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

Fukuma, N.; Hulke, M. L.; Brener, M. I.; Golob, S.; Zilinyi, R.; Zhou, Z.; Tzimas, C.; Russo, I.; McGroder, C.; Pfeiffer, R.; Chong, A.; Zhang, G.; Burkhoff, D.; Leon, M. B.; Maurer, M.; Moses, J. W.; Uhlemann, A.-C.; Hibshoosh, H.; Uriel, N.; Szabolcs, M. J.; Redfors, B.; Marboe, C. C.; Baldwin, M. R.; Tucker, N. R.; Tsai, E. J.

doi:10.1101/2021.07.27.453843

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bioRxiv · 10.1101/2021.07.27.453843

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

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Abstract

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.

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Fukuma, N., Hulke, M. L., Brener, M. I., Golob, S., Zilinyi, R., Zhou, Z., Tzimas, C., Russo, I., McGroder, C., Pfeiffer, R., Chong, A., Zhang, G., Burkhoff, D., Leon, M. B., Maurer, M., Moses, J. W., Uhlemann, A.-C., Hibshoosh, H., Uriel, N., Szabolcs, M. J., Redfors, B., Marboe, C. C., Baldwin, M. R., Tucker, N. R., Tsai, E. J.. 2021-07-27. Molecular Pathophysiology of Cardiac Injury and Cardiac Microthrombi in Fatal COVID-19: Insights from Clinico-histopathologic and Single Nuclei RNA Sequencing Analyses. https://doi.org/10.1101/2021.07.27.453843

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