LAUSR

To the Editor: We read with interest the report by Yaghi et al1 outlining the rates of ischemic stroke in patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus (coronavirus disease 2019 [COVID-19]). Concerningly, the cryptogenic stroke subtype was significantly over-represented compared with historical controls. Further the patients were younger, and the mechanism was presumed to be acquired hypercoagulability with resultant stroke. We postulate a mechanism for increased cerebral thrombogenesis during COVID-19 infection, due to its interaction with ACE2 (angiotensin-converting enzyme 2). ACE2 is an integral membrane protein that counteracts the renin-angiotensin system and is widely expressed in the endothelium, heart, lungs, and kidneys. Recent findings from our research demonstrated a novel association between circulating plasma ACE2 activity and embolic stroke of unknown source.3 The SARSCoV-2 spike protein binds to ACE2 to initiate entry into cells and is then thought to downregulate ACE2.4 Endothelial dysfunction is associated with markedly increased risk for cerebrovascular events. The reninangiotensin system pathway and angiotensin II are associated with reduced nitric oxide bioavailability and endothelial dysfunction resulting in concurrent inflammation and thrombosis within the vasculature. Angiotensin II is the major substrate for ACE2 and results in both degradation of Ang II and the production of the vasodilator, angiotensin 1 to 7. Preclinical murine ACE2 knock out models have demonstrated cerebral endothelial dysfunction.5 The association between circulating plasma ACE2 and stroke in humans is limited. We previously demonstrated significantly higher plasma ACE2 activity in patients with embolic stroke of unknown source compared with a risk factor matched control group (10.16 versus 7.24 pmol/mL per min, P=0.04).3 This may provide a plausible explanation for the increased occurrence of stroke in young patients with COVID-19. The increased plasma ACE2 activity noted in patients with stroke may result from shedding of ACE2 from the cellular architecture, with a concomitant reduction in cellular ACE2 receptors. This would result in unopposed and detrimental effects of the reninangiotensin system system on the cerebral vasculature. In these susceptible patients, a coexisting infection with COVID-19 may lead to further downregulation of ACE2 receptors. This double hit could act as a catalyst for further endothelial dysfunction, platelet activation, and accelerated thrombogenesis resulting in stroke. Downregulation of ACE2 receptors may also account for the observation of ischemic stroke in patients with seemingly mild respiratory symptoms and absence of a systemic inflammatory response. Conversely, a systemic inflammatory response and stroke from distal embolization cannot be discounted. Further data is urgently needed to assess the importance of ACE2 in COVID-19 and whether therapies to counteract the potential downregulation of ACE2 receptors in patients with COVID-19 can improve outcomes.