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

Abstract

Background In post-COVID-19 conditions (Long COVID), systemic vascular dysfunction is implicated but the mechanisms are uncertain, and treatment is imprecise. Methods Patients convalescing after hospitalisation 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. Results Thirty-seven patients, including 27 (mean age 57 years, 48% women, 41% cardiovascular disease) three 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%CI: 67.8, 71.7]; picrosirius red 68.6% [95% CI: 64.4, 72.8]) versus 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.

Post COVID-19 Large Vessel Vasculopathy in a Previously Healthy Young Male

“…5 Sykes et al performed a study evaluating biomarkers and the arterial histology of small gluteal vessels in a matched cohort of patients, 3 months after hospitalization for COVID-19 with risk factor-matched controls. 7 This showed similar findings of increased intercellular adhesion molecule 1, vascular cell adhesion molecule 1, peak CRP, and peak ferritin; VWF activity, factor VIII levels, and fibrinogen were increased at enrolment; and factor VIII remained persistently high at 28 to 60 days postdischarge. Gluteal small artery biopsy showed greater collagen abundance as well as enhanced vascular fibrosis and myosin light change phosphorylation.…”

Targeting the High-Density Lipoprotein Proteome for the Treatment of Post-Acute Sequelae of SARS-CoV-2

“…In addition, MYL6 is associated with neutrophil extracellular trap (NET) formation, which is linked to inflammatory and prothrombotic pathways [36]. Sykes et al reported increased myosin light chain phosphorylation and Rho-kinase activation in small resistance arteries from PCS patients [37]. Vessels showed impaired relaxation in response to nitric oxide (NO), which could be restored by a Rho-kinase-inhibitor.…”

Increased blood pressure after nonsevere COVID-19

“…The observed effects with a predominantly higher DBP in the post-COVID-19 cohort could thus rather point to vascular constriction of resistance vessels as a possible mechanism. Indeed, enhanced vasoconstriction and reduced vasorelaxation has been observed after COVID-19 [ 37 ]. The vascular inflammation described following COVID-19 with the involvement of innate and adaptive immunity may contribute to the increased DBP [ 38 ].…”