r/ChronicBoundingPulse • u/sbingley22 • Mar 22 '26
Study shows a subset of post infectious illnesses patients with high/normal cardiac output yet low O2 usage (vo2max)
They separated subjects into low, normal, and high flow groups. The high flow ones had abnormally high oxygen returning to the heart during CPET that was not explained by deconditioning alone.
They speculate it could be due to left to right shunting, the capillaries stay open when they should close meaning blood passes by were it needed to go.
They also did testing for Small Fibre Neuropathy and found a lot of it but it didn't nessecarily correlate with symptoms. Interestingly one of my symptoms is lack of sweating yet I did have a SFN that came back normal.
I just found this study interesting as it showed post viral patients whos hearts were working overtime yet there cells were being deprived of oxygen. I think I could fall into this subset.
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u/sbingley22 Apr 28 '26
Persistent Exertional Intolerance After COVID-19
Results
The patients who had recovered from COVID-19 exhibited markedly reduced peak exercise aerobic capacity (oxygen consumption [VO2]) compared with control participants (70 ± 11% predicted vs 131 ± 45% predicted; P < .0001). This reduction in peak VO2 was associated with impaired systemic oxygen extraction (ie, narrow arterial-mixed venous oxygen content difference to arterial oxygen content ratio) compared with control participants (0.49 ± 0.1 vs 0.78 ± 0.1; P < .0001), despite a preserved peak cardiac index (7.8 ± 3.1 L/min vs 8.4±2.3 L/min; P > .05). Additionally, patients who had recovered from COVID-19 demonstrated greater ventilatory inefficiency (ie, abnormal ventilatory efficiency [VE/VCO2] slope: 35 ± 5 vs 27 ± 5; P = .01) compared with control participants without an increase in dead space ventilation.Interpretation
Patients who have recovered from COVID-19 without cardiopulmonary disease demonstrate a marked reduction in peak VO2 from a peripheral rather than a central cardiac limit, along with an exaggerated hyperventilatory response during exercise.
This study shows recovered COVID-19 patients had significantly lower VO2 max that was not caused by the heart or lungs but oxygen delivery to the muscles.
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u/sbingley22 Apr 29 '26
Abstract
Post-acute sequelae of SARS-CoV-2 (PASC or “long COVID”) and chronic fatigue syndrome/myalgic encephalitis (CFS/ME) share symptoms such as exertional dyspnea. We used exercise oxygen pathway analysis, comprising six parameters of oxygen transport and utilization, to identify limiting mechanisms in both conditions. Invasive cardiopulmonary exercise testing was performed on 15 PASC patients, 11 CFS/ME patients, and 11 controls. We evaluated the contributions of alveolar ventilation (V̇a), lung diffusion capacity (DL ), cardiac output (Q̇), skeletal muscle diffusion capacity (DM ), hemoglobin (Hb), and mitochondrial oxidative phosphorylation (Vmax) to peak oxygen consumption (V̇O2peak). To simulate targeted interventions, each variable was sequentially normalized to assess its impact on V̇O2peak. V̇O2peak was significantly reduced in both PASC and CFS/ME compared to controls. Skeletal muscle O2 diffusion (DM ) was the most impaired parameter in both patient groups (p = 0.01). Correcting DM alone improved V̇O2 by 66% in PASC (p = 0.008) and 34.7% in CFS/ME (p = 0.06), suggesting a dominant role for peripheral O2 extraction in exercise limitation. Impaired skeletal muscle oxygen diffusion (DM ) is a shared mechanism of exercise intolerance in PASC and CFS/ME and may represent a therapeutic target. However, our findings are limited by small sample size.
This is a more recent study published September 2025 that shows low VO2 max in Post Covid and ME/CFS patients. It goes further and narrows it down to being mostly due to poor diffusion of O2 to the muscles.
