Long QT Syndrome Patients Research Articles

Support vector machine-based assessment of the T-wave morphology improves long QT syndrome diagnosis.

Diagnosing long QT syndrome (LQTS) is challenging due to a considerable overlap of the QTc-interval between LQTS patients and healthy controls. The aim of this study was to investigate the added value of T-wave morphology markers obtained from 12-lead electrocardiograms (ECGs) in diagnosing LQTS in a large cohort of gene-positive LQTS patients and gene-negative family members using a support vector machine. A retrospective study was performed including 688 digital 12-lead ECGs recorded from genotype-positive LQTS patients and genotype-negative relatives at their first visit. Two models were trained and tested equally: a baseline model with age, gender, RR-interval, QT-interval, and QTc-intervals as inputs and an extended model including morphology features as well. The best performing baseline model showed an area under the receiver-operating characteristic curve (AUC) of 0.821, whereas the extended model showed an AUC of 0.901. Sensitivity and specificity at the maximal Youden's indexes changed from 0.694 and 0.829 with the baseline model to 0.820 and 0.861 with the extended model. Compared with clinically used QTc-interval cut-off values (>480 ms), the extended model showed a major drop in false negative classifications of LQTS patients. The support vector machine-based extended model with T-wave morphology markers resulted in a major rise in sensitivity and specificity at the maximal Youden's index. From this, it can be concluded that T-wave morphology assessment has an added value in the diagnosis of LQTS.

Prevalence and clinical phenotype of concomitant long QT syndrome and arrhythmogenic bileaflet mitral valve prolapse

BackgroundMitral valve prolapse (MVP), including the recently described arrhythmogenic bileaflet MVP syndrome (ABiMVPS), is associated with repolarization abnormalities and may represent an underestimated cause of sudden cardiac death. The impact of concomitant MVP or ABiMVPS on long QT syndrome (LQTS) clinical severity is unknown. Methods and resultsRetrospective review of 754 LQTS patients [445 females (58%) and mean QTc 471 ± 41 ms] with available echocardiographic data was performed to identify LQTS patients with not only MVP, but also a pro-arrhythmic ABiMVPS phenotype defined as bileaflet MVP, inferolateral T-wave inversions, and frequent complex ventricular ectopy/arrhythmia. As expected, 18/754 (2%) LQTS patients had concomitant MVP. Of these, 5/18 (28%) LQTS patients with MVP satisfied ABiMVPS diagnostic criteria. No difference in symptomatology, degree of QT prolongation, or clinical management was observed between LQTS patients with and without MVP. In contrast, LQTS plus ABiMVPS resulted in a severe cardiac phenotype as illustrated by symptomatic status (LQTS-ABiMVPS; 5/5; 100%; vs LQTS: 279/736; 39%; p = .008), degree of baseline QTc prolongation (LQTS-ABiMVPS: 536 ± 58 ms; vs LQTS: 470 ± 40 ms; p = .009), and number of patients experiencing ≥1 on-therapy break-through cardiac event (LQTS-ABiMVPS: 4/5; 80%; vs LQTS: 48/736; 7%; p < .001]. Lastly, individuals with LQTS plus ABiMVPS were more likely to experience appropriate ICD therapies post-cardiac denervation (LQTS-ABiMVPS: 2/3; 67% vs LQTS: 4/49; 8%; p = .03]. Conclusions and relevanceThe co-existence of LQTS and ABiMVPS may lead to a rare, but malignant, clinical entity characterized by potentially life-threatening arrhythmias despite maximal LQTS therapy.

Genetic and Phenotypic Characterization of Community Hospital Patients With QT Prolongation.

