Long QT Syndrome Patients Research Articles

Association Between Syncope Trigger Type and Risk of Subsequent Life-Threatening Events in Patients With Long QT Syndrome

Syncope is the most powerful predictor for subsequent life-threatening events (LTEs) in patients with congenital long QT syndrome (LQTS). Whether distinct syncope triggers are associated with differential subsequent risk of LTEs is unknown. To evaluate the association between adrenergic (AD)- and nonadrenergic (non-AD)-triggered syncopal events and the risk of subsequent LTEs in patients with LQT types 1 to 3 (LQT1-3). This retrospective cohort study included data from 5 international LQTS registries (Rochester, New York; the Mayo Clinic, Rochester, Minnesota; Israel, the Netherlands, and Japan). The study population comprised 2938 patients with genetically confirmed LQT1, LQT2, or LQT3 stemming from a single LQTS-causative variant. Patients were enrolled from July 1979 to July 2021. Syncope by AD and non-AD triggers. The primary end point was the first occurrence of an LTE. Multivariate Cox regression was used to determine the association of AD- or non-AD-triggered syncope on the risk of subsequent LTE by genotype. Separate analysis was performed in patients with β-blockers. A total of 2938 patients were included (mean [SD] age at enrollment, 29 [7] years; 1645 [56%] female). In 1331 patients with LQT1, a first syncope occurred in 365 (27%) and was induced mostly with AD triggers (243 [67%]). Syncope preceded 43 subsequent LTEs (68%). Syncopal episodes associated with AD triggers were associated with the highest risk of subsequent LTE (hazard ratio [HR], 7.61; 95% CI, 4.18-14.20; P < .001), whereas the risk associated with syncopal events due to non-AD triggers was statistically nonsignificant (HR, 1.50; 95% CI, 0.21-4.77; P = .97). In 1106 patients with LQT2, a first syncope occurred in 283 (26%) and was associated with AD and non-AD triggers in 106 (37%) and 177 (63%), respectively. Syncope preceded 55 LTEs (56%). Both AD- and non-AD-triggered syncope were associated with a greater than 3-fold increased risk of subsequent LTE (HR, 3.07; 95% CI, 1.66-5.67; P ≤ .001 and HR, 3.45, 95% CI, 1.96-6.06; P ≤ .001, respectively). In contrast, in 501 patients with LQT3, LTE was preceded by a syncopal episode in 7 (12%). In patients with LQT1 and LQT2, treatment with β-blockers following a syncopal event was associated with a significant reduction in the risk of subsequent LTEs. The rate of breakthrough events during treatment with β-blockers was significantly higher among those treated with selective agents vs nonselective agents. In this study, trigger-specific syncope in LQTS patients was associated with differential risk of subsequent LTE and response to β-blocker therapy.

Long QT syndrome-associated calmodulin variants disrupt the activity of the slowly activating delayed rectifier potassium channel.

Calmodulin (CaM) is a highly conserved mediator of calcium (Ca2+ )-dependent signalling and modulates various cardiac ion channels. Genotyping has revealed several CaM mutations associated with long QT syndrome (LQTS). LQTS patients display prolonged ventricular recovery times (QT interval), increasing their risk of incurring life-threatening arrhythmic events. Loss-of-function mutations to Kv7.1 (which drives the slow delayed rectifier potassium current, IKs, a key ventricular repolarising current) are the largest contributor to congenital LQTS (>50% of cases). CaM modulates Kv7.1 to produce a Ca2+ -sensitive IKs, but little is known about the consequences of LQTS-associated CaM mutations on Kv7.1 function. Here, we present novel data characterising the biophysical and modulatory properties of three LQTS-associated CaM variants (D95V, N97I and D131H). We showed that mutations induced structural alterations in CaM and reduced affinity for Kv7.1, when compared with wild-type (WT). Using HEK293T cells expressing Kv7.1 channel subunits (KCNQ1/KCNE1) and patch-clamp electrophysiology, we demonstrated that LQTS-associated CaM variants reduced current density at systolic Ca2+ concentrations (1μm), revealing a direct QT-prolonging modulatory effect. Our data highlight for the first time that LQTS-associated perturbations to CaM's structure impede complex formation with Kv7.1 and subsequently result in reduced IKs. This provides a novel mechanistic insight into how the perturbed structure-function relationship of CaM variants contributes to the LQTS phenotype. KEY POINTS: Calmodulin (CaM) is a ubiquitous, highly conserved calcium (Ca2+ ) sensor playing a key role in cardiac muscle contraction. Genotyping has revealed several CaM mutations associated with long QT syndrome (LQTS), a life-threatening cardiac arrhythmia syndrome. LQTS-associated CaM variants (D95V, N97I and D131H) induced structural alterations, altered binding to Kv7.1 and reduced IKs. Our data provide a novel mechanistic insight into how the perturbed structure-function relationship of CaM variants contributes to the LQTS phenotype.

Individualized QT interval (QTi) is a powerful diagnostic tool in long QT syndrome: results from a large validation study.

