Cardiovascular illnesses, such as high blood pressure and heart problems, are often treated with angiotensin-converting enzyme (ACE) inhibitors. The ACE inhibitors lower blood pressure by relaxing veins and arteries. They have recently received a lot of attention due to concern that they could increase the fatality of COVID-19. However, multiple studies now dispute this.
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Image Credit: Explode / Shutterstock.com
How do ACE inhibitors work?
The precise mechanism of ACE inhibitors is not well known, apart from the fact that they interfere with the renin-angiotensin-aldosterone system while not directly being related to renin levels in the blood. ACE inhibitors target an enzyme involved in the production of angiotensin II from angiotensin I.
Angiotensin II narrows the body’s blood vessels (also called vasoconstriction), which can contribute to high blood pressure and thus affect the heart. In addition to this, angiotensin II causes the release of hormones that raise blood pressure.
ACE inhibitors prevent the production of angiotensin II, and therefore effectively stop the increase in blood pressure. The decreased angiotensin II levels also inhibit the remodeling of smooth muscle and cardiac myocytes. It is also hypothesized that ACE inhibitors disturb the degradation of bradykinin. Bradykinin is a peptide causing vasodilation.
Use and effects of ACE inhibitors
While the main use of ACE inhibitors is in reducing blood pressure, they can also be used for coronary artery disease, diabetes, migraines, and certain chronic kidney diseases. They are a relatively safe form of treatment, but they are still closely monitored.
There is evidence that the effectiveness of ACE inhibitors differs by age and race, which is why their use is sometimes inconsistent. One of the more common side effects of ACE inhibitors is the development of a dry cough, which occurs in 10% or less of users. There is no clear treatment for this cough.
One of the most significant side effects of ACE inhibitors is angioedema, which can affect the tongue, glottis and/or larynx and thus obstruct the airways. Angioedema occurs more commonly in the African American population than other racial groups in America, but treatments of angioedema are varied. Some evidence shows that adrenaline can help, whereas newer research has indicated that bradykinin blocking agents can improve angioedema.
There are some cases where ACE inhibitors can be contraindicated, meaning they can be more harmful than beneficial. This can be the case in patients with a history of angioedema, either in their medical history or in their family history.
In addition to this, ACE inhibitors are contraindicated in patients taking direct renin inhibitors and patients who are pregnant as this can cause skull hypoplasia, anuria, hypotension, skeletal deformations, and death.
Lastly, ACE inhibitors can be dangerous when used in combination with angiotensin II receptor blockers (ARBs), as they can cause life-threatening hyperkalemia in patients with heart failure.
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ACE inhibitors and COVID-19
There have been concerns throughout the pandemic that ACE inhibitors could increase susceptibility to COVID-19. These concerns were based on the biological plausibility of such an effect and the observation that patients with hypertension and other cardiovascular comorbidities are overrepresented among those with poor COVID-19 outcomes.
On the other side, there has also been some speculation that ACE inhibitors could have a beneficial role in COVID-19, based on some clinical studies in patients with other viral respiratory infections. Research regarding this theory is limited.
One of the targets of ACE inhibitors, angiotensin-converting enzyme 2, is a co-receptor for viral entry of the virus, SARS-CoV-2. It has furthermore been implicated in the extended pathogenesis of COVID-19. However, there is limited information on the direct link between the gene expression of angiotensin covering enzyme 2 and COVID-19 pathogenesis and mortality.
Those with hypertension are recognized as having an increased risk of severe illness from COVID-19, as stated by organizations such as the CDC. However it is unclear whether hypertension directly causes increased severity as it could be because of associated variables such as age or risk factors such as other cardiovascular diseases, and the severity of the actual hypertension could also influence COVID-19 outcomes.
Since hypertension is often treated with ACE inhibitors, they were suspected to have a confounding role in the severity of COVID-19, however multiple studies now suggest that this is not the case.
A report from the World Health Organization (WHO) in May 2021 indicated that ACE inhibitors did not have detrimental effects in relation to COVID-19. Of the 11 observational studies they analyzed, a history of using ACE inhibitors was not associated with increased severity of COVID-19.
Moreover, in the BRACE CORONA trial, a randomized clinical trial carried out in 2020 and published in January 2021, ACE inhibitors were not found to have an effect on the mean number of days alive and out of hospital amidst a cohort of hospitalized mild to moderate COVID-19 patients. Thus, the findings do not support patients with these symptoms discontinuing existing ACE inhibitor medication.
Another study published in The Lancet, February 2021, found that ACE inhibitors were not associated with increased risk of COVID-19 hospitalization or diagnosis, also suggesting that users of ACE inhibitors should not discontinue their use to reduce COVID-19 risk.
This sentiment has been echoed by the Council on Hypertension of the European Society of Cardiology, the American Heart Association, the Heart Failure Society of America, and the American College of Cardiology.
References
- Beyerstedt, S., Casaro, E.B. & Rangel, É.B. (2021). COVID-19: angiotensin-converting enzyme 2 (ACE2) expression and tissue susceptibility to SARS-CoV-2 infection. Eur J Clin Microbiol Infect Dis. doi: 10.1007/s10096-020-04138-6
- Herman LL, Padala SA, Annamaraju P, et al. Angiotensin-Converting Enzyme Inhibitors (ACEI). In: StatPearls [Online]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: <https://www.ncbi.nlm.nih.gov/books/NBK431051/>
- Lopes R.D., et al. (2021) Effect of Discontinuing vs Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on Days Alive and Out of the Hospital in Patients Admitted With COVID-19: A Randomized Clinical Trial. JAMA, 325(3):254–264. doi:10.1001/jama.2020.25864
- Mayo Clinic. 2019. Angiotensin-Converting Enzyme (ACE) Inhibitors. [online] Available at: <https://www.mayoclinic.org/diseases-conditions/high-blood-pressure/in-depth/ace-inhibitors/art-20047480> [Accessed 7 June 2020].
- Morales, D.R. et al. (2021). Renin–angiotensin system blockers and susceptibility to COVID-19: an international, open science, cohort analysis. The Lancet, 3(2):E98-E114. doi:10.1016/S2589-7500(20)30289-2
- Patel, A. & Verma, A. (2020). COVID-19 and Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers. Journal of the American Medical Association, 323(18), pp.1769-1770. doi: 10.1001/jama.2020.4812
- Salazar, M.R. (2020) Is hypertension without any other comorbidities an independent predictor for COVID‐19 severity and mortality? The Journal of Clinical Hypertension, 23(2):232-234. doi: 10.1111/jch.14144
- World Health Organization. 2020. COVID-19 And The Use Of Angiotensin-Converting Enzyme Inhibitors And Receptor Blockers. [online] Available at: <https://www.who.int/news-room/commentaries/detail/covid-19-and-the-use-of-angiotensin-converting-enzyme-inhibitors-and-receptor-blockers> [Accessed 7 June 2020].
Further Reading