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Clinico-histopathologic and single-nuclei RNA-sequencing insights into cardiac injury and microthrombi in critical COVID-19

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...

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Autores principales: Brener, Michael I., Hulke, Michelle L., Fukuma, Nobuaki, Golob, Stephanie, Zilinyi, Robert S., Zhou, Zhipeng, Tzimas, Christos, Russo, Ilaria, McGroder, Claire, Pfeiffer, Ryan D., Chong, Alexander, Zhang, Geping, Burkhoff, Daniel, Leon, Martin B., Maurer, Mathew S., 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8855793/
https://www.ncbi.nlm.nih.gov/pubmed/34905515
http://dx.doi.org/10.1172/jci.insight.154633
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author Brener, Michael I.
Hulke, Michelle L.
Fukuma, Nobuaki
Golob, Stephanie
Zilinyi, Robert S.
Zhou, Zhipeng
Tzimas, Christos
Russo, Ilaria
McGroder, Claire
Pfeiffer, Ryan D.
Chong, Alexander
Zhang, Geping
Burkhoff, Daniel
Leon, Martin B.
Maurer, Mathew S.
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.
author_facet Brener, Michael I.
Hulke, Michelle L.
Fukuma, Nobuaki
Golob, Stephanie
Zilinyi, Robert S.
Zhou, Zhipeng
Tzimas, Christos
Russo, Ilaria
McGroder, Claire
Pfeiffer, Ryan D.
Chong, Alexander
Zhang, Geping
Burkhoff, Daniel
Leon, Martin B.
Maurer, Mathew S.
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.
author_sort Brener, Michael I.
collection PubMed
description 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.
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spelling pubmed-88557932022-02-22 Clinico-histopathologic and single-nuclei RNA-sequencing insights into cardiac injury and microthrombi in critical COVID-19 Brener, Michael I. Hulke, Michelle L. Fukuma, Nobuaki Golob, Stephanie Zilinyi, Robert S. Zhou, Zhipeng Tzimas, Christos Russo, Ilaria McGroder, Claire Pfeiffer, Ryan D. Chong, Alexander Zhang, Geping Burkhoff, Daniel Leon, Martin B. Maurer, Mathew S. 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. JCI Insight Research Article 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. American Society for Clinical Investigation 2022-01-25 /pmc/articles/PMC8855793/ /pubmed/34905515 http://dx.doi.org/10.1172/jci.insight.154633 Text en © 2022 Brener et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Brener, Michael I.
Hulke, Michelle L.
Fukuma, Nobuaki
Golob, Stephanie
Zilinyi, Robert S.
Zhou, Zhipeng
Tzimas, Christos
Russo, Ilaria
McGroder, Claire
Pfeiffer, Ryan D.
Chong, Alexander
Zhang, Geping
Burkhoff, Daniel
Leon, Martin B.
Maurer, Mathew S.
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.
Clinico-histopathologic and single-nuclei RNA-sequencing insights into cardiac injury and microthrombi in critical COVID-19
title Clinico-histopathologic and single-nuclei RNA-sequencing insights into cardiac injury and microthrombi in critical COVID-19
title_full Clinico-histopathologic and single-nuclei RNA-sequencing insights into cardiac injury and microthrombi in critical COVID-19
title_fullStr Clinico-histopathologic and single-nuclei RNA-sequencing insights into cardiac injury and microthrombi in critical COVID-19
title_full_unstemmed Clinico-histopathologic and single-nuclei RNA-sequencing insights into cardiac injury and microthrombi in critical COVID-19
title_short Clinico-histopathologic and single-nuclei RNA-sequencing insights into cardiac injury and microthrombi in critical COVID-19
title_sort clinico-histopathologic and single-nuclei rna-sequencing insights into cardiac injury and microthrombi in critical covid-19
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8855793/
https://www.ncbi.nlm.nih.gov/pubmed/34905515
http://dx.doi.org/10.1172/jci.insight.154633
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