Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and ME/CFS, Haffke, Scheibenbogen et al, 2022

[Kalliope]

Transl Med
Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS) Milan Haffke et al

Abstract
Background: Fatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients fulfilling criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). As SARS-CoV-2 infects endothelial cells, causing endotheliitis and damaging the endothelium, we investigated endothelial dysfunction (ED) and endothelial biomarkers in patients with PCS.

Methods: We studied the endothelial function in 30 PCS patients with persistent fatigue and exertion intolerance as well as in 15 age- and sex matched seronegative healthy controls (HCs). 14 patients fulfilled the diagnostic criteria for ME/CFS. The other patients were considered to have PCS. Peripheral endothelial function was assessed by the reactive hyperaemia index (RHI) using peripheral arterial tonometry (PAT) in patients and HCs. In a larger cohort of patients and HCs, including post-COVID reconvalescents (PCHCs), Endothelin-1 (ET-1), Angiopoietin-2 (Ang-2), Endocan (ESM-1), IL-8, Angiotensin-Converting Enzyme (ACE) and ACE2 were analysed as endothelial biomarkers.

Results: Five of the 14 post-COVID ME/CFS patients and five of the 16 PCS patients showed ED defined by a diminished RHI (< 1.67), but none of HCs exhibited this finding. A paradoxical positive correlation of RHI with age, blood pressure and BMI was found in PCS but not ME/CFS patients. The ET-1 concentration was significantly elevated in both ME/CFS and PCS patients compared to HCs and PCHCs. The serum Ang-2 concentration was lower in both PCS patients and PCHCs compared to HCs.

Conclusion: A subset of PCS patients display evidence for ED shown by a diminished RHI and altered endothelial biomarkers. Different associations of the RHI with clinical parameters as well as varying biomarker profiles may suggest distinct pathomechanisms among patient subgroups.

 

[Kalliope]

Spotted on twitter via prof. Kunst who comments:

In a new #LongCovid study, one in three patients showed endothelial dysfunction (i.e., diminished ability to widen blood vessels when needed). Also of note, 15 of the 30 patients qualified for #MECFS for which this impairment is frequently observed.

 

[ME/CFS Science Blog]

This figure seems to show the main results. Doesn't look like a large difference.

 

[SNT Gatchaman]

The cut-off of 1.67 to define normal / abnormal appears to be derived from comparison of the EndoPAT 2000 device against the gold standard evaluation of endothelial dysfunction: direct catheter left main coronary artery challenge with acetylcholine.

From the manufacturer's Datasheet:

The RHI (Reactive Hyperemia Index) is the post-to-pre occlusion PAT™ signal ratio in the occluded arm, relative to the same ratio in the control arm, corrected for baseline vascular tone of the occluded arm where:

Normal: RHI > 1.67
Abnormal: RHI ≤ 1.67​

This index and threshold were used in the validation study presented at section 1.2 of this manual and they reflect endothelial function.

The gold-standard is defined as:

Normal coronary endothelial function is defined as an increase in CBF of >50% and an increase or less than 20% decrease in the coronary artery diameter in response to the maximum dose of intra-coronary Ach

(ΔCBF > 50% and ΔCAD > -20%)

Fig. 1 in the paper shows that HCs can get close to that threshold.

 

[arnoble]

The EndoPAT device seems to no longer be in production, and this 2012 paper had doubts about what it was actually measuring (although perhaps they addressed issues for the thread paper)

Endothelial function as measured by the EndoPAT could be physiologically different from endothelial function as measured by conventional techniques.

In any case, I agree with:

Doesn't look like a large difference.

 

[Hutan]

Here are the findings for ET-1 for the initial study cohort and the validation cohort

Serum ET-1 concentrations. The serum ET-1 concentrations were measured in the PAT study cohort (a) and in a second validation cohort (b). The median (IQR) serum ET-1 concentration is shown. For statistical analysis, the Kruskal–Wallis with Dunn´s post-hoc multiple comparisons test was used. P values ≤ 0.05 were considered statistically significant. ET-1 Endothelin-1; IQR interquartile range; RH-PAT reactive hyperaemia peripheral arterial tonometry

There do seem to be some people in the ME/CFS and PCS groups with values higher than the healthy controls.

 

[arnoble]

Here are the findings for ET-1 for the initial study cohort and the validation cohort


View attachment 28609View attachment 28608



There do seem to be some people in the ME/CFS and PCS groups with values higher than the healthy controls.

Yet this 2021 study says

Studies in healthy adults have shown that basal plasma and serum ET-1 levels are normally between 0.7 and 5 pg/mL [8,13].

 

[Hutan]

Thanks @arnoble, that's very useful. I guess the assay method might be different, but it does put the variation in context.

There is quite a lot of variation even in just the mean ETS-1 value of the first control sample in the ME/CFS study and the mean ETS-1 value of the validation control sample (roughly 1.25 versus 0.8).

Also, ETS-1 is known to increase with age. The samples weren't perfectly matched. In the validation sample, the mean age of the ME/CFS sample was 46.5 years, whereas the mean ages of the post-Covid syndrome, healthy control and post-Covid healthy control samples were 37, 38 and 36.5 years respectively.