Cardiovascular Signatures of COVID-19 Predict Mortality and Identify Barrier Stabilizing Therapies


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Background Endothelial cell (EC) activation, endotheliitis, vascular permeability, and thrombosis have been observed in patients with severe 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 Evaluating the prevalence of circulating inflammatory, cardiac and EC activation markers, and the development of a microRNA atlas in 241 patients with suspected SARS-CoV-2 infection, allowed their prognostic value to be assessed by 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. Evidence before this study While diagnostic testing has allowed for the rapid identification of COVID-19 cases, the lack of post-diagnosis risk assessment metrics, especially among the highest-risk subgroups, thereby undermined the cascade and allocation of care. To date, the integration of clinical data with broad omics technologies has opened up new avenues for efficiently delineating complex patient phenotypes and their associations with clinical outcomes, with circulating profiles of plasma microRNAs (miRNA), in particular, having been shown to be tightly associated with disease, and capable of providing not only detailed prognostic information but also mechanistic insight. Added value of this study Markers of endothelial dysfunction at presentation, while indicative of poor outcomes in COVID-19-positive patients, likely reflect systemic vascular dysfunction in critically ill patients and are not specific to SARS-CoV-2 infection. More so, the generation of a plasma microRNA atlas uncovers COVID-19-specific prognostic markers and multiple disease-specific pathways of interest, including endothelial barrier dysfunction. Furthermore, synthesis of electronic health record data with clinically relevant multi-omic datasets using a machine learning approach provides substantially better metrics by which mortality can be estimated in patients with severe COVID-19. Finally, targeted stabilization of the endothelial barrier with Q-Peptide and Slit2-N are novel therapeutic avenues that should be explored in COVID-19 patients. Implications of all the available evidence Together, our work provides biological insight into the role of the endothelium in SARS-CoV-2 infection, the importance of miRNA as disease- and pathway-specific biomarkers, and the exciting possibility that endothelial barrier stabilizing treatments might hold promise in COVID-19. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work utilized infrastructure generously provided by the Peter Munk Cardiac Centre Biobank and the University Health Networks PRESERVE-Pandemic Response Biobank for coronavirus samples, University Health Network Biospecimen Services, REB # 20-5364. In addition, we would like to acknowledge all those responsible for the collection of biospecimens at St. Michaels Hospital through the COVID-19 Longitudinal Biomarkers of Lung Injury Study ([NCT04747782][1], REB 20-078). D.G. is funded by a Banting and Best Canadian Graduate Doctoral Scholarship and a Ted Rogers Centre for Heart Research studentship. Coronavirus Disease 2019 research in the laboratories of K.H., P.T., J.E.F., and K.L.H is supported by an innovation grant from the Peter Munk Cardiac Center and an innovation grant from the Ted Rogers Center for Heart Research. U.T., C.D., and A.B., received funding from the St. Michaels Hospital Foundation through an internal competitive grant, the Canadian Institutes of Health Research and COVID-19 Immunity Task Force (COVID-19 Opportunity Grant), and salary support through the Dorothy and Robert Pitt Research Chair in Acute and Emergency Medicine. K.C.K. is supported by a Tier 1 Canada Research Chair, a CIHR Foundation grant (FDN-148439), a CIHR COVID-19 grant (VR3-172649), and a FAST grant. M.W. is supported by a Tier 2 Canada Research Chair in Comparative Genomics. H.H. was supported by Genome Canada and a Genome Canada, Genomics Technology Platform grant. P.T. is supported by a Tier 2 Canada Research Chair in Cardio-Oncology. Research in the laboratory of J.E.F is supported by Project Grants from the Canadian Institutes of Health Research (Grant: PJT148487 and PJT173489); and infrastructure funding from the Canada Foundation for Innovation, the John R. Evans Leaders Fund, and the Ontario Research Fund. J.E.F. is supported by a Tier 2 Canada Research Chair in Vascular Cell and Molecular Biology from the Canadian Institutes of Health. Research in the laboratory of K.H. is supported by a CIHR Project Grant (PJT178006), the Wylie Scholar Program, Peter Munk Cardiac Centre, University Health Network, and the Toronto Academic Vascular Surgeons. We would also like to gratefully acknowledge the participants who graciously contributed to the study, teams of research coordinators, as well as the clinicians, nurses, and biobank members who assisted with the collection of samples that were utilized in this study. Parts of figures (including the entire graphical abstract) was created with ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study, and consenting, was conducted in accordance with protocols approved by the Research Ethics Board (REB) of the University Health Network (REB#: 20-5453.6; Cardiovascular Disease and Outcomes among Patients with SARS-CoV-2 Infection During Admission and Post-Discharge [The COVID study]) or St. Michaels Hospital (REB#: 20-078; COVID-19 Longitudinal Biomarkers in Lung Injury [COLOBILI]). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04747782&atom=%2Fmedrxiv%2Fearly%2F2022%2F02%2F09%2F2022.02.08.22270636.atom
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