The long QT syndrome: a prospective international study. Moss A J,Schwartz P J,Crampton R S,Locati E,Carleen E Circulation During the past 4 years 196 patients with the idiopathic long QT syndrome were enrolled in a prospective international study conducted to obtain a better understanding of the clinical course of this unusual repolarization disorder. The mean patient age was 24 years, 64% were female, and 88% had family members with QT prolongation. During an average follow-up of 26 months per patient, four patients died suddenly (1.3% per year) and 27 patients had one or more syncopal episodes (8.6% per year). Multivariate analysis identified congenital deafness, history of syncope, female gender, and a documented episode of torsades de pointes or ventricular fibrillation as independent risk factors for postenrollment syncope or sudden death. Two types of treatment (left stellate ganglionectomy and beta-blocker therapy) were associated with a significant reduction in the occurrence of cardiac events during follow-up. 10.1161/01.cir.71.1.17
    The automatic implantable cardioverter-defibrillator in young patients. Kron J,Oliver R P,Norsted S,Silka M J Journal of the American College of Cardiology An international survey identified 40 patients less than 20 years old who underwent surgical implantation of an automatic implantable cardioverter-defibrillator (AICD). There was a history of aborted sudden cardiac death or sustained ventricular tachycardia in 92.5% of these patients. Twenty-two patients (55%) had structural heart disease; dilated and hypertrophic cardiomyopathy were the most common diagnoses. Eighteen patients (45%) had primary electrical abnormalities including seven with the congenital long QT syndrome. There were no perioperative deaths associated with device implantation. Concomitant drug therapy was administered to 75% of the patients. Defibrillator discharge occurred in 70% of the patients, with 17 patients (42.5%) receiving at least one appropriate shock. There were two sudden and two nonsudden deaths at 28.2 months' median follow-up. Sudden death-free survival rates by life table analysis at 12 and 33 months were 0.94 and 0.88, respectively. Total survival rates at 12 and 33 months were 0.94 and 0.82, respectively. The AICD represents an effective treatment approach for young patients with life-threatening ventricular tachyarrhythmias. 10.1016/s0735-1097(10)80338-9
    Left cardiac sympathetic denervation in the therapy of congenital long QT syndrome. A worldwide report. Schwartz P J,Locati E H,Moss A J,Crampton R S,Trazzi R,Ruberti U Circulation BACKGROUND:Long QT syndrome (LQTS) is a congenital disorder accompanied by a high incidence of sudden cardiac death. beta-Adrenergic blockade is the therapy of choice, and it is successful in 75-80% of patients. For those in whom cardiac events (syncope or cardiac arrest) are not prevented by beta-blockade, experimental studies suggest that left cardiac sympathetic denervation (LCSD) may be useful. METHODS AND RESULTS:We identified 85 LQTS patients worldwide who underwent LCSD, and we provide here the first large-scale evaluation of its efficacy. The time interval between the first cardiac event and LCSD and the follow-up period after LCSD were similar (5.6 +/- 6.1 versus 5.9 +/- 5.7 years). The mean age of the patients at surgery was 20 +/- 13 years. LCSD was followed by highly significant (p less than 0.0001) decreases in the number of patients with cardiac events (from 99% to 45%), in the number of cardiac events per patient (from 22 +/- 32 to 1 +/- 3), and in the number of patients with five or more cardiac events (from 71% to 10%). There were seven sudden deaths (8%), and the 5-year survival rate was 94%. The marked reduction in the incidence of tachyarrhythmic syncope suggests that LCSD has also reduced the risk for sudden death in this high-risk population. CONCLUSIONS:The present findings demonstrate that for LQTS patients who continue with syncope or cardiac arrest despite the use of beta-blockers, LCSD is a very effective therapy. 10.1161/01.cir.84.2.503
    The long QT syndrome. Prospective longitudinal study of 328 families. Moss A J,Schwartz P J,Crampton R S,Tzivoni D,Locati E H,MacCluer J,Hall W J,Weitkamp L,Vincent G M,Garson A Circulation BACKGROUND:The Long QT Syndrome (LQTS) is an infrequently occurring familial disorder in which affected individuals have electrocardiographic QT interval prolongation and a propensity to ventricular tachyarrhythmic syncope and sudden death. We prospectively investigated the clinical characteristics and the long-term course of 3,343 individuals from 328 families in which one or more members were identified as affected with LQTS (QTc greater than 0.44 sec1/2). METHODS AND RESULTS:The first member of a family to be identified with LQTS, the proband, was usually brought to medical attention because of a syncopal episode during childhood or teenage years. Probands (n = 328) were younger at first contact (age 21 +/- 15 years), more likely to be female (69%), and had a higher frequency of preenrollment syncope or cardiac arrest with resuscitation (80%), congenital deafness (7%), a resting heart rate less than 60 beats/min (31%), QTc greater than or equal to 0.50 sec1/2 (52%), and a history of ventricular tachyarrhythmia (47%) than other affected (n = 688) and unaffected (n = 1,004) family members. Arrhythmogenic syncope often occurred in association with acute physical, emotional, or auditory arousal. The syncopal episodes were frequently misinterpreted as a seizure disorder. By age 12 years, 50% of the probands had experienced at least one syncopal episode or death. The rates of postenrollment syncope (one or more episodes) and probable LQTS-related death (before age 50 years) for probands (n = 235; average follow-up 54 months per patient) were 5.0% per year and 0.9% per year, respectively; these event rates were considerably higher than those observed among affected and unaffected family members. CONCLUSIONS:Among 232 probands and 1,264 family members with prospective follow-up, three factors made significant independent contributions to the risk of subsequent syncope or probable LQTS-related death before age 50 years, whichever occurred first (Cox hazard ratio; 95% confidence limits): 1) QTc (1.052; 1.017, 1.088), 2) history of cardiac event (3.1; 1.3, 7.2), and 3) heart rate (1.017; 1.004, 1.031). The findings from this prospective longitudinal study highlight the clinical features, risk factors, and course of LQTS. 10.1161/01.cir.84.3.1136
    The congenital long QT syndromes in childhood. Weintraub R G,Gow R M,Wilkinson J L Journal of the American College of Cardiology Twenty-three children and young persons with a congenital long QT syndrome were identified; the median age at the time of referral was 10 years (range 4 days to 19 years) and 14 patients (61%) had a family history of the syndrome. Among the 19 patients with symptoms, the initial symptom was syncope in 13 (69%), aborted sudden death in 5 (26%) and near drowning in 1 (5%). There were three deaths during a combined follow-up period of 67 patient-years (average annual mortality rate 4.5%). Patients who did not respond to therapy with a beta-adrenergic blocker and those who died were significantly younger than the remaining patients at the time of diagnosis (p less than or equal to 0.05 for both). Analysis of 44 treadmill exercise tests performed by 16 patients revealed significant prolongation of the median corrected QT (QTc) interval in response to exercise, with maximal prolongation present after 2 min of recovery (median QTc interval 0.52 s versus a baseline value of 0.47 s, p less than 0.001). Characteristic changes in T wave configuration were noted in 8 of 15 patients on at least one occasion during ambulatory Holter electrocardiographic monitoring, including T wave alternation in two patients, both of whom died shortly afterward. It is suggested that the congenital long QT syndrome is associated with a significant mortality rate in childhood despite the use of conventional therapy in symptomatic patients. Ambulatory Holter monitoring and treadmill exercise testing may be helpful, both in confirming the diagnosis of a long QT syndrome and in monitoring the adequacy of treatment.(ABSTRACT TRUNCATED AT 250 WORDS) 10.1016/0735-1097(90)90359-w
    Multiple mechanisms in the long-QT syndrome. Current knowledge, gaps, and future directions. The SADS Foundation Task Force on LQTS. Roden D M,Lazzara R,Rosen M,Schwartz P J,Towbin J,Vincent G M Circulation The congenital long-QT syndrome (LQTS) is characterized by prolonged QT intervals, QT interval lability, and polymorphic ventricular tachycardia. The manifestations of the disease vary, with a high incidence of sudden death in some affected families but not in others. Mutations causing LQTS have been identified in three genes, each encoding a cardiac ion channel. In families linked to chromosome 3, mutations in SCN5A, the gene encoding the human cardiac sodium channel, cause the disease, Mutations in the human ether-à-go-go-related gene (HERG), which encodes a delayed-rectifier potassium channel, cause the disease in families linked to chromosome 7. Among affected individuals in families linked to chromosome 11, mutations have been identified in KVLQT1, a newly cloned gene that appears to encode a potassium channel. The SCN5A mutations result in defective sodium channel inactivation, whereas HERG mutations result in decreased outward potassium current. Either mutation would decrease net outward current during repolarization and would thereby account for prolonged QT intervals on the surface ECG. Preliminary data suggest that the clinical presentation in LQTS may be determined in part by the gene affected and possibly even by the specific mutation. The identification of disease genes in LQTS not only represents a major milestone in understanding the mechanisms underlying this disease but also presents new opportunities for combined research at the molecular, cellular, and clinical levels to understand issues such as adrenergic regulation of cardiac electrophysiology and mechanisms of susceptibility to arrhythmias in LQTS and other settings. 10.1161/01.cir.94.8.1996
    A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Neyroud N,Tesson F,Denjoy I,Leibovici M,Donger C,Barhanin J,Fauré S,Gary F,Coumel P,Petit C,Schwartz K,Guicheney P Nature genetics The Jervell and Lange-Nielsen (JLN) syndrome (MIM 220400) is an inherited autosomal recessive disease characterized by a congenital bilateral deafness associated with a QT prolongation on the electrocardiogram, syncopal attacks due to ventricular arrhythmias and a high risk of sudden death. JLN syndrome is a rare disease, which seems to affect less than one percent of all deaf children. Linkage to chromosome 11p15.5 markers was found by analysing four consanguinous families. Recombinants allowed us to map the JLN gene between D11S922 and D11S4146, to a 6-cM interval where KVLQT1, a potassium channel gene causing Romano-Ward (RW) syndrome, the dominant form of long QT syndrome, has been previously localized. An homozygous deletion-insertion event (1244, -7 +8) in the C-terminal domain of this gene was detected in three affected children of two families. We found that KVLQT1 is expressed in the stria vascularis of mouse inner ear by in situ hybridization. Taken together, our data indicate that KVLQT1 is responsible for both JLN and RW syndromes and has a key role not only in the ventricular repolarization but also in normal hearing, probably via the control of endolymph homeostasis. 10.1038/ng0297-186
    Pharmacological targeting of long QT mutant sodium channels. Wang D W,Yazawa K,Makita N,George A L,Bennett P B The Journal of clinical investigation The congenital long QT syndrome (LQTS) is an inherited disorder characterized by a delay in cardiac cellular repolarization leading to cardiac arrhythmias and sudden death often in young people. One form of the disease (LQT3) involves mutations in the voltage-gated cardiac sodium channel. The potential for targeted suppression of the LQT defect was explored by heterologous expression of mutant channels in cultured human cells. Kinetic and steady state analysis revealed an enhanced apparent affinity for the predominantly charged, primary amine compound, mexiletine. The affinity of the mutant channels in the inactivated state was similar to the wild type (WT) channels (IC50 approximately 15-20 microM), but the late-opening channels were inhibited at significantly lower concentrations (IC50 = 2-3 microM) causing a preferential suppression of the late openings. The targeting of the defective behavior of the mutant channels has important implications for therapeutic intervention in this disease. The results provide insights for the selective suppression of the mutant phenotype by very low concentrations of drug and indicate that mexiletine equally suppresses the defect in all three known LQT3 mutants. 10.1172/JCI119335
    Sodium channel block with mexiletine is effective in reducing dispersion of repolarization and preventing torsade des pointes in LQT2 and LQT3 models of the long-QT syndrome. Shimizu W,Antzelevitch C Circulation BACKGROUND:This study examines the contribution of transmural heterogeneity of transmembrane activity to phenotypic T-wave patterns and the effects of pacing and of sodium channel block under conditions mimicking HERG and SCN5A defects linked to the congenital long-QT syndrome (LQTS). METHODS AND RESULTS:A transmural ECG and transmembrane action potentials from epicardial, M, and endocardial or Purkinje cells were simultaneously recorded in an arterially perfused wedge of canine left ventricle. d-Sotalol was used to mimic LQT2, whereas ATX-II mimicked LQT3. d-Sotalol caused a preferential prolongation of the M cell action potential duration (APD90, 291+/-14 to 354+/-35 ms), giving rise to broad and sometimes low-amplitude bifurcated T waves and an increased transmural dispersion of repolarization (TDR, 51+/-15 to 72+/-17 ms). QT interval increased from 320+/-13 to 385+/-37 ms. ATX-II produced a preferential prolongation of the M cell APD90 (280+/-25 to 609+/-49 ms) and caused a marked delay in the onset of the T wave and a sharp rise in TDR (40+/-5 to 168+/-40 ms). QT-, APD90-, and dispersion-rate relations were much steeper in the ATX-II than in the d-sotalol model. Mexiletine (2 to 20 micromol/L) dose-dependently abbreviated the QT interval and APD90 of all cell types, more in the ATX-II than in the d-sotalol model, but decreased TDR equally in the two models. Mexiletine 2 to 5 micromol/L totally suppressed spontaneous torsade de pointes (TdP) and reduced the vulnerable window during which single extrastimuli could induce TdP in both models. Higher concentrations of mexiletine (10 to 20 micromol/L) totally suppressed stimulation-induced TdP. CONCLUSIONS:Our results suggest that although pacing and sodium channel block are very effective in abbreviating the QT interval and TDR in LQT3, these therapeutic approaches may also be valuable in reducing the incidence of arrhythmogenesis in LQT2. 10.1161/01.cir.96.6.2038
    Rate adaptation of QT intervals during and after exercise in children with congenital long QT syndrome. Swan H,Toivonen L,Viitasalo M European heart journal OBJECTIVES:To improve the diagnostic criteria of the congenital long QT syndrome in borderline cases we examined rate adaptation of ventricular repolarization phases during exercise and subsequent recovery in children with the long QT syndrome and controls. METHODS:Nineteen children with definite long QT syndrome and 19 healthy controls underwent exercise testing. QT intervals were measured to the apex (early QT), to the end (total QT) and from apex to the end of the T wave (late QT) at heart rates from 90 by steps of 10 to 150 beats, min-1. RESULTS:In 11/19 long QT syndrome patients (61%) and 2/19 controls (12%) the total QT lengthened during the recovery phase compared with exercise (P = 0.005) at the lowest comparable heart rate. No difference was found between the groups during exercise. The sensitivity of rate adaptation of repolarization intervals was analysed by calculating linear regression slopes relating the QT intervals to the heart rates. During recovery, slopes relating the total QT to heart rate were steeper in long QT syndrome patients than those in controls (-2.50 +/- 0.82 vs -1.79 +/- 0.47, P = 0.003). Total QT/heart rate slopes differed between exercise and recovery phases in the long QT syndrome group only (-1.77 +/- 0.71 vs 2.50 +/- 0.82, P = 0.009). In long QT syndrome patients, the difference in total QT/heart rate slopes was mainly because the late QT/heart rate slopes indicating inhomogeneity of repolarization were steeper during recovery (-1.27 +/- 0.74) than during exercise (-0.46 +/- 0.29, P < 0.0001). CONCLUSIONS:After exercise in long QT syndrome children the QT interval lengthens abnormally and inhomogeneity of repolarization increases. Evaluation of the QT interval, and especially its late portion after exercise, may help in establishing the diagnosis of long QT syndrome. 10.1053/euhj.1997.0764
    Improvement of repolarization abnormalities by a K+ channel opener in the LQT1 form of congenital long-QT syndrome. Shimizu W,Kurita T,Matsuo K,Suyama K,Aihara N,Kamakura S,Towbin J A,Shimomura K Circulation BACKGROUND:This study used monophasic action potential (MAP) to examine the effect of nicorandil, a K+ channel opener, on repolarization abnormalities induced by epinephrine in the LQT1 form of congenital long-QT syndrome in which the KvLQT1 mutation underlies the defect in the channel responsible for the slowly activating component of the delayed rectifier potassium current. METHODS AND RESULTS:MAPs were recorded simultaneously from two or three sites on the right ventricular and left ventricular endocardium in 6 patients with a congenital form of LQT1 syndrome with KvLQT1 defect (17 sites) and 8 control patients (24 sites). In LQT1 patients, epinephrine infusion prolonged the QT interval and 90% MAP duration (MAPD90) and increased the dispersion of MAPD90. Epinephrine also induced early after depolarizations (EADs) as well as ventricular premature complexes (VPCs) in 2 of the 6 patients. Nicorandil during epinephrine infusion abbreviated the QT interval and MAPD90, decreased the dispersion of MAPD90, and abolished the EADs as well as the VPCs in 1 patient. Addition of propranolol completely reversed the effect of epinephrine in prolonging the QT interval and MAPD90 and increasing the dispersion and eliminated the EADs and VPCs in another patient. In control patients, the effect of epinephrine and that of additional nicorandil and propranolol on repolarization parameters were much less than in the LQT1 patients. CONCLUSIONS:Our results suggest that nicorandil, a K+ channel opener, improves repolarization abnormalities in the LQT1 form of congenital long-QT syndrome with KvLQT1 defect. 10.1161/01.cir.97.16.1581
    Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry. Locati E H,Zareba W,Moss A J,Schwartz P J,Vincent G M,Lehmann M H,Towbin J A,Priori S G,Napolitano C,Robinson J L,Andrews M,Timothy K,Hall W J Circulation BACKGROUND:Unexplained female predominance is observed in long-QT syndrome (LQTS), a congenital autosomal disorder with prolonged repolarization and syncope or sudden death due to ventricular tachyarrhythmias. Our objectives were to evaluate age- and sex-related differences in events among LQTS patients referred to the LQTS International Registry. METHODS AND RESULTS:Age- and sex-related occurrence of events was analyzed in 479 probands (70% females) and 1041 affected family members (QTc >440 ms, 58% females). LQTS-gene mutations were identified in 162 patients: 69 LQT1 carriers (KVLQT1 on 11p15.5), 62 LQT2 carriers (HERG on 7q35-36), and 31 LQT3 carriers (SCN5A on 3p21-24). Females predominated among 366 probands (71% females) and 230 symptomatic family members (62% females). Male probands were younger than females at first event (8+/-7 versus 14+/-10 years, P<0.0001) and had higher event rates by age 15 years than females (74% versus 51%, P<0.0001). Affected family members had similar findings. By Cox analysis adjusting for QTc duration, the hazard ratio for female probands of experiencing events by age 15 years was 0.48 (P<0.001), and it was 1.87 (P=0.09) by age 15 to 40 years. In female family members, the hazard ratio was 0.58 (P<0.001) by age 15 years, and it was 3.25 (P<0.001) by age 15 to 40 years. The event rate was higher in male than female LQT1 carriers (69% versus 32%, P=0.001). No age-sex difference in event rate was detected in LQT2 and LQT3 carriers. CONCLUSIONS:Among LQTS patients, the risk of cardiac events was higher in males until puberty and higher in females during adulthood. The same pattern was evident among LQT1 gene carriers. Unknown sex factors modulate QT duration and arrhythmic events, with preliminary evidence of gene-specific differences in age-sex modulation. 10.1161/01.cir.97.22.2237
    A recessive variant of the Romano-Ward long-QT syndrome? Priori S G,Schwartz P J,Napolitano C,Bianchi L,Dennis A,De Fusco M,Brown A M,Casari G Circulation BACKGROUND:The congenital long-QT syndrome (LQTS) is a genetically heterogeneous disease characterized by prolonged ventricular repolarization and life-threatening arrhythmias. Mutations of the KVLQT1 gene, a cardiac potassium channel, generate two allelic diseases: the Romano-Ward syndrome, inherited as a dominant trait, and the Jervell and Lange-Nielsen syndrome, inherited as an autosomal recessive trait. METHODS AND RESULTS:A consanguineous family with the clinical phenotype of LQTS was screened for mutations in the KVLQT1 gene. Complementary RNAs for injection into Xenopus oocytes were prepared, and currents were recorded with the double microelectrode technique. A homozygous missense mutation, leading to an alanine-to-threonine substitution at the beginning of the pore domain of the KVLQT1 channel, was found in the proband, a 9-year-old boy with normal hearing, a prolonged QT interval, and syncopal episodes during physical exercise. The parents of the proband were heterozygous for the mutation and had a normal QT interval. The functional evaluation of the mutant channel activity showed reduction in total current, a hyperpolarizing shift in activation, and a faster activation rate consistent with a mild mutation likely to require homozygosity to manifest the phenotype. CONCLUSIONS:These findings provide the first evidence for a recessive form of the Romano-Ward long-QT syndrome and indicate that homozygous mutations on KVLQT1 do not invariably produce the Jervell and Lange-Nielsen syndrome. The implications of this observation prompt a reconsideration of the penetrance of different mutations responsible for LQTS and suggest that mild mutations in LQTS genes may be present among the general population and may predispose to drug-induced ventricular arrhythmias. 10.1161/01.cir.97.24.2420
    Novel LQT-3 mutation affects Na+ channel activity through interactions between alpha- and beta1-subunits. An R H,Wang X L,Kerem B,Benhorin J,Medina A,Goldmit M,Kass R S Circulation research The congenital long-QT syndrome (LQT), an inherited cardiac arrhythmia characterized in part by prolonged ventricular repolarization, has been linked to 5 loci, 4 of which have been shown to harbor genes that encode ion channels. Previously studied LQT-3 mutations of SCN5A (or hH1), the gene that encodes the human Na+ channel alpha-subunit, have been shown to encode voltage-gated Na+ channels that reopen during prolonged depolarization and hence directly contribute to the disease phenotype: delayed repolarization. Here, we report the functional consequences of a novel SCN5A mutation discovered in an extended LQT family. The mutation, a single A-->G base substitution at nucleotide 5519 of the SCN5A cDNA, is expected to cause a nonconservative change from an aspartate to a glycine at position 1790 (D1790G) of the SCN5A gene product. We investigated ion channel activity in human embryonic kidney (HEK 293) cells transiently transfected with wild-type (hH1) or mutant (D1790G) cDNA alone or in combination with cDNA encoding the human Na+ channel beta1-subunit (hbeta1) using whole-cell patch-clamp procedures. Heteromeric channels formed by coexpression of alpha- and beta1-subunits are affected: steady-state inactivation is shifted by -16 mV, but there is no D1790G-induced sustained inward current. This effect is independent of the beta1-subunit isoform. We find no significant effect of D1790G on the biophysical properties of monomeric alpha- (hH1) channels. We conclude that the effects of the novel LQT-3 mutation on inactivation of heteromeric channels are due to D1790G-induced changes in alpha- and beta1-interactions. 10.1161/01.res.83.2.141
    Influence of the genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group. Zareba W,Moss A J,Schwartz P J,Vincent G M,Robinson J L,Priori S G,Benhorin J,Locati E H,Towbin J A,Keating M T,Lehmann M H,Hall W J The New England journal of medicine BACKGROUND:The congenital long-QT syndrome, caused by mutations in cardiac potassium-channel genes (KVLQT1 at the LQT1 locus and HERG at the LQT2 locus) and the sodium-channel gene (SCN5A at the LQT3 locus), has distinct repolarization patterns on electrocardiography, but it is not known whether the genotype influences the clinical course of the disease. METHODS:We determined the genotypes of 541 of 1378 members of 38 families enrolled in the International Long-QT Syndrome Registry: 112 had mutations at the LQT1 locus, 72 had mutations at the LQT2 locus, and 62 had mutations at the LQT3 locus. We determined the cumulative probability and lethality of cardiac events (syncope, aborted cardiac arrest, or sudden death) occurring from birth through the age of 40 years according to genotype in the 246 gene carriers and in all 1378 members of the families studied. RESULTS:The frequency of cardiac events was higher among subjects with mutations at the LQT1 locus (63 percent) or the LQT2 locus (46 percent) than among subjects with mutations at the LQT3 locus (18 percent) (P<0.001 for the comparison of all three groups). In a multivariate Cox analysis, the genotype and the QT interval corrected for heart rate were significant independent predictors of a first cardiac event. The cumulative mortality through the age of 40 among members of the three groups of families studied was similar; however, the likelihood of dying during a cardiac event was significantly higher (P<0.001) among families with mutations at the LQT3 locus (20 percent) than among those with mutations at the LQT1 locus (4 percent) or the LQT2 locus (4 percent). CONCLUSIONS:The genotype of the long-QT syndrome influences the clinical course. The risk of cardiac events is significantly higher among subjects with mutations at the LQT1 or LQT2 locus than among those with mutations at the LQT3 locus. Although cumulative mortality is similar regardless of the genotype, the percentage of cardiac events that are lethal is significantly higher in families with mutations at the LQT3 locus. 10.1056/NEJM199810013391404
    Cellular basis for the ECG features of the LQT1 form of the long-QT syndrome: effects of beta-adrenergic agonists and antagonists and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes. Shimizu W,Antzelevitch C Circulation BACKGROUND:This study examines the cellular basis for the phenotypic appearance of broad-based T waves, increased transmural dispersion of repolarization (TDR), and torsade de pointes (TdP) induced by beta-adrenergic agonists under conditions mimicking the LQT1 form of the congenital long-QT syndrome. METHODS AND RESULTS:A transmural ECG and transmembrane action potentials from epicardial, M, and endocardial cells were recorded simultaneously from an arterially perfused wedge of canine left ventricle. Chromanol 293B, a specific IKs blocker, dose-dependently (1 to 100 micromol/L) prolonged the QT interval and action potential duration (APD90) of the 3 cell types but did not widen the T wave, increase TDR, or induce TdP. Isoproterenol 10 to 100 nmol/L in the continued presence of chromanol 293B 30 micromol/L abbreviated the APD90 of epicardial and endocardial cells but not that of the M cell, resulting in widening of the T wave and a dramatic accentuation of TDR. Spontaneous as well as programmed electrical stimulation (PES)-induced TdP was observed only after exposure to the IKs blocker and isoproterenol. Therapeutic concentrations of propranolol (0.5 to 1 micromol/L) prevented the actions of isoproterenol to increase TDR and to induce TdP. Mexiletine 2 to 20 micromol/L abbreviated the APD90 of M cells more than that of epicardial and endocardial cells, thus diminishing TDR and the effect of isoproterenol to induce TdP. CONCLUSIONS:This experimental model of LQT1 indicates that a deficiency of IKs alone does not induce TdP but that the addition of beta-adrenergic influence predisposes the myocardium to the development of TdP by increasing transmural dispersion of repolarization, most likely as a result of a large augmentation of residual IKs in epicardial and endocardial cells but not in M cells, in which IKs is intrinsically weak. Our data provide a mechanistic understanding of the cellular basis for the therapeutic actions of beta-adrenergic blockers in LQT1 and suggest that sodium channel block with class IB antiarrhythmic agents may be effective in suppressing TdP in LQT1, as they are in LQT2 and LQT3, as well as in acquired (drug-induced) forms of the long-QT syndrome. 10.1161/01.cir.98.21.2314
    Auditory stimuli as a trigger for arrhythmic events differentiate HERG-related (LQTS2) patients from KVLQT1-related patients (LQTS1). Wilde A A,Jongbloed R J,Doevendans P A,Düren D R,Hauer R N,van Langen I M,van Tintelen J P,Smeets H J,Meyer H,Geelen J L Journal of the American College of Cardiology OBJECTIVE:This study was performed to identify a possible relationship between genotype and phenotype in the congenital familial long QT syndrome (cLQTS). BACKGROUND:The cLQTS, which occurs as an autosomal dominant or recessive trait, is characterized by QT-interval prolongation on the electrocardiogram and torsade de pointes arrhythmias, which may give rise to recurrent syncope or sudden cardiac death. Precipitators for cardiac events are exercise or emotion and occasionally acoustic stimuli. METHODS:The trigger for cardiac events (syncope, documented cardiac arrhythmias, sudden cardiac death) was analyzed in 11 families with a familial LQTS and a determined genotype. RESULTS:The families were subdivided in KVLQT1-related families (LQTS1, n = 5) and HERG (human ether-a-gogo-related gene)-related families (LQTS2, n = 6) based on single-strand conformation polymorphism analysis and sequencing. Whereas exercise-related cardiac events dominate the clinical picture of LQTS1 patients, auditory stimuli as a trigger for arrhythmic events were only seen in LQTS2 patients. CONCLUSIONS:Arrhythmic events triggered by auditory stimuli may differentiate LQTS2 from LQTS1 patients. 10.1016/s0735-1097(98)00578-6
    Novel mechanism associated with an inherited cardiac arrhythmia: defective protein trafficking by the mutant HERG (G601S) potassium channel. Furutani M,Trudeau M C,Hagiwara N,Seki A,Gong Q,Zhou Z,Imamura S,Nagashima H,Kasanuki H,Takao A,Momma K,January C T,Robertson G A,Matsuoka R Circulation BACKGROUND:The congenital long-QT syndrome (LQTS) is an inherited disorder characterized by a prolonged cardiac action potential and a QT interval that leads to arrhythmia. Mutations in the human ether-a-go-go-related gene (HERG), which encodes the rapidly activating component of the delayed rectifier current (IKr), cause chromosome 7-linked LQTS (LQT2). Studies of mutant HERG channels in heterologous systems indicate that the mechanisms mediating LQT2 are varied and include mutant subunits that form channels with altered kinetic properties or nonfunctional mutant subunits. We recently reported a novel missense mutation of HERG (G601S) in an LQTS family that we have characterized in the present work. METHODS AND RESULTS:To elucidate the electrophysiological properties of the G601S mutant channels, we expressed these channels in mammalian cells and Xenopus oocytes. The G601S mutant produced less current than wild-type channels but exhibited no change in kinetic properties or dominant-negative suppression when coexpressed with wild-type subunits. To examine the cellular trafficking of mutant HERG channel subunits, enhanced green fluorescent protein tagging and Western blot analyses were performed. These showed deficient protein trafficking of the G601S mutant to the plasma membrane. CONCLUSIONS:Our results from both the Xenopus oocyte and HEK293 cell expression systems and green fluorescent protein tagging and Western blot analyses support the conclusion that the G601S mutant is a hypomorphic mutation, resulting in a reduced current amplitude. Thus, it represents a novel mechanism underlying LQT2. 10.1161/01.cir.99.17.2290
    Congenital long-QT syndrome caused by a novel mutation in a conserved acidic domain of the cardiac Na+ channel. Wei J,Wang D W,Alings M,Fish F,Wathen M,Roden D M,George A L Circulation BACKGROUND:Congenital long-QT syndrome (LQTS) is an inherited condition of abnormal cardiac excitability characterized clinically by an increased risk of ventricular tachyarrhythmias. One form, LQT3, is caused by mutations in the cardiac voltage-dependent sodium channel gene, SCN5A. Only 5 SCN5A mutations have been associated with LQTS, and more work is needed to improve correlations between SCN5A genotypes and associated clinical syndromes. METHODS AND RESULTS:We researched a 3-generation white family with autosomal dominant LQTS who exhibited a wide clinical spectrum from mild bradycardia to sudden death. Molecular genetic studies revealed a single nucleotide substitution in SCN5A exon 28 that caused the substitution of Glu1784 by Lys (E1784K). The mutation occurs in a highly conserved domain within the C-terminus of the cardiac sodium channel containing multiple, negatively charged amino acids. Two-electrode voltage-clamp recordings of a recombinant E1784K mutant channel expressed in Xenopus oocytes revealed a defect in fast inactivation characterized by a small, persistent current during long membrane depolarizations. Coexpression of the mutant with the human sodium channel beta1-subunit did not affect the persistent current, even though we did observe shifts in the voltage dependence of steady-state inactivation. Neutralizing multiple, negatively charged residues in the same region of the sodium channel C-terminus did not cause a more severe functional defect. CONCLUSIONS:We characterized the genetics and molecular pathophysiology of a novel SCN5A sodium channel mutation, E1784K. The functional defect exhibited by the mutant channel causes delayed myocardial repolarization, and our data on the effects of multiple charge neutralizations in this region of the C-terminus suggest that the molecular mechanism of channel dysfunction involves an allosteric rather than a direct effect on channel gating. 10.1161/01.cir.99.24.3165
    Spectrum of ST-T-wave patterns and repolarization parameters in congenital long-QT syndrome: ECG findings identify genotypes. Zhang L,Timothy K W,Vincent G M,Lehmann M H,Fox J,Giuli L C,Shen J,Splawski I,Priori S G,Compton S J,Yanowitz F,Benhorin J,Moss A J,Schwartz P J,Robinson J L,Wang Q,Zareba W,Keating M T,Towbin J A,Napolitano C,Medina A Circulation BACKGROUND:Congenital long-QT syndrome (LQTS) is caused by mutations of genes encoding the slow component of the delayed rectifier current (LQT1, LQT5), the rapid component of the delayed rectifier current (LQT2, LQT6), or the Na(+) current (LQT3), resulting in ST-T-wave abnormalities on the ECG. This study evaluated the spectrum of ST-T-wave patterns and repolarization parameters by genotype and determined whether genotype could be identified by ECG. METHODS AND RESULTS:ECGs of 284 gene carriers were studied to determine ST-T-wave patterns, and repolarization parameters were quantified. Genotypes were identified by individual ECG versus family-grouped ECG analysis in separate studies using ECGs of 146 gene carriers from 29 families and 233 members of 127 families undergoing molecular genotyping, respectively. Ten typical ST-T patterns (4 LQT1, 4 LQT2, and 2 LQT3) were present in 88% of LQT1 and LQT2 carriers and in 65% of LQT3 carriers. Repolarization parameters also differed by genotype. A combination of quantified repolarization parameters identified genotype with sensitivity/specificity of 85%/70% for LQT1, 83%/94% for LQT2, and 47%/63% for LQT3. Typical patterns in family-grouped ECGs best identified the genotype, being correct in 56 of 56 (21 LQT1, 33 LQT2, and 2 LQT3) families with mutation results. CONCLUSIONS:Typical ST-T-wave patterns are present in the majority of genotyped LQTS patients and can be used to identify LQT1, LQT2, and possibly LQT3 genotypes. Family-grouped ECG analysis improves genotype identification accuracy. This approach can simplify genetic screening by targeting the gene for initial study. The multiple ST-T patterns in each genotype raise questions regarding the pathophysiology and regulation of repolarization in LQTS. 10.1161/01.cir.102.23.2849
    Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. Moss A J,Zareba W,Hall W J,Schwartz P J,Crampton R S,Benhorin J,Vincent G M,Locati E H,Priori S G,Napolitano C,Medina A,Zhang L,Robinson J L,Timothy K,Towbin J A,Andrews M L Circulation BACKGROUND:beta-blockers are routinely prescribed in congenital long-QT syndrome (LQTS), but the effectiveness and limitations of beta-blockers in this disorder have not been evaluated. METHODS AND RESULTS:The study population comprised 869 LQTS patients treated with beta-blockers. Effectiveness of beta-blockers was analyzed during matched periods before and after starting beta-blocker therapy, and by survivorship methods to determine factors associated with cardiac events while on prescribed beta-blockers. After initiation of beta-blockers, there was a significant (P<0.001) reduction in the rate of cardiac events in probands (0.97+/-1.42 to 0.31+/-0.86 events per year) and in affected family members (0. 26+/-0.84 to 0.15+/-0.69 events per year) during 5-year matched periods. On-therapy survivorship analyses revealed that patients with cardiac symptoms before beta-blockers (n=598) had a hazard ratio of 5.8 (95% CI, 3.7 to 9.1) for recurrent cardiac events (syncope, aborted cardiac arrest, or death) during beta-blocker therapy compared with asymptomatic patients; 32% of these symptomatic patients will have another cardiac event within 5 years while on prescribed beta-blockers. Patients with a history of aborted cardiac arrest before starting beta-blockers (n=113) had a hazard ratio of 12.9 (95% CI, 4.7 to 35.5) for aborted cardiac arrest or death while on prescribed beta-blockers compared with asymptomatic patients; 14% of these patients will have another arrest (aborted or fatal) within 5 years on beta-blockers. CONCLUSIONS:beta-blockers are associated with a significant reduction in cardiac events in LQTS patients. However, syncope, aborted cardiac arrest, and LQTS-related death continue to occur while patients are on prescribed beta-blockers, particularly in those who were symptomatic before starting this therapy. 10.1161/01.cir.101.6.616
    Differential effects of beta-adrenergic agonists and antagonists in LQT1, LQT2 and LQT3 models of the long QT syndrome. Shimizu W,Antzelevitch C Journal of the American College of Cardiology OBJECTIVES:To define the cellular mechanisms responsible for the development of life-threatening arrhythmias in response to sympathetic activity in the congenital and acquired long QT syndromes (LCQTS). METHODS:Transmembrane action potentials (AP) from epicardial (EPI), M and endocardial (ENDO) cells and a transmural electrocardiogram were simultaneously recorded from an arterially perfused wedge of canine left ventricle. We examined the effect of beta-adrenergic agonists and antagonists on action potential duration (APD90), transmural dispersion of repolarization (TDR) and the development of Torsade de Pointes (TdP) in models of LQT1, LQT2 and LQT3 forms of LQTS. RESULTS:I(Ks) block with chromanol 293B (LQT1) homogeneously prolonged APD90 of the three cell types without increasing TDR. Addition of isoproterenol prolonged QT and APD90 of M but abbreviated that of EPI and ENDO, causing a persistent increase in TDR; Torsade de Pointes developed or could be induced only in the presence of isoproterenol. I(Kr) block with d-sotalol (LQT2) and augmentation of late I(Na) with ATX-II (LQT3) prolonged APD90 of M more than EPI and ENDO, causing increases in QT and TDR. TdP developed in the absence of isoproterenol. In LQT2 isoproterenol initially prolonged, then abbreviated, the APD90 of M but always abbreviated EPI, thus transiently increasing TDR and the incidence of TdP. In LQT3, isoproterenol always abbreviated APD90 of the three cell types, causing a persistent decrease in TDR and suppression of TdP. The arrhythmogenic as well as protective actions of isoproterenol were reversed by propranolol. CONCLUSIONS:Our data suggest that beta-adrenergic stimulation induces TdP by increasing transmural dispersion of repolarization in LQT1 and LQT2 but suppresses TdP by decreasing dispersion in LQT3. The data indicate that beta-blockers are protective in LQT1 and LQT2 but may facilitate TdP in LQT3. 10.1016/s0735-1097(99)00582-3
    Effects of flecainide in patients with new SCN5A mutation: mutation-specific therapy for long-QT syndrome? Benhorin J,Taub R,Goldmit M,Kerem B,Kass R S,Windman I,Medina A Circulation BACKGROUND:Mutations in the cardiac sodium channel gene (SCN5A) can cause one variant of the congenital long-QT syndrome. The effects of some of these mutations on the alpha-subunit channel properties can be blocked by type Ib antiarrhythmic drugs. Recently, we have described a new SCN5A mutation (D1790G) that affects the channel properties in a manner suggesting that sodium blockers of the Ib type will be ineffective in carriers of this mutation. Hence, the ECG effects of flecainide-acetate, a type Ic sodium blocker, were evaluated in carriers of this mutation. METHODS AND RESULTS:Eight asymptomatic mutation carriers and 5 control subjects were studied. Intravenous lidocaine was tested first in only 2 mutation carriers and had no significant effect on any ECG parameter. Flecainide significantly shortened all heart rate-corrected repolarization duration parameters only in carriers and not in control subjects: QT(c) shortened by 9.5% (from 517+/-45 to 468+/-36 ms, P=0.011), and the S-offset to T-onset interval shortened by 64.7% (from 187+/-88 to 66+/-50 ms, P=0.0092). Flecainide also normalized the marked baseline repolarization dispersion in most mutation carriers. These effects among carriers were maintained during long-term (9 to 17 months) outpatient flecainide therapy with no adverse effects. CONCLUSIONS:This report is the first to describe SCN5A mutation carriers who significantly responded to flecainide therapy yet did not respond to lidocaine. These results have important implications for long-QT allele-specific therapeutic strategies. 10.1161/01.cir.101.14.1698
    A revised view of cardiac sodium channel "blockade" in the long-QT syndrome. Kambouris N G,Nuss H B,Johns D C,Marbán E,Tomaselli G F,Balser J R The Journal of clinical investigation Mutations in SCN5A, encoding the cardiac sodium (Na) channel, are linked to a form of the congenital long-QT syndrome (LQT3) that provokes lethal ventricular arrhythmias. These autosomal dominant mutations disrupt Na channel function, inhibiting channel inactivation, thereby causing a sustained ionic current that delays cardiac repolarization. Sodium channel-blocking antiarrhythmics, such as lidocaine, potently inhibit this pathologic Na current (I(Na)) and are being evaluated in patients with LQT3. The mechanism underlying this effect is unknown, although high-affinity "block" of the open Na channel pore has been proposed. Here we report that a recently identified LQT3 mutation (R1623Q) imparts unusual lidocaine sensitivity to the Na channel that is attributable to its altered functional behavior. Studies of lidocaine on individual R1623Q single-channel openings indicate that the open-time distribution is not changed, indicating the drug does not block the open pore as proposed previously. Rather, the mutant channels have a propensity to inactivate without ever opening ("closed-state inactivation"), and lidocaine augments this gating behavior. An allosteric gating model incorporating closed-state inactivation recapitulates the effects of lidocaine on pathologic I(Na). These findings explain the unusual drug sensitivity of R1623Q and provide a general and unanticipated mechanism for understanding how Na channel-blocking agents may suppress the pathologic, sustained Na current induced by LQT3 mutations. 10.1172/JCI9212
    Arrhythmogenic mechanism of an LQT-3 mutation of the human heart Na(+) channel alpha-subunit: A computational analysis. Wehrens X H,Abriel H,Cabo C,Benhorin J,Kass R S Circulation BACKGROUND:D1790G, a mutation of SCN5A, the gene that encodes the human Na(+) channel alpha-subunit, is linked to 1 form of the congenital long-QT syndrome (LQT-3). In contrast to other LQT-3-linked SCN5A mutations, D1790G does not promote sustained Na(+) channel activity but instead alters the kinetics and voltage-dependence of the inactivated state. METHODS AND RESULTS:We modeled the cardiac ventricular action potential (AP) using parameters and techniques described by Luo and Rudy as our control. On this background, we modified only the properties of the voltage-gated Na(+) channel according to our patch-clamp analysis of D1790G channels. Our results indicate that D1790G-induced changes in Na(+) channel activity prolong APs in a steeply heart rate-dependent manner not directly due to changes in Na(+) entry through mutant channels but instead to alterations in the balance of net plateau currents by modulation of calcium-sensitive exchange and ion channel currents. CONCLUSIONS:We conclude that the D1790G mutation of the Na(+) channel alpha-subunit can prolong the cardiac ventricular AP despite the absence of mutation-induced sustained Na(+) channel current. This prolongation is calcium-dependent, is enhanced at slow heart rates, and at sufficiently slow heart rate triggers arrhythmogenic early afterdepolarizations. 10.1161/01.cir.102.5.584
    Effects of a K(+) channel opener to reduce transmural dispersion of repolarization and prevent torsade de pointes in LQT1, LQT2, and LQT3 models of the long-QT syndrome. Shimizu W,Antzelevitch C Circulation BACKGROUND:This study examines the effects of nicorandil, a K(+) channel opener, on transmural dispersion of repolarization (TDR) and induction of torsade de pointes (TdP) under conditions mimicking the LQT1, LQT2, and LQT3 forms of the congenital long-QT syndrome (LQTS). METHODS AND RESULTS:Transmembrane action potentials of epicardial, M, and endocardial cells were recorded simultaneously from an arterially perfused wedge of canine left ventricle together with a transmural ECG. Chromanol 293B (30 micromol/L) was used to block I(Ks) (LQT1 model). Isoproterenol (50 to 100 nmol/L) was used to mimic an increase in beta-adrenergic tone, d-sotalol (100 micromol/L) to block I(Kr) (LQT2 model), and ATX-II (20 nmol/L) to augment late I(Na) (LQT3 model). Isoproterenol+chromanol 293B, d-sotalol, and ATX-II produced preferential prolongation of the action potential duration at 90% repolarization (APD(90)) of the M cell, an increase of TDR, and spontaneous as well as stimulation-induced TdP (LQT1, 3/6; LQT2, 3/6; LQT3, 5/6). Nicorandil (2 to 20 micromol/L) abbreviated the QT interval and APD(90) of the 3 cell types in the 3 models. High concentrations (10 to 20 micromol/L) completely reversed the effects of 293B+/-isoproterenol and those of d-sotalol to increase APD(90) and TDR and to induce TdP in LQT1 and LQT2 models. Nicorandil 20 micromol/L reversed only 50% of the effect of ATX-II and failed to completely suppress TdP in the LQT3 model (5/6 to 3/6). CONCLUSIONS:Our data suggest that K(+) channel openers may be capable of abbreviating the long QT interval, reducing TDR, and preventing spontaneous and stimulation-induced TdP when congenital or acquired LQTS is secondary to reduced I(Kr) or I(Ks) but less so when it is due to augmented late I(Na). 10.1161/01.cir.102.6.706
    Molecular pharmacology of the sodium channel mutation D1790G linked to the long-QT syndrome. Abriel H,Wehrens X H,Benhorin J,Kerem B,Kass R S Circulation BACKGROUND:Multiple mutations of SCN5A, the gene that encodes the human Na(+) channel alpha-subunit, are linked to 1 form of the congenital long-QT syndrome (LQT-3). D1790G (DG), an LQT-3 mutation of the C-terminal region of the Na(+) channel alpha-subunit, alters steady-state inactivation of expressed channels but does not promote sustained Na(+) channel activity. Recently, flecainide, but not lidocaine, has been found to correct the disease phenotype, delayed ventricular repolarization, in DG carriers. METHODS AND RESULTS:To understand the molecular basis of this difference, we studied both drugs using wild-type (WT) and mutant Na(+) channels expressed in HEK 293 cells. The DG mutation conferred a higher sensitivity to lidocaine (EC(50), WT=894 and DG=205 micromol/L) but not flecainide tonic block in a concentration range that is not clinically relevant. In contrast, in a concentration range that is therapeutically relevant, DG channels are blocked selectively by flecainide (EC(50), WT=11.0 and DG=1.7 micromol/L), but not lidocaine (EC(50), WT=318.0 and DG=176 micromol/L) during repetitive stimulation. CONCLUSIONS:These results (1) demonstrate that the DG mutation confers a unique pharmacological response on expressed channels; (2) suggest that flecainide use-dependent block of DG channels underlies its therapeutic effects in carriers of this gene mutation; and (3) suggest a role of the Na(+) channel alpha-subunit C-terminus in the flecainide/channel interaction. 10.1161/01.cir.102.8.921
    Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Schwartz P J,Priori S G,Spazzolini C,Moss A J,Vincent G M,Napolitano C,Denjoy I,Guicheney P,Breithardt G,Keating M T,Towbin J A,Beggs A H,Brink P,Wilde A A,Toivonen L,Zareba W,Robinson J L,Timothy K W,Corfield V,Wattanasirichaigoon D,Corbett C,Haverkamp W,Schulze-Bahr E,Lehmann M H,Schwartz K,Coumel P,Bloise R Circulation BACKGROUND:The congenital long-QT syndrome (LQTS) is caused by mutations on several genes, all of which encode cardiac ion channels. The progressive understanding of the electrophysiological consequences of these mutations opens unforeseen possibilities for genotype-phenotype correlation studies. Preliminary observations suggested that the conditions ("triggers") associated with cardiac events may in large part be gene specific. METHODS AND RESULTS:We identified 670 LQTS patients of known genotype (LQT1, n=371; LQT2, n=234; LQT3, n=65) who had symptoms (syncope, cardiac arrest, sudden death) and examined whether 3 specific triggers (exercise, emotion, and sleep/rest without arousal) differed according to genotype. LQT1 patients experienced the majority of their events (62%) during exercise, and only 3% occurred during rest/sleep. These percentages were almost reversed among LQT2 and LQT3 patients, who were less likely to have events during exercise (13%) and more likely to have events during rest/sleep (29% and 39%). Lethal and nonlethal events followed the same pattern. Corrected QT interval did not differ among LQT1, LQT2, and LQT3 patients (498, 497, and 506 ms, respectively). The percent of patients who were free of recurrence with ss-blocker therapy was higher and the death rate was lower among LQT1 patients (81% and 4%, respectively) than among LQT2 (59% and 4%, respectively) and LQT3 (50% and 17%, respectively) patients. CONCLUSIONS:Life-threatening arrhythmias in LQTS patients tend to occur under specific circumstances in a gene-specific manner. These data allow new insights into the mechanisms that relate the electrophysiological consequences of mutations on specific genes to clinical manifestations and offer the possibility of complementing traditional therapy with gene-specific approaches. 10.1161/01.cir.103.1.89
    Novel arrhythmogenic mechanism revealed by a long-QT syndrome mutation in the cardiac Na(+) channel. Abriel H,Cabo C,Wehrens X H,Rivolta I,Motoike H K,Memmi M,Napolitano C,Priori S G,Kass R S Circulation research Variant 3 of the congenital long-QT syndrome (LQTS-3) is caused by mutations in the gene encoding the alpha subunit of the cardiac Na(+) channel. In the present study, we report a novel LQTS-3 mutation, E1295K (EK), and describe its functional consequences when expressed in HEK293 cells. The clinical phenotype of the proband indicated QT interval prolongation in the absence of T-wave morphological abnormalities and a steep QT/R-R relationship, consistent with an LQTS-3 lesion. However, biophysical analysis of mutant channels indicates that the EK mutation changes channel activity in a manner that is distinct from previously investigated LQTS-3 mutations. The EK mutation causes significant positive shifts in the half-maximal voltage (V(1/2)) of steady-state inactivation and activation (+5.2 and +3.4 mV, respectively). These gating changes shift the window of voltages over which Na(+) channels do not completely inactivate without altering the magnitude of these currents. The change in voltage dependence of window currents suggests that this alteration in the voltage dependence of Na(+) channel gating may cause marked changes in action potential duration because of the unique voltage-dependent rectifying properties of cardiac K(+) channels that underlie the plateau and terminal repolarization phases of the action potential. Na(+) channel window current is likely to have a greater effect on net membrane current at more positive potentials (EK channels) where total K(+) channel conductance is low than at more negative potentials (wild-type channels), where total K(+) channel conductance is high. These findings suggest a fundamentally distinct mechanism of arrhythmogenesis for congenital LQTS-3. 10.1161/hh0701.089668
    De novo mutation in the SCN5A gene associated with early onset of sudden infant death. Wedekind H,Smits J P,Schulze-Bahr E,Arnold R,Veldkamp M W,Bajanowski T,Borggrefe M,Brinkmann B,Warnecke I,Funke H,Bhuiyan Z A,Wilde A A,Breithardt G,Haverkamp W Circulation BACKGROUND:Congenital long QT syndrome (LQTS), a cardiac ion channel disease, is an important cause of sudden cardiac death. Prolongation of the QT interval has recently been associated with sudden infant death syndrome, which is the leading cause of death among infants between 1 week and 1 year of age. Available data suggest that early onset of congenital LQTS may contribute to premature sudden cardiac death in otherwise healthy infants. METHODS AND RESULTS:In an infant who died suddenly at the age of 9 weeks, we performed mutation screening in all known LQTS genes. In the surface ECG soon after birth, a prolonged QTc interval (600 ms(1/2)) and polymorphic ventricular tachyarrhythmias were documented. Mutational analysis identified a missense mutation (Ala1330Pro) in the cardiac sodium channel gene SCN5A, which was absent in both parents. Subsequent genetic testing confirmed paternity, thus suggesting a de novo origin. Voltage-clamp recordings of recombinant A1330P mutant channel expressed in HEK-293 cells showed a positive shift in voltage dependence of inactivation, a slowing of the time course of inactivation, and a faster recovery from inactivation. CONCLUSIONS:In this study, we report a de novo mutation in the sodium channel gene SCN5A, which is associated with sudden infant death. The altered functional characteristics of the mutant channel was different from previously reported LQTS3 mutants and caused a delay in final repolarization. Even in families without a history of LQTS, de novo mutations in cardiac ion channel genes may lead to sudden cardiac death in very young infants. 10.1161/hc3501.095361
