SUPPRESSION OF CELLULAR ALTERNANS IN GUINEA PIG VENTRICULAR MYOCYTES WITH LQT2: INSIGHTS FROM THE LUO–RUDY MODEL

Abstract

Genetic and drug-induced abnormalities of cardiac repolarization have been linked to fatal arrhythmias. These arrhythmias result from a complex interaction of the remaining currents during excitation and repolarization. In this review, we examine recent advancement in investigations of genetic heart diseases and mechanisms of arrhythmia generation. We also present our simulation of repolarization during rapid pacing for different levels of block of the rapid delayed rectifier current, IKr, and pharmacological interventions using the Luo–Rudy model. Control simulations showed the development of alternans at a basic cycle length (BCL) of 131 ms. Two levels of IKrblock were simulated corresponding to type 2 of familial long QT syndrome, LQT2. At 100% IKrblock, the threshold BCL for the appearance of alternans increased to 145 ms and for shorter cycle lengths showed increasingly complex patterns of periodic and chaotic behavior. We examined the potential of other currents to correct this complex behavior. Improvement of the threshold for bifurcation as a function of BCL was achieved by: (1) 100% block of a nonspecific Ca2+-activated current; (2) 15% block of L-type Ca2+current; (3) 20% increase of Na+/ K+pump current; (4) 50% increase of SERCA2 pump activity. Conversely, increased L-type Ca2+current, decreased Na+/ K+pump current, or decreased SERCA2 pump activity increased the threshold BCL. Modification of several other currents had little effect. Alternans and chaotic activity develop at fast pacing rates in model guinea pig ventricular myocytes through a sequence of bifurcations. We elucidated mechanisms that modify the development of alternans which may provide novel targets for treatment of patients with LQT2.