BackgroundCongenital long‐QT syndrome (LQTS) is a genetic disorder characterized by prolongation of the corrected QT interval (QTc) on an ECG. The aim of the present study was to estimate the prevalence of pathogenic and likely pathogenic sequence variants in patients who had at least 1 ECG with a QTc ≥500 ms.Methods and ResultsTelemark Hospital Trust is a community hospital within the Norwegian national health system, serving ≈173 000 inhabitants. We searched the ECG database at Telemark Hospital Trust, Norway, from January 2004 to December 2014, and identified 1531 patients with at least 1 ECG with a QTc ≥500 ms. At the time of inclusion in this study (2015), 766 patients were alive. A total of 733 patients were invited to participate, and 475 accepted. The 17 genes that have been reported to cause monogenic LQTS were sequenced among the patients. Pro‐QTc score was calculated for each patient. A molecular genetic cause of LQTS was detected in 31 (6.5%) of 475 patients. These patients had a lower pro‐QTc score than those without pathogenic or likely pathogenic variants (1.7±1.0 versus 2.8±1.6; P<0.001).ConclusionsCompared with the general population, hospitalized patients with a QTc ≥500 ms in at least 1 ECG recording had an increased likelihood for pathogenic and likely pathogenic variants in LQTS genes. We recommend increased awareness of the possibility of LQTS in patients with at least 1 ECG with a QTc ≥500 ms.

Implantable cardioverter-defibrillators in patients with long QT syndrome: a multicentre study.

Implantable cardioverter-defibrillator (ICD) therapy has been proven effective in the prevention of sudden cardiac death, but data on outcomes of ICD therapy in the young and otherwise healthy patients with long QT syndrome (LQTS) are limited. We sought to collect data on appropriate and inappropriate ICD discharges, risk factors, and ICD-related complications. All LQTS patients implanted with an ICD in 14 centres were investigated. Demographic, clinical, and ICD therapy data were collected. The study included 67 patients (88% female). Median age at ICD implantation was 31 years (12-77 years). ICD indication was based on resuscitated cardiac arrest in 46 patients, syncope in 18 patients, and malignant family history in three patients. During a median follow-up of 48 months, 39 (58%) patients received one or more ICD therapies. Time to first appropriate discharge was up to 55 months. Inappropriate therapies were triggered by fast sinus rhythm, atrial fibrillation, and T-wave oversensing. No predictors of inappropriate shocks were identified. Risk factors for appropriate ICD therapy were: (1) recurrent syncope despite b-blocker treatment before ICD implantation, (2) pacemaker therapy before ICD implantation, (3) single-chamber ICD, and (4) noncompliance to b-blockers. In 38 (57%) patients, at least one complication occurred. ICD therapy is effective in nearly half the patient population; however, the rates of early and late complica-tions are high. Although the number of unnecessary ICD shocks and reimplantation procedures may be lowered by modern programming and increased longevity of newer ICD generators, other adverse events are less likely to be reduced.

Primary prevention with the implantable cardioverter-defibrillator in high-risk long-QT syndrome patients.

Prospective data regarding the role of implantable cardioverter-defibrillator (ICD) for the primary prevention of sudden cardiac death in patients with long QT syndrome (LQTS) is scarce. Herein, we explore the prospective Rochester LQTS ICD registry to assess the risk for appropriate shock in primary prevention in a real-world setting. We studied 212 LQTS patients that had ICD implantation for primary prevention. Best-subsets proportional-hazards regression analysis was used to identify clinical variables that were associated with the first appropriate shock. Conditional models of Prentice, Williams, and Peterson were utilized for the analysis of recurrent appropriate shocks. During a median follow-up of 9.2 ± 4.9 years, there were 42 patients who experienced at least one appropriate shock and the cumulative probability of appropriate shock at 8 years was 22%. QTc ≥ 550 ms [hazard ratio (HR) 3.94, confidence interval (CI) 2.08-7.46; P < 0.001) and prior syncope on β-blockers (HR 1.92, CI 1.01-3.65; P = 0.047) were associated with increased risk of appropriate shock. History of syncope while on β-blocker treatment (HR 1.87, CI 1.28-2.72; P = 0.001), QTc 500-549 ms (HR 1.68, CI 1.10-2.81; P = 0.048), and QTc ≥ 550 ms (HR 3.66, CI 2.34-5.72; P < 0.001) were associated with increased risk for recurrent appropriate shocks, while β-blockers were not protective (HR 1.03, CI 0.63-1.68, P = 0.917). LQT2 (HR 2.10, CI 1.22-3.61; P = 0.008) and multiple mutations (HR 2.87, CI 1.49-5.53; P = 0.002) were associated with higher risk for recurrent shocks as compared with LQT1. In this prospective ICD registry, we identified clinical and genetic variables that were associated appropriate shock risk. These data can be used for risk stratification in high-risk patients evaluated for primary prevention with ICD.

