Download Point of View The Long QT Interval Syndrome

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Point of View
The Long QT Interval Syndrome
A Rosetta Stone for Sympathetic
Related Ventricular Tachyarrhythmias
Douglas P. Zipes, MD
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T he long QT interval syndrome (LQTS) has a
low incidence in the general population, but,
like the Wolff-Parkinson-White (WPW) syndrome, it has a major impact. While the WPW
syndrome is the Rosetta stone of reentry, the LQTS
may be the Rosetta Stone for ventricular tachyarrhythmias dependent on sympathetic stimulation.
Present Study
In a recent issue of Circulation, Schwartz et all
provided further evidence of this sympathetic link by
demonstrating the beneficial effects of left-sided cardiac sympathetic denervation in 85 patients, 84 of
whom (91%) continued to have syncope or cardiac
arrest before denervation despite receiving ,3-adrenoceptor blockade. After surgery, the number of patients
with cardiac events, the number of cardiac events per
patient, and the number of patients with five or more
cardiac events all decreased significantly. However,
there still were seven (8%) sudden deaths, reducing the
5-year survival to 94%.
Importance
Despite criticisms of study design - no controls,
lack of uniform surgical procedure, continued oral
therapy with ,B-adrenoceptor blockers in 84% of
patients after surgery, and no reliable proof that all
patients worldwide who underwent this procedure
were included in the data analysis (e.g., did many
physicians not report their surgical failures to the
international registry?) - the study is important from
several standpoints. First and foremost, it provides
the most complete and important data found anywhere on a therapeutic modality for patients with
symptomatic LQTS. Second, it offers a clue to the
arrhythmogenic role of sympathetic stimulation (see
below). Last, it is a fine example of international
cooperation in medicine.
The opinions expressed in this article are not necessarily those
of the editors or of the American Heart Association.
From the Krannert Institute of Cardiology and Indiana University School of Medicine, Indianapolis, Ind.
Address for correspondence: Douglas P. Zipes, MD, Krannert
Institute of Cardiology, 1111 W. 10th St., Indianapolis, IN 462024800.
Long QT Interval Syndrome
The idiopathic LQTS comprises three groups of
patients with a congenital disorder characterized by
abnormally prolonged ventricular repolarization that
contributes to the development of ventricular tachyarrhythmias, often torsades de pointes. The JervellLange-Nielsen syndrome is transmitted as an autosomal recessive pattern and includes congenital neural
deafness. Patients with the Romano-Ward syndrome
have normal hearing and autosomal dominant transmission, whereas the sporadic form comprises a
nonfamilial group with normal hearing.2,3
Hypotheses
Any hypothesis put forth to explain this syndrome
must account for all of its features, namely the long
QT interval and abnormal T or TU waves, T wave
alternans, a lower than normal heart rate especially
in children, sinus pauses, and ventricular tachycardia, particularly torsades de pointes, that is usually
precipitated by physical or emotional stress and
causes syncope and sudden cardiac death.2,3 Of the
several hypotheses proposed,23 cardiac sympathetic
imbalance and an intrinsic myocardial abnormality
of repolarization appear most plausible. Other neurocardiological mechanisms may be operative in
occasional patients.4
ECG Changes and Sympathetic Imbalance
The sympathetic imbalance concept proposes that
reduced right cardiac sympathetic innervation (presumably on a congenital basis) results in reflex elevation of left cardiac sympathetic activity.3 This hypothesis can account for the sinus node abnormalities
and perhaps the beneficial effects of left-sided cardiac sympathetic denervation1 but, in the view of this
writer, inadequately explains the remaining features.
The justification for sympathetic imbalance causing QT prolongation is rooted in a 25-year-old observation in dogs showing that left stellate ganglion
stimulation and right stellate ganglion interruption
prolong the QT interval. The opposite did not occur.
That is, left stellate ganglion interruption and right
stellate ganglion stimulation produced no measurable change in the QT interval.5 In that pivotal study,
the QT interval was measured in only one electro-
Zipes Long QT Interval Syndrome
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cardiographic lead and increased in all but one dog
by 20-40 msec after right stellate ganglion interruption and by 46 msec (mean), for 1-5 minutes, after
termination of left stellate ganglion stimulation. Because sympathetic stimulation is well recognized to
shorten ventricular repolarization, the authors explained the QT prolongation by the unmasking of
previously cancelled repolarization forces,6 a concept
incompletely validated.
Several years later, one of the original authors,
reinvestigating these observations, showed (again recording one ECG lead) that 1-3 seconds of either
left or right sympathetic stimulation prolonged the
QT interval 10-30 msec, for up to several minutes,
usually in the 10-30-second period after termination
of stimulation.7 Stimulation of right or left sympathetic nerves for 30 seconds to 5 minutes, such as
might be expected to occur in an exercising patient
with the LQTS, always shortened the QT interval, at
times after transient prolongation. Rapid injection of
norepinephrine and epinephrine transiently prolonged and then shortened the QT interval while
slow, prolonged infusion shortened it.7 These data
show, at most, that neural or intravenous adrenergic
stimulation can transiently prolong the QT interval,
followed by shortening, and offer no evidence that
reduced right and increased left cardiac sympathetic
activity are responsible.
