Plasma angiotensin-converting enzyme 2: novel biomarker in heart failure with implications for COVID-19.

TLDR: Re recombinant human ACE2 in pre-clinical models and patients with pulmonary arterial hypertension and acute lung injury led to a prompt increase in the Ang 1-7/Ang II ratio, reflecting ACE2 action, thus providing a direct link between the tissue and systemic RAS.

Abstract: Angiotensin-converting enzyme 2 (ACE2) has emerged as the negative regulator of the renin–angiotensin system (RAS) and was more recently identified as the SARS-CoV-2 receptor responsible for the current COVID-19 pandemic. The high burden of illness and high case fatality rate in patients with COVID-19 is driven in part by the high affinity of SARS-CoV-2 for ACE2, leading to viral entry and multisystem illness with pulmonary, gut, renal, central nervous stystem, and cardiovascular manifestations. The novel dual role of ACE2 in the RAS and as the SARS-CoV-2 receptor provides a fundamental connection between viral infection, immunity, and cardiovascular disease. Direct clinical evidence came from SARS and the current COVID-19 pandemic, where there is down-regulation of tissue ACE2 through endocytosis and proteolytic processing which leads to a corresponding increase in plasma angiotensin II (Ang II) levels as seen in COVID-19 patients (linearly correlated with SARS-CoV-2 viral load), thus providing a direct link between the tissue and systemic RAS. The SARS-CoV genome was detected in postmortem autopsy heart samples of patients who succumbed to SARS infection, suggesting prompt viral infiltration of myocardial tissue during infection. These hearts had markedly decreased myocardial ACE2 expression levels with a concomitant increase in myocardial inflammation and fibrosis. The RAS is an endogenous peptide system with key physiological and pathophysiological roles in cardiovascular disease, as illustrated by the success of its pharmacological blockers [including ACE inhibitors, angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs)] in mitigating cardiovascular disease progression. Ang II (octapeptide) is produced through proteolytic cleavage of Ang I (decapeptide) by ACE which activates angiotensin type 1 receptors (AT1Rs), thereby mediating downstream pathophysiological effects. The ACE2/Ang 1-7 counter-regulatory axis, by removing a single C-terminus, inactivates Ang II and forms Ang 1-7. This septapeptide acts upon the Mas receptor to initiate vasodilatory and anti-inflammatory effects mediated through beneficial signalling pathways (Figure 1). ACE2 is widely expressed and, in the cardiovascular system, ACE2 is localized to cardiomyocytes, cardiac fibroblasts, pericytes, vascular endothelium, and vascular smooth cells. Various diseases including heart failure, hypertension, and diabetes are characterized by a relative ACE2-deficient state, reducing the homeostatic protective mechanism. Importantly, recombinant human ACE2 in pre-clinical models and patients with pulmonary arterial hypertension and acute lung injury led to a prompt increase in the Ang 1-7/Ang II ratio, reflecting ACE2 action. During this unprecedented time of a rapidly expanding global epidemic, both the lay and medical communities are struggling to find relevant information concerning medical therapies to mitigate the impact of COVID-19. With the current paucity of data, associations which generally would be insufficient to guide medical therapy are given more weight than would be anticipated under more usual circumstances. The coronavirus SARS-CoV-2 and COVID-19 interface with the RAS with ACE2 led to a great deal of speculation regarding the role of pharmacological inhibitors of the RAS and COVID-19 infection. Pharmacological antagonists of the RAS, such as ACE inhibitors and ARBs, protect the cardiovascular system partly by increasing ACE2 levels in disease states, thereby dampening the effects of an activated RAS. The major conundrum is that these drugs which are used to treat cardiovascular disorders may facilitate COVID-19 infection, while, on the other hand, discontinuing their use will augment