Biomarkers of sustained systemic inflammation and microvascular dysfunction associated with post-COVID-19 condition symptoms at 24 months after SARS-CoV-2-infection

Jacobs, Lotte M. C.; Wintjens, Marieke S. J. N.; Nagy, Magdolna; Willems, Loes; ten Cate, Hugo; Spronk, Henri M. H.; van Kuijk, Sander M. J.; Ghossein-Doha, Chahinda; Netea, Mihai G.; Groh, Laszlo A.; van Petersen, André S.; Warlé, Michiel C.

doi:10.3389/fimmu.2023.1182182

Cited by 7 publications

(3 citation statements)

References 34 publications

(37 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This suggests a potential association between ME/CFS and heightened ET-1 mediated vasoconstriction, indicated by diminished nitrogen oxide levels [ 11 ]. A study conducted by Prof. Warlé [ 39 ] revealed correlations between ET-1 levels and long COVID symptoms at 2 years after acute COVID-19 infection. Under physiological conditions, ET-1 production is small and bioavailability of nitric oxide (NOx) is preserved, inducing vasorelaxation.…”

Section: Discussionmentioning

confidence: 99%

Association of circulating biomarkers with illness severity measures differentiates myalgic encephalomyelitis/chronic fatigue syndrome and post-COVID-19 condition: a prospective pilot cohort study

Domingo,

Battistini,

Cordobilla

et al. 2024

J Transl Med

View full text Add to dashboard Cite

Background Accumulating evidence suggests that autonomic dysfunction and persistent systemic inflammation are common clinical features in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID. However, there is limited knowledge regarding their potential association with circulating biomarkers and illness severity in these conditions. Methods This single-site, prospective, cross-sectional, pilot cohort study aimed to distinguish between the two patient populations by using self-reported outcome measures and circulating biomarkers of endothelial function and systemic inflammation status. Thirty-one individuals with ME/CFS, 23 individuals with long COVID, and 31 matched sedentary healthy controls were included. All study participants underwent non-invasive cardiovascular hemodynamic challenge testing (10 min NASA lean test) for assessment of orthostatic intolerance. Regression analysis was used to examine associations between outcome measures and circulating biomarkers in the study participants. Classification across groups was based on principal component and discriminant analyses. Results Four ME/CFS patients (13%), 1 with long COVID (4%), and 1 healthy control (3%) presented postural orthostatic tachycardia syndrome (POTS) using the 10-min NASA lean test. Compared with matched healthy controls, ME/CFS and long COVID subjects showed higher levels of ET-1 (p < 0.05) and VCAM-1 (p < 0.001), and lower levels of nitrites (NOx assessed as NO2- + NO3-) (p < 0.01). ME/CFS patients also showed higher levels of serpin E1 (PAI-1) and E-selectin than did both long COVID and matched control subjects (p < 0.01 in all cases). Long COVID patients had lower TSP-1 levels than did ME/CFS patients and matched sedentary healthy controls (p < 0.001). As for inflammation biomarkers, both long COVID and ME/CFS subjects had higher levels of TNF-α than did matched healthy controls (p < 0.01 in both comparisons). Compared with controls, ME/CFS patients had higher levels of IL-1β (p < 0.001), IL-4 (p < 0.001), IL-6 (p < 0.01), IL-10 (p < 0.001), IP-10 (p < 0.05), and leptin (p < 0.001). Principal component analysis supported differentiation between groups based on self-reported outcome measures and biomarkers of endothelial function and inflammatory status in the study population. Conclusions Our findings revealed that combining biomarkers of endothelial dysfunction and inflammation with outcome measures differentiate ME/CFS and Long COVID using robust discriminant analysis of principal components. Further research is needed to provide a more comprehensive characterization of these underlying pathomechanisms, which could be promising targets for therapeutic and preventive strategies in these conditions.

show abstract

Section: Discussionmentioning

confidence: 99%

Association of circulating biomarkers with illness severity measures differentiates myalgic encephalomyelitis/chronic fatigue syndrome and post-COVID-19 condition: a prospective pilot cohort study

Domingo,

Battistini,

Cordobilla

et al. 2024

J Transl Med

View full text Add to dashboard Cite

show abstract

“…The sensory nerves that contain and release neuropeptides such as CGRP are primarily unmyelinated sensory C-fibers and myelinated Aδ-fibers [75]. The importance of CGRP, and its release from sensory nerves, for the activation of the Na + /K + -ATPase and for diminishing muscle fatigue has been experimentally demonstrated under conditions of stimulation and inhibition [76,77]. After the degeneration of these fibers, by which CGRP is produced, there should be a deficiency in CGRP that adds to the stimulatory deficit of the Na + /K + -ATPase during exercise, which is already caused by ß2AdR dysfunction to aggravate and fix the disturbance.…”

Section: Mitochondrial Dysfunctionmentioning

confidence: 99%

Microvascular Capillary and Precapillary Cardiovascular Disturbances Strongly Interact to Severely Affect Tissue Perfusion and Mitochondrial Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Evolving from the Post COVID-19 Syndrome