In a study on the effects of stellectomy, Schwartz et
a18 showed that right stellectomy shortened refractoriness 3-5 msec at the right ventricular apex (opposite to that found by Yanowitz et a15, while left
stellectomy increased refractoriness 4-7 msec, as did
bilateral stellectomy. Schwartz et a18 explained shortening of refractoriness after right stellectomy by a
reflex increase in left sympathetic activity. They
postulated that the reflex increase in right sympathetic activity after left stellectomy was insufficient to
counteract the loss of left sympathetic effects, and
ventricular refractoriness increased. They concluded
that both stellate ganglia exert qualitatively similar
effects that shorten cardiac refractoriness but the left
stellate exerted quantitatively greater effects. The
QT interval was not mentioned.
Other experimental models have been studied.
Recently it has been demonstrated that neonatal rats
injected with an antiserum to nerve growth factor
developed an abnormal sympathetic innervation pattern and a long QT interval. No mention was made of
a right/left sympathetic imbalance pattern, however.9
In the chick embryo, removal of the premigratory
surface ectoderm in the area of the right nodose
placode caused a 25 -msec QT increase in the ECG
obtained through the egg shell (and corrected by
Bazett's formula) compared with control embryos,
but no arrhythmias.10 The relevance of these models
is not known.
Finally, clinical studies of sympathetic innervation
patterns determined by metaiodobenzylguanidine
(MIBG) scintigraphy in patients with the LQTS show
conflicting patterns. We found no evidence of appar-
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ent left/right imbalance11; however, another recent
study noted reduced or absent MIBG uptake in the
diaphragmatic part of the left ventricle in patients
with the long QT syndrome.12
To summarize, the often-quoted studies that purport to establish the foundation for the ECG characteristics of LQTS show that refractory period and T
wave changes with stellate ganglion manipulation are
small compared with the QT changes in patients with
the LQTS. While T wave alternans and changes in T
wave contour can be produced with left stellate
ganglion stimulation,3 the bizarre T-U morphology
commonly seen in patients with the LQTS rarely
occurs. Further, discrepancies exist among the results
of the different studies investigating QT and refractory period changes.5'7,8 In the present study,' QTc
shortened after left sympathectomy in patients who
became asymptomatic, but not for the group as a
whole. However, in another study of 10 patients with
the LQTS who remained symptomatic after left
stellectomy, QTc shortened 50 msec.13
It is important to remember that just because
patients with the LQTS have increased risk for
developing ventricular tachyarrhythmias, that does
not mean that all other states characterized by QT
prolongation confer a similar risk. In fact, it is the
aim of potassium channel blocking drugs to prolong
refractoriness (and the QT interval) and thereby
suppress arrhythmias. Not all QT interval prolongation is arrhythmogenic, nor is all QT interval shortening antiarrhythmic. Uniform changes in refractoriness throughout the ventricle are probably more
important. Whether such dispersion in recovery of
excitability causes arrhythmias in patients with the
LQTS is unclear.14
Arrhythmias and Sympathetic Imbalance
Sympathetic imbalance has been invoked to explain the arrhythmogenic potential of the LQTS on
the basis of reflexly increased left sympathetic activity.3 One study showed an increased prevalence of
ventricular tachycardia and fibrillation during a 1090-second coronary occlusion in 11 dogs after right
stellate ganglion blockade and a reduction of ventricular arrhythmias after left stellate ganglion blockade.15 However, data from subsequent studies are
less convincing and can be briefly summarized: 1) in
dogs subjected to 5-minute coronary occlusions, left
stellate ganglion stimulation increased the number of
dogs with ventricular fibrillation from one of 20 to
five of 20, but left stellate ganglion interruption did
not reduce ventricular arrhythmias; after right stellectomy, arrhythmias were unchanged in seven dogs,
increased from none to development of premature
ventricular complexes in three dogs, and increased
from none to ventricular fibrillation in one dog16; 2)
in 72 dogs undergoing circumflex coronary occlusion,
both right and left stellate ganglionectomy reduced
the incidence of early and total ischemia-induced
ventricular tachycardia and ventricular fibrillation
and improved outcome, with left stellate ganglionec-
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Circulation Vol 84, No 3 September 1991
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tomy more effective than right17; 3) in conscious dogs,
premature ventricular complexes increased during
exercise in two of 25 dogs that were normally innervated and in six of seven dogs after right stellate
ganglion interruption'8; 4) in neonatal rats with
lengthened QT intervals treated with antibody to