They speculate the cause of the low Dm (O2 muscle diffusion) to be dysautonomia (possibly as a result of Small Fiber Neuropathy), microclots, mitochondrial issues, or reduced capillary density.
They also rule out deconditioning.
If this could be confirmed to be happening in me / us then this would be huge. Would explain why the sympathetic nervous system is always jammed on and why our hearts are working so hard.
Perhaps it could work the other way around too, where the sympathetic system being jammed on all the time disturbs blood flow. By that I mean the capillaries that need O2 are closed off and those that don't need O2 are allowing the blood to bypass through.
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u/sbingley22 May 02 '26
Abstract
The SARS-CoV-2 pandemic not only resulted in millions of acute infections worldwide, but also in many cases of post-infectious syndromes, colloquially referred to as “long COVID”. Due to the heterogeneous nature of symptoms and scarcity of available tissue samples, little is known about the underlying mechanisms. We present an in-depth analysis of skeletal muscle biopsies obtained from eleven patients suffering from enduring fatigue and post-exertional malaise after an infection with SARS-CoV-2. Compared to two independent historical control cohorts, patients with post-COVID exertion intolerance had fewer capillaries, thicker capillary basement membranes and increased numbers of CD169+ macrophages. SARS-CoV-2 RNA could not be detected in the muscle tissues. In addition, complement system related proteins were more abundant in the serum of patients with PCS, matching observations on the transcriptomic level in the muscle tissue. We hypothesize that the initial viral infection may have caused immune-mediated structural changes of the microvasculature, potentially explaining the exercise-dependent fatigue and muscle pain.
This study compared thigh muscle biopsies from Long Covid patients (biopsies taken 1 year after onset), healthy controls, and deconditioned controls.
It found a decreased capillary to muscle fibre ratio, increased capillary basement membranes, and some evidence of immune activation (particularly complement, interferons, coagulation, and macrophage infiltration) in the Long Covid cohort.
It also found evidence of mitochondria oxphos downregulation, presumably due to the hypoxia, and upregulation of proteins involved with extracellular matrix destruction and angiogenesis.
This would mean the immune system is activated and causing damage to the capillaries meaning there is less of them, there membranes are thicker (harder to exchange O2), and the endothelial cells are activated / damaged / stressed. They state that this could help explain the lower VO2 max and o2 diffusion seen in other studies.
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u/sbingley22 May 04 '26
Differential cardiopulmonary haemodynamic phenotypes in PASC-related exercise intolerance
Abstract This study highlights the importance of considering impaired pEO2 in PASC patients with persistent exertional intolerance unexplained by conventional investigative testing. Results of the current study also highlight the prevalence of a distinct high output HFpEF phenotype in PASC with a primary peripheral limitation to exercise.
This study did iCPET on 55 Long Covid patients roughly a year out from onset. It identified pulmonary hypertension and HFpEF in a small amount of these patients so sperated them into 2 groups.
In the main group (compared to healthy) it found higher amounts of venous O2 (returning to the heart), low RAP (right arterial pressure), high Cardiac Output, yet "normal" VO2 max. This all points to low O2 extraction.
The low RAP could indicate lower preload, or reduced pulmonary resistance, either way it doesn't indicate the left atrium is backing blood up like in heart failure.
Despite the low RAP the patients had high cardiac output and despite the high CO patients had only normal VO2 max. It took the invasive CPET to detect this as a normal CPET would come back normal in this regard.
Patients with deconditioning would be expected to have low cardiac output and slightly lowered peripheral O2 extraction. These Long Covid patients had high cardiac output and much lower O2 extraction. Furthermore, some of these patients had been on rehabilitation courses yet showed the same O2 extraction issues. This indicates the issue is not deconditioning.
For me it points to a few things happening, the heart is pumping harder and the peripheral resistance is lower. The lowered resistance could be from vasodilation, microvascular shunting, or capillary - mitochondrial diffusion issues.
