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Introduction COVID-19 has been linked to cardiovascular complications, including myocarditis and vascular dysfunction. Cardiac troponin elevation is relatively common in hospitalised patients with COVID-19, but not usually associated with myocarditis. The prevalent rise in cardiac troponin associated with COVID-19 remains largely unexplained. We hypothesised cardiac troponin elevation associated with COVID-19 is linked to systemic vascular injury.Methods This was a prospective, multicentre cohort study in the West of Scotland, involving post-COVID-19 patients enrolled during their hospitalisation or shortly after discharge (CISCO-19; NCT04403607). Convalescent COVID-19 patients underwent comprehensive phenotyping, including blood biomarker analysis and imaging (MRI, Siemens 3.0T PRISMA; CT chest and pulmonary angiography, Canon Aquilion ONE). Myocarditis was adjudicated using the Modified Lake Louise Criteria. Plasma proteomics (SOMAscan) analysed 7,288 proteins at enrolment and 28–60 days The statistical analysis of SOMAscan proteins was performed using R (v4.4.1) and Python (v3.11.5) using the Searchlight2 workflow. Differential gene expression with Benjamini-Hochberg adjustment and pathway analysis (GO-CC) were performed for participants with adjudication available and plasma proteomics at enrolment (n=155) and follow-up (n=154). An adjusted two-tailed p<0.05 was considered statistically significant. Gluteal subcutaneous biopsies were obtained from a sub-study of 37 participants (27 COVID-19, 10 controls; mean age 57, 48% women, 41% cardiovascular disease) to evaluate small resistance arteries using immunohistochemistry.Results Among participants with plasma proteomics (n=155, mean age: 55 years; 43% female), 72 (47%) had a history of cardiovascular disease. A high likelihood of myocarditis was adjudicated in 12.9%. Peak admission troponin (n=192, median=4.00ng/L, IQR=9.0), ranged from 0.5ng/L to 40,404ng/L.There was downregulation of actin and myosin-related pathways [figure 1]. Myosin light (MYL) proteins (MYL3, MYL5, MYL6, MYL6B, MYL9, MYL11, MYL12A, MYL12B) were downregulated at follow-up. These MYL proteins are expressed mainly in skeletal and vascular smooth muscle cells (Human Protein Atlas v24.0 [table 1]). At enrolment, differentially expressed MYL proteins were positively correlated with hsTnI (n=208), but did not have a consistent positive correlation with NT-proBNP (n=208). No consistent positive correlations were observed with strain measurements obtained from cardiac MRI, including right (n=155) or left (n=155) ventricular global longitudinal strain, left ventricular circumferential strain (n=154), or radial strain (n=154).Phosphorylated myosin light chain antibody uptake was greater in COVID-19 arterioles (40.1%) versus controls (10.0%, p<0.001).Abstract 2-023 Figure 1Downregulated proteinsAbstract 2-023 Table 1Human protein atlas expression of myosin light (MYL) proteins Human Protein Atlas Expression Protein Cardiomyocytes Myocytes (Skeletal) Smooth muscle cells Kidney MYL11HighMediumMediumNoneMYL12AMediumMediumHighNot availableMYL12BMediumMediumMediumGlomeruli(Medium)/Tubules(Low)MYL3HighMediumNoneCollecting duct(High)MYL5Not availableNot available Not available Glomeruli(Low)MYL6MediumHighMediumGlomeruli(Low)MYL6BHighHighMediumGlomeruli(Low)MYL9MediumLowMediumNoneConclusion This study provides novel insights to explain commonly observed troponin elevations not associated with clinically significant sequelae.