Diagnosis of Long QT syndrome (LQTS) is based on prolongation of the QT interval corrected for heart rate (QTc) on surface ECG and genotyping. However, up to 25% of genotype positive patients have a normal QTc interval. We recently showed that individualized QT interval (QTi) derived from 24 h holter data and defined as the QT value at the intersection of an RR interval of 1,000 ms with the linear regression line fitted through QT-RR data points of each individual patient was superior over QTc to predict mutation status in LQTS families. This study aimed to confirm the diagnostic value of QTi, fine-tune its cut-off value and evaluate intra-individual variability in patients with LQTS. From the Telemetric and Holter ECG Warehouse, 201 recordings from control individuals and 393 recordings from 254 LQTS patients were analysed. Cut-off values were obtained from ROC curves and validated against an in house LQTS and control cohort. ROC curves indicated very good discrimination between controls and LQTS patients with QTi, both in females (AUC 0.96) and males (AUC 0.97). Using a gender dependent cut-off of 445 ms in females and 430 ms in males, a sensitivity of 88% and specificity of 96% were achieved, which was confirmed in the validation cohort. No significant intra-individual variability in QTi was observed in 76 LQTS patients for whom at least two holter recordings were available (483 ± 36 ms vs. 489 ± 42 ms, p = 0.11). This study confirms our initial findings and supports the use of QTi in the evaluation of LQTS families. Using the novel gender dependent cut-off values, a high diagnostic accuracy was achieved.

PO-04-159 PREVALENCE AND CHARACTERISTICS OF PATIENTS WITH LONG QT SYNDROME (LQTS) WHO APPEAR NON-RESPONSIVE TO CONVENTIONAL LQTS THERAPIES

Long QT syndrome (LQTS) is a potentially lethal cardiac channelopathy with a 1% to 5% annual risk of LQTS-triggered syncope/seizures or sudden cardiac arrest/death (SCA/SCD). Despite maximal LQTS-directed therapies, a subset of patients experience breakthrough cardiac events (BCEs). To describe the phenotype of “non-responders” defined as LQTS patients with recurrent BCEs despite maximal LQTS-directed therapy. Among the 1731 LQTS patients evaluated and treated at Mayo Clinic, a retrospective analysis was performed to identify those who experienced ≥1 BCE while on maximum treatment (combination of ≥2 device/denervation and/or pharmacologic therapies at maximally tolerated doses). Basic demographics, clinical characteristics, and frequency/type of BCEs defined as syncope/seizures, appropriate ICD shocks, SCA, or SCD were extracted from the electronic medical record. Overall, 32/1731 LQTS patients (2%) experienced ≥1 BCE with 13 (41%) occurring in the setting of medication nonadherence. Of the remaining 19 patients (1% of all LQTS patients; 37% female, mean age at last event of 11±8 years and mean QTc of 537±92ms), 7 (37%) had compound heterozygous (n=6) or homozygous (n=1) disease involving either KCNQ1 or KCNH2, including one Jervell and Lange-Nielsen syndrome patient, and 2 (11%) had high-risk minor LQTS genotypes (CALM2-mediated LQTS and CACNA1C-mediated Timothy syndrome). Notably, 5 (26%) had a complex cardiac sodium channelopathy with predominant features of LQT3 and multifocal ectopic Purkinje-related premature contractions. The remaining patients had treatment-refractory LQT2 (n=3; 16%) or LQT3 (n=2; 11%). At last follow-up, 2 patients (11%) died and 4 (2%) underwent cardiac transplant. For the remaining 13 patients, treatment was escalated after their last BCE. Twelve patients (92%) received an ICD and either atrial pacing (AP) + beta-blocker (BB) + mexiletine (MEX) [n=1, 8%], AP + left cardiac sympathetic denervation (LCSD) + ≥2 antiarrhythmic drugs (AADs) [n=4, 31%], bilateral denervation + BB [n=2, 15%], or LCSD + ≥1 AAD [n=5, 38%]. One patient (8%) was on LCSD + BB + MEX. Despite safe and effective treatment options, 1% of LQTS patients experience recurrent BCEs on maximal LQTS-directed therapy. Adherence to the outlined treatment program needs to be reinforced. In addition, compound heterozygous/homozygous KCNQ1-mediated disease and complex SCN5A-mediated channelopathies represent high-risk LQTS subsets in need of alternative management strategies.

