Wilhelm Haverkamp, Paulus Kirchhof, Lars Eckardt, Gerold Mönnig, Martin Borggrefe, Günter Breithardt.
Hospitalof the Westfälische Wilhelms-University, Department of Cardiology and Angiology and Institute for Arteriosclerosis Research, Münster, Germany
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More than 30 years after its first detailed description, the congenital
LQTS has now become the focus of considerable scientific attention. This is primarily due to the recent discovery
that the disorder is a genetic channelopathy. Mutations causing the disease have been identified in four genes
(KCNQ1, KCNE1, KCNE2, HERG, SCN5A), each encoding a cardiac ion channel protein. The fact that the rapidly
activating potassium current IKr (encoded by HERG) is involved in both, the pathogenesis of the congenital as
well as the acquired form of LQTS, has led to the suggestion that there may be a genetic predisposition for
acquired LQTS. Mutations in HERG have been found to account for approximately 20% of all cases of congenital
LQTS. However, recent studies in patients with drug-induced QT prolongation and TDP have yielded only a small
number of individual cases in whom the clinical setting had suggested an acquired form of the syndrome and
genetic analysis revealed a familial form. In our own series of 17 patients with drug-induced LQTS who
underwent SSCP analysis and direct sequencing of the genes known to cause congenital LQTS, a mutation
was found in only 4 patients (23%)5. Although these findings do not exclude that other channels are involved,
they favor a multifactorial origin of acquired LQTS. It is conceivable that modifier genes that influence the
pattern and clinical manifestation of the disease and other factors that control the expression and translation
of genes may play a role. This has also been suggested to account for two major clinical aspects of congenital
LQTS, namely the female preponderance (which can be found in both, the congenital and the acquired form of
the disease) and the marked heterogeneity of the clinical manifestation (phenotypic heterogeneity) of the
disorder.
Although only a small segment of the population seems to be at risk for acquired abnormal QT prolongation and
TDP, experimental data suggest that, the adequate circumstances and the presence of triggers provided, the
ability to develop TDP is an intrinsic property of almost any heart. We have recently studied the ability of
clofilium, d,l-sotalol and erythromycin to produce TDP in the isolated rabbit heart6. The experimental model
was designed to reproduce conditions that are clinically known to be associated with an increased propensity
to the development of TDP (i.e. hypokalemia and severe bradycardia). Episodes of TDP established in almost all
hearts when AV-block and potassium was lowered and sufficiently high drug concentrations were present.
The concept of multifactorial origin of acquired abnormal QT prolongation and TDP is further illustrated in figure
1. In patients with the congenital form of the syndrome, ion channel mutations form the major substrate for
abnormal QT prolongation and the development of TDP. Activation of the adrenergic system is the prominent
trigger for arrhythmias in most patients. Presumably due to the presence of modifier genes, the frequency of
syncope, i.e. arrhythmia, varies from patients to patients. Many patients have a lot of events because the
substrate dominates. However, some patients have ion channel mutations which, under normal conditions,
do not significantly affect channel function and, thus, do not result in QT prolongation. In these patients who
can be suggested to have a “form fruste” of the congenital long QT syndrome, abnormal QT prolongation only
becomes manifest in the presence of active triggers. The majority of individuals (with “acquired” QT syndrome)
does not have mutations in genes encoding ion channels involved in the repolarization process. However, e.g.
female gender and other genetic factors may increase their propensity to the development of TDP to a level
higher than that of the majority of the population. The adequate triggers (e.g. treatment with erythromycin) and
environmental factors (administration of an inhibitor of the cytochrome P450 system and bradycardia) provided,
TDP may develop.
Fig. 1: Spectrum of mechanisms of QT syndromes.
Since these patients form a spectrum with varying degree of propensity to TDP, it takes very little in some of them
to develop TDP while others need high drug concentration, bradycardia, and hypokalemia. However, the
situation in which the arrhythmia becomes manifest is usually very unique and in most patients it occurs only
once during life-time. If this hypothesis would be true, genetic screening of the genes known to be causative for
a congenital QT syndrome would be able to identify a subgroup of patients with an increased propensity to TDP
(i.e. those patients with a ´forme fruste´ of the congenital long QT syndrome) but it would not allow to identify all
patients at risk for acquired TDP and, more importantly, it would not allow to exclude an increased propensity to
develop this particular form of proarrhythmia prior to drug exposure.
Despite the improvement in our understanding which the recent identification of the genes causing congenital
LQTS has made, many aspects of the mechanisms underlying abnormal QT prolongation and TDP are not yet
elucidated. The initial hope that most cases of acquired LQTS, like individuals with the congenital variant of the
syndrome, have mutations of ion channel genes, has not come true. Currently, there is no evidence to suggest
that the majority of patients with acquired LQTS suffer from a subclinical variant (form fruste) of the congenital
form of the syndrome, although this may be the case in individual patients. However, this does not exclude that
acquired LQTS has a genetic background. Current evidence suggest that the disease has a multifactorial origin
with environmental factors significantly modulating the genetic basis. A better understanding of the mechanisms
underlying acquired LQT will require integration of molecular genetic data with cellular electrophysiological
information that can relate the phenomenon of drug-induced abnormal QT prolongation and TDP to changes in
presumably both environmental and genetically determined ion channel structure, expression, and/or regulation.
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