Connecting the clinic to the bench : modelling the functional effects of a titin variant associated with atrial and ventricular arrhythmias
department or school: Medicine, Faculty of
department or school: Medicine, Department of
data provider: DSpace
degree campus: UBCV
creator: Huang, Kate
issued: 2025-05-08T23:20:14Z
issued: 2025
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Atrial fibrillation (AF) is a common arrhythmia linked to increased risk of stroke, heart failure, and death. In AF patients without known clinical risk factors, genetic factors are likely contributors to disease pathogenesis. Studies into the genetic risk factors of AF showed a strong association between truncating variants in the titin gene and increased risk of AF in structurally normal hearts. Titin truncating variants (TTNtv) are a well-established cause of dilated cardiomyopathy (DCM), and recent studies have also shown an increased risk of atrial and ventricular fibrillation (VF) in DCM patients with TTNtv. The effect of TTNtv on risk of AF compared to modifiable risk factors is unclear. Furthermore, the cellular effects of TTNtv in atrial and ventricular arrhythmias without dilated cardiomyopathy is unknown. The objectives of this dissertation were 1) to evaluate the association between titin variants and increased risk of AF compared to modifiable risk factors and 2) to examine the cellular effects of TTNtv identified in atrial and ventricular fibrillation patients without structural disease. We used genetic epidemiology approaches and data from UK Biobank to assess the risk of AF in titin variant carriers, and we used patient-specific induced pluripotent stem cell-derived atrial- and ventricular-like cardiomyocytes and engineered heart tissue constructs to model a TTNtv implicated in AF and VF. We demonstrated an additive effect between titin variant status and modifiable risk factors on the risk of AF. In the AF model, the TTNtv led to sarcomere disarray, reduced contractility, increased arrhythmogenicity, and transcriptional changes implicating substrate alterations. In the VF model, the TTNtv resulted in calcium transient shortening and impaired electrophysiological response to β-adrenergic stimulation. These findings highlight the utility of genetic testing to identify TTNtv carriers who are at increased risk of developing AF and the importance of cli…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/91068
note: CONNECTING THE CLINIC TO THE BENCH: MODELLING THE FUNCTIONAL EFFECTS OF A TITIN VARIANT ASSOCIATED WITH ATRIAL AND VENTRICULAR ARRHYTHMIAS by Kate Huang B.Sc., The University of British Columbia, 2018 A DISSERTATION SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Experimental Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) May 2025 © Kate Huang, 2025 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Connecting the clinic to the bench: modelling the functional effects of a titin variant associated with atrial and ventricular arrhythmias submitted by Kate Huang in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Experimental Medicine Examining Committee: Dr. Liam Brunham, Associate Professor, Department of Medicine, University of British Columbia Supervisor Dr. Zachary Laksman, Assistant Professor, Department of Medicine and School of Biomedical Engineering, University of British Columbia Co-supervisor Dr. Pascal Bernatchez, Associate Professor, Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia University Examiner Dr. Francis Lynn, Associate Professor, Department of Surgery and School of Biomedical Engineering, University of British Columbia University Examiner Dr. Wenbin Liang, Associate Professor, Department of Cellular and Molecular Medicine, University of Ottawa Heart Institute External Examiner Additional Supervisory Committee Members: Glen Tibbits, Professor, Departments of Biomedical Physiology and Kinesiology and Molecular Biology and Biochemistry, Simon Fraser University Supervisory Committee Member Fabio Rossi, Professor, Department of Medical Genetics and School of Biomedical Engineering, University of British Columbia Supervisory Committee Member iii Abstract Atri…
has type: Thesis/Dissertation
date issued: 2025-11
is shown at: 10.14288/1.0448824
language: eng
degree discipline: Experimental Medicine
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
contributor: Brunham, Liam
contributor: Laksman, Zachary
type: Text
identifier URI: http://hdl.handle.net/2429/91068