Accelerated QT adaptation following atropine-induced heart rate increase in LQT1 patients versus healthy controls: A sign of disturbed hysteresis.

Hysteresis, a ubiquitous regulatory phenomenon, is a salient feature of the adaptation of ventricular repolarization duration to heart rate (HR) change. We therefore compared the QT interval adaptation to rapid HR increase in patients with the long QT syndrome type 1 (LQT1) versus healthy controls because LQT1 is caused by loss-of-function mutations affecting the repolarizing potassium channel current IKs , presumably an important player in QT hysteresis. The study was performed in an outpatient hospital setting. HR was increased in LQT1 patients and controls by administering an intravenous bolus of atropine (0.04 mg/kg body weight) for 30 s. RR and QT intervals were recorded by continuous Frank vectorcardiography. Atropine induced transient expected side effects but no adverse arrhythmias. There was no difference in HR response (RR intervals) to atropine between the groups. Although atropine-induced ΔQT was 48% greater in 18 LQT1 patients than in 28 controls (p < 0.001), QT adaptation was on average 25% faster in LQT1 patients (measured as the time constant τ for the mono-exponential function and the time for 90% of ΔQT; p < 0.01); however, there was some overlap between the groups, possibly a beta-blocker effect. The shorter QT adaptation time to atropine-induced HR increase in LQT1 patients on the group level corroborates the importance of IKs in QT adaptation hysteresis in humans and shows that LQT1 patients have a disturbed ultra-rapid cardiac memory. On the individual level, the QT adaptation time possibly reflects the effect-size of the loss-of-function mutation, but its clinical implications need to be shown.

To Modify or Not to Modify: Allele-Specific Effects of 3'UTR-KCNQ1 Single Nucleotide Polymorphisms on Clinical Phenotype in a Long QT 1 Founder Population Segregating a Dominant-Negative Mutation.

Background There are conflicting reports with regard to the allele-specific gene suppression effects of single nucleotide polymorphisms (SNPs) in the 3'untranslated region (3'UTR) of the KCNQ1 gene in long QT syndrome type 1 (LQT1) populations. Here we assess the allele-specific effects of 3 previously published 3'UTR-KCNQ1's SNPs in a LQT1 founder population segregating a dominant-negative mutation. Methods and Results Bidirectional sequencing of the KCNQ1's 3'UTR was performed in the p.Y111C founder population (n=232, 147 genotype positive), with a minor allele frequency of 0.1 for SNP1 (rs2519184) and 0.6 for linked SNP2 (rs8234) and SNP3 (rs107980). Allelic phase was assessed in trios aided by haplotype data, revealing a high prevalence of derived SNP2/3 in cis with p.Y111C (89%). Allele-specific association analyses, corrected using a relatedness matrix, were performed between 3'UTR-KCNQ1 SNP genotypes and clinical phenotypes. SNP1 in trans was associated with a significantly higher proportion of symptomatic phenotype compared with no derived SNP1 allele in trans (58% versus 32%, corrected P=0.027). SNP2/3 in cis was associated with a significantly lower proportion of symptomatic phenotype compared with no derived SNP2/3 allele in cis (32% versus 69%, corrected P=0.010). Conclusions Allele-specific modifying effects on symptomatic phenotype of 3'UTR-KCNQ1 SNPs rs2519184, rs8234, and rs107980 were seen in a LQT1 founder population segregating a dominant-negative mutation. The high prevalence of suppressive 3'UTR-KCNQ1 SNPs segregating with the founder mutation could contribute to the previously documented low incidence of cardiac events in heterozygous carriers of the p.Y111C KCNQ1 mutation.

NOS1AP polymorphisms reduce NOS1 activity and interact with prolonged repolarization in arrhythmogenesis.