A wearable remote monitoring system for the identification of subjects with a prolonged QT interval or at risk for drug-induced long QT syndrome

BackgroundA correct measurement of the QT interval in the out-of-hospital setting is important whenever the long QT syndrome (LQTS) is suspected or a therapy might lead to drug-induced LQTS (diLQTS) because QT interval monitoring in the initial days of therapy could alert to dangerous QT prolongation. We explored whether automated QTc measurements (BGM) by BodyGuardian™ (BG), a wearable remote monitoring system, are sufficiently reliable compared to our own manual measurements (MM) performed on the same beats during 12‑lead Holter recordings in LQTS patients (pts) and in healthy controls. MethodsWe performed 351 measurements in 20 LQTS pts and 16 controls. MM and BGM were compared by a Bland-Altman plot (BAp). High values of BAp indicate large differences between measurements. ResultsIn all 36 subjects QTc was 446 ± 41 and 445 ± 47 ms in MM and BGM, respectively. The mean ± SE BAp was −1.4 ± 1.8 ms for QTc in all subjects, 8.3 ± 2.3 and −7.2 ± 2.5 ms respectively in controls and LQTS. The disagreement between BGM and MM <15 ms in all, in controls, and in LQTS was respectively 57%, 63% and 54%. Among controls, there were only 3/132 false positive measurements (BGM QTc >470 ms when MM QTc <440 ms) in 3 different subjects. Among LQTS, there were 10/219 false negative measurements (BGM QTc <440 ms when MM QTc >470 ms) in 6 pts, but only two had multiple false negative values. ConclusionsThis wearable monitoring system reliably identifies a prolonged QT interval and probably also subjects at risk for diLQTS.

QTc interval prolongation in critically ill patients: Prevalence, risk factors and associated medications.

PurposeTo investigate the prevalence and risk factors of acquired long QT syndrome (LQTS) on admission to a general Intensive Care Unit (ICU), and to assess the risk of LQTS associated with prescribed medications.MethodsProspective observational, cross-sectional study approved by the Institutional Review Board. Between May 2014 and July 2016, 412 patients >18 years-old consecutively admitted to the ICU of a university hospital were included. LQTS was defined as a QT interval on the admission electrocardiogram corrected using Bazett’s formula (QTc) >460 ms for men and >470 ms for women. All medications administered within 24 hours before admission were recorded. Logistic regression was used.ResultsLQTS prevalence was 27.9%. In LQTS patients, 70.4% had ≥ 1 LQTS-inducing drug prescribed in the 24 hours prior to ICU admission versus 70.4% in non-LQTS patients (p = 0.99). Bradycardia and Charlson morbidity index score are independent risk factors for LQTS. Haloperidol (OR 4.416), amiodarone (OR 2.509) and furosemide (OR 1.895) were associated with LQTS, as well as another drug not yet described, namely clopidogrel (OR 2.241).ConclusionsThe LQTS is highly prevalent in critically ill patients, ICU patients are often admitted with LQTS-inducing medications, and patients with slow heart rate or with high Charlson comorbidity index should be evaluated for LQTS.

Maximum QTc on Holter electrocardiography in children.

Corrected QT interval (QTc) on electrocardiography (ECG) at rest and after exercise in a short daytime recording period may be insufficient for the diagnosis and management of long QT syndrome (LQTS), especially for LQTS type 2 and 3. Therefore, examination of QTc on Holter ECG is important. We designed a method of analyzing QTc on Holter ECG that can be performed in daily clinical practice by combining automatic and manual measurements. We reviewed the charts of healthy children (n = 210) and LQTS patients (n = 35) aged <16years and analyzed QTc at rest and after exercise, and the maximum QTc on Holter ECG. The QTc (Fridericia's correction) of most controls and LQTS patients reached the maximum at night or early in the morning. QTc differed according to sex and age. In the control group, QTc on ECG of all three types tended to lengthen with age. QTc after exercise was slightly longer than QTc at rest, and the maximum QTc on Holter ECG was much longer than both, reaching >450ms in boys and 500ms in girls. In most LQTS type 1 patients, QTc after exercise and that on Holter ECG tended to be long. In most LQTS type 2 and 3 patients, QTc at rest and that after exercise was long, and that on Holter ECG tended to be much longer. The present method of analyzing QTc on Holter ECG, in which automatic and manual measurements are combined, is practical and may be useful for diagnosis and risk stratification of LQTS.

