Research May Explain Why Men Are More Susceptible to COVID-19 Than Women

Coronavirus spike protein and receptor, illustration
Molecular model of a coronavirus spike (S) protein (red) bound to an angiotensin-converting enzyme 2 (ACE2) receptor (blue) on a human cell. S proteins are found in the viral membrane, they bind to receptors on host cell membranes and facilitate the virus's entry to the cell. Once inside the cell, the virus uses the cells' machinery to make more copies of itself. Both SARS (severe acute respiratory syndrome) and the new coronavirus SARS-CoV-2 (previously 2019-CoV) bind to this receptor. SARS-CoV-2 emerged in Wuhan, China, in December 2019. The virus causes the disease Covid-19, a respiratory illness that can lead to pneumonia and can be fatal in some cases.

European research shows that men with heart failure have higher levels of a protein called angiotensin converting enzyme 2 than women, which could increase their risk for coronavirus infection.

Angiotensin converting enzyme 2 (ACE2) is a common target for cardiovascular disease therapies, as it plays a role in regulation of blood pressure. Cardiac drugs such as ACE inhibitors or angiotensin receptor blockers (ARBs) can impact levels of this protein.

COVID-19 infects cells by binding to the ACE2 protein, found on the surface of cells in the lungs, cardiovascular system, kidneys and in the gut. Because of this, it has been suggested that treatment with drugs that raise levels of ACE2 in the blood might increase a person’s risk of contacting the coronavirus.

However, the research, published in the European Heart Journal, showed that treatment with these drugs did not significantly impact levels of ACE2 in blood plasma in a group of 2608 men and 1112 women with heart failure. Indeed, patients taking these drugs seemed to have slightly lower levels of the enzyme than others in the two groups.

The biggest predictor of high ACE2 levels was being male. Dr Iziah Sama from UMC Groningen in the Netherlands, who is the first author of the study, commented: “When we found that one of the strongest biomarkers, ACE2, was much higher in men than in women, I realised that this had the potential to explain why men were more likely to die from COVID-19 than women.”

Overall, the researchers looked at two groups of heart failure patients, one of 1485 men and 537 women, recruited from 11 European countries and a validation cohort of 1123 men and 575 women from Scotland. The median age of the men and women ranged from 69-76 years across both groups.

While the researchers did not include patients with Covid-19 in the study, and caution that they only tested for plasma levels of ACE2 and not tissue levels, the confirmation that the use of ACE inhibitors or ARBs did not appear to impact levels of ACE2 is useful.  Doctors treating cardiovascular disease patients who might be concerned that the drugs their patients are being treated with could be harmful can take some reassurance from this research.

The gene encoding the ACE2 protein is X-linked and there are particularly high levels of the protein found in the testes, which could explain the higher levels seen in men.

Whether this entirely explains the reason that men are more vulnerable to Covid-19 remains to be seen. Another idea that is being investigated is that women may be protected from infection by female hormones such as estrogen.

There are many research studies being conducted at the moment that are trying to make sense of the way Covid-19 infects the body. Previous research in mice suggests that ACE2 may actually have a protective effect against the lung damage seen in Covid-19 patients by increasing levels of another protein called angiotensin, which helps to dilate the blood vessels.

However, regardless of the role that is played by ACE2 in Covid-19 patients, the current results and the higher levels of ACE2 seen in the men in the group do offer an interesting insight that could go some way to explaining the gender differences seen in incidence of Covid-19.

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