Molecular Pathophysiology of Cardiac Injury and Cardiac Microthrombi in Fatal COVID-19: Insights from Clinico-histopathologic and Single Nuclei RNA Sequencing Analyses

Fukuma, Nobuaki; Hulke, Michelle L.; Brener, Michael I.; Golob, Stephanie; Zilinyi, Robert; Zhou, Zhipeng; Tzimas, Christos; Russo, Ilaria; McGroder, Claire; Pfeiffer, Ryan; Chong, Alexander; Zhang, Geping; Burkhoff, Daniel; Leon, Martin B.; Maurer, Mathew; Moses, Jeffrey W.; Uhlemann, Anne-Catrin; Hibshoosh, Hanina; Uriel, Nir; Szabolcs, Matthias J.; Redfors, Björn; Marboe, Charles C.; Baldwin, Matthew R.; Tucker, Nathan R.; Tsai, Emily J.

Cardiac injury is associated with critical COVID-19, yet its etiology remains debated. To elucidate the pathogenic mechanisms of COVID-19-associated cardiac injury, we conducted a single-center prospective cohort study of 69 COVID-19 decedents. Of six cardiac histopathologic features, microthrombi was the most commonly detected (n=48, 70%). We tested associations of cardiac microthrombi with biomarkers of inflammation, cardiac injury, and fibrinolysis and with in-hospital antiplatelet therapy, therapeutic anticoagulation, and corticosteroid treatment, while adjusting for multiple clinical factors, including COVID-19 therapies. Higher peak ESR and CRP during hospitalization were independently associated with higher odds of microthrombi. Using single nuclei RNA-sequence analysis, we discovered an enrichment of pro-thrombotic/anti-fibrinolytic, extracellular matrix remodeling, and immune-potentiating signaling amongst cardiac fibroblasts in microthrombi-positive COVID-19 hearts relative to microthrombi-negative COVID-19. Non-COVID-19 non-failing hearts were used as reference controls. Our cumulative findings identify the specific transcriptomic changes in cardiac fibroblasts as salient features of COVID-19-associated cardiac microthrombi.