Po-01-205 computational modeling uncovers a unifying mechanism linking conduction block to vt localization and stability in arrhythmogenic cardiomyopathy

We recently showed in a murine model of arrhythmogenic cardiomyopathy (ACM) that VT was driven by discrete rotors deep within the RV. Mechanisms underlying the evolution of these RV-pinned rotors, however, remained unknown considering that the initial wavebreaks that preceded VT were at the LV/RV interface. We hypothesized that the unique spatial action potential duration (APD) profile (RV>LV) in ACM during rapid pacing and adrenergic stimulation, independent of other factors such as structural remodeling, is sufficient to explain the rapid evolution of wavebreaks into discrete rotors that efficiently translocate and stabilize in the RV to maintain VT. We developed 2D virtual sheets of mouse ventricular myocardium using isotropic cellular automaton models with realistic restitution properties that mimic experimentally measured LV to RV APD gradients in wildtype (WT) and ACM hearts (Fig A). VT rotors were induced by burst stimulus trains at increasing frequencies. VT threshold was defined as the duration of the burst stimulus train required to initiate stable VT. Rotors were localized in space and time using phase singularity (PS) analysis. To determine the relationship between spatial APD profile and rotor dynamics, we varied the steepness of the LV-to-RV APD gradient. Once induced, we examined rotor dynamics, speed of rotor drift, meander, stability and dominant frequency (DF). VT threshold was markedly decreased in ACM (2.9s) vs WT (14.5s) reflecting increased vulnerability. VT rotors were more readily induced when stimuli were applied from the zone of short versus long APD. While VT rotors were randomly distributed across homogeneous tissues, PS density analysis revealed exclusive localization of VT rotors within areas of increased APD in heterogeneous tissues (Fig B). Varying the slope of the APD gradient revealed divergent effects on forward drift and DF of VT rotors (Fig C). As the slope of the APD gradient steepened, the velocity of rotor forward drift to the RV increased exponentially while rotor DF decreased in a linear manner consistent with increased stability. Simulation of experimentally measured LV-to-RV APD gradient in ACM caused forward drift of multiple rotors at 2.18cm/sec before pinning within narrow RV loci. The unique spatial APD profile at early stages of ACM is sufficient to explain not only the initiation but also the translocation, dynamics and stability of VT rotors within the RV.