Renin-Angiotensin System Inhibitors and COVID-19

The recent SARS-CoV-2 Coronavirus pandemic and subsequent spread of the disease called
COVID-19 brought back to the discussion a topic already highlighted during the SARS-CoV-4
crown-related SARS epidemic of 2002. In particular, the angiotensin converting enzyme 2
(ACE2) has been identified as a functional receptor for coronaviruses, therefore including
SARS-CoV-2. ACE2 is strongly expressed in the heart and lungs. SARS-CoV-2 mainly invades
alveolar epithelial cells, resulting in respiratory symptoms. These symptoms could be made
more severe in the presence of increased expression of ACE2. ACE2 levels can be increased by
the use of renin-angiotensin system inhibitors (RAS). This therapeutic class is particularly
widespread, as it represents the most important pharmacological protection for widespread
diseases such as high blood pressure, heart failure and ischemic heart disease. It is
therefore possible to hypothesize that pharmacological treatment with RAS inhibitors may be
associated with a more severe symptomatology and clinic than COVID-19.

However, several observations from studies on SARSCoV, which are most likely also relevant
for SARS-CoV-2 seem to suggest otherwise. Indeed, it has been shown that the binding of
coronavirus to ACE2 leads to downregulation of ACE2, which in turn causes an ACE / ACE2
imbalance excessive production of angiotensin by the related ACE enzyme. Angiotensin II
receptor 1 (AT1R) stimulated by angiotensin causes an increase in pulmonary vascular
permeability, thereby mediating an increase in lung damage. Therefore, according to this
hypothesis, the upregulation of ACE2, caused by the chronic intake of AT1R and ACE
Inhibitors, could be protective through two mechanisms: the first, that of blocking in the
AT1 receptor; second, increasing ACE2 levels decreases ACE production of angiotensin and
increases ACE2 production of angiotensin 1-7.

The quickest approach to evaluating these two opposing hypotheses is to analyze the medical
records of COVID-19 patients to determine whether patients on RAS antagonist therapy have a
different disease outcome than patients without the above therapy.

This research aims to verify whether the chronic intake of RAS inhibitors modifies the
prevalence and severity of the clinical manifestation of COVID-19.