Plasma Proteomics of COVID-19–Associated Cardiovascular Complications

• Plasma proteomics identifies key biological processes associated with cardiac injury and stress in COVID-19. • Among 4,996 analytes measured, ADAMTS13, the vWF-cleaving protease whose loss-of-function causes microvascular thrombosis, displays the most significant inverse association with myocardial injury in COVID-19. Mendelian randomization of ADAMTS13 cis-pQTLs supports a causal role of ADAMTS13 deficiency in myocardial injury. • Increased Activin/TGFβ signaling is strongly associated with the heart failure biomarker NT-proBNP in COVID-19. • SASP, a marker of biological aging, is the dominant process associated with disease severity and cardiac involvement in COVID-19. SARS-CoV2 infection in hamsters induced a similar pattern of SASP expression, suggesting a potentially bidirectional interaction: senescence may enhance susceptibility to SARS-CoV2, which may in turn induce premature senescence. To gain insights into the mechanisms driving cardiovascular complications in COVID-19, we performed a case-control plasma proteomics study in COVID-19 patients. Our results identify the senescence-associated secretory phenotype, a marker of biological aging, as the dominant process associated with disease severity and cardiac involvement. FSTL3, an indicator of senescence-promoting Activin/TGFβ signaling, and ADAMTS13, the von Willebrand Factor–cleaving protease whose loss-of-function causes microvascular thrombosis, were among the proteins most strongly associated with myocardial stress and injury. Findings were validated in a larger COVID-19 patient cohort and the hamster COVID-19 model, providing new insights into the pathophysiology of COVID-19 cardiovascular complications with therapeutic implications.