Insights from accurate modeling of structural and functional heterogeneities in cardiac tissue

The objective of this research was to investigate the roles of heterogeneous myocardial properties in the initiation and termination of arrhythmias. Electrophysiological heterogeneities in acute regional ischemia phase 1A, wave pinning to millimeter-sized anatomical obstacles, and the influence of irregularly-shaped micro-scale ventricular structures on low-voltage termination of ventricular tachycardia using virtual electrode polarization (VEP) were studied.;A slice model of regional ischemia was developed, which included a central ischemic zone, transmural gradients of IK(ATP) activation, and [K+]o and ischemic border zones (BZs) representing ischemia 2-10 min post-occlusion. Re-entry was induced using premature stimulation. Increased dispersion of refractoriness and conduction velocity in the BZs with time post-occlusion led to increased arrhythmogenesis, and re-entry was rarely sustained without a transmural gradient of IK(ATP) activation.;Perturbation and entrainment of waves pinned to millimeter-sized objects using low-energy field pulses were investigated by pairing cell culture and simulation models. Waves pinned to obstacles were subjected to single pulses and pulse trains. Single pulses created refractory regions that temporarily forced pinned waves away from the obstacles, but were rarely able to permanently detach waves. Periodic stimulation entrained pinned waves to stimulation frequency. As stimulation rate increased, entrainment became unstable, and sometimes terminated.;The effect of endocardial microstructure on low-voltage termination of polymorphic ventricular tachycardia (PVT) was investigated by developing a high-resolution model of the right-ventricular (RV) free wall. Tachycardia was initiated, and trains of low-energy field stimuli were applied to perturb the re-entrant wave. Tachycardia was terminated at low shock strengths, most effectively when the pulses were applied at 88% of the period of the re-entry. This technique holds promise for replacing cardioversion shocks as the therapy used to terminate PVT in patients.;These studies contribute to the understanding of the initiation, perturbation, and termination of re-entry. They rely on the incorporation of electrophysiological and meso- to micro-structural anatomical heterogeneities in simulation models of the heart. Those details are used to provide new mechanistic insight into the disease states and therapies involved in sudden cardiac death and its mitigation by implantable devices and drugs.