ABSTRACT
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/TGFß 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.
ABSTRACT
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/TGFß signaling, was the most significantly upregulated protein associated with the heart failure biomarker, NTproBNP (ß = 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 (ß=-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.