AIMS: NOS1AP single-nucleotide polymorphisms (SNPs) correlate with QT prolongation and cardiac sudden death in patients affected by long QT syndrome type 1 (LQT1). NOS1AP targets NOS1 to intracellular effectors. We hypothesize that NOS1AP SNPs cause NOS1 dysfunction and this may converge with prolonged action-potential duration (APD) to facilitate arrhythmias. Here we test (i) the effects of NOS1 inhibition and their interaction with prolonged APD in a guinea pig cardiomyocyte (GP-CMs) LQT1 model; (ii) whether pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from LQT1 patients differing for NOS1AP variants and mutation penetrance display a phenotype compatible with NOS1 deficiency. METHODS AND RESULTS: In GP-CMs, NOS1 was inhibited by S-Methyl-L-thiocitrulline acetate (SMTC) or Vinyl-L-NIO hydrochloride (L-VNIO); LQT1 was mimicked by IKs blockade (JNJ303) and ß-adrenergic stimulation (isoproterenol). hiPSC-CMs were obtained from symptomatic (S) and asymptomatic (AS) KCNQ1-A341V carriers, harbouring the minor and major alleles of NOS1AP SNPs (rs16847548 and rs4657139), respectively. In GP-CMs, NOS1 inhibition prolonged APD, enhanced ICaL and INaL, slowed Ca2+ decay, and induced delayed afterdepolarizations. Under action-potential clamp, switching to shorter APD suppressed 'transient inward current' events induced by NOS1 inhibition and reduced cytosolic Ca2+. In S (vs. AS) hiPSC-CMs, APD was longer and ICaL larger; NOS1AP and NOS1 expression and co-localization were decreased. CONCLUSION: The minor NOS1AP alleles are associated with NOS1 loss of function. The latter likely contributes to APD prolongation in LQT1 and converges with it to perturb Ca2+ handling. This establishes a mechanistic link between NOS1AP SNPs and aggravation of the arrhythmia phenotype in prolonged repolarization syndromes.

QT correction using Bazett's formula remains preferable in long QT syndrome type 1 and 2.

BACKGROUND: The heart rate (HR) corrected QT interval (QTc) is crucial for diagnosis and risk stratification in the long QT syndrome (LQTS). Although its use has been questioned in some contexts, Bazett's formula has been applied in most diagnostic and prognostic studies in LQTS patients. However, studies on which formula eliminates the inverse relation between QT and HR are lacking in LQTS patients. We therefore determined which QT correction formula is most appropriate in LQTS patients including the effect of beta blocker therapy and an evaluation of the agreement of the formulae when applying specific QTc limits for diagnostic and prognostic purposes. METHODS: Automated measurements from routine 12-lead ECGs from 200 genetically confirmed LQTS patients from two Swedish regions were included (167 LQT1, 33 LQT2). QT correction was performed using the Bazett, Framingham, Fridericia, and Hodges formulae. Linear regression was used to compare the formulae in all patients, and before and after the initiation of beta blocking therapy in a subgroup (n = 44). Concordance analysis was performed for QTc ≥ 480 ms (diagnosis) and ≥500 ms (prognosis). RESULTS: The median age was 32 years (range 0.1-78), 123 (62%) were female and 52 (26%) were children ≤16 years. Bazett's formula was the only method resulting in a QTc without relation with HR. Initiation of beta blocking therapy did not alter the result. Concordance analyses showed clinically significant differences (Cohen's kappa 0.629-0.469) for diagnosis and prognosis in individual patients. CONCLUSION: Bazett's formula remains preferable for diagnosis and prognosis in LQT1 and 2 patients.

Left Cardiac Sympathetic Denervation Monotherapy in Patients With Congenital Long QT Syndrome.

BACKGROUND: Videoscopic left cardiac sympathetic denervation (LCSD) is an effective antifibrillatory, minimally invasive therapy for patients with potentially life-threatening arrhythmia syndromes like long QT syndrome (LQTS). Although initially used primarily for treatment intensification following documented LQTS-associated breakthrough cardiac events while on beta-blockers, LCSD as 1-time monotherapy for certain patients with LQTS requires further evaluation. We are presenting our early experience with LCSD monotherapy for carefully selected patients with LQTS. METHODS: Among the 1400 patients evaluated and treated for LQTS, a retrospective review was performed on the 204 patients with LQTS who underwent LCSD at our institution since 2005 to identify the patients where the LCSD served as stand-alone, monotherapy. Clinical data on symptomatic status before diagnosis, clinical, and genetic diagnosis, and breakthrough cardiac events after diagnosis were analyzed to determine efficacy of LCSD monotherapy. RESULT: Overall, 64 of 204 patients (31%) were treated with LCSD alone (37 [58%] female, mean QTc 466±30 ms, 16 [25%] patients were symptomatic before diagnosis with a mean age at diagnosis 17.3±11.8 years, 5 had [8%] ≥1 breakthrough cardiac event after diagnosis, and mean age at LCSD was 21.1±11.4 years). The primary motivation for LCSD monotherapy was an unacceptable quality of life stemming from beta-blocker related side effects (ie, beta-blocker intolerance) in 56/64 patients (88%). The underlying LQTS genotype was LQT1 in 36 (56%) and LQT2 in 20 (31%). There were no significant LCSD-related surgical complications. With a mean follow-up of 2.7±2.4 years so far, only 3 patients have experienced a nonlethal, post-LCSD breakthrough cardiac event in 180 patient-years. CONCLUSIONS: LCSD may be a safe and effective stand-alone therapy for select patients who do not tolerate beta-blockers. However, LCSD is not curative and patient selection will be critical when potentially considering LCSD as monotherapy.

