May 11, 2020

expert reaction to study looking at the ACE2 enzyme in men and women with heart failure, some of whom were taking ACE inhibitors or angiotensin receptor blockers, and making suggestions about sex differences in COVID-19

A study, published in the European Heart Journal, has looked at the ACE2 enzyme in men and women whilst investigating possible reasons for the differences in susceptibility to COVID-19 between men and women.

Prof Paolo Madeddu, Professor of Experimental Cardiovascular Medicine, University of Bristol, said:

“This is an interesting article, but I do not agree with the authors’ conclusions and I don’t understand how they have made any conclusions about COVID-19 – this study did not look at COVID-19 patients.

“The authors report the results of an observational study on the levels of circulating ACE2 in patients with heart failure.  ACE2 is a protein expressed on the surface of human cells in various organs including the heart and blood vessels.  The coronavirus has developed an intelligent tactic using the cell membrane-bound ACE2 as a doorway to unlock and infect human cells.  Another enzyme chops the part of ACE2 that sits outside the cell membrane, allowing this cleaved part to enter the blood circulation.  This cleaved molecule is what the authors have measured in patients with heart failure.

“ACE2 has important roles in preserving the function of heart and blood vessels by balancing the action of a similar but opposite protein named ACE.  In doing so, it acts like drugs called ACE inhibitors used to treat patients with heart disease and high blood pressure.  The role of cleaved ACE2 in blood is less clear.  In fact, it may protect human cells by sponging and blocking the virus in the circulation, allowing immune cells to kill it and thus impeding the virus from reaching and infecting the human cells.  Other researchers are exploiting this possibility to generate drugs that block the virus, while waiting for a vaccine.

“Dr Sama and colleagues found that blood levels of ACE2 were higher in male than in female in two distinct cohorts, and were associated with more frequent heart arrhythmia.  And they conclude that these data may explain why males are more at risk for COVID-19.  On the other hand, since the patients taking ACE inhibitors have similar levels of ACE2 than those on other drugs, they propose that there is no additional risk from taking ACE inhibitors.

“There are some limitations.  ACE2 level was measured only once, therefore we can’t know what individual variability in the levels might be.  It is well known, for instance, that the ACE isoform has a circadian cycle.  Whether the same is true for ACE2 remains unclear.  This could be tested by the authors in future if they re-analyse whether ACE2 levels change with time of blood sampling.  It should be also noted that the difference between males and females, although significant, was in the order of decimal points.  Therefore, any biological or medical interpretation of the difference should be taken with caution.  This particularly applies to the extrapolation to COVID-19, considering the impact that a precipitous interpretation of data can have on doctors and laypersons.  This was not a study in COVID-19 patients.

“In their conclusion, the authors state that these data might explain the higher incidence and fatality rate of COVID-19 in men.  It is important to emphasise this is purely speculation and is not supported by the data provided, and should be tempered.  Studies in COVID patients are needed to determine whether circulating and cellular levels of ACE2 are a predictor of severity in COVID-19.

“The second message from Dr Sama’s article is that the levels of ACE2 did not differ between patients on ACE inhibitors compared with those on other therapies.  The study does not report the pretreatment values in the two groups.  The authors conclude that there is no evidence that ACE inhibitors increase vulnerability to COVID-19.

“International societies recommend that these drugs should not be discontinued in COVID-19.  Nonetheless, typical reasons not to start ACE inhibitors remain valid as they did before, for instance in patients with previous history of angioedema or reported adverse reactions, once more considering the risk for frail COVID-19 patients.

“In conclusion, the article by Sama provides interesting evidence of modestly higher, though significant, levels of circulating ACE2 in cardiovascular male patients.  Nonetheless, in my opinion, it is premature to use ACE2 measurements to make prognostic and treatment decisions in COVID-19 patients.  Biomarkers are laboratory tests that help to diagnose a disease, predict disease outcome and decide what is the best treatment.  Biomarkers different from ACE2 have been used so far to understand patients at risk in COVID-19.”

Prof John Boyd Chambers, Professor of Clinical Cardiology and Consultant Cardiologist, Guy’s and St Thomas’ Hospitals, said:

“I think the authors provide a reasonable list of limitations themselves:

“1.Their patients had heart failure and were not necessarily representative of fit people of a similar age.

“2.They measured circulating and not membrane-bound ACE2 and obviously it is the membrane-bound protein to which the SARS-COV-2 virus might attach.

“3. This was an observational study and there was no prospective assessment of the risk of developing covid-19 according to circulating ACE2 level.

“So this study is hypothesis-generating and suggests that future work should assess whether ACE2 levels affect the risk of developing covid-19 or the severity of the disease.  The most important result is I think that ACE2 levels were not raised by treatment with ACE inhibitor or ARB drugs.  There had previously been speculation that these drugs may have explained the higher risk from heart failure or hypertension.”