    Gating-dependent mechanisms for flecainide action in SCN5A-linked arrhythmia syndromes. Viswanathan P C,Bezzina C R,George A L,Roden D M,Wilde A A,Balser J R Circulation BACKGROUND:Mutations in the cardiac sodium (Na) channel gene (SCN5A) give rise to the congenital long-QT syndrome (LQT3) and the Brugada syndrome. Na channel blockade by antiarrhythmic drugs improves the QT interval prolongation in LQT3 but worsens the Brugada syndrome ST-segment elevation. Although Na channel blockade has been proposed as a treatment for LQT3, flecainide also evokes "Brugada-like" ST-segment elevation in LQT3 patients. Here, we examine how Na channel inactivation gating defects in LQT3 and Brugada syndrome elicit proarrhythmic sensitivity to flecainide. METHODS AND RESULTS:We measured whole-cell Na current (I(Na)) from tsA-201 cells transfected with DeltaKPQ, a LQT3 mutation, and 1795insD, a mutation that provokes both the LQT3 and Brugada syndromes. The 1795insD and DeltaKPQ channels both exhibited modified inactivation gating (from the closed state), thus potentiating tonic I(Na) block. Flecainide (1 micromol/L) tonic block was only 16.8+/-3.0% for wild type but was 58.0+/-6.0% for 1795insD (P<0.01) and 39.4+/-8.0% (P<0.05) for DeltaKPQ. In addition, the 1795insD mutation delayed recovery from inactivation by enhancing intermediate inactivation, with a 4-fold delay in recovery from use-dependent flecainide block. CONCLUSIONS:We have linked 2 inactivation gating defects ("closed-state" fast inactivation and intermediate inactivation) to flecainide sensitivity in patients carrying LQT3 and Brugada syndrome mutations. These results provide a mechanistic rationale for predicting proarrhythmic sensitivity to flecainide based on the identification of specific SCN5A inactivation gating defects. 10.1161/hc3501.093797
    Sympathetic stimulation produces a greater increase in both transmural and spatial dispersion of repolarization in LQT1 than LQT2 forms of congenital long QT syndrome. Tanabe Y,Inagaki M,Kurita T,Nagaya N,Taguchi A,Suyama K,Aihara N,Kamakura S,Sunagawa K,Nakamura K,Ohe T,Towbin J A,Priori S G,Shimizu W Journal of the American College of Cardiology OBJECTIVES:The study compared the influence of sympathetic stimulation on transmural and spatial dispersion of repolarization between LQT1 and LQT2 forms of congenital long QT sYndrome (LQTS). BACKGROUND:Cardiac events are more associated with sympathetic stimulation in LQT1 than in LQT2 or LQT3 syndrome. Experimental studies have suggested that the interval between Tpeak and Tend (Tp-e) in the electrocardiogram (ECG) reflects transmural dispersion of repolarization across the ventricular wall. METHODS:We recorded 87-lead body-surface ECGs before and after epinephrine infusion (0.1 microg/kg/min) in 13 LQT1, 6 LQT2, and 7 control patients. The Q-Tend (QT-e), Q-Tpeak (QT-p), and Tp-e were measured automatically from 87-lead ECGs, corrected by Bazett's method (QTc-e, QTc-p, Tcp-e), and averaged among all 87-leads and among 24-leads, which reflect the potential from the left ventricular free wall. As an index of spatial dispersion of repolarization, the dispersion of QTc-e (QTc-eD) and QTc-p (QTc-pD) were obtained among 87-leads and among 24-leads, and were defined as the interval between the maximum and the minimum of the QTc-e and the QTc-p, respectively. RESULTS:Epinephrine significantly increased the mean QTc-e but not the mean QTc-p, resulting in a significant increase in the mean Tcp-e in both LQT1 and LQT2, but not in control patients. The epinephrine-induced increases in the mean QTc-e and Tcp-e were larger in LQT1 than in LQT2, and were more pronounced when the averaged data were obtained from 24-leads than from 87-leads. Epinephrine increased the maximum QTc-e but not the minimum QTc-e, producing a significant increase in the QTc-eD in both LQT1 and LQT2 patients, but not in control patients. The increase in the QTc-eD was larger in LQT1 than in LQT2 patients. CONCLUSIONS:Our data suggest that sympathetic stimulation produces a greater increase in both transmural and spatial dispersion of repolarization in LQT1 than in LQT2 syndrome, and this may explain why LQT1 patients are more sensitive to sympathetic stimulation. 10.1016/s0735-1097(00)01200-6
    Gene-specific response of dynamic ventricular repolarization to sympathetic stimulation in LQT1, LQT2 and LQT3 forms of congenital long QT syndrome. Noda T,Takaki H,Kurita T,Suyama K,Nagaya N,Taguchi A,Aihara N,Kamakura S,Sunagawa K,Nakamura K,Ohe T,Horie M,Napolitano C,Towbin J A,Priori S G,Shimizu W European heart journal AIMS:Differences in the sensitivity of the genotype of the congenital long QT syndrome to sympathetic stimulation have been suggested. This study compared the influence of sympathetic stimulation on continuous corrected QT (QTc) intervals between LQT1, LQT2 and LQT3 forms of the congenital long QT syndrome. METHODS AND RESULTS:We recorded a 12-lead electrocardiogram continuously before and after bolus injection (0.1 microg x kg(-1)) of epinephrine followed by continuous infusion (0.1 microg x kg(-1) min(-1)) in 12 LQT1, 10 LQT2, 6 LQT3, and 13 control patients. The QT intervals and previous RR intervals of all beats were measured semi-automatically, and the QTc intervals of all beats were calculated by Bazett's method. The dynamic response of the RR interval to epinephrine was no different between the four groups. The QTc was prolonged remarkably (477+/-42 to 631+/- 59 ms; P<0.0005, % delta prolongation =+32%) as the RR was maximally decreased (at peak of epinephrine), and remained prolonged at steady state conditions of epinephrine (556+/-56 ms; P<0.0005 vs baseline, +17%) in LQT1 patients. Epinephrine also prolonged the QTc dramatically (502+/-23 to 620+/-39 ms; P<0.0005, +24%) at peak of epinephrine in LQT2 patients, but this shortened to baseline levels at steady state (531+/-25 ms; P=ns vs baseline, +6%). The QTc was much less prolonged at peak of epinephrine in LQT3 (478+/-44 to 532+/-41 ms; P<0.05, +11%) and controls (394+/-21 to 456+/-18 ms; P<0.0005, +16%) than in LQT1 and LQT2 patients, and shortened to the baseline levels (LQT3; 466+/-49 ms, -3%, controls; 397+/-16 ms, +1%; P=ns vs baseline) at steady state. CONCLUSION:Our data suggest that the dynamic response of ventricular repolarization to sympathetic stimulation differs between LQT1, LQT2 and LQT3 syndromes, and may explain why the trigger of cardiac events differs between the genotypes. 10.1053/euhj.2001.3079
    Differential effects of beta-blockade on dispersion of repolarization in the absence and presence of sympathetic stimulation between the LQT1 and LQT2 forms of congenital long QT syndrome. Shimizu Wataru,Tanabe Yasuko,Aiba Takeshi,Inagaki Masashi,Kurita Takashi,Suyama Kazuhiro,Nagaya Noritoshi,Taguchi Atsushi,Aihara Naohiko,Sunagawa Kenji,Nakamura Kazufumi,Ohe Tohru,Towbin Jeffrey A,Priori Silvia G,Kamakura Shiro Journal of the American College of Cardiology OBJECTIVES:This study compared the effects of beta-blockade on transmural and spatial dispersion of repolarization (TDR and SDR, respectively) between the LQT1 and LQT2 forms of congenital long QT syndrome (LQTS). BACKGROUND:The LQT1 form is more sensitive to sympathetic stimulation and more responsive to beta-blockers than either the LQT2 or LQT3 forms. METHODS:Eighty-seven-lead, body-surface electrocardiograms (ECGs) were recorded before and after epinephrine infusion (0.1 microg/kg body weight per min) in the absence and presence of oral propranolol (0.5-2.0 mg/kg per day) in 11 LQT1 patients and 11 LQT2 patients. The Q-T(end) interval, the Q-T(peak) interval and the interval between T(peak) and T(end) (T(p-e)), representing TDR, were measured and averaged from 87-lead ECGs and corrected by Bazett's method (corrected Q-T(end) interval [cQT(e)], corrected Q-T(peak) interval [cQT(p)] and corrected interval between T(peak) and T(end) [cT(p-e)]). The dispersion of cQT(e) (cQT(e)-D) was obtained among 87 leads and was defined as the interval between the maximum and minimum values of cQT(e). RESULTS:Propranolol in the absence of epinephrine significantly prolonged the mean cQT(p) value but not the mean cQT(e) value, thus decreasing the mean cT(p-e) value in both LQT1 and LQT2 patients; the differences with propranolol were significantly larger in LQT1 than in LQT2 (p < 0.05). The maximum cQT(e), minimum cQT(e) and cQT(e)-D were not changed with propranolol. Propranolol completely suppressed the influence of epinephrine in prolonging the mean cQT(e), maximum cQT(e) and minimum cQT(e) values, as well as increasing the mean cT(p-e) and cQT(e)-D values in both groups. CONCLUSIONS:Beta-blockade under normal sympathetic tone produces a greater decrease in TDR in the LQT1 form than in the LQT2 form, explaining the superior effectiveness of beta-blockers in LQT1 versus LQT2. Beta-blockers also suppress the influence of sympathetic stimulation in increasing TDR and SDR equally in LQT1 and LQT2 syndrome. 10.1016/s0735-1097(02)01894-6
    Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). Tristani-Firouzi Martin,Jensen Judy L,Donaldson Matthew R,Sansone Valeria,Meola Giovanni,Hahn Angelika,Bendahhou Said,Kwiecinski Hubert,Fidzianska Anna,Plaster Nikki,Fu Ying-Hui,Ptacek Louis J,Tawil Rabi The Journal of clinical investigation 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. 10.1172/JCI15183
    Insights into the molecular mechanisms of bradycardia-triggered arrhythmias in long QT-3 syndrome. Clancy Colleen E,Tateyama Michihiro,Kass Robert S The Journal of clinical investigation Congenital long QT syndrome is a rare disease in which the electrocardiogram QT interval is prolonged due to dysfunctional ventricular repolarization. Variant 3 (LQT-3) is associated with mutations in SCN5A, the gene coding for the heart Na(+) channel alpha subunit. Arrhythmias in LQT-3 mutation carriers are more likely to occur at rest, when heart rate is slow. Several LQT-3 Na(+) channel mutations exert their deleterious effects by promoting a mode of Na(+) channel gating wherein a fraction of channels fails to inactivate. This gating mode, termed "bursting, " results in sustained macroscopic inward Na(+) channel current (I(sus)), which can delay repolarization and prolong the QT interval. However, the mechanism of heart-rate dependence of I(sus) has been unresolved at the single-channel level. We investigate an LQT-3 mutant (Y1795C) using experimental and theoretical frameworks to elucidate the molecular mechanism of I(sus) rate dependence. Our results indicate that mutation-induced changes in the length of time mutant channels spend bursting, rather than how readily they burst, determines I(sus) inverse heart-rate dependence. Our results indicate that mutation-induced changes in the length of time mutant channels spend bursting, rather than how readily they burst, determines I(sus) inverse heart-rate dependence. These results link mutation-induced changes in Na+ channel gating mode transitions to heart rate-dependent changes in cellular electrical activity underlying a key LQT-3 clinical phenotype. 10.1172/JCI15928
    Novel insights in the congenital long QT syndrome. Wehrens Xander H T,Vos Marc A,Doevendans Pieter A,Wellens Hein J J Annals of internal medicine BACKGROUND:The congenital long QT syndrome is a potentially fatal, inherited cardiac syndrome. Early diagnosis and preventive treatment are instrumental to prevent sudden cardiac death in patients with the congenital long QT syndrome. PURPOSE:To review new insights in genetics and cellular electrophysiology, as well as the current understanding of the clinical diagnosis and treatment of the congenital long QT syndrome. DATA SOURCES:Authors' personal databases and search of PubMed database from 1966 to 2001. STUDY SELECTION:Experimental and clinical studies on the congenital long QT syndrome. DATA EXTRACTION:Data from peer-reviewed studies were manually extracted, classified, and summarized. DATA SYNTHESIS:The congenital long QT syndrome is characterized by abnormally prolonged ventricular repolarization, which predisposes patients to syncope, ventricular arrhythmias, and sudden cardiac death. The recent discovery of mutations in genes encoding ion channels has improved our understanding of the cellular origin of this condition. The congenital long QT syndrome may result from inherited defects in cardiac K+ and Na+ channels, which both result in prolongation of the ventricular action potential. The diagnosis is based on electrocardiographic and clinical criteria. Genetic screening of symptomatic patients or asymptomatic family members may identify patients at risk for life-threatening ventricular arrhythmias. beta-Blocking agents are the mainstay of treatment. Certain patients may also benefit from a pacemaker or implantable cardioverter defibrillator. Recent studies suggest that genotype-specific treatment of the congenital long QT syndrome will be feasible in the near future. CONCLUSIONS:The congenital long QT syndrome is a potentially life-threatening condition caused by mutations in genes encoding cardiac ion channels. Better understanding of the mechanisms responsible for this condition will guide genotype-specific therapy in the near future. 10.7326/0003-4819-137-12-200212170-00012
    Epinephrine unmasks latent mutation carriers with LQT1 form of congenital long-QT syndrome. Shimizu Wataru,Noda Takashi,Takaki Hiroshi,Kurita Takashi,Nagaya Noritoshi,Satomi Kazuhiro,Suyama Kazuhiro,Aihara Naohiko,Kamakura Shiro,Sunagawa Kenji,Echigo Shigeyuki,Nakamura Kazufumi,Ohe Tohru,Towbin Jeffrey A,Napolitano Carlo,Priori Silvia G Journal of the American College of Cardiology OBJECTIVES:This study was designed to test the hypothesis that epinephrine infusion may be a provocative test able to unmask nonpenetrant KCNQ1 mutation carriers. BACKGROUND:The LQT1 form of congenital long QT syndrome is associated with high vulnerability to sympathetic stimulation and appears with incomplete penetrance. METHODS:The 12-lead electrocardiographic parameters before and after epinephrine infusion were compared among 19 mutation carriers with a baseline corrected QT interval (QTc) of > or =460 ms (Group I), 15 mutation carriers with a QTc of <460 ms (Group II), 12 nonmutation carriers (Group III), and 15 controls (Group IV). RESULTS:The mean corrected Q-Tend (QTce), Q-Tpeak (QTcp), and Tpeak-end (Tcp-e) intervals among 12-leads before epinephrine were significantly larger in Group I than in the other three groups. Epinephrine (0.1 microg/kg/min) increased significantly the mean QTce, QTcp, Tcp-e, and the dispersion of QTcp in Groups I and II, but not in Groups III and IV. The sensitivity and specificity of QTce measurements to identify mutation carriers were 59% (20/34) and 100% (27/27), respectively, before epinephrine, and the sensitivity was substantially improved to 91% (31/34) without the expense of specificity (100%, 27/27) after epinephrine. The mean QTce, QTcp, and Tcp-e before and after epinephrine were significantly larger in 15 symptomatic than in 19 asymptomatic mutation carriers in Groups I and II, and the prolongation of the mean QTce with epinephrine was significantly larger in symptomatic patients. CONCLUSIONS:Epinephrine challenge is a powerful test to establish electrocardiographic diagnosis in silent LQT1 mutation carriers, thus allowing implementation of prophylactic measures aimed at reducing sudden cardiac death. 10.1016/s0735-1097(02)02850-4
    A new oral therapy for long QT syndrome: long-term oral potassium improves repolarization in patients with HERG mutations. Etheridge Susan P,Compton Steven J,Tristani-Firouzi Martin,Mason Jay W Journal of the American College of Cardiology OBJECTIVES:We sought to determine whether oral potassium supplementation safely increases serum K(+) and results in sustained improvement of repolarization parameters in long QT syndrome type 2 (LQT2) subjects. BACKGROUND:Mutations in HERG (LQT2), the gene encoding the rapid delayed rectifier K(+) current I(Kr), account for a significant proportion of congenital long QT syndrome (LQTS). The magnitude of I(Kr) is paradoxically increased by an increase in extracellular K(+). We tested the hypothesis that long-term oral potassium supplementation results in a mild, sustainable increase in serum K(+) that improves repolarization abnormalities in subjects with LQT2. METHODS:After an initial evaluation consisting of electrocardiography, electrolytes, blood urea nitrogen, and creatinine, escalating doses of potassium chloride (KCl) and spironolactone were administered to eight subjects with six distinct HERG mutations. Medications were continued for four weeks, at which time, the final evaluation was undertaken. Beta-adrenergic blocking therapy was maintained. RESULTS:The subjects ranged in age from 11 to 52 years. The average daily KCl and spironolactone dose was 3.3 +/- 1.5 mEq/kg and 3.5 +/- 1.2 mg/kg, respectively, and this regimen resulted in an increase in serum K(+) from 4.0 +/- 0.3 to 5.2 +/- 0.3 mEq/l. There were no serious complications associated with therapy. The increase in serum K(+) resulted in a decrease in the corrected QT interval from 526 +/- 94 to 423 +/- 36 ms (mean +/- SD; lead V(2)). Both QT dispersion and T-wave morphology improved in most subjects. CONCLUSIONS:Long-term oral potassium administration increases serum K(+) in patients with LQT2. This can be achieved safely and results in improvement in repolarization. Further studies are warranted to determine whether this will reduce the incidence of life-threatening events in LQTS patients. 10.1016/j.jacc.2003.07.006
    Mutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation in the LQT1 form of congenital long QT syndrome: multicenter study in Japan. Shimizu Wataru,Horie Minoru,Ohno Seiko,Takenaka Kotoe,Yamaguchi Masato,Shimizu Masami,Washizuka Takashi,Aizawa Yoshifusa,Nakamura Kazufumi,Ohe Tohru,Aiba Takeshi,Miyamoto Yoshihiro,Yoshimasa Yasunao,Towbin Jeffrey A,Priori Silvia G,Kamakura Shiro Journal of the American College of Cardiology OBJECTIVES:We sought to compare the arrhythmic risk and sensitivity to sympathetic stimulation of mutations located in transmembrane regions and C-terminal regions of the KCNQ1 channel in the LQT1 form of congenital long QT syndrome (LQTS). BACKGROUND:The LQT1 syndrome is frequently manifested with variable expressivity and incomplete penetrance and is much more sensitive to sympathetic stimulation than the other forms. METHODS:Sixty-six LQT1 patients (27 families) with a total of 19 transmembrane mutations and 29 patients (10 families) with 8 C-terminal mutations were enrolled from five Japanese institutes. RESULTS:Patients with transmembrane mutations were more frequently affected based on electrocardiographic (ECG) diagnostic criteria (82% vs. 24%, p < 0.0001) and had more frequent LQTS-related cardiac events (all cardiac events: 55% vs. 21%, p = 0.002; syncope: 55% vs. 21%, p = 0.002; aborted cardiac arrest or unexpected sudden cardiac death: 15% vs. 0%, p = 0.03) than those with C-terminal mutations. Patients with transmembrane mutations had a greater risk of first cardiac events occurring at an earlier age, with a hazard ratio of 3.4 (p = 0.006) and with an 8% increase in risk per 10-ms increase in corrected Q-Tend. The baseline ECG parameters, including Q-Tend, Q-Tpeak, and Tpeak-end intervals, were significantly greater in patients with transmembrane mutations than in those with C-terminal mutations (p < 0.005). Moreover, the corrected Q-Tend and Tpeak-end were more prominently increased with exercise in patients with transmembrane mutations (p < 0.005). CONCLUSIONS:In this multicenter Japanese population, LQT1 patients with transmembrane mutations are at higher risk of congenital LQTS-related cardiac events and have greater sensitivity to sympathetic stimulation, as compared with patients with C-terminal mutations. 10.1016/j.jacc.2004.03.043
