Spatial transcriptomic profiling of coronary endothelial cells in SARS-CoV-2 myocarditis

Abstract

ABSTRACTObjectivesOur objective was to examine coronary endothelial and myocardial programming in patients with severe COVID-19 utilizing digital spatial transcriptomics.BackgroundSevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has well-established links to thrombotic and cardiovascular events. Endothelial cell infection was initially proposed to initiate vascular events; however, this paradigm has sparked growing controversy. The significance of myocardial infection also remains unclear.MethodsAutopsy-derived cardiac tissue from control (n = 4) and COVID-19 (n = 8) patients underwent spatial transcriptomic profiling to assess differential expression patterns in myocardial and coronary vascular tissue. Our approach enabled transcriptional profiling in situ with preserved anatomy and unaltered local SARS-CoV-2 expression. In so doing, we examined the paracrine effect of SARS-CoV-2 infection in cardiac tissue.ResultsWe observed heterogeneous myocardial infection that tended to colocalize with CD31 positive cells within coronary capillaries. Despite these differences, COVID-19 patients displayed a uniform and unique myocardial transcriptional profile independent of local viral burden. Segmentation of tissues directly infected with SARS-CoV-2 showed unique, pro-inflammatory expression profiles including upregulated mediators of viral antigen presentation and immune regulation. Infected cell types appeared to primarily be capillary endothelial cells as differentially expressed genes included endothelial cell markers. However, there was limited differential expression within the endothelium of larger coronary vessels.ConclusionsOur results highlight altered myocardial programming during severe COVID-19 that may in part be associated with capillary endothelial cells. However, similar patterns were not observed in larger vessels, diminishing endotheliitis and endothelial activation as key drivers of cardiovascular events during COVID-19.Condensed AbstractSARS-CoV-2 is linked to thrombotic and cardiovascular events; however, the mechanism remains uncertain. Our objective was to examine coronary endothelial and myocardial programming in patients with severe COVID-19 utilizing digital spatial transcriptomics. Autopsy-derived coronary arterial and cardiac tissues from control and COVID-19 patients underwent spatial transcriptomic profiling. Our approach enabled transcriptional profiling in situ with preserved anatomy and unaltered local SARS-CoV-2 expression. We observed unique, pro-inflammatory expression profiles among all COVID-19 patients. While heterogeneous viral expression was noted within the tissue, SARS-CoV-2 tended to colocalize with CD31 positive cells within coronary capillaries and was associated with unique expression profiles. Similar patterns were not observed in larger coronary vessels. Our results highlight altered myocardial programming during severe COVID-19 that may in part be associated with capillary endothelial cells. Such results diminish coronary arterial endotheliitis and endothelial activation as key drivers of cardiovascular events during COVID-19 infection.LIST OF HIGHLIGHTSSARS-CoV-2 has variable expression patterns within the myocardium of COVID-19 patientsSARS-CoV-2 infection induces a unique myocardial transcriptional programming independent of local viral burdenSARS-CoV-2 myocarditis is predominantly associated with capillaritis, and tissues directly infected with SARS-CoV-2 have unique, pro-inflammatory expression profilesDiffuse endothelial activation of larger coronary vessels was absent, diminishing large artery endotheliitis as a significant contributor to cardiovascular events during COVID-19 infection.