PO-05-083 ICD THERAPY CHARACTERISTICS IN PATIENTS WITH ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY, BRUGADA SYNDROME, AND LONG QT SYNDROME

Arrhythmogenic right ventricular cardiomyopathy (ARVC), Brugada syndrome (BrS) and Long QT syndrome (LQTS) are inherited arrhythmia disorders that frequently result in sudden death in young populations. ARVC often presents with monomorphic VT amenable to antitachycardia pacing (ATP) therapy, whereas BrS and LQTS are traditionally characterized by polymorphic VT or torsade de pointes requiring shock therapy. To assess the rates of ATP and shock therapies in a cohort of patients with ARVC, BrS and LQTS. Patients with ICD indications for ARVC, BrS and LQTS from the ALTITUDE database (Boston Scientific, Natick, MA) between 2011-2021 were identified. ATP and shock-free survival rates were calculated by Kaplan-Meier (KM) method and hazard ratios were analyzed by the Cox proportional hazards model. A total of 103 ARVC, 218 BrS, and 509 LQTS patients were identified. Mean age (46.6 ± 17.4) did not differ between groups while LQT had more female (69.2%) compared to ARVC (34%) and BrS (30.7%). Mean follow-up was 3.7 years. A total of 47 (45.6%) ARVC patients, 39 (17.9%) BrS, and 136 (26.7%) LQTS patients received any therapies during the follow-up period. Episodes in ARVC patients were significantly less likely to result in a shock (71/402, 18%) compared to BrS (73/157, 47%) and LQTS (333/581, 57%) (p<0.001). Per 100 patient-years (Figure 1a), ARVC patients had arrhythmia episodes requiring only ATP therapy 4.7 times the frequency of episodes requiring shock therapy (89.0 versus 19.1), whereas BrS and LQTS patients had comparable rates of ATP only vs shocks (10.2 versus 8.8 in BrS and 13.5 vs 18.2 in LQTS). From KM curve analysis, three-year rate of an ATP-only event was 43.0% in ARVC, 10.3% in BrS and 18.0% in LQTS. As compared with ARVC, risk of ATP only events in BrS (HR 0.20, 95% CI 0.12-0.33, p<0.001) and LQTS (HR 0.44, 95% CI 0.30-0.65, p<.0.001) were significantly lower. Three-year rate of events requiring shock therapy was 33.4% in ARVC, 14.5% in BrS and 20.0% in LQTS. As compared with ARVC, risk of a shock in BrS (HR 0.33, 95% CI 0.20-0.54, p<0.001) and LQTS (HR 0.62, 95% CI 0.41-0.93, p=0.020) were also significantly lower. ARVC patients had more ventricular arrhythmia episodes. When therapy was triggered, episodes in ARVC were less likely to be treated with a shock compared to BrS and LQTS. This may help guide programming parameters and device type selection in high-risk individuals with inherited arrhythmia syndromes.

Novel methods for enhancing ECG visualization research

All Long QT syndrome (LQTS) patients are at elevated risk for channelopathy-induced delayed myocardial repolarization and consequently potentially life-threatening cardiac events with 90% of initial cardiac events occurring between preteen and 40 years old. Utilizing ECG and derived vectorcardiographic parameters, including T wave Vector Magnitude (TwVM) measurement data, this study attempts to determine whether TwVM from baseline ECGs is effectively predictive of future cardiac events for genotype-positive LQTS patients.Verified carriers of established LQTS disease-causing genotypes were selected from University of Minnesota patient encounters between 2010 and 2020 for inclusion in this retrospective study. Baseline and predictive ECG and derived vectorcardiographic parameter evaluation, clinical data, and statistical analysis were compared between patients with and patients without cardiac events. First recorded ECG was at presentation to our hospital and final ECG is defined as ECG just prior to cardiac event (event defined below in Methods) or the most final documented ECG before cut-off year of 2020 for the event-free group.Of 41 participants, 15 experienced cardiac events and 26 did not. While many baseline electrocardiographic parameter measurements did not show significant differences between patient groups, vectorcardiographic parameters at baseline, specifically the QRS vector magnitude (QRSVM) and azimuth of the spatial ventricular gradient, showed significance. Additionally, final vectorcardiographic parameters, particularly the QRSVM, TwVM, and azimuth of the spatial ventricular gradient showed significant differences between patient groups. Final T-wave frontal axis was significantly larger in those without cardiac events. Significant Kaplan-Meier curve separation between patient groups was noted based on a QRSVM of 1.43 mV or lower, with additional consideration to patient age, genotype, and beta blocker use.This study shows evidence of ECG and derived vectorcardiographic parameters, including TwVM, being effective in early prediction of cardiac events in genotype-positive LQTS patients.

PO-03-145 BETA BLOCKERS IN PATIENTS WITH LONG QT SYNDROME: MOVING AWAY FROM ONE-SIZE-FITS-ALL?