    Classification and mechanism of Torsade de Pointes initiation in patients with congenital long QT syndrome. Noda Takashi,Shimizu Wataru,Satomi Kazuhiro,Suyama Kazuhiro,Kurita Takashi,Aihara Naohiko,Kamakura Shiro European heart journal AIMS:To examine the initiating mode of Torsade de Pointes (TdP) in patients with congenital long QT syndrome (LQTS). METHODS AND RESULTS:We evaluated 111 episodes of TdP recorded on the electrocardiograms of 24 patients with congenital LQTS, and clarified the initiating mode, the three consecutive preceding RR intervals defined as C(2), C(1), and C(0), the timing of initiating premature ventricular contraction (PVC) and the cycle length (CL) of TdP. Three different initiating patterns were observed: (1) a "short-long-short" sequence (SLS) pattern (23 patients, 72 TdP, 65%) defined as one or more short-long cardiac cycles followed by an initiating short-coupled PVC (C(1)>C(2) and C(0)), (2) an "increased sinus rate" (ISR) pattern (8 patients, 28 TdP, 25%) defined as a gradual increase in sinus rate with or without T-wave alternans (C(2)>/=C(1)>/=C(0)), and (3) a "changed depolarization" (CD) pattern (5 patients, 11 TdP, 10%) defined as a sudden long-coupled PVC or fusion beat followed by short-coupled PVC. The C(0) was shorter in ISR than SLS and CD (mean C(0): 488 vs. 587 and 603 ms, respectively; P<0.05). Therefore, the initiating PVC appeared near the T-wave peak of the last beat before onset in ISR, while it occurred after the T-wave peak in SLS and CD. The CL of TdP was shorter in ISR than in SLS (256 vs. 295 ms, P<0.05). CONCLUSIONS:Our data show the existence of three predominant initiating modes of TdP in patients with congenital LQTS and suggests a differential mechanism of initiation of TdP for each mode. 10.1016/j.ehj.2004.08.020
    KCNH2-K897T is a genetic modifier of latent congenital long-QT syndrome. Crotti Lia,Lundquist Andrew L,Insolia Roberto,Pedrazzini Matteo,Ferrandi Chiara,De Ferrari Gaetano M,Vicentini Alessandro,Yang Ping,Roden Dan M,George Alfred L,Schwartz Peter J Circulation BACKGROUND:Clinical heterogeneity among patients with long-QT syndrome (LQTS) sharing the same disease-causing mutation is usually attributed to variable penetrance. One potential explanation for this phenomenon is the coexistence of modifier gene alleles, possibly common single nucleotide polymorphisms, altering arrhythmia susceptibility. We demonstrate this concept in a family segregating a novel, low-penetrant KCNH2 mutation along with a common single nucleotide polymorphism in the same gene. METHODS AND RESULTS:The proband is a 44-year-old white woman with palpitations associated with presyncope since age 20, who presented with ventricular fibrillation and cardiac arrest. Intermittent QT prolongation was subsequently observed (max QTc, 530 ms), and LQT2 was diagnosed after the identification of a missense KCNH2 mutation (A1116V) altering a conserved residue in the distal carboxyl-terminus of the encoded HERG protein. The proband also carried the common KCNH2 polymorphism K897T on the nonmutant allele. Relatives who carried A1116V without K897T were asymptomatic, but some exhibited transient mild QTc prolongation, suggesting latent disease. Heterologous expression studies performed in cultured mammalian cells and using bicistronic vectors linked to different fluorescent proteins demonstrated that coexpression of A1116V with K897T together resulted in significantly reduced current amplitude as compared with coexpression of either allele with WT-HERG. Thus, the presence of KCNH2-K897T is predicted to exaggerate the IKr reduction caused by the A1116V mutation. These data explain why symptomatic LQTS occurred only in the proband carrying both alleles. CONCLUSIONS:We have provided evidence that a common KCNH2 polymorphism may modify the clinical expression of a latent LQT2 mutation. A similar mechanism may contribute to the risk for sudden death in more prevalent cardiac diseases. 10.1161/CIRCULATIONAHA.105.549071
    Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population. Brink Paul A,Crotti Lia,Corfield Valerie,Goosen Althea,Durrheim Glenda,Hedley Paula,Heradien Marshall,Geldenhuys Gerhard,Vanoli Emilio,Bacchini Sara,Spazzolini Carla,Lundquist Andrew L,Roden Dan M,George Alfred L,Schwartz Peter J Circulation BACKGROUND:In the congenital long-QT syndrome (LQTS), there can be a marked phenotypic heterogeneity. Founder effects, by which many individuals share a mutation identical by descent, represent a powerful tool to further understand the underlying mechanisms and to predict the natural history of mutation-associated effects. We are investigating one such founder effect, originating in South Africa in approximately ad 1700 and segregating the same KCNQ1 mutation (A341V). METHODS AND RESULTS:The study population involved 320 subjects, 166 mutation carriers (MCs) and 154 noncarriers. When not taking beta-blocker therapy, MCs had a wide range of QTc values (406 to 676 ms), and 12% of individuals had a normal QTc (< or =440 ms). A QTc >500 ms was associated with increased risk for cardiac events (OR=4.22; 95% CI, 1.12 to 15.80; P=0.033). We also found that MCs with a heart rate <73 bpm were at significantly lower risk (OR=0.23; 95% CI, 0.06 to 0.86; P=0.035). This study also unexpectedly determined that KCNQ1-A341V is associated with greater risk than that reported for large databases of LQT1 patients: A341V MCs are more symptomatic by age 40 years (79% versus 30%) and become symptomatic earlier (7+/-4 versus 13+/-9 years, both P<0.001). Accordingly, functional studies of KCNQ1-A341V in CHO cells stably expressing IKs were conducted and identified a dominant negative effect of the mutation on wild-type channels. CONCLUSIONS:KCNQ1-A341V is a mutation associated with an unusually severe phenotype, most likely caused by the dominant negative effect of the mutation. The availability of an extended kindred with a common mutation allowed us to identify heart rate, an autonomic marker, as a novel risk factor. 10.1161/CIRCULATIONAHA.105.572453
    Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism. Anderson Corey L,Delisle Brian P,Anson Blake D,Kilby Jennifer A,Will Melissa L,Tester David J,Gong Qiuming,Zhou Zhengfeng,Ackerman Michael J,January Craig T Circulation BACKGROUND:The KCNH2 or human ether-a-go-go related gene (hERG) encodes the Kv11.1 alpha-subunit of the rapidly activating delayed rectifier K+ current (IKr) in the heart. Type 2 congenital long-QT syndrome (LQT2) results from KCNH2 mutations that cause loss of Kv11.1 channel function. Several mechanisms have been identified, including disruption of Kv11.1 channel synthesis (class 1), protein trafficking (class 2), gating (class 3), or permeation (class 4). For a few class 2 LQT2-Kv11.1 channels, it is possible to increase surface membrane expression of Kv11.1 current (IKv11.1). We tested the hypotheses that (1) most LQT2 missense mutations generate trafficking-deficient Kv11.1 channels, and (2) their trafficking-deficient phenotype can be corrected. METHODS AND RESULTS:Wild-type (WT)-Kv11.1 channels and 34 missense LQT2-Kv11.1 channels were expressed in HEK293 cells. With Western blot analyses, 28 LQT2-Kv11.1 channels had a trafficking-deficient (class 2) phenotype. For the majority of these mutations, the class 2 phenotype could be corrected when cells were incubated for 24 hours at reduced temperature (27 degrees C) or in the drugs E4031 or thapsigargin. Four of the 6 LQT2-Kv11.1 channels that had a wild-type-like trafficking phenotype did not cause loss of Kv11.1 function, which suggests that these channels are uncommon sequence variants. CONCLUSIONS:This is the first study to identify a dominant mechanism, class 2, for the loss of Kv11.1 channel function in LQT2 and to report that the class 2 phenotype for many of these mutant channels can be corrected. This suggests that if therapeutic strategies to correct protein trafficking abnormalities can be developed, it may offer clinical benefits for LQT2 patients. 10.1161/CIRCULATIONAHA.105.570200
    Epinephrine QT stress testing in the evaluation of congenital long-QT syndrome: diagnostic accuracy of the paradoxical QT response. Vyas Himeshkumar,Hejlik Joseph,Ackerman Michael J Circulation BACKGROUND:A paradoxical increase in the uncorrected QT interval during infusion of low-dose epinephrine appears pathognomonic for type 1 long-QT syndrome (LQT1). We sought to determine the diagnostic accuracy of this response among patients referred for clinical evaluation of congenital long-QT syndrome (LQTS). METHODS AND RESULTS:From 1999 to 2002, 147 genotyped patients (125 untreated and 22 undergoing beta-blocker therapy) had an epinephrine QT stress test that involved a 25-minute infusion protocol (0.025 to 0.3 microg.kg(-1).min(-1)). A 12-lead ECG was monitored continuously, and repolarization parameters were measured. The sensitivity, specificity, and positive and negative predictive values for the paradoxical QT response (defined as a > or =30-ms increase in QT during infusion of < or =0.1 microg.kg(-1).min(-1) epinephrine) was determined. The 125 untreated patients (44 genotype negative, 40 LQT1, 30 LQT2, and 11 LQT3) constituted the primary analysis. The median baseline corrected QT intervals (QTc) were 444 ms (gene negative), 456 ms (LQT1), 486 ms (LQT2), and 473 ms (LQT3). The median change in QT interval during low-dose epinephrine infusion was -23 ms in the gene-negative group, 78 ms in LQT1, -4 ms in LQT2, and -58 ms in LQT3. The paradoxical QT response was observed in 37 (92%) of 40 patients with LQT1 compared with 18% (gene-negative), 13% (LQT2), and 0% (LQT3; P<0.0001) of the remaining patients. Overall, the paradoxical QT response had a sensitivity of 92.5%, specificity of 86%, positive predictive value of 76%, and negative predictive value of 96% for LQT1 status. Secondary analysis of the subset undergoing beta-blocker therapy indicated inferior diagnostic utility in this setting. CONCLUSIONS:The epinephrine QT stress test can unmask concealed type 1 LQTS with a high level of accuracy. 10.1161/CIRCULATIONAHA.105.600445
    Cost-effectiveness of neonatal ECG screening for the long QT syndrome. Quaglini Silvana,Rognoni Carla,Spazzolini Carla,Priori Silvia G,Mannarino Savina,Schwartz Peter J European heart journal AIMS:A significant number of preventable cardiac deaths in infancy and childhood are due to long QT syndrome (LQTS) and to unrecognized neonatal congenital heart diseases (CHDs). Both carry a serious risk for avoidable mortality and morbidity but effective treatments exist to prevent lethal arrhythmias or to allow early surgical correction before death or irreversible cardiac damage. As an electrocardiogram (ECG) allows recognition of LQTS and of some of the CHDs that have escaped medical diagnosis, and as LQTS also contributes to sudden infant death syndrome, we have analysed the cost-effectiveness of a nationwide programme of neonatal ECG screening. Our primary analysis focused on LQTS alone; a secondary analysis focused on the possibility of identifying some CHDs also. METHODS AND RESULTS:A decision analysis approach was used, building a decision tree for the strategies 'screening'-'no screening'. Markov processes were used to simulate the natural or clinical histories of the patients. To assess the impact of potential errors in the estimates of the model parameters, a Monte Carlo sensitivity analysis was performed by varying all baseline values by +/-30%. Incremental cost-effectiveness analysis for the primary analysis shows that with the screening programme, the cost per year of life saved is very low: 11,740 euro. The cost for saving one entire life of 70 years would be 820,000 euro. Even by varying model parameters by +/-30%, the cost per year of life saved remains between 7400 euro and 20,400 euro. These figures define 'highly cost-effective' screening programmes. The secondary analysis provides even more cost-effective results. CONCLUSION:A programme of neonatal ECG screening performed in a large European country is cost-effective. An ECG performed in the first month of life will allow the early identification of still asymptomatic infants with LQTS and also of infants with some correctable CHDs not recognized by routine neonatal examinations. Appropriate therapy will prevent unnecessary deaths in infants, children, and young adults. 10.1093/eurheartj/ehl115
    Defining the cellular phenotype of "ankyrin-B syndrome" variants: human ANK2 variants associated with clinical phenotypes display a spectrum of activities in cardiomyocytes. Mohler Peter J,Le Scouarnec Solena,Denjoy Isabelle,Lowe John S,Guicheney Pascale,Caron Lise,Driskell Iwona M,Schott Jean-Jacques,Norris Kris,Leenhardt Antoine,Kim Richard B,Escande Denis,Roden Dan M Circulation BACKGROUND:Mutations in the ankyrin-B gene (ANK2) cause type 4 long-QT syndrome and have been described in kindreds with other arrhythmias. The frequency of ANK2 variants in large populations and molecular mechanisms underlying the variability in the clinical phenotypes are not established. More importantly, there is no cellular explanation for the range of severity of cardiac phenotypes associated with specific ANK2 variants. METHODS AND RESULTS:We performed a comprehensive screen of ANK2 in populations (control, congenital arrhythmia, drug-induced long-QT syndrome) of different ethnicities to discover unidentified ANK2 variants. We identified 7 novel nonsynonymous ANK2 variants; 4 displayed abnormal activity in cardiomyocytes. Including the 4 new variants, 9 human ANK2 loss-of-function variants have been identified. However, the clinical phenotypes associated with these variants vary strikingly, from no obvious phenotype to manifest long-QT syndrome and sudden death, suggesting that mutants confer a spectrum of cellular phenotypes. We then characterized the relative severity of loss-of-function properties of all 9 nonsynonymous ANK2 variants identified to date in primary cardiomyocytes and identified a range of in vitro phenotypes, including wild-type, simple loss-of-function, and severe loss-of-function activity, seen with the variants causing severe human phenotypes. CONCLUSIONS:We present the first description of differences in cellular phenotypes conferred by specific ANK2 variants. We propose that the various degrees of ankyrin-B loss of function contribute to the range of severity of cardiac dysfunction. These data identify ANK2 variants as modulators of human arrhythmias, provide the first insight into the clinical spectrum of "ankyrin-B syndrome," and reinforce the role of ankyrin-B-dependent protein interactions in regulating cardiac electrogenesis. 10.1161/CIRCULATIONAHA.106.656512
    Female predominance and transmission distortion in the long-QT syndrome. Imboden Medea,Swan Heikki,Denjoy Isabelle,Van Langen Irene Marijke,Latinen-Forsblom Päivi Johanna,Napolitano Carlo,Fressart Véronique,Breithardt Guenter,Berthet Myriam,Priori Silvia,Hainque Bernard,Wilde Arthur Arnold Maria,Schulze-Bahr Eric,Feingold Josué,Guicheney Pascale The New England journal of medicine BACKGROUND:Congenital long-QT syndrome is a disorder resulting in ventricular arrhythmias and sudden death. The most common forms of the long-QT syndrome, types 1 and 2, are caused by mutations in the potassium-channel genes KCNQ1 and KCNH2, respectively. Although inheritance of the long-QT syndrome is autosomal dominant, female predominance has often been observed and has been attributed to an increased susceptibility to cardiac arrhythmias in women. We investigated the possibility of an unbalanced transmission of the deleterious trait. METHODS:We investigated the distribution of alleles for the long-QT syndrome in 484 nuclear families with type 1 disease and 269 nuclear families with type 2 disease, all with fully genotyped offspring. The families were recruited in five European referral centers for the long-QT syndrome. Mutation segregation, sex ratio, and parental transmission were analyzed after correction for single ascertainment. RESULTS:Classic mendelian inheritance ratios were not observed in the offspring of either female carriers of the long-QT syndrome type 1 or male and female carriers of the long-QT syndrome type 2. Among the 1534 descendants, the proportion of genetically affected offspring was significantly greater than that expected according to mendelian inheritance: 870 were carriers of a mutation (57%), and 664 were noncarriers (43%, P<0.001). Among the 870 carriers, the allele for the long-QT syndrome was transmitted more often to female offspring (476 [55%]) than to male offspring (394 [45%], P=0.005). Increased maternal transmission of the long-QT syndrome mutations to daughters was also observed, possibly contributing to the excess of female patients with autosomal dominant long-QT syndrome. CONCLUSIONS:Positive selection of the mutated alleles that cause the long-QT syndrome leads to transmission distortion, with increased proportions of mutation carriers among the offspring of affected families. Alleles for the long-QT syndrome are more often transmitted to daughters than to sons. 10.1056/NEJMoa042786
    Corrected QT variability in serial electrocardiograms in long QT syndrome: the importance of the maximum corrected QT for risk stratification. Goldenberg Ilan,Mathew Jehu,Moss Arthur J,McNitt Scott,Peterson Derick R,Zareba Wojciech,Benhorin Jesaia,Zhang Li,Vincent G Michael,Andrews Mark L,Robinson Jennifer L,Morray Brian Journal of the American College of Cardiology OBJECTIVES:We evaluated the incremental prognostic information provided by multiple corrected QT (QTc) measurements on serial electrocardiograms (ECGs) in patients with the inherited long QT syndrome (LQTS). BACKGROUND:A baseline QTc of > or =500 ms has been shown to be associated with increased risk of cardiac events among LQTS patients. However, the value of QTc measurements on follow-up ECGs in risk assessment has not been determined. METHODS:The risk of a first LQTS-related cardiac event during adolescence was assessed in 375 patients enrolled in the International LQTS Registry for whom serial follow-up ECGs were recorded before age 10. RESULTS:The mean +/- SD difference between the minimum and maximum QTc values on serial ECGs recorded in study patients was 47 +/- 40 ms. The maximum QTc interval recorded before age 10 was the strongest predictor of cardiac events during adolescence (adjusted hazard ratio [HR] = 2.74; p < 0.001). Other follow-up QTc measures, including the baseline, the mean, and the most recent QTc interval recorded before age 10, were less significant risk factors. After adjusting for the maximum QTc value during follow-up, no significant association remained between the baseline QTc value and the risk of subsequent cardiac events (HR = 1.04; p = 0.91). CONCLUSIONS:In LQTS patients, there is a considerable variability in QTc measures in serial follow-up ECGs. The maximum QTc interval provides incremental prognostic information beyond the baseline measurement. We suggest that risk stratification in LQTS patients should include follow-up ECG data. 10.1016/j.jacc.2006.06.033