nerve growth factor, no spontaneous ventricular arrhythmias occurred9; 5) in an abstract on cats after
right stellectomy, emotion lengthened the QT interval and most commonly caused AV nodal tachycardia, with frequent premature ventricular complexes
and ventricular tachycardia in some cats (no quantitative data provided or information given on the
number of cats with sustained or nonsustained ventricular tachycardia)19; 6) in dogs, right stellate ganglion interruption reduced the ventricular fibrillation
threshold 48% compared with a 72% increase following left stellate ganglion interruption20; 7) in a clinical abstract, exercise-induced ventricular arrhythmias (type not specified) occurred in six of 34
patients after right stellectomy for Raynaud's syndrome (no prestellectomy control results) compared
with one of 32 neurally intact patients, one of 19 with
left stellectomy and none of 18 patients with bilateral
stellectomy21; 8) in a more recent clinical abstract, 26
patients underwent right and then left high thoracic
sympathetic interruption for primary palmar hyperhidrosis and had no arrhythmias.22
From the present study1 one might reason that if
sympathetic imbalance were the arrhythmogenic
mechanism, even partial surgical relief (assuming it
was properly done) should provide a cure. One would
not think that total left-sided cardiac sympathectomy
would be necessary to reestablish "balance." Yet,
after surgery, six patients still had sudden death, and
27 still had syncope or cardiac arrest.' A counterargument to this logic might be that sympathetic imbalance from birth creates permanent myocardial
changes9 corrected only by complete left-sided sympathetic denervation. In a recent report,23 however,
one patient after autotransplantation and complete
cardiac denervation continued to have the long QT
interval, sporadic ventricular tachyarrhythmias and,
eventually, sudden cardiac death.
From these and other uncited studies (for reviews
see Corr24 and Schwartz and Priori25), it would
appear reasonable to conclude that left and bilateral
sympathetic interruption can be antiarrhythmic, particularly during acute myocardial ischemia and in the
LQTS, and that left and bilateral sympathetic stimulation can be arrhythmogenic,24-26 but that right
stellectomy does not seem to be particularly arrhythmogenic. This conclusion would again challenge the
hypothesis of sympathetic imbalance.
Intrinsic Abnormality in Repolarization
The second hypothesis, that of an intrinsic abnormality in myocardial repolarization,2, 3can explain the
QT prolongation, prominent and peculiar T and U
waves, T wave alternans, and ventricular tachyarrhythmias. In addition, it can serve as the mechanism
for the acquired LQTS, which the sympathetic imbalance concept cannot.27,28 It might also explain the
apparent sinus node abnormalities if the involved
channel contributed to normal sinus node activity.
This hypothesis assumes that the cause of abnormal repolarization lies within the heart itself, perhaps an abnormal channel protein reducing or blocking an outward repolarizing potassium current or
increasing an inward depolarizing calcium or sodium
current. This results in afterdepolarizations, probably
early afterdepolarizations, that cause triggered activity and torsades de pointes. Blockade of potassium
channels29-33 or augmentation of the calcium current3435 can produce early afterdepolarizations that
lengthen repolarization and cause triggered activity
and ventricular tachyarrhythmias experimentally.
Antiarrhythmic agents such as the class 1A drugs that
provoke the acquired LQTS and torsades de pointes
are potent potassium and sodium channel blockers.
Magnesium suppresses the early afterdepolarizations
and ventricular tachyarrhythmias in these animal
models32,36 as it suppresses ventricular tachyarrhythmias in patients with the acquired LQTS.37 In addition, deflections consistent with early afterdepolarizations have been recorded from the hearts of
patients with the idiopathic LQTS38-40 and a patient
with the acquired LQTS.41
Where does this leave the role of sympathetic
stimulation? In the animal model of LQTS produced
by cesium chloride administration, bilateral and left
ansae subclaviae stimulation produces larger early
afterdepolarizations and increases the prevalence of
spontaneous ventricular tachyarrhythmias to a
greater degree than does right ansae subclaviae
stimulation. However, during norepinephrine infusion, the amplitude of early afterdepolarizations increases equivalently in both ventricles in a doserelated fashion.27 These findings suggest that there is
nothing unique in the response of the right and left
ventricles to cesium or to uniform catecholamine
stimulation by drug infusion, only to left ansae subclaviae stimulation. The larger early afterdepolarization amplitude in the left ventricle during left or
bilateral ansae subclaviae stimulation may simply
reflect more norepinephrine released and more myocardium affected. It is known that the left ansae
subclaviae innervates most of the ventricular myocardium 5,8,24,25,42,43 or at least a much larger amount of
the ventricle than does the right stellate ganglion.