Beyond the length and look of repolarization: Defining the non-QTc electrocardiographic profiles of patients with congenital long QT syndrome

Little is known about the spectrum and prevalence of ECG features beyond the length and morphology of repolarization in patients with congenital long QT syndrome (LQTS). The purpose of this study was to characterize the full ECG phenotype of LQTS patients and evaluate differences by age and LQTS genotype. Retrospective review of 943 patients with LQTS (57% female; median age 25 years; interquartile range 9-34 years) was performed. Comprehensive analysis of their initial evaluation ECG was performed using definitions outlined in professional guidelines. Bradycardia was common (n = 320 [34%]), regardless of beta-blocker use. Left-axis deviation (n = 33 [3.5%]) and bundle branch block (n = 5 [0.5%]) were uncommon. T-wave inversion (TWI) involving leads V1 and V3 was more common in LQTS type 2 compared to LQTS type 1 or type 3 (odds ratio [OR] for V1: 2.67, 95% confidence interval [CI] 1.8-3.9; OR for V3: 1.76, 95% CI 1.2-2.6), whereas TWI in leads III and aVF was most common in LQTS type 3 (OR for III: 2.38, 95% CI 1.4-4.2; OR for aVF: 3.14, 95% CI 1.6-6.4). Notched T waves were most apparent at younger ages (48% in patients age 4-10 compared to 12% in patients age >40: P <.0001). Beyond the QT interval and bradycardia, ECG abnormalities are uncommon in LQTS patients, and patients almost never have concomitant bundle branch block. Notably, 19% of LQTS patients overall and 27% of LQTS type 2 patients exhibit anterior TWI that would satisfy a diagnostic criterion for arrhythmogenic right ventricular cardiomyopathy, thus creating the potential for diagnostic miscues.

Mental stress test: a rapid, simple, and efficient test to unmask long QT syndrome.

QT prolongation during mental stress test (MST) has been associated with familial idiopathic ventricular fibrillation. In long QT syndrome (LQTS), up to 30% of mutation carriers have normal QT duration. Our aim was to assess the QT response during MST, and its accuracy in the diagnosis of concealed LQTS. All patients who are carrier of a KCNQ1 or KCNH2 mutations without QT prolongation were enrolled. A control group was constituted of patients with negative exercise and epinephrine tests. Electrocardiogram were recorded at rest and at the maximum heart rate during MST and reviewed by two physicians. Among the 70 patients enrolled (median age 41±2.1 years, 46% male), 36 were mutation carrier for LQTS (20 KCNQ1 and 16 KCNH2), and 34 were controls. KCNQ1 and KCNH2 mutation carriers presented a longer QT interval at baseline [405(389; 416) and 421 (394; 434) ms, respectively] compared with the controls [361(338; 375)ms; P < 0.0001]. QT duration during MST varied by 9 (4; 18) ms in KCNQ1, 3 (-6; 16) ms in KCNH2, and by -22 (-29; -17) ms in controls (P < 0.0001). These QT variations were independent of heart rate (P < 0.3751). Receiver operating characteristic curve analysis identified a cut-off value of QT variation superior to -11 ms as best predictor of LQTS. It provided 97% sensitivity and 97% specificity of QT prolongation in the diagnosis of LQTS. We identified a paradoxical response of the QT interval during MST in LQTS. Easy to assess, MST may be efficient to unmask concealed LQTS in patients at risk of this pathology.

Meta-analysis of Tpeak–Tend and Tpeak–Tend/QT ratio for risk stratification in congenital long QT syndrome