    Electrocardiographic risk stratification in families with congenital long QT syndrome. Mönnig Gerold,Eckardt Lars,Wedekind Horst,Haverkamp Wilhelm,Gerss Joachim,Milberg Peter,Wasmer Kristina,Kirchhof Paulus,Assmann Gerd,Breithardt Günter,Schulze-Bahr Eric European heart journal AIMS:The QT interval in the surface ECG is one of the most often used risk stratifiers in families with congenital long QT syndrome (LQTS). The best ECG lead for clinical management of LQTS families remains unclear. METHODS AND RESULTS:The predictive power of the QTc interval in all ECG leads was studied in 200 consecutive genotyped LQTS family members to identify mutation carriers (n = 103; age: 35+/-19 years) and high-risk LQTS patients (n = 16 with survived sudden cardiac arrest) using receiver operating curve (ROC) analysis (ROC = area under curve). Additionally, the risk for events (syncope and sudden cardiac arrest) was calculated for QTc decile in all individuals. The predictive power was highest in lead II and lead V5 for identifying carriers in LQTS families. These ECG leads were optimal for risk stratification (ROC range 0.83-0.87). In these leads, positive predictive value (PPV) and negative predictive value (NPV) were highest for suggested QTc cut-offs (440 and 500 ms) for identification of LQTS mutation carriers and high-risk patients (PPV between 78-81 and 73-80%, respectively). The risk for events in QTc deciles increased exponentially from 10 to 80% and was 40% for QTc > 500 ms. CONCLUSION:On the basis of these data, QTc is the best diagnostic and prognostic ECG parameter in LQTS families. A single measurement should be obtained in lead II if measurable and then in left precordial leads (preferably V5) as a second choice. 10.1093/eurheartj/ehl159
    Nonsense mutations in hERG cause a decrease in mutant mRNA transcripts by nonsense-mediated mRNA decay in human long-QT syndrome. Gong Qiuming,Zhang Li,Vincent G Michael,Horne Benjamin D,Zhou Zhengfeng Circulation BACKGROUND:Long-QT syndrome type 2 (LQT2) is caused by mutations in the human ether-a-go-go-related gene (hERG). More than 30% of the LQT2 mutations result in premature termination codons. Degradation of premature termination codon-containing mRNA transcripts by nonsense-mediated mRNA decay is increasingly recognized as a mechanism for reducing mRNA levels in a variety of human diseases. However, the role of nonsense-mediated mRNA decay in LQT2 mutations has not been explored. METHODS AND RESULTS:We examined the expression of hERG mRNA in lymphocytes from patients carrying the R1014X mutation using a technique of allele-specific transcript quantification. The R1014X mutation led to a reduced level of mutant mRNA compared with that of the wild-type allele. The decrease in mutant mRNA also was observed in the LQT2 nonsense mutations W1001X and R1014X using hERG minigenes expressed in HEK293 cells or neonatal rat ventricular myocytes. Treatment with the protein synthesis inhibitor cycloheximide or RNA interference-mediated knockdown of the Upf1 protein resulted in the restoration of mutant mRNA to levels comparable to that of the wild-type minigene, suggesting that hERG nonsense mutations are subject to nonsense-mediated mRNA decay. CONCLUSIONS:These results indicate that LQT2 nonsense mutations cause a decrease in mutant mRNA levels by nonsense-mediated mRNA decay rather than production of truncated proteins. Our findings suggest that the degradation of hERG mutant mRNA by nonsense-mediated mRNA decay is an important mechanism in LQT2 patients with nonsense or frameshift mutations. 10.1161/CIRCULATIONAHA.107.708818
    SCN4B-encoded sodium channel beta4 subunit in congenital long-QT syndrome. Medeiros-Domingo Argelia,Kaku Toshihiko,Tester David J,Iturralde-Torres Pedro,Itty Ajit,Ye Bin,Valdivia Carmen,Ueda Kazuo,Canizales-Quinteros Samuel,Tusié-Luna Maria Teresa,Makielski Jonathan C,Ackerman Michael J Circulation BACKGROUND:Congenital long-QT syndrome (LQTS) is potentially lethal secondary to malignant ventricular arrhythmias and is caused predominantly by mutations in genes that encode cardiac ion channels. Nearly 25% of patients remain without a genetic diagnosis, and genes that encode cardiac channel regulatory proteins represent attractive candidates. Voltage-gated sodium channels have a pore-forming alpha-subunit associated with 1 or more auxiliary beta-subunits. Four different beta-subunits have been described. All are detectable in cardiac tissue, but none have yet been linked to any heritable arrhythmia syndrome. METHODS AND RESULTS:We present a case of a 21-month-old Mexican-mestizo female with intermittent 2:1 atrioventricular block and a corrected QT interval of 712 ms. Comprehensive open reading frame/splice mutational analysis of the 9 established LQTS-susceptibility genes proved negative, and complete mutational analysis of the 4 Na(vbeta)-subunits revealed a L179F (C535T) missense mutation in SCN4B that cosegregated properly throughout a 3-generation pedigree and was absent in 800 reference alleles. After this discovery, SCN4B was analyzed in 262 genotype-negative LQTS patients (96% white), but no further mutations were found. L179F was engineered by site-directed mutagenesis and heterologously expressed in HEK293 cells that contained the stably expressed SCN5A-encoded sodium channel alpha-subunit (hNa(V)1.5). Compared with the wild-type, L179F-beta4 caused an 8-fold (compared with SCN5A alone) and 3-fold (compared with SCN5A + WT-beta4) increase in late sodium current consistent with the molecular/electrophysiological phenotype previously shown for LQTS-associated mutations. CONCLUSIONS:We provide the seminal report of SCN4B-encoded Na(vbeta)4 as a novel LQT3-susceptibility gene. 10.1161/CIRCULATIONAHA.106.659086
    Progesterone regulates cardiac repolarization through a nongenomic pathway: an in vitro patch-clamp and computational modeling study. Nakamura Hiroaki,Kurokawa Junko,Bai Chang-Xi,Asada Ken,Xu Jun,Oren Ronit V,Zhu Zheng I,Clancy Colleen E,Isobe Mitsuaki,Furukawa Tetsushi Circulation BACKGROUND:Female sex is an independent risk factor for torsade de pointes in long-QT syndrome. In women, QT interval and torsade de pointes risk fluctuate dynamically during the menstrual cycle and pregnancy. Accumulating clinical evidence suggests a role for progesterone; however, the effect of progesterone on cardiac repolarization remains undetermined. METHODS AND RESULTS:We investigated the effects of progesterone on action potential duration and membrane currents in isolated guinea pig ventricular myocytes. Progesterone rapidly shortened action potential duration, which was attributable mainly to enhancement of the slow delayed rectifier K+ current (I(Ks)) under basal conditions and inhibition of L-type Ca2+ currents (I(Ca,L)) under cAMP-stimulated conditions. The effects of progesterone were mediated by nitric oxide released via nongenomic activation of endothelial nitric oxide synthase; this signal transduction likely takes place in the caveolae because sucrose density gradient fractionation experiments showed colocalization of the progesterone receptor c-Src, phosphoinositide 3-kinase, Akt, and endothelial nitric oxide synthase with KCNQ1, KCNE1, and Ca(V)1.2 in the caveolae fraction. We used computational single-cell and coupled-tissue action potential models incorporating the effects of progesterone on I(Ks) and I(Ca,L); the model reproduces the fluctuations of cardiac repolarization during the menstrual cycle observed in women and predicts the protective effects of progesterone against rhythm disturbances in congenital and drug-induced long-QT syndrome. CONCLUSIONS:Our data show that progesterone modulates cardiac repolarization by nitric oxide produced via a nongenomic pathway. A combination of experimental and computational analyses of progesterone effects provides a framework to understand complex fluctuations of QT interval and torsade de pointes risks in various hormonal states in women. 10.1161/CIRCULATIONAHA.107.702407
    Risk factors for aborted cardiac arrest and sudden cardiac death in children with the congenital long-QT syndrome. Goldenberg Ilan,Moss Arthur J,Peterson Derick R,McNitt Scott,Zareba Wojciech,Andrews Mark L,Robinson Jennifer L,Locati Emanuela H,Ackerman Michael J,Benhorin Jesaia,Kaufman Elizabeth S,Napolitano Carlo,Priori Silvia G,Qi Ming,Schwartz Peter J,Towbin Jeffrey A,Vincent G Michael,Zhang Li Circulation BACKGROUND:The congenital long-QT syndrome (LQTS) is an important cause of sudden cardiac death in children without structural heart disease. However, specific risk factors for life-threatening cardiac events in children with this genetic disorder have not been identified. METHODS AND RESULTS:Cox proportional-hazards regression modeling was used to identify risk factors for aborted cardiac arrest or sudden cardiac death in 3015 LQTS children from the International LQTS Registry who were followed up from 1 through 12 years of age. The cumulative probability of the combined end point was significantly higher in boys (5%) than in girls (1%; P<0.001). Risk factors for cardiac arrest or sudden cardiac death during childhood included corrected QT interval [QTc] duration > 500 ms (hazard ratio [HR]; 2.72; 95% confidence interval [CI], 1.50 to 4.92; P=0.001) and prior syncope (recent syncope [< 2 years]: HR, 6.16; 95% CI 3.41 to 11.15; P<0.001; remote syncope [> or = 2 years]: HR, 2.67; 95% CI, 1.22 to 5.85; P=0.01) in boys, whereas prior syncope was the only significant risk factor among girls (recent syncope: HR, 27.82; 95% CI, 9.72 to 79.60; P<0.001; remote syncope: HR, 12.04; 95% CI, 3.79 to 38.26; P<0.001). Beta-blocker therapy was associated with a significant 53% reduction in the risk of cardiac arrest or sudden cardiac death (P=0.01). CONCLUSIONS:LQTS boys experience a significantly higher rate of fatal or near-fatal cardiac events than girls during childhood. A QTc duration > 500 ms and a history of prior syncope identify risk in boys, whereas prior syncope is the only significant risk factor among girls. Beta-blocker therapy is associated with a significant reduction in the risk of life-threatening cardiac events during childhood. 10.1161/CIRCULATIONAHA.107.701243
    NOS1AP is a genetic modifier of the long-QT syndrome. Crotti Lia,Monti Maria Cristina,Insolia Roberto,Peljto Anna,Goosen Althea,Brink Paul A,Greenberg David A,Schwartz Peter J,George Alfred L Circulation BACKGROUND:In congenital long-QT syndrome (LQTS), a genetically heterogeneous disorder that predisposes to sudden cardiac death, genetic factors other than the primary mutation may modify the probability of life-threatening events. Recent evidence indicates that common variants in NOS1AP are associated with the QT-interval duration in the general population. METHODS AND RESULTS:We tested the hypothesis that common variants in NOS1AP modify the risk of clinical manifestations and the degree of QT-interval prolongation in a South African LQTS population (500 subjects, 205 mutation carriers) segregating a founder mutation in KCNQ1 (A341V) using a family-based association analysis. NOS1AP variants were significantly associated with the occurrence of symptoms (rs4657139, P=0.019; rs16847548, P=0.003), with clinical severity, as manifested by a greater probability for cardiac arrest and sudden death (rs4657139, P=0.028; rs16847548, P=0.014), and with greater likelihood of having a QT interval in the top 40% of values among all mutation carriers (rs4657139, P=0.03; rs16847548, P=0.03). CONCLUSIONS:These findings indicate that NOS1AP, a gene first identified as affecting the QTc interval in a general population, also influences sudden death risk in subjects with LQTS. The association of NOS1AP genetic variants with risk for life-threatening arrhythmias suggests that this gene is a genetic modifier of LQTS, and this knowledge may be clinically useful for risk stratification for patients with this disease, after validation in other LQTS populations. 10.1161/CIRCULATIONAHA.109.879643
    Prevalence of the congenital long-QT syndrome. Schwartz Peter J,Stramba-Badiale Marco,Crotti Lia,Pedrazzini Matteo,Besana Alessandra,Bosi Giuliano,Gabbarini Fulvio,Goulene Karine,Insolia Roberto,Mannarino Savina,Mosca Fabio,Nespoli Luigi,Rimini Alessandro,Rosati Enrico,Salice Patrizia,Spazzolini Carla Circulation BACKGROUND:The prevalence of genetic arrhythmogenic diseases is unknown. For the long-QT syndrome (LQTS), figures ranging from 1:20 000 to 1:5000 were published, but none was based on actual data. Our objective was to define the prevalence of LQTS. METHODS AND RESULTS:In 18 maternity hospitals, an ECG was performed in 44 596 infants 15 to 25 days old (43 080 whites). In infants with a corrected QT interval (QTc) >450 ms, the ECG was repeated within 1 to 2 weeks. Genetic analysis, by screening 7 LQTS genes, was performed in 28 of 31 (90%) and in 14 of 28 infants (50%) with, respectively, a QTc >470 ms or between 461 and 470 ms. A QTc of 451 to 460, 461 to 470, and >470 ms was observed in 177 (0.41%), 28 (0.06%), and 31 infants (0.07%). Among genotyped infants, disease-causing mutations were found in 12 of 28 (43%) with a QTc >470 ms and in 4 of 14 (29%) with a QTc of 461 to 470 ms. One genotype-negative infant (QTc 482 ms) was diagnosed as affected by LQTS on clinical grounds. Among family members of genotype-positive infants, 51% were found to carry disease-causing mutations. In total, 17 of 43 080 white infants were affected by LQTS, demonstrating a prevalence of at least 1:2534 apparently healthy live births (95% confidence interval, 1:1583 to 1:4350). CONCLUSIONS:This study provides the first data-based estimate of the prevalence of LQTS among whites. On the basis of the nongenotyped infants with QTc between 451 and 470 ms, we advance the hypothesis that this prevalence might be close to 1:2000. ECG-guided molecular screening can identify most infants affected by LQTS and unmask affected relatives, thus allowing effective preventive measures. 10.1161/CIRCULATIONAHA.109.863209
    Active cascade screening in primary inherited arrhythmia syndromes: does it lead to prophylactic treatment? Hofman Nynke,Tan Hanno L,Alders Marielle,van Langen Irene M,Wilde Arthur A M Journal of the American College of Cardiology OBJECTIVES:The purpose of this study was to investigate the follow-up and treatment of the mutation-carrying relatives of a proband with an inherited arrhythmia syndrome. BACKGROUND:The congenital long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS) are primary inherited arrhythmia syndromes that may cause syncope and sudden cardiac death in young individuals. After establishing the disease-causing deoxyribonucleic acid (DNA) mutation in probands, we actively conducted cascade screening to identify, most often asymptomatic, relatives who are also at risk of life-threatening arrhythmias. METHODS:We retrospectively collected data from our cardiogenetics database and patient records and analyzed whether the identified carriers received prophylactic treatment. RESULTS:From 1996 to 2008, 130 probands with a disease-causing mutation in one of the involved genes were identified, and 509 relatives tested positive for the disease-causing familial mutation. These subjects subsequently underwent cardiologic investigation (electrocardiography, exercise testing, Holter monitoring, ajmaline testing, echocardiography, where appropriate). After a mean follow-up of 69 +/- 31 months (LQTS), 60 +/- 19 months (CPVT), and 56 +/- 21 months (BrS), treatment was initiated and ongoing in 65% (199 of 308), 71% (85 of 120), and 6% (5 of 81) of the relatives in the LQTS, CPVT, and BrS families, respectively. Eight carriers were lost to follow-up. Treatment included drug treatment (n = 249) or implantation of pacemakers (n = 26) or cardioverter-defibrillators (n = 14). All mutation carriers received lifestyle instructions and a list of drugs to be avoided. CONCLUSIONS:Cascade screening in families with LQTS, BrS, or CPVT, which was based on DNA mutation carrying and subsequent cardiologic investigation, resulted in immediate prophylactic treatment in a substantial proportion of carriers, although these proportions varied significantly between the different diseases. 10.1016/j.jacc.2009.12.063
    Modelling the long QT syndrome with induced pluripotent stem cells. Itzhaki Ilanit,Maizels Leonid,Huber Irit,Zwi-Dantsis Limor,Caspi Oren,Winterstern Aaron,Feldman Oren,Gepstein Amira,Arbel Gil,Hammerman Haim,Boulos Monther,Gepstein Lior Nature The ability to generate patient-specific human induced pluripotent stem cells (iPSCs) offers a new paradigm for modelling human disease and for individualizing drug testing. Congenital long QT syndrome (LQTS) is a familial arrhythmogenic syndrome characterized by abnormal ion channel function and sudden cardiac death. Here we report the development of a patient/disease-specific human iPSC line from a patient with type-2 LQTS (which is due to the A614V missense mutation in the KCNH2 gene). The generated iPSCs were coaxed to differentiate into the cardiac lineage. Detailed whole-cell patch-clamp and extracellular multielectrode recordings revealed significant prolongation of the action-potential duration in LQTS human iPSC-derived cardiomyocytes (the characteristic LQTS phenotype) when compared to healthy control cells. Voltage-clamp studies confirmed that this action-potential-duration prolongation stems from a significant reduction of the cardiac potassium current I(Kr). Importantly, LQTS-derived cells also showed marked arrhythmogenicity, characterized by early-after depolarizations and triggered arrhythmias. We then used the LQTS human iPSC-derived cardiac-tissue model to evaluate the potency of existing and novel pharmacological agents that may either aggravate (potassium-channel blockers) or ameliorate (calcium-channel blockers, K(ATP)-channel openers and late sodium-channel blockers) the disease phenotype. Our study illustrates the ability of human iPSC technology to model the abnormal functional phenotype of an inherited cardiac disorder and to identify potential new therapeutic agents. As such, it represents a promising paradigm to study disease mechanisms, optimize patient care (personalized medicine), and aid in the development of new therapies. 10.1038/nature09747
    Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Yazawa Masayuki,Hsueh Brian,Jia Xiaolin,Pasca Anca M,Bernstein Jonathan A,Hallmayer Joachim,Dolmetsch Ricardo E Nature Individuals with congenital or acquired prolongation of the QT interval, or long QT syndrome (LQTS), are at risk of life-threatening ventricular arrhythmia. LQTS is commonly genetic in origin but can also be caused or exacerbated by environmental factors. A missense mutation in the L-type calcium channel Ca(V)1.2 leads to LQTS in patients with Timothy syndrome. To explore the effect of the Timothy syndrome mutation on the electrical activity and contraction of human cardiomyocytes, we reprogrammed human skin cells from Timothy syndrome patients to generate induced pluripotent stem cells, and differentiated these cells into cardiomyocytes. Electrophysiological recording and calcium (Ca(2+)) imaging studies of these cells revealed irregular contraction, excess Ca(2+) influx, prolonged action potentials, irregular electrical activity and abnormal calcium transients in ventricular-like cells. We found that roscovitine, a compound that increases the voltage-dependent inactivation of Ca(V)1.2 (refs 6-8), restored the electrical and Ca(2+) signalling properties of cardiomyocytes from Timothy syndrome patients. This study provides new opportunities for studying the molecular and cellular mechanisms of cardiac arrhythmias in humans, and provides a robust assay for developing new drugs to treat these diseases. 10.1038/nature09855
    Drug evaluation in cardiomyocytes derived from human induced pluripotent stem cells carrying a long QT syndrome type 2 mutation. Matsa Elena,Rajamohan Divya,Dick Emily,Young Lorraine,Mellor Ian,Staniforth Andrew,Denning Chris European heart journal AIMS:Congenital long QT syndromes (LQTSs) are associated with prolonged ventricular repolarization and sudden cardiac death. Limitations to existing clinical therapeutic management strategies prompted us to develop a novel human in vitro drug-evaluation system for LQTS type 2 (LQT2) that will complement the existing in vitro and in vivo models. METHODS AND RESULTS:Skin fibroblasts from a patient with a KCNH2 G1681A mutation (encodes I(Kr) potassium ion channel) were reprogrammed to human induced pluripotent stem cells (hiPSCs), which were subsequently differentiated to functional cardiomyocytes. Relative to controls (including the patient's mother), multi-electrode array and patch-clamp electrophysiology of LQT2-hiPSC cardiomyocytes showed prolonged field/action potential duration. When LQT2-hiPSC cardiomyocytes were exposed to E4031 (an I(Kr) blocker), arrhythmias developed and these presented as early after depolarizations (EADs) in the action potentials. In contrast to control cardiomyocytes, LQT2-hiPSC cardiomyocytes also developed EADs when challenged with the clinically used stressor, isoprenaline. This effect was reversed by β-blockers, propranolol, and nadolol, the latter being used for the patient's therapy. Treatment of cardiomyocytes with experimental potassium channel enhancers, nicorandil and PD118057, caused action potential shortening and in some cases could abolish EADs. Notably, combined treatment with isoprenaline (enhancers/isoprenaline) caused EADs, but this effect was reversed by nadolol. CONCLUSIONS:Findings from this paper demonstrate that patient LQT2-hiPSC cardiomyocytes respond appropriately to clinically relevant pharmacology and will be a valuable human in vitro model for testing experimental drug combinations. 10.1093/eurheartj/ehr073
    Risk of recurrent cardiac events after onset of menopause in women with congenital long-QT syndrome types 1 and 2. Buber Jonathan,Mathew Jehu,Moss Arthur J,Hall W Jackson,Barsheshet Alon,McNitt Scott,Robinson Jennifer L,Zareba Wojciech,Ackerman Michael J,Kaufman Elizabeth S,Luria David,Eldar Michael,Towbin Jeffrey A,Vincent Michael,Goldenberg Ilan Circulation BACKGROUND:Women with congenital long-QT syndrome experience an increased risk for cardiac events after the onset of adolescence that is more pronounced among carriers of the LQT2 genotype. We hypothesized that the hormonal changes associated with menopause may affect clinical risk in this population. METHODS AND RESULTS:We used a repeated-events analysis to evaluate the risk for recurrent syncope during the menopause transition and postmenopausal periods (5 years before and after the age at onset of menopause, respectively) among 282 LQT1 (n=151) and LQT2 (n=131) women enrolled in the Long-QT Syndrome Registry. Multivariate analysis showed that the risk for recurrent syncope (n=150) among LQT2 women was significantly increased during both menopause transition (hazard ratio, 3.38; P=0.005) and the postmenopausal period (hazard ratio, 8.10; P<0.001) compared with the reproductive period. The risk increase was evident among women who did or did not receive estrogen therapy. In contrast, among LQT1 women, the onset of menopause was associated with a reduction in the risk for recurrent syncope (hazard ratio, 0.19; P=0.05; P=0.02 for genotype-by-menopause interaction). Only 22 women (8%) experienced aborted cardiac arrest or sudden cardiac death during follow-up. The frequency of aborted cardiac arrest/sudden cardiac death showed a similar genotype-specific association with the onset of menopause. CONCLUSIONS:The onset of menopause is associated with a significant increase in the risk of cardiac events (dominated by recurrent episodes of syncope) in LQT2 women, suggesting that careful follow-up and continued long-term therapy are warranted in this population. 10.1161/CIRCULATIONAHA.110.000620
    Phenotypic manifestations of mutations in genes encoding subunits of cardiac potassium channels. Shimizu Wataru,Horie Minoru Circulation research Since 1995, when a potassium channel gene, hERG (human ether-à-go-go-related gene), now referred to as KCNH2, encoding the rapid component of cardiac delayed rectifier potassium channels was identified as being responsible for type 2 congenital long-QT syndrome, a number of potassium channel genes have been shown to cause different types of inherited cardiac arrhythmia syndromes. These include congenital long-QT syndrome, short-QT syndrome, Brugada syndrome, early repolarization syndrome, and familial atrial fibrillation. Genotype-phenotype correlations have been investigated in some inherited arrhythmia syndromes, and as a result, gene-specific risk stratification and gene-specific therapy and management have become available, particularly for patients with congenital long-QT syndrome. In this review article, the molecular structure and function of potassium channels, the clinical phenotype due to potassium channel gene mutations, including genotype-phenotype correlations, and the diverse mechanisms underlying the potassium channel gene-related diseases will be discussed. 10.1161/CIRCRESAHA.110.224600
    Not all beta-blockers are equal in the management of long QT syndrome types 1 and 2: higher recurrence of events under metoprolol. Chockalingam Priya,Crotti Lia,Girardengo Giulia,Johnson Jonathan N,Harris Katy M,van der Heijden Jeroen F,Hauer Richard N W,Beckmann Britt M,Spazzolini Carla,Rordorf Roberto,Rydberg Annika,Clur Sally-Ann B,Fischer Markus,van den Heuvel Freek,Kääb Stefan,Blom Nico A,Ackerman Michael J,Schwartz Peter J,Wilde Arthur A M Journal of the American College of Cardiology OBJECTIVES:The purpose of this study was to compare the efficacy of beta-blockers in congenital long QT syndrome (LQTS). BACKGROUND:Beta-blockers are the mainstay in managing LQTS. Studies comparing the efficacy of commonly used beta-blockers are lacking, and clinicians generally assume they are equally effective. METHODS:Electrocardiographic and clinical parameters of 382 LQT1/LQT2 patients initiated on propranolol (n = 134), metoprolol (n = 147), and nadolol (n = 101) were analyzed, excluding patients <1 year of age at beta-blocker initiation. Symptoms before therapy and the first breakthrough cardiac events (BCEs) were documented. RESULTS:Patients (56% female, 27% symptomatic, heart rate 76 ± 16 beats/min, QTc 472 ± 46 ms) were started on beta-blocker therapy at a median age of 14 years (interquartile range: 8 to 32 years). The QTc shortening with propranolol was significantly greater than with other beta-blockers in the total cohort and in the subset with QTc >480 ms. None of the asymptomatic patients had BCEs. Among symptomatic patients (n = 101), 15 had BCEs (all syncopes). The QTc shortening was significantly less pronounced among patients with BCEs. There was a greater risk of BCEs for symptomatic patients initiated on metoprolol compared to users of the other 2 beta-blockers combined, after adjustment for genotype (odds ratio: 3.95, 95% confidence interval: 1.2 to 13.1, p = 0.025). Kaplan-Meier analysis showed a significantly lower event-free survival for symptomatic patients receiving metoprolol compared to propranolol/nadolol. CONCLUSIONS:Propranolol has a significantly better QTc shortening effect compared to metoprolol and nadolol, especially in patients with prolonged QTc. Propranolol and nadolol are equally effective, whereas symptomatic patients started on metoprolol are at a significantly higher risk for BCEs. Metoprolol should not be used for symptomatic LQT1 and LQT2 patients. 10.1016/j.jacc.2012.07.046
    Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes. Matsa Elena,Dixon James E,Medway Christopher,Georgiou Orestis,Patel Minal J,Morgan Kevin,Kemp Paul J,Staniforth Andrew,Mellor Ian,Denning Chris European heart journal AIMS:Long-QT syndromes (LQTS) are mostly autosomal-dominant congenital disorders associated with a 1:1000 mutation frequency, cardiac arrest, and sudden death. We sought to use cardiomyocytes derived from human-induced pluripotency stem cells (hiPSCs) as an in vitro model to develop and evaluate gene-based therapeutics for the treatment of LQTS. METHODS AND RESULTS:We produced LQTS-type 2 (LQT2) hiPSC cardiomyocytes carrying a KCNH2 c.G1681A mutation in a IKr ion-channel pore, which caused impaired glycosylation and channel transport to cell surface. Allele-specific RNA interference (RNAi) directed towards the mutated KCNH2 mRNA caused knockdown, while leaving the wild-type mRNA unaffected. Electrophysiological analysis of patient-derived LQT2 hiPSC cardiomyocytes treated with mutation-specific siRNAs showed normalized action potential durations (APDs) and K(+) currents with the concurrent rescue of spontaneous and drug-induced arrhythmias (presented as early-afterdepolarizations). CONCLUSIONS:These findings provide in vitro evidence that allele-specific RNAi can rescue diseased phenotype in LQTS cardiomyocytes. This is a potentially novel route for the treatment of many autosomal-dominant-negative disorders, including those of the heart. 10.1093/eurheartj/eht067
    Ranolazine for congenital and acquired late INa-linked arrhythmias: in silico pharmacological screening. Moreno Jonathan D,Yang Pei-Chi,Bankston John R,Grandi Eleonora,Bers Donald M,Kass Robert S,Clancy Colleen E Circulation research RATIONALE:The antianginal ranolazine blocks the human ether-a-go-go-related gene-based current IKr at therapeutic concentrations and causes QT interval prolongation. Thus, ranolazine is contraindicated for patients with preexisting long-QT and those with repolarization abnormalities. However, with its preferential targeting of late INa (INaL), patients with disease resulting from increased INaL from inherited defects (eg, long-QT syndrome type 3 or disease-induced electric remodeling (eg, ischemic heart failure) might be exactly the ones to benefit most from the presumed antiarrhythmic properties of ranolazine. OBJECTIVE:We developed a computational model to predict if therapeutic effects of pharmacological targeting of INaL by ranolazine prevailed over the off-target block of IKr in the setting of inherited long-QT syndrome type 3 and heart failure. METHODS AND RESULTS:We developed computational models describing the kinetics and the interaction of ranolazine with cardiac Na(+) channels in the setting of normal physiology, long-QT syndrome type 3-linked ΔKPQ mutation, and heart failure. We then simulated clinically relevant concentrations of ranolazine and predicted the combined effects of Na(+) channel and IKr blockade by both the parent compound ranolazine and its active metabolites, which have shown potent blocking effects in the therapeutically relevant range. Our simulations suggest that ranolazine is effective at normalizing arrhythmia triggers in bradycardia-dependent arrhythmias in long-QT syndrome type 3 as well tachyarrhythmogenic triggers arising from heart failure-induced remodeling. CONCLUSIONS:Our model predictions suggest that acute targeting of INaL with ranolazine may be an effective therapeutic strategy in diverse arrhythmia-provoking situations that arise from a common pathway of increased pathological INaL. 10.1161/CIRCRESAHA.113.301971
    A molecular mechanism for adrenergic-induced long QT syndrome. Wu Jie,Naiki Nobu,Ding Wei-Guang,Ohno Seiko,Kato Koichi,Zang Wei-Jin,Delisle Brian P,Matsuura Hiroshi,Horie Minoru Journal of the American College of Cardiology OBJECTIVES:This study sought to explore molecular mechanisms underlying the adrenergic-induced QT prolongation associated with KCNQ1 mutations. BACKGROUND:The most frequent type of congenital long QT syndrome is LQT1, which is caused by mutations in the gene (KCNQ1) that encodes the alpha subunit of the slow component of delayed rectifier K(+) current (IKs) channel. We identified 11 patients from 4 unrelated families that are heterozygous for KCNQ1-G269S. Most patients remained asymptomatic, and their resting corrected QT intervals ranged from normal to borderline but were prolonged significantly during exercise. METHODS:Wild-type (WT) KCNQ1 and/or KCNQ1-G269S (G269S) were expressed in mammalian cells with KCNE1. IKs-like currents were measured in control conditions or after isoproterenol or protein kinase A (PKA) stimulation using the patch-clamp technique. Additionally, experiments that incorporated the phosphomimetic KCNQ1 substitution, S27D, in WT or KCNQ1-G269S were also performed. RESULTS:The coexpression of WT-KCNQ1 with varying amounts of G269S decreased IKs, shifted the current-voltage I-V relation of IKs to more positive potentials, and accelerated the IKs deactivation rates in a concentration-dependent manner. In addition, the coexpression of G269S and WT blunted the activation of IKs in response to isoproterenol or PKA stimulation. Lastly, a phosphomimetic substitution in G269S did not show an increased IKs. CONCLUSIONS:G269S modestly affected IKs in control conditions, but it almost completely blunted IKs responsiveness in conditions that simulate or mimic PKA phosphorylation of KCNQ1. This insensitivity to PKA stimulation may explain why patients with G269S mutation showed an excessive prolongation of QT intervals on exercise. 10.1016/j.jacc.2013.08.1648
    Electrophysiologic substrate in congenital Long QT syndrome: noninvasive mapping with electrocardiographic imaging (ECGI). Vijayakumar Ramya,Silva Jennifer N A,Desouza Kavit A,Abraham Robert L,Strom Maria,Sacher Frederic,Van Hare George F,Haïssaguerre Michel,Roden Dan M,Rudy Yoram Circulation BACKGROUND:Congenital Long QT syndrome (LQTS) is an arrhythmogenic disorder that causes syncope and sudden death. Although its genetic basis has become well-understood, the mechanisms whereby mutations translate to arrhythmia susceptibility in the in situ human heart have not been fully defined. We used noninvasive ECG imaging to map the cardiac electrophysiological substrate and examine whether LQTS patients display regional heterogeneities in repolarization, a substrate that promotes arrhythmogenesis. METHODS AND RESULTS:Twenty-five subjects (9 LQT1, 9 LQT2, 5 LQT3, and 2 LQT5) with genotype and phenotype positive LQTS underwent ECG imaging. Seven normal subjects provided control. Epicardial maps of activation, recovery times, activation-recovery intervals, and repolarization dispersion were constructed. Activation was normal in all patients. However, recovery times and activation-recovery intervals were prolonged relative to control, indicating delayed repolarization and abnormally long action potential duration (312±30 ms versus 235±21 ms in control). Activation-recovery interval prolongation was spatially heterogeneous, with repolarization gradients much steeper than control (119±19 ms/cm versus 2.0±2.0 ms/cm). There was variability in steepness and distribution of repolarization gradients between and within LQTS types. Repolarization gradients were steeper in symptomatic patients (130±27 ms/cm in 12 symptomatic patients versus 98±19 ms/cm in 13 asymptomatic patients; P<0.05). CONCLUSIONS:LQTS patients display regions with steep repolarization dispersion caused by localized action potential duration prolongation. This defines a substrate for reentrant arrhythmias, not detectable by surface ECG. Steeper dispersion in symptomatic patients suggests a possible role for ECG imaging in risk stratification. 10.1161/CIRCULATIONAHA.114.011359
    Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval. Ghouse Jonas,Have Christian Theil,Weeke Peter,Bille Nielsen Jonas,Ahlberg Gustav,Balslev-Harder Marie,Appel Emil Vincent,Skaaby Tea,Olesen Søren-Peter,Grarup Niels,Linneberg Allan,Pedersen Oluf,Haunsø Stig,Hastrup Svendsen Jesper,Hansen Torben,Kanters Jørgen Kim,Salling Olesen Morten European heart journal AIMS:We studied whether variants previously associated with congenital long QT syndrome (cLQTS) have an effect on the QTc interval in a Danish population sample. Furthermore, we assessed whether carriers of variants in cLQTS-associated genes are more prone to experience syncope compared with non-carriers and whether carriers have an increased mortality compared with non-carriers. METHODS AND RESULTS:All genetic variants previously associated with cLQTS were surveyed using the Human Gene Mutation Database. We screened a Danish population-based sample with available whole-exome sequencing data (n = 870) and genotype array data (n = 6161) for putative cLQTS genetic variants. In total, 33 of 1358 variants previously reported to associate with cLQTS were identified. Of these, 10 variants were found in 8 or more individuals. Electrocardiogram results showed normal mean QTc intervals in carriers compared with non-carriers. Syncope data analysis between variant and non-variant carriers showed that 4 of 227 (1.8%) and 95 of 5861 (1.6%) individuals, respectively, had experienced syncope during follow-up (P = 0.80). There was no significant difference in overall mortality rates between carriers [7/217 (3.2%)] and non-carriers [301/6453 (4.7%)] (P = 0.24). CONCLUSION:We present QTc data and register data, indicating that 26 cLQTS-associated variants neither had any effect on the QTc intervals nor on syncope propensity or overall mortality. Based on the frequency of individual gene variants, we suggest that the 10 variants frequently identified, assumed to relate to cLQTS, are less likely to associate with a dominant monogenic form of the disease. 10.1093/eurheartj/ehv297
