Ventricular arrhythmogenesis leading to sudden cardiac death is a major cause of clinical mortality. Brugada Syndrome (BrS) is one important cause of sudden cardiac death from fast polymorphic ventricular tachycardia (VT) or ventricular fibrillation in middle age. It is typified by electrocardiographic right bundle branch block and right precordial ST elevation, often unmasked by flecainide challenge. Previously used canine wedge model preparations required application of potentially non-specific pharmacological agents to replicate the BrS phenotype. However, 30% of BrS patients show a loss of Na+ channel function associated with SCN5A gene mutations. A Scn5a+/- mouse, a heterozygous knock-out for the cardiac voltage-gated Na+ channel, might then help model its physiological arrhythmogenic mechanisms [1]. These had been variously suggested to involve loss of the epicardial cardiac action potential dome increasing vulnerability to early, phase II re-entry from the endocardium or conduction delays particularly in the right ventricular outflow tract (RVOT). The murine model reproduces clinical arrhythmic and electrocardiographic features of BrS: intact anaesthetized animals show ventricular tachycardia (VT) as well as ST elevation, conduction abnormalities detected as increased PR intervals and AV block, and repolarization abnormalities appearing as increased QT dispersion, all exacerbated or unmasked by flecainide but relieved by quinidine [2]. RT-PCR and Western blots demonstrated that Scn5a+/- hearts show reduced Nav1.5 expression relative to wild-type (WT), and reduced right (RV) relative to left ventricular (LV) Nav1.5 expression. Both Scn5a+/- and WT show increased RV relative to LV Kv1.4 and KCHIP2 expression. Scn5a+/- ventricular myocytes show correspondingly reduced transient and persistent Na+ currents (INa and IpNa) relative to WT, and reduced INa in RV relative to LV. Both Scn5a+/- and WT showed similarly increased RV relative to LV maximum transient outward currents (Ito). Scn5a+/- correspondingly showed reduced maximum rates of both LV and RV action potential increase (dV/dtmax) compared to WT, and greater RV compared to LV dV/dtmax. Similarly, action potential durations at 90% recovery (APD90s) were lower in Scn5a+/- than WT in the RV, similar between the two variants in the LV, and therefore lower in the RV than the LV in Scn5a+/- but not WT [3]. Arrhythmogenecity might then arise from abnormalities in either or both depolarization and repolarization in RVs of Scn5a+/- hearts. Monophasic action potential and bipolar electrogram studies in intact Langendorff-perfused Scn5a+/- hearts indeed demonstrated increased spatial and temporal heterogeneities in activation latencies, repolarization times, refractory periods and electrogram fractionation, and discordant alternans specifically involving their RVs [4]. Thus, Scn5a+/- showed shorter APDs than WT. Their shorter RV than LV epicardial but similar RV and LV endocardial APDs, gave strongly positive transmural APD gradients particularly in the RV further accentuated by flecainide and reduced by quinidine [5]. However, although epicardial ventricular effective refractory periods (VERPs) were shorter in the RV than the LV in both variants, they were greater in Scn5a+/- in all cardiac regions studied. Furthermore they were increased by both flecainide and quinidine in both variants in all regions. This gave constant VERP/APD ratios through all regions in both variants, larger in Scn5a+/- reflecting their larger VERPs but smaller APD70, reducing the likelihood of early re-entry events [6]. Furthermore, multi-electrode mapping array explorations in spontaneously beating flecainide-treated hearts implicated lines of functional conduction block arising in the RV, leading to reentrant circuits, in their VT. Activation epicardial propagation maps showed single planar intra-epicardial wavefronts proceeding from apex to base during sinus activity but with greater activation time differences and crowded isochronal lines, in both the RV and LV of Scn5a+/- than WT. These were increased by flecainide, but not quinidine, particularly in the Scn5a+/- RV. Superimposed premature beats then produced a line of block with impulse propagation flowing around it in the RV, with subsequent beats in the resulting VT showing different lines of block creating a non-stationary vortex, and polymorphic arrhythmia [7].