ItHome Hypertension Op-Ed: RAS Imbalance Is COVID’s Razor

Op-Ed: RAS Imbalance Is COVID’s Razor

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A computer rendering of a coronavirus entering a cell

Occam’s Razor posits that “the simplest explanation is usually correct.” With COVID-19 the simplest explanation is that the coronavirus strikes one cellular target but does so in essentially every organ and tissue within the human body, such that a single mechanism underpins all coronavirus effects. To accomplish this, the target must be a cellular pathway that impacts nearly every bodily system.

COVID-19 defied public expectations of a flu-like respiratory illness, and instead presented something unpredictably menacing. A maelstrom of unexpected coronavirus complications perplexed the medical community, from renal failure to silent hypoxia, from hyperglycemia to loss of olfactory sensation, from a Kawasaki-like myocarditis syndrome in children to blood clots and strokes in young adults.

Simultaneously dysregulating blood clotting and gastrointestinal function, damaging kidneys and lungs, perturbing neuronal processes and immunological function, the coronavirus appeared to be disrupting myriad cellular pathways simultaneously. But that would indicate that a tiny RNA virus, incapable of even replicating itself independently, can perform a staggering array of disruptive cellular actions.

RAS, the renin-angiotensin system, is well known as a circulating corrective mechanism, restoring blood pressure and blood volume in the event of hemorrhage or dehydration. But RAS is also a pervasive regulator of myriad tissue-level functions, ranging across the spectrum of bodily systems: glucose metabolism, cardiovascular functions, hypoxia sensing, neural crosstalk, inflammatory response, coagulation, and more.

During stress response to severe injury, the priority is re-establishing physiologic homeostasis compatible with survival and that requires integrated responses by almost all organ systems. Evolution made RAS the master regulator coordinating these processes.

The classical depiction of RAS is a linear cascade of enzymatic activations, beginning with angiotensinogen conversion to angiotensin I (AI) by renin, followed by AI conversion to angiotensin II (AII) by ACE. This sequential pathway is called “the ACE axis.” AII binds the AT1 receptor, initiating its multiple effects, including renal sodium conservation, coagulation, inflammation, fibrotic repair, and cell death.

RAS contains additional components that counterbalance the ACE axis. The AT2 receptor offers an alternative for AII binding, yielding anti-coagulation, anti-inflammation, and anti-fibrosis effects. And ACE2, a “younger brother enzyme” to ACE, metabolizes AII, so that it is unavailable to bind AT1.

ACE2 converts AII into an anti-inflammatory counterpart called A1-7. ACE2 also diverts AI out of the ACE axis, converting AI to an anti-inflammatory precursor, A1-9, thereby preventing creation of AII. Thus, “the ACE2 axis” decreases activation of AT1 by AII, and acts as a counterweight to the ACE axis. RAS is not linear after all, but rather a web of interlinked enzymatic processes.

SARS-CoV-2 enters cells by binding cell-surface ACE2, traveling as an uninvited guest when a cell recalls ACE2 to its interior. Once inside, coronavirus shuts down cellular production of ACE2, leaving the ACE axis running amok.

AII overproduction by unbalanced ACE triggers unnecessary coagulation leading to blood clots and strokes; it provokes inflammation and fibrosis that damage renal tissue and promote arrhythmias. And it disables glucose-regulating functions of the insulin receptor, leading to hyperglycemia and diabetes.

AII also disrupts cellular volume regulation and triggers inappropriate cell death, both of which may explain carotid body failure to register hypoxemia, leading to silent hypoxia, as well as loss of olfactory neurons, which disables sense of smell.

COVID-19 is deadly because it targets the RAS master-regulator, and there is no backup quarterback. Multiple organ functions spiral into disarray, as SARS-CoV-2 turns the guardian of our evolutionary survival against us.

Importantly, many population subsets demonstrating worse COVID-19 outcomes express a pre-existing RAS imbalance, with elevated ACE activity and diminished ACE2 counterweight, before ever encountering SARS-CoV-2. These include people with diabetes, people with hypertension, people who smoke nicotine products, people with obesity, certain cancer patients, males, and older adults.

In addition, there is evidence that some African Americans and Hispanics may carry genetic predisposition to RAS imbalance, due to ancient evolutionary pressures from water and sodium scarcity in tropical climates.

In essence, coronavirus pushes organ function toward a cliff by downregulating ACE2; but high-risk individuals who have baseline ACE overactivity and low ACE2, begin closer to that cliff, and thus are more likely to be pushed over it by the virus.

This does not indicate that RAS imbalance is the only factor responsible for COVID-19 severity. People with diabetes, cancer patients, older adults, and people with obesity have demonstrable nutritional deficiencies and immune impairment. Males have recognized differences in immune function compared to females, and males typically have higher rates of smoking.

Socioeconomic disadvantages have been rightly emphasized when assessing mortality disparities breaking along ethnic lines.

Yet the fingerprints of RAS imbalance are clearly found across the widespread organ damage and demographic outcomes in COVID-19, suggesting that RAS is in fact the common denominator.

ACE inactivates the vasodilatory mediator bradykinin, so RAS imbalance would trigger bradykinin depletion, the root of the COVID-19 bradykinin hypothesis. And although a recent study did not find increased levels of circulating inflammatory mediators in COVID-19 patients, evidence from the hypertension realm suggests that tissue RAS is more important than circulating RAS for organ system damage and tissue levels of RAS and cytokines are not as easily quantified in humans.

Hence, the evidence suggests that ameliorating RAS imbalance, via ACE inhibitors or angiotensin receptor blockers, should be the urgent focus of more widespread clinical trials.

There are multiple ongoing or planned ACE inhibitor and angiotensin receptor blocker trials, but many are looking at the same agents, rather than exploring many other available drugs in those classes. All of these have distinct pharmacologic properties that may influence potential effectiveness — including some that cross the blood brain barrier and thus may impact COVID-19 neurological dysfunction.

In addition, recombinant ACE2, entered in one European COVID-19 trial, and an AT2 agonist C21, trialed in pulmonary fibrosis, could be more widely studied. The vitamin D receptor inhibits RAS at the tissue level, and African Americans and older adults more frequently exhibit vitamin D insufficiency, so targeted vitamin D trials in higher-risk COVID-19 populations may yield benefit.

As COVID-19 continues raging through many parts of the world, and new outbreaks emerge in areas once deemed under control, finding the means to blunt the mechanism of COVID-19’s destructiveness grows only more urgent. Evidence suggests RAS imbalance is that mechanism.

We already possess pharmacological tools to squash ACE axis overactivity; we should use them all.

Maureen E. Czick, MD, is a board certified anesthesiologist and was previously an adjunct professor of physiology at Central Connecticut State University. Her prior publications explore the physiologic basis of anesthetic ventilatory depression, and the implications of atrial fibrillation pathophysiology for treatment outcomes. Christine L. Shapter, MD, is a board certified psychiatrist; she is medical director of Greenbrook TMS, and a graduate advisory board member for University of Saint Joseph, both in West Hartford, Connecticut. Her previous publications explore the link between psychiatry and cardiac disease. Robert K. Shapter, MD, is board certified in family medicine. He served as a physician in the Canadian Air Force before transitioning to work for the U.S. pharmaceutical industry. Shapter previously chaired the Family Medicine Residency Program at Middlesex Hospital in Middletown, Connecticut, and has been a medical writer and editor for 4 decades.

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