Mutations in the genes KCND2 and KCND3 encoding the ion channels Kv4.2 and Kv4.3, conducting the cardiac fast transient outward current (ITO,f), are not a frequent cause of long QT syndrome

BACKGROUND: Long QT syndrome (LQTS) is a hereditary cardiac arrhythmogenic disorder characterized by prolongation of the QT interval in the electrocardiogram, torsades de pointes arrhythmia, and syncopes and sudden death. LQTS is caused by mutations in ion channel genes. However, only in half of the families is it possible to identify mutations in one of the seven known LQTS genes, why further genetic heterogeneity is expected. The genes KCND2 and KCND3, encoding the alpha-subunits of the voltage-gated potassium channels Kv4.2 and Kv4.3 conducting the fast transient outward current (I(TO,f)) of the cardiac action potential (AP) in the myocardium, have been associated with prolongation of AP duration and QT prolongation in murine models. METHODS: KCND2 and KCND3 were examined for mutations using single-strand conformation polymorphism (SSCP) analysis in 43 unrelated LQTS patients, where mutations in the coding regions of known LQTS genes had been excluded. RESULTS: Seven single nucleotide polymorphismsm (SNPs) were found, two exonic SNPs in KCND2 and three exonic and two intronic in KCND3. None of the five exonic SNPs had coding effect. All seven SNPs are considered normal variants. CONCLUSION: The data suggest that mutations in KCND2 and KCND3 are not a frequent cause of long QT syndrome.     

Genotype-specific clinical manifestation in long QT syndrome

The congenital form of long QT syndrome (LQTS) is characterized by QT prolongation in the electrocardiogram (ECG) and a polymorphic ventricular tachycardia, Torsade de Pointes (TdP) mainly as a result of an increased sympathetic tone during exercise or mental stress. Recent genetic studies have so far identified seven forms of congenital LQTS caused by mutations in genes of the potassium and sodium channels or membrane adapter located on chromosomes 3, 4, 7, 11, 17 and 21. It is of particular importance to examine the genotype-phenotype correlation, especially in the LQT1, LQT2 and LQT3 forms of LQTS, which make up more than 90% of genotyped patients with LQTS, because it would enable us to manage and treat genotyped patients more effectively.     

Genotype-specific clinical manifestation in long QT syndrome

The congenital form of long QT syndrome (LQTS) is characterized by QT prolongation in the electrocardiogram (ECG) and a polymorphic ventricular tachycardia, Torsade de Pointes (TdP) mainly as a result of an increased sympathetic tone during exercise or mental stress. Recent genetic studies have so far identified seven forms of congenital LQTS caused by mutations in genes of the potassium and sodium channels or membrane adapter located on chromosomes 3, 4, 7, 11, 17 and 21. It is of particular importance to examine the genotype–phenotype correlation, especially in the LQT1, LQT2 and LQT3 forms of LQTS, which make up more than 90% of genotyped patients with LQTS, because it would enable us to manage and treat genotyped patients more effectively.     

Depressive symptoms in the congenital long QT syndrome

Background. A proportion of patients with congenital long QT syndrome (LQTS) experience potentially life-threatening cardiac arrhythmias.

Aim. To examine whether depressive symptoms are related to arrhythmic events among symptomatic and asymptomatic LQTS patients, and syncope events among their relatives not carrying the family's LQTS-causing mutation.

Methods. The participants were 569 molecularly defined LQTS mutation carriers and 622 non-carrier relatives from the Finnish LQTS registry. Depressive symptoms were self-rated with a revised version of the Beck Depression Inventory.

Results. LQTS patients with arrhythmic events scored higher on depressive symptoms than those without (P=0.011) or the control group (P=0.005). In addition, in the binary logistic regression analysis including symptomatic and asymptomatic LQTS mutation carriers, depressive symptoms showed an age- and sex-adjusted association of odds ratio (OR) 1.40 (95% confidence interval (CI) 1.12–1.74) with symptomatic status of LQTS. In similar analysis including non-carriers of the LQTS mutation, there was no association between depressive symptoms and history of syncope events OR 1.23 (95% CI 0.99–1.53).