Electro-mechanical (dys-)function in long QT syndrome type 1.

BACKGROUND: Prolonged repolarization is the hallmark of long QT syndrome (LQTS), which is associated with subclinical mechanical dysfunction. We aimed at elucidating mechanical cardiac function in LQTS type 1 (loss of IKs) and its modification upon further prolongation of the action potential (AP) by IKr-blockade (E-4031). METHODS: Transgenic LQT1 and wild type (WT) rabbits (n = 12/10) were subjected to tissue phase mapping MRI, ECG, and epicardial AP recording. Protein and mRNA levels of ion channels and Ca2+ handling proteins (n = 4/4) were determined. In silico single cell AP and tension modeling was performed. RESULTS: At baseline, QT intervals were longer in LQT1 compared to WT rabbits, but baseline systolic and diastolic myocardial peak velocities were similar in LQT1 and WT. E-4031 prolonged QT more pronouncedly in LQT1. Additionally, E-4031 increased systolic and decreased diastolic peak velocities more markedly in LQT1 - unmasking systolic and diastolic LQT1-specific mechanical alterations. E-4031-induced alterations of diastolic peak velocities correlated with the extent of QT prolongation. CONCLUSION: While baseline mechanical function is normal in LQT1 despite a distinct QT prolongation, further prolongation of repolarization by IKr-blocker E-4031 unmasks mechanical differences between LQT1 and WT with enhanced systolic and impaired diastolic function only in LQT1. These data indicate an importance of the extent of QT prolongation and the contribution of different impaired ion currents for conveying mechanical dysfunction.

A pore-localizing CACNA1C-E1115K missense mutation, identified in a patient with idiopathic QT prolongation, bradycardia, and autism spectrum disorder, converts the L-type calcium channel into a hybrid nonselective monovalent cation channel.

BACKGROUND: Gain-of-function variants in the CACNA1C-encoded L-type calcium channel (LTCC, Cav1.2) cause type 8 long QT syndrome (LQT8). The pore region contains highly conserved glutamic acid (E) residues that collectively form the LTCC's selectivity filter. Here, we identified and characterized a pore-localizing missense variant, E1115K, that yielded a novel perturbation in the LTCC. OBJECTIVE: The purpose of this study was to determine whether CACNA1C-E1115K alters the LTCC's selectivity and is the substrate for the patient's LQTS. METHODS: The proband was a 14-year-old male with idiopathic QT prolongation and bradycardia. Genetic testing revealed a missense variant, CACNA1C-E1115K. The whole-cell patch clamp technique was used to measure CACNA1C-WT and -E1115K currents when heterologously expressed in TSA201 cells. RESULTS: The CACNA1C-E1115K channel exhibited no inward calcium current. Instead, robust cardiac transient outward potassium current (Ito)-like outward currents that were blocked significantly by nifedipine were measured when 2 mM/0.1 mM extracellular/intracellular CaCl2 or 4 mM/141 mM extracellular/intracellular KCl was applied. Furthermore, when 140 mM extracellular NaCl was applied, the CACNA1C-E1115K channel revealed both robust inward persistent Na+ currents with slower inactivation and outward currents, which were also nifedipine sensitive. In contrast, CACNA1C-WT revealed only a small inward persistent Na+ current without a robust outward current. CONCLUSION: This CACNA1C-E1115K variant destroyed the LTCC's calcium selectivity and instead converted the mutant channel into a channel with a marked increase in sodium-mediated inward currents and potassium-mediated outward currents. Despite the anticipated 50% reduction in LTCC, the creation of a new population of channels with accentuated inward and outward currents represents the likely pathogenic substrates for the patient's LQTS and arrhythmia phenotype.

