Is there a role for purinergic signalling in this hypothesis?
I have long been interested in the idea that under shear stress red blood cells are mechanically squeezed in a way that emits ATP.
It always struck me that shear stress that did not resolve could create an ATP shortage in red blood cells, an oversupply of ATP downstream metabolites (e.g. adenosine) in circulation, and also a state of immune hyper surveillance, seeing as though extracellular ATP is perceived as a damage signal.
Does this fit into your hypothesis?
purinergic signalling could plausibly intersect with the model, particularly as a mediator between mechanical stress and vascular inflammatory responses. Purinergic pathways were not explicitly included in our current hypothesis, which focused more narrowly on eNOS coupling, redox balance, and shear-mediated endothelial responses. But they could certainly represent an upstream modulator or parallel pathway worth investigating
@YiannisK, I am sorry to hear that you also have this condition. May I ask, do you have all the symptoms and bio markers of the specific subset that your paper deals with?
Yes broadly speaking, my personal clinical picture overlaps with the subgroup discussed in the hypothesis.
I was a healthy endurance runner before infection, with strong aerobic fitness and no meaningful prior limitations. After an initially mild acute COVID illness, I gradually developed the now-familiar Long COVID pattern: reduced exercise tolerance, disproportionate heart-rate response, decline in performance capacity, and eventually a clear post-exertional crash consistent with PEM.
Over time this was accompanied by fatigue, cognitive symptoms, chest tightness, and marked fluctuation based on exertion level. Standard cardiac and routine diagnostic investigations have been largely reassuring, which many patients will recognize, despite significant functional limitation.
The positive side is that I am no longer in the severe early phase. Through careful pacing and gradual management staying consistently below the PEM trigger threshold while maintaining gentle activity just above what I describe as the lower shear-stress threshold I currently function at a partial but meaningful level compared with my pre-illness baseline.
To be clear, I do not mean conventional graded exercise therapy. I mean carefully regulated, low-intensity movement intended to preserve vascular signaling without provoking delayed worsening.
In practical terms, I do not focus on heart rate alone, since many patients show rapid pulse increases with even minor activity. Instead, I watch the relationship between walking pace, heart rate, and breathing rate together. For example, if a steady pace produces stable values over several minutes, I treat that as a temporary baseline. If later the same pace begins to require a progressively higher heart rate and faster breathing, disproportionate to workload, I reduce intensity until those variables stabilize again.
Heart rate itself is not necessarily the enemy. The cardiovascular system is highly adaptive, and an increased pulse may simply reflect the body attempting to maintain perfusion, oxygen delivery, or autonomic balance under stress. In that sense, the rise in heart rate may be compensatory rather than pathological.
What matters more, in my view, is when the same workload begins to require progressively higher heart rate and breathing effort, suggesting declining efficiency or rising physiological strain. That distinction may be more informative than the absolute number itself.
Many explanations have been proposed for this phenomenon. Our hypothesis offers one possible framework. Time and proper testing will determine whether it is supported or rejected.
This is only an individual observation, not proof, but it strongly influenced the conceptual framework of the hypothesis.
There Hypotheses are actually measuring exertion intolerance as they are expecting they wont be fully completed. From the very beginning they are showing they do not understand how the disease is described as working and have a protocol that will failure to measure it. They seem to be doing and trying to measure it as part of phase 1 to then set up phase 2 to attempt to measure PEM. There are serious ethical concerns here with intentionally inducing PEM in severe and very severe patients.
I understand the ethical concern, and it is an important one. No severe or very severe patient should ever be pushed into PEM for speculative research purposes. Patient safety must always come first.
However, I think there are two separate issues here:
- Mechanism discovery
Before any provocation studies, there is already substantial room to investigate resting and low-burden abnormalities: microcirculatory dysfunction, endothelial biomarkers, impaired oxygen extraction, autonomic instability, cerebral or peripheral perfusion changes, wearable physiology patterns, and post-viral vascular responses.
- Carefully designed validation
If a hypothesis eventually requires exertional testing, that should only occur under strict ethical safeguards, in mild/moderate volunteers with informed consent, stopping rules, rescue protocols, and the least harmful stimulus possible.
My own view is that many patients are dismissed because standard tests (routine imaging, conventional stress tests, basic labs) can appear normal while functional vascular or autonomic problems remain invisible to those tools. That gap is exactly why better biomarkers and safer assessment methods are needed.
So I agree ethics matter deeply. But avoiding harmful provocation should motivate smarter research design, not abandonment of investigation.
pmc.ncbi.nlm.nih.gov
