All are invited to attend Dr. Jafri's talk for the Bioinformatics Colloquium, Tues Sept. 10 4:30-6:00 p.m. in Bull Run Hall #248

Title: Computational Studies of Cardiac Excitation-Contraction Coupling: From Molecule to Arrhythmia

Calcium dynamics in the cardiac myocyte links the electrical excitation of the heart to contraction in a process known as excitation-contraction coupling. Dysfunction of critical calcium signaling proteins in heart is associated with lethal inherited cardiac arrhythmias. However, how the altered proteins lead to arrhythmias remains both unknown and controversial. We have used computational models to investigate fundamental mechanisms that underlie calcium-dependent arrhythmias, the same class of arrhythmias that follow myocardial infarction, heart failure and diverse genetic arrhythmic diseases. Even very common arrhythmias (one episode of sudden cardiac death in a month) are rare when normalized to the events occurring within a single cell over the period of a typical long experiment (e.g. one hour). Stochastic modeling, however, with the powerful computer clusters available and with our recent advances in computational algorithms, enable us to examine stochastic model systems over prolonged periods without missing the rare events. We start with the most elementary event of cardiac calcium release, the calcium spark, and construct stochastic models that explain mechanisms of calcium release termination, calcium homeostasis and the sarcoplasmic reticulum calcium leak, and the generation of arrhythmias from defects in calcium signaling. These insights begin to provide insight in to the normal and abnormal physiology of cardiac excitation-contraction coupling.