Differential Diagnosis Between Catecholaminergic Polymorphic Ventricular Tachycardia and Long QT Syndrome Type 1　- Modified Schwartz Score.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) has been often misdiagnosed as long QT syndrome (LQTS) type 1 (LQT1), which phenotypically mimics CPVT but has a relatively better prognosis. Methods and Results: The derivation and validation cohorts consisted of 146 and 21 patients, respectively, all of whom had exercise- or emotional stress-induced cardiac events. In the derivation cohort, 42 and 104 patients were first clinically diagnosed with CPVT and LQTS, respectively. Nine of 104 patient who had initial diagnosis of LQTS were found to carry RYR2 mutations. They were misdiagnosed due to 4 different reasons: (1) transient QT prolongation after cardiopulmonary arrest; (2) QT prolongation after epinephrine test; (3) absence of ventricular arrhythmia after the exercise stress test (EST); and (4) assumption of LQTS without evidence. Based on genetic results, we constructed a composite scoring system by modifying the Schwartz score: replacing the corrected QT interval (QTc) at 4 min recovery time after EST >480 ms with that at 2 min, or with ∆QTc (QTc at 2 min of recovery-QTc before exercise) >40 ms and assigning a score of -1 for ∆QTc <10 ms or documented polymorphic ventricular arrhythmias. This composite scoring yielded 100% sensitivity and specificity for the clinical differential diagnosis between LQT1 and CPVT when applied to the validation cohort. CONCLUSIONS: The modified Schwartz score facilitated the differential diagnosis between LQT1 and CPVT.

Comparison of automated interval measurements by widely used algorithms in digital electrocardiographs.

BACKGROUND: Automated measurements of electrocardiographic (ECG) intervals by current-generation digital electrocardiographs are critical to computer-based ECG diagnostic statements, to serial comparison of ECGs, and to epidemiological studies of ECG findings in populations. A previous study demonstrated generally small but often significant systematic differences among 4 algorithms widely used for automated ECG in the United States and that measurement differences could be related to the degree of abnormality of the underlying tracing. Since that publication, some algorithms have been adjusted, whereas other large manufacturers of automated ECGs have asked to participate in an extension of this comparison. METHODS: Seven widely used automated algorithms for computer-based interpretation participated in this blinded study of 800 digitized ECGs provided by the Cardiac Safety Research Consortium. All tracings were different from the study of 4 algorithms reported in 2014, and the selected population was heavily weighted toward groups with known effects on the QT interval: included were 200 normal subjects, 200 normal subjects receiving moxifloxacin as part of an active control arm of thorough QT studies, 200 subjects with genetically proved long QT syndrome type 1 (LQT1), and 200 subjects with genetically proved long QT syndrome Type 2 (LQT2). RESULTS: For the entire population of 800 subjects, pairwise differences between algorithms for each mean interval value were clinically small, even where statistically significant, ranging from 0.2 to 3.6milliseconds for the PR interval, 0.1 to 8.1milliseconds for QRS duration, and 0.1 to 9.3milliseconds for QT interval. The mean value of all paired differences among algorithms was higher in the long QT groups than in normals for both QRS duration and QT intervals. Differences in mean QRS duration ranged from 0.2 to 13.3milliseconds in the LQT1 subjects and from 0.2 to 11.0milliseconds in the LQT2 subjects. Differences in measured QT duration (not corrected for heart rate) ranged from 0.2 to 10.5milliseconds in the LQT1 subjects and from 0.9 to 12.8milliseconds in the LQT2 subjects. CONCLUSIONS: Among current-generation computer-based electrocardiographs, clinically small but statistically significant differences exist between ECG interval measurements by individual algorithms. Measurement differences between algorithms for QRS duration and for QT interval are larger in long QT interval subjects than in normal subjects. Comparisons of population study norms should be aware of small systematic differences in interval measurements due to different algorithm methodologies, within-individual interval measurement comparisons should use comparable methods, and further attempts to harmonize interval measurement methodologies are warranted.

Architectural T-Wave Analysis and Identification of On-Therapy Breakthrough Arrhythmic Risk in Type 1 and Type 2 Long-QT Syndrome.

