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Am J Physiol Heart Circ Physiol 290: H77–H78, 2006;
doi:10.1152/ajpheart.00954.2005.
Editorial Focus
In vivo dispersion in repolarization and arrhythmias in the human heart
Tobias Opthof
Experimental and Molecular Cardiology Groups, Academic Medical Center, Amsterdam; and
Department of Medical Physiology, University Medical Center, Utrecht, The Netherlands
HISTORICAL ASPECTS
Durrer and colleagues (12) described in 1970 the total activation of the normal human heart in great detail. Had they looked
another 350 ms later in their recordings, we would now know the
repolarization pattern of the human heart at the same accuracy (9).
Our present understanding is that at 1 Hz total repolarization takes
⬍400 ms, yet we do not know the repolarization pattern. Dispersion in repolarization is considered highly arrhythmogenic. The
assessment of such dispersion is not without debate (for review,
see Ref. 6), and it has been questioned whether local dispersion
can be appreciated from the surface ECG at all (4). To date, it
seems reasonable to assume that a large QT dispersion in the ECG
results from a large dispersion in RT, which is highly arrhythmogenic. However, normal QT dispersion does not necessarily exclude substantial dispersion in local RT as an underlying factor of
arrhythmogenesis. The explanation for this semiparadox is probably the fact that over 90% of all repolarization signals from the
ventricles is cancelled in the surface ECG, as was described
almost four decades ago by Burgess and colleagues (3). The
duration of the T wave in the ECG reflects dispersion of the whole
repolarization process in the whole heart, which is not the same as
dispersion in the local moments of recovery from inexcitability
(dispersion in complete RT). The latter parameter has been assessed previously in the epicardium of the human heart where it
was reported that dispersion in RT is only 14 ms, whereas the
dispersion in activation time is 23 ms (11). Therefore, repolarization seems a highly synchronized process despite the fact that the
underlying signal (phase 3 or the repolarization phase of the
Address for reprint requests and other correspondence: T. Opthof,
Experimental and Molecular Cardiology Groups, Academic Medical Center, M0-107 Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands (e-mail:
[email protected]).
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ventricular action potential) is in itself very slow compared with
the depolarizing fast upstroke of the action potential.
Thus far the dispersion in the end of the T wave but also the
configuration of the T wave lack reasonable detailed explanations.
Roughly, three types of repolarization inhomogeneities play a
role: 1) differences between right and left ventricle, 2) differences
between apex-base and anterior-posterior, and finally 3) transmural differences (6). The involvement of M cells in transmural
dispersion is still a matter of debate (1, 2, 7, 18).
COMPARISON WITH OTHER STUDIES
The study of Chauhan et al. (5) shows overall RT dispersion of
17 and 51 ms along the RV endocardium and LV epicardium,
respectively, in patients without VTs or TWA (see Fig. 2, bottom
panel in Ref. 5). This epicardial value is somewhat higher than
that observed in previous studies where it was 14 ms (11) or 41 ms
(13) in patients with preserved LV function undergoing bypass
surgery. It is suggested that this is due to the underlying cardiomyopathy. In patients with VTs or positive TWA the overall RT
dispersion was 73 and 66 ms along the RV endocardium and LV
epicardium, respectively. This is substantially more than previously reported (11,13), but it should be underscored that the
underlying pathophysiology differs. Furthermore, whole dispersion in RT is sensitive to the dimensions of the area of assessment,
and if the entire endocardium or epicardium has not been mapped,
we may assume that the total RT is an underestimation of the real
total RT in this study (and in other studies). There is no satisfactory explanation for the difference in dispersion in RT between the
groups with and without VTs. It is probably not a coincidence that
the difference in adjacent RT (10 –12 vs. 2–3 ms/mm in the
groups with and without VTs or TWA; see bottom panels of Figs.
2 and 3 in Ref. 5) was much larger than the differences in total RT
between the two groups. It is tempting to ascribe this to wall
motion abnormalities.
It has previously been shown that the dispersion in refractoriness of normal myocardium in patients with a healed myocardial
infarction may determine the severity of an arrhythmia (16).
Patients had either VT or ventricular fibrillation as the index
arrhythmia. During subsequent surgical correction of the infarcted
area, ventricular fibrillation was provoked by a battery. Dispersion
of ventricular fibrillation intervals was twice as large in patients
who had been presenting with ventricular fibrillation compared
with patients in which the index arrhythmia had been restricted to
VT. This underscores that dispersion in RT of normal myocardium adjacent to diseased myocardium plays a prominent role in
arrhythmogenesis.
