Persistent renin-angiotensin system and inflammatory dysregulation following COVID-19 impairs ischemic stroke recovery

Previous studies indicate that stroke recovery is worse in patients with prior COVID-19, suggesting persistent biological perturbations. We investigated lingering renin-angiotensin system (RAS) and inflammatory alterations after COVID-19 to uncover mechanisms driving impaired ischemic stroke recovery. We conducted a prospective observational cohort study comparing clinical and molecular profiles of ischemic stroke patients with and without recent COVID-19 infection to age-matched healthy controls. Plasma angiotensin-(1-7), angiotensin II, and soluble ACE2 were quantified, high-throughput proteomic profiling was performed using the Olink® Explore platform, and RNA sequencing was conducted to identify molecular mechanisms related to COVID-19-associated stroke and stroke outcomes (90-day modified Rankin Scale (mRS)). A total of 189 participants (38 COVID-19-associated stroke, 77 non-COVID-19 stroke, and 74 healthy controls) were enrolled. COVID-19-associated stroke patients exhibited significantly higher proportions of cryptogenic strokes (21.1 % vs 10.4 %), earlier hospital presentation (mean 185 vs 310 min), greater use of endovascular thrombectomy (97.4 % vs. 52.6 %), yet poorer functional outcomes (mRS ≥3) at 3 months (73 % vs. 47 %, all p < 0.05). Both stroke groups showed elevated angiotensin-(1-7) levels compared to controls, but angiotensin II levels were notably higher only in non-COVID-19 stroke patients. Proteomic analysis revealed sustained elevation of interferon-gamma (IFN-γ) signaling in COVID-19-associated stroke patients. Reduced AKT3 levels emerged as a significant predictor of poor outcomes, independent of renin-angiotensin biomarkers (adjusted OR 0.40; 95 % CI 0.16-0.94). Stroke patients with low AKT3 levels and poor outcomes exhibited significant upregulation of ribosomal proteins (RPS15, RPS4X, RPS7, RPS18, RPSA, RPS27A, RPS13, RPS23), reflecting heightened translational stress. Persistent RAS and inflammatory dysregulation following COVID-19 may contribute to worse stroke recovery. Future studies should validate and investigate the therapeutic implications of these findings.