BACKGROUND: Although the hallmark of long-QT syndrome (LQTS) is abnormal cardiac repolarization, there are varying degrees of phenotypic expression and arrhythmic risk. Our aim was to evaluate the performance of a morphological T-wave analysis program in defining breakthrough LQTS arrhythmic risk beyond the QTc value. METHODS AND RESULTS: We analyzed 407 genetically confirmed patients with LQT1 (n=246; 43% men) and LQT2 (n=161; 41% men) over the mean follow-up period of 6.4±3.9 years. ECG analysis was conducted using a novel, proprietary T-wave analysis program. Time to a LQTS-associated cardiac event was analyzed using Cox proportional hazards regression methods. Twenty-three patients experienced ≥1 defined breakthrough cardiac arrhythmic events with 5- and 10-year event rates of 4% and 7%. Two independent predictors of future LQTS-associated cardiac events from the surface ECG were identified: left slope of T wave in lead V6 (hazard ratio=0.40 [0.24-0.69]; P<0.001) and T-wave center of gravity x axis (last 25% of wave) in lead I (hazard ratio=1.90 [1.21-2.99]; P=0.005), C statistic of 0.77 (0.65-0.89). When added to the QTc (C statistic 0.68 for QTc alone), discrimination improved to 0.78. Genotype analysis showed weaker association between these T-wave variables and LQT1-triggered events while these features were stronger in patients with LQT2 and significantly outperformed the QTc (C statistic, 0.82 [0.71-0.93]). CONCLUSION: Detailed morphological analysis of the T wave provides novel insights into risk of breakthrough arrhythmic events in LQTS, particularly LQT2. This observation has the potential to guide clinical decision making and further refine risk stratification.

T-Wave Morphology Analysis in Congenital Long QT Syndrome Discriminates Patients From Healthy Individuals.

OBJECTIVES: This study aims to assess the capability of T-wave analysis to: 1) identify genotype-positive long QT syndrome (LQTS) patients; 2) identify LQTS patients with borderline or normal QTc interval (≤460 ms); and 3) classify LQTS subtype. BACKGROUND: LQTS often presents with a nondiagnostic electrocardiogram (ECG). T-wave abnormalities may be the only marker of this potentially lethal arrhythmia syndrome. METHODS: ECGs taken at rest in 108 patients (43 with LQTS1, 20 with LQTS2, and 45 control subjects) were evaluated for T-wave flatness, asymmetry, and notching, which produces a morphology combination score (MCS) of the 3 features (MCS = 1.6 × flatness + asymmetry + notch) using QT Guard Plus Software (GE Healthcare, Milwaukee, Wisconsin). To assess for heterogeneity of repolarization, the principal component analysis ratio 2 (PCA-2) was calculated. RESULTS: Mean QTc intervals were 486 ± 50 ms (LQTS1), 479 ± 36 ms (LQTS2), and 418 ± 24 ms (control subjects) (p < 0.05). MCS and PCA-2 differed between LQTS patients and control subjects (MCS: 117.8 ± 57.4 vs. 71.9 ± 16.2; p < 0.001; PCA-2: 20.2 ± 10.4% vs. 14.6 ± 5.5%; p < 0.001), LQTS1 and LQTS2 patients (MCS: 96.3 ± 28.7 vs. 164 ± 75.2; p < 0.001; PCA-2: 17.8 ± 8.3% vs. 25 ± 12.6%; p < 0.001), and between LQTS patients with borderline or normal QTc intervals (n = 17) and control subjects (MCS: 105.7 ± 49.9 vs. 71.9 ± 16.2; p < 0.001; PCA-2: 18.1 ± 7.2% vs. 14.6 ± 5.5%; p < 0.001). T-wave metrics were consistent across multiple ECGs from individual patients based on the average intraclass correlation coefficient (MCS: 0.96; PCA-2: 0.86). CONCLUSIONS: Automated T-wave morphology analysis accurately discriminates patients with pathogenic LQTS mutations from control subjects and between the 2 most common LQTS subtypes. Mutation carriers without baseline QTc prolongation were also identified. This may be a useful tool for screening families of LQTS patients, particularly when the QTc interval is subthreshold and genetic testing is unavailable.

Genetic Modifiers for the Long-QT Syndrome: How Important Is the Role of Variants in the 3' Untranslated Region of KCNQ1?