Conclusion. Our results from this relatively large genotyped LQTS patient cohort indicate that depressive symptoms are associated with arrhythmic events in LQTS patients. Whether depressive symptoms are causally related to arrhythmias in LQTS remains uncertain.     

Clinical Value of Electrocardiographic Parameters in Genotyped Individuals with Familial Long QT Syndrome

MOENNIG, G., et al. : Clinical Value of Electrocardiographic Parameters in Genotyped Individuals with Familial Long QT Syndrome. Rate corrected QT interval (QTc) and QT dispersion (QTd) have been suggested as markers of an increased propensity to arrhythmic events and efficacy of therapy in patients with long QT syndrome (LQTS). To evaluate whether QTc and QTd correlate to genetic status and clinical symptoms in LQTS patients and their relatives, ECGs of 116 genotyped individuals were analyzed. JTc and QTc were longest in symptomatic patients (  n = 28  ). Both QTd and JTd were significantly higher in symptomatic patients than in asymptomatic (  n = 29  ) or unaffected family members (  n = 59  ). The product of QTd/JTd and QTc/JTc was significantly different among all three groups. Both dispersion and product put additional and independent power on identification of mutation carriers when adjusted for sex and age in a logistic regression analysis. Thus, symptomatic patients with LQTS show marked inhomogenity of repolarization in the surface ECG. QT dispersion and QT product might be helpful in finding LQTS mutation carriers and might serve as additional ECG tools to identify asymptomatic LQTS patients.     

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.     

The variation of the sarcolipin gene (SLN) in atrial fibrillation, long QT syndrome and sudden arrhythmic death syndrome

BACKGROUND: Mutations in genes responsible for the cardiac action potential and control of intracellular Ca(2+)-distribution are associated with cardiac arrhythmia and sudden death. Sarcolipin is a 31-amino acid protein that inhibits the sarcoplasmic reticulum Ca(2+) ATPase pump (SERCA2). The sarcolipin gene, SLN, is expressed in the heart and a candidate gene for cardiomyopathy as well as atrial fibrillation (AF), long QT syndrome (LQTS) or sudden arrhythmic death syndrome (SADS). We examined the genetic variation of SLN in patients with the arrhythmic disorders AF, LQTS and SADS. METHODS: We screened the coding region of SLN for mutations using single strand conformation polymorphism/heteroduplex analysis on PCR-amplified genomic DNA from 95 unrelated LQTS patients, 59 SADS cases and 147 patients with atrial fibrillation (AF) and 92 controls. Aberrant conformers were sequenced. RESULTS: No mutations or polymorphisms were found in the coding sequence. A G>C transition in the highly conserved position +1 of the 3'untranslated region (3'UTR) was found in two SADS cases. A polymorphism, a G>C transition at position -65 in the 5'untranslated region (5'UTR), was found with a G allele frequency of 0.48. A borderline significant difference in genotype distribution of the latter polymorphism was found between the AF group and controls. CONCLUSION: Mutations in the coding region of SLN are not frequently involved in LQTS, SADS or AF. Whether the described 3'- and 5'UTR variants have functional significance must await further studies.     

