ACE/RAAS Inhibitors and Covid-19
Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19. Vaduganathan M, Vardeny O, et al. New Eng J Med. 2020 Mar 30; DOI: 10.1056/NEJMsr2005760
Is There an Association Between COVID-19 Mortality and the Renin-Angiotensin System—a Call for Epidemiologic Investigations. Hanff TC, Harhay MO, et al. Clin Infect Dis. 2020 Mar 26; DOI: 10.1093/cid/ciaa329
Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19. Reynolds HR, Adhikari S, et al. N Engl J Med. 2020 May 1. doi: 10.1056/NEJMoa2008975.
[back to paper list]
The Renin-Angiotensin-Aldosterone System (RAAS)
- renin (blocked by aliskiren) converts angiotensinogen to angiotensin I
- angiotensin converting enzyme (ACE, blocked by ACEIs: captopril, enalapril, ...) converts angiotensin I to angiotensin II
- angiotensin II (blocked by ARBs: losartan, valsartan, ...) constricts blood vessels (↑ BP) and increases release of aldosterone
- aldosterone (blocked by spironolactone) increases salt and water retention (↑ BP)
Angiotensin converting enzyme 2 (ACE2) is the receptor for SARS-CoV-2. It is antihypertensive and anti-inflammatory (and may have additional roles) and is broadly expressed: lungs, heart, kidneys, GI tract...
RAAS Modulation in Covid-19
- SARS-CoV-2 entry decreases cell surface ACE2:
- Do ACE1 inhibitors used for hypertension also bind ACE2?
No.
...but SPOKE has edges... - Some studies in animals have suggested RAAS inhibitors increase ACE2 expression, raising concerns about their safety in patients with Covid-19.
RAAS Inhibitors Might Actually Help
Various studies suggest that heart and lung injury in Covid-19 may be due in part to high angiotensin II activity after ACE2 surface expression is downregulated by the virus. Clinical trials are in the works for treating Covid-19 with recombinant ACE2 (is the rationale its activity or as decoy?) (NCT04287686) or with losartan (NCT04312009, NCT04311177).
Current evidence does not indicate withdrawal of RAAS inhibitors in Covid-19: “RAAS inhibitors have established benefits in protecting the kidney and myocardium, and their withdrawal may risk clinical decompensation in high-risk patients.”
The Reynolds et al. paper found “no substantial increase in the likelihood of a positive test for Covid-19 or in the risk of severe Covid-19 among patients who tested positive in association with five common classes of antihypertensive medications.” (ACE inhibitors, ARBs, β-blockers, calcium-channel blockers, thiazide diuretics) (N=12,594 patients, 5894 Covid-19-positive, 4357 history of hypertension, 2573 both)
Other Recent Findings
Additional papers showing ACEIs/ARBs do not worsen Covid-19:
• Mehra et al.,
Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19
• Mancia et al.,
Renin–Angiotensin–Aldosterone System Blockers and the Risk of Covid-19
• Fosbøl et al.,
Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With COVID-19 Diagnosis and Mortality
Lower ACE2 expression in the nasal epithelium of children relative to adults may explain their lower prevalence of COVID-19 (JAMA...)
The virus can affect the heart muscle, with as many as 1 in 5 patients suffering cardiac damage... (Kaiser Health News...)
Acute kidney injury is the next emerging healthcare and resource issue in this pandemic... (Medscape...)
Several recent papers postulate ACE2 differences in obesity (Kassir, Obesity Reviews; Jia et al., Pathology & Pathobiology; Al Heialy, et al., bioRxiv)
ACE2-regulatory effects of estrogen may explain worse toll on men (NYT 4/27/2020); anti-androgens decrease ACE2 expression on heart cells (UCSF Magazine Summer 2020)