Background and objectivesCongenital long QT syndrome (LQTS) predisposes affected individuals to ventricular tachycardia/fibrillation (VF/VF), potentially resulting in sudden cardiac death. The Tpeak–Tend interval and the Tpeak–Tend/QT ratio, electrocardiographic markers of dispersion of ventricular repolarization, were proposed for risk stratification but their predictive values in LQTS have been controversial. A systematic review and meta-analysis was conducted to examine the value of Tpeak–Tend intervals and Tpeak–Tend/QT ratios in predicting arrhythmic and mortality outcomes in congenital LQTS. MethodPubMed and Embase databases were searched until 9th May 2017, identifying 199 studies. ResultsFive studies on long QT syndrome were included in the final meta-analysis. Tpeak–Tend intervals were longer (mean difference [MD]: 13ms, standard error [SE]: 4ms, P=0.002; I2=34%) in congenital LQTS patients with adverse events [syncope, ventricular arrhythmias or sudden cardiac death] compared to LQTS patients without such events. By contrast, Tpeak–Tend/QT ratios were not significantly different between the two groups (MD: 0.02, SE: 0.02, P=0.26; I2=0%). ConclusionThis meta-analysis showed that Tpeak–Tend interval is significant higher in individuals who are at elevated risk of adverse events in congenital LQTS, offering incremental value for risk stratification.

Clinical aspects of the three major genetic forms of long QT syndrome (LQT1, LQT2, LQT3).

A comprehensive report on the clinical course of the three major genotypes of the long QT syndrome (LQTS) in a large U.S. patient cohort is lacking. Our study consisted of 1,923 U.S. subjects from the Rochester-based LQTS Registry with genotype-positive LQT1 (n=879), LQT2 (n=807), and LQT3 (n=237). We evaluated the risk of a first cardiac event (syncope, aborted cardiac arrest, or sudden cardiac death, whichever occurred first) from birth through age 50years. Cox proportional hazards regression models incorporating clinical covariates were used to assess genotype-specific risk of cardiac events. For all three genotypes, the cumulative probability of a first cardiac event increased most markedly during adolescence. Multivariate analysis identified proband status and QTc>500ms as predictors of cardiac events in all three genotypes, and males <14years and females >14years as predictors of cardiac events in LQT1 and LQT2 only. Beta-blockers significantly reduced the risk of cardiac events in LQT1 (HR: 0.49, p=.002) and LQT2 patients (HR: 0.48, p=.001). A trend toward beta-blocker benefit in reducing cardiac events was found in LQT3 females (HR: 0.32, p=.078), but not in LQT3 males (HR: 1.37, p=.611). Risk factors and outcomes in LQTS patients varied by genotype. In all three genotypes, proband status and prolonged QTc were risk factors for cardiac events. Younger males and older females experienced increased risk in LQT1 and LQT2 only. Beta-blockers were most effective in reducing cardiac events in LQT1 and LQT2, with a potential benefit in LQT3 females.

Significance of T-wave inversion triggered by spontaneous atrial premature beats in patients with long QT syndrome

In patients with the long QT syndrome (LQTS), a sudden increase in heart rate can cause T-wave alternans (TWA) with beat-to-beat alternating polarity of T wave. We hypothesized that LQTS patients at high risk for torsades de pointes (TdP) may exhibit momentary atrial or sinoatrial premature beat-induced T-wave inversion (APB-TWI). The purpose of this study was to assess the association of APB-TWI with TdP history and with microvolt TWA. Twenty-four-hour continuous 12-lead electrocardiograms (ECGs) were recorded in 18 healthy subjects and 39 consecutive patients with LQTS types 1 (n = 21), 2 (n = 4), 3 (n = 4), and unidentified (n = 10). Peak TWA was determined by the modified moving average method. The 39 LQTS patients were divided into 2 groups: 10 LQTS patients with TdP history (TdP group) and 29 without (non-TdP group). None of the healthy subjects showed APB-TWI, whereas 38.5% of the LQTS patients (15/39) exhibited APB-TWI. The incidences of APB-TWI and TWA ≥42 μV were significantly higher in the TdP group than in the non-TdP group (APB-TWI: 80% vs 24.1%, P = .006; TWA ≥42 μV: 100% vs 65.5%, P = .04). APB-TWI was inferior in sensitivity for an association with TdP history to TWA ≥42 μV (80% vs 100%) but superior in specificity (75.9% vs 51.7%). Patients with APB-TWI exhibited significantly higher TWA values than those without [median (interquartile range) 73 (55-106.5) vs 48 (37.5-71.8) μV, P = .02]. APB-TWI is an easily measurable ECG pattern and is strongly associated with TdP history as well as TWA ≥42 μV in LQTS patients. APB-TWI and TWA may share pathophysiological mechanisms.

