Circulation. 1995;92:2786-2789
(Circulation. 1995;92:2786-2789.)
© 1995 American Heart Association, Inc.
Congenital Long QT Syndromes
Toward Molecular Dissection of Arrhythmia Substrates
Andrew A. Grace, PhD, MRCP;
Kenneth R. Chien, MD, PhD
From the Department of Medicine (A.A.G., K.R.C.), Center for Molecular
Genetics (K.R.C.), and the American Heart Association-Bugher Foundation Center
for Molecular Biology (A.A.G., K.R.C.), University of California, San Diego,
School of Medicine, La Jolla, Calif; the Departments of Medicine and
Biochemistry, University of Cambridge, England (A.A.G.); and the Department of
Cardiology, Papworth Hospital (A.A.G.), Cambridge, England.
Correspondence to Andrew A. Grace, PhD, MRCP, American Heart
Association-Bugher Foundation Center for Molecular Biology, Department of
Medicine, 0613-C, University of California, San Diego, 9500 Gilman Dr, La
Jolla, CA 92093-0613.
Key Words: editorials arrhythmia genetics molecular biology
 |
Introduction
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The last 12 months could be viewed as the
annus mirabilis for
the molecular delineation of
ventricular arrhythmia substrates,
analogous to the
celebration of the molecular determinants of
gating and selectivity of
potassium channels in a previous year.
1 In 1991, the first
genetic locus (LQT
1) for the congenital
long QT syndromes
was identified on chromosome 11, and close
linkage to the
H-
ras-1 gene was reported in a landmark
article.
2 Although the candidate gene was mechanistically
appealing and
was implicated in each of the first 6 families
examined,
3 no
mutations of the H-
ras-1 locus
were found, and it has been formally
excluded as a site of the genetic
defect.
4 Subsequent studies
that utilized linkage
analysis documented that the disease was
genotypically
heterogeneous, which is consistent with the
complexity
of the repolarization process.
4 In 1994, two
further loci,
(LQT
2 and LQT
3) were reported on
chromosomes 7 and 3, respectively.
Currently, the genetic loci for the
majority of families have
been accounted for,
5 with
linkage not yet achieved in only
3 of 27 lineages studied by the Salt
Lake City group.
6 The
scientific pace maintained by that
group has been breathtaking,
resulting in the characterization of
candidate genes at two
of the more recently described
locations
6 7 along with powerful
evidence that these
genes
encode sodium and potassium
channels.
6 7 8 Therefore, as has
been previously suspected,
9 the proximal
cause of most
autosomal dominant long QT syndromes (LQTS) is
a sarcolemmal ion
channel defect determining repolarization.
10 The details
of these molecular advances have been summarized
recently by
Keating.
4 The present issue of
Circulation
contains
one of the first reports to examine the correlations between
the
clinical phenotype and different genetic
loci.
11 Moss et al
11 have convincingly shown
that individual gene defects substantially
determine repolarization
morphology, with evidence of conservation
within a given kindred. In
addition to providing a finer definition
of LQTS, their findings also
suggest the value of pursuing diverse
clinical and experimental
approaches to determine how these
findings have relevance to
ventricular arrhythmogenesis extending
beyond the bounds of
this rare condition. Herein, we briefly
discuss a few of the
implications of this latest report for
the pathogenesis of LQTS and
consider the impact of these findings
on the ontogeny of the field of
"cardiac molecular electrophysiology,"
ie, clinical and basic
cardiac electrophysiology underpinned
by a molecular understanding of
ion channel function and regulation.
