Microvascular remodeling and endothelial dysfunction across the Post-COVID-19 spectrum: a prospective observational case-control study

BACKGROUND: Post-viral diseases, including post-COVID-19 syndrome (PCS) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), cause substantial long-term morbidity. Persistent cardiovascular risk after acute infection highlights the need for accessible tools to quantify microvascular health. METHODS: All Eyes on PCS is a prospective, observational study investigating the retinal microcirculation using retinal vessel analysis (RVA). We compared RVA parameters in 102 PCS patients with 204 age- and sex-matched healthy controls (matched from n = 303). Secondary matched analyses included never infected controls (n = 96), recovered individuals (n = 102), PCS patients, and PCS patients fulfilling ME/CFS criteria (n = 62). Laboratory variables, circulating markers of endothelial dysfunction and inflammation were compared between cohorts and their associations with RVA parameters were examined. RESULTS: Compared with healthy controls, PCS patients showed reduced venular flicker-induced dilation (3.7 ± 2.2% vs. 4.5 ± 2.7%, p = 0.005, Cohen´s d: 0.32), narrow retinal arterioles (CRAE, 178.3 ± 15.5 µm vs. 183.3 ± 15.9 µm, p = 0.009, d: 0.32), and lower arteriolar-to-venular ratio (0.83 ± 0.06 vs. 0.86 ± 0.07, p = 0.004, d: 0.35). Findings persisted after adjustment for cardiovascular risk factors and remained evident in an extended secondary matched analysis across never infected, recovered, and PCS patients. ME/CFS patients showed the most pronounced alterations. PCS severity correlated with lower AVR (r = -0.21, p = 0.037) and reduced arteriolar flicker-induced dilation (r = -0.21, p = 0.039), particularly for neurocognitive symptoms. IL-6, ICAM-1 and VCAM-1 were elevated in PCS and ME/CFS and lower AVR correlated with inflammatory and iron-related markers (all adjusted p < 0.01). A combined model discriminated ME/CFS patients with good accuracy (AUC = 0.80). CONCLUSIONS: PCS is associated with persistent endothelial dysfunction, most pronounced in ME/CFS patients and linked to symptom severity and ongoing inflammation. These findings support the potential use of RVA as a non-invasive tool for assessing and monitoring endothelial health in post-viral syndromes, with implications for cardiovascular risk stratification. TRIAL REGISTRATION: The All Eyes on PCS Study has previously been registered at ClinicalTrials.gov (NCT05635552).