Clinico-histopathologic and single-nuclei RNA-sequencing insights into cardiac injury and microthrombi in critical COVID-19.
Michael I Brener, Michelle L Hulke, Nobuaki Fukuma, Stephanie Golob, Robert S Zilinyi, Zhipeng Zhou, Christos Tzimas, Ilaria Russo, Claire McGroder, Ryan D Pfeiffer, Alexander Chong, Geping Zhang, Daniel Burkhoff, Martin B Leon, Mathew S Maurer, Jeffrey W Moses, Anne-Catrin Uhlemann, Hanina Hibshoosh, Nir Uriel, Matthias J Szabolcs, Björn Redfors, Charles C Marboe, Matthew R Baldwin, Nathan R Tucker, Emily J Tsai
Author Information
Michael I Brener: Division of Cardiology, Columbia University Irving Medical Center (CUIMC), New York, New York, USA.
Michelle L Hulke: Masonic Medical Research Institute, Utica, New York, USA.
Nobuaki Fukuma: Division of Cardiology, Columbia University Irving Medical Center (CUIMC), New York, New York, USA.
Stephanie Golob: Department of Medicine, CUIMC, New York, New York, USA.
Robert S Zilinyi: Department of Medicine, CUIMC, New York, New York, USA.
Zhipeng Zhou: Cardiovascular Research Foundation, New York, New York, USA.
Christos Tzimas: Division of Cardiology, Columbia University Irving Medical Center (CUIMC), New York, New York, USA.
Ilaria Russo: Division of Cardiology, Columbia University Irving Medical Center (CUIMC), New York, New York, USA.
Claire McGroder: Division of Pulmonary, Allergy & Critical Care Medicine.
Ryan D Pfeiffer: Masonic Medical Research Institute, Utica, New York, USA.
Alexander Chong: Division of Infectious Diseases, and.
Geping Zhang: Department of Pathology and Cell Biology, CUIMC, New York, New York, USA.
Daniel Burkhoff: Cardiovascular Research Foundation, New York, New York, USA.
Martin B Leon: Division of Cardiology, Columbia University Irving Medical Center (CUIMC), New York, New York, USA.
Mathew S Maurer: Division of Cardiology, Columbia University Irving Medical Center (CUIMC), New York, New York, USA.
Jeffrey W Moses: Division of Cardiology, Columbia University Irving Medical Center (CUIMC), New York, New York, USA.
Anne-Catrin Uhlemann: Division of Infectious Diseases, and.
Hanina Hibshoosh: Department of Pathology and Cell Biology, CUIMC, New York, New York, USA.
Nir Uriel: Division of Cardiology, Columbia University Irving Medical Center (CUIMC), New York, New York, USA.
Matthias J Szabolcs: Department of Pathology and Cell Biology, CUIMC, New York, New York, USA.
Björn Redfors: Cardiovascular Research Foundation, New York, New York, USA.
Charles C Marboe: Department of Pathology and Cell Biology, CUIMC, New York, New York, USA.
Matthew R Baldwin: Division of Pulmonary, Allergy & Critical Care Medicine.
Nathan R Tucker: Masonic Medical Research Institute, Utica, New York, USA.
Emily J Tsai: Division of Cardiology, Columbia University Irving Medical Center (CUIMC), New York, New York, USA.
Acute cardiac injury is prevalent in critical COVID-19 and associated with increased mortality. Its etiology remains debated, as initially presumed causes - myocarditis and cardiac necrosis - have proved uncommon. To elucidate the pathophysiology of COVID-19-associated cardiac injury, we conducted a prospective study of the first 69 consecutive COVID-19 decedents at CUIMC in New York City. Of 6 acute cardiac histopathologic features, presence of microthrombi was the most commonly detected among our cohort. 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 erythrocyte sedimentation rate and C-reactive protein were independently associated with increased odds of microthrombi, supporting an immunothrombotic etiology. Using single-nuclei RNA-sequencing analysis on 3 patients with and 4 patients without cardiac microthrombi, we discovered an enrichment of prothrombotic/antifibrinolytic, extracellular matrix remodeling, and immune-potentiating signaling among cardiac fibroblasts in microthrombi-positive, relative to microthrombi-negative, COVID-19 hearts. Non-COVID-19, nonfailing hearts were used as reference controls. Our study identifies a specific transcriptomic signature in cardiac fibroblasts as a salient feature of microthrombi-positive COVID-19 hearts. Our findings warrant further mechanistic study as cardiac fibroblasts may represent a potential therapeutic target for COVID-19-associated cardiac microthrombi.