Compound heterozygosity for mutations Asp611-->Tyr in KCNQ1 and Asp609-->Gly in KCNH2 associated with severe long QT syndrome

LQTS (long QT syndrome) is an inherited cardiac disorder characterized by prolongation of QT interval, torsades de pointes and sudden death. We have identified two heterozygous missense mutations in the KCNQ1 and KCNH2 (also known as HERG) genes [Asp611-->Tyr (D611Y) in KCNQ1 and Asp609-->Gly (D609G) in KCNH2] in a 2-year-old boy with LQTS. The aim of the present study was to characterize the contributions of the mutations in the KCNQ1 and KCNH2 genes relative to the clinical manifestations and electrophysiological properties of LQTS. Six of 11 carriers of D611Y in KCNQ1 had long QT intervals. D609G in KCNH2 was detected only in the proband. Studies on the electrophysiological alterations due to the two missense mutations revealed that the D611Y mutation in KCNQ1 did not show a significant suppression of the currents compared with wild-type, but the time constants of current activation in the mutants were increased compared with that in the wild-type. In contrast, the D609G mutation in KCNH2 showed a dominant-negative suppression. Our results suggest that the mild phenotype produced by the D611Y mutation in KCNQ1 became more serious by addition of the D609G mutation in KCNH2 in the proband.     

Swimming, a gene-specific arrhythmogenic trigger for inherited long QT syndrome

OBJECTIVE: To determine the genetic basis for long QT syndrome (LQTS) in a cohort of patients with a personal history or an extended family history of a swimming-triggered cardiac event. PATIENTS AND METHODS: After review of the Mayo Clinic unit medical record system, blood samples or archived autopsy tissue samples were obtained from a retrospective cohort of 35 cases diagnosed as having autosomal dominant LQTS. Exon-specific amplification by polymerase chain reaction and direct sequence analyses were performed on the entire KVLQT1 gene. RESULTS: Six cases had a personal history or an extended family history of a near drowning or drowning. In all 6 cases, LQTS-causing mutations in KVLQT1 gene were identified: 3 deletion mutations, 2 donor splice site mutations, and 1 missense mutation. One of the mutations, a novel donor splicing defect, was determined by postmortem molecular analysis of a paraffin-embedded tissue block from a 12-year-old girl who died in 1976. Distinct KVLQT1 mutations were demonstrated in 3 of the remaining 29 cases. The overall frequency of KVLQT1 defects in LQTS was 100% (6/6) in those with and 10% (3/29) in those without a personal history or an extended family history of drowning or near drowning (P<.001). CONCLUSION: Swimming appears to be a gene-specific (KVLQT1) arrhythmogenic trigger for LQTS. This study provides proof of principle that an unexplained drowning or near drowning may have a genetic basis.     

Congenital long QT syndrome: considerations for primary care physicians

Congenital long QT syndrome is an inherited disorder of cardiac repolarization that predisposes to syncope and to sudden death from polymorphic ventricular tachycardia. The disorder should be suspected when the electrocardiogram shows characteristic QT abnormalities, or when there is a family history of long QT syndrome or of an event that raises suspicion of long QT syndrome, such as sudden death, syncope, or ill-defined "seizure" disorder. We can now classify some types of congenital long QT syndrome according to their genetic mutations and their triggers, such as exercise, rest, or startle.     

Recent developments in the management of patients at risk for sudden cardiac death

Sudden cardiac death (SCD) due to ventricular tachyarrhythmias is an important cause of mortality in the United States, 4% of which occurs in patients with structurally normal hearts. At least some arrhythmias are caused by ≥ 1 mutation in 1 of the genes that control electrical conduction through the heart by altering calcium homeostasis or depolarization or repolarization gradients in the ventricle. Although SCD may be the first presentation, patients may often present with symptoms of palpitations or hemodynamic compromise, such as dizziness, seizure, or syncope, particularly following exertion. They may also be made aware of possibly having the condition due to symptoms in other family members. The primary care physician is ideally placed to investigate these symptoms, including detailed clinical and family histories and examining the baseline electrocardiogram. In all inherited cardiac death syndromes, first-degree relatives should be referred to a cardiologist, and should undergo testing appropriate for the condition. While management of patients at risk of SCD largely centers on risk stratification and, if necessary, insertion of an implantable cardioverter-defibrillator, there are a number of other treatments being developed. β-Blockers are often very effective in preventing arrhythmic episodes associated with catecholaminergic polymorphic ventricular tachycardia and some subtypes of long QT syndrome. In certain situations, calcium channel blockers may also be used. Quinidine and isoproterenol can be useful in treating Brugada syndrome. Left cervicothoracic stellectomy may occasionally be used in the treatment of long QT syndrome. As the genetic basis of these diseases becomes known, genetic testing is forming an increasingly important part of diagnosis, and gene-specific therapy is an area under investigation.     

