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Coronary Progenitor Cells and Soluble Biomarkers in Cardiovascular Prognosis after Coronary Angioplasty
Published on: January 28, 2020
Cardiovascular signatures of COVID-19 predict mortality and identify barrier stabilizing therapies
Dakota Gustafson1, Michelle Ngai2, Ruilin Wu1
1Toronto General Hospital Research Institute, University Health Network, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
Insights
Biomarkers and microRNAs predict COVID-19 mortality, revealing vascular dysfunction. Therapies targeting endothelial cells show promise for treating COVID-19 and other diseases involving vascular damage.
Area of Science:
- Cardiovascular Research
- Infectious Disease Research
- Genomics and Proteomics
Background:
- Severe COVID-19 impacts vasculature, causing endothelial cell activation, inflammation, and thrombosis.
- The predictive value and specificity of vascular markers for COVID-19 outcomes remain unclear.
- Therapeutic targeting of vascular permeability in COVID-19 requires further investigation.
Purpose of the Study:
- To assess if circulating vascular markers predict clinical outcomes in COVID-19 patients.
- To determine if these markers are unique to COVID-19.
- To explore therapeutic strategies for vascular permeability.
Main Methods:
- Prospective evaluation of inflammatory, cardiac, and endothelial cell activation markers in 241 unvaccinated patients.
- Development of a microRNA atlas and application of Random Forest machine learning for prognostic value.
- Ex vivo assessment of endothelial cell permeability and gene regulatory networks.
Main Results:
- Multiple biomarkers correlated with mortality in COVID-19 and matched SARS-CoV-2-negative patients.
- Specific microRNA dysregulation predicted poor COVID-19 outcomes and identified disease pathways.
- Machine learning integration improved in-hospital mortality prediction; patient plasma induced endothelial dysfunction, treatable with angiopoietin-1 mimetic or Slit2-N.
Conclusions:
- Multi-omics data integration identified prognostic microRNA and vascular biomarkers for COVID-19 mortality.
- Vascular stabilizing therapies are potential treatments for endothelial dysfunction in COVID-19.
- Endothelial dysfunction plays a central role in severe diseases, suggesting broader therapeutic applications.
Background:
Endothelial cell (EC) activation, endotheliitis, vascular permeability, and thrombosis have been observed in patients with severe coronavirus disease 2019 (COVID-19), indicating that the vasculature is affected during the acute stages of SARS-CoV-2 infection. It remains unknown whether circulating vascular markers are sufficient to predict clinical outcomes, are unique to COVID-19, and if vascular permeability can be therapeutically targeted.
Methods:
Prospectively evaluating the prevalence of circulating inflammatory, cardiac, and EC activation markers as well as developing a microRNA atlas in 241 unvaccinated patients with suspected SARS-CoV-2 infection allowed for prognostic value assessment using a Random Forest model machine learning approach. Subsequent ex vivo experiments assessed EC permeability responses to patient plasma and were used to uncover modulated gene regulatory networks from which rational therapeutic design was inferred.
Findings:
Multiple inflammatory and EC activation biomarkers were associated with mortality in COVID-19 patients and in severity-matched SARS-CoV-2-negative patients, while dysregulation of specific microRNAs at presentation was specific for poor COVID-19-related outcomes and revealed disease-relevant pathways. Integrating the datasets using a machine learning approach further enhanced clinical risk prediction for in-hospital mortality. Exposure of ECs to COVID-19 patient plasma resulted in severity-specific gene expression responses and EC barrier dysfunction, which was ameliorated using angiopoietin-1 mimetic or recombinant Slit2-N.
Interpretation:
Integration of multi-omics data identified microRNA and vascular biomarkers prognostic of in-hospital mortality in COVID-19 patients and revealed that vascular stabilizing therapies should be explored as a treatment for endothelial dysfunction in COVID-19, and other severe diseases where endothelial dysfunction has a central role in pathogenesis.
Funding:
This work was directly supported by grant funding from the Ted Rogers Center for Heart Research, Toronto, Ontario, Canada and the Peter Munk Cardiac Center, Toronto, Ontario, Canada.
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