Good or bad: Application of RAAS inhibitors in COVID-19 patients with cardiovascular comorbidities

Abstract

The coronavirus disease 2019 (COVID-19) pandemic is caused by a newly emerged coronavirus (CoV) called Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). COVID-19 patients with cardiovascular disease (CVD) comorbidities have significantly increased morbidity and mortality. The use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor type 1 blockers (ARBs) improve CVD outcomes; however, there is concern that they may worsen the prognosis of CVD patients that become infected with SARS-CoV-2 because the virus uses the ACE2 receptor to bind to and subsequently infect host cells. Thus, some health care providers and media sources have questioned the continued use of ACE inhibitors and ARBs. In this brief review, we discuss the effect of ACE inhibitor-induced bradykinin on the cardiovascular system, on the renin-angiotensin-aldosterone system (RAAS) regulation in COVID-19 patients, and analyze recent clinical studies regarding patients treated with RAAS inhibitors. We propose that the application of RAAS inhibitors for COVID-19 patients with CVDs may be beneficial rather than harmful.

Keywords: Bradykinin; COVID-19; Hypertension; Inflammation; RAAS inhibitors.

Fig. 1

Genomic structure of SARS-CoV-2, SARS-CoV and MERS-CoV. The genomic structures of SARS-CoV-2, SARS-CoV and MERS-CoV each contain two long polypeptides represented as pp1a (red box) and pp1b (pink box) and four structural proteins (spike protein, S, light blue box; envelope protein, E, light purple box; membrane protein, M, yellow box; nucleocapsid protein, N, green box), and accessory proteins (orange boxes). The different lengths of the genomes and spike proteins are marked for each strain. NCBI reference sequences: NC_045512.2 (SARS-CoV-2), NC_004718.3 (SARS-CoV), NC_019843.3 (MERS-CoV).

Fig. 2

Mechanism of ACE2 desensitization after infection of SARS-CoV-2. Endocytosis of SARS-CoV-2 along with ACE2 causes reduction of surface ACE2. Infection of SARS-CoV-2 leads to upregulation of ADAM metallopeptidase domain 17 (ADAM-17), which mediates ectodomain shedding of ACE2. ADAM-17 also causes subsequent liberation of membrane bound cytokine precursors IL-4 and IFN-γ, which repress ACE2 mRNA transcription.

Fig. 3

Relationship between viral entry of SARS-CoV-2 and the renin-angiotensin-aldosterone system. Angiotensin-converting enzyme (ACE) converts angiotensin I (Ang I) to Ang II, which activates angiotensin type 1 receptor (AT₁R) and angiotensin type 2 receptor (AT₂R). ACE also mediates breakdown of bradykinin. ACE2 cleaves Ang II into Ang-(1–7), which activates AT₂R, MAS receptor, and MAS-related G protein-coupled receptor (MrgD receptor) to induce protective effects. SARS-CoV-2 spike protein binds ACE2 to facilitate endocytosis. Viral endocytosis reduces ACE2 expression which results in Ang II accumulation and increased vasoconstriction, inflammatory responses and myocardial injury. Other abbreviations: ACE inhibitor, ACEI; and ARB, angiotensin-receptor blocker.