George Mason University
Understanding how genetic variation manifests itself as phenotype is major unanswered question in biology. We explore this issue in the context of heart disease. A certain class of cardiac arrhythmia results from defects in intracellular calcium dynamics. Of these many can be attributed to genetic mutations in proteins in calcium cycling. Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT1-5) has variants depending upon the calcium cycling protein involved. In this disease patients are seeming normal, however unexpected they can suffer a fatal arrhythmia during or immediately following exercise or stress. We specifically used multiscale computational models to study CPVT1 and CPVT2 which result from defects in the ryanodine receptor type 2 (RyR2) and calsequestrin (CASQ), respectively. These mutations increase the open probability of the RyR2 under resting conditions and to a much greater during β-adrenergic stimulation. The proposed mechanism for this type of arrhythmia is that the combination of increased sarcoplasmic reticulum (SR) Ca2+ load and increased RyR2 open probability during β-adrenergic stimulation can lead to large spontaneous Ca2+ release events resulting in arrhythmia. However, this raises a paradox. One expects considerations of changes in Ca2+ pump-leak balance across the SR due to the CPVT and the consequent changes in Ca2+ pump-leak balance across the sarcolemmal membrane to be largely self-correcting. Our multiscale computational model explores these mutations and offers explanations behind the mechanism of arrhythmia in CPVT1-2.
Talk starts at 4:00 PM (Krasnow Building, Room 229)