The Abuse of Rest as a Therapeutic Agent

Abstract

Sudden cardiac death (SCD) due to ventricular tachyarrhythmias is an important cause of mortality in the United States, 4% of which occurs in patients with structurally normal hearts. At least some arrhythmias are caused by ≥ 1 mutation in 1 of the genes that control electrical conduction through the heart by altering calcium homeostasis or depolarization or repolarization gradients in the ventricle. Although SCD may be the first presentation, patients may often present with symptoms of palpitations or hemodynamic compromise, such as dizziness, seizure, or syncope, particularly following exertion. They may also be made aware of possibly having the condition due to symptoms in other family members. The primary care physician is ideally placed to investigate these symptoms, including detailed clinical and family histories and examining the baseline electrocardiogram. In all inherited cardiac death syndromes, first-degree relatives should be referred to a cardiologist, and should undergo testing appropriate for the condition. While management of patients at risk of SCD largely centers on risk stratification and, if necessary, insertion of an implantable cardioverter-defibrillator, there are a number of other treatments being developed. β-Blockers are often very effective in preventing arrhythmic episodes associated with catecholaminergic polymorphic ventricular tachycardia and some subtypes of long QT syndrome. In certain situations, calcium channel blockers may also be used. Quinidine and isoproterenol can be useful in treating Brugada syndrome. Left cervicothoracic stellectomy may occasionally be used in the treatment of long QT syndrome. As the genetic basis of these diseases becomes known, genetic testing is forming an increasingly important part of diagnosis, and gene-specific therapy is an area under investigation.     

A single strand conformation polymorphism/heteroduplex (SSCP/HD) method for detection of mutations in 15 exons of the KVLQT1 gene, associated with long QT syndrome

Congenital long QT syndrome (LQTS) is characterised by prolongation of the QT interval on ECG and cardiac arrhythmias, syncopes and sudden death. A rapid and reliable genetic diagnosis of the disease may be of great importance for diagnosis and treatment of LQTS. Mutations in the KVLQT1 gene, encoding a potassium-channel subunit of importance for the depolarisation of cardiac myocytes, is believed to be associated with 50% of all LQTS cases. Our data confirms that KvLQT1 isoform 1 is encoded by 16 exons, and not 15, as reported previously. We have used genomic DNA sequences to design intronic PCR primers for amplification of 15 exons of KVLQT1 and optimised a non-radioactive single stranded conformation polymorphism/heteroduplex (SSCP/HD) method for detection of mutations in KVLQT1. The sensitivity of the method was 100% when it was tested on 15 in vitro constructed mutants. By multiplexing the PCR amplification of KVLQT1, it is possible to cover all 15 exons in four PCR reactions.     

Molecular characterization of two founder mutations causing long QT syndrome and identification of compound heterozygous patients

