Circulating Plasma Concentrations of ACE2 in Primary Aldosteronism and Cardiovascular Outcomes

Evidence before this study We did a systematic review of studies that focused on the angiotensin-converting enzyme 2 (ACE2) expression after targeted treatments in patients with primary aldosteronism (PA), along with comparisons to patients with essential hypertension (EH). ACE2 is a component of the counter-regulatory renin–angiotensin system, which has important roles in various cardiovascular events. Major electronic databases (including, but not limited to, PubMed, Embase, medRXIV, and Web of Science, without language restriction) were searched for related articles published by Nov, 2021. This search was complemented by interrogation of grey literature and manual searching of reference lists by abstracts and titles to identify relevant studies. The review was done in accordance with PRISMA guidelines. We identified no prospective or retrospective cohort report that specifically focused on PA patients and changes of their ACE2 levels with treatments as well as cardiovascular events. It was reported that the imbalance of ACE2 can be shed by both metalloprotease 17 (ADAM17) and type II transmembrane serine protease (TMPRSS2). Added value of this study This study provides the first epidemiological analysis of the plasma ACE2 concentrations ([pACE2]) in incident PA patients from a multi-center inception registration, and patients’ blood pressure readings were followed regularly before and after treatments. We found that the PA, together with EH, patients had similarly higher pACE2 levels and cellular TMPRSS2 from peripheral blood mononuclear cells (PBMCs), in comparison to those of normotensive controls. Such higher [pACE2] in PA patients are concordant to the known association of increased [pACE2] and worse cardiovascular disease outcomes and metabolic abnormalities. Additionally, we revealed unprecedentedly that adrenalectomy could attenuate [pACE2] and TMPRSS2 expression in PBMCs among unilateral PA (uPA) patients, regardless of their hypertension remission. We found such attenuation was not observed in those treated with mineralocorticoid receptor antagonist (MRA), in a large combined cohort of uPA and bilateral PA patients. Pre-treated PA, MRA-treated PA and EH patients have higher [pACE2] than those of the PA patients who had complete hypertension-remission and those normotensive controls. Implications of all the available evidence The known association between SARS-CoV-2 and ACE2 implicates a probable link of hypertension in COVID-19 pathogenesis. Increased pACE2 concentrations and expression of TMPRSS2 in PBMCs of PA patients could indicate augmented risks of SARS-CoV-2 infection in PA and hypertensive patients. Our study found that unilateral PA patients had attenuated pACE2 and TMPRSS2 levels after adrenalectomy, regardless of hypertension-remission or not. High pACE2 in PA was associated with all-cause mortality and incident cardiovascular events after targeted treatments. No similar reduction of pACE2 was noticed after MRA treatment, implicating the importance of early PA diagnosis and advising adrenalectomy as an optimal treatment for uPA patients. Elevated [pACE2] (> 23ng/ml) after targeted treatments was associated the risk of mortality and incident cardiovascular events.