Genetics

2024 | Clonal haematopoiesis is associated with major adverse cardiovascular events in patients with hypertrophic cardiomyopathy

 150 150 fraser.amos@uhn.ca
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Authors: Fernando L. Scolari, Darshan Brahmbhatt, Sagi Abelson, Deacon Lee, Raymond H. Kim, Ali Pedarzadeh, Ali Sakhnini, Arnon Adler, Raymond H. Chan, John E. Dick, Harry Rakowski, and Filio Billia

Short Description: Hypertrophic cardiomyopathy (HCM) is an inherited cardiovascular disorder, affecting 1 in 500 individuals. However, germline pathogenic or likely pathogenic (P/LP) genetic variants, such as MYH7 and MYBPC3 genes, are identified in only 25–40% of patients. A wide heterogeneity and distinct morphologies of left ventricular (LV) hypertrophy are described, even amongst family members carrying similar genetic variants. Interestingly, interstitial fibrosis is detected in 40–70% of patients and is associated with sudden cardiac death (SCD). Although HCM can be well tolerated, a subset of patients may require advanced treatments such as orthotopic heart transplant (OHT) and LV assist devices. The underlying mechanisms involved in the heterogeneous clinical presentation of HCM patients are not well understood. Clonal haematopoiesis (CH) has emerged as a new risk factor for the development of atherosclerosis, heart failure and cardiogenic shock and is associated with worse outcomes.

Interest: Cardiac magnetic resonance imaging, Clonal haematopoiesis, Fibrosis, Hypertrophic cardiomyopathy, Inflammation

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2025 | Multiomic Landscape of Extracellular Vesicles in Human Carotid Atherosclerotic Plaque Reveals Endothelial Communication Networks

 150 150 fraser.amos@uhn.ca
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Authors: Sneha Raju, Mandy E. Turner, Christian Cao, Majed Abdul-Samad, Neil Punwasi, Mark C. Blaser, Rachel M.E. Cahalane, Steven R. Botts, Kamalben Prajapati, Sarvatit Patel, Ruilin Wu, Dakota Gustafson, Natalie J. Galant, Lindsey Fiddes, Melody Chemaly, Ulf Hedin, Ljubica Matic, Michael A. Seidman, Vallijah Subasri, Sasha A. Singh, Elena Aikawa, Jason E. Fish, and Kathryn L. Howe

Short Description: Carotid atherosclerosis is orchestrated by cell-cell communication that drives progression along a clinical continuum (asymptomatic to symptomatic). Extracellular vesicles (EVs) are cell-derived nanoparticles representing a new paradigm in cellular communication. Little is known about their biological cargo, cellular origin/destination, and functional roles in human atherosclerotic plaque.

Our findings indicate that EVs may drive dynamic changes in plaques through EV–vascular cell communication and effector functions that typify vulnerability to rupture, precipitating symptomatic disease. The discovery of endothelial-directed angiogenic processes mediated by EVs creates new therapeutic avenues for atherosclerosis.

Interest: Arteriosclerosis, Thrombosis, and Vascular Biology

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2023 | Large scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy

 150 150 sabrina.agostini@uhn.ca
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Authors: Rafik Tadros, Sean L. Zheng,  Christopher Grace, Paloma Jordà, Catherine Francis, Sean J. Jurgens, Kate L. Thomson,  Andrew R. Harper, Elizabeth Ormondroyd, Dominique M. West, Xiao Xu, Pantazis Theotokis, Rachel J. Buchan, Kathryn A. McGurk, Francesco Mazzarotto, Beatrice Boschi, Elisabetta Pelo, Michael Lee, Michela Noseda, Amanda Varnava, Alexa Mc Vermeer, Roddy Walsh, Ahmad S. Amin, Marjon A van Slegtenhorst, Nicole Roslin, Lisa J. Strug, Erika Salvi, Chiara Lanzani, Antonio de Marvao, Hypergenes InterOmics Collaborators, Jason D. Roberts, Maxime Tremblay-Gravel, Genevieve Giraldeau, Julia Cadrin-Tourigny, Philippe L’Allier, Patrick Garceau, Mario Talajic, Yigal Pinto, Harry Rakowski, Antonis Pantazis, John Baksi, Brian P. Halliday, Sanjay K. Prasad, Paul Jr Barton, Declan P. O’Regan, Stuart A. Cook, Rudolf A. de Boer, Imke Christiaans, Michelle Michels, Christopher Kramer, Carolyn Y. Ho, Stefan Neubauer, HCMR Investigators, Paul M. Matthews, Arthur A. Wilde, Jean-Claude Tardif, Iacopo Olivotto, Arnon Adler, Anuj Goel, James S. Ware, Connie R. Bezzina, Hugh Watkins

Short Description: Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. We here report results from the largest HCM genome-wide association study (GWAS) and multi-trait analysis (MTAG) including 5,900 HCM cases, 68,359 controls, and 36,083 UK Biobank (UKB) participants with cardiac magnetic resonance (CMR) imaging. We identified a total of 70 loci (50 novel) associated with HCM, and 62 loci (32 novel) as sociated with relevant left ventricular (LV) structural or functional traits. Amongst the common variant HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin, showing that rare truncating SVIL variants cause HCM. Mendelian randomization analyses support a causal role of increased LV contractility in both obstructive and non-obstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, the findings significantly increase our understanding of the genetic basis and molecular mechanisms of HCM, with potential implications for disease management.

Interest: Cardiac Magnetic Resonance Imaging, Cardiac Imaging, Genetics, Genetic Testing, Hypertrophic Cardiomyopathy

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2020 | Genetic Testing for Diagnosis of Hypertrophic Cardiomyopathy Mimics: Yield and Clinical Significance

 150 150 sabrina.agostini@uhn.ca
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Authors: Sara Hoss, Manhal Habib, Josh Silver, Melanie Care, Raymond H. Chan, Kate Hanneman, Chantal F. Morel, Robert M. Iwanochko, Michael H. Gollob, Harry Rakowski, Arnon Adler 

Short Description: Genetic testing is helpful for diagnosis of hypertrophic cardiomyopathy (HCM) mimics. Little data are available regarding the yield of such testing and its clinical impact. The HCM genetic database at our center was used for identification of patients who underwent HCM-directed genetic testing including at least 1 gene associated with an HCM mimic (GLA, TTR, PRKAG2, LAMP2, PTPN11, RAF1, and DES). Charts were retrospectively reviewed and genetic and clinical data extracted.

Interest: Fabry Disease, Genetic Testing, Genetics, Hypertrophic Cardiomyopathy

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