Experts in the field recommend using nadolol at 1mg/kg/day and propranolol at 2-3mg/kg/day for patients with long QT syndrome (LQTS), but there are no available studies defining the most effective dose. In our experience, most but not all patients tolerate beta blocker at full dose. To describe our institutional experience with utilizing exercise stress testing (EST) in the subset of LQTS patients who did not tolerate standard beta-blocker dosing. We queried our Inherited Arrhythmia Registry and identified patients with LQTS who were on "submaximal" nadolol/propranolol doses (defined as < 1mg/kg/day for nadolol and < 2mg/kg/day for propranolol) and who had at least one follow up appointment. For those patients, we have devised a practical approach for demonstrating sufficient beta blockade effect by assessing for heart rate (HR) blunting at maximal exercise, which was defined as at least 15-20% decrease from maximal HR. Of 166 patients with LQTS, 51 (53% females, 53% probands) were on “submaximal” beta blocker therapy at time of last follow up and formed our study cohort. Median age at diagnosis and QTc were 15.8 yrs (range: 0.1-50.9 yrs) and 484 ms (400-610 ms) respectively. In terms of LQTS type: 24 had LQT1, 22 had LQT2, 2 had LQT5, 1 had LQT1 + LQT2, 1 had LQT3, and 1 patient had a VUS in CALM3 gene. Cardiac events included: cardiac arrest in 4 (8%) prompting ICD implantation, bradycardia-induced Torsades de Pointes in 2 (4%) prompting pacemaker implantation, recurrent cardiac syncope prompting sympathectomy in 2 (4%) and cardiac syncope in 10 (20%). The distribution of beta blocker dose is shown in Figure 1A and % predicted peak HR on EST as a function of beta blocker dose is shown in Figure 1B. EST data was available in 37 (73%) patients and demonstrated that HR blunting can be achieved with “submaximal” doses. Over a median follow up of 6.3 years and while on intentional “submaximal” beta blocker therapy, 1 (2%) patient had recurrent appropriate ICD shocks prompting referral for sympathectomy, and no patient (0/34, 0%) with adequate HR blunting had a cardiac event. In our institutional LQTS experience, adequate heart rate blunting may be achieved with "submaximal" beta blocker dose. EST may be a useful modality to devise an individualized treatment plan and titrate beta blocker dose to effect, especially in those that cannot tolerate the recommended guideline directed dose.

Right ventricular epicardial arrhythmogenic substrate in long-QT syndrome patients at risk of sudden death.

The long-QT syndrome (LQTS) represents a leading cause of sudden cardiac death (SCD). The aim of this study was to assess the presence of an underlying electroanatomical arrhythmogenic substrate in high-risk LQTS patients. The present study enrolled 11 consecutive LQTS patients who had experienced frequent implantable cardioverter-defibrillator (ICD discharges triggered by ventricular fibrillation (VF). We acquired electroanatomical biventricular maps of both endo and epicardial regions for all patients and analyzed electrograms sampled from several myocardial regions. Abnormal electrical activities were targeted and eliminated by the means of radiofrequency catheter ablation. VF episodes caused a median of four ICD discharges in eleven patients (6 male, 54.5%; mean age 44.0 ± 7.8 years, range 22-53) prior to our mapping and ablation procedures. The average QTc interval was 500.0 ± 30.2 ms. Endo-epicardial biventricular maps displayed abnormally fragmented, low-voltage (0.9 ± 0.2 mV) and prolonged electrograms (89.9 ± 24.1 ms) exclusively localized in the right ventricular epicardium. We found electrical abnormalities extending over a mean epicardial area of 15.7 ± 3.1 cm2. Catheter ablation of the abnormal epicardial area completely suppressed malignant arrhythmias over a mean 12 months of follow-up (median VF episodes before vs. after ablation, 4 vs. 0; P = 0.003). After the procedure, the QTc interval measured in a 12-lead ECG analysis shortened to a mean of 461.8 ± 23.6 ms (P = 0.004). This study reveals that, among high-risk LQTS patients, regions localized in the epicardium of the right ventricle harbour structural electrophysiological abnormalities. Elimination of these abnormal electrical activities successfully prevented malignant ventricular arrhythmia recurrences.

ICD harm and benefit: risk scores applied to the Swedish ICD-treated LQTS population

Objectives. The use of implantable cardioverter defibrillators (ICDs) in long QT syndrome (LQTS) patients is essential in high-risk patients. However, it is sometimes used in patients without high-risk profiles for whom the expected benefit may be lower than the risk of ICD harm. Here, we evaluated ICD benefit and harm by assessing risk according to risk scores and pre-ICD clinical characteristics. Design. We studied 109 Swedish LQTS patients drawn from the Swedish ICD and Pacemaker Registry with data collected from medical records. In addition to clinical characteristics, we used two risk scores to assess pre-ICD risk, and evaluated ICD benefit and harm. Results. Twenty percent of all patients received ≥1 appropriate shock with a first appropriate shock incidence rate of 4.3 per 100 person-years. A long QTc (≥550 ms) and double mutations were significantly associated with appropriate shock. Low risk scores among patients without pre-ICD aborted cardiac arrest were not significantly associated with low risk of first appropriate shock. The incidence rates of a first inappropriate shock and first complication were 3.0 and 7.6 per 100 person-years, respectively. Conclusion. Our findings on ICD harm emphasize the importance of careful individual pre-ICD consideration. When we applied two risk scores to patients without pre-ICD aborted cardiac arrest, we could not validate their ability to identify patients with low risk of appropriate shocks and patients who were assessed as having a low risk still received appropriate shocks. This further supports the complexity of risk stratification and the difficulty of using risk scores.

Targeted deep sequencing analyses of long QT syndrome in a Japanese population.

