Does ex vivo Rho-kinase inhibition with fasudil improve vascular dysfunction in small resistance arteries from patients with post-COVID-19 conditions?
Patients with post-COVID-19 conditions exhibit enhanced vascular fibrosis and Rho-kinase-mediated vascular dysfunction, identifying Rho-kinase as a potential therapeutic target.
BACKGROUND: In post-coronavirus disease-19 (post-COVID-19) conditions (long COVID), systemic vascular dysfunction is implicated, but the mechanisms are uncertain, and the treatment is imprecise. METHODS AND RESULTS: Patients convalescing after hospitalization for COVID-19 and risk factor matched controls underwent multisystem phenotyping using blood biomarkers, cardiorenal and pulmonary imaging, and gluteal subcutaneous biopsy (NCT04403607). Small resistance arteries were isolated and examined using wire myography, histopathology, immunohistochemistry, and spatial transcriptomics. Endothelium-independent (sodium nitroprusside) and -dependent (acetylcholine) vasorelaxation and vasoconstriction to the thromboxane A2 receptor agonist, U46619, and endothelin-1 (ET-1) in the presence or absence of a RhoA/Rho-kinase inhibitor (fasudil), were investigated. Thirty-seven patients, including 27 (mean age 57 years, 48% women, 41% cardiovascular disease) 3 months post-COVID-19 and 10 controls (mean age 57 years, 20% women, 30% cardiovascular disease), were included. Compared with control responses, U46619-induced constriction was increased (P = 0. 002) and endothelium-independent vasorelaxation was reduced in arteries from COVID-19 patients (P < 0. 001). This difference was abolished by fasudil. Histopathology revealed greater collagen abundance in COVID-19 arteries Masson's trichrome (MT) 69. 7% 95% confidence interval (CI): 67. 8-71. 7; picrosirius red 68. 6% 95% CI: 64. 4-72. 8 vs. controls MT 64. 9% (95% CI: 59. 4-70. 3) (P = 0. 028) ; picrosirius red 60. 1% (95% CI: 55. 4-64. 8), (P = 0. 029). Greater phosphorylated myosin light chain antibody-positive staining in vascular smooth muscle cells was observed in COVID-19 arteries (40. 1%; 95% CI: 30. 9-49. 3) vs. controls (10. 0%; 95% CI: 4. 4-15. 6) (P < 0. 001). In proof-of-concept studies, gene pathways associated with extracellular matrix alteration, proteoglycan synthesis, and viral mRNA replication appeared to be upregulated. CONCLUSION: Patients with post-COVID-19 conditions have enhanced vascular fibrosis and myosin light change phosphorylation. Rho-kinase activation represents a novel therapeutic target for clinical trials.
Sykes et al. (Wed,) studied this question.