There is an increasing body of evidence that wall motion
abnormalities do play an important role in the genesis of arrhythmias (10, 14) and that they increase dispersion in QTc intervals as
well (17). There is, however, thus far no direct evidence that wall
motion abnormalities also increase dispersion in ARIs and RTs. In
the present study, wall motion abnormalities were not different
between the two patient groups (see Table 2 in Ref. 5), although
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of American Journal of Physiology-Heart and Circulatory Physiology, Chauhan and colleagues (5) have measured
dispersion in ventricular repolarization time (RT) in patients with
cardiomyopathy and an ejection fraction ⱕ40%. Such data are
sparse in humans in general. The measurements have been made
at the right ventricular (RV) endocardium and at the left ventricular (LV) epicardium by a catheter in the great cardiac vein. This
study by Chauhan et al. (5) is one of the very few with data from
the endocardium and epicardium in the same patients. Also, the
patients were conscious. RT dispersion was in the order of 10 –12
ms/mm in 12 patients in which either ventricular tachycardias
(VT) could be provoked or in which there was positive microvolt
T wave alternans (TWA). In 10 patients without VTs or TWA, RT
dispersion was limited to 2–3 ms/mm. A similar increased dispersion in activation-recovery intervals (ARI; an index of local
action potential duration), but not dispersion in activation times,
was shown to underlie the difference in RT dispersion between
the two patient groups.
IN THIS ISSUE
Editorial Focus
H78
FUTURE ASPECTS
Chauhan et al. (5) mention that the repolarization proceded
from base to apex in about 60% of the patients along both
endocardium and epicardium. Apparently, the direction of the
repolarization front may vary. In addition, it is intriguing that there
is a difference in endocardial versus epicardial RT. The point that
the endocardial RTs were measured in the RV and the epicardial
RTs on the LV is well taken, but still, as Chauhan et al. claim in
their description of Fig. 1 of their study, the sites of measurement
were adjacent. From the functional point of view, in terms of
genesis of the T wave, it does not matter whether a signal arises
from the LV or the RV. We emphasize that there was no
difference between endocardial and epicardial RT in the patients
without VT or TWA (288 vs. 287 ms, Table 3 in Ref. 5), whereas
these numbers were 269 vs. 249 ms in patients with VT or TWA.
One would expect that this has consequences for the configuration
of the T wave in the two patient groups, but the present study does
not provide us with this type of information. Janse and colleagues
(15) recently described that there is no transmural gradient of
repolarization in the intact canine left ventricle, and therefore it
cannot be expected that this contributes to the configuration of the
T wave or to dispersion in RT. There is sparse information that
this also applies to the human heart (6, 8). There is a need for
experiments that both unravel the repolarization of the human
ventricle on a detailed scale as known for the activation and assess
AJP-Heart Circ Physiol • VOL
the impact of wall motion abnormality/mechanoelectrical feedback on the repolarization process including its dispersion. In the
meantime the present study of Chauhan et al. (5) is important in
corroborating the notion that dispersion in repolarization remains
highly relevant for arrhythmogenesis in the human heart.
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it should be emphasized that this study does not permit a direct
assessment of the interaction, because there was no direct relationship between the areas of assessment of wall motion abnormality and of the electrophysiological measurements. Interestingly, ARIs as well as RTs tended to be shorter in patients with
VTs or positive TWA (see Table 3 in Ref. 5) in addition to the
differences in dispersion.
It is well known that ARIs tend to become shorter in the
direction of propagation (6, 13). Thus when activation time
increases, ARIs become increasingly shorter. With a slope of ⫺1
between the two parameters, differences in activation time would
be exactly compensated by differences in ARIs. If this happens in
a whole heart, there would be no dispersion in repolarization and
therefore no T wave. Comparison of the relationships between
activation time and ARIs along the endocardium and epicardium
in the two patient groups is given in Figs. 4 and 5 in the study of
Chauhan et al. (5). On the average, the correlation coefficients
were ⫺0.65 ⫾ 0.08 and ⫺0.66 ⫾ 0.14 along the RV endocardium
and LV epicardium of patients without VTs or TWA. In patients
with VTs or positive TWA, these correlation coefficients were
⫺0.35 ⫾ 0.13 and only 0.1 ⫾ 0.2 along the RV endocardium and
LV epicardium. Correlation coefficients are not the same as slopes
of regression lines, and the authors provide us with values of
⫺0.7 ⫾ 0.1 in patients without VTs or TWA along the RV
endocardium and ⫺1.3 ⫾ 0.2 along their LV epicardium. It seems
as if the patients without a tendency to arrhythmias were still able
to shorten ARI, whereas the patients with VTs or positive TWA
were not, as is the case in patients with atrial fibrillation. Of
course, the loss of this characteristic also increases dispersion in
RT. It cannot be determined with certainty whether the increase in
adjacent RT (larger on a distance scale, but smaller in absolute
terms) or, alternatively, the increase in whole organ RT is the most
important factor.