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.