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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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-01-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.154633 |
| _version_ | 1828807669629059072 |
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| author | 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_facet | 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_sort | Michael I. Brener |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-12T08:28:25Z |
| format | Article |
| id | doaj.art-2de2e76911bc473598fb90fee54b07f0 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-12T08:28:25Z |
| publishDate | 2022-01-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-2de2e76911bc473598fb90fee54b07f02022-12-22T00:31:10ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-01-0172Clinico-histopathologic and single-nuclei RNA-sequencing insights into cardiac injury and microthrombi in critical COVID-19Michael I. BrenerMichelle L. HulkeNobuaki FukumaStephanie GolobRobert S. ZilinyiZhipeng ZhouChristos TzimasIlaria RussoClaire McGroderRyan D. PfeifferAlexander ChongGeping ZhangDaniel BurkhoffMartin B. LeonMathew S. MaurerJeffrey W. MosesAnne-Catrin UhlemannHanina HibshooshNir UrielMatthias J. SzabolcsBjörn RedforsCharles C. MarboeMatthew R. BaldwinNathan R. TuckerEmily J. TsaiAcute 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.https://doi.org/10.1172/jci.insight.154633COVID-19Cardiology |
| spellingShingle | 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 Clinico-histopathologic and single-nuclei RNA-sequencing insights into cardiac injury and microthrombi in critical COVID-19 JCI Insight COVID-19 Cardiology |
| 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 | COVID-19 Cardiology |
| url | https://doi.org/10.1172/jci.insight.154633 |
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