Long QT syndrome (LQTS) is one of the most common inherited arrhythmias and multiple genes have been reported as causative. Presently, genetic diagnosis for LQTS patients is becoming widespread and contributing to implementation of therapies. However, causative genetic mutations cannot be detected in about 20% of patients. To elucidate additional genetic mutations in LQTS, we performed deep-sequencing of previously reported 15 causative and 85 candidate genes for this disorder in 556 Japanese LQTS patients. We performed in-silico filtering of the sequencing data and found 48 novel variants in 33 genes of 53 cases. These variants were predicted to be damaging to coding proteins or to alter the binding affinity of several transcription factors. Notably, we found that most of the LQTS-related variants in the RYR2 gene were in the large cytoplasmic domain of the N-terminus side. They might be useful for screening of LQTS patients who had no known genetic factors. In addition, when the mechanisms of these variants in the development of LQTS are revealed, it will be useful for early diagnosis, risk stratification, and selection of treatment.

Abstract 15229: An Artificial Intelligence Deep Neural Network Analysis of the 12-lead Electrocardiogram Distinguishes Patients With Congenital Long Qt Syndrome From Patients With Acquired Qt Prolongation

Introduction: Over 100 FDA-approved medications, electrolyte perturbations, and many disease states can prolong the QTc beyond its 99 th percentile value resulting in acquired QT prolongation. In contrast, approximately 1 in 2000 people have congenital long QT syndrome (LQTS) hallmarked by pathological QT prolongation secondary to genetic defects in the heart. Hypothesis: An artificial intelligence (AI) deep neural network (DNN) can distinguish patients with LQTS from those with acquired QT prolongation. Methods: The study cohort included all patients with LQTS evaluated in the Windland Smith Rice Genetic Heart Rhythm Clinic and controls from Mayo Clinic’s ECG data vault comprising over 2.5 million patients. For the AI-DNN model, every patient/control with ≥ 1 ECG above age- and sex- specific 99 th percentile values for QTc [&gt; 460 ms for all patients (male/female) &lt; 13 years of age, or &gt; 470 ms for men and &gt; 480 ms for women above this age] was included. An AI-DNN involving a multi-layer c onvolutional n eural n etwork (CNN) was developed to classify patients. LQTS patients were age- and sex- matched to controls at 1:5 ratio. Results: Among the 1,599 patients with genetically confirmed LQTS, 808 had ≥ 1 ECG with QTc above the threshold (2,987 ECGs) compared to 361,069/2.5M controls (14% of Mayo Clinic patients getting an ECG, ‘presumed negative’; 989,313 ECGs). Following age- and sex- matching and splitting, 3,309 (training), 411 (validation) and 887 (testing) control ECGs were used. This model distinguished LQTS from those with acquired QT prolongation with an AUC of 0.896 (accuracy 85%, sensitivity 77%, specificity 88%, PPV 0.58, NPV 0.94). After exclusion of patients with a wide QRS (&gt;150 ms) or pacemaker, the model remained successful in distinguishing the two groups (AUC 0.85, accuracy 78%, sensitivity 78%, specificity 87%, PPV 59%, NPV 94%). Conclusions: For patients with a QTc exceeding its 99 th percentile values, this novel AI-DNN functions as a LQTS mutation detector being able to identify patients with abnormal QT prolongation secondary to a LQTS-causative mutation rather than acquired QT prolongation with a &gt;50% positive predictive value. This algorithm may facilitate screening for this potentially lethal, yet highly treatable, genetic heart disease.

Abstract 13568: Characterization of the Maladaptive QTc Response During the Treadmill Exercise Test in Untreated Patients With Long QT Syndrome

Background: Long QT syndrome (LQTS) is a genetic heart disease affecting about 1 in 2000 persons. Around 40% of patients with LQTS can have a nondiagnostic, normal QTc at rest. The treadmill exercise stress test (TEST) can help unmask patients with concealed LQTS with a characteristic maladaptive, paradoxical increase in QTc ( 460 ms) during the recovery phase. In fact, the recovery phase QTc value has been added to the latest diagnostic score for LQTS. Objective: To characterize the TEST-derived QTc profile of untreated patients with LQTS and determine its diagnostic and prognostic utility. Methods: Retrospective analysis was performed on TEST data derived from 249 patients with LQTS (129 LQT1, 64 LQT2 and 56 LQT3) untreated at the time of their TEST compared with 236 controls. The Bazett’s corrected QTc was calculated at rest (sitting, supine, and standing), during exercise at 1 min, 3 mins, and peak exercise, and during recovery phase at 1, 3 and 5 mins. Results: The mean resting QTc was significantly higher in LQTS patients (457 ± 30 ms) compared to controls (420 ± 24 ms; p&lt;0.0001) as well as at every stage during the TEST (p&lt;0.001). For LQT1 patients, highest QTc was observed at peak exercise (mean 496 ± 38 ms) and during the third minute of recovery phase (mean 500 ± 40 ms). In contrast, LQT2 patients showed the lowest QTc (mean 452 ± 48 ms) during peak exercise but the greatest QTc latency (QTc at 5 min - QTc at 1 min recovery; mean QTc latency 33 ± 77 ms; p=0.005) compared to controls. For LQT3, the mean QTc was greatest at rest compared to controls (p&lt;0.001), and there was no difference during exercise and recovery phases. Among 162 LQT1 and LQT2 patients that presented with concealed LQTS, 119 (73%) showed a maladaptive QT response. ROC analysis showed that in patients with LQT1, a maladaptive QTc &gt; 523 ms at 3 min of recovery was highly predictive of breakthrough cardiac events (AUC 0.84; sensitivity 100%, specificity 72%); no such association was identified for LQT2 or 3. Conclusions: This comprehensive characterization of the QTc response before, during, and after a TEST in the largest untreated cohort of patients with LQTS provides important genotype-specific characteristics and can be used as a predictor for potential LQT1-triggered cardiac events after diagnosis and treatment.

