RESULTS
Under baseline conditions, APs from Endo were recorded from all preparations (n=15) and APs from Epi from 8 preparations. A significant spike and dome morphology of the AP was consistently recorded on the Epi surface of the RVOT in all 8 preparations in which Epi was measured (Fig. 1 and Table 1 ). In contrast to the relatively homogeneous distribution of an AP notch (spike and dome morphology) on Epi, a marked spatial heterogeneity of spike and dome morphology was observed in the Endo of the RVOT, ranging from none to very prominent (Fig. 1 ). An AP morphology lacking a notch was commonly recorded on the smooth surface of Endo, whereas a prominent notch was recorded deep within the inter-trabecular structures (Fig. 1 ). The RVOT Epi displayed a prominent AP notch. However, phase 0 amplitude, phase 1 magnitude, and phase 1 amplitude were larger in deep trabecular Endo vs. Epi RVOT (Fig. 2 , Table 1). No arrhythmias were recorded under baseline conditions.
Under experimental conditions pharmacologically mimicking BrS (i.e., terfenadine-mediated block of INa and ICa; 5-8 µM; ≥ 1.5 hour), our principal focus in these studies was to determine spatial differences in the AP characteristics of Endo given the fact that we had a limited period of time to collect these data prior to development of VT/VF. It is noteworthy that the characteristics of right ventricular Epi AP and phase 2-reentry in the setting of BrS are well documented.13-15 Out of the 15 preparations studied, high quality APs were recorded from the Endo regions in 12 (due to an “early” onset of persistent VF in 3 of the preparations). Terfenadine markedly accentuated the spike and dome morphology of APs recorded from the intra-trabecular region of RVOT Endo, but caused little change in the early phases of the AP recorded from the smooth Endo surface (Fig. 3; Table 2 ). Marked heterogeneities were commonly observed in the AP notch recorded from the intra-trabecular structures of the RVOT Endo, ranging from a significant augmentation of the AP dome and delay in the onset of phase 2 to loss of the AP dome (Fig. 4 ). Under similar conditions, little heterogeneity was observed in the characteristics of APs recorded from the smooth surface of the RVOT Endo (Fig. 4 ). Accentuation of the AP notch leading to delay in the onset of phase 2 and in some cases to loss of AP dome in the intra-trabecular Endo was associated with the development of phase 2 reentrant extrasystoles (Fig. 4 ). When considering preparations in which the origin of the premature beats could be reasonably determined (based on the polarity of the QRS in the ECG traces; n=9 preparations; Fig. 5 ), an Epi and Endo origin of the extrasystole was observed in 8 and 5 preparations, respectively, with 5 of these preparations displaying both Epi and Endo origin, and 4 and 1 preparations displaying only Epi or only Endo origin, respectively.
In the setting of experimental BrS, closely-coupled extrasystoles were recorded in 14/15 preparations, giving rise to polymorphic VT/VF in 12/15 preparations. The first episode of VT/VF appeared after 93-120 minutes of perfusion with terfenadine. We observed ≥ 3 self-terminating episodes of VT/VF in each of the 12 preparations and in 7 of them VT/VF was persistent (> 1 hour). Figure 6 depicts examples in which VF was initiated by extrasystoles originating from either Epi or Endo of the RVOT.