BACKGROUND: Long-QT syndrome is an inherited cardiac channelopathy characterized by delayed repolarization, risk of life-threatening arrhythmia, and significant clinical variability even within families. Three single-nucleotide polymorphisms (SNPs) in the 3' untranslated region of KCNQ1 were recently suggested to be associated with suppressed gene expression and hence decreased disease severity when located on the same haplotype with a disease-causing KCNQ1 mutation. We sought to replicate this finding in a larger and a genetically more homogeneous population of KCNQ1 mutation carriers. METHODS AND RESULTS: The 3 SNPs (rs2519184, rs8234, and rs10798) were genotyped in a total of 747 KCNQ1 mutation carriers with A341V, G589D, or IVS7-2A>G mutation. The SNP haplotypes were assigned based on family trees. The SNP allele frequencies and clinical severity differed between the 3 mutation groups. The different SNP haplotypes were neither associated with heart rate-corrected QT interval duration (QTc) nor cardiac events in any of the 3 mutation groups. When the mutation groups were combined, the derived SNP haplotype of rs8234 and rs10798 located on the same haplotype with the mutation was associated with a shorter QTc interval (P<0.05) and a reduced occurrence of cardiac events (P<0.01), consistent with the previous finding. However, when the population-specific mutation was controlled for, both associations were no longer evident. CONCLUSIONS: 3' Untranslated region SNPs are not acting as genetic modifiers in a large group of LQT1 patients. The confounding effect of merging a genetically and clinically heterogeneous group of patients needs to be taken into account when studying disease modifiers.

Experience with bisoprolol in long-QT1 and long-QT2 syndrome.

BACKGROUND: The protective effect of beta-blockers in patients with inherited Long-QT syndrome is well established. Recent reports have suggested that beta-blockers are not equally effective in Long-QT (LQT). Bisoprolol is an attractive candidate for use in LQT because of its cardioselective properties and favorable side-effect profile. METHODS: We performed a retrospective cohort study of 114 consecutive patients with gene-positive Long-QT syndrome type 1 (LQT1) or Long-QT syndrome type 2 (LQT2) treated with bisoprolol, nadolol or atenolol with a total of 580 person-years of follow-up. Electrocardiogram (ECG) parameters and cardiac events during follow-up were compared. In addition, exercise treadmill testing was performed in bisoprolol-treated patients. RESULTS: Fifty-nine patients were treated with bisoprolol, 39 with atenolol and 16 with nadolol. Overall, 59 % were females and 62 % had LQT1. Baseline heart rate and corrected QT (QTc) interval were similar between the groups. QTc shortening was observed in individuals on bisoprolol (ΔQTc -5 ± 31 ms; p = 0.049) and nadolol (ΔQTc -13 ± 16 ms; p = 0.02) but not on atenolol (ΔQTc +9 ± 24 ms; p = 0.16). Median follow-up was similar for bisoprolol and nadolol (3 years), but longer for atenolol (6 years; p = 0.03); one cardiac event occurred in the bisoprolol group (1.7 %) and two events occurred in the atenolol group (5.1 %; p = 0.45), whereas none occurred in nadolol-treated patients. Beta-blocker efficacy was not affected by the underlying genotype. The antiadrenergic effect of bisoprolol correlated with the reduction of peak heart rates at exercise testing. CONCLUSIONS: Bisoprolol treatment results in QTc shortening in gene-positive LQT1 and LQT2 patients and is well tolerated during long-term administration. The equivalence of bisoprolol for protection from ventricular arrhythmia in LQT patients compared to established beta-blockers remains unknown. Further large-scale studies are required.

KCNQ1 mutations associated with Jervell and Lange-Nielsen syndrome and autosomal recessive Romano-Ward syndrome in India-expanding the spectrum of long QT syndrome type 1.

