(Circulation. 1995;92:2786-2789.)
© 1995 American Heart Association, Inc.
Articles |
Congenital Long QT Syndromes
Toward Molecular Dissection of Arrhythmia Substrates
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
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Introduction |
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 Top Introduction Mechanism of Repolarization...Implications for...Relevance to the Pathogenesis...Molecular Analysis of...
Conclusions References |
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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 (LQT1) 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, (LQT2 and LQT3) 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 locations6 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 al11 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
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Mechanism of Repolarization Changes |
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TopIntroductionMechanism of Repolarization...Implications for...Relevance to the Pathogenesis...Molecular Analysis of...
Conclusions References |
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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 LQT2 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 (IKr).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-adrenergic–mediated events (see below). The LQT3 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 LQT3 mutation increases QTonset c and LQT2 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.
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Implications for Arrhythmogenesis in LQTS |
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TopIntroductionMechanism of Repolarization...Implications for...Relevance to the Pathogenesis...Molecular Analysis of...
Conclusions References |
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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.
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Relevance to the Pathogenesis and Treatment of Ventricular Arrhythmias |
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TopIntroductionMechanism of Repolarization...Implications for...Relevance to the Pathogenesis...Molecular Analysis of...
Conclusions References |
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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 arrhythmias12 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 QTc 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.
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Molecular Analysis of Arrhythmia Substrates |
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TopIntroductionMechanism of Repolarization...Implications for...Relevance to the Pathogenesis...Molecular Analysis of...
Conclusions References |
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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
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Conclusions |
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TopIntroductionMechanism of Repolarization...Implications for...Relevance to the Pathogenesis...Molecular Analysis of...
Conclusions References |
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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 conditions12 41 analogous to recent advances in cardiac hypertrophy45 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 paradigm12 for the analysis of ventricular arrhythmias.
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Acknowledgments |
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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).
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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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References |
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