Prof Ian Hall, Professor of Molecular Medicine, and Director of the Nottingham Biomedical Research Centre, University of Nottingham, said:

“This paper describes work looking at possible reasons why men seem to be more susceptible to severe COVID19 disease than women.  The investigators found that men with heart failure have slightly higher circulating levels of ACE2, the receptor used by SARS-COV 2 to enter cells, and speculate this may explain the difference in disease susceptibility between men and women.  In addition, they found that levels of ACE2 in the blood were not affected by commonly used blood pressure treatments, which had previously been suggested to increase the risk of developing COVID19.  These latter results are in keeping with clinical studies which have recently reported that taking these medications (ACE inhibitors and angiotensin receptor antagonists) does not seem to increase risk of severe COVID19 disease.

“The study has been carefully performed and the number of subjects including is reasonably large so the results are likely to be generalizable to the real world setting.  There are two caveats worth noting, which the authors acknowledge, the most important being that ACE2 was measured in blood rather than the most important site (i.e. the airways), and the second being that the patients studied had pre-existing heart failure and so may not be entirely representative of the general population.

“Putting together this work with other recent studies, I think we can be reassured that patients taking ACE inhibitors or angiotensin receptor antagonists are not at increased risk form COVID19 just because they are taking these drugs, although some may of course have underlying conditions (including heart failure) which are known to increase risk of severe COVID19 disease.  So anyone taking these drugs should not discontinue them because of anxiety over developing COVID19.

“With respect to the differences in ACE2 expression in men and women, my personal view is that these differences are unlikely by themselves to account for the difference in risk of developing severe COVID19.  The actual difference in ACE2 levels between men and women, whilst statistically significant, is in real terms small, and I believe it likely that whilst this might contribute in a small way there must be other explanations as to why men are at increased risk of severe disease.  One potential explanation would be that differential immune responses to the virus, regulated by genetic differences between men and women, may also underlie this difference in susceptibility.”

Prof Francesco Cappuccio, Professor of Cardiovascular Medicine & Epidemiology and Consultant Physician, University of Warwick and UHCW NHS Trust, Coventry, said:

“The current paper should be interpreted in the context of the other evidence accumulating by the hour which attempts to answer two questions: [1] why are individuals with underlying cardiovascular conditions, such as high blood pressure, diabetes, coronary heart disease and heart failure, more likely to develop severe Covid-19 and die than those without underlying conditions? and [2] does the regular use of angiotensin-converting-enzyme inhibitors (ACE-i) or angiotensin-receptor blockers (ARB) – medicine for heart failure and high blood pressure – make patients more likely to get infected and to die of Covid-19?

“One theory suggested to explain these early observations during the pandemic is that a rise in the circulating and tissue levels of the ACE2, an enzyme that in cells in the lab and in animal experiments can be a carrier for the coronavirus to enter cells, would be the explanation.  ACE2 levels can be raised in patients on regular treatment with drugs (ACE-I and ARB) widely used and effective in high bloody pressure, diabetes, coronary heart disease and heart failure.  The theory, without direct evidence in support, has led to dangerous calls by some for patients to stop ACE-I and ARB therapies.

“The present study has strengths: it is large, uses index and validation groups of people, measures circulating blood levels of the enzyme ACE2, and is the first in patients with heart failure.  There are however several caveats.  It is an observational study and statistically it presents unadjusted comparisons only, which means some of the observed patterns could be due to confounding factors.  It lacks a control group.  It is only able to find associations rather than clinical predictors implying cause and effect – this means it cannot offer evidence of the implication (or lack of it) of the ACE2 in the high fatality rate in this group.  Circulating ACE2 rather than tissue ACE2 was measured.  Finally, no patient in the study had confirmed Covid-19.

“The study also shows that heart failure patients taking ACE-I or ARB did not have higher concentrations of ACE2 in their blood.  The authors’ final recommendation is compatible with evidence published in the New England Journal of Medicine on May 3rd, suggesting that neither ACE-I nor ARB are associated with greater risk of SARS-CoV-2 infection (Mancia et al.) or severity (Reynolds et al.) or risk of death (Mehra et al.) in Covid-19 patients.

“The evidence so far, including in this study, does not support the discontinuation of ACE-I or ARB.  Patients on these drugs, whether for heart failure or for high blood pressure or diabetes, should not stop them unless advised and under strict medical supervision and with the addition of a suitable replacement medicine.”

‘Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin–angiotensin–aldosterone inhibitors’ by Iziah E. Sama et al. was published in the European Heart Journal at 00:05 UK time on Monday 11 May 2020.

DOI: 10.1093/eurheartj/ehaa373

All our previous output on this subject can be seen at this weblink: 

www.sciencemediacentre.org/tag/covid-19

Declared interests

Prof Ian Hall: “No conflicts.  I am Director of the NIHR Nottingham BRC but don’t work directly in this area.”

Prof Francesco Cappuccio: “None to declare.”