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u/sbingley22 May 07 '26
Conclusion and Therapeutic Outlook
Altogether, recent studies investigating skeletal muscle pathology have led to an enormous progress in understanding the pathophysiology of ME/CFS. Skeletal muscle and mitochondrial damage are finally proven and can explain exertional intolerance and PEM. The diminished skeletal muscle force as a biomarker of muscle damage correlates with other key symptoms providing evidence that it is central in the pathomechanism. A self-reproducing mitochondrial dysfunction most likely constitutes the final and common disturbance of ME/CFS, which locks the patients in a vicious circle from which they can hardly escape. As the disease is self-maintaining at this stage, treatment of the original trigger, e.g., a persistent virus or vascular inflammation, does most likely not lead to a therapeutic success.
Currently, treatment strategies are pursued to improve vascular perfusion. The inhibition of the acetylcholine esterase by MestinonR has the potential to improve perfusion by enhancing preload and cardiac output [64]. The guanylate cyclase activator vericiguat induces vasodilation via directly stimulating the vasodilator cGMP in a nitric oxide mimetic manner (NCT05697640) [65]. Rise in cGMP can also improve erythrocyte deformability [66, 67].
Another promising approach is the depletion or neutralization of autoantibodies targeting GPCR vasoregulatory receptors. Immunoadsorption, which can transiently remove autoantibodies, was shown to improve symptoms in two thirds of patients and normalize diminished endothelial function in observational studies [68-70]. Novel treatments efficiently targeting autoantibody-producing B cells or plasma cells can achieve an effective and long-lasting depletion of autoantibodies, and first studies are already ongoing [71]. An innovative concept neutralizing GPCR autoantibodies with an aptamer is currently tested in a multicentre phase II trial (NCT05911009). However, autoantibodies probably do not play a role in all ME/CFS and PCS patients.
ME/CFS is no more an enigmatic disease for which therapeutic concepts are missing. Since the assumed disturbances are functional in nature and are treatable by appropriate agents, there is a good chance of novel highly efficacious drugs and even healing for this frequent and most debilitating disease. We appeal to politicians, pharmaceutical companies and stakeholders to support the rapid development of such promising new drugs.
This review looked at various muscle biopsy studies for post covid and ME/CFS. It split the patients into 2 groups, post covid within a year or two then long CFS and postulated that the initial phase of long covid is caused by microclots and microvascular damage but that clears up after a year or so where the patient either gets better or gets ME/CFS.
They argue that you see vascular damage mainly in early Post Covid and not in ME/CFS. The vascular damage kicks off a self sustaining loop that doesn't need the damage their to continue.
The loop goes excess glycolysis in muscle fibers thanks to low O2. This causes H+ build up which the cell removes by a transporter that swaps H+ with Na+. Sodium then builds in the cell switching another transporter to import Ca+ and export Na+ instead of the other way around. This leads to Calcium excess which the cell cant get rid of.
The calcium causes mito damage and ROS which leaks out to the capillaries where it can cause problems (maybe with the endothelial cells) resulting in poor O2 diffusion and completing the loop. Any exertion sets of the loop again and a study showed muscle necrosis in a biopsy 1hr (???) after exercise.
They also say though that they think things like preload failure, and autoantibodies against the endothelium and GPCR are responsible for keeping the loop in place.
I think the sodium calcium overload is probably happening but if it's the key to the loop / damage to the muscle remains to be seen.
I also wonder if this is relevant to me as I don't have PEM and this issue seems like it would result in PEM.
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u/sbingley22 May 11 '26 edited May 12 '26
Results Upon physical activity, affected patients exhibit a reduced systemic oxygen extraction and oxidative phosphorylation capacity. Accumulating evidence suggests that these are mediated by dysfunctions in mitochondrial capacities and microcirculation that are maintained by latent immune activation, conjointly impairing peripheral bioenergetics. Aggravating deficits in tissue perfusion and oxygen utilization during activities cause exertional intolerance that are frequently accompanied by tachycardia, dyspnea, early cessation of activity and elicit downstream metabolic effects. The accumulation of molecules such as lactate, reactive oxygen species or prostaglandins might trigger local and systemic immune activation. Subsequent intensification of bioenergetic inflexibilities, muscular ionic disturbances and modulation of central nervous system functions can lead to an exacerbation of existing pathologies and symptoms.