BACKGROUND: Mutations of at least six different genes have been found to cause long QT syndrome (LQTS), an inherited arrhythmic disorder characterized by a prolonged QT interval on the electrocardiogram (ECG), ventricular arrhythmias and risk of sudden death. AIM: The aims were to define the yet undetermined phenotypic characteristics of two founder mutations and to study clinical features in compound heterozygotes identified during the course of the study. METHODS: To maximize identification of the compound heterozygotes, we used an extended group of LQTS patients comprising 700 documented or suspected cases. Functional studies were carried out upon transient expression in COS-7 or HEK293 cells. RESULTS: The KCNQ1 IVS7-2A>G (KCNQ1-FinB) mutation associated with a mean QTc interval of 464 ms and a complete loss-of-channel function. The HERG R176W (HERG-FinB) mutation caused a reduction in current density as well as slight acceleration of the deactivation kinetics in vitro, and its carriers had a mean QTc of 448 ms. The HERG R176W mutation was also present in 3 (0.9%) out of 317 blood donors. A total of six compound heterozygotes were identified who had the HERG R176W mutation in combination with a previously reported LQTS mutation (KCNQ1 G589D or IVS7-2A>G). When present simultaneously with an apparent LQTS-causing mutation, the HERG R176W mutation may exert an additional in vivo phenotypic effect. CONCLUSIONS: The HERG R176W mutation represents a population-prevalent mutation predisposing to LQTS. Compound heterozygosity for mutant LQTS genes may modify the clinical picture in LQTS.     

Catecholamine-induced T-wave lability in congenital long QT syndrome: a novel phenomenon associated with syncope and cardiac arrest

OBJECTIVE: To determine the effects of phenylephrine and dobutamine on repolarization lability in patients with genotyped long QT syndrome (LQTS). PATIENTS AND METHODS: Between December 1998 and August 2000, 23 patients with genotyped LQTS (13 LQT1, 7 LQT2, and 3 LQT3) and 16 controls underwent electrocardiographic stress testing at the Mayo Clinic in Rochester, Minn. Aperiodic repolarization lability was quantified from digitized electrocardiograms recorded during catecholamine stress testing with phenylephrine and dobutamine. T-wave lability was quantified as a root-mean-square of the differences between corresponding signal values of subsequent beats. The magnitude of aperiodic T-wave lability was quantified by using a newly derived T-wave lability index (TWLI). RESULTS: The TWLI was significantly greater in patients with LQTS than in controls (0.0945 +/- 0.0517 vs 0.0445 +/- 0.0123; P < .003). Marked T-wave lability (TWLI > or = 0.095) was detected in all 3 LQTS genotypes (10/23) but in no controls (P < .003). There was no correlation between the TWLI and the baseline corrected QT interval. All high-risk patients having either a history of out-of-hospital cardiac arrest or syncope had a TWLI of 0.095 or greater. CONCLUSIONS: Beat-to-beat nonalternating T-wave lability occurs in LQT1, LQT2, and LQT3 patients during catecholamine provocation and is associated with a history of prior cardiac events. The quantification of this novel phenomenon may assist in identifying LQTS patients with increased risk of sudden cardiac death.     

The genetic basis for cardiac dysrhythmias and the long QT syndrome.

Cardiac muscle excitation is the result of ion fluxes through cellular membrane channels. Any alterations in channel proteins that produce abnormal ionic fluxes will change the cardiac action potential and the pattern of electrical firing within the heart. The idiopathic long QT syndrome (LQTS) is an inherited cardiac pathology localized to mutated genes encoding for myocardial, voltage-activated sodium and potassium ion channels. The expression of abnormal sodium and potassium channels results in aberrant ionic fluxes that produce a prolonged ventricular repolarization. This prolonged time to repolarization is the electrophysiologic basis for prolongation of the QT interval. Individuals with LQTS are at significant risk for developing lethal ventricular dysrhythmias due to an abnormal pattern of cardiac excitation. Identification of a genetic basis for LQTS has had significant implications for genetic counseling, the development of effective antidysrhythmic drug therapies, and nursing interventions.     