Wirth,

Löhn

2024

Medicina

View full text Add to dashboard Cite

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent, debilitating and still enigmatic disease. There is a broad overlap in the symptomatology of ME/CFS and the Post-COVID-19 Syndrome (PCS). A fraction of the PCS patients develop the full clinical picture of ME/CFS. New observations in microvessels and blood from patients suffering from PCS have appeared and include microclots and malformed pathological blood cells. Capillary blood flow is impaired not only by pathological blood components but also by prothrombotic changes in the vascular wall, endothelial dysfunction, and the expression of adhesion molecules in the capillaries. These disturbances can finally cause a low capillary flow and even capillary stasis. A low cardiac stroke volume due to hypovolemia and the inability of the capacitance vessels to adequately constrict to deliver the necessary cardiac preload generate an unfavorable low precapillary perfusion pressure. Furthermore, a predominance of vasoconstrictor over vasodilator influences exists, in which sympathetic hyperactivity and endothelial dysfunction play a strong role, causing the constriction of resistance vessels and of precapillary sphincters, which leads to a fall in capillary pressure behind the sphincters. The interaction of these two precapillary cardiovascular mechanisms causing a low capillary perfusion pressure is hemodynamically highly unfavorable in the presence of a primary capillary stasis, which is already caused by the pathological blood components and their interaction with the capillary wall, to severely impair organ perfusion. The detrimental coincidence of microcirculatory and precapillary cardiovascular disturbances may constitute the key disturbance of the Post-COVID-19 syndrome and finally lead to ME/CFS in predisposed patients because the interaction causes a particular kind of perfusion disturbance—capillary ischemia/reperfusion—which has a high potential of causing mitochondrial dysfunction by inducing sodium- and calcium-overload in skeletal muscles. The latter, in turn, worsens the vascular situation through the generation of reactive oxygen species to close a vicious cycle from which the patient can hardly escape.

show abstract

“…The sensory nerves that contain and release neuropeptides such as CGRP are primarily unmyelinated sensory C-fibers and myelinated Aδ-fibers [75]. The importance of CGRP, and its release from sensory nerves, for the activation of the Na + /K + -ATPase and for diminishing muscle fatigue has been experimentally demonstrated under conditions of stimulation and inhibition [76,77]. After the degeneration of these fibers, by which Presumably, enhanced sodium loading is not enough to cause a rise in sodium to an extent that it causes calcium overload by reversing the transport mode of the NCX.…”

Section: Mitochondrial Dysfunctionmentioning

confidence: 99%

Microvascular Capillary and Precapillary Cardiovascular Disturbances Strongly Interact to Severely Affect Tissue Perfusion and Mitochondrial Function in ME/CFS Evolving from the Post COVID-19 Syndrome

Wirth,

Löhn

2023

Preprint

View full text Add to dashboard Cite

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent, debilitating and still enigmatic disease. There is a broad overlap in the symptomatology of ME/CFS and the Post-COVID Syndrome (PCS). A fraction of the PCS patients develops the full clinical picture of ME/CFS. New observations in microvessels and blood from patients suffering from PCS have appeared and include microclots and malformed pathological blood cells. Capillary blood flow is impaired not only by pathological blood components but also by prothrombotic changes in the vascular wall, endothelial dysfunction, and expression of adhesion molecules in the capillaries. These disturbances can finally cause a low capillary flow and even capillary stasis. A low cardiac stroke volume due to hypovolemia and the inability of the capacitance vessels to adequately constrict to deliver the necessary cardiac preload generate an unfavorable low precapillary perfusion pressure. Furthermore, a predominance of vasoconstrictor over vasodilator influences exists, in which sympathetic hyperactivity and endothelial dysfunction play a strong role, causing constriction of resistance vessels and of precapillary sphincters which leads to a fall in capillary pressure behind the sphincters. The interaction of these two precapillary cardiovascular mechanisms causing a low capillary perfusion pressure is hemodynamically highly unfavorable in the presence of a primary capillary stasis already caused by the pathological blood components and their interaction with the capillary wall, to severely impair organ perfusion. The detrimental coincidence of the microcirculatory with the precapillary cardiovascular disturbances may constitute the key disturbance of the Post-COVID-19 syndrome and finally lead to ME/CFS in pre-disposed patients because the interaction causes a particular kind of perfusion disturbance - capillary ischemia-reperfusion - which has a high potential of causing mitochondrial dysfunction by inducing sodium- and calcium-overload in skeletal muscles. The latter in turns worsens the vascular situation by the generation of reactive oxygen species to close a vicious cycle from which the patient can hardly escape.

show abstract

Biomarkers of sustained systemic inflammation and microvascular dysfunction associated with post-COVID-19 condition symptoms at 24 months after SARS-CoV-2-infection

Cited by 7 publications

References 34 publications

Association of circulating biomarkers with illness severity measures differentiates myalgic encephalomyelitis/chronic fatigue syndrome and post-COVID-19 condition: a prospective pilot cohort study

Association of circulating biomarkers with illness severity measures differentiates myalgic encephalomyelitis/chronic fatigue syndrome and post-COVID-19 condition: a prospective pilot cohort study

Microvascular Capillary and Precapillary Cardiovascular Disturbances Strongly Interact to Severely Affect Tissue Perfusion and Mitochondrial Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Evolving from the Post COVID-19 Syndrome

Microvascular Capillary and Precapillary Cardiovascular Disturbances Strongly Interact to Severely Affect Tissue Perfusion and Mitochondrial Function in ME/CFS Evolving from the Post COVID-19 Syndrome

Contact Info

Product

Resources

About