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Comment
. 2020 Nov 1;41(41):4047-4049.
doi: 10.1093/eurheartj/ehaa761.

New data on soluble ACE2 in patients with atrial fibrillation reveal potential value for treatment of patients with COVID-19 and cardiovascular disease

Iziah E Sama  1 , Adriaan A Voors  1 , Dirk J van Veldhuisen  1
Affiliations
Comment

New data on soluble ACE2 in patients with atrial fibrillation reveal potential value for treatment of patients with COVID-19 and cardiovascular disease

Iziah E Sama et al. Eur Heart J. .
No abstract available

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Figures

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Take home figure Hypothetical representation of the regulation of ACE2 in cardiovascular disease with and without SARS-CoV-2 infection. The COVID-19 pandemic accentuates the failure to adequately inhibit the RAAS-associated increase in morbidity and mortality of patients with cardiovascular diseases. We therefore need to learn more about the role of ACE2 in relation to an activated RAAS and risk factors causing higher/lower ACE2 activity. (A) In non-infected patients, male sex and diabetes are associated with elevated levels of soluble ACE2 (sACE2) which can be shed by ADAM17 from membrane-bound ACE2 in tissues into the circulation. The loss of membrane-bound ACE2 elevates angiotensin II, and thus perturbs tissue RAAS. Higher concentrations of sACE2 are associated with greater disease severity (diabetes, congestive heart failure) and can be identified by elevated concentrations of circulating biomarkers, such as NT-proBNP, hs-cTnT, GDF-15, and D-dimer (Wallentin et al.7). The enzymatic activity of ACE2 is highly pH dependent (almost inactive at pH 5.0). In acidic blood (e.g. in diabetes), lower activity of sACE2 will increase angiotensin II concentrations. An elevated angiotensin II in turn could inhibit ACE2 activity and might forge a positive feedback loop for more ACE2 expression. (B) Upon eventual SARS coronavirus encounter, cells that still have ACE2 as receptors (including neighbouring cells that were induced to express more ACE2 by the feedback loop) will internalize and replicate the virus. Cells expressing viral particles on their surfaces can also bind neighbouring ACE2-expressing cells to form syncytia, further increasing viral yield and spread. Meanwhile some sACE2, virus, and virus-bound ACE2 will be shed into the circulation. Consequently, membrane-/tissue-bound ACE2 is further depleted, leading to a vicious cycle of worsening RAAS perturbation and increased viraemia and induction of ACE2 expression. Increasing levels of virus-bound soluble ACE2 (which is not an antibody–antigen complex) in the circulation might lead to thrombotic vascular occlusion, autoimmune inflammation, coagulopathy, and multiorgan ischaemia. These outcomes have been observed in COVID-19 patients. If the positive feedback loop were not plausible, virus re-infection and replication would be limited.
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