19. Clinicians should continue to use RAAS inhibitors during the COVID-19 pandemic according to current standards of care. Scientists must focus on addressing several knowledge gaps to inform clinical management of COVID-19, particularly among those patients with underlying pulmonary and cardiovascular disease.