12
The T wave is a defining component of repolarization, but the precise
mechanisms underlying its inscription have so far escaped
elucidation.13 14 What is clear is that the T wave is
a
sensitive index of physiological and pathological
changes within ventricular
myocardium14 and that, in addition, T wave
abnormalities with a range of configurations are documented in
LQTS.9 15 16 17 Specific
molecular defects in LQTS are now
shown to generally correlate with relatively subtle phenotypic
alterations encompassing the T wave.11 In certain
respects, the T wave and the QTc interval must be
considered in unity, and the present report11 raises
interesting questions in regard to terminology. The assessment of the
QTc interval is restricted to quantifying duration,
although T waves clearly have other morphological features that allow
for a more complex description. The well-documented overlap of
QTc intervals between symptomatic LQTS and
unaffected control subjects18 indicated that a key step
toward obtaining genetic linkage was establishing a tight definition of
QTc criteria.4 In view of the potential
presence of T wave abnormalities with normal QTc, it
is possible that T wave abnormalities may prove, at the very least, to
be a clinically useful independent descriptive characteristic of LQTS.
If such proves the case, the banner heading of "congenital
repolarization syndromes" may have more than just semantic appeal in
that it may encourage clinicians to consider the possibility of the
diagnosis even in the absence of QTc prolongation. Although
the relatively small kindreds will pose difficulties, it may also
become of interest to review T wave appearances in other conditions
such as idiopathic ventricular fibrillation that have
considerable clinical similarities to LQTS in the absence of
QTc prolongation.19 20
 |
Mechanism of Repolarization Changes
|
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How does the molecular pathology of LQTS result in relatively
conserved
morphological changes of repolarization? It seems probable
that
specific final characteristics are determined both by the effects
of
the individual ion channel phenotype and the anatomic
distribution
of the mutated channels. The LQT
2 locus is
associated with mutations
in the
Human
Ether-á-go-go-
Related
Gene (
HERG), which
encodes a potassium channel
with biophysical characteristics
identical to the rapid component of
the delayed rectifier potassium
current
(I
Kr).
6 8 HERG mutations have a
dominant-negative effect
on channel function and possess a
cyclic-nucleotide binding
domain, thereby providing a
link with ß-adrenergicmediated
events (see below). The
LQT
3 locus mutation arises from an intragenic
deletion
between D3 and D4 of the sodium channel (SCN5A) and
is presumed to
result in delayed channel inactivation.
7 The
effects of
both mutations are predicted to delay repolarization
and, until the
present report,
11 had undetermined specific
functional
consequences.
4 However, the finding that the
LQT
3 mutation increases QT
onset c and
LQT
2 reduces T wave amplitude
is, at the very least,
consistent with specific ion channel
effects.
T waves represent the summation of complex, temporally
dispersed events having considerable regional
heterogeneity.14 Different cell
populations in endocardial, midmyocardial, and epicardial layers
display distinct patterns of expression of sodium and potassium
currents, thereby reflecting variation in relevant channel
distribution.21 22 Modification of the function of
scattered mutated channels might disturb necessarily regimented
patterns, which could then be exaggerated under conditions of stress.
Therefore, the most probable explanation for the repolarization changes
observed by Moss et al11 and emphasized
previously15 16 is dispersion of repolarization
secondary
to differential current activity, reflecting a mixture of mutated and
wild-type channels at individual myocardial
locations.22 23 The specific myocardial regions that
produce such heterogeneity are not established, and
their identification clearly will be of interest. Of course, one cannot
exclude a role of afterdepolarizations in contributing to some reported
T wave morphologies.15 16 However, the implied
relative
stability of most reported changes seems to argue for cellular
heterogeneity being a more important determinant.
 |
Implications for Arrhythmogenesis in LQTS
|
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Two principal hypotheses have been proposed for arrhythmia
generation
in LQTS, incorporating, respectively, increased
inhomogeneity
or afterdepolarizations. However, as has been widely
pointed
out, these are not mutually exclusive; for example, each
responds
to adrenergic triggers.
14 24 If
repolarization
changes are
the ECG manifestations of delayed or
inhomogeneous repolarization,
they also point to a
substrate for arrhythmogenesis. There is
other evidence suggesting that
such inhomogeneity is a component
of the substrate in this condition,
including increased QT
dispersion.
25 26 27 In addition, the
characterization of a generalized intraventricular
conduction
abnormality with increased fractionation of
ventricular electrograms
after premature stimulation is
also relevant (Dr R. Saumarez,
personal written communication, August
1995), being analogous
to the abnormalities of the supposed substrate
reported in hypertrophic
cardiomyopathy and primary
ventricular fibrillation.
