Karipidis & Karipidis (2026)
- Authors: Yiannis K. Karipidis, Konstantinos Y. Karipidis
- Institutes: Department of Physiotherapy, International Hellenic University, Thessaloniki, Greece
- Publisher: ResearchGate
- Link: DOI
Summary
This paper introduces a transformative ‘Two-Threshold Model’ that explains Post-Exertional Malaise (PEM) as a result of microvascular ‘nitric oxide misdirection’ rather than simple deconditioning. It provides a biological rationale for why traditional exercise can be harmful and offers a new framework for clinicians to safely manage activity levels based on endothelial shear stress tolerance. This approach allows for a shift from capacity-focused rehabilitation to one that protects and restores vascular health.
What was researched?
The research presents a mechanistic hypothesis exploring how SARS-CoV-2-induced endothelialitis leads to eNOS uncoupling and ‘pseudo-hypoxia’ in Long COVID patients. It specifically investigates the relationship between exertional load, hemodynamic shear stress patterns, and the delayed symptom exacerbation known as PEM.
Why was it researched?
Standard cardiac investigations often fail to explain PEM and reduced functional capacity in Long COVID, leaving patients and clinicians without clear physiological guidance. The study aims to provide a testable biochemical explanation for why minimal movement can trigger systemic oxidative stress.
How was it researched?
This work is a theoretical and mechanistic study that synthesizes existing evidence on nitro-oxidative stress, vascular biology, and Long COVID pathology. The authors developed a ‘Two-Threshold’ clinical framework and defined four distinct patient phenotypes to guide rehabilitation science and future biomarker validation.
What has been found?
The study proposes that a depletion of Tetrahydrobiopterin (BH4) 💊 causes eNOS to produce harmful superoxide instead of protective nitric oxide, creating a self-sustaining cycle of damage. It distinguishes between a PEM threshold (where oxidative stress spikes) and a shear stress tolerance threshold (where laminar flow maintains vascular health), noting that these two must be managed separately to avoid further clinical decline.
Discussion
A significant limitation is the current lack of longitudinal clinical trials to validate the specific phenotype classifications and the proposed biomarker panel. However, the model’s strength lies in its ability to differentiate between protective laminar shear and harmful oscillatory shear, which standard heart rate monitoring cannot detect.
Conclusion & Future Work
The paper concludes that physiotherapy for the ‘vascular-PEM’ phenotype must focus on maintaining shear tolerance rather than conventional capacity building. It calls for dynamic pre- and post-exertion biomarker monitoring to validate this nitro-oxidative mechanism in clinical settings.