Cardiovascular and haematological pathology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): A role for viruses

Nunes, J. Massimo; Kell, Douglas B.; Pretorius, Etheresia

doi:10.1016/j.blre.2023.101075

Cited by 18 publications

(21 citation statements)

References 320 publications

(488 reference statements)

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“…Even though this association was weaker after controlling for confounders, this aligns with recent findings describing ED in PCS patients with additional CFS [ 46 ] and patients with CFS independently of SARS-CoV-2 infection [ 51 , 52 ]. Besides SARS-CoV-2, many viruses are known to infect endothelial cells and trigger endotheliitis, and post-viral fatigue is causally attributed more and more to ED [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation

Kuchler,

Günthner,

Ribeiro

et al. 2023

Angiogenesis

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Background Post-COVID-19 syndrome (PCS) is a lingering disease with ongoing symptoms such as fatigue and cognitive impairment resulting in a high impact on the daily life of patients. Understanding the pathophysiology of PCS is a public health priority, as it still poses a diagnostic and treatment challenge for physicians. Methods In this prospective observational cohort study, we analyzed the retinal microcirculation using Retinal Vessel Analysis (RVA) in a cohort of patients with PCS and compared it to an age- and gender-matched healthy cohort (n = 41, matched out of n = 204). Measurements and main results PCS patients exhibit persistent endothelial dysfunction (ED), as indicated by significantly lower venular flicker-induced dilation (vFID; 3.42% ± 1.77% vs. 4.64% ± 2.59%; p = 0.02), narrower central retinal artery equivalent (CRAE; 178.1 [167.5–190.2] vs. 189.1 [179.4–197.2], p = 0.01) and lower arteriolar-venular ratio (AVR; (0.84 [0.8–0.9] vs. 0.88 [0.8–0.9], p = 0.007). When combining AVR and vFID, predicted scores reached good ability to discriminate groups (area under the curve: 0.75). Higher PCS severity scores correlated with lower AVR (R = − 0.37 p = 0.017). The association of microvascular changes with PCS severity were amplified in PCS patients exhibiting higher levels of inflammatory parameters. Conclusion Our results demonstrate that prolonged endothelial dysfunction is a hallmark of PCS, and impairments of the microcirculation seem to explain ongoing symptoms in patients. As potential therapies for PCS emerge, RVA parameters may become relevant as clinical biomarkers for diagnosis and therapy management. Trial registration This study was previously registered at ClinicalTrials (“All Eyes on PCS—Analysis of the Retinal Microvasculature in Patients with Post-COVID-19 Syndrome”. NCT05635552. https://clinicaltrials.gov/ct2/show/NCT05635552). Graphical abstract Persistent endothelial dysfunction in post-COVID-19 syndrome. Acute SARS-CoV-2 infection indirectly or directly causes endotheliitis in patients. N = 41 PCS patients were recruited and retinal vessel analysis was performed to assess microvascular endothelial function. Images of SVA and DVA are illustrative for RVA data analysis. For each PCS patient and healthy cohort, venular vessel diameter of the three measurement cycles was calculated and plotted on a diameter-time curve. Patients exhibited reduced flicker-induced dilation in veins (vFID) measured by dynamic vessel analysis (DVA) and lower central retinal arteriolar equivalent (CRAE) and arteriolar-venular ratio (AVR) and a tendency towards higher central retinal venular equivalent (CRVE) when compared to SARS-CoV-2 infection naïve participants. Created with BioRender.com

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Section: Discussionmentioning

confidence: 99%

Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation

Kuchler,

Günthner,

Ribeiro

et al. 2023

Angiogenesis

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“…In particular, as summarized by Komaroff and Lipkin [ 7 ], autonomic dysfunction has been well documented in both ME/CFS and PCC. Significant platelet hyperactivity and endothelial dysfunction as well as circulatory disorders were documented in both PCC and ME/CFS, although in PCC, possible pro-atherogenic evidence was registered [ 8 ], while in ME/CFS (also related to viral etiology), the circulatory disorders look like non-atherosclerotic cardiological disease and “it seems that neurological (autonomic) dysfunction underlies these abnormalities” [ 9 ]. Abnormalities of both the sympathetic and parasympathetic arms of the autonomic nervous system have been reported, with the imbalance favoring expression of the sympathetic system [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Similar Patterns of Dysautonomia in Myalgic Encephalomyelitis/Chronic Fatigue and Post-COVID-19 Syndromes