20 28 Regional
differences,
exaggerated by sympathetic stimulation, could give rise to
marked
dispersion of repolarization and refractoriness, thereby
encouraging
reentry. In view of these observations, it is possible that
the
further characterization and possible quantification of different
repolarization
morphologies, as a readily observed index of
inhomogeneity,
could further refine prediction of risk.
The sympathetic nervous system has been the focus of critical interest
in LQTS.9 12 Indeed, for many years, the primary
defect
was suggested to be the result of asymmetrical cardiac sympathetic
input. The detailed exploration of this possibility has provided many
useful mechanistic and therapeutic insights.9 12 An
important role for sympathetic activation in triggering has been
supported by effective, albeit formally untested, therapies with
ß-blockers and left cardiac sympathetic
denervation.12 The direct autonomic modulation of both
normal and dysfunctional channels, coupled with spatial
heterogeneity, may account for exaggerated T wave
appearances following adrenergic stress and exercise and documented
before the onset of torsade de pointes.9 Further
investigation of individual coupling of channels to specific
adrenoceptors, therefore, may have potentially important therapeutic
implications.
 |
Relevance to the Pathogenesis and Treatment of
Ventricular Arrhythmias
|
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The question also arises of whether these clinical correlates
of
molecular genetic defects in LQTS patients have relevance
to
ventricular arrhythmias in other clinical
situations. The
LQTS have been proposed as the Rosetta stone of
autonomically
mediated cardiac arrhythmias
12 that
occur in diverse clinical
populations and in the apparently normal
population.
29 Minor
abnormalities of the T wave are not
uncommon, occurring with
frequencies as high as 15% of young control
subjects in LQTS
studies,
15 possibly
representing polygenic influences on repolarization
that
may potentially confer risk in the general population,
as is the case
with the QT
c interval.
30 31 In addition, a
modified
pattern of repolarization, expressed most explicitly as
reversed
T wave polarity, is sensitive to both ventricular
hypertrophy
and failure.
14 The pattern of ion
channel expression and distribution
is likely to be considerably
influenced by altered patterns
of expression of cardiac genes in the
context of cardiac hypertrophy.
32 33 In
cardiomyopathies, such a phenomenon could
represent a
primary substrate. Conversely, in
ventricular tachycardia associated
with old
myocardial infarction, macroreentry may sustain the
arrhythmia
but similar localized, inhomogeneous circuits may
be
responsible for its initiation.
34
Analysis of the LQTS problem has important implications in
regard to drug design and development. The delayed rectifier has been a
target in the development of class III agents, with the aim being to
create a dysfunctional, albeit antiarrhythmic, repolarization
syndrome.35 36 Although there is a suggestion of
clinical benefit from some class III agents,37 there is
also anecdotal evidence from pilot studies of the induction by some
drugs of T wave morphological changes similar to those seen with LQTS.
Thus, in certain clinical circumstances, pharmacological block of
currents that are primarily responsible for repolarization might
promote conditions that could encourage arrhythmia development.
Clearly, this is becoming an important consideration in the application
of class III antiarrhythmic agents, especially in the context of
damaged ventricles in which dispersion may already be
exaggerated.29 38 Unfortunately, improved targeting
to
specific ion channels or their domains may not necessarily prove more
effective, as nonspecific repolarization delay and increased dispersion
may be inescapable outcomes. Such a point may be clarified by survival
analyses related to different LQTS mutations; it is even
possible such data may prove valuable in the further development of
these agents.
 |
Molecular Analysis of Arrhythmia
Substrates
|
|---|
The dissection of the LQTS has raised the possibility of wider
application
of molecular approaches to increase our understanding of
the
behavior of arrhythmia substrates. Until recently, in situ
hybridization
and immunolocalization have had limited applicability in
defining
ion channel distribution, in view of the low levels of
expression
of these channels in individual cells and the difficulties
caused
by cross-reactivity among highly conserved isoforms.
