Best Cardiovascular Translational Science of the Decade Award Nominations

Nomination 1

Cameron-Vendrig, A., Reheman, A., Siraj, M. A., Xu, X., Wang, Y., Ni, H., … & Husain, M. (2016). Glucagon-like peptide 1 receptor activation attenuates platelet aggregation and thrombosis. Diabetes, 65(6), 1714–1723.

Bibliometrics (Citations per Year)* – 12

Bibliometrics (Field-Weighted Citation Impact)* – 3.12

This seminal paper by Cameron-Vendrig and colleagues, published in Diabetes in 2016 [131 citations], uncovered a novel antithrombotic mechanism of GLP-1 receptor (GLP-1R) agonists. This study revealed that human megakaryocytes and platelets express functional GLP-1Rs. Furthermore, through elegant in vitro cell line models, ex vivo flow condition perfusion chamber models, and in vivo quantitative laser injury cremaster arterial thrombosis mouse models, the authors demonstrate that GLP-1R activation inhibits platelet aggregation and arterial thrombosis via cAMP signaling and eNOS-dependent pathways. These findings reveal a previously unrecognized mechanism that likely underlie the demonstrated cardiovascular benefits of GLP-1R agonists and led to an application for a U.S. patent entitled Methods for inhibiting platelet aggregation using GLP-1 receptor agonists [#US61/721,819]. This paradigm-shifting work offers a clear innovative therapeutic avenue for reducing thrombotic risk in diabetes and cardiovascular disease. It exemplifies Canadian leadership in translational cardiovascular science with the clinical potential for global impact.

Nomination 2

Zhao Y, Rafatian N, Feric NT, Cox BJ, Aschar-Sobbi R, Wang EY, Aggarwal P, Zhang B, Conant G, Ronaldson-Bouchard K, Pahnke A, Protze S, Lee JH, Davenport Huyer L, Jekic D, Wickeler A, Naguib HE, Keller GM, Vunjak-Novakovic G, Broeckel U, Backx PH, Radisic M. A Platform for Generation of Chamber-Specific Cardiac Tissues and Disease Modeling. Cell. 2019 Feb 7;176(4):913-927.e18. doi: 10.1016/j.cell.2018.11.042. Epub 2019 Jan 24. PMID: 30686581; PMCID: PMC6456036.

Bibliometrics (Citations per Year)* – 71.167

Bibliometrics (Field-Weighted Citation Impact)* – 12.09

Zhao (TRCHR EF recipient) and Radisic co-invented the Biowire heart-on-a-chip technology that switched the paradigm from “one-size fits all” cardiac drug discovery and testing in inbred animals towards precision discovery in human tissues with functional readouts. The nominated paper (>500 citations; UofT-UHN collaboration) describes the next-gen Biowire II, which won the 2018 Frost & Sullivan North American Technology Innovation Award and was commercialized by TARA Biosystems, a company co-founded by Zhao & Radisic. TARA raised >$30M in venture funding growing to >20 employees before its acquisition by Valo Health in April 2022. Abbive, GSK, Lilly, Regeneron, Myokardia and dozens of other pharmas have used the technology in their drug development programs. At Valo, Biowire II is the engine for AI-powered drug testing and validation in human cardiac tissues with genetic mutations. In 2025, a $4.6B deal was announced for cardiometabolomic drug discovery by Novo Nordisk using Valo’s Biowire II-enabled platform.

Nomination 3

Dhahri W, Sadikov Valdman T, Wilkinson D, Pereira E, Ceylan E, Andharia N, Qiang B, Masoudpour H, Wulkan F, Quesnel E, Jiang W, Funakoshi S, Mazine A, Gomez-Garcia MJ, Latifi N, Jiang Y, Huszti E, Simmons CA, Keller G, Laflamme MA. In vitro matured human pluripotent stem cell-derived cardiomyocytes form grafts with enhanced structure and function in injured hearts. Circulation. 2022 May;145(18):1412-1426. Journal Impact Factor 29.69.

