| Sudden cardiac death arises when the electrical impulses in the heart become rapid (ventricular tachycardia, VT) or chaotic (ventricular fibrillation, VF). Although there has been much research on the transition from VT to VF, less is known about the mechanisms of disrupting sinus rhythm in the heart. The focus of this project was arrhythmogenesis, which is the study of how wave of excitation form the sinus node "breaks" as it propagates through heart tissue and "reenters" to override intrinsic heart rhythm. The window of opportunity when conditions initiate reentry is called the vulnerability window. Using computer simulations of cardiac tissue with and without heterogeneity, we found the vulnerability window described as a function of premature stimulus. There are some key factors that have been considered in early electrophysiology experiments, but there has been no computational investigation until recently. We report that steep APD restitution, a known factor in spiral wave break up which causes ventricular fibrillation, actually decreased the vulnerability window and protected against arrhythmias. Next, applying non-linear dynamics mathematics to a simple action potential model of the cardiac cell, we proposed a new theory for the emergence of abnormal voltage oscillations that are called early afterdepolarizations (EADs). EADs are known "triggers" of the most malignant form of cardiac arrhythmias, including several forms of ventricular tachycardia and fibrillation. The main contributions of this work are: (1) the dynamical and physiological mechanisms of EAD formation in single cardiac myocytes; (2) a new theory in arrhythmogenesis; we now understand how voltage fluctuations on the scale of single cells can self-organize and manifest into tissue-level arrhythmias; and (3) a theoretical basis to develop a therapeutic strategy for EAD prevention that can be tested in experiments. Collaboration with other laboratories confirmed our biological theories and provided supporting experimental evidence. |
