Nabil El-Sherif, Dmitry O. Kozhevnikov, Gioia Turitto.
Cardiology Division, Department of Medicine, State University of New York Health Science Center and Department of Veterans Affairs New York Harbor Health Care System, Brooklyn, New York, USA
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Figure 1 illustrates the effects of AP-A in the in vivo
canine heart using high resolution tridimensional isochronal mapping of both activation and
repolarization. To map tridimensional repolarization in vivo activation-recovery intervals
(ARIs)11 were measured from unipolar extracellular electrograms
recorded by multi-electrode plunge
needles. The ARI was shown to correspond to local repolarization5,12.
Microelectrode studies
in transmural preparations have shown that epicardial (Epi), midmyocardial (M) and endocardial
(End) cells respond differently to changes in cycle length (CL): the M cells had the steepest
APD-CL relationship, followed by End cells. The least relationship was observed in Epi cells13,14.
Figure 1A illustrates eight transmural unipolar electrograms recorded across the baso-lateral wall
of a canine left ventricle during AP-A infusion at four different CLs. The figure shows that as the
CL increased, the calculated ARI at M sites (#3 to #6) increased significantly more, compared to
End sites (#1 and #2) and Epi sites (#7 and #8). This resulted in a steep gradient of ARI,
especially between Epi and M sites. This behavior is illustrated graphically in figure 1B, which
shows composite data of ARI distribution collected from 12 unipolar plunge needle recordings
from the same heart.
Fig. 1: A = recordings of eight transmural unipolar electrograms, 1 mm apart, across the
basolateral wall of the left ventricle at CLs of 400, 600, and 1400 msec, from a canine heart following
AP-A infusion. The calculated activation-recovery interval (ARI) is shown next to each electrogram
(in msec). The figure illustrates the steep ARI-CL relation of midmyocardial sites compared with
subepicardial (Epi) and subendocardial (Endo) sites, resulting in steep gradients of ARI distribution
collected from 12 unipolar plunge needle recordings in the basolateral wall of the left ventricle in a
4 x 10 mm section from the same experiment. After AP-A, ARIs increased two to three times compared
with control at similar CLs. The steepest increase occurred at midmyocardial zones. At 600 msec, ARIs
were slightly longer in midmyocardial zones, but the differences were not statistically significant. At
1000 and 1400 msec, a significant increase in ARIs was apparent in midmyocardial electrodes 3 to 6
compared with both subendocardial electrodes 1 and 2 and subepicardial electrodes 7 and 8. There
was, however, marked variation in ARI dispersion at the two transitional zones between
midmyocardial sites and both Epi and Endo sites. Differences in ARIs of up to 80 msec (at aCL of
1400 to 1500 msec) between contiguous sites, 1 mm apart, at the transition zones were not
uncommon. C = diagrammatic illustration of the plunge needle electrode used to collect ARI data
(modified with permission from EI-Sherif et al5).
Figure 2 illustrates the contribution of the tridimensional dispersion of repolarization shown above
to the in vivo electrophysiologic mechanism of TdP. The figure shows the tridimensional activation
pattern of a 12-beat run of nonsustained TdP. Figure 2A shows that the initiating beat of TdP
arose from a focal subendocardial activity most probably secondary to an early afterdepolarization
from a Purkinje fiber. The activation wavefront encountered multiple zones of functional conduction
block that developed at contiguous sites with disparate refractoriness as shown in figure 1. The
wavefront proceeded in a very slow counterclockwise circular pathway around the left ventricular
cavity before reactivating sites in sections 3 and 4 at isochrone #20 to initiate the first reentrant
cycle. Figure 2, B to E shows that all subsequent beats of TdP were due to reentrant excitation
with varying tridimensional activation pattern. The TdP VT terminated when the reentrant
wavefront blocked, thus ending the reentrant activity. The twisting of the QRS axis during this run
of TdP was more evident in the inferior lead, aVF. The initial transition in QRS axis (between V7
and V10) correlated with the bifurcation of a predominantly single rotating wavefront (scroll) into
two separate simultaneous wavefronts rotating around the left ventricular (LV) and right
ventricular (RV) cavities. The final transition in QRS axis (between V10 and V11) correlated with the
termination of the RV circuit and the reestablishment of a single LV circulating wavefront. In this
and other examples of TdP the initiating mechanism for the bifurcation of the single wavefront
frequently was the development of functional conduction block between the anterior or posterior
RV free wall and the interventricular septum. The termination of the RV wavefront was also
frequently associated with the development of functional conduction block ahead of the circulating
wavefront between the RV free wall and the anterior or posterior border of the septum. In other
instances, the RV circulating wavefront was extinguished through collision with an opposing
wavefront in the interventricular septum. The RV circulating wavefront usually did not exhibit a
localized zone of slow conduction. This may suggest that the conduction block that develops at
the border between the thin RV free wall and the much thicker interventricular septum may be, at
least in part, secondary to an impedance-mismatch mechanism15. On the other hand, LV circuits
frequently encompassed a varying zone of slow conduction, and conduction block usually
developed in this slow zone probably secondary to decremental conduction. Although it was more
difficult to correlate accurately, there was evidence that a period of transitional complexes
covering more than one cycle was associated with gradual dominance of one of the two
circulating wavefronts before termination of the other wavefront (see the transitional QRS
complexes labeled V8 and V9 in Fig. 2). Although the AP-A model seems to represent many of the
phenotypic features of LQTS, it should be obvious that “sanitized” surrogate experimental models
do not reflect the complex pathophysiology that is present in the clinical LQTS where multiple
factors tend to modulate the phenotypic expression of the disease.
Fig. 2: A to E = tridimensional ventricular activation patterns of a 12-beat nonsustained
TdP ventricular tachycardia (VT). The maps are presented as if the heart was cut transversely into
five sections, oriented with the basal section on top and the apical section on bottom and labeled
1 to 5. In panels B to E, section 1 was deleted. The activation isochrones were drawn as closed
contour at 20-msec intervals and labeled as 1, 2, 3 and so on to make it easier to follow the activation
patterns of successive beats of the VT. Functional conduction block is represented in the maps by
heavy solid lines. The thick bars under the surface ECG lead mark the time intervals covered by each
of the tridimensional maps. The V1 beat arose as a focal subendocardial activity (marked by a star in
section 1). Panel A shows selected local electrograms recorded along the reentrant pathway during
the V1, which illustrates complete diastolic bridging during the first reentrant cycle of 400-msec
duration. Bipolar electrograms recorded from the very slow conducting component of the circuit in
section 4 had a wide multicomponent configuration. Electrograms recorded in close proximity to
arcs of functional conduction block had double potentials representing an electronic potential (E)
and an activation potential (A), respectively. Note that the electrotonic potentials were
synchronous with activation an the opposite side of arcs of functional block (electrograms J, K
and Q). All subsequent beats of TdP were due to reentrant excitation with varying configuration
of the reentrant circuit (B to E). The twisting QRS patterns was more evident in lead aVF during
the second half of the VT episode. The transition in QRS axis (between V7 and V10) correlated with
the bifurcation of a predominantly single rotating wavefront (scroll) into two separate simultaneous
wavefronts rotating around the LV and RV cavities. The final transition in QRS axis (between V10
and V11) correlated with the termination of the RV circuit and the reestablishment of a single LV
circulating wave front. P indicates P waves (modified with permission from El-Sherif et
al6).
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