Bibliometrics (Citations per Year)* – 23.33

Bibliometrics (Field-Weighted Citation Impact)* – 7.35

This study by Dhahri et al described practical methods for the scaled manufacturing of mature human pluripotent stem cell-derived cardiomyocytes (hPSC-CM), and it provided the first evidence that the transplantation of more mature cardiomyocytes yields better outcomes in vivo. hPSC-CMs had been previously shown to improve contractile function in preclinical models of myocardial infarction (MI), but their therapeutic potential was limited by an immature phenotype and an elevated risk of graft-related arrhythmias. In this report, we demonstrated that in vitro matured hPSC-CMs engrafted efficiently in a guinea pig MI model and formed implants with more adult-like myocardial structure, enhanced host-graft electromechanical integration, reduced pro-arrhythmic behavior, and greater beneficial effects on contractile function than immature cardiomyocytes. This work has had a significant impact on the cardiac cell therapy field and inspired greater focus on the need to generate a more mature cell product. It has been cited 80+ times since publication.

Nomination 4

Nikolaev SI, Vetiska S, Bonilla X, Boudreau E, Jauhiainen S, Jahromi BR, Khyzha N, DiStefano P, Suutarinen MB, Kiehl TM, Pereira VM, Antonarakis SE, Krings T, Andrade-Barazarte H, Tung T, Valiante T, Zadeh G, Tymianski M, Antonarakis SE, Wythe JD, Rauramaa T, Yla-Herttuala S, #Frosen J, #Fish JE, #Radovanovic I, Somatic activating KRAS mutations in arteriovenous malformations of the brain. New England Journal of Medicine. 2018 Jan 18;378(3):250-261. http://doi.org/10.1056/NEJMoa1709449

Bibliometrics (Citations per Year)* – 51.571

Bibliometrics (Field-Weighted Citation Impact)* – 19.03

This manuscript generated a new paradigm regarding how somatic mutations impact cardiovascular disease. We discovered that somatic activating mutations in the KRAS gene occur in the endothelium in the majority of patients with sporadic brain arteriovenous malformations. We went on to show that expressing mutant KRAS in endothelial cells results in an increase in the size and migratory capacity of endothelial cells and induces the breakdown of junctions between the cells. This manuscript was the first to describe how inhibiting the MEK pathway downstream of KRAS signaling can reverse phenotypes. Since this discovery, clinical studies have revealed that MEK inhibitors are a promising therapy for arteriovenous malformations. This is an important advance as surgical techniques are the only treatment approach, and this is not available for all patients because of excessive risk. This article has been cited 488 times, and the findings have led to new treatments for this disease.

Nomination 5

Hosseini SM, Kim R, Udupa S, Costain G, Jobling R, Liston E, Jamal SM, Szybowska M, Morel CF, Bowdin S, Garcia J, Care M, Sturm AC, Novelli V, Ackerman MJ, Ware JS, Hershberger RE, Wilde AAM, Gollob MH; National Institutes of Health Clinical Genome Resource Consortium. Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome. Circulation. 2018 Sep 18;138(12):1195-1205. doi: 10.1161/CIRCULATIONAHA.118.035070. PMID: 29959160; PMCID: PMC6147087.

Bibliometrics (Citations per Year)* – 41.43

Bibliometrics (Field-Weighted Citation Impact)* – 11.9

One of the ongoing challenges in clinical genetics is to generate and evaluate the evidence associating each gene with disease. This is critical for the application of genetic discoveries into clinical care. Researchers from Sickkids and UHN were involved in the first gene-curation initiative with regard to Brugada Syndrome, an inherited arrhythmia. In the nominated work, they evaluated the evidence behind 21 genes reportedly associated with Brugada syndrome. In their review of the evidence, they found that only one gene met the threshold for definitive evidence, whereas the remaining 20 had disputed evidence for the gene-disease association. This work was largely influential in the clinical genetics space in demonstrating that evidence thresholds had not been met for a large number of genes that were being evaluated clinically in patients with Brugada syndrome. This led to changes in clinical genetic testing practices for patients with this condition.

* Bibliometrics were collected from Scopus.