Cardiac Profibrotic Phenotype Evokes Er-Stress Dependent Pathways During Ecm Remodeling with Covid-19 in Situ

We recently described a subgroup of autopsied COVID-19 subjects (~40%), termed ‘profibrotic phenotype,’ who exhibited clusters of myofibroblasts (Mfbs), which were positive for the collagen-specific chaperone heat shock protein 47 (HSP47+) in situ. Recruitment of CD163+ macrophages (Mφs) and collagen α1(l)(COLα1) were also identified within HSP47+ “hot spots” relative to controls and other COVID subjects. We now characterize profibrotic extracellular matrix (ECM) phenotypes, identifying increases in and regional distribution of periostin (POSTN) and fibroblast activating proteins (FAP) as well as COLα1. These data support induction of the endoplasmic reticulum (ER) stress response for mitigation of proteostasis (i.e., protein homeostasis) dysfunction. ECM shifts occur without significant increases in either trichrome positive staining or myocardial injury based quantitively on standard H&E scoring among controls, non-profibrotic or profibrotic COVID-19 subjects. Our findings also suggest distinct mechanism(s) for ECM remodeling in the setting of SARS-CoV-2 infection. The ratio of CD163/CD68+ cells is increased in hot spots of profibrotic hearts compared with either controls or outside hot spots in COVID-19 subjects. Taken together, the matrix remodeling of human COVID-19 hearts in situ is characterized by pro-fibrotic/-inflammatory mediated (e.g., HSP47+ Mfbs, CD163+ Mφs) modifications in ECM (i.e., Colα1(I), POSTN, FAP). Given the established associations of viral infection (e.g., HIV), myocardial fibrosis and sudden cardiac death, early screening tools (e.g., plasma biomarkers, noninvasive cardiac magnetic resonance) for diagnosis, monitoring and treatment of fibrotic ECM remodeling are warranted for COVID-19 high-risk populations.