A recent New England Journal of Medicine article proposed "endothelialitis" as the unifying mechanism for the widespread pathology of COVID-19. In a prior Medscape interview, Medscape contributor Andrew N. Wilner, MD, discussed this intriguing hypothesis with William Li, MD, one of the article's authors.
An alternative view suggests that virus-induced upregulation of the renin-angiotensin system (RAS) — a hormonal network that regulates blood pressure fluid, and electrolytes — accounts for the diverse systemic effects of COVID-19. Maureen Czick, MD, a proponent of this theory, is an anesthesiologist at the University of Connecticut with an academic interest in cell biology and coronavirus pathophysiology. Dr Czick was kind enough to share her insights in an email interview with Dr Wilner.
What is your medical background and experience with COVID-19? How did you come up with this concept around the RAS?
When I was in the middle of my first year of anesthesiology residency in 2003, the original SARS coronavirus struck East Asia. One of my mentors, Dr Joseph McIsaac, an expert on hospital preparedness for epidemics and mass casualties, told me then, "Pay attention to this thing, because it'll be back." So I began to follow the SARS basic science research, especially the emerging work on angiotensin-converting enzyme (ACE) 2, which helped me understand that the RAS has extensive physiologic reach, much more than just blood pressure regulation.
Anesthesia is commonly mislabeled as "sleep." Many surgeons rib their anesthesia colleagues, "The patient is asleep, so now you can relax and read a magazine." Yet anesthesia drugs create artificial unconsciousness, not sleep, and in doing so, they perturb the physiology of essentially every organ system. To manage this dysregulated physiology, anesthesiologists must have broad understanding of the physiology and pathophysiology of every organ rather than focusing on one or two organs, as is more typical in many medical specialties.
Before medical school, I had done graduate study in cell biology, so I approached clinical medicine from the perspective that basic science can clarify treatment options and inform clinical decision-making. As I worked to expand my own physiology knowledge base for anesthesia practice, at every step I encountered the RAS: in hypoxemia sensing in the carotid body and in ventilation-perfusion matching in the lungs to prevent hypoxemia, arrhythmia promotion and heart failure, apoptosis regulation and maintenance of blood-brain barrier integrity, inflammation and coagulation, insulin signaling, cancer metastasis, immune function, and on and on.
When the COVID-19 pandemic reached the West, many aspects were deemed startling because "it was supposed to be a run-of-the-mill respiratory virus." Myocarditis, renal failure, hypercoagulability, silent hypoxia, loss of glucose regulation, and neurologic dysfunction might be shocking coming from a true respiratory-exclusive pathogen, but they are not surprising when viewed through the lens of what the RAS does in the body and what coronavirus does to the RAS.
Please explain how RAS dysfunction accounts for COVID-19 pathology. For example, does the RAS promote myocarditis?
When the unexpected aspects of COVID began emerging, such as strokes in younger patients without risk factors, renal failure, prolonged neurologic dysfunction, and myocarditis, among others, the temptation was perhaps to think, "Whoa! This virus is doing so many different, destructive things to the body!" But this is a tiny virus, which doesn't have much genetic material. It's much more likely that coronavirus is doing one damaging thing — but it's doing it in every bodily system. It's like those amazing domino videos: One initial domino ends up starting three or four or five simultaneous chains of falling dominoes.
From an evolutionary survival vantage point, when acute illness or injury strikes, survival hinges upon prompt damage control and marshaling of resources where they are most needed. All systems have to play a role concurrently: coagulation and vasoconstriction to prevent hemorrhage, inflammation to fight off pathogens, sympathetic nervous system and metabolic changes to coordinate and fuel the cardiorespiratory augmentation and skeletal muscle for fight or flight, renal resorption of ions and water to maintain blood pressure in the face of blood loss, and suppression of gastrointestinal function to avoid diverting energy from organs more critical to survival at that moment. Something has to coordinate and regulate all these simultaneously enacted changes. That something is the RAS. It's the quarterback, directing the whole team. The coronavirus is so destructive because it strikes at the master regulator of all these processes.
The RAS has two basic "arms" of action that counterbalance each other. The ACE/angiotensin II/AT1 receptor axis promotes coagulation, inflammation, fibrosis, and insulin resistance. The ACE2/angiotensin1-7/Mas receptor/AT2 receptor axis does largely the opposite: anti-inflammatory, anticoagulant, and so on. Both original SARS and SARS-CoV-2 use ACE2 to hitchhike inside cells, then they highjack cellular machinery for viral replication and halt cellular expression of ACE2. Without the ACE2 counterbalance, the destructive potential of unchecked ACE/angiotensin II/AT1 is unleashed.