D242N, a KV7.1 LQTS Mutation Uncovers a KEY Residue for IKS Voltage Dependence

KV7.1 and KCNE1 co-assemble to give rise to the IKs current, one of the most important repolarizing currents of the cardiac action potential. Its relevance is underscored by the identification of more than 500 mutations in KV7.1 and, at least, 36 in KCNE1, that cause Long QT Syndrome (LQTS). The aim of this study was to characterize the biophysical and cellular consequences of the D242N KV7.1 mutation associated with the LQTS. The mutation is located in the S4 transmembrane segment, within the voltage sensor of the KV7.1 channel, disrupting the conserved charge balance of this region. Perforated patch-clamp experiments show that, unexpectedly, the mutation did not disrupt the voltage-dependent activation but it removed the inactivation and slowed the activation kinetics of D242N KV7.1 channels. Biotinylation of cell-surface protein and co-immunoprecipitation experiments revealed that neither plasma membrane targeting nor co-assembly between KV7.1 and KCNE1 was altered by the mutation. However, the association of D242N KV7.1 with KCNE1 strongly shifted the voltage dependence of activation to more depolarized potentials (+50mV), hindering IKs current at physiologically relevant membrane potentials. Both functional and computational analysis suggest that the clinical phenotype of the LQTS patients carrying the D242N mutation is due to impaired action potential adaptation to exercise and, in particular, to increase in heart rate. Moreover, our data identify D242 aminoacidic position as a potential residue involved in the KCNE1-mediated regulation of the voltage dependence of activation of the KV7.1 channel. Funded by SAF2013-45800-R, SAF2016-75021-R, BFU2014-54928-R, RIC RD12/0042/0019 and CIBER CB/11/00222.

The long-QT syndrome and exercise practice: The never-ending debate.

Today, understanding the true risk of adverse events in long-QT syndrome (LQTS) populations may be extremely complex and potentially dependent on many factors such as the affected gene, mutation location, degree of QTc prolongation, age, sex, and other yet unknown factors. In this context, risk stratification by genotype in LQTS patients has been extremely difficult, also during exercise practice, especially due to the lack of studies that would lead to a better understanding of the natural history of each mutation and its impact upon athletes. The creation of individualized guidelines for sport participation is a goal yet to be achieved not only due to the complexity of genotype effect on the phenotype in this patient population, but also due to penetrance in genotype-positive patients. This article summarizes current knowledge and raises questions concerning the difficult relationship between exercise practice and LQTS.

Automated QT analysis on Holter monitors in pediatric patients can differentiate long QT syndrome from controls

Borderline QTc is a common referral to the pediatric cardiology clinic. Evaluation is challenging due to significant overlap of normal and abnormal QTc ranges. We hypothesized that automated QT analysis on Holter could differentiate between patients with long QT syndrome (LQTS) and healthy controls. We conducted a retrospective review of 39 patients with known genotype-positive, phenotype-positive LQTS who underwent Holter monitoring between January 2010 and January 2016. They were compared 2:1 to age- and sex-matched controls. Automated QT analysis data were analyzed. Significant differences were found in all automated QT and QTc fields, except minimum QTc interval (P=0.57). Mean QTc interval (LQTS 479±28ms vs controls 429±16ms; P≤0.001) and percent QTc intervals (%QTc)>450ms (LQTS 80±28%vs controls 14±16%; P≤0.001) were selected for further analysis. A receiver operating characteristic curve was generated for each variable demonstrating high area under the curve values of 0.9494 and 0.9540, respectively. Threshold values of≥461ms for mean QTc (sensitivity 79.49%, specificity 98.72%) and≥65% of %QTc>450ms (sensitivity 79.49%, specificity 98.72%) allowed highly specific discrimination between cohorts (false positive rate 1.09%). Similarly, thresholds of<434ms (sensitivity 97.44, specificity 61.54) for mean QTc and<32% (sensitivity 89.74, specificity 87.18) for %QTc>450ms resulted in highly sensitive discrimination (false negative rates 2.17% and 8.7%). Holter monitor testing with automated QT analysis may be a useful tool to differentiate LQTS and control patients.