Ryabkova,

Rubinskiy,

Marchenko

et al. 2024

Pathophysiology

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Background: There is a considerable overlap between the clinical presentation of post-COVID-19 condition (PCC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Many of their common symptoms can be linked to dysregulation of the autonomic nervous system (dysautonomia). This study aimed to objectively assess autonomic function in a general group of patients with PCC and in a group of patients with ME/CFS whose disease was not related to COVID-19. We hypothesize that the similarity in the chronic symptoms of patients with PCC and ME/CFS extends to objective autonomic nervous system abnormalities. Methods: Synchronous recordings of an electrocardiogram and continuous dynamics of blood pressure in the digital artery using the Penaz method were obtained using the spiroarteriocardiorhythmography method in 34 patients diagnosed with ME/CFS, in whom the onset of the disease was not associated with COVID-19, 29 patients meeting the PCC definition and 32 healthy controls. Heart rate variability (HRV) and systolic and diastolic blood pressure variability (BPV) were assessed at rest and in tests with fixed respiratory rates. Indicators of baroreflex regulation (baroreflex effectiveness index and baroreflex sensitivity) were additionally determined at rest. Results: The total power and power of low-frequency and high-frequency of RR interval variability at rest as well as baroreflex sensitivity were significantly lower both in PCC and ME/CFS patients compared to healthy controls. Several diagnostic prediction models for ME/CFS were developed based on HRV parameters. During slow breathing, the HRV parameters returned to normal in PCC but not in ME/CFS patients. The correlation analysis revealed a close relationship of HRV, BPV parameters and baroreflex sensitivity with fatigue, but not with HADS depressive/anxiety symptoms in the ME/CFS and PCC patients. Conclusions: A similar pattern of HRV and baroreflex failure with signs of a pathological acceleration of age-dependent dysautonomia was identified in the ME/CFS and PCC patients. The clinical, diagnostic and therapeutic implications of these findings are discussed, in light of previously described relationships between inflammation, vascular pathology, atherosclerotic cardiovascular disease and autonomic dysfunction.

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“…Homo- and hetero-polymerisation and their catalysis are then referred to, respectively, as (self-)’seeding’ [140,152-166] and ‘cross-seeding’ [153,167-174]. More recently, we have established the prevalence of these fibrinaloid microclots in post-viral diseases such as Long COVID [106,175-178] (and see [179]) and ME/CFS (myalgic encephalopathy/chronic fatigue syndrome) [180,181]. The lower amyloidogenicity of omicron versus earlier variants of SARS-CoV-2 is also reflected in its lower virulence [182], implying that these microclots are on the aetiological pathway of the disease, and they can explain many symptoms [183], including fatigue [184], post-exertional symptom exacerbation [185], autoantibody generation [107] and Postural Orthostatic Tachycardia Syndrome (POTS) [186].…”

Section: Introductionmentioning

confidence: 99%

Automated microscopic measurement of fibrinaloid microclots and their degradation by nattokinase, the main natto protease

Grixti,

Theron,

Salcedo-Sora

et al. 2024

Preprint

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Nattokinase, from the Japanese fermented food natto, is a protease with fibrinolytic activity that can thus degrade conventional blood clots. In some cases, however, including in Long COVID, fibrinogen can polymerise into an anomalous amyloid form to create clots that are resistant to normal fibrinolysis and that we refer to as fibrinaloid microclots. These can be detected with the fluorogenic stain thioflavin T. We describe an automated microscopic technique for the quantification of fibrinaloid microclot formation, which also allows the kinetics of their formation and aggregation to be recorded. We also here show that recombinant nattokinase is effective at degrading the fibrinaloid microclotsin vitro. This adds to the otherwise largely anecdotal evidence, that we review, that nattokinase might be anticipated to have value as part of therapeutic treatments for individuals with Long COVID and related disorders that involve fibrinaloid microclots.

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Cardiovascular and haematological pathology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): A role for viruses

Cited by 18 publications

References 320 publications

Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation

Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation

Similar Patterns of Dysautonomia in Myalgic Encephalomyelitis/Chronic Fatigue and Post-COVID-19 Syndromes

Automated microscopic measurement of fibrinaloid microclots and their degradation by nattokinase, the main natto protease

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