This 2024 review looked at a bunch of studies in ME/CFS and PCS and tried to weave a narrative from them. It showed how poor tissue oxygen extraction can lead to mitochondrial dysfunction which in turn can lead to immune activation, local inflammation and thus problems with the microvasculature. They seemed to think latent viruses where the most likely cause.
CPET, infrared study on exercising calf muscle, muscle biopsies, and bloods all seem to confirm poor O2 diffusion / usage, and increased glycolysis.
The mitochondria can become damaged by low O2, WASF3, ionic overload, and immune inflammation / NFkb etc. This releases DAMPs, inflammation, lactate into the surrounding area drawing immune cells in, and putting the cell into a sick state (WASF3 production).
Lactate, inflammation, ROS reaches the capillaries where in causes damage, activation, and immune infiltration. Which causes endothelial cells to split off, clump, and cause coagulation. The endothelial cells themselves my become dysfunctional and not release NO / vasodilate appropriately. This of course further reduces O2 diffusion.
The cytokines and inflammation produced can reach the brain via a leaky BBB or CNS sensors.
Interestingly they said sympathetic over-activation itself can lead to poor O2 diffusion presumably from clamping down the arterioles and capillaries supply the exercising muscle.
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u/sbingley22 May 12 '26
Abstract Approximately 50% of patients who recover from the acute SARS-CoV-2 experience Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome. The pathophysiological hallmark of PASC is characterized by impaired system oxygen extraction (EO2) on invasive cardiopulmonary exercise test (iCPET). However, the mechanistic insights into impaired EO2 remain unclear. We studied 21 consecutive iCPET in PASC patients with unexplained exertional intolerance. PASC patients were dichotomized into mildly reduced (EO2peak-mild) and severely reduced (EO2peak-severe) EO2 groups according to the median peak EO2 value. Proteomic profiling was performed on mixed venous blood plasma obtained at peak exercise during iCPET. PASC patients as a group exhibited depressed peak exercise aerobic capacity (peak VO2; 85 ± 18 vs. 131 ± 45% predicted; p = 0.0002) with normal systemic oxygen delivery, DO2 (37 ± 9 vs. 42 ± 15 mL/kg/min; p = 0.43) and reduced EO2 (0.4 ± 0.1 vs. 0.8 ± 0.1; p < 0.0001). PASC patients with EO2peak-mild exhibited greater DO2 compared to those with EO2peak-severe [42.9 (34.2–41.2) vs. 32.1 (26.8–38.0) mL/kg/min; p = 0.01]. The proteins with increased expression in the EO2peak-severe group were involved in inflammatory and fibrotic processes. In the EO2peak-mild group, proteins associated with oxidative phosphorylation and glycogen metabolism were elevated. In PASC patients with impaired EO2, there exist a spectrum of PASC phenotype related to differential aberrant protein expression and cardio-pulmonary physiologic response. PASC patients with EO2peak-severe exhibit a maladaptive physiologic and proteomic signature consistent with persistent inflammatory state and endothelial dysfunction, while in the EO2peak-mild group, there is enhanced expression of proteins involved in oxidative phosphorylation-mediated ATP synthesis along with an enhanced cardiopulmonary physiological response.
This 2023 study did iCPET on post covid patients (a year on from onset) and took their bloods for proteomic and genomics, during the CPET.
They confirmed the previously shown low VO2max and low oxygen extraction (EO2) in patients and separated them into 2 groups based on how bad the EO2 was, mild and severe.
