Genetic characterization of KCNQ1 variants improves risk stratification in type 1 long QT syndrome patients.

AIMS: KCNQ1 mutations cause QTc prolongation increasing life-threatening arrhythmias risks. Heterozygous mutations [type 1 long QT syndrome (LQT1)] are common. Homozygous KCNQ1 mutations cause type 1 Jervell and Lange-Nielsen syndrome (JLNS) with deafness and higher sudden cardiac death risk. KCNQ1 variants causing JLNS or LQT1 might have distinct phenotypic expressions in heterozygous patients. The aim of this study is to evaluate QTc duration and incidence of long QT syndrome-related cardiac events according to genetic presentation. METHODS AND RESULTS: We enrolled LQT1 or JLNS patients with class IV/V KCNQ1 variants from our inherited arrhythmia clinic (September 1993 to January 2023). Medical history, ECG, and follow-up were collected. Additionally, we conducted a thorough literature review for JLNS variants. Survival curves were compared between groups, and multivariate Cox regression models identified genetic and clinical risk factors. Among the 789 KCNQ1 variant carriers, 3 groups were identified: 30 JLNS, 161 heterozygous carriers of JLNS variants (HTZ-JLNS), and 550 LQT1 heterozygous carriers of non-JLNS variants (HTZ-Non-JLNS). At diagnosis, mean age was 3.4 ± 4.7 years for JLNS, 26.7 ± 21 years for HTZ-JLNS, and 26 ± 21 years for HTZ-non-JLNS; 55.3% were female; and the mean QTc was 551 ± 54 ms for JLNS, 441 ± 32 ms for HTZ-JLNS, and 467 ± 36 ms for HTZ-Non-JLNS. Patients with heterozygous JLNS mutations (HTZ-JLNS) represented 22% of heterozygous KCNQ1 variant carriers and had a lower risk of cardiac events than heterozygous non-JLNS variant carriers (HTZ-Non-JLNS) [hazard ratio (HR) = 0.34 (0.22-0.54); P < 0.01]. After multivariate analysis, four genetic parameters were independently associated with events: haploinsufficiency [HR = 0.60 (0.37-0.97); P = 0.04], pore localization [HR = 1.61 (1.14-1.2.26); P < 0.01], C-terminal localization [HR = 0.67 (0.46-0.98); P = 0.04], and group [HR = 0.43 (0.27-0.69); P < 0.01]. CONCLUSION: Heterozygous carriers of JLNS variants have a lower risk of cardiac arrhythmic events than other LQT1 patients.

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.

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.

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.

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.

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.

Identification of Low-Risk Adult Congenital LQTS Patients.

INTRODUCTION: To date, most risk stratification studies in long-QT syndrome (LQTS) have focused on identification of high-risk subjects. Current data on the long-term clinical course of low-risk adult LQTS patients are limited. METHODS AND RESULTS: Patients in this study were from the Rochester-based LQTS Registry. We hypothesized that long-term survival of LQT1-2 patients with QTc <500 milliseconds and no cardiac symptoms before age 20 (n = 523) would be similar to that of their unaffected genotype-negative family members (n = 1,134). Kaplan-Meier survival analysis and multivariate Cox proportional hazards regression models were used to evaluate the incidence and risk of all-cause mortality in the study population. The low-risk LQTS study group comprised 27% (523/1,919) of genetically confirmed LQTS Registry patients alive at age 20. The cumulative probability of all-cause mortality between age 20 and 65 was similar in the low-risk LQTS group and the genotype-negative control group (4.3% and 4.4%, respectively at age 65; P = 0.49 for overall difference). Multivariate analysis showed no significant difference in the risk of all-cause mortality between the 2 groups (HR = 0.89; 95% CI 0.33-2.43, P = 0.82). Consistent results were revealed in subgroup analyses in female and male LQTS patients and in patients with genetically identified LQT1 and LQT2 mutations. CONCLUSIONS: We identified a sizeable proportion of low-risk, adult LQTS patients with no cardiac symptoms before age 20 and QTc<500 milliseconds who had 45-year survival similar to unaffected family members.

Effect of beta-blockers on QT dynamics in the long QT syndrome: measuring the benefit.

