Computational Predictions of Tissue-Specific Consequences of Long QT Mutations: Role of the Purkinje Fiber

Abstract

The long QT syndrome (LQTS) is a heritable cardiac disorder that leads to prolongation of ventricular repolarization, episodes of ventricular arrhythmia, and sudden cardiac death. Mounting evidence has implicated the Purkinje fiber (PF) conduction system in the genesis of ventricular arrhythmias. This study assesses for tissue-specific consequences of the biophysical alterations induced by LQTS-related mutations, using computational models of ventricular and PF cells. Mutations causing LQT1 and LQT2 (in KCNQ1 and HERG, respectively) are first simulated by reducing density of the respective components of the delayed rectifier current. These mutations prolong action potential duration (APD) in ventricular myocytes more than in their PF counterparts, due to differences in the conductance and activation of plateau potassium currents between the two cell types. Next, the canonical LQT3 mutation delKPQ (in the cardiac NaV 1.5 sodium channel, encoded by SCN5A) is modeled in both tissue types (as described previously, by increasing entry into a bursting mode of channel gating, producing substantial late non-inactivating inward current). Marked APD prolongation is confirmed in both tissue types, exacerbated by slow stimulation rates or pauses in pacing. Simulation of another SCN5A mutation, F1473C, which clinically produces severe QT prolongation and heavy arrhythmia burden, is shown to have a markedly larger effect on PF cells than ventricular myocytes (including a propensity for repetitive early afterdepolarizations), owing to a depolarizing shift in the mutant channel availability and lower plateau potential in PF. Finally, the interactions between PF and ventricular cells at the tissue level are investigated in the context of these mutations in a cable model representing a section of ventricular wall. In conclusion, the biophysical alterations induced by LQT mutations may have significant tissue-specific consequences, with important implications for arrhythmia and its therapy.