BACKGROUND: Timothy syndrome is a multisystem disorder associated with QT 
interval prolongation and ventricular cardiac arrhythmias. The syndrome has been 
linked to mutations in Ca(V)1.2 resulting in gain of function of the L-type 
calcium current (I(Ca,L)). Ranolazine is an antianginal agent shown to exert an 
antiarrhythmic effect in experimental models of long QT syndrome.
OBJECTIVE: The purpose of this study was to develop and characterize an 
experimental model of Timothy syndrome by using BayK8644 to mimic the gain of 
function of I(Ca,L) and to examine the effects of ranolazine.
METHODS: Action potentials from epicardial and M regions and a 
pseudo-electrocardiogram (ECG) were simultaneously recorded from 
coronary-perfused left ventricular wedge preparations, before and after addition 
of BayK8644 (1 microM).
RESULTS: BayK8644 preferentially prolonged action potential duration of the M 
cell, leading to prolongation of the QT interval and an increase in transmural 
dispersion of repolarization (from 44.3 +/- 7 ms to 86.5 +/- 25 ms). Stimulation 
at cycle lengths of 250-500 ms led to ST-T wave alternans due to alternation of 
the plateau voltage of the M cell action potential as well as development of 
delayed afterdepolarizations in epicardial and M cell action potentials. 
Ventricular extrasystoles and tachycardia (monomorphic, bidirectional, or 
torsades de pointes) developed spontaneously or after rapid pacing. Peak and 
late I(Na) were unaffected by BayK8644. Clinically relevant concentrations of 
ranolazine (10 microM) suppressed all actions of BayK8644.
CONCLUSION: A left ventricular wedge model of long QT syndrome created by 
augmentation of I(Ca,L) recapitulates the ECG and arrhythmic manifestations of 
Timothy syndrome, which can be suppressed by ranolazine.