QT Interval Variability and Adaptation to Heart Rate Changes in Patients with Long QT Syndrome

Background: Increased QT variability (QTV) has been reported in conditions associated with ventricular arrhythmias. Data on QTV in patients with congenital long QT syndrome (LQTS) are limited.
Methods: Ambulatory electrocardiogram recordings were analyzed in 23 genotyped LQTS patients and in 16 healthy subjects (C). Short-term QTV was compared between C and LQTS. The dependence of QT duration on heart rate was evaluated with three different linear models, based either on the RR interval preceding the QT interval (RR₀), the RR interval preceding RR₀ (RR_-1), or the average RR interval in the 60-second period before QT interval (mRR).
Results: Short-term QTV was significantly higher in LQTS than in C subjects (14.94 ± 9.33 vs 7.31 ± 1.29 ms; P < 0.001). It was also higher in the non-LQT1 than in LQT1 patients (23.00 ± 9.05 vs 8.74 ± 1.56 ms; P < 0.001) and correlated positively with QTc in LQTS (r = 0.623, P < 0.002). In the C subjects, the linear model based on mRR predicted QT duration significantly better than models based on RR₀ and RR_-1. It also provided better fit than any nonlinear model based on RR₀. This was also true for LQT1 patients. For non-LQT1 patients, all models provided poor prediction of QT interval.
Conclusions: QTV is elevated in LQTS patients and is correlated with QTc in LQTS. Significant differences with respect to QTV exist among different genotypes. QT interval duration is strongly affected by noninstantaneous heart rate in both C and LQT1 subjects. These findings could improve formulas for QT interval correction and provide insight on cellular mechanisms of QT adaptation.     

Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome

Long QT syndrome (LQTS) is a heritable disease associated with ECG QT interval prolongation, ventricular tachycardia, and sudden cardiac death in young patients. Among genotyped individuals, mutations in genes encoding repolarizing K+ channels (LQT1:KCNQ1; LQT2:KCNH2) are present in approximately 90% of affected individuals. Expression of pore mutants of the human genes KCNQ1 (KvLQT1-Y315S) and KCNH2 (HERG-G628S) in the rabbit heart produced transgenic rabbits with a long QT phenotype. Prolongations of QT intervals and action potential durations were due to the elimination of IKs and IKr currents in cardiomyocytes. LQT2 rabbits showed a high incidence of spontaneous sudden cardiac death (>50% at 1 year) due to polymorphic ventricular tachycardia. Optical mapping revealed increased spatial dispersion of repolarization underlying the arrhythmias. Both transgenes caused downregulation of the remaining complementary IKr and IKs without affecting the steady state levels of the native polypeptides. Thus, the elimination of 1 repolarizing current was associated with downregulation of the reciprocal repolarizing current rather than with the compensatory upregulation observed previously in LQTS mouse models. This suggests that mutant KvLQT1 and HERG interacted with the reciprocal wild-type alpha subunits of rabbit ERG and KvLQT1, respectively. These results have implications for understanding the nature and heterogeneity of cardiac arrhythmias and sudden cardiac death.     

Molecular genetic analysis of long QT syndrome in Norway indicating a high prevalence of heterozygous mutation carriers

Mutations in the KCNQ1, HERG, SCN5A, minK and MiRP1 genes cause long QT syndrome (LQTS), of which there are two forms: the Romano Ward syndrome and the Jervell and Lange-Nielsen syndrome. We have performed DNA sequencing of the LQTS-associated genes in 169 unrelated patients referred for genetic testing with respect to Romano Ward syndrome and in 13 unrelated patients referred for genetic testing with respect to Jervell and Lange-Nielsen syndrome. A total of 37 different mutations in the 5 genes, of which 20 were novel, were identified. Among patients with the most stringent clinical criteria of Romano Ward syndrome, a mutation was identified in 71%. Twelve of the 13 unrelated patients referred for genetic testing with respect to Jervell and Lange-Nielsen syndrome were provided with a molecular genetic diagnosis. Cascade genetic screening of 505 relatives of index patients with molecularly defined LQTS identified 251 mutation carriers. The observed penetrance was 41%. Although caution must be exerted, the prevalence of heterozygotes for mutations in the LQTS-associated genes in Norway could be in the range 1/100-1/300, based on the prevalence of patients with Jervell and Lange-Nielsen syndrome.