From Cape Town to Hanoi: Let it Go. Let it....Read More
by Cort Johnson | Jul 29, 2021
The detail article
This new ME/CFS / long-COVID paper, “Endothelial Senescence and Chronic Fatigue Syndrome, a COVID-19 Based Hypothesis”, highlights something we’d hoped would occur with COVID-19: new eyes being placed on, and new perspectives being produced on chronic fatigue syndrome (ME/CFS).
The group that wrote this paper is an interesting case in point. Their June 2020 paper, “Intoxication With Endogenous Angiotensin II: A COVID-19 Hypothesis“, proposed that endothelial dysfunction was a key aspect of COVID – and linked it to high angiotensin II (Ang II) levels. They suggested that the high Ang II levels in COVID-19 had caused “premature vascular senescence”.
That was intriguing given the really interesting place that high Ang II levels, and something called the RAAS or RAS paradox, inhabits in the ME/CFS/POTS universe.
The paradox concerns the renin-angiotensin-aldosterone pathway that’s supposed to kick in when low blood volume levels occur. Even in context of the very low blood volumes found in ME/CFS/POTS, the pathway doesn’t kick in, and its critical endpoint, aldosterone, remains at normal or even low levels. This is despite the fact that the levels of Ang II – found in the middle of the pathway – tend to be very high.
Wirth and Scheibenbogen were the first, to my knowledge, to possibly explain the RAAS paradox. They proposed that balky B2AdR receptors and high bradykinin levels had interfered with two of the three major factors needed to stimulate the RAA pathway; i.e. the signal to increase blood volume in ME/CFS has gotten “annihilate(d)”.
The current authors brought a whole new perspective to the high Ang II levels found in ME/CFS/POTS. They proposed that high ANG II levels are knocking out the mitochondria in endothelial cells lining the blood vessels – reducing nitric oxide (N0) levels (inhibiting the blood vessels from dilating properly), and triggering something they called “vascular aging”.
They also believe high Ang II levels in the brain are producing cognitive and other symptoms. Abilify sprang to mind when they proposed that dopamine-enhancing antipsychotic drugs may be protective against the central nervous system effects of COVID-19. The exhausted cytotoxic T and NK cells found in COVID-19 provided another possible touchpoint with ME/CFS.
ME/CFS, however, was never mentioned.
Jump forward a year and this group of researchers – hailing from California, Texas, France, and Mexico – have now become fully embedded in ME/CFS research. Their dense, technical paper, “Endothelial Senescence and Chronic Fatigue Syndrome, a COVID-19 Based Hypothesis“, attempts to link long COVID and ME/CFS together in several novel ways.
The really fascinating thing, though, is how much of the paper centers on and expands on a key part of ME/CFS – the renin-angiotensin-aldosterone system (RAAS or RAS) paradox, and those high Ang II levels in particular.
It’s upon those high Ang II levels that much may hang in ME/CFS and long COVID.
At high levels, Ang II can produce a remarkably wide array of nasty effects. High levels of Ang II produce inflammation, fibrosis, inhibit muscle repair, damage the endothelial cells lining the blood vessels, produce vasoconstriction (narrowing) in the blood vessels, jack up oxidative stress levels – producing peroxynitrite, and reducing the levels of nitric oxide – an important vasodilator.
Ang II also inhibits the phagocytosis or swallowing of damaged and dead cells (efferocytosis) – possibly allowing damaged endothelial cells to accumulate – and the intestinal dysbiosis to worsen.
When phagocytic cells such as macrophages fail to cleanly envelop or swallow damaged cells, the contents of those cells (called damage-associated molecular pattern (DAMP)) can leak into the bloodstream, causing an immune response. High DAMP levels have been associated with unexplained fatigue, chronic pain, exhaustion, and muscle dysfunction in other diseases.
Let’s not forget telomere attrition. Three years after the CDC found telomere attrition in ME/CFS, telomere attrition was linked to high Ang II levels in COVID-19.
In the current paper, the authors move from their focus on the blood vessels to the gut. The epithelial part of the intestinal barrier is a fragile one – a single layer of epithelial cells covered up with mucous.
Besides all the other things it can do, Ang II can apparently trigger the death of that fragile line of intestinal epithelial cells. It also may be able to alter the junction molecules (claudins) that control barrier permeability. Either way, the intestinal barrier breaks down, allowing bad actors like lipopolysaccharides (LPS) to move into the bloodstream – sparking an immune response that may reach all the way to the brain.
The authors write that the fact that:
“… a dysfunctional RAS can trigger barrier disruption, dysbiosis and amino acid malabsorption…(makes it) not surprising that COVID-19 and ME/CFS have been associated with both aberrant immune responses and dysfunctional intestinal permeability.”