ACE2: A Valuable Biomarker for COVID19 Susceptibility in Heart Patients

By Sahana Shankar, Ph.D. Candidate

A new study from Europe reports that men with heart failure are more prone to COVID-19 due to higher ACE2 levels in their blood, a key enzyme involved in viral entry.

COVID-19 is overwhelming the global healthcare system with not just infections in healthy patients but also posing higher risks to a wide spectrum of people with pre-existing medical conditions. While clinicians are working on treating patients, they are also putting together epidemiologic data to better understand risk groups, prognosis, and treatment options for different sets of patients. COVID-19 attacks the pulmonary system and hence poses a high risk for people with cardiovascular diseases.

Older people are another high-risk group for COVID-19 infections, and the elderly with cardiovascular disease are increasingly vulnerable. There is data from the previous SARS epidemic in 2003 that men fared worse with a fatality rate of 21.9% as against women at 13.2%, and approximately 70% of COVID19 deaths in Italy were men. This suggests that men, especially the elderly, are more likely to be infected and may have a poor prognosis.

ACE2 and COVID Susceptibility

Angiotensin-converting enzyme 2 (ACE2) is the receptor through which the SARS-CoV-2 virus enters the cells, and it is a known predictor of heart failure. A current study, published in the European Heart Journal, analyzed the blood plasma levels of ACE2 in elderly heart failure patients under anti-ACE2 medication across 11 countries. The samples from Biobank were divided into two cohorts- the index cohort, consisting of 1485 men and 537 women and the validation cohort-a second group of 1123 men and 575 women. The index cohort was to test the hypothesis that an increased concentration of ACE2 in the blood was more apparent in men than in women, making them more vulnerable to COVID-19 infection. The validation cohort was to check for reproducibility and validation of their data. The participants were aged between 69 and 76 years.

The study used a high-throughput multiplex immunoassay to assess relative ACE2 levels and correlated it with demographic and clinical variables. By analyzing ACE2 concentrations and possible causative clinical parameters such as the use of drugs-ACE inhibitors, angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs) and the history of pulmonary disease and coronary surgery, the authors observed that:

(a) male sex was the strongest predictor of higher ACE2 levels in the blood

(b) Use of ACE2 inhibitors, ARBs, and MRAs are not associated with elevated ACE2 in blood in the index cohort, and this was partly substantiated in the validation cohort. There was a slight correlation of MRA use with increased plasma ACE2 levels only in the validation cohort.

However, this does not warrant the discontinuation of MRAs in heart failure patients with COVID-19 since “the effect of MRAs on ACE2 concentrations is not clear.'” Prof Voors said, “they are a very effective treatment for heart failure, and the hypothetical effects on viral infection should be weighed carefully against their proven benefits.”

Some recent data indicated that common cardiovascular drugs that target the renin-angiotensin-aldosterone system, commonly called RAAS inhibitors, may increase blood levels of ACE2 and hence increase the risk of COVID-19 in cardiovascular patients. However, this study indicates that specifically in the case of heart failure patients on RAAS inhibitor drugs, there is no marked increase in the concentration of ACE2 in the blood.

Lead author, Prof.Adriaan Voors (MD-PhD), Professor of Cardiology at the University Medical Center, Groningen (The Netherlands), said, “Our findings do not support the discontinuation of these drugs in COVID-19 patients as has been suggested by earlier reports.” Nonetheless, the study is limited by the fact that it does not study the effect of RAAS inhibitors on COVID-19 patients with or without a heart condition and that it is restricted to examining the ACE2 levels in the blood and not in other tissues such as lungs where ACE2 levels are high, and SARS-CoV-2 is known to wreak significant damage.

In a special issue that focused on clinical reviews, editorials and research articles on the emerging data on COVID-19 and cardiovascular disease, the European Heart Journal published this study since “the results obtained in heart failure patients in the pre-COVID-19 period offer supporting evidence to continue ACE inhibitors or ARBs in patients at risk for SARS-CoV-2 infection.” Dr. Gavin Y Oudit, from the University of Edmonton, Canada, and Dr.Marc A Pfeffer, from Harvard Medical School, Boston wrote an accompanying editorial explaining the physiological and clinical importance of ACE2 system and contextualizing this clinical review of ACE2 data. “Moving ahead, measuring plasma angiotensin peptides and plasma ACE2 levels and activity in COVID-19 patients can provide a direct evaluation of the state of the RAS and guide therapeutic interventions as we await the results of ongoing randomized clinical trials”, providing a roadmap to navigate heart ailments in the time of COVID-19.

Related Article: Mutations Observed in Coronavirus “Spike” Caution

References

1. https://academic.oup.com/eurheartj/article/41/19/1810/5834647
2. https://academic.oup.com/eurheartj/article/41/19/1818/5834646
3. https://www.escardio.org/The-ESC/Press-Office/Press-releases/Men-s-blood-contains-greater-concentrations-of-enzyme-that-helps-COVID-19-infect-cells

Author

Sahana Shankar