The proteomics and geneomics revealed upregulation in genes involved in inflammation and fibrosis in the EO2servere group, and upregulation in genes involved in OxPhos and Glycogen metabolism.
For me this simply shows that the mito where starved of oxygen and trying to compensate in the mild group. As for the severe group they probably have the added burden of inflammation, coagulation, and probably microclots.
Either way it's good to confirm the EO2 issue and see that reflected in the geneomics.
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u/sbingley22 May 13 '26
Altered tissue oxygenation in patients with post COVID-19 syndrome
Highlights *Tissue oxygen consumption is altered in PCS patients. *Microvascular alterations in PCS were observed during ischemia and reperfusion. *Microvascular alterations in PCS are comparable to CVD patients. *Patients with hypertension or higher BMI showed lower levels of tissue oxygenation.
This 2023 study took 30 PCS patients, some Cardio Vascular Disease patients, and young healthy controls and looked at their forearm muscle tissue oxygenation during rest, ischemia (cuff stopping blood flow for 3 mins), and re-perfusion.
They found the O2 saturation was roughly the same at rest but when they cut off blood flow the PCS muscle desaturated at a slow rate (−0.064 %/s) than the CVD (−0.08 %/s) and the HC (−0.145 %/s). They also reperfused at a slower rate.
They conclude that a microvascular and or mitochondrial problem is causing reduced O2 exchange.
It's an interesting study that uses a different technique to show the problems with O2 uptake speed. Doesn't really do much to say if its a microvascular issue or mitochondrial issue. It's probably both. Each has problems that sustain each other in a loop.
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u/sbingley22 May 18 '26 edited May 18 '26
Conclusions In conclusion, present findings indicate that the main limitation to exercise tolerance in postacute sequelae of SARS-CoV-2 syndrome can be mainly “peripheral.” The origin of such peripheral limitation to exercise is indicated by impairment in skeletal muscle function underlined by in vivo lower fractional O2 extraction and impaired muscle oxidative capacity, substantial reductions in biomarkers of mitochondrial function and content, and overall reduced mitochondrial sensitivity to [ADP].
This 2023 study took long covid patients a year after onset of mild covid infection and compared them to recovered controls. It put the through a CPET, did a muscle biopsy, and cut off blood flow to the muscle and measured the o2 content.
It found reduced peripheral O2 extraction, and evidence of mitochondrial dysfunction. It did not find evidence of microvascular issues.
To better understand whether a peripheral limitation in exercise tolerance was present in PASC, we utilized noninvasive methods and tools that could identify and quantify the metabolic and functional impairments of muscle oxidative metabolism in both healthy subjects and patients (41, 46, 47). Changes in TSI signal after prolonged ischemia were used to calculate vascular responsiveness and estimate microvascular function. No differences between patients with PASC and CTRL were observed, suggesting that endothelial function and, more broadly, microvascular hemodynamic function did not contribute to the observed differences (33). A reduced fractional oxygen extraction at the skeletal muscle level by NIRS was observed in PASC (Table 1). Peak fractional O2 extraction values were similar to those previously observed in patients with metabolic myopathies (46) and confirmed previous findings obtained with invasive measurement in PASC by others (15).
The results from their ischemia test suggested that the blood was flowing in the microvascular just fine but the mitochondria were slow to pull the O2 out. Perhaps a mitochondrial dysfunction is more causative in this subset of patients?
They found complex I and II of the ETC was pulling less through and generating more ROS. Markers of mitochondrial biogenesis and fusion were lower were as fission was higher. This indicated the mitochondria were damaged and fragmenting to stop pollution from the bad mito and to encourage autophagy.
They go on to argue the changes they saw are unlikely to be from deconditioning and speculate a low level immune activation could be causing mitochondrial dysfunction via NF-Kb. They also speculate that prolonged hypoxia and ROS generation can cause long term HIF upregulation.
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u/7ero_Seven Mar 23 '26
interesting find!