    Molecular Pathophysiology of Congenital Long QT Syndrome. Bohnen M S,Peng G,Robey S H,Terrenoire C,Iyer V,Sampson K J,Kass R S Physiological reviews Ion channels represent the molecular entities that give rise to the cardiac action potential, the fundamental cellular electrical event in the heart. The concerted function of these channels leads to normal cyclical excitation and resultant contraction of cardiac muscle. Research into cardiac ion channel regulation and mutations that underlie disease pathogenesis has greatly enhanced our knowledge of the causes and clinical management of cardiac arrhythmia. Here we review the molecular determinants, pathogenesis, and pharmacology of congenital Long QT Syndrome. We examine mechanisms of dysfunction associated with three critical cardiac currents that comprise the majority of congenital Long QT Syndrome cases: 1) I, the slow delayed rectifier current; 2) I, the rapid delayed rectifier current; and 3) I, the voltage-dependent sodium current. Less common subtypes of congenital Long QT Syndrome affect other cardiac ionic currents that contribute to the dynamic nature of cardiac electrophysiology. Through the study of mutations that cause congenital Long QT Syndrome, the scientific community has advanced understanding of ion channel structure-function relationships, physiology, and pharmacological response to clinically employed and experimental pharmacological agents. Our understanding of congenital Long QT Syndrome continues to evolve rapidly and with great benefits: genotype-driven clinical management of the disease has improved patient care as precision medicine becomes even more a reality. 10.1152/physrev.00008.2016
    Cryo-EM Structure of a KCNQ1/CaM Complex Reveals Insights into Congenital Long QT Syndrome. Sun Ji,MacKinnon Roderick Cell KCNQ1 is the pore-forming subunit of cardiac slow-delayed rectifier potassium (I) channels. Mutations in the kcnq1 gene are the leading cause of congenital long QT syndrome (LQTS). Here, we present the cryoelectron microscopy (cryo-EM) structure of a KCNQ1/calmodulin (CaM) complex. The conformation corresponds to an "uncoupled," PIP-free state of KCNQ1, with activated voltage sensors and a closed pore. Unique structural features within the S4-S5 linker permit uncoupling of the voltage sensor from the pore in the absence of PIP. CaM contacts the KCNQ1 voltage sensor through a specific interface involving a residue on CaM that is mutated in a form of inherited LQTS. Using an electrophysiological assay, we find that this mutation on CaM shifts the KCNQ1 voltage-activation curve. This study describes one physiological form of KCNQ1, depolarized voltage sensors with a closed pore in the absence of PIP, and reveals a regulatory interaction between CaM and KCNQ1 that may explain CaM-mediated LQTS. 10.1016/j.cell.2017.05.019
    Calcium Signaling and Cardiac Arrhythmias. Landstrom Andrew P,Dobrev Dobromir,Wehrens Xander H T Circulation research There has been a significant progress in our understanding of the molecular mechanisms by which calcium (Ca) ions mediate various types of cardiac arrhythmias. A growing list of inherited gene defects can cause potentially lethal cardiac arrhythmia syndromes, including catecholaminergic polymorphic ventricular tachycardia, congenital long QT syndrome, and hypertrophic cardiomyopathy. In addition, acquired deficits of multiple Ca-handling proteins can contribute to the pathogenesis of arrhythmias in patients with various types of heart disease. In this review article, we will first review the key role of Ca in normal cardiac function-in particular, excitation-contraction coupling and normal electric rhythms. The functional involvement of Ca in distinct arrhythmia mechanisms will be discussed, followed by various inherited arrhythmia syndromes caused by mutations in Ca-handling proteins. Finally, we will discuss how changes in the expression of regulation of Ca channels and transporters can cause acquired arrhythmias, and how these mechanisms might be targeted for therapeutic purposes. 10.1161/CIRCRESAHA.117.310083
    Physiological genomics identifies genetic modifiers of long QT syndrome type 2 severity. Chai Sam,Wan Xiaoping,Ramirez-Navarro Angelina,Tesar Paul J,Kaufman Elizabeth S,Ficker Eckhard,George Alfred L,Deschênes Isabelle The Journal of clinical investigation Congenital long QT syndrome (LQTS) is an inherited channelopathy associated with life-threatening arrhythmias. LQTS type 2 (LQT2) is caused by mutations in KCNH2, which encodes the potassium channel hERG. We hypothesized that modifier genes are partly responsible for the variable phenotype severity observed in some LQT2 families. Here, we identified contributors to variable expressivity in an LQT2 family by using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and whole exome sequencing in a synergistic manner. We found that iPSC-CMs recapitulated the clinical genotype-phenotype discordance in vitro. Importantly, iPSC-CMs derived from the severely affected LQT2 patients displayed prolonged action potentials compared with cells from mildly affected first-degree relatives. The iPSC-CMs derived from all patients with hERG R752W mutation displayed lower IKr amplitude. Interestingly, iPSC-CMs from severely affected mutation-positive individuals exhibited greater L-type Ca2+ current. Whole exome sequencing identified variants of KCNK17 and the GTP-binding protein REM2, providing biologically plausible explanations for this variable expressivity. Genome editing to correct a REM2 variant reversed the enhanced L-type Ca2+ current and prolonged action potential observed in iPSC-CMs from severely affected individuals. Thus, our findings showcase the power of combining complementary physiological and genomic analyses to identify genetic modifiers and potential therapeutic targets of a monogenic disorder. Furthermore, we propose that this strategy can be deployed to unravel myriad confounding pathologies displaying variable expressivity. 10.1172/JCI94996
    Mechanisms of KCNQ1 channel dysfunction in long QT syndrome involving voltage sensor domain mutations. Huang Hui,Kuenze Georg,Smith Jarrod A,Taylor Keenan C,Duran Amanda M,Hadziselimovic Arina,Meiler Jens,Vanoye Carlos G,George Alfred L,Sanders Charles R Science advances Mutations that induce loss of function (LOF) or dysfunction of the human KCNQ1 channel are responsible for susceptibility to a life-threatening heart rhythm disorder, the congenital long QT syndrome (LQTS). Hundreds of mutations have been identified, but the molecular mechanisms responsible for impaired function are poorly understood. We investigated the impact of 51 KCNQ1 variants with mutations located within the voltage sensor domain (VSD), with an emphasis on elucidating effects on cell surface expression, protein folding, and structure. For each variant, the efficiency of trafficking to the plasma membrane, the impact of proteasome inhibition, and protein stability were assayed. The results of these experiments combined with channel functional data provided the basis for classifying each mutation into one of six mechanistic categories, highlighting heterogeneity in the mechanisms resulting in channel dysfunction or LOF. More than half of the KCNQ1 LOF mutations examined were seen to destabilize the structure of the VSD, generally accompanied by mistrafficking and degradation by the proteasome, an observation that underscores the growing appreciation that mutation-induced destabilization of membrane proteins may be a common human disease mechanism. Finally, we observed that five of the folding-defective LQTS mutant sites are located in the VSD S0 helix, where they interact with a number of other LOF mutation sites in other segments of the VSD. These observations reveal a critical role for the S0 helix as a central scaffold to help organize and stabilize the KCNQ1 VSD and, most likely, the corresponding domain of many other ion channels. 10.1126/sciadv.aar2631
    SCN5A mutations in 442 neonates and children: genotype-phenotype correlation and identification of higher-risk subgroups. Baruteau Alban-Elouen,Kyndt Florence,Behr Elijah R,Vink Arja S,Lachaud Matthias,Joong Anna,Schott Jean-Jacques,Horie Minoru,Denjoy Isabelle,Crotti Lia,Shimizu Wataru,Bos Johan M,Stephenson Elizabeth A,Wong Leonie,Abrams Dominic J,Davis Andrew M,Winbo Annika,Dubin Anne M,Sanatani Shubhayan,Liberman Leonardo,Kaski Juan Pablo,Rudic Boris,Kwok Sit Yee,Rieubland Claudine,Tfelt-Hansen Jacob,Van Hare George F,Guyomarc'h-Delasalle Béatrice,Blom Nico A,Wijeyeratne Yanushi D,Gourraud Jean-Baptiste,Le Marec Hervé,Ozawa Junichi,Fressart Véronique,Lupoglazoff Jean-Marc,Dagradi Federica,Spazzolini Carla,Aiba Takeshi,Tester David J,Zahavich Laura A,Beauséjour-Ladouceur Virginie,Jadhav Mangesh,Skinner Jonathan R,Franciosi Sonia,Krahn Andrew D,Abdelsayed Mena,Ruben Peter C,Yung Tak-Cheung,Ackerman Michael J,Wilde Arthur A,Schwartz Peter J,Probst Vincent European heart journal Aims:To clarify the clinical characteristics and outcomes of children with SCN5A-mediated disease and to improve their risk stratification. Methods and results:A multicentre, international, retrospective cohort study was conducted in 25 tertiary hospitals in 13 countries between 1990 and 2015. All patients ≤16 years of age diagnosed with a genetically confirmed SCN5A mutation were included in the analysis. There was no restriction made based on their clinical diagnosis. A total of 442 children {55.7% boys, 40.3% probands, median age: 8.0 [interquartile range (IQR) 9.5] years} from 350 families were included; 67.9% were asymptomatic at diagnosis. Four main phenotypes were identified: isolated progressive cardiac conduction disorders (25.6%), overlap phenotype (15.6%), isolated long QT syndrome type 3 (10.6%), and isolated Brugada syndrome type 1 (1.8%); 44.3% had a negative electrocardiogram phenotype. During a median follow-up of 5.9 (IQR 5.9) years, 272 cardiac events (CEs) occurred in 139 (31.5%) patients. Patients whose mutation localized in the C-terminus had a lower risk. Compound genotype, both gain- and loss-of-function SCN5A mutation, age ≤1 year at diagnosis in probands and age ≤1 year at diagnosis in non-probands were independent predictors of CE. Conclusion:In this large paediatric cohort of SCN5A mutation-positive subjects, cardiac conduction disorders were the most prevalent phenotype; CEs occurred in about one-third of genotype-positive children, and several independent risk factors were identified, including age ≤1 year at diagnosis, compound mutation, and mutation with both gain- and loss-of-function. 10.1093/eurheartj/ehy412
    Towards Precision Medicine With Human iPSCs for Cardiac Channelopathies. Wu Joseph C,Garg Priyanka,Yoshida Yoshinori,Yamanaka Shinya,Gepstein Lior,Hulot Jean-Sébastien,Knollmann Björn C,Schwartz Peter J Circulation research Long-QT syndrome, a frequently fatal inherited arrhythmia syndrome caused by genetic variants (congenital) or drugs (acquired), affects 1 in 2000 people worldwide. Its sentinel event is often sudden cardiac death, which makes preclinical diagnosis by genetic testing potentially life-saving. Unfortunately, clinical experience with genetic testing has shown that it is difficult to correctly identify genetic variants as disease causing. These current deficiencies in accurately assigning pathogenicity led to the discovery of increasing numbers of rare variants classified as variant of uncertain significance. To overcome these challenges, new technologies such as clustered regularly interspaced short palindromic repeats (CRISPR) genome editing can be combined with human induced pluripotent stem cell-derived cardiomyocytes to provide a new approach to decipher pathogenicity of variants of uncertain significance and to better predict arrhythmia risk. To that end, the overarching goal of our network is to establish the utility of induced pluripotent stem cell-based platforms to solve major clinical problems associated with long-QT syndrome by determining how to (1) differentiate pathogenic mutations from background genetic noise, (2) assess existing and novel variants associated with congenital and acquired long-QT syndrome, and (3) provide genotype- and phenotype- guided risk stratification and pharmacological management of long-QT syndrome. To achieve these goals and to further advance the use of induced pluripotent stem cells in disease modeling and drug discovery, our team of investigators for this Leducq Foundation Transatlantic Networks of Excellence proposal will work together to (1) improve differentiation efficiency, cellular maturation, and lineage specificity, (2) develop new assays for high throughput cellular phenotyping, and (3) train young investigators to clinically implement patient-specific genetic modeling. 10.1161/CIRCRESAHA.119.315209
    Association of Genetic and Clinical Aspects of Congenital Long QT Syndrome With Life-Threatening Arrhythmias in Japanese Patients. Shimizu Wataru,Makimoto Hisaki,Yamagata Kenichiro,Kamakura Tsukasa,Wada Mitsuru,Miyamoto Koji,Inoue-Yamada Yuko,Okamura Hideo,Ishibashi Kohei,Noda Takashi,Nagase Satoshi,Miyazaki Aya,Sakaguchi Heima,Shiraishi Isao,Makiyama Takeru,Ohno Seiko,Itoh Hideki,Watanabe Hiroshi,Hayashi Kenshi,Yamagishi Masakazu,Morita Hiroshi,Yoshinaga Masao,Aizawa Yoshiyasu,Kusano Kengo,Miyamoto Yoshihiro,Kamakura Shiro,Yasuda Satoshi,Ogawa Hisao,Tanaka Toshihiro,Sumitomo Naotaka,Hagiwara Nobuhisa,Fukuda Keiichi,Ogawa Satoshi,Aizawa Yoshifusa,Makita Naomasa,Ohe Tohru,Horie Minoru,Aiba Takeshi JAMA cardiology Importance:Long QT syndrome (LQTS) is caused by several ion channel genes, yet risk of arrhythmic events is not determined solely by the responsible gene pathogenic variants. Female sex after adolescence is associated with a higher risk of arrhythmic events in individuals with congenital LQTS, but the association between sex and genotype-based risk of LQTS is still unclear. Objective:To examine the association between sex and location of the LQTS-related pathogenic variant as it pertains to the risk of life-threatening arrhythmias. Design, Setting, and Participants:This retrospective observational study enrolled 1124 genotype-positive patients from 11 Japanese institutions from March 1, 2006, to February 28, 2013. Patients had LQTS type 1 (LQT1), type 2 (LQT2), and type 3 (LQT3) (616 probands and 508 family members), with KCNQ1 (n = 521), KCNH2 (n = 487) and SCN5A (n = 116) genes. Clinical characteristics such as age at the time of diagnosis, sex, family history, cardiac events, and several electrocardiographic measures were collected. Statistical analysis was conducted from January 18 to October 10, 2018. Main Outcomes and Measures:Sex difference in the genotype-specific risk of congenital LQTS. Results:Among the 1124 patients (663 females and 461 males; mean [SD] age, 20 [15] years) no sex difference was observed in risk for arrhythmic events among those younger than 15 years; in contrast, female sex was associated with a higher risk for LQT1 and LQT2 among those older than 15 years. In patients with LQT1, the pathogenic variant of the membrane-spanning site was associated with higher risk of arrhythmic events than was the pathogenic variant of the C-terminus of KCNQ1 (HR, 1.60; 95% CI, 1.19-2.17; P = .002), although this site-specific difference in the incidence of arrhythmic events was observed in female patients only. In patients with LQT2, those with S5-pore-S6 pathogenic variants in KCNH2 had a higher risk of arrhythmic events than did those with others (HR, 1.88; 95% CI, 1.44-2.44; P < .001). This site-specific difference in incidence, however, was observed in both sexes. Regardless of the QTc interval, however, female sex itself was associated with a significantly higher risk of arrhythmic events in patients with LQT2 after puberty (106 of 192 [55.2%] vs 19 of 94 [20.2%]; P < .001). In patients with LQT3, pathogenic variants in the S5-pore-S6 segment of the Nav1.5 channel were associated with lethal arrhythmic events compared with others (HR, 4.2; 95% CI, 2.09-8.36; P < .001), but no sex difference was seen. Conclusions and Relevance:In this retrospective analysis, pathogenic variants in the pore areas of the channels were associated with higher risk of arrhythmic events than were other variants in each genotype, while sex-associated differences were observed in patients with LQT1 and LQT2 but not in those with LQT3. The findings of this study suggest that risk for cardiac events in LQTS varies according to genotype, variant site, age, and sex. 10.1001/jamacardio.2018.4925
    Long-term proarrhythmic pharmacotherapy among patients with congenital long QT syndrome and risk of arrhythmia and mortality. Weeke Peter E,Kellemann Jesper S,Jespersen Camilla Bang,Theilade Juliane,Kanters Jørgen K,Hansen Michael Skov,Christiansen Michael,Marstrand Peter,Gislason Gunnar H,Torp-Pedersen Christian,Bundgaard Henning,Jensen Henrik K,Tfelt-Hansen Jacob European heart journal AIMS:It is Class I recommendation that congenital long QT syndrome (cLQTS) patients should avoid drugs that can cause torsades de pointes (TdP). We determined use of TdP risk drugs after cLQTS diagnosis and associated risk of ventricular arrhythmia and all-cause mortality. METHODS AND RESULTS:Congenital long QT syndrome patients (1995-2015) were identified from four inherited cardiac disease clinics in Denmark. Individual-level linkage of nation-wide registries was performed to determine TdP risk drugs usage (www.crediblemeds.org) and associated risk of ventricular arrhythmias and all-cause mortality. Risk analyses were performed using Cox-hazards analyses. During follow-up, 167/279 (60%) cLQTS patients were treated with a TdP risk drug after diagnosis. Most common TdP risk drugs were antibiotics (34.1%), proton-pump inhibitors (15.0%), antidepressants (12.0%), and antifungals (10.2%). Treatment with a TdP risk drug decreased 1 year after diagnosis compared with 1 year before (28.4% and 23.2%, respectively, P < 0.001). Five years after diagnosis, 33.5% were in treatment (P < 0.001). Risk factors for TdP risk drug treatment were age at diagnosis (5-year increment) [hazard ratio (HR) = 1.07, confidence interval (CI) 1.03-1.11] and previous TdP risk drug treatment (HR = 2.57, CI 1.83-3.61). During follow-up, nine patients were admitted with ventricular arrhythmia (three were in treatment with a TdP risk drug). Eight patients died (four were in treatment with a TdP risk drug). No significant association between TdP risk drug use and ventricular arrhythmias or all-cause mortality was found (P = 0.53 and P = 0.93, respectively), but events were few. CONCLUSION:Torsades de pointes risk drug usage was common among cLQTS patients after time of diagnosis and increased over time. A critical need for more awareness in prescribing patterns for this high-risk patient group is needed. 10.1093/eurheartj/ehz228