Grant: Operating Grant -PA: Inst of Circulatory and Respiratory Health - Bridge Funding

Most deaths associated with heart attacks ("myocardial infarction"; MI) are caused by a lethal form of cardiac arrhythmias so-called "Polymorphic Ventricular Tachycardia" (PVTs). Without appropriate medical assistance, PVTs develop into ventricular fibrillation (VF) and cardiac pump arrest. Paradoxically, the source of PVTs remains unknown. In clinic, early signs of the arrhythmias are detected in the cardiac conduction (Purkinje fibers)in patients with MI. Studies of dog heart with experimental MI confirmed that Purkinje cells (Pcells) isolated from the infarcted region generate abnormal electrical signals. Cellular imaging techniques demonstrated that spontaneous electrical activity was caused by local oscillations of intracellular calcium (Ca2+) concentration. Our studies of this phenomenon first revealed that healthy Pcells had a highly specific but poorly documented mechanism of cellular Ca2+ handling. In 2005, our group published the first model of Ca2+ handling of Pcells. We propose to pursue our research on the molecular dysfunctions responsible for the abnormal Ca2+ activity in Pcells. Using a combination of cellular imaging and computational techniques and a clinically relevant model of MI heart in the pig (Yucatan miniature pig), we will: 1) improve our model by dissecting experimentally the mechanism governing Ca2+ handling in normal Pcells, 2) develop an advanced computer modeling system that will simulate alterations on each component of Ca2+ handling mechanism of Pcells and predict which ones of the tested conditions are most likely to induce arrhythmias, 3) test experimentally on live Pcells the assumptions arising from the simulation. Our goals are 1) to identify new targets for more selective anti-arrhythmic drugs that will prevent or interrupt the progression of PVTs into VF during the heart attack, and 2) to assist clinical procedures in the control of the risk for PVTs in emergency situations of severe heart attack.