In This Article
- The receptor for SARS-CoV-2 on the lung and other organs is angiotensin converting enzyme 2 (ACE2), which decreases following infection with this virus, putatively resulting in more severe pulmonary infection
- Increasing ACE2 could create greater susceptibility to viral entry, but on the other hand, increasing ACE2 might reduce the risk of severe pulmonary infection
- As of March 17, 2020, numerous professional societies recommend continuing ACE inhibitor and angiotensin II receptor blocker (ARB) therapy for all patients already receiving these medications
- In treatment guidance released on March 17, 2020, Mass General does not recommend starting or stopping ACE inhibitors or ARBs for patients who develop COVID-19
- Mass General advises continuing a statin for anyone who is on a statin and hospitalized with COVID-19. Statins have an anti-inflammatory effect. There not yet enough evidence to suggest starting a statin among patients hospitalized with COVID-19
There's controversy about whether angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) have a role in the pathogenesis of COVID-19, the disease caused by the SARS-CoV-2 virus. Given the possibility of infection with the novel coronavirus, SARS-CoV-2, should patients stop taking ACEi and ARBs? Additionally, statins are anti-inflammatory but it is unclear yet if starting a statin during COVID-19 can help. There are potential downsides of statin use and this needs to be studied further.
At a cardiology grand rounds session at Massachusetts General Hospital on March 18, 2020, Gregory D. Lewis, MD, Heart Failure section head and medical director of Cardiac Transplantation at Mass General, and Tomas Neilan, MD, MPH, director of the Cardio-Oncology Program, addressed these questions and concerns.
ACEi and ARBs: The ACE2 Conundrum
The receptor for SARS-CoV-2 is angiotensin-converting enzyme 2 (ACE2), which is present in the lung epithelium and also on the heart, intestine and kidney. ACE2 converts angiotensin II, the main mediator in the renin–angiotensin–aldosterone system, to a vasodilatory peptide called Ang-(1–7). The net effect is less vasoconstriction.
Once infection with the coronavirus occurs, expression of ACE2 decreases, and that is theorized to be associated with more severe pulmonary infection. In a past study of avian-origin influenza, ACE2-knockout mice developed more severe acute lung injury than wild-type mice did.
In rats, the administration of ACEi/ARBs has been linked to increased ACE2 expression, but a human study out of Australia contradicted those results. Another uncertainty is whether increased ACE2 is helpful or harmful. Increased ACE2 could create greater susceptibility to viral entry, but on the other hand, it might reduce the risk of severe pulmonary infection.
As of March 17, 2020, the American Heart Association, the American College of Cardiology and numerous other professional societies recommend the continuation of ACEi and ARBs for all patients already prescribed these medications for indications such as heart failure, hypertension or ischemic heart disease.
On the other hand, Mass General does not recommend starting ACEi or ARBs for patients who develop COVID-19. Its treatment guidance for frontline clinicians, first released on March 17, 2020, is subject to revision.
One thing is clear: ACE2 is an important therapeutic target. Investigators at the University of Minnesota will soon launch a randomized, controlled trial of losartan for outpatients with COVID-19.
Statins in COVID-19
Long before SARS-CoV-2 came along, it was known that statins attenuate viral RNA, reduce levels of the pro-inflammatory cytokine interleukin-6 and promote innate immune responses. Statins are also inhibitors of the MYD88 pathway, which activates the nuclear factor kappa B pathway and leads to marked inflammation. The MYD88 gene was shown to be highly induced by infection with the SARS-CoV coronavirus of the 2002–2003 epidemic.
Given the low chance of harm and the multiple possible benefits, the Mass General treatment guidance advises continuing statins if the patient is already on one and testing in a clinical trial whether statins may be helpful in patients hospitalized with COVID-19.
The statin should be held for alanine or aspartate transaminase levels above three times the upper limit of normal.
COVID-19 Therapies and the CV System
In its COVID-19 treatment guidance, Mass General allows off-label treatment with several drugs that are FDA-approved for other indications. Close monitoring for cardiac toxicity is often advisable:
- Hydroxychloroquine and chloroquine — In rare cases, these agents can be cardiotoxic over months to years of use; QTc prolongation is also a rare effect in chronic users
- Lopinavir and ritonavir — have been linked to cardiomyopathy in rare cases
- Interferon-beta B1 — can cause hypotension and myocarditis
- Tocilizumab — Increased IL-6 is associated with adverse outcomes with COVID-19. The increase in IL-6 is due to an exaggerated inflammatory response. There are multiple IL-6 antagonists; according to preprint data from a single-center study of 21 patients with severe or critical COVID-19 who were administered an IL-6 antagonist, temperature normalized rapidly in all patients, 19 exhibited a significant reduction of C-reactive protein and all are recovering
In a companion report from the grand rounds session, Dr. Lewis and Dr. Neilan explain risk factors for severe COVID-19 in patients who become infected with SARS-CoV-2, as well as risk factors that can serve as early indicators of poor prognosis.
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