Computational rabbit models to investigate the initiation, perpetuation, and termination of ventricular arrhythmia

Abstract

Current understanding of cardiac electrophysiology has been greatly aided by computational work performed using rabbit ventricular models. This article reviews the contributions of multiscale models of rabbit ventricles in understanding cardiac arrhythmia mechanisms. This review will provide an overview of multiscale modeling of the rabbit ventricles. It will then highlight works that provide insights into the role of the conduction system, complex geometric structures, and heterogeneous cellular electrophysiology in diseased and healthy rabbit hearts to the initiation and maintenance of ventricular arrhythmia. Finally, it will provide an overview on the contributions of rabbit ventricular modeling on understanding the mechanisms underlying shock-induced defibrillation.

Keywords: Cardiac electrophysiology; Computational modeling; Defibrillation; Ischemia; Myocardial infarction; Ventricular arrhythmia.

Fig. 1

Multi-scale modeling of rabbit cardiac electrophysiology. (A) Family of simulated rabbit ventricular myocyte APs and intracellular calcium ([Ca2+]) transients, produced using the model by Mahajan, Shiferaw et al. (Mahajan et al., 2008). Physiologically-relevant variability in shape and duration was achieved by using hundreds of stochastically-generated parameter combinations to modify behavior of repolarizing currents (Gemmell et al., 2014). APD50 and APD90 ranges are shown as blue and red shaded areas, respectively. (Reprinted with permission from (Gemmel et al., 2014)). (B) UC San Diego rabbit heart geometry with tetrahedral element edges shown in inset. (C) Structurally-detailed rabbit mesh of the rabbit ventricles including an image-based representation of the free-running Purkinje system (pink). (Reprinted with permission from (Vadakkumpadan et al., 2009))

Fig. 2

Premature ventricular contractions (PVCs) originating in the Purkinje system (PS). (A) 3D map showing locations of initial excitation that triggered PVCs in a model of the rabbit PS and ventricles. All cells in the model were prone to delayed afterdepolarization (DAD)-induced excitation due to spontaneous calcium release, but such activity occurred exclusively in the PS due to lower source-sink mismatch. PMJ = Purkinje-myocardial junction. (Reprinted with permission from Ref (Campos et al., 2015)) (B) 3D map showing activation times in a cutaway view of the rabbit ventricles and PS during a post-pause propagating response caused by DAD. Asterisks show locations where DADs occurred in the PS, leading to propagating excitation that eventually caused a PVC. (Reprinted with permission from (Zamiri et al., 2014))

Fig. 3

Reentry induction due to structural heterogeneity and decreased sodium channel expression. Activation maps showing reentry induced via pacing from an electrode (E1) located on the RV outflow tract. The corresponding safety factor map show that areas with critically low SF (<1) corresponds with site of conduction block at the RVOT insertion point. (Modified and reprinted with permission from (Boyle et al., 2014))

Fig. 4

Role of LV/RV APD heterogeneity on VF dynamics. Transmembrane potential distributions during VF for model with heterogeneous APD (i.e. left, LV, and right, RV, ventricles have different APDs) and for model with homogenous APD. The dashed black line denotes the border between regions characterized by a different APD. Epicardial phase singularities are marked with solid black circles. (Modified and reprinted with permission from Ref (Arevalo et al., 2007))

Fig. 5

Post-infarction arrhythmogenesis. (A) High-resolution MRI-based model of the infarcted rabbit ventricle with fibroblasts incorporated in the zone of infarct. (B) Coupling of fibroblasts to myocytes (80% in the scar and 10% in the PZ) results in arrhythmia. Red arrow indicates the location of the premature activation. (Modified and reprinted with permission from (McDowell et al., 2011))

Fig. 6

Vulnerability to shock-induced arrhythmia in rabbits with healed infarction. Distribution of shock-end Vm show less tissue was excited in the infarction model (purple arrows). Right-most panel shows the Vm difference between infarction and control models, computed as control Vm minus infarction Vm. (Reprinted with permission from (Rantner et al., 2012))