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.

• MeSH
• Action Potentials MeSH
• Anti-Arrhythmia Agents therapeutic use   MeSH
• Time Factors MeSH
• Child MeSH
• Adult MeSH
• Electrocardiography * MeSH
• Phenotype MeSH
• Genetic Predisposition to Disease MeSH
• Risk Assessment MeSH
• Kaplan-Meier Estimate MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Predictive Value of Tests MeSH
• Heart Conduction System drug effects   physiopathology   MeSH
• Proportional Hazards Models MeSH
• Risk Factors MeSH
• Romano-Ward Syndrome diagnosis   drug therapy   genetics   physiopathology   MeSH
• Chi-Square Distribution MeSH
• Heart Rate drug effects   MeSH
• Long QT Syndrome diagnosis   drug therapy   genetics   physiopathology   MeSH
• Treatment Outcome MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

AIMS: Mutations in KCNQ1, encoding for Kv7.1, the α-subunit of the IKs channel, cause long-QT syndrome type 1, potentially predisposing patients to ventricular tachyarrhythmias and sudden cardiac death, in particular, during elevated sympathetic tone. Here, we aim at characterizing the p.Lys557Glu (K557E) Kv7.1 mutation, identified in a Dutch kindred, at baseline and during (mimicked) increased adrenergic tone. METHODS AND RESULTS: K557E carriers had moderate QTc prolongation that augmented significantly during exercise. IKs characteristics were determined after co-expressing Kv7.1-wild-type (WT) and/or K557E with minK and Yotiao in Chinese hamster ovary cells. K557E caused IKs loss of function with slowing of the activation kinetics, acceleration of deactivation kinetics, and a rightward shift of voltage-dependent activation. Together, these contributed to a dominant-negative reduction in IKs density. Confocal microscopy and western blot indicated that trafficking of K557E channels was not impaired. Stimulation of WT IKs by 3'-5'-cyclic adenosine monophosphate (cAMP) generated strong current up-regulation that was preserved for K557E in both hetero- and homozygosis. Accumulation of IKs at fast rates occurred both in WT and in K557E, but was blunted in the latter. In a computational model, K557E showed a loss of action potential shortening during β-adrenergic stimulation, in accordance with the lack of QT shortening during exercise in patients. CONCLUSION: K557E causes IKs loss of function with reduced fast rate-dependent current accumulation. cAMP-dependent stimulation of mutant IKs is preserved, but incapable of fully compensating for the baseline current reduction, explaining the long QT intervals at baseline and the abnormal QT accommodation during exercise in affected patients.

• MeSH
• Adrenergic beta-Agonists pharmacology   MeSH
• Action Potentials MeSH
• Cyclic AMP metabolism   MeSH
• CHO Cells MeSH
• Cricetulus MeSH
• Cytoskeletal Proteins genetics   metabolism   MeSH
• Heredity MeSH
• Adult MeSH
• Potassium Channels, Voltage-Gated genetics   metabolism   MeSH
• KCNQ1 Potassium Channel drug effects   genetics   metabolism   MeSH
• Electrocardiography MeSH
• Phenotype MeSH
• Ion Channel Gating * drug effects   MeSH
• Genetic Predisposition to Disease MeSH
• Kinetics MeSH
• A Kinase Anchor Proteins genetics   metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Models, Cardiovascular MeSH
• Mutation * MeSH
• Mutagenesis, Site-Directed MeSH
• Computer Simulation MeSH
• Dogs MeSH
• Romano-Ward Syndrome diagnosis   genetics   metabolism   physiopathology   MeSH
• Case-Control Studies MeSH
• Second Messenger Systems MeSH
• Transfection MeSH
• Up-Regulation MeSH
• Animals MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Dogs MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH