Long QT Research Articles

Prolonged QT syndrome in children: An uncommon but potentially fatal entity

Prolonged QT syndrome may be either congenital, as in Jervell and Lange-Nielsen or Romano-Ward syndromes, or acquired in nature. Affected children are at risk for syncope, seizures, dysrhythmias and sudden death. Physicians should consider long QT syndrome (LQTS) in all patients who present with syncope. A thorough personal and family history should be documented, with particular attention to prior syncopal episodes, congenital deafness, and unexplained sudden death. Syncope that is either recurrent or induced by exercise or stress is concerning and also should be noted. An electrocardiogram with manual calculation of the QT interval should be performed on all patients with a suggestive history. Furthermore, the diagnosis of LQTS warrants evaluation of all other family members. With recognition and appropriate treatment of affected patients, the potentially fatal consequences of LQTS may be prevented.

Expanding Role of Catheter Ablation for Ventricular Arrhythmias

Recently, patients with idiopathic ventricular fibrillation (VF) were treated successfully with catheter ablation, targeted at premature ventricular contractions (PVCs) that arose from the right ventricular outflow tract (RVOT) or from the Purkinje system ( Circulation 2002; 106:962). Now, researchers have performed similar mapping and ablation in 4 patients with the long-QT syndrome (LQTS) and 3 with …

Interaction with GM130 during HERG Ion Channel Trafficking: DISRUPTION BY TYPE 2 CONGENITAL LONG QT SYNDROME MUTATIONS

Many mutations in the Human Ether-à-go-go-Related Gene (HERG) cause type 2 congenital long QT syndrome (LQT2) by disrupting trafficking of the HERG-encoded potassium channel. Beyond observations that some mutations trap channels in the endoplasmic reticulum, little is known about how trafficking fails. Even less is known about what checkpoints are encountered in normal trafficking. To identify protein partners encountered as HERG channels are transported among subcellular compartments, we screened a human heart library with the C terminus of HERG using yeast two-hybrid technology. Among the proteins isolated was GM130, a Golgi-associated protein involved in vesicular transport. The interaction mapped to two non-contiguous regions of HERG and to a region just upstream of the GRASP-65 interaction domain of GM130. GM130 did not interact with the N or C terminus of either KvLQT1 or Shaker channels. LQT2-causing mutations in the HERG C terminus selectively disrupted interactions with GM130 but not Tara, another HERG-interacting protein. Native GM130 and stably expressed HERG were co-immunoprecipitated from HEK-293 cells using GM130 antibodies. In rat cardiac myocytes and HEK-293 cells, confocal immunocytochemistry showed co-localization of GM130 and HERG to the Golgi apparatus. Overexpression of GM130 suppressed HERG current amplitude in Xenopus oocytes, as if by providing an excess of substrate at the Golgi checkpoint. These findings indicate that GM130 plays a previously undefined role in cargo transport. We propose that the cytoplasmic C terminus of HERG participates in the tethering or possibly targeting of HERG-containing vesicles within the Golgi via its interaction with GM130.

Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome).

Andersen syndrome (AS) is a rare, inherited disorder characterized by periodic paralysis, long QT (LQT) with ventricular arrhythmias, and skeletal developmental abnormalities. We recently established that AS is caused by mutations in KCNJ2, which encodes the inward rectifier K(+) channel Kir2.1. In this report, we characterized the functional consequences of three novel and seven previously described KCNJ2 mutations using a two-microelectrode voltage-clamp technique and correlated the findings with the clinical phenotype. All mutations resulted in loss of function and dominant-negative suppression of Kir2.1 channel function. In mutation carriers, the frequency of periodic paralysis was 64% and dysmorphic features 78%. LQT was the primary cardiac manifestation, present in 71% of KCNJ2 mutation carriers, with ventricular arrhythmias present in 64%. While arrhythmias were common, none of our subjects suffered sudden cardiac death. To gain insight into the mechanism of arrhythmia susceptibility, we simulated the effect of reduced Kir2.1 using a ventricular myocyte model. A reduction in Kir2.1 prolonged the terminal phase of the cardiac action potential, and in the setting of reduced extracellular K(+), induced Na(+)/Ca(2+) exchanger-dependent delayed afterdepolarizations and spontaneous arrhythmias. These findings suggest that the substrate for arrhythmia susceptibility in AS is distinct from the other forms of inherited LQT syndrome.

Mechanism of sudden cardiac arrest while swimming in a child with the prolonged QT syndrome

We describe the abrupt sequence of events resulting in cardiac arrest while swimming in a 12-year-old with long QT syndrome. Diving into cold water resulted in an irregular cardiac rhythm and further prolongation of the QT interval, followed by a premature ventricular complex, which initiated pulseless ventricular tachycardia (rate >300/minute). The transition from sinus rhythm to ventricular tachycardia occurred in <5 seconds and was followed by a successful implantable cardioverter-defibrillator rescue shock. (J Pediatr 2002;141:283-4)

Rate-dependent QT shortening mechanism for the LQT3 deltaKPQ mutant.

For the congenital long QT (LQT) syndrome involving mutations of the cardiac sodium channel gene SCN5A, LQT3, the initiation of sudden cardiac death tends to be bradycardia- or pause-dependent, contrary to other LQT syndromes that tend to be adrenergic dependent. Enhanced shortening of the prolonged QT interval with increased heart rate has been reported in LQT3 patients. We hypothesized that the rate-dependent shortening of the QT interval may be attributed to the kinetic properties of inactivation the late sodium current (I(Na)) in LQT3. The deltaKPQ mutant of the human heart voltage-gated sodium channel alpha-subunit was stably transfected into a mammalian cell line (HEK293). I(Na) was recorded using a whole-cell patch-clamp technique. A train of 50 depolarizing pulses or a train of 50 ventricular action potential waveforms was applied with different interpulse durations. Peak I(Na) for the 50th pulse compared with that of I(Na) in the first pulse was decreased <2% for interpulse durations as short as 20 ms, but late I(Na) amplitude measured at the end of the pulse was decreased 95, 78, 68, 56 and 47% with 1000, 500, 200, 100, 20 ms interpulse intervals, respectively. Using the action potential waveform a similar rate-dependent reduction of late I(Na) was found with minimal reduction of peak I(Na). Late I(Na) amplitude in the deltaKPQ mutation is strongly rate dependent. Rate-dependent reductions of late I(Na) may cause shortening the QT interval at higher rates. This provides a mechanism correlating the genotype with the clinical phenotype, and provides a rationale for the effectiveness of pacemaker therapy in LQT3 patients.

Pharmacological rescue of human K(+) channel long-QT2 mutations: human ether-a-go-go-related gene rescue without block.

Defective protein trafficking is a consequence of gene mutations. Human long-QT (LQT) syndrome results from mutations in several genes, including the human ether-a-go-go-related gene (HERG), which encodes a delayed rectifier K(+) current. Trafficking-defective mutant HERG protein is a mechanism for reduced delayed rectifier K(+) current in LQT2, and high-affinity HERG channel-blocking drugs can result in pharmacological rescue. Methods and Results- We postulated that drug molecules modified to remove high-affinity HERG block may still stabilize mutant proteins in a conformation required for rescue. We tested terfenadine carboxylate (fexofenadine) and terfenadine, structurally similar drugs with markedly different affinities for HERG block, for rescue of trafficking-defective LQT2 mutations. Terfenadine rescued the N470D mutation but blocked the channels. In contrast, fexofenadine rescued N470D with a half-maximal rescue concentration of 177 nmol/L, which is approximately 350-fold lower than the half-maximal channel block concentration. The G601S mutation was also rescued without channel block. Pharmacological rescue can occur without channel block. This could represent a new antiarrhythmic paradigm in the treatment of some trafficking-defective LQT2 mutations.

Na(+) channel mutation that causes both Brugada and long-QT syndrome phenotypes: a simulation study of mechanism.

Complex physiological interactions determine the functional consequences of gene abnormalities and make mechanistic interpretation of phenotypes extremely difficult. A recent example is a single mutation in the C terminus of the cardiac Na(+) channel, 1795insD. The mutation causes two distinct clinical syndromes, long QT (LQT) and Brugada, leading to life-threatening cardiac arrhythmias. Coexistence of these syndromes is seemingly paradoxical; LQT is associated with enhanced Na(+) channel function, and Brugada with reduced function. Using a computational approach, we demonstrate that the 1795insD mutation exerts variable effects depending on the myocardial substrate. We develop Markov models of the wild-type and 1795insD cardiac Na(+) channels. By incorporating the models into a virtual transgenic cell, we elucidate the mechanism by which 1795insD differentially disrupts cellular electrical behavior in epicardial and midmyocardial cell types. We provide a cellular mechanistic basis for the ECG abnormalities observed in patients carrying the 1795insD gene mutation. We demonstrate that the 1795insD mutation can cause both LQT and Brugada syndromes through interaction with the heterogeneous myocardium in a rate-dependent manner. The results highlight the complexity and multiplicity of genotype-phenotype relationships, and the usefulness of computational approaches in establishing a mechanistic link between genetic defects and functional abnormalities.

ICDs for Most -- but Not All -- Patients with the Brugada ECG Pattern

In patients without known heart disease, sudden cardiac death may be caused by one of several conditions, including long-QT syndrome, arrhythmogenic

Genetic aspects in acquired long QT syndrome ? a piece in the puzzle

Torsade de pointes (TdP) is a serious complication which is induced by a large variety of cardiovascular and non-cardiovascular drugs. Many clinical conditions and risk factors for the occurrence of TdP during administration of drugs with a proarrhythmic potential have been identified. All such drugs have in common that they reversibly alter myocardial repolarization due to the prolongation of the action potential (acquired QT interval prolongation) which is per se not arrhythmogenic. TdP is initiated (acquired long QT (LQT) syndrome) only when a threshold level is reached leading to early after-depolarizations (EADs) and triggered beats together with a marked dispersion in recovery of excitability. The underlying mechanisms of TdP are not yet satisfactorily elucidated but, in general, alterations in cardiac ion currents which tune the normal action potential play a major role in arrhythmogenesis. Following recent advances in molecular biology and genetics, it has become clear that in some clinical instances (e.g. congestive heart failure or cardiac hypertrophy) ion channel genes become less expressed (down-regulated) and the consequent reduced ion currents (e.g. IKr) are likely to cause prolonged myocardial repolarization. In this setting, the use of drugs with action potential-prolonging properties could possibly be harmful and could not be compensated by the normal cardiac ‘repolarization reserve’. In congenital LQT syndrome some of the same ion channel components were found to be genetically altered, suggesting that either quantitative or qualitative changes of ion currents may be involved in ventricular arrhythmogenesis through similar mechanisms (‘final common pathway’). A variable clinical expressivity and, especially, an incomplete penetrance has been found in patients carrying the same LQT genotype, even when near-relatives, which raises the question on the frequency and importance of ‘silent’ (i.e. minor functional) ion channel gene mutations that may become functionally significant in presence of action potential prolonging drugs and other coexisting factors. The observation of adverse drug reactions in apparently healthy (‘normal heart’) individuals is suggestive of a genetic susceptibility for ‘acquired’ arrhythmias. This report reviews and summarizes the recent knowledge on unapparent ion channel gene mutations and preliminary concepts about ‘acquired’ arrhythmias.

Inherited Brugada and Long QT-3 Syndrome Mutations of a Single Residue of the Cardiac Sodium Channel Confer Distinct Channel and Clinical Phenotypes

Defects of the SCN5A gene encoding the cardiac sodium channel alpha-subunit are associated with both the long QT-3 (LQT-3) subtype of long-QT syndrome and Brugada syndrome (BrS). One previously described SCN5A mutation (1795insD) in the C terminus results in a clinical phenotype combining QT prolongation and ST segment elevation, indicating a close interrelationship between the two disorders. Here we provide additional evidence that these two disorders are closely related. We report the analysis of two novel mutations on the same codon, Y1795C (LQT-3) and Y1795H (BrS), expressed in HEK 293 cells and characterized using whole-cell patch clamp procedures. We find marked and opposing effects on channel gating consistent with activity associated with the cellular basis of each clinical disorder. Y1795H speeds and Y1795C slows the onset of inactivation. The Y1795H, but not the Y1795C, mutation causes a marked negative shift in the voltage dependence of inactivation, and neither mutation affects the kinetics of the recovery from inactivation. Interestingly, both mutations increase the expression of sustained Na+ channel activity compared with wild type (WT) channels, although this effect is most pronounced for the Y1795C mutation, and both mutations promote entrance into an intermediate or a slowly developing inactivated state. These data confirm the key role of the C-terminal tail of the cardiac Na+ channel in the control of channel gating, illustrate how subtle changes in channel biophysics can have significant and distinct effects in human disease, and, additionally, provide further evidence of the close interrelationship between BrS and LQT-3 at the molecular level.

A novel long-QT 5 gene mutation in the C-terminus (V109I) is associated with a mild phenotype.

Mutations in the human minK gene KCNE1 have been linked to autosomal dominant and autosomal recessive long-QT (LQT) syndrome, a cardiac condition predisposing to ventricular arrhythmias. minK and KvLQT1, the LQT1 gene product, form a native cardiac K+ channel that regulates the slowly delayed rectifier potassium current I(Ks). We used single-strand conformation polymorphism and sequencing techniques to identify novel KCNE1 mutations in patients with a congenital LQT syndrome of unknown genetic origin. In 150 unrelated index patients a missense mutation (V109I) was identified that significantly reduced the wild-type I(Ks) current amplitude (by 36%) when coexpressed with KvLQT1 in Xenopus oocytes. Other biophysical properties of the I(Ks) channel were not altered. Since we observed incomplete penetrance (only one of two mutation carriers could be diagnosed by clinical criteria), and the family's history was unremarkable for sudden cardiac death, the 109I allele most likely causes a mild phenotype. This finding may have implications for the occurrence of "acquired" conditions for ventricular arrhythmias and thereby the potential cardiac risk for asymptomatic mutation carriers still remains to be determined.

Functional consequences of the arrhythmogenic G306R KvLQT1 K+ channel mutant probed by viral gene transfer in cardiomyocytes.

IKs, the slow component of the delayed rectifier potassium current, figures prominently in the repolarization of heart cells. The K+ channel gene KvLQT1 is mutated in the heritable long QT (LQT) syndrome. Heterologous coexpression of KvLQT1 and the accessory protein minK yields an IKs-like current. Nevertheless, the links between KvLQT1 and cardiac IKs are largely inferential. Since the LQT syndrome mutant KvLQT1-G306R suppresses channel activity when coexpressed with wild-type KvLQT1 in a heterologous system, overexpression of this mutant in cardiomyocytes should reduce or eliminate native IKs if KvLQT1 is indeed the major molecular component of this current. To test this idea, we created the adenovirus AdRMGI-KvLQT1-G306R, which overexpresses KvLQT1-G306R channels. In > 60 % of neonatal mouse myocytes, a sizable IKs could be measured using perforated-patch recordings (8.0 +/- 1.6 pA pF-1, n = 13). IKs was increased by forskolin and blocked by clofilium or indapamide but not by E-4031. While cells infected with a reporter virus expressing only green fluorescent protein (GFP) displayed IKs similar to that in uninfected cells, AdRMGI-KvLQT1-G306R-infected cells showed a significantly reduced IKs (2.4 +/- 1.1 pA pF-1, n = 10, P < 0.01) when measured 60-72 h after infection. Similar results were observed in adult guinea-pig myocytes (5.9 +/- 1.2 pA pF-1, n = 9, for control vs. 0.1 +/- 0.1 pA pF-1, n = 5, for AdRMGI-KvLQT1-G306R-infected cells). We conclude that KvLQT1 is the major molecular component of IKs. Our results further establish a dominant-negative mechanism for the G306R LQT syndrome mutation.

IKr: The hERG Channel

G.-N. Tseng. IKr: The hERG Channel. Journal of Molecular and Cellular Cardiology (2001) 33, 835–849. The rapid delayed rectifier (IKr) channel is important for cardiac action potential repolarization. Suppressing IKrfunction, due to either genetic defects in its pore-forming subunit (hERG) or adverse drug effects, can lead to long-QT (LQT) syndrome that carries increased risk of life-threatening arrhythmias. The implication of IKrin cardiac arrhythmias and in anti-arrhythmic/pro-arrhythmic actions of drugs has driven intensive research interests in its structure–function relationship, the linkage between LQT-associated mutations and changes in channel function, and the mechanism of drug actions. This review will cover the following topics: (1) heterogeneous contribution of IKrto action potential repolarization in the heart, (2) structure–function relationship of IKr/hERG channels, (3) role of regulatory β subunits in IKr/hERG channel function, (4) structural basis for the unique pharmacological properties of IKr/hERG channels, and (5) IKr/hERG channel modulation by changes in cellular milieu under physiological and pathological conditions of the heart. It is anticipated that further advances in our understanding of IKr/hERG, particularly in the areas of roles of different (α and β) subunits in native IKrfunction, alterations in IKrfunction in diseased hearts, and the 3-dimensional structure of the IKr/hERG pore based on homology modeling using the KcsA model, will help us better define the role of IKrin arrhythmias and design therapeutic agents that can increase IKrand are useful for LQT syndrome.

Molecular biology and the prolonged QT syndromes

The prolonged QT syndromes are characterized by prolongation of the QT interval corrected for heart rate (QTc) on the surface electrocardiogram associated with T-wave abnormalities, relative bradycardia, and ventricular tachyarrhythmias, including polymorphic ventricular tachycardia and torsades de pointes. These patients tend to present with episodes of syncope, seizures, or sudden death typically triggered by exercise, emotion, noise, or, in some cases, sleep. These disorders of cardiac repolarization are commonly inherited, with the autosomal dominant form, Romano-Ward syndrome, most common. A rare autosomal recessive form associated with sensorineural deafness, Jervell and Lange-Nielsen syndrome, in which the cardiac disorder is autosomal dominant and deafness is a recessive trait, also occurs. The underlying genetic causes of these forms of prolonged QT interval syndromes are heterogeneous, with at least seven genes responsible for the clinical syndromes. All of the five genes identified to date encode ion channel proteins, suggesting this to be an ion channelopathy. In this review, the genetic basis of the prolonged QT interval syndromes will be discussed, genotype-phenotype correlations identified, and the approaches to genetic testing and treatments will be outlined.

ECG Patterns Identify Genotypes in Patients with Long-QT Syndrome

Congenital long-QT syndrome (LQTS) is caused by mutations of genes that encode various cardiac potassium and sodium channels; 5 genes have been

Correlation of genetic etiology with response to beta-adrenergic blockade among symptomatic patients with familial long-QT syndrome.

Mutations in any of the five genes KCNQ1, KCNH2, KCNE1, KCNE2, and SCN5A can be responsible for familial long QT syndrome (LQTS), an arrhythmogenic disorder that entails a high risk of sudden death. beta-Adrenergic blocking agents are the first therapeutic choice, and 80% of patients treated with these agents show symptomatic relief; however the remaining 20% do not respond well. We previously performed a nationwide analysis of familial long QT syndrome (LQTS) in Japan and identified 32 mutations in the KCNQ1 and KCNH2 genes. In the present retrospective study, we found that patients carrying mutations in the KCNQ1 gene responded better to beta-adrenergic blocking agents than those with KCNH2 mutations (12 of 13 vs 1 of 5; P = 0.0077, Fisher's exact test). This is a good example of the power of genetic diagnosis to direct the selection of appropriate therapy for patients with diseases of heterogeneous genetic etiology.

Etiology and management of sustained ventricular tachycardia.

Ventricular tachyarrhythmias secondary to a variety of underlying cardiovascular problems pose a therapeutic challenge to the clinician. The initial presentation may be as sudden cardiac death, which underlies its public health problem. The underlying conditions predisposing to this arrhythmia include ischemic heart disease, dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmiogenic right ventricle dysplasia and certain postoperative states including corrective surgery for tetralogy of Fallot and valve replacement. Other causes include prolonged QT syndrome, idiopathic right and left ventricle tachycardia and bundle branch re-entry tachycardia. Ischaemic heart disease is the most common cause of ventricular tachycardia and therapy has evolved considerably over the past two decades. The development of and refinements in the implantable cardioverter-defibrillator (ICD) have introduced a new dimension in therapeutic options and markedly improved survival in these patients. Insights in the dichotomy between arrhythmia suppression and total mortality have reoriented drug therapy with a decrease in the use of sodium channel blockers. beta-blockers have emerged as antiarrhythmic drugs in their own right and their synergistic effects with amiodarone have strengthened the antiarrhythmic drug arm. The role of these drugs in patients with hemodynamically stable ventricular tachycardia, especially in relatively preserved ventricles needs to be explored. Catheter ablation techniques have provided curative therapy in patients with idiopathic and bundle branch reentry tachycardia. Further advances in radiofrequency ablation, including use of newer mapping techniques, promise a greater role for ablation of ischemic ventricular tachycardia in the future. A hybrid approach consisting of drugs, catheter ablation and/ or ICD may provide effective therapeutic approach in some situations. Further innovations and technologic developments promise a further reorientation in therapy towards identification and treatment of the underlying arrhythmogenic substrate.

The Child Who Passes Out

1. Hassib Narchi, MD* 1. 2. *Pediatric Department, Sandwell General Hospital, West Bromwich, United Kingdom. After completing this article, readers should be able to: 1. Distinguish among seizures; breath-holding or pallid spells; vasovagal syncope; cardiac, neuropsychiatric, and sleep disturbances; tics; syncope; and gastroesophageal reflux. 2. Describe the etiologies for breath-holding spells. 3. Recognize prolonged QT syndrome in a patient who has syncope. 4. Delineate the importance of cardiovascular evaluation in patients who have syncopal or presyncopal episodes with exercise. 5. Plan the evaluation of a child who has recurrent unexplained syncope. 6. Design a therapeutic program for the management of breath-holding spells. A previously well 2-year-old boy who had an uneventful neonatal period; normal growth parameters and developmental milestones; and a negative family history for seizures, syncope, or sudden death was referred for evaluation of episodes of loss of consciousness that were stereotypic and occurred twice weekly over the previous 6 months. He developed unexpected episodes of sudden pallor after a minor trauma, followed by a fall, loss of consciousness, turning of the eyes, opisthotonos, and clonic movements for 30 seconds. He recovered normal consciousness and activity over the next few minutes before drifting to sleep. There was no cyanosis or sweating, and the episodes were not related to exercise or fasting. Results of a complete physical examination, including growth parameters, vital signs, and neurologic examination, were normal. Results of a tilt table test were normal, electrocardiography (ECG) showed a sinus rhythm, the corrected QTc interval was 0.40 seconds, and electroencephalographic (EEG) findings were normal. An EEG with an ocular compression test revealed bradycardia with a brief reversible asystole of 4 seconds, which recovered spontaneously, confirming the diagnosis of pallid spells or reflex anoxic seizures. Syncope or fainting, defined as a sudden and usually brief loss of consciousness and postural tone, is caused by a transient decrease in cerebral blood flow. Presyncope is the feeling that one is “about to pass …

Analysis of the human KCNH2(HERG) gene: identification and characterization of a novel mutation Y667X associated with long QT syndrome and a non-pathological 9 bp insertion.

Long QT (LQT) syndrome is a potentially life-threatening disorder, characterized by a distinct cardiac arrhythmia known as torsades de pointes. Mutations within a number of genes linked to the familial form, including that coding for a cardiac potassium channel called KCNH2 (HERG), have been described based on the characterized genomic organization. A standardized method was developed to screen the entire gene for gene variants. We report a single base pair substitution, introducing a premature STOP codon at codon 667 of the gene in a healthy individual with an extended QTc interval (460 msec). In vitro expression of the codon Y667X variant in Xenopus oocyte suggests that the autosomal dominant variant does not function in a dominant/negative manner and cannot co-assemble to form a channel, resulting in a reduction of the KCNH2 current, and an extension of the QT interval. This indicates that pathogenic LQT gene variants exist in the apparently normal population, the prognosis and clinical consequences of which remain to be determined. The assays described should facilitate future studies into this area.