However,
the application of antibodies with improved specificity should
facilitate
refined analysis (eg, mapping and possible
quantification) of
temporal and spatial patterns of expression,
possibly allowing
definition of the extent of
heterogeneity of channel topology
in
disease.
39 These techniques have been applied to
describing
the distribution of the human Kv1.5 potassium channel
protein,
which has delayed rectifier properties and localized
expression
to the region of the intercalated disk.
40 Other
techniques
also show potential value. For example, heterologous
expression
of human cardiac ion channel proteins in
Xenopus
oocytes has
been used to characterize
HERG8 41
and documents the advantages
of studying the isolated channel outside
the context of the
cardiac myocyte, in the absence of potentially
confounding elements.
However, it may also be necessary to examine the
activity of
these channels in the cardiac cell context, as regulation
by
covalent modification and other cardiac signaling pathways become
of
interest.
The investigation of the molecular determinants of a complex
phenotype, such as repolarization, will ultimately require in
vivo analysis that uses experimental approaches coupling
genetics to appropriate assessments of cardiac
electrophysiology.39 The techniques required for the
cardiac-specific expression of constitutively active or
dominant-negative ion channel proteins, as well as the genetic
ablation or manipulation of individual ion channels, are now in place.
The use of such technology should allow a systematic analysis
of channel function in in vivo
electrophysiological phenotypes.
This approach would be analogous to what has been accomplished in the
assessment of determinants of myocardial
contractility,42 43
hypertension,44 and hypertrophy45
and will be advanced further by the use of conditional and
tissue-specific knockouts of cardiac genes via Cre-lox
technology for homologous recombination.46 The expression
of mutated ion channels, which could include those of the LQTS type,
may ultimately allow the generation of models with
macroelectrophysiological properties,
which could have applications beyond the consideration of LQTS per se.
The analysis of mouse models resulting from the specific
genetic manipulation of ion channels could then be compared with
electrophysiological phenotypes
arising in transgenic and gene-targeted mice having characteristics
of structural cardiac disease, eg, hypertrophy and
cardiomyopathy.45 47 48 49
However,
general application of these approaches will first require establishing
that the mouse has fidelity to other mammalian systems. It is already
well established that individual ion channel expression and integrated
whole organ electrophysiology is highly species-dependent, and the
mouse may also provide specific technical problems, such as basal heart
rates in excess of 350 beats per minute, that will complicate
experimental analysis. We would, however, confidently envision
that such hurdles are likely to be surmounted, as has been the case for
other complex cardiovascular
phenotypes.43 45 50
 |
Conclusions
|
|---|
In conclusion, analysis of the LQTS is a quintessential
example
of the application of state-of-the-art molecular
technology
to a problem in the mainstream of clinical
cardiology. The dissection
of this genetic substrate is
beginning to fulfill the promise
of improving our fundamental
understanding of arrhythmogenesis
in a range of clinically diverse
conditions
12 41 analogous
to recent advances in
cardiac
hypertrophy
45 and hypertrophic
cardiomyopathy.
49 51 These
accomplishments represent a culmination of the
long-standing
efforts of outstanding clinicians who have carefully
characterized
the clinical phenotype of LQTS,
9 52
and the molecular expertise
of the Keating laboratory. This large body
of work is a clear
demonstration of the value of collaborative work
between clinical
and molecular cardiologists. As outside observers, we
look forward
to the next chapter on this rare disorder, which may
ultimately
define a new experimental and clinical
paradigm
12 for the analysis
of
ventricular arrhythmias.
 |
Acknowledgments
|
|---|
Dr Grace is a British Heart Foundation Clinical Scientist
Research
Fellow and holds a Fulbright Senior Research Scholarship. Dr
Chien
is supported by grants from the NIH/NHLBI (1 RO1 HL-51549, PO1
HL-46345,
and HL-53773) and the American Heart Association
(91-022170).
 |
Footnotes
|
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The opinions expressed in this editorial are not necessarily
those of the
editors or of the American Heart Association.
 |
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