Production of RAS components in circulation has the most notoriety, but many tissues — including the kidney, brain, and heart — have their own local production of RAS proteins, independent of the bloodstream. The function of all these can be thrown into disarray by coronavirus downregulation of ACE2 and consequent ACE axis overactivation.
As for myocarditis, T cells of the immune system have their own innate RAS, which promotes their migration to areas of inflammation during infections and augments their production of inflammatory cytokines. The T-cell RAS is necessary to fight infection but is terrible if dysregulated. And this fits with the RAS model for coronavirus. The heart's myocytes express ACE2, so the coronavirus can enter those cells and then turn off ACE2, leading to locally produced inflammation. That inflammation would then attract entry of T cells to the inflamed heart, but the function of those T cells would also be dysregulated by the effects of coronavirus on the RAS. This is consistent with basic science experimental results. Angiotensin II acting at the AT1 receptor promotes myocarditis in animal models, via T cells, but angiotensin receptor blocker drugs blunt myocarditis.
A recent New England Journal of Medicine article proposed endothelialitis as the critical pathophysiology of COVID-19. Is this concept compatible with the RAS theory?
The endothelialitis hypothesis is compatible with the role of the RAS in COVID-19 because the RAS is a critical regulator of endothelial function. In health, the vascular endothelium suppresses inflammation and coagulation because those processes would damage organs if brought into action when they aren't necessary. But after injury, coagulation is needed to stop hemorrhage, and inflammation is needed to combat pathogens entering through the wound. So, during injury response, the RAS drives the vascular endothelium to change its tune and instead promotes inflammation and coagulation.
In RAS overactivation disease states, such as diabetes and atherosclerosis, the endothelium is pushed into promoting inflammation and clotting when they aren't needed, leading to the increased vascular pathology, strokes, myocardial infarctions in those diseases. In COVID-19, ACE axis overactivation explains the unprovoked clotting and strokes. But the full array of COVID symptoms also includes things that cannot easily be explained by endothelial perturbation alone: for instance, loss of taste and smell sensation, arrhythmia promotion, and loss of glucose control. These things still fall under the pathophysiologic umbrella of the RAS but are not due to endothelial dysfunction.
Obesity is a risk factor for increased morbidity and mortality with COVID-19. Does this association have anything to do with RAS dysfunction?
It's important to note that although the fingerprints of RAS overactivation are found across the spectrum of COVID effects, that doesn't mean that the RAS doesn't have accomplices. Obesity significantly impairs lung mechanics, so that is almost certainly contributing to poorer COVID outcomes.
But the RAS is at work here too. RAS dysfunction and impaired lung mechanics probably synergize. Adipose tissue also has its own intrinsic RAS, and ACE/angiotensin II/AT1 levels are highly upregulated in obesity, while the ACE2 axis is diminished. ACE/angiotensin II/AT1 leads to production of oxygen free radicals that impair the ability of the insulin receptor to mediate glucose regulation. This explains the link between diabetes and obesity. But insulin also has a lot of anti-inflammatory and antifibrotic protective effects, which is why there is so much vascular and organ system damage in diabetics. If you conceptualize COVID-19 organ system damage as a cliff, individuals with preexisting ACE axis overactivation would start closer to the edge of that cliff, and the coronavirus would be more likely to push them over it.
There have been observations of racial disparities, with African American persons more severely affected by COVID-19 than White persons. Is this a socioeconomic or a physiologic phenomenon?
This is a complex issue but, in my view, also another area of likely synergy. Socioeconomic disadvantages have been shown to impair health outcomes, increasing rates of obesity, diabetes, and hypertension that worsen COVID-19 prognosis. Poverty also impairs nutrition, which in turn impairs immune function.
Historically, racism negatively affected socioeconomic attainment for African Americans. President Woodrow Wilson resegregated the federal government in 1913, and many Black people lost lucrative jobs. The 1919 Hoop Spur massacre in Arkansas was a violent attempt to stop Black tenant farmers from organizing a union to prevent White landowners from driving Black tenants into permanent debt by not honoring market prices for cotton. During the 1921 Tulsa massacre, a White mob burned down prosperous "Black Wall Street" businesses and middle-class homes. In Northern states, restrictive housing covenants often forced Black persons into poorer urban areas with inadequate schools. Because of the coalescing of these and other factors, in 1966, 40% of African Americans lived below the federal poverty line.
