ACE-inhibitors and angiotensin receptor 1- blockers in the COVID-19 era

Angiotensin conversion enzyme-inhibitors (ACE-inhibitors) and angiotensin receptor 1- blockers (ARBs) are renin-angiotensin-aldosteron system (RAAS) inhibitors approved since decades for the treatment of hypertension and various cardiovascular disorders. ACE-inhibitors inhibit the enzyme which is responsible for the conversion of angiotensin-I into angiotensin-II. The latter then activates the angiotensin receptor 1, which leads (among other effects) to vasoconstriction and elevation of blood pressure. Additionally, angiotensin-II is biodegraded by the angiotensin conversion enzyme 2 (ACE2) to form angiotensin (1-7), which counteracts the effects of angiotensin-II and attenuates vasoconstriction, sodium retention, and fibrosis. The ACE2 enzyme is present in the cell membranes of various tissues, including the heart and kidneys, but also type II pneumocytes, responsible for the reproduction of lung alveolar epithelial cells and the secretion of lung surfactant. Additionally, it exists in low amounts as a soluble enzyme in plasma. This enzyme is not blocked by ACE-inhibitors. As far as it is known today, the SARS-CoV-2 virus binds with its spikes (forming the “corona”) to ACE2, which leads to the cellular uptake of the virus, the first step in infection and virus replication. It has hence been speculated that the use of ACE inhibitors and ARBs, respectively, may lead to an overexpression of ACE2 and thereby may facilitate the entry of SARS-CoV-2 into the alveolar
epithelial cell.

However, there is no clinical evidence to date supporting such a relationship between the chronic intake of ACE-inhibitors or ARBs and a higher risk for COVID-19 infection or increased severity of the disease. Indeed, it is not known whether the amount of membrane-bound ACE2 enzyme is upregulated or not in people who are on a stable therapy with ACE-inhibitors or ARBs. Additionally, because ACE-inhibitors lower the concentrations of angiotensin-II, while ARBs do not (they even increase the concentrations as counterregulation of the receptor blockade (Czajka et al., 1997)), one might assume that the two classes have different effects on ACE2. Animal studies have shown mixed and sometimes contradictory effects, and they are thus not helpful in answering the question (Vaduganathan et al., 2020). There are two clinical studies in patients who have shown that treatment with ACE-inhibitors do not influence angiotensin (1-7) concentrations in the short term (Campbell et al., 2004; Luque et al., 1996), while after a six-months treatment with the ACE-inhibitor captopril, the angiotensin (1-7) concentrations increased (Luque et al., 1996). It may be speculated that neprilysin, an enzyme which forms angiotensin (1-7) from angiotensin-I (Rice et al., 2004) may be responsible for this finding. However, when it comes to the expression and activity of ACE2 in patients treated with ACE-inhibitors or ARBs, few data are available with partly not uniform effects across RAAS inhibitors or even responses within the same drug class. Regarding the lung-specific expression of ACE2 data are lacking (Vaduganathan et al., 2020). In summary, it is unclear if and if yes, which, effects ACE-inhibitors and ARBs exert on the expression and activity of ACE2, the putative target of SARS-CoV-2 for cell entry, particularly in lung tissues.

After entering the cell via ACE2, the SARS-CoV-2 appears to downregulate ACE2 expression. This may prevent the biotransformation of angiotensin-II to angiotensin (1-7) and contribute to organ injury in COVID-19 patients (Gurwitz, 2020). In vitro and animal experiments suggest such mechanisms, which may lead to an immune-system mediated lung injury in response to the local angiotensin-II accumulation (Vaduganathan et al., 2020). In this context, a blockade of the RAAS would even be expected to be beneficial, and trials which test this hypothesis are underway (Vaduganathan et al., 2020).

Besides these considerations, it has to be pointed out that poorly controlled hypertension or cardiovascular disease represent a risk factor by itself for COVID-19-related morbidity and mortality, and the beneficial and preventive effects of ACE-inhibitors and ARBs on overall cardiovascular morbidity and mortality have repeatedly been proven in several large, randomized and controlled studies. Since the action of ACE-inhibitors and ARBs on both the risk for SARS-CoV-2 infection and COVID-19 severity and time course is unclear to date, patients have to be strongly advised against stopping their treatments with ACE-inhibitors or ARBs. There are even reports on clinical observations that patients who use ACE-inhibitors or ARBs may have less severe disease courses than hypertensive patient under other treatments (Meng et al., 2020). Accordingly, the Swiss Society of Cardiology and the Swiss Society of Hypertension, as most foreign cardiovascular societies and medicine agencies like the EMA recommend to continue treatments with ACE-inhibitors or ARBs.

There is no scientific evidence to date that these agents are harmful in COVID-19, and particularly that such a harm would outweigh the benefits of ACE-inhibitors or ARBs in treatment and prevention of cardiovascular diseases. Yet, ongoing studies might soon bring new clinical observations and insights to inform medical practice regarding the possible interaction between ACE-inhibitors and/or ARBs and the COVID-19 infection.

(written by Alexander Jetter, MD, SSCPT president, on April 08, 2020)


Literature:

  • Campbell DJ, Zeitz CJ, Esler MD, Horowitz JD. Evidence against a major role for angiotensin converting enzyme-related carboxypeptidase (ACE2) in angiotensin peptide metabolism in the human coronary circulation. J Hypertens 2004; 22: 1971-1976.
  • Csajka C, Buclin T, Brunner HR, Biollaz J. Pharmacokinetic-pharmacodynamic profile of angiotensin II receptor antagonists. Clin Pharmacokinet. 1997; 32(1): 1-29.
  • Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res. 2020 Mar 4. doi: 10.1002/ddr.21656. [Epub ahead of print].
  • Luque M, Martin P, Martell N, Fernandez C, Brosnihan KB, Ferrario CM. Effects of captopril related to increased levels of prostacyclin and angiotensin-(1-7) in essential hypertension. J Hypertens 1996; 14: 799-805.
  • Meng J, Xiao G, Zhang J, He X, Ou M, Bi J, Yang R, Di W, Wang Z, et al. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Emerg Microbes Infect. 2020; 9(1): 757-760. doi: 10.1080/22221751.2020.1746200.
  • Rice GI, Thomas DA, Grant PJ, Turner AJ, Hooper NM. Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J. 2004; 383(Pt 1): 45-51.
  • Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19. N Engl J Med. 2020 Mar 30. doi: 10.1056/NEJMsr2005760. [Epub ahead of print].
  • https://www.ema.europa.eu/en/news/ema-advises-continued-use-medicines-hypertensionheart-kidney-disease-during-covid-19-pandemic
  • http://www.swisscardio.ch/