From Bench to Bedside: Investigating the molecular mechanisms of sudden cardiac death while exploring stakeholder perspectives on risk predictive genetic testing

Abstract

Pediatric sudden cardiac death (SCD) is often linked to genetic conditions such as arrhythmogenic cardiomyopathy (ACM) and congenital heart disease (CHD). This thesis takes a multidisciplinary approach to investigate the molecular basis of SCD and the implications of predictive genetic testing in at-risk populations. A biology-focused approach identified a novel genetic mechanism for autosomal recessive ACM associated with loss-of-function variants in TAX1BP3. Using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), pharmacological inhibition of TRPV4 mitigated calcium leak and spark frequency–highlighting a potential therapeutic target for ACM. Additionally, this thesis investigated several genetic mechanisms of hypoplastic left heart syndrome (HLHS), a severe form of CHD, by evaluating levels of apoptosis and cell proliferation in iPSC-CMs. Preliminary findings suggest increased apoptosis and reduced cell proliferation may lead to the underdeveloped left ventricle seen in patients, however, overall findings warrant further investigation into other mechanisms. A global health approach was additionally incorporated by establishing a Community Advisory Board (CAB) to explore the ethical and clinical challenges of genetic risk prediction in CHD. Thematic analysis from the pilot CAB discussion highlighted concerns around clinical decision-making, resource allocation, and psychosocial impacts–emphasizing the need for standardized guidelines to ensure equitable and responsible use of genetic information. Altogether, this research advances precision medicine in pediatric cardiology by bridging molecular mechanisms with ethical considerations in genetic risk disclosure.