Electrophysiologic Substrate in Congenital Long QT Syndrome

Abstract

Background Congenital Long QT syndrome (LQTS) is an arrhythmogenic disorder that causes syncope and sudden death. While its genetic basis has become well-understood, the mechanisms whereby mutations translate to arrhythmia susceptibility in the in situ human heart have not been fully defined. We used noninvasive ECG imaging (ECGI) to map the cardiac electrophysiologic substrate and examine whether LQTS patients display regional heterogeneities in repolarization, a substrate which promotes arrhythmogenesis. Methods and Results 25 subjects (9 LQT1, 9 LQT2, 5 LQT3 and 2 LQT5) with genotype and phenotype positive LQTS underwent ECGI. Seven normal subjects provided control. Epicardial maps of activation, recovery times (RT), Activation-recovery intervals (ARI) and repolarization dispersion were constructed. Activation was normal in all patients. However, RT and ARI were prolonged relative to control, indicating delayed repolarization and abnormally long APD (312 ± 30 ms vs. 235 ± 21 ms in control). ARI prolongation was spatially heterogeneous, with repolarization gradients much steeper than control (119 ± 19 ms/cm vs. 2.0 ± 2.0 ms/cm). There was variability in steepness and distribution of repolarization gradients between and within LQTS types. Repolarization gradients were steeper in symptomatic patients (130 ± 27 ms/cm in 12 symptomatic patients vs. 98 ± 19 ms/cm in 13 asymptomatic patients; P < 0.05). Conclusions LQTS patients display regions with steep repolarization dispersion caused by localized APD prolongation. This defines a substrate for reentrant arrhythmias, not detectable by surface ECG. Steeper dispersion in symptomatic patients suggests a possible role for ECGI in risk stratification.

Automated Algorithm for J-Tpeak and Tpeak-Tend Assessment of Drug-Induced Proarrhythmia Risk

“…In addition, a recent in vivo study of dofetilide in dogs showed that dofetilide caused significant interventricular delay in repolarization and that for notched T-waves the two peaks could correspond to either ventricle repolarizing [34]. This observation is consistent with the in silico results presented by Sadrieh and colleagues and suggest that T-wave notches may arise as a result of increased spatial dispersion, which could potentially be due to a difference in expression of cardiac ion channels [35]. Fortunately, in the context of assessing drug-induced ECG changes in healthy volunteers this is a manageable problem, as only 42 notches were observed in the vector magnitude lead in FDA study 1 [9], which included two potent selective hERG potassium channel blockers (dofetilide and quinidine) causing T-wave notching and substantial QTc prolongation (~80 ms).…”

Life-long tailoring of diagnosis and management of patients with idiopathic ventricular fibrillation—future perspectives in research

“…In healthy individuals, ECGI demonstrated that dispersion is small, for example for repolarisation in humans [20, 21]. However, ECGI did show increased dispersion in several arrhythmogenic diseases.…”

“…In long QT syndrome [20] and Brugada syndrome [21], patients had abnormally steep repolarisation gradients. Repolarisation gradients were steeper in symptomatic patients, suggesting increased dispersion is predictive for arrhythmia risk [20]. We have validated ECGI’s ability to assess depolarisation and repolarisation accurately.…”

Noninvasive ECG imaging (ECGI): Mapping the arrhythmic substrate of the human heart

“…In LQTS 3 , maps of epicardial activation, recovery times (RT) and activation-recovery intervals (ARI; surrogate for local action potential duration (APD)) were reconstructed and compared with those of healthy volunteers. Activation was normal in all patients.…”