Cardiovascular signatures of COVID-19 predict mortality and identify barrier stabilizing therapies
Dakota Gustafson,
Michelle Ngai,
Ruilin Wu,
Huayun Hou,
Alice Carvalhal Schoffel,
Clara Erice,
Serena Mandla,
Filio Billia,
Michael D. Wilson,
Milica Radisic,
Eddy Fan,
Uriel Trahtemberg,
Andrew Baker,
Chris McIntosh,
Chun-Po S. Fan,
Claudia C. dos Santos,
Kevin C. Kain,
Kate Hanneman,
Paaladinesh Thavendiranathan,
Jason E. Fish,
Kathryn L. Howe
Affiliations
Dakota Gustafson
Toronto General Hospital Research Institute, University Health Network, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
Michelle Ngai
Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
Ruilin Wu
Toronto General Hospital Research Institute, University Health Network, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
Huayun Hou
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada
Alice Carvalhal Schoffel
Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, Canada
Clara Erice
Johns Hopkins School of Medicine, Baltimore, USA
Serena Mandla
Institute of Biomedical Engineering, University of Toronto, Toronto, Canada
Filio Billia
Toronto General Hospital Research Institute, University Health Network, Toronto, Canada; Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, Canada
Michael D. Wilson
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Canada
Milica Radisic
Institute of Biomedical Engineering, University of Toronto, Toronto, Canada
Eddy Fan
Toronto General Hospital Research Institute, University Health Network, Toronto, Canada; Interdepartmental Division of Critical Care and Institute of Medical Sciences, University of Toronto, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada
Uriel Trahtemberg
Keenan Research Center for Biomedical Research, Unity Health Toronto, Toronto, Canada; Critical Care Department, Galilee Medical Center, Nahariya, Israel
Andrew Baker
Interdepartmental Division of Critical Care and Institute of Medical Sciences, University of Toronto, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; Critical Care Department, Galilee Medical Center, Nahariya, Israel
Chris McIntosh
Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, Canada; Joint Department of Medical Imaging, University Health Network, University of Toronto, Toronto, Canada; Techna Institute, University Health Network, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Canada; Vector Institute, University of Toronto, Toronto, Canada
Chun-Po S. Fan
Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, Canada
Claudia C. dos Santos
Interdepartmental Division of Critical Care and Institute of Medical Sciences, University of Toronto, Toronto, Canada; Keenan Research Center for Biomedical Research, Unity Health Toronto, Toronto, Canada
Kevin C. Kain
Toronto General Hospital Research Institute, University Health Network, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
Kate Hanneman
Toronto General Hospital Research Institute, University Health Network, Toronto, Canada; Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, Canada; Joint Department of Medical Imaging, University Health Network, University of Toronto, Toronto, Canada
Paaladinesh Thavendiranathan
Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; Joint Department of Medical Imaging, University Health Network, University of Toronto, Toronto, Canada; Ted Rogers Program in Cardiotoxicity Prevention, Toronto General Hospital, Toronto, Canada
Jason E. Fish
Toronto General Hospital Research Institute, University Health Network, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; Jason Fish, Toronto General Hospital Research Institute, University Health Network, 101 College Street, 3-308 Princess Margaret Cancer Research Tower, Toronto, Ontario, Canada, M5G 1L7, Tel: +1-(416)-581-7496, Fax: +1-(416)-581-7484
Kathryn L. Howe
Toronto General Hospital Research Institute, University Health Network, Toronto, Canada; Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; Division of Vascular Surgery, Department of Surgery, University of Toronto, Toronto, Canada; Corresponding authors: Kathryn Howe, Toronto General Hospital Research Institute, Peter Munk Cardiac Centre, University Health Network, Division of Vascular Surgery, Department of Surgery, University of Toronto, 200 Elizabeth Street, 6 EN-220 Toronto General Hospital, Toronto, Ontario, Canada, M5G 2C4, Tel: +1(416)-340-5193, Fax: +1(416)-340-5029
Summary: 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 Information: 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.
