According to a large study published on May 10, men have higher concentrations of angiotensin-converting enzyme 2 (ACE2) in their blood than women. Since ACE2 is an enzyme that helps the coronavirus infect healthy cells, this may be a potential explanation for why men are more susceptible to coronavirus disease 2019 (COVID-19) than women, according to the study, published by the European Society of Cardiology.2

Although COVID-19 infects everyone, the data have demonstrated that more men (58.1%) than women (41.9%) are testing positive for COVID-19. This was also the case in the previous severe acute respiratory syndrome coronavirus (SARS-CoV) epidemic in 2003, in which men had a higher mortality rate than women (21.9% vs 13.2%).2

A recent report from Italy supported these data with further evidence that demonstrated that 70% of the patients who died of COVID-19 in Italy were male and mostly elderly.1

Furthermore, the most susceptible population seem to be elderly men with cardiovascular disease and comorbid conditions. This could be related to the increased concentrations of ACE2 in their blood, as ACE2 is known to increase the risk of heart failure. ACE2 acts not only as an enzyme, but also as a receptor for both SARS-CoV and SARS-CoV-2.2

ACE2 has been found to be mostly present in the heart, testis, kidneys, and lungs. It is then shed into the plasma, which is the liquid part of blood, from these locations.2

Prior research has shown that inhibitors of the renin–angiotensin–aldosterone system (RAAS), such as ACE inhibitors or angiotensin receptor blockers (ARBs), may increase ACE2 concentrations in plasma. This would suggest that cardiovascular patients taking these drugs are at a higher risk of COVID-19.2

However, the new study demonstrated that this is not the case. The study was able to confirm that heart failure patients taking drugs that target RAAS did not have higher concentrations of ACE2 in their blood.2

“Our findings do not support the discontinuation of these drugs in COVID-19 patients, as has been suggested by earlier reports,” said lead study author Adriaan Voors, MD, PhD, professor of cardiology at the University Medical Center Groningen, in a press release.1

Voors and his colleagues were studying differences between men and women in regard to biomarkers of disease in the blood before COVID-19, so the results of their research were available at the start of the pandemic.2

“When we found that one of the strongest biomarkers, ACE2, was much higher in men than in women, I realized that this had the potential to explain why men were more likely to die from COVID-19 than women,” said study co-author Iziah Sama, PhD, from UMC Groningen.1

In order to test this hypothesis, the researchers measured ACE2 concentrations in blood taken from heart failure patients from 11 European countries. There were 2 groups in the study, with 1485 men and 537 women in the first group, and 1123 men and 575 women in the second. The average age of the participants in the first group was 69 years for men and 75 years for women, while in the second group the average age was 74 years for men and 76 years for women.2

Upon looking at a number of factors that might affect ACE2 concentrations, the researchers found that male sex was the greatest predictor of high ACE2 concentrations. The researchers speculated further that this may be due to the higher concentration of ACE2 in the testes, which would explain why men have a higher ACE2 concentration and are thus more vulnerable to COVID-19.2

However, the researchers acknowledged that a potential limitation to the study is that they only measured concentrations of ACE2 in plasma, and not in tissues. For this reason, the researchers cannot confirm whether concentrations in the blood are similar to those in tissues. This may be important because the ACE2 in lung tissues is considered relevant to viral infection in the lungs. Further research will be necessary to understand the presence of ACE2 concentrations in lung tissues as well, the study authors concluded.2

REFERENCES
  1. Men's blood contains greater concentrations of enzyme that helps COVID-19 infect cells [news release]. European Society of Cardiology; May 10, 2020. eurekalert.org/pub_releases/2020-05/esoc-mbc050720.php. Accessed May 11, 2020.
  2. Sama IE, Ravera A, Santema BT. Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin–angiotensin–aldosterone inhibitors. European Heart Journal. 2020. doi: 10.1093/eurheartj/ehaa373.