Long QT syndrome type 1 (LQT1) is the most common type of all Long QT syndromes (LQTS) and occurs due to mutations in KCNQ1. Biallelic mutations with deafness is called Jervell and Lange-Nielsen syndrome (JLNS) and without deafness is autosomal recessive Romano-Ward syndrome (AR RWS). In this prospective study, we report biallelic mutations in KCNQ1 in Indian patients with LQT1 syndrome. Forty patients with a clinical diagnosis of LQT1 syndrome were referred for molecular testing. Of these, 18 were excluded from the analysis as they did not fulfill the inclusion criteria of broad T wave ECG pattern of the study. Direct sequencing of KCNQ1 was performed in 22 unrelated probands, parents and at-risk family members. Mutations were identified in 17 patients, of which seven had heterozygous mutations and were excluded in this analysis. Biallelic mutations were identified in 10 patients. Five of 10 patients did not have deafness and were categorized as AR RWS, the rest being JLNS. Eight mutations identified in this study have not been reported in the literature and predicted to be pathogenic by in silico analysis. We hypothesize that the homozygous biallelic mutations identified in 67% of families was due to endogamous marriages in the absence of consanguinity. This study presents biallelic gene mutations in KCNQ1 in Asian Indian patients with AR JLNS and RWS. It adds to the scant worldwide literature of mutation studies in AR RWS. © 2016 Wiley Periodicals, Inc.

Effect of Left Cardiac Sympathetic Denervation on the Electromechanical Window in Patients with either Type 1 or Type 2 Long QT Syndrome: A Pilot Study.

BACKGROUND: Left cardiac sympathetic denervation (LCSD) exerts significant antifibrillatory effects in patients with long QT syndrome (LQTS). Recently, electromechanical window (EMW) has emerged as a novel torsadogenic marker in LQTS, superior to QT interval (QTc) in distinguishing symptomatic from asymptomatic patients. OBJECTIVE: To explore the hypothesis that LCSD improves EMW most favorably in patients with LQT1. DESIGN: From September 2006 to July 2015, 44 LQT1 and 25 LQT2 patients underwent LCSD. Subset analysis was performed on the six LQT1 and seven LQT2 patients who had echocardiograms both pre-LCSD and ≥3 months post-LCSD. EMW is defined as the time difference (ms) between aortic valve closure and the end of the QT interval, measured from an ECG on the concurrent echocardiogram. RESULTS: Compared to published normal EMW values of 22 ± 19 ms, pre-LCSD EMW mean values were -78 ± 36 ms in LQT1 and -71 ± 35 ms in LQT2 (P < .001). Following LCSD, there was a 57 ± 35 ms decrease in QTc in LQT1 (P = .16) and 23 ± 21 ms decrease in QTc in LQT2 (P = .3). Overall, there was a 35 ± 57 ms mean improvement in EMW post-LCSD (P = .04). Five of the 6 (83%) LQT1 subjects had a favorable EMW change post-LCSD (mean improvement 56 ± 25 ms, P = .04). Five of the 7 (71%) LQT2 subjects had a favorable EMW change post-LCSD (mean improvement 18 ± 19 ms, P = .2). CONCLUSIONS: The precise mechanism of the LCSD therapeutic effect in LQTS patients is not fully understood. This pilot study raises the possibility that LCSD's antitorsadogenic effect in patients with LQT1 could be conferred in part by restoration of electromechanical order, evidenced by normalization of the EMW.

Stop-codon and C-terminal nonsense mutations are associated with a lower risk of cardiac events in patients with long QT syndrome type 1.

BACKGROUND: In long QT syndrome type 1 (LQT1), the location and type of mutations have been shown to affect the clinical outcome. Although haploinsufficiency, including stop-codon and frameshift mutations, has been associated with a lower risk of cardiac events in patients with LQT1, nonsense mutations have been presumed functionally equivalent. OBJECTIVE: The purpose of this study was to evaluate clinical differences between patients with nonsense mutations. METHODS: The study sample comprised 1090 patients with genetically confirmed mutations. Patients were categorized into 5 groups, depending on mutation type and location: missense not located in the high-risk cytoplasmic loop (c-loop) (n = 698), which is used as reference; missense c-loop (n = 192); stop-codon (n = 67); frameshift (n = 39); and others (n = 94). The primary outcome was a composite end point of syncope, aborted cardiac arrest, and long QT syndrome-related death (cardiac events). Outcomes were evaluated using the multivariate Cox proportional hazards regression analysis. Standard patch clamp techniques were used. RESULTS: Compared to patients with missense non-c-loop mutations, the risk of cardiac events was reduced significantly in patients with stop-codon mutations (hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.34-0.96; P = .035), but not in patients with frameshift mutations (HR 1.01; 95% CI 0.58-1.77; P = .97). Our data suggest that currents of the most common stop-codon mutant channel (Q530X) were larger than those of haploinsufficient channels (wild type: 42 ± 6 pA/pF, n = 20; Q530X+wild type: 79 ± 14 pA/pF, n = 20; P < .05) and voltage dependence of activation was altered. CONCLUSION: Stop-codon mutations are associated with a lower risk of cardiac events in patients with LQT1, while frameshift mutations are associated with the same risk as the majority of the missense mutations. Our data indicate functional differences between these previously considered equivalent mutation subtypes.