Abstract 11237: Dose Response and Long QT Genotype During Exercise Stress Testing in Children

Introduction: Beta-blockers (BB) are first-line therapy for long QT syndrome (LQTS). Many physicians rely on repeated exercise stress tests (ESTs) to establish the optimal dose in each patient. Hypothesis: Increased BB dose is associated with a decrease in maximum heart rate, influenced by precision-medicine factors including genotype. Methods: Retrospective chart review of treadmill ESTs with the outcome variable “% predicted heart rate (HR)” = (maximum HR achieved/(220-age))*100. Genotype positive patients had pathogenic or likely pathogenic variants, re-adjudicated in 2022. Doses of BB other than nadolol were converted to nadolol equivalents using an established methodology. Results: We evaluated 345 ESTs in 132 LQTS patients (58% genotype positive) from 2003-21. The mean age at first EST was 12.5 years (standard deviation 4.0 years). Most patients were prescribed nadolol (59%) or atenolol (28%). When controlled for person-level fixed effects, we observed an inverse relationship between BB dose and % predicted HR. The dose-response slope was steeper in genotype positive patients than genotype negative patients (-4.8 vs. -3.3, Figure , p&lt;0.01). We observed mild decreases in blood pressure as BB dose increased, (mean 5 mmHg decrease in systolic blood pressure per 1 mg/kg increase in BB). However, neither maximum VO2 nor maximum respiratory exchange ratio were affected by increased BB dose (the slope of each was indistinguishable from 0 in person-level fixed effects models). Conclusion: In children with LQTS, genotype positive patients were more sensitive to BB than genotype negative patients. We developed a multivariate model to predict the dose of BB required to achieve therapeutic beta-blockade, conditional on individual patient demographics and genotype. The model may decrease the need for serial ESTs. BB dose did not affect maximum VO2 or respiratory exchange ratio, which is reassuring for children and adolescents with LQTS who exercise.

Abstract 11999: Molecular and Cellular Characterization of RyR2 Mutations Linked to Long-QT Syndrome

Long-QT syndrome (LQTS) is a cardiac disorder characterized by prolonged QT interval and abnormal T waves on the electrocardiogram. Electrical abnormality can lead to severe arrhythmias, syncope and sudden cardiac death. Mutations in the Na + and K + channels or associated proteins account for the majority of cases; however, the genetic causes of about 20% of LQTS cases remain poorly understood. Recent genetic studies revealed novel LQTS-associated variants on the cardiac ryanodine receptor (RyR2), a Ca 2+ channel responsible for Ca 2+ -induced Ca 2+ release and excitation-contraction coupling. Given the important roles of RyR2 in the electrical activity of heart and previous evidence of RyR2 mutations in other inherited arrhythmias, we hypothesized that RyR2 mutations lead to functional alterations of the channels and contribute to dysregulated Ca 2+ release and pathological electrical remodeling. Eleven novel RyR2 mutations were identified in genetic studies of LQTS patients, including S166C, H877P, R1760W, G2094S, R2824W, R2920Q, R3673W, Y4287N, V4298M, P4534S and K4594Q. [3H] ryanodine (RyR2 ligand) binding assays revealed variable effects of the mutations on the opening probability of the RyR2 channel. In cell lines with stable expression of RyR2, Ca 2+ overload activates RyR2 channels and leads to spontaneous Ca 2+ release into the cytoplasm. Compared to WT RyR2, LQTS-associated RyR2 mutations cause an increase in the proportion of cells that exhibit spontaneous Ca 2+ release at various Ca 2+ concentrations, suggesting an increase in luminal Ca 2+ sensitivity of the channels. A transgenic mouse model carrying the R2920Q mutation was used to investigate the cellular and molecular pathways leading to LQTS. Homozygous mice showed prolonged QT interval and QTc at 5 months. Electrophysiological studies of the isolated cardiomyocytes revealed a depolarized resting membrane potential in the homozygous R2920Q cardiomyocytes and prolonged action potential duration in both heterozygous and homozygous R2920Q cardiomyocytes, compared to the WT cells. The availability of a mouse model that recapitulates the cardinal signs of LQTS will allow for deeper mechanistic insight into the role of RyR2 dysfunction as a driver of this arrhythmogenic syndrome.

Long QT syndrome: long story short.

