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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2022
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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. |
format | Online Article Text |
id | pubmed-8855793 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
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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