Kaiser Family Foundation data from 2019 suggested that although Black Americans have made enormous income gains, halving the poverty rate from 50 years ago, the poverty rate among African American persons were still more than double that of White persons: 21% vs 9%, respectively. So does poverty alone explain why African-American COVID-19 mortality rates are doubled relative to those among White persons?
National Health and Nutrition Examination Survey data showed that from 1988 to 1994, African American and White American men had identical obesity rates, but African Americans had a 46% higher rate of hypertension. Most African American persons with hypertension have elevated blood pressure despite low circulating renin levels, owing to gene polymorphisms that increase aldosterone effects and, through negative feedback, suppress circulating RAS. But these studies do not measure tissue RAS levels, only blood levels, and African-American hypertensives have higher rates of RAS-mediated hypertensive organ damage, which studies show is more dependent on tissue than circulating RAS.
Increased prevalence and severity of hypertension in African Americans has been linked to gene polymorphisms that augment ACE axis activity. Ethnobiological studies hypothesize that during ancient times, RAS upregulation polymorphisms may have conferred survival benefit in salt-scarce tropical areas. But with modern, high-salt diets, what was once potentially advantageous has become deleterious. Just as in the case of obesity, having an ACE axis overactivation polymorphism would probably position a person closer to that "coronavirus cliff edge."
In addition, Black people typically have higher rates of vitamin D deficiency. The vitamin D receptor inhibits the ACE/angiotensin II/AT1 axis, so it should be a protective mechanism against the coronavirus' mechanism of organ damage. A study in the Journal of Clinical Endocrinology and Metabolism recently reported that 80% of hospitalized patients with COVID had low vitamin D.
Could you comment on why men are more likely than women to die of COVID-19?
This is yet another area of potential synergy. There are myriad differences in immune response between men and women, but the gender disparity in death rates from both SARS and COVID-19 point also to sex hormone–mediated gender differences in the RAS. Estrogen increases the protective ACE2 arm of the RAS and downregulates the ACE arm. Thus women, particularly premenopausal women, would have a degree of protection from the destructive effects of RAS imbalance because they start at a higher ACE2 baseline. They would start further back from that "cliff edge."
If RAS dysfunction is responsible for the morbidity and mortality of COVID-19, do we have any current medications that might help? For example, do angiotensin receptor blockers or ACE inhibitors help or hinder recovery, or do they have any effect at all? Are clinical trials looking at this?
Doctors and scientists have been combating overactive ACE axis for decades in patients with hypertension and those with diabetes. The key is that all ACE inhibitors and angiotensin receptor blockers are not interchangeable; the individual drugs have pharmacologic distinctiveness. In the hypertension literature, RAS-blocking drugs with high tissue penetration have not yielded consistently higher benefit. But that may be a function of combating RAS effects at the endothelium and thus not needing deep tissue penetration.
In the dementia literature, on the other hand, it's clear that RAS blockers that can cross the blood-brain barrier confer better cognitive protection in animal models, compared with RAS blockers that cannot cross. In the context of COVID-19 organ damage and post-COVID neurologic dysfunction, RAS blockers with more tissue penetration may work better. But for combating hypercoagulability, would less tissue-penetrating agents work better? Maybe.
There are several ongoing trials of ACE inhibitors and angiotensin receptor blockers. In addition, in Europe, recombinant ACE2 is being trialed for COVID. C21, an agonist of the protective AT2 receptor, has been studied in animal models of pulmonary fibrosis and dementia, but there are no human trials for COVID-19.
That's a very persuasive argument for a crucial role of the RAS in the pathophysiology of COVID-19. Is there anything else you would like to add?
Thank you so much for giving me the opportunity to speak with you about this important topic. I'd also like to thank my "COVID's Razor" co-authors, Dr Christine Shapter and Dr Robert Shapter, who toiled with me to summarize all these links between the RAS and COVID. And of course, I'd like to thank the legions of researchers whose work elucidating these mechanisms too often goes unheralded. Without their critical studies, my responses to your questions would have been a lot shorter.
Many thanks for sharing your insights regarding the relationship between the RAS and COVID-19. Continued research should help clarify COVID-19 pathophysiology and facilitate the quest for therapies effective against the novel coronavirus SARS CoV-2.
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Cite this: Could RAS Dysfunction Explain COVID's Effects? - Medscape - Dec 18, 2020.
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