The first report of long QT syndrome (LQTS) dates back to 1856 when Friedrich Ludwig Meissner, a German obstetrician and pediatrician, described a child with deafness, who died while being publicly reprimanded by the schoolteacher.1 It took nearly a century to document the very first electrocardiogram (ECG) of a prolonged QT interval coinciding with deafness and syncope.2 The association between sudden deaths in children with congenital deafness and QT prolongation was brought up by two concurrent publications authored by Anton Jervell with Fred Lange-Nielsen and Samuel A. Levine with Clyde R. Woodworth.3 Following closely, Cesarino Romano et al. and Owen C. Ward described analogous cases in the absence of the auditory component.3 Although Levine and Woodworth’s contribution was never acknowledged, two eponyms, Jervell-Lange-Nielsen and Romano-Ward syndromes, were coined with reference to the congenital form of LQTS with or without deafness, respectively.3 Because syncope and cardiac arrest mainly occurred in stressful situation, sympathetic imbalance was long believed to underlie LQTS.3 It would take 40 years to find the fault in the genes. With the biological Rosetta stone deciphered, research has become ever more crucial to translate gene expression into clinical care for LQTS. While the spectrum of mutations initially encompassed 17 genes reported to be linked to LQTS, 7 are now classified as having disputed evidence.4 Mutations in three genes (KCNQ1, KCNH2, and SCN5A) encoding for cardiac voltage-gated K+ (Kv7.1 or KCNQ1, Kv11.1 or hERG) and Na+ channels (Nav1.5) causing a delay in cardiac repolarization account for the majority of LQTS forms (types 1, 2, and 3, respectively).4 LQTS types 1 and 2 are based on a loss-of-function in Kv7.1 and Kv11.1 channels, respectively, reducing repolarizing outward K+ currents (IKs and IKr). In contrast, LQTS type 3 relates to an increased late Na+ inward current (INa, late) resulting from gain-of-function in Nav1.5 channels.4 While LQTS type 1 typically manifests during childhood, LQTS types 2 and 3 patients become symptomatic after the onset of puberty. Because of the decreased Kv11.1 channel density compared to male as well as the direct inhibitory effect of estrogen, female LQTS type 2 patients are at particular risk for arrhythmias.4 Such cardiac events predominantly occur at rest in LQTS type 3. In contrast, exercise and acoustic/emotional stimuli may trigger malignant arrhythmias in patients with LQTS type 1 and type 2, respectively. Mechanistically, the LQTS heart fails to adapt (impaired repolarization reserve) in response to the excess Ca2+ inflow resulting from sustained adrenergic tone (exercise) or an adrenergic surge (sudden arousal).4 Given the crucial role of sympathetic activity, it is no surprise that beta-blockers are advocated for LQTS patients. Late Na+ channel blockers present a viable adjunct in the pharmacological treatment of LQTS type 3. Left cardiac sympathetic denervation is a surgical antiadrenergic intervention mainly reserved to patients refractory to standard of care. An implantable cardioverter-defibrillator is considered in high-risk and resuscitated patients for the prevention of sudden cardiac death.4 Collectively, none of these treatment modalities addresses the cause of LQTS. In addition, some LQTS patients continue to experience breakthrough cardiac events despite maximal therapy, sparking research efforts in developing new treatment strategies.

Methadone-Induced QT Interval Prolongation and Torsades de Pointes

: The most common cause of acquired long QT syndrome in patients without physiological and structural cardiovascular disease is the use of medications. Chronic high-dose methadone usage can cause prolongation of QT interval that may provoke the life-threatening arrhythmia Torsades de Pointes. In this study, we present a 41-year-old man with chronic high-dose methadone usage who developed Torsades de Pointes triggered by short-coupled premature ventricular contraction.

Assessment of absolute risk of life-threatening cardiac events in long QT syndrome patients.

BackgroundRisk stratification in long QT syndrome (LQTS) patients is important for optimizing patient care and informing clinical decision making. We developed a risk prediction algorithm with prediction of 5-year absolute risk of the first life-threatening arrhythmic event [defined as aborted cardiac arrest, sudden cardiac death, or appropriate implantable cardioverter defibrillator (ICD) shock] in LQTS patients, accounting for individual risk factors and their changes over time.MethodsRochester-based LQTS Registry included the phenotypic cohort consisting of 1,509 LQTS patients with a QTc ≥ 470 ms, and the genotypic cohort including 1,288 patients with single LQT1, LQT2, or LQT3 mutation. We developed two separate risk prediction models which included pre-specified time-dependent covariates of beta-blocker use, syncope (never, syncope while off beta blockers, and syncope while on beta blockers), and sex by age < and ≥13 years, baseline QTc, and genotype (for the genotypic cohort only). Follow-up started from enrollment in the registry and was censored at patients’ 50s birthday, date of death due to reasons other than sudden cardiac death, or last contact, whichever occurred first. The predictive models were externally validated in an independent cohort of 1,481 LQTS patients from Pavia, Italy.ResultsIn Rochester dataset, there were 77 endpoints in the phenotypic cohort during a median follow-up of 9.0 years, and 47 endpoints in the genotypic cohort during a median follow-up of 9.8 years. The time-dependent extension of Harrell’s generalized C-statistics for the phenotypic model and genotypic model were 0.784 (95% CI: 0.740–0.827) and 0.785 (95% CI: 0.721–0.849), respectively, in the Rochester cohort. The C-statistics obtained from external validation in the Pavia cohort were 0.700 (95% CI: 0.610–0.790) and 0.711 (95% CI: 0.631–0.792) for the two models, respectively. Based on the above models, an online risk calculator estimating a 5-year risk of life-threatening arrhythmic events was developed.ConclusionThis study developed two risk prediction algorithms for phenotype and genotype positive LQTS patients separately. The estimated 5-year absolute risk can be used to quantify a LQTS patient’s risk of developing life-threatening arrhythmic events and thus assisting in clinical decision making regarding prophylactic ICD therapy.