\u03b2-adrenergic stimulation augments transmural dispersion of repolarization via modulation of delayed rectifier currents IKs and IKr in the human ventricle

Long QT syndrome (LQTS) is an inherited or drug induced condition associated with delayed repolarization and sudden cardiac death. The cardiac potassium channel, IKr, and the adrenergic-sensitive cardiac potassium current, IKs, are two primary contributors to cardiac repolarization. This study aimed to elucidate the role of β-adrenergic (β-AR) stimulation in mediating the contributions of IKr and IKs to repolarizing the human left ventricle (n = 18). Optical mapping was used to measure action potential durations (APDs) in the presence of the IKs blocker JNJ-303 and the IKr blocker E-4031. We found that JNJ-303 alone did not increase APD. However, under isoprenaline (ISO), both the application of JNJ-303 and additional E-4031 significantly increased APD. With JNJ-303, ISO decreased APD significantly more in the epicardium as compared to the endocardium, with subsequent application E-4031 increasing mid- and endocardial APD80 more significantly than in the epicardium. We found that β-AR stimulation significantly augmented the effect of IKs blocker JNJ-303, in contrast to the reduced effect of IKr blocker E-4031. We also observed synergistic augmentation of transmural repolarization gradient by the combination of ISO and E-4031. Our results suggest β-AR-mediated increase of transmural dispersion of repolarization, which could pose arrhythmogenic risk in LQTS patients.

In This Issue: November

In This Issue: November

Re-evaluatingpathogenicity of variants associated with the long QT syndrome.

Genetic testing for congenital long QT syndrome (LQTS) has become common. Recent studies have shown that some variants labelled as pathogenic might be misclassified due to sparse case reports and relatively common allele frequencies (AF) in the general population. This study aims to evaluate the presence of LQTS-associated variants in the Genome Aggregation Database (gnomAD) population, and assess the functional impact of these variants. Variants associated with LQTS from the Human Gene Mutation Database were extracted and matched to the gnomAD to evaluate population-based AF. We used MetaSVM to predict the function of LQTS variants. Allele distribution by protein topology in KCNQ1, KCNH2, and SCN5A was compared between gnomAD (n=123,136) and a cohort of LQTS patients aggregated from eight published studies (n=2,683). Among the 1,415 LQTS-associated single nucleotide variants in 30 genes, 347 (25%) are present in gnomAD; 24% of the 347 variants were predicted as functionally tolerated compared with 4% of variants not present in gnomAD (P<0.001). Of the 347 pathogenic variants in gnomAD, seven (2%) had an AF of ≥ 0.001 and 65 (19%) variants had an AF of ≥ 0.0001. In KCNQ1, KCNH2, and SCN5A, allele distribution by protein functional region was significantly different with gnomAD alleles appearing less frequently in highly pathogenic domains than case alleles. A significant number of LQTS variants have insufficient evidence for pathogenicity and relatively common AF in the general population. Caution should be used when ascribing pathogenicity to these variants.

D242N, a KV7.1 LQTS mutation uncovers a key residue for IKs voltage dependence

KV7.1 and KCNE1 co-assemble to give rise to the IKs current, one of the most important repolarizing currents of the cardiac action potential. Its relevance is underscored by the identification of >500 mutations in KV7.1 and, at least, 36 in KCNE1, that cause Long QT Syndrome (LQTS). The aim of this study was to characterize the biophysical and cellular consequences of the D242N KV7.1 mutation associated with the LQTS. The mutation is located in the S4 transmembrane segment, within the voltage sensor of the KV7.1 channel, disrupting the conserved charge balance of this region. Perforated patch-clamp experiments show that, unexpectedly, the mutation did not disrupt the voltage-dependent activation but it removed the inactivation and slowed the activation kinetics of D242N KV7.1 channels. Biotinylation of cell-surface protein and co-immunoprecipitation experiments revealed that neither plasma membrane targeting nor co-assembly between KV7.1 and KCNE1 was altered by the mutation. However, the association of D242N KV7.1 with KCNE1 strongly shifted the voltage dependence of activation to more depolarized potentials (+50mV), hindering IKs current at physiologically relevant membrane potentials. Both functional and computational analysis suggest that the clinical phenotype of the LQTS patients carrying the D242N mutation is due to impaired action potential adaptation to exercise and, in particular, to increase in heart rate. Moreover, our data identify D242 aminoacidic position as a potential residue involved in the KCNE1-mediated regulation of the voltage dependence of activation of the KV7.1 channel.