Angiotensin-converting enzyme 2, sex differences, and COVID-19: The missing link.

We read with interest the article by Elgendy and Pepine [1] regarding the still poorly understood factors contributing to the observed sex differences in COVID-19 outcomes in men and women. Although the authors made an attempt to connect differential expression of angiotensin-converting enzyme 2 (ACE2) in men and women with COVID-19 outcomes, the proposed link is tenuous. In the study they cite, no differences could be demonstrated in plasma ACE2 between healthy men and women at any age [2]. Recently, a study in heart failure patients (who are known to have lower ACE2 levels) showed a slight (6%), but significantly, higher plasma ACE2 level in men compared with women [3]. Differential COVID-19 outcomes in men and women might thus rather reflect the overall higher incidence of cardiovascular risk factors and disease in men, and the inherent differences in immune response to viral infections in the two sexes, than a speculative difference in ACE2 expression.

The authors hypothesized that increased ACE2 expression might predispose to COVID-19 infection via increased viral entry into cells. However, lower ACE2 expression leads to less conversion of angiotensin II to angiotensin-(1–7), resulting in toxic accumulation of angiotensin II, especially when ACE2 receptors are being blocked and downregulated by the viruses [4]. This mechanism might be the main contributor to severe cardiopulmonary injury and worse outcomes in COVID-19, despite its role in viral entry [5].

ACE2 is important in the pathophysiology of COVID-19, but whether there are gender differences that impart divergent outcomes requires further research.

Declaration of Competing Interest

The authors report no relationships that could be construed as a conflict of interest.