Plasma Proteomics of COVID-19 Associated Cardiovascular Complications: Implications for Pathophysiology and Therapeutics

Roh, Jason; Kitchen, Robert; Guseh, J Sawalla; McNeill, Jenna; Aid, Malika; Martinot, Amanda; Yu, Andy; Platt, Colin; Rhee, James; Weber, Brittany; Trager, Lena; Hastings, Margaret; Ducat, Sarah; Xia, Peng; Castro, Claire; Atlason, Bjarni; Churchill, Timothy; Di Carli, Marcelo; Ellinor, Patrick; Barouch, Dan; Ho, Jennifer; Rosenzweig, Anthony

Cardiovascular complications are common in COVID-19 and strongly associated with disease severity and mortality. However, the mechanisms driving cardiac injury and failure in COVID-19 are largely unknown. We performed plasma proteomics on 80 COVID-19 patients and controls, grouped according to disease severity and cardiac involvement. Findings were validated in 305 independent COVID-19 patients and investigated in an animal model. Here we show that senescence-associated secretory proteins, markers of biological aging, strongly associate with disease severity and cardiac involvement even in age-matched cohorts. FSTL3, an indicator of Activin/TGFβ signaling, was the most significantly upregulated protein associated with the heart failure biomarker, NTproBNP (β = 0.4;p(adj)=4.6x10(−7)), while ADAMTS13, a vWF-cleaving protease whose loss-of-function causes microvascular thrombosis, was the most downregulated protein associated with myocardial injury (β=−0.4;p(adj)=8x10(−7)). Mendelian randomization supported a causal role for ADAMTS13 in myocardial injury. These data provide important new insights into the pathophysiology of COVID-19 cardiovascular complications with therapeutic implications.