Vascular mechanisms of post-COVID-19 conditions: Rho-kinase is a novel target for therapy.

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.

Cognitive outcome after on- and off-pump coronary artery bypass grafting surgery: a systematic review and meta-analysis.

OBJECTIVE: The aim of this study was to compare cognition following coronary artery bypass grafting (CABG) surgery with or without cardiopulmonary bypass (CPB) (on- or off-pump). DESIGN: Systematic review and meta-analysis of randomized control trials comparing cognitive outcome in patients undergoing CABG surgery on- or off-pump as assessed by continuous measures from a battery of 7 psychometric tests. SETTING: Multi-institutional centers performing CABG surgery. PARTICIPANTS: Patients with coronary artery disease requiring CABG surgery. INTERVENTIONS: CABG surgery with or without CPB. MEASUREMENTS AND MAIN RESULTS: A structured literature search identified 13 randomized control trials that included a total of 2,405 patients. Results from 7 psychometric tests were grouped into early (≤3 months) and late (6-12 months) postoperative periods. No significant differences were found between on- and off-pump groups in any of the 7 psychometric tests in either the early (p range 0.21-0.78) or late (p range 0.09-0.93) postoperative period. CONCLUSION: The results suggested that CPB may not be associated with cognitive decline that is associated with CABG surgery.