Dual LQT1 and HCM phenotypes associated with tetrad heterozygous mutations in KCNQ1, MYH7, MYLK2, and TMEM70 genes in a three-generation Chinese family.

AIMS: Hypertrophic cardiomyopathy (HCM) mainly results from autosomal-dominant inherited single heterozygous mutations in cardiac sarcomere genes. Contributions of multiple gene mutations to disease heterogeneity in a three-generation family were investigated. METHODS: Clinical, electrocardiographic (ECG), and echocardiographic examination in members of a three-generation Chinese family was followed by exon and boarding intron analysis of 96 genes in the proband using second-generation sequencing. The identified mutations were confirmed by bi-directional Sanger sequencing in all family members and 300 healthy controls. RESULTS: Four missense mutations were detected in the family. These were two novel MYH7-H1717Q and MYLK2-K324E mutations accompanied by the KCNQ1-R190W and TMEM70-I147T mutations. The proband carried all four mutations and showed overlapping HCM and LQT1 phenotypes. Five family members each carried two mutations. Subject II-2 only carried TMEM70-I147T. MYH7-H1717Q and TMEM70-I147T came from the paternal side, whereas KCNQ1-R190W and MYLK2-K324E came from the maternal side. Left ventricle mass indices in MYH7-H1717Q carriers were significantly higher than in non-H1717Q carriers (90.05 ± 7.33 g/m(2), 63.20 ± 4.53 g/m(2), respectively, P < 0.01). Four KCNQ1-R190W carriers showed QTc intervals that were significantly more prolonged than those in non-R190W carriers (472.25 ± 16.18 and 408.50 ± 7.66 ms, respectively, P < 0.05). All MYLK2-K324E carriers showed inverted ECG T waves. The subject with only a TMEM70-I147T mutation showed normal ECG and echocardiographs, suggesting that this had less pathological effects at least in this family. CONCLUSIONS: We demonstrate dual LQT1 and HCM phenotypes in this multiple LQT1- and HCM-related gene mutation carrier family for the first time and suggest that LQT-related gene mutations associate with QT interval prolongation and/or arrhythmia in HCM patients.

"QT clock" to improve detection of QT prolongation in long QT syndrome patients.

BACKGROUND: The QT interval is a risk marker for cardiac events such as torsades de pointes. However, QT measurements obtained from a 12-lead ECG during clinic hours may not capture the full extent of a patient's daily QT range. OBJECTIVE: The purpose of this study was to evaluate the utility of 24-hour Holter ECG recording in patients with long QT syndrome (LQTS) to identify dynamic changes in the heart rate-corrected QT interval and to investigate methods of visualizing the resulting datasets. METHODS: Beat-to-beat QTc (Bazett) intervals were automatically measured across 24-hour Holter recordings from 202 LQTS type 1, 89 type 2, and 14 type 3 genotyped patients and a reference group of 200 healthy individuals. We measured the percentage of beats with QTc greater than the gender-specific threshold (QTc ≥470 ms in women and QTc ≥450 ms in men). The percentage of beats with QTc prolongation was determined across the 24-hour recordings. RESULTS: Based on the median percentage of heartbeats per patient with QTc prolongation, LQTS type 1 patients showed more frequent QTc prolongation during the day (~3 PM) than they did at night (~3 AM): 97% vs 48%, P ~10(-4) for men, and 68% vs 30%, P ~10(-5) for women. LQTS type 2 patients showed less frequent QTc prolongation during the day compared to nighttime: 87% vs 100%, P ~10(-4) for men, and 62% vs 100%, P ~10(-3) for women. CONCLUSION: In patients with genotype-positive LQTS, significant differences exist in the degree of daytime and nocturnal QTc prolongation. Holter monitoring using the "QT clock" concept may provide an easy, fast, and accurate method for assessing the true personalized burden of QTc prolongation.