Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS)

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.

Keywords: Endothelial dysfunction; Endothelin-1; Myalgic encephalomyelitis/chronic fatigue syndrome; Post-COVID syndrome; Reactive hyperaemia index.

Fig. 1

Endothelial dysfunction (ED) assessed by RH-PAT. ED was found in five of 14 ME/CFS patients and in five of 16 PCS patients but not in healthy controls (HCs). The RHI value for each patient is plotted. The dotted line indicates the RHI cut-off value of ≤ 1.67 defining ED. [RHI = reactive hyperaemia index; RH-PAT = reactive hyperaemia peripheral arterial tonometry]

Fig. 2

Correlation of age, blood pressure and BMI with the reactive hyperaemia index (RHI). Correlations of the RHI with age (a–c), systolic blood pressure (d–f), diastolic blood pressure (g–i) and BMI (j, k) for ME/CFS patients (n = 14; a, d, g, j), PCS patients (n = 16; b, e, h, k) and healthy controls (HC) (n = 15; c, f, i). Correlation analysis was performed using the nonparametric Spearman coefficient. A two-tailed p value ≤ 0.05 was considered statistically significant

Fig. 3

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

Fig. 4

Serum Ang-2 levels. Serum Ang-2 levels were measured in the PAT study cohort (a) and in a second validation cohort (b). Levels are depicted as the median (IQR) of the fold change (FC) compared to that in HCs, as the standard was 1.5-fold higher in the ELISA of the ^nd validation cohort compared to the PAT study cohort. For statistical analysis, the Kruskal–Wallis with Dunn´s post-hoc multiple comparisons test was used. P values ≤ 0.05 were considered statistically significant. [Ang-2 = Angiopoietin-2; IQR = interquartile range; RH-PAT = reactive hyperaemia peripheral arterial tonometry]