Structural and cellular heterogeneities influence coordination of Purkinje and ventricular activity
Description
Proper cardiac function relies on the coordination of heterogeneous tissues by the spread of an electrical impulse. Disruption of impulse spread produces arrhythmias that can cause discomfort or death. To gain a better understanding of the mechanisms responsible for these arrhythmias, I integrated computational modeling and experimentation with isolated rabbit heart preparations to examine the coordination of heterogeneous tissues present in the ventricles. In particular, I focused on the interaction between the Purkinje (P) system and ventricular (V) activation sequences, emphasizing structural heterogeneities in both P and V tissues and incorporating cellular membrane differences. I found that endocardial point stimulation produces nonuniform activation sequences during transmural wavefront expansion due to the structural heterogeneity of the changing fiber orientation with intramural depth. This nonuniform activation sequence, in conjunction with the existing cellular heterogeneity, produces intramural dispersion of repolarization that is favorable to reentrant arrhythmia formation. Following this study, I found that discrete coupling between P and V layers coordinates a uniform activation sequence through trabeculated endocardium except during slow propagation. Slow propagation compromises the advantages of rapid P conduction by unmasking spatial heterogeneities within the activation sequence. Finally, I showed how asymmetric structural and cellular characteristics decreased PV synchrony during premature stimulation and spontaneous beats. These findings suggest that endocardial excitation is governed by heterogeneous tissues that coordinate rapid ventricular excitation when effectively integrated but that provide an arrhythmogenic substrate when not adequately integrated