Assessment of time irreversibility in a time series using visibility graphs.

In this paper, we studied the time-domain irreversibility of time series, which is a fundamental property of systems in a nonequilibrium state. We analyzed a subgroup of the databases provided by University of Rochester, namely from the THEW Project. Our data consists of LQTS (Long QT Syndrome) patients and healthy persons. LQTS may be associated with an increased risk of sudden cardiac death (SCD), which is still a big clinical problem. ECG-based artificial intelligence methods can identify sudden cardiac death with a high accuracy. It follows that heart rate variability contains information about the possibility of SCD, which may be extracted, provided that appropriate methods are developed for this purpose. Our aim was to assess the complexity of both groups using visibility graph (VG) methods. Multivariate analysis of connection patterns of graphs built from time series was performed using multiplex visibility graph methods. For univariate time series, time irreversibility of the ECG interval QT of patients with LQTS was lower than for the healthy. However, we did not observe statistically significant difference in the comparison of RR intervals time series of the two groups studied. The connection patterns retrieved from multiplex VGs have more similarity with each other in the case of LQTS patients. This observation may be used to develop better methods for SCD risk stratification.

Long QT syndrome-associated calmodulin mutations and their interactions with the Kv7.1 voltage-gated potassium channel

Abstract Introduction Calmodulin (CaM) is a highly conserved mediator of calcium (Ca2+) dependent signalling. Its flexible structure allows CaM to bind and modulate many targets, including cardiac ion channels. Genotyping has revealed several CaM mutations associated with congenital disorders of heart rhythm, known as long QT-syndrome (LQTS). LQTS patients suffer from prolonged ventricular recovery times (QT-interval) which increases their risk of significant cardiac events. Loss of function KV7.1 mutations are the largest cause of LQTS, accounting for &amp;gt;50% of cases. CaM facilitates Ca2+-sensitivity to KV7.1 in producing IKs, Kv7.1 mutations which reduce CaM binding promote LQTS pathology. However, the effects of LQTS-associated CaM mutations on Kv7.1 function remain unknown. Purpose To determine the biophysical consequences of congenital LQTS-associated CaM mutations and how they alter modulation of Kv7.1 in producing the ventricular repolarising IKs current. Methods WT and mutant CaM proteins were recombinantly expressed and purified for biophysical characterisation. Using circular dichroism, secondary structures and thermostability of proteins were quantified. Isothermal titration calorimetry was used to quantitatively measure interactions between CaM proteins and binding sites of KV7.1 (Helix B). NMR was employed to study the conformations of target-bound WT and mutant proteins. Whole cell currents were determined using voltage clamp electrophysiology in HEK cells. Results Mutations significantly changed the thermostability and secondary structure distributions of CaM, and also caused site-dependent increases in susceptibility to protease digestion. CaM interacted with Helix B (KV7.1) via both Ca2+-dependent and independent mechanisms. Ca2+ dependent binding to Helix B was much higher affinity than Ca2+-independent binding, with &amp;gt;2000-fold reduction in dissociation constant measured. LQTS-CaM variants reduced Helix B affinity with the largest reductions found in EF-hand IV mutants. These mutants also adopted most distinct conformations when Helix B-bound. Calmodulation of the KV7.1 channel produced larger (IKs) currents without altering channel activation kinetics. IKs exhibited Ca2+-sensitivity, in response to increased cytosolic Ca2+, larger currents were generated. Modulation by CaM mutants reduced current density at systolic Ca2+-concentrations (1000 nM), within physiological time periods (0.35 s), revealing a direct QT-prolonging modulatory effect. Conclusions Provided here are mechanistic insights as to how LQTS-associated CaM variants contribute to electrical disease of the heart. Mutations in the highly conserved structure of CaM disrupt protein conformation and perturb complex formation with KV7.1. This results in aberrant Ca2+-sensitivity of Kv7.1, reducing IKs generation. This ultimately decreases the repolarisation capacity of cells and would extend the QT interval of myocytes. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Intermediate Basic Science Research Fellowship

DETECTION OF CONGENITAL LONG QT SYNDROME WITH ARTIFICIAL INTELLIGENCE

DETECTION OF CONGENITAL LONG QT SYNDROME WITH ARTIFICIAL INTELLIGENCE