Unraveling a New Potassium Channelopathy using a Realistic Membrane-Based Computational Model of the Human Heart M. Potse, P. F. H. M. van Dessel, F. van den Heuvel and A. Vinet Canadian Cardiovascular Congress 2005 ref: M. Potse, P. F. van Dessel, F. van den Heuvel, and A. Vinet. Unraveling a new potassium channelopathy using a realistic membrane-based computational model of the human heart. Can. J. Cardiol., 21 Suppl. C:86C, 2005. INTRODUCTION In an 8-years old patient, ST-elevation was observed in practically all standard ECG leads. Na-channel abnormalities were excluded. The patient suffered from frequent malignant tachyarrhythmias and received an implantable defibrillator (ICD). Pharmacological treatment was attempted to reduce the very frequent ICD discharges. The best results were obtained with flecainide (a Na-channel blocker) and phenytoin (a Na/K pump stimulator). Still, arrhythmia remained so frequent that a heart transplant was indicated. A mutation disabling the inactivation of the transient outward current (Ito) and producing a more sustained repolarization current was argued to account for both ECG changes and arrhythmogenicity. This hypothesis was tested in a realistic computer model of the human heart. METHODS Membrane activation and repolarization were computed using a 12-million-node monodomain model of the human heart including endocardial to epicardial rotation in fiber direction. Membrane ionic currents at each node were represented by the Priebe-Beuckelmann model of the human ventricular myocyte adapted to represent endocardial, epicardial, and M-cells. Surface electrocardiograms were computed from the distribution of membrane potentials using an inhomogeneous torso model. The hypothesized mutation was simulated by removing the inactivation variable from the model of Ito current. As an alternative method to enhance the post-upstroke outward current, the effect of an increase in the number of Ito channels was examined. RESULTS Because the density of Ito is higher in epicardial cells, their action potential was more sensitive to the mutation, and became of a nearly triangular shape. The ST elevations observed in the clinical ECG were matched very well by the simulated ECG based on disabled inactivation of Ito. The mutation led to a heart-rate-dependent reduction of intracellular potassium concentration ([K+]i), which induced a depolarization of the resting membrane potential (Vr), e.g. -84 mV at 1000 ms, -75 mV at 600 ms. A sufficient rise in Vr leads to a reduction of excitability. This may explain the arrhythmogenicity in the patient. The alternative hypothesis of augmented Ito conductivity produced an ECG that resembled much less the clinical ECG. CONCLUSION The results explain why phenytoin, which increases the Na/K pump function and thus counteracts the reduction of [K+]i, was found to be effective, and suggest that a higher dose could have been more appropriate. If similar cases exist our results call for the development of clinically acceptable Ito blockers.