Grant: Doctoral Research Award: Canada Graduate Scholarships

Some heartbeat rhythm disorders (i.e. arrhythmias), such as catecholaminergic polymorphic ventricular tachycardia (CPVT), have a high risk of leading to a sudden stop in electrical heart activity (i.e. sudden cardiac arrest). Most CPVT cases result from inherited mutations in a large protein needed for normal electrical signals in heart cells known as the cardiac ryanodine receptor (RyR2). In 'typical' CPVT cases, mutations in RyR2 cause the protein to be overactive, and exercise stress testing serves as an accurate diagnostic tool in these patients. However, in cases where RyR2 mutations lead to underactivity, patients still experience arrhythmia and cardiac arrest but test negative on exercise stress testing. These cases were previously referred to as 'atypical' CPVT. Recent studies have shown that 'atypical' CPVT may be completely distinct from CPVT, with different cellular mechanisms by which electrical activity is disrupted. This newly identified condition is referred to as calcium release deficiency syndrome (CRDS). Importantly, there are currently no approved diagnostic tests for CRDS patients, hence patients remain at high risk for misdiagnosis and sudden cardiac arrest. To improve our understanding of CRDS, we are proposing to study a CRDS-associated RyR2 variant (A4142T) in human heart cells derived from induced pluripotent stem cells. Using various electrophysiological methods, we will identify the specific mechanism by which this mutation disrupts electrical activity in human heart cells. In addition, we will examine the biochemical changes associated with this variant to reveal its impact on RyR2 protein structure and function. In doing so, our study can help build the foundation for novel diagnostics and pharmacotherapies for precise and personalized care for CRDS patients.