An earlier blog focused on the “renin-aldosterone paradox” in chronic fatigue syndrome (ME/CFS) and postural orthostatic tachycardia syndrome (POTS). The renin-angiotensin-aldosterone system (RAAS) regulates blood volume and a whole bunch of other factors.
Given the low blood volume regularly found in ME/CFS and POTS, all three factors of the RAAS system (renin, angiotensin and aldosterone) should be high. While angiotensin II levels are high (very high), renin and aldosterone levels are paradoxically low.
That combination of factors can lead to several problems including low blood volume (from low aldosterone levels) and increased sympathetic nervous system activation, blood vessel narrowing (vasoconstriction), inflammation and oxidative stress (from high Ang II levels).
Two studies suggest that the activity of the ACE-2 enzyme which transforms Ang II to Ang (1-7) and angiotensin to Ang (1-9) is reduced, but it’s not clear why. Miwa speculates that a blunted HPA axis (aldosterone is produced by the adrenal glands) could account for the low aldosterone levels.
After two decades of on and off study, why the RAAS system is so paradoxically off in these diseases remains a mystery.
Then came the SARS-CoV-2 coronavirus and COVID-19 pandemic. The pandemic has offered an opportunity for understanding how infections can morph into diseases like chronic fatigue syndrome (ME/CFS), fibromyalgia and POTS.
Something, however, differentiates the present coronavirus from the other pathogens associated with ME/CFS. The SARS-CoV-2 virus appears to mess with the same renin-angiotensin (RAS) system that has gone whacky in ME/CFS and POTS.
A Tangled Web
This is a tangled web about which little is known with certainty. Only a few studies have been done in POTS, and fewer in ME/CFS, and research into COVID-19 is still just beginning. This blog, then, contains a lot of speculation.
The two arms of the renin-angiotensin (RAS) system:
- Classical (Inflammatory) Arm – the ACE (or ACE1) arm – produces angiotensin II and increases blood pressure, blood vessel vasoconstriction, sympathetic nervous activity and inflammation.
- Anti-inflammatory Arm – the ACE2 arm counteracts the first arm. It breaks up Ang II to produce Ang (1-7) and angiotensin to form Ang (1-9). Ang (1-7). In contrast to the ACE arm, the ACE2 arm is vasodilatory, anti-inflammatory and anti-oxidative.
Several researchers have hypothesized that the dysregulation of the RAS system – specifically an over-activation of the ACE1/Ang II arm – by the SARS coronavirus is “at the center” of the harms caused by COVID-19. The entire hypothesis rides on the inability of the ACE-2 enzyme to keep the inflammatory arm of the virus in check.
Note that thus far the same scenario – reduced ACE2 activation and increased activation of the classical or inflammatory arm of the RAS – is posited for both COVID-19 and ME/CFS/POTS.
It perhaps bears noting that the full implications of ACE2 inhibition are not assessed in the papers focused on blood volume and blood flow issues in POTS. Receptors for ACE-2 are found across the body (central nervous system, airways, blood vessels, gut, lungs, heart liver, eyes, kidneys) and reduced ACE2 activation has been associated with lowered white blood cell counts, impaired oxygen uptake by hemoglobin, increased oxidative stress, leaky gut, problems with lung perfusion, reduced vasodilation of the blood vessels, inflammation, and heart issues in other diseases.
There appears to be plenty of room for ACE2 inhibition, if it is indeed present in ME/CFS and POTS, to have widespread consequences.
The Super Computer Study
ME/CFS and COVID-19 appeared to be oddly on track with each other until the supercomputer study came along. The study, “A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm“, which was published in eLife Science Digests in July, blew a big hole in the ACE2 hypothesis for COVID-19 and ME/CFS. While it was doing that, though, it opened up even more intriguing connections.
Thomas Smith, of Medium, reported that one of the fastest supercomputers in the world at Oakridge National Lab in Tennessee had been sweating data big time earlier this year. Given the task of assessing the expression of 40,000 genes from 17,000 lung samples from COVID-19 patients, it took the supercomputer over a week to complete the analysis. When it did, though, a new hypothesis had emerged: the bradykinin storm hypothesis.
Dr. Jacobson, the lead researcher, called it a “eureka’ moment. Not only could the hypothesis explain the fundamentals of COVID-19, it also potentially explained many of the bizarre elements associated with the disease.
Jacobson’s study, though, suggested that instead of the ACE2 receptors in COVID-19 being downregulated, as van de Veerdonk suggested (and as some studies had shown), they were dramatically upregulated. Ang (1-9) – one of the countervailing forces against Ang II – appeared to be dramatically increased as well. (But then, so was the receptor for Ang II.) Jacobson believed that the angiotensin pathway had been shifted towards Ang (1-9), which gets metabolized to Ang (1-7), which turns on bradykinin – a vasodilator.
Jacobson found that the genes tasked with responding to bradykinin were being expressed at a feverish pitch. So were the genes for the enzymes that activated the kinin pathway that bradykinin is a part of.
Jacobson’s study suggested that the opposite situation to ME/CFS was occurring. ACE2 was elevated, not reduced. Instead of high levels of Ang II sparking vasoconstriction and inflammation, high levels of Ang (1-9) were triggering a bradykinin explosion.
The Bradykinin Connection
While Jacobson’s findings were opposite to what van de Veerdonk had proposed, it’s in van de VeerDonk’s hypothesis that COVID-19 and ME/CFS/POTS perhaps start to merge again.
In his hypothesis, van de Veerdonk went back 15 years to a Nature paper, which found that increased levels of the ACE2 enzyme protected against severe lung damage with the first SARS virus. (High levels of Ang II, on the other hand, worsened lung damage.) Several other studies found reduced ACE2 activation in the first SARS-CoV-2 virus.
van de Veerdonk then linked the reduced ACE2 activation to the lung damage in COVID-19. ACE2, it should be noted, does not itself inactivate bradykinin, but it does the next best thing; it inactivates the activators of bradykinin.
While van de Veerdonk may be wrong about COVID-19, his hypothesis may make sense regarding ME/CFS/POTS. The upshot is that people with COVID-19 and ME/CFS may both have issues with the RAS system – and both could possibly be facing a bradykinin storm.
The real amazing thing is that two years ago, Wirth and Scheibenbogen predicted that bradykinin – a substance rarely associated with ME/CFS – plays a major role in the disease.
- Next up – The Bradykinin Storms in COVID-19 and ME/CFS
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