Anti-hypertensive drugs possibly affect COVID-19 outcome through the double-edged sword ACE2*

J.A. Offerhaus, C.R. Bezzina

Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam UMC, Location Academic Medical Center, Amsterdam, The Netherlands

*Weergave van bespreking tijdens Journal Club meeting van de afdelingen cardiologie van Amsterdam UMC en OLVG d.d. 25 maart 2020

Discussion is ongoing whether specific anti-hypertensive drugs (AHD), like ACE-inhibitors (ACE-i) and Angiotensin Receptor Blockers (ARBs), can affect the outcome of a COVID-19 infection.

Such an effect is hypothesized to occur through the membrane protein, Angiotensin Converting Enzyme 2 (ACE2), which functions as the receptor through which SARS-COV-2 infects the cell.1

ACE2 is expressed in various tissues, including the heart.2 Preclinical studies have suggested that the expression of ACE2 is increased by AHD.3

In this respect, AHD may increase the risk of a SARS-COV-2 infection. On the other hand, other preclinical studies conducted on SARS-COV-1 (which also uses ACE2 for cell entry) have shown that upon infection, the level of ACE2 in the cell decreases.

ACE2 converts Ang2 into Ang1-7 and has thereby been considered an interesting target for treating cardiovascular disease.4

Thus, a decrease in ACE2 is expected to be detrimental, at least in part due to accumulation of Ang2.5

In this respect, an increase in ACE2 by AHD can counteract the potential negative effects of Ang2.6

A first retrospective study seems to indicate a (small) beneficial effect of ACE-i/ARBs usage.7

References

  1. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. 2020 Apr 16;181(2):271-280.e8. doi: 10.1016/j.cell.2020.02.052. Epub 2020 Mar 5.
  2. Chen L, Li X, Chen M, Feng Y, Xiong C. The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovascular Research, 30 Mar 2020, 116(6):1097-1100. DOI: 1093/cvr/cvaa078 PMID: 32227090.
  3. Ferrario CM, Jessup J, Chappell MC, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. 2005 May 24;111(20):2605-10. Epub 2005 May 16.
  4. Donoghue M, Hsieh F, Baronas E, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res.2000 Sep 1;87(5):E1-9.
  5. Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med.2005 Aug;11(8):875-9. Epub 2005 Jul 10.
  6. 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].
  7. Zhang P, Zhu L, Cai J, et al. Association of Inpatient Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients With Hypertension Hospitalized With COVID-19. Circ Res.2020 Apr 17. doi: 10.1161/CIRCRESAHA.120.317134. [Epub ahead of print].