Bos, Johan M

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

BackgroundProlongation of the QT on the surface electrocardiogram can be due to either genetic or acquired causes. Distinguishing congenital long QT syndrome (LQTS) from acquired QT prolongation has important prognostic and management implications. We aimed to investigate if quantitative T‐wave analysis could provide a tool for the physician to differentiate between congenital and acquired QT prolongation.MethodsPatients were identified through an institution‐wide computer‐based QT screening system which alerts the physician if the QTc ≥ 500 ms. ECGs were retrospectively analyzed with an automated T‐wave analysis program. Congenital LQTS was compared in a 1:3 ratio to those with an identified acquired etiology for QT prolongation (electrolyte abnormality and/or prescription of known QT prolongation medications). Linear discriminant analysis was performed using 10‐fold cross‐validation to statistically test the selected features.ResultsThe 12‐lead ECG of 38 patients with congenital LQTS and 114 patients with drug‐induced and/or electrolyte‐mediated QT prolongation were analyzed. In lead V5, patients with acquired QT prolongation had a shallower T wave right slope (−2,322 vs. −3,593 mV/s), greater T‐peak‐Tend interval (109 vs. 92 ms), and smaller T wave center of gravity on the x axis (290 ms vs. 310 ms; p < .001). These features could distinguish congenital from acquired causes in 77% of cases (sensitivity 90%, specificity 58%).ConclusionT‐wave morphological analysis on lead V5 of the surface ECG could successfully differentiate congenital from acquired causes of QT prolongation.

Noonan syndrome (NS; MIM 163950) is an autosomal dominant disorder and a member of a family of developmental disorders termed “RASopathies,” which are caused mainly by gain-of-function mutations in genes encoding RAS/MAPK signaling pathway proteins. Whole exome sequencing (WES) and trio-based genomic triangulation of a 15-year-old female with a clinical diagnosis of NS and concomitant cardiac hypertrophy and her unaffected parents identified a de novo variant in MRAS -encoded RAS-related protein 3 as the cause of her disease. Mutation analysis using in silico mutation prediction tools and molecular dynamics simulations predicted the identified variant, p.Gly23Val-MRAS, to be damaging to normal protein function and adversely affect effector interaction regions and the GTP-binding site. Subsequent ectopic expression experiments revealed a 40-fold increase in MRAS activation for p.Gly23Val-MRAS compared with WT-MRAS. Additional biochemical assays demonstrated enhanced activation of both RAS/MAPK pathway signaling and downstream gene expression in cells expressing p.Gly23Val-MRAS. Mutational analysis of MRAS in a cohort of 109 unrelated patients with phenotype-positive/genotype-negative NS and cardiac hypertrophy yielded another patient with a sporadic de novo MRAS variant (p.Thr68Ile, c.203C>T). Herein, we describe the discovery of mutations in MRAS in patients with NS and cardiac hypertrophy, establishing MRAS as the newest NS with cardiac hypertrophy-susceptibility gene.

Background— Congenital long QT syndrome (LQTS) is characterized by QT prolongation. However, the QT interval itself is insufficient for diagnosis, unless the corrected QT interval is repeatedly ≥500 ms without an acquired explanation. Further, the majority of LQTS patients have a corrected QT interval below this threshold, and a significant minority has normal resting corrected QT interval values. Here, we aimed to develop and validate a novel, quantitative T wave morphological analysis program to differentiate LQTS patients from healthy controls. Methods and Results— We analyzed a genotyped cohort of 420 patients (22±16 years, 43% male) with either LQT1 (61%) or LQT2 (39%). ECG analysis was conducted using a novel, proprietary T wave analysis program that quantitates subtle changes in T wave morphology. The top 3 discriminating features in each ECG lead were determined and the lead with the best discrimination selected. Classification was performed using a linear discriminant classifier and validated on an untouched cohort. The top 3 features were Tpeak–Tend interval, T wave left slope, and T wave center of gravity x axis (last 25% of the T wave). Lead V6 had the best discrimination. It could distinguish 86.8% of LQTS patients from healthy controls. Moreover, it distinguished 83.33% of patients with concealed LQTS from controls, despite having essentially identical resting corrected QT interval values. Conclusions— T wave quantitative analysis on the 12-lead surface ECG provides an effective, novel tool to distinguish patients with either LQT1/LQT2 from healthy matched controls. It can provide guidance while mutation-specific genetic testing is in motion for family members.