Further, norepinephrine content is greater in the left
than in the right ventricle.44 Finally, left stellate
ganglion stimulation results in a greater overflow of
norepinephrine in coronary sinus blood than does
right stellate ganglion stimulation.45
These data suggest that the left stellate ganglion
exerts a quantitatively greater adrenergic influence
on the ventricles than does the right stellate ganglion.58242527 This quantitative difference, which results in more ventricular mass being affected because
of more norepinephrine being released, rather than
qualitative differences between stellate ganglia or left
Zipes Long QT Interval Syndrome
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and right stellate imbalance, may be the basis for the
greater arrhythmogenic potential of left stellate ganglion stimulation compared with right. It also may
account for the beneficial effects after surgical interruption of the left stellate ganglion. Sympathetic
stimulation, primarily left, caused by physical or
emotional stress could periodically increase the amplitude of early afterdepolarizations that were present because of the intrinsic repolarization abnormality, to reach threshold and provoke ventricular
tachyarrhythmias. Surgical interruption of the left
stellate ganglion could eliminate the arrhythmias
without consistently shortening the QT interval because the early afterdepolarization would still exist,
but would be subthreshold.
Analysis of the observations of Schwartz et all
offers further insight into the arrhythmogenic actions
of sympathetic neural stimulation. The fact that
surgical interruption of the left stellate ganglion
reduces the incidence of syncope and sudden death
after unsuccessful treatment with p-adrenoceptor
blockers underscores the potential arrhythmogenic
role of a-adrenoceptor stimulation in the LQTS,
because severing neural innervation provides a- as
well as j3-adrenoceptor interruption. That conclusion
suggested a series of experiments in which we showed
that a1-adrenoceptor stimulation increased and aladrenoceptor blockade decreased early afterdepolarization amplitude and ventricular tachycardia prevalence.35,46,47 It is possible that there are groups of
patients with the long QT syndrome in whom a1
rather than ,l-adrenoceptor stimulation is more arrhythmogenic, or vice versa. Results from specific
autonomic challenges might better direct therapy.
For example, patients who have induction of largeamplitude early afterdepolarizations and replication
of their ventricular tachyarrhythmias during phenylephrine infusion and not during isoproterenol infusion might be better treated with a- than 3-adrenoceptor blockers. They may represent the treatment
failures to f3-adrenoceptor blockers. If the reverse
occurred, /-adrenoceptor blockade might be preferable. Combined a- and ,B-adrenoceptor blockade
might be tried. Recent data suggest that use of drugs
that increase potassium conductance48 or even prostaglandins49 might also be considered.
In summary, the weight of the evidence suggests
that an intrinsic myocardial abnormality in repolarization is responsible for the LQTS, leading to early
afterdepolarizations, triggered activity, and ventricular tachyarrhythmias. It would seem reasonable that
pieces of myocardium obtained at surgery or by
endomyocardial biopsy could be studied by modern
biochemical and electrophysiologic approaches, including voltage clamp analysis of disaggregated myocytes, patch membrane, and lipid bilayer techniques.
We used the lipid bilayer method to study a myocardial biopsy from one patient with aborted sudden
cardiac death caused by the LQTS. The patient had
early afterdepolarizations demonstrated during epinephrine challenge but had a normally functioning
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calcium-activated potassium channel during the lipid
bilayer study.50 We were not able to estimate the
number or distribution of calcium-activated potassium channels, however.
Conclusions
The current study presents an important advance
that offers therapy capable of saving many young
lives. Nevertheless, cardiac events still occurred, indicating that left cardiac sympathectomy is not universally successful,13 possibly because of a mixed
population of patients. For some patients, long-term
pacing51 and/or implantation of a cardioverter-defibrillator may be necessary.
In the future, further attempts at understanding
the electrophysiologic and genetic abnormalities
should be made.52,53 Recently, a DNA marker at the
Harvey ras-1 locus was shown to be linked to the long
QT syndrome. This finding confirms the genetic basis
of the disorder and localizes this gene to the short
arm of chromosome 1 1.54 Either ras or a gene tightly
linked to ras appears responsible. A molecular probe
to the gene would unerringly be able to detect
patients who have the long QT syndrome. Interestingly, the protein encoded by the gene is one of the G
proteins and may help control the passage of potassium ions through membrane channels. It should be
possible to identify, clone, and map the abnormal
gene and even express it in transgenic mice.55 In this
way, one can identify precisely the repolarization
abnormality for this Rosetta stone and possibly direct
therapy with more specificity than producing leftsided sympathetic denervation of the heart.
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Zipes Long QT Interval Syndrome
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KEY WORDS * long QT syndrome * ventricular tachyarrhythmia
* sympathetic stimulation * Point of View
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The long QT interval syndrome. A Rosetta stone for sympathetic related ventricular
tachyarrhythmias.
D P Zipes
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Circulation. 1991;84:1414-1419
doi: 10.1161/01.CIR.84.3.1414
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