AIMS: Beta-blockers are the standard of care for the treatment of long QT syndrome (LQTS), and have been shown to reduce recurrent syncope and mortality in patients with type 1 LQTS (LQT1). Although beta-blockers have minimal effect on the resting corrected QT interval, their effect on the dynamics of the non-corrected QT interval is unknown, and may provide insight into their protective effects. METHODS AND RESULTS: Twenty-three patients from eight families with genetically distinct mutations for LQT1 performed exercise stress testing before and after beta-blockade. One hundred and fifty-two QT, QTc, and Tpeak-Tend intervals were measured before starting beta-blockers and compared with those at matched identical cycle lengths following beta-blockade. Beta-blockers demonstrated heart-rate-dependent effects on the QT and QTc intervals. In the slowest heart rate tertile (<90 b.p.m.), beta-blockade increased the QT and QTc intervals (QT: 405 vs. 409 ms; P = 0.06; QTc: 459 vs. 464 ms; P = 0.06). In the fastest heart rate tertile (>100 b.p.m.), the use of beta-blocker was associated with a reduction in both the QT and QTc intervals (QT: 367 vs. 358 ms; P < 0.0001; QTc: 500 vs. 486 ms; P < 0.0001). The Tpeak-Tend interval showed minimal change at slower heart rates (<90 b.p.m.) (93 vs. 87 ms; P = 0.09) and at faster heart rates (>100 b.p.m.) (87 vs. 84 ms; P = NS) following beta-blockade. CONCLUSION: Beta-blockers have heart-rate-dependent effects on the QT and QTc intervals in LQTS. They appear to increase the QT and QTc intervals at slower heart rates and shorten them at faster heart rates during exercise.

The Romano-Ward syndrome--1964-2014: 50 years of progress.

This year marks the 50th anniversary of publication in the then Journal of the Irish Medical Association of the seminal work by Irish paediatrician Professor Conor Ward entitled 'A new familial Cardiac Syndrome in Children'. The condition soon became known by the eponym Romano-Ward Syndrome and is now recognised as the congenital Long QT Syndrome. Here we review the major developments in the field over the past fifty years, with special mention of the important contributions made by Irish researches.

Mutation location effect on severity of phenotype during exercise testing in type 1 long-QT syndrome: impact of transmembrane and C-loop location.

BACKGROUND: Targeted mutation site-specific differences have correlated C-loop missense mutations with worse outcomes and increased benefit of beta-blockers in LQT1. This observation has implicated the C-loop region as being mechanistically important in the altered response to sympathetic stimulation known to put patients with LQT1 at risk of syncope and sudden cardiac death. OBJECTIVE: The objective of this study was to determine if there is mutation site-specific response to sympathetic stimulation and beta-blockers using exercise testing. METHODS: This study is a retrospective review of LQT1 patients undergoing exercise testing at 3 academic referral centers. RESULTS: A total of 123 patients (age 28 ± 17 years, 59 male) were studied including 34 patients (28%) with C-loop mutations. There were no significant differences in supine, standing, peak exercise and 1-minute recovery QTc duration between patients with C-loop mutations and patients with alternate mutation sites. In 37 patients that underwent testing on and off beta-blockers, beta-blocker use was associated with a significant reduction in supine, standing and peak exercise QTc. This difference was not seen in the small group of patients (7/37) with C-loop mutations. There was no difference in QTc at 1 and 4 minutes into recovery. CONCLUSIONS: Genetically confirmed LQT1 patients in this study cohort with C-loop mutations did not demonstrate the expected increase in QTc in response to exercise, or resultant response to beta-blocker. The apparent increased risk of cardiac events associated with C-loop mutation sites and the marked benefit received from beta-blocker therapy are not reflected by exercise-mediated effects on QTc in this study population.

Gene-specific effect of beta-adrenergic blockade on corrected QT interval in the long QT syndrome.

