Angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers and risk of COVID 19: information from Bartter's and Gitelman's syndromes patients

The COVID-19 pandemic has focused interest on the renin-angiotensin system (RAS), as it is not only part of its infection process but also of the lung injury, a major cause of its morbidity and mortality. The current state of our understanding of RAS has led to conflicting suggestions regarding how RAS and its role in COVID-19 should inform treating COVID-19. It has been suggested that angiotensin-converting enzyme (ACE) inhibitors or angiotensin II-type 1 receptor blockers (ARBs) be avoided, as they potentially upregulate ACE2, the entry point for SARS-CoV-2 [1], which however has been criticized [2]. Conversely, there are suggestions that ARBs might be beneficial [3], as SARS-CoV-2 causes ACE2 downregulation slowing the Ang II conversion to the vasodilatory, anti-inflammatory and antiatherosclerotic Ang 1–7 [4–6], while the use of ARBs would be beneficial by blocking the excessive Ang II-mediated Ang II type-1 receptors activation, upregulating ACE2 activity and increasing Ang 1–7 levels. Our interest in RAS is as a result of our decades long use of Gitelman's and Bartter's syndromes patients as nature's experiments to explore and better define the human RAS system [7]. Specifically, these patients have an activated RAS and high Ang II levels, yet blunted Ang II cardiovascular effects, normotension or hypotension representing a model of endogenous Ang II antagonism [7]. Of note and directly relevant to the discussion regarding ACE2, they have increased and correlated levels of both ACE2 and Ang 1–7 [8]. These human data would suggest increasing ACE2 increases Ang 1–7, which supports that increasing ACE2 via ARBs and ACE inhibitors might be beneficial for patients infected by SARS-CoV-2 as has been shown for ACE2 in hyperoxic lung injury [9]. Furthermore, our cohort of Gitelman's and Bartter's patients provide evidence, admittedly anecdotal, against the hypothesis that increased ACE2 might provide more targets for the CoV-2 virus. A telephone survey of over 100 Gitelman's and Bartter's patients, all from the Northern Italy regions of Veneto, Lombardia and Emilia Romagna, the hotspots of the COVID-19 pandemic in Italy, found none of them infected with COVID-19, which might further support that the increased risk to COVID-19 due to increased ACE2 is unlikely. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.