Proinflammatory cytokines driving cardiotoxicity in COVID-19
© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology..
AIMS: Cardiac involvement is common in patients hospitalized with COVID-19 and correlates with an adverse disease trajectory. While cardiac injury has been attributed to direct viral cytotoxicity, serum-induced cardiotoxicity secondary to serological hyperinflammation constitutes a potentially amenable mechanism that remains largely unexplored.
METHODS AND RESULTS: To investigate serological drivers of cardiotoxicity in COVID-19 we have established a robust bioassay that assessed the effects of serum from COVID-19 confirmed patients on human embryonic stem cell (hESC)-derived cardiomyocytes. We demonstrate that serum from COVID-19 positive patients significantly reduced cardiomyocyte viability independent of viral transduction, an effect that was also seen in non-COVID-19 acute respiratory distress syndrome (ARDS). Serum from patients with greater disease severity led to worse cardiomyocyte viability and this significantly correlated with levels of key inflammatory cytokines, including IL-6, TNF-α, IL1-β, IL-10, CRP, and neutrophil to lymphocyte ratio with a specific reduction of CD4+ and CD8+ cells. Combinatorial blockade of IL-6 and TNF-α partly rescued the phenotype and preserved cardiomyocyte viability and function. Bulk RNA sequencing of serum-treated cardiomyocytes elucidated specific pathways involved in the COVID-19 response impacting cardiomyocyte viability, structure, and function. The observed effects of serum-induced cytotoxicity were cell-type selective as serum exposure did not adversely affect microvascular endothelial cell viability but resulted in endothelial activation and a procoagulant state.
CONCLUSION: These results provide direct evidence that inflammatory cytokines are at least in part responsible for the cardiovascular damage seen in COVID-19 and characterise the downstream activated pathways in human cardiomyocytes. The serum signature of patients with severe disease indicates possible targets for therapeutic intervention.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:120 |
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| Enthalten in: |
Cardiovascular research - 120(2024), 2 vom: 13. März, Seite 174-187 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Colzani, Maria [VerfasserIn] |
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| Links: |
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| Themen: |
COVID-19 |
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| Anmerkungen: |
Date Completed 14.03.2024 Date Revised 20.03.2024 published: Print CommentIn: Cardiovasc Res. 2024 Jan 25;:. - PMID 38270957 Citation Status MEDLINE |
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| doi: |
10.1093/cvr/cvad174 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM365324213 |
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| 100 | 1 | |a Colzani, Maria |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Proinflammatory cytokines driving cardiotoxicity in COVID-19 |
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| 500 | |a published: Print | ||
| 500 | |a CommentIn: Cardiovasc Res. 2024 Jan 25;:. - PMID 38270957 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. | ||
| 520 | |a AIMS: Cardiac involvement is common in patients hospitalized with COVID-19 and correlates with an adverse disease trajectory. While cardiac injury has been attributed to direct viral cytotoxicity, serum-induced cardiotoxicity secondary to serological hyperinflammation constitutes a potentially amenable mechanism that remains largely unexplored | ||
| 520 | |a METHODS AND RESULTS: To investigate serological drivers of cardiotoxicity in COVID-19 we have established a robust bioassay that assessed the effects of serum from COVID-19 confirmed patients on human embryonic stem cell (hESC)-derived cardiomyocytes. We demonstrate that serum from COVID-19 positive patients significantly reduced cardiomyocyte viability independent of viral transduction, an effect that was also seen in non-COVID-19 acute respiratory distress syndrome (ARDS). Serum from patients with greater disease severity led to worse cardiomyocyte viability and this significantly correlated with levels of key inflammatory cytokines, including IL-6, TNF-α, IL1-β, IL-10, CRP, and neutrophil to lymphocyte ratio with a specific reduction of CD4+ and CD8+ cells. Combinatorial blockade of IL-6 and TNF-α partly rescued the phenotype and preserved cardiomyocyte viability and function. Bulk RNA sequencing of serum-treated cardiomyocytes elucidated specific pathways involved in the COVID-19 response impacting cardiomyocyte viability, structure, and function. The observed effects of serum-induced cytotoxicity were cell-type selective as serum exposure did not adversely affect microvascular endothelial cell viability but resulted in endothelial activation and a procoagulant state | ||
| 520 | |a CONCLUSION: These results provide direct evidence that inflammatory cytokines are at least in part responsible for the cardiovascular damage seen in COVID-19 and characterise the downstream activated pathways in human cardiomyocytes. The serum signature of patients with severe disease indicates possible targets for therapeutic intervention | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a COVID-19 | |
| 650 | 4 | |a Cardiotoxicity | |
| 650 | 4 | |a Inflammation | |
| 650 | 4 | |a Stem cell derived cardiomyocytes | |
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| 700 | 1 | |a Bargehr, Johannes |e verfasserin |4 aut | |
| 700 | 1 | |a Mescia, Federica |e verfasserin |4 aut | |
| 700 | 1 | |a Williams, Eleanor C |e verfasserin |4 aut | |
| 700 | 1 | |a Knight-Schrijver, Vincent |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Jonathan |e verfasserin |4 aut | |
| 700 | 1 | |a Summers, Charlotte |e verfasserin |4 aut | |
| 700 | 1 | |a Mohorianu, Irina |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, Kenneth G C |e verfasserin |4 aut | |
| 700 | 1 | |a Lyons, Paul A |e verfasserin |4 aut | |
| 700 | 1 | |a Sinha, Sanjay |e verfasserin |4 aut | |
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