BACKGROUND: In the long QT syndrome (LQTS) the effects of beta-blocker treatment on prevention of cardiac events differs according to the genotype. We aimed to assess the effect of beta-blocker treatment on QT/QTc duration in Type 1 LQTS (LQT1) and Type 2 LQTS (LQT2) patients. METHODS: 24-hour digital Holter ECG were recorded before and after beta-blocking therapy initiation in LQT1 (n = 30) and LQT2 patients (n = 16). QT duration was measured on consecutive 1-minute averaged QRS-T complexes leading to up to 1440 edited QT-RR pairs for each recording. We computed subject- and treatment-specific log/log QT/RR relationships which were used to correct the QT intervals. The QT duration was also evaluated at predefined heart rates and after correction using Bazett and Fridericia coefficients. RESULTS: At baseline, individual QT/RR coefficients were higher in LQT2 than in LQT1 patients (0.53 ± 0.10 vs. 0.40 ± 0.11, P < 0.001) and QT1000 was longer in LQT2 than in LQT1 patients (521 ± 38 vs. 481 ± 39 ms, P < 0.01). Beta-blockers significantly prolonged the mean RR interval (from 827 ± 161 to 939 ± 197 ms, P < 0.0001). The individual QT/RR coefficients were not significantly modified by beta-blockers. Beta-blocker treatment was associated with a prolongation of the QT1000 interval (from 481 ± 39 to 498 ± 43 ms, P < 0.01) in LQT1 patients but with a shortening in LQT2 patients (from 521 ± 38 to 503 ± 32 ms, P < 0.01). CONCLUSIONS: The effect of beta-adrenergic blockade on QTc duration is different in LQT1 and LQT2 patients. Our data suggest that, in LQT1 patients, the well-known positive effect of beta-blockade might be associated with a prolongation of QTc duration. The mechanisms of beta-blockade protection may be different in LQT1 and in LQT2 patients.

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.

Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome.

Type 2 congenital long QT syndrome (LQT-2) is linked to mutations in the human ether a-go-go-related gene (HERG) and is characterized by rate-corrected QT interval (QTc) prolongation, ventricular arrhythmias, syncope, and sudden death. Recognized triggers of these cardiac events include emotional and acoustic stimuli. Here we investigated the repeated occurrence of fever-induced polymorphic ventricular tachycardia and ventricular fibrillation in 2 LQT-2 patients with A558P missense mutation in HERG. ECG analysis showed increased QTc with fever in both patients. WT, A558P, and WT+A558P HERG were expressed heterologously in HEK293 cells and were studied using biochemical and electrophysiological techniques. A558P proteins showed a trafficking-deficient phenotype. WT+A558P coexpression caused a dominant-negative effect, selectively accelerated the rate of channel inactivation, and reduced the temperature-dependent increase in the WT current. Thus, the WT+A558P current did not increase to the same extent as the WT current, leading to larger current density differences at higher temperatures. A similar temperature-dependent phenotype was seen for coexpression of the trafficking-deficient LQT-2 F640V mutation. We postulate that the weak increase in the HERG current density in WT-mutant coassembled channels contributes to the development of QTc prolongation and arrhythmias at febrile temperatures and suggest that fever is a potential trigger of life-threatening arrhythmias in LQT-2 patients.

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.

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.

Síndrome de QT largo congénito y bradicardia fetal: la importancia del diagnóstico / Congenital long QT syndrome and fetal bradycardia: the importance of the diagnosis

Antecedentes: El síndrome de QT largo es una canalopatía que afecta a la repolarización ventricular y aumenta el riesgo de sufrir arritmias ventriculares graves. Puede ser congénito o adquirido, y es una causa conocida de muerte súbita. Caso clínico: Gestante primigesta, de 28 años, sin antecedentes de interés. En ecografías prenatales se objetivó en el feto bradicardia sinusal mantenida desde la semana 28, sin repercusión hemodinámica, que persistió hasta la finalización de la gestación (semana 37+3). Al nacimiento se realizaron electrocardiogramas seriados que mostraron alteraciones en la repolarización con alargamiento del intervalo QT corregido. Se realizó estudio genético que confirmó síndrome de QT largo tipo 1 y se inició tratamiento oral con beta-bloqueantes, con buena respuesta. Conclusiones: El síndrome de QT largo suele diagnosticarse posnatalmente. Es importante conocer sus características clínicas prenatales para poder establecer un diagnóstico precoz y minimizar así el riesgo de muerte súbita de estos pacientes.

Background: Long QT syndrome is a channelopathy that affects ventricular repolarization and increases the risk of severe ventricular arrhythmias. It can be congenital or acquired, and is a known cause of sudden cardiac death. Case report: A 28-year-old primigravida with no significant medical history. Prenatal ultrasounds revealed sustained fetal sinus bradycardia from week 28, without hemodynamic repercussion, which persisted until the end of gestation (at 37+3 weeks). Serial electrocardiograms were performed after birth, showing repolarization abnormalities with prolonged corrected QT interval. A genetic study confirmed long QT syndrome type 1, and oral treatment with beta-blockers was initiated, showing a positive response. Conclusions: Long QT syndrome is often diagnosed postnatally. It is important to be aware of his prenatal clinical features in order to establish an early diagnosis and minimize the risk of sudden death in these patients.

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.