Objectives: There is no evidence regarding the effect of ondansetron on the QT interval in pediatric patients in the ICU. This study aimed to describe the effect of ondansetron on the corrected QT interval in patients cared for in the PICU. Design: Retrospective cohort, consecutive enrollment study. Setting: Single-center, tertiary-level, medical/surgical PICU. Patients: All patients less than 8 years old who received ondansetron over an 11-month period were included. Exclusion criteria were atrial arrhythmia, bundle-branch block, known congenital long QT syndrome, and concomitant administration of proarrhythmic antiarrhythmic agents. Interventions: None. Measurements and Main Results: Overall, 210 doses of ondansetron were administered to 107 patients, with a mean age 10.5 ± 4.8 years; 49% were men. Corrected QT interval increased to 460–500 ms in 29% and to more than 500 ms in 11% of events of ondansetron administration. The mean baseline corrected QT interval even before ondansetron administration was higher for these groups (460–500 and > 500 ms; 457 ± 33 and 469 ± 45, respectively; p ≤ 0.05). In multivariate analysis, both groups were associated significantly with underlying electrolyte abnormalities (odds ratio, 2.2; 95% CI, 1.1–4.4 and odds ratio, 5.1; 95% CI, 1.8–15.7, respectively); the group with corrected QT interval more than 500 ms was also significantly associated with organ dysfunction (odds ratio, 3.2; 95% CI, 1.1–9.4). As the numbers of risk factors increased from only ondansetron to three additional QT aggravating factors (electrolyte abnormalities, administration of other QT-prolonging drugs, and organ dysfunction), the likelihood of being associated with corrected QT interval more than 500 ms increased. Conclusions: Prolonged QT interval is observed commonly in PICUs following the administration of ondansetron. Underlying risk factors, such as electrolyte abnormalities and organ dysfunction, seem to pose the highest risk of prolongation of QT interval in these patients. The awareness of prevalent risk factors for increased corrected QT interval may help identify patients at high risk for arrhythmias.

Background— A portion of sudden cardiac deaths can be attributed to structural heart diseases, such as hypertrophic cardiomyopathy (HCM) or cardiac channelopathies such as long-QT syndrome (LQTS); however, the underlying molecular mechanisms are distinct. Here, we identify a novel CACNA1C missense mutation with mixed loss-of-function/gain-of-function responsible for a complex phenotype of LQTS, HCM, sudden cardiac death, and congenital heart defects. Methods and Results— Whole exome sequencing in combination with Ingenuity variant analysis was completed on 3 affected individuals and 1 unaffected individual from a large pedigree with concomitant LQTS, HCM, and congenital heart defects and identified a novel CACNA1C mutation, p.Arg518Cys, as the most likely candidate mutation. Mutational analysis of exon 12 of CACNA1C was completed on 5 additional patients with a similar phenotype of LQTS plus a personal or family history of HCM-like phenotypes and identified 2 additional pedigrees with mutations at the same position, p.Arg518Cys/His. Whole cell patch clamp technique was used to assess the electrophysiological effects of the identified mutations in Ca V 1.2 and revealed a complex phenotype, including loss of current density and inactivation in combination with increased window and late current. Conclusions— Through whole exome sequencing and expanded cohort screening, we identified a novel genetic substrate p.Arg518Cys/His-CACNA1C, in patients with a complex phenotype including LQTS, HCM, and congenital heart defects annotated as cardiac-only Timothy syndrome. Our electrophysiological studies, identification of mutations at the same amino acid position in multiple pedigrees, and cosegregation with disease in these pedigrees provide evidence that p.Arg518Cys/His is the pathogenic substrate for the observed phenotype.