Another article caught my attention while scouring the New England Journal Medicine site devoted to COVID-19. It is an article by Vaduganathan et al titled Renin-Angiotensin-Aldosterone-System Inhibitors in patients with COVID-19. I was aroused because the RAAS plays a key role in the development of high blood pressure. The RAAS is a hormone system that regulates blood pressure and fluid and electrolyte balance as well as systemic vascular resistance. Several antihypertensives in use interfere or inhibit some mechanisms of the RAAS. 

The authors acknowledged this in their introduction to the piece- the renin–angiotensin–aldosterone system (RAAS) is an elegant cascade of vasoactive peptides that orchestrate key processes in human physiology.  The authors note that the severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and SARS-CoV-2, which have been responsible for the SARS epidemic in 2002 to 2004 and for the more recent coronavirus disease 2019 (Covid-19) pandemic, respectively, interface with the RAAS. This is through angiotensin-converting enzyme 2 (ACE2), an enzyme that physiologically counters RAAS activation but also functions as a receptor for both SARS viruses. Angiotensin-converting enzyme 2 (ACE2) is an enzyme attached to the outer surface of cells in the lungs, arteries, heart, kidney and intestines. ACE2 lowers blood pressure by catalyzing the degradation of angiotensin ll (a vasoconstrictor) into angiotensin (a vasodilator). ACE2 therefore counters the activity of the related angiotensin-converting enzyme (ACE) by reducing the amount of angiotensin ll.

The interaction between the SARS viruses and ACE2 has been proposed as a potential factor in their infectivity and there are concerns about the use of RAAS inhibitors (e.g. some antihypertensives) that may alter ACE2 and whether variation in ACE2 expression may be in part responsible for disease virulence in the ongoing Covid-19 pandemic. Indeed, there have been calls from certain quarters for for the discontinuation of ACE inhibitors and angiotensin-receptor blockers (ARBs), both prophylactically and in the context of suspected Covid-19.

Given the common use of ACE inhibitors and ARBs worldwide, guidance on the use of these drugs in patients with Covid-19 is urgently needed.

Initial reports have called attention to the potential over-representation of hypertension among patients with Covid-19. In the largest of several case series from China that have been released during the Covid-19 pandemic hypertension was the most frequent coexisting condition in some patients. This estimate appears to be lower than the estimated prevalence of hypertension seen with other viral infections and in the general population in China.

Coexisting conditions, including hypertension, have consistently been reported to be more common among patients with Covid-19 who have had severe illness, been admitted to the intensive care unit, received mechanical ventilation, or died than among patients who have had mild illness. There are concerns that medical management of these coexisting conditions, including the use of RAAS inhibitors, may have contributed to the adverse health outcomes observed. However, these conditions appear to track closely with advancing age, which is emerging as the strongest predictor of Covid-19–related death.

Unfortunately, reports to date have not rigorously accounted for age or other key factors that contribute to health as potential confounders in risk prediction. With other infective illnesses, coexisting conditions such as hypertension have been key prognostic determinants, and this also appears to be the case with Covid-19.

In population-based studies estimate that only 30 to 40% of patients in China who have hypertension are treated with any antihypertensive therapy. RAAS inhibitors are used alone or in combination in 25 to 30% of these treated patients. Given such estimates, only a fraction of patients with Covid-19, at least in China, are anticipated to have been previously treated with RAAS inhibitors.

Tissue-specific and circulating components of the RAAS make up a complex intersecting network of regulatory and counterregulatory peptides. ACE2 is a key counterregulatory enzyme that degrades angiotensin II to angiotensin, thereby attenuating its effects on vasoconstriction, sodium retention, and fibrosis. Although angiotensin II is the primary substrate of ACE2, that enzyme also cleaves angiotensin I to angiotensin and participates in the hydrolysis of other peptides.

In studies in humans, tissue samples from fifteen organs have shown that ACE2 is expressed broadly, including in the heart and kidneys, as well as on the principal target cells for SARS-CoV-2 (and the site of dominant injury), the lung alveolar epithelial cells. The circulating levels of soluble ACE2 are low and the functional role of ACE2 in the lungs appears to be relatively minimal under normal conditions but may be increased in certain clinical states. The authors note that in spite of the substantial structural similarity between ACE and ACE2, their enzyme active sites are distinct. As a result, ACE inhibitors in clinical use do not directly affect ACE2 activity.

SARS-CoV-2 appears not only to gain initial entry through ACE2 but also to subsequently downregulate ACE2 expression such that the enzyme is unable to exert protective effects in organs. After the initial engagement of SARS-CoV-2 spike protein, there is subsequent down-regulation of ACE2 abundance on cell surfaces. Continued viral infection and replication contribute to reduced membrane ACE2 expression. In a small study, patients with Covid-19 appeared to have elevated levels of plasma angiotensin II, which were in turn correlated with total viral load and degree of lung injury.

Markers of myocardial injury have been shown to be elevated during the disease course of Covid-19 and to increase rapidly with clinical deterioration and preceding death. Many viruses are cardiotropic, and subclinical viral myocarditis is commonly seen in viraemia associated with a wide range of infectious agents. The authors note that in spite of these uncertainties there is clear potential for harm related to the withdrawal of RAAS inhibitors in patients in otherwise stable condition. Covid-19 is particularly severe in patients with underlying cardiovascular diseases, and in many of these patients, active myocardial injury, myocardial stress, and cardiomyopathy develop during the course of illness. RAAS inhibitors have established benefits in protecting the kidney and myocardium, and their withdrawal may risk complications in high-risk patients.

In the Quinapril Heart Failure Trial, among patients with chronic symptomatic heart failure, withdrawal of quinapril resulted in a progressive decline in clinical status.  In the TRED-HF trial, among asymptomatic patients with heart failure with recovered left ventricular ejection fraction, the phased withdrawal of medical therapy (including RAAS inhibitors) resulted in rapid relapse of dilated cardiomyopathy. In addition, RAAS inhibitors are a cornerstone of therapy after myocardial infarction- maintenance of therapy in the days to weeks after the index event has been shown to reduce early mortality.

The authors end by noting that in spite  concerns and uncertainty regarding the effect of RAAS inhibitors on ACE2 and the way in which these medicines might affect the propensity for or severity of Covid-19, RAAS inhibitors should be continued in patients in otherwise stable condition who are at risk for, are being evaluated for, or have Covid-19. Meanwhile, stay safe, keep to all the hygiene measures advised and consume more polyphenol-rich cocoa to strengthen your immune system.




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