Abstract 17250: Quantitative T Wave Morphology Analysis in Rett Syndrome Patients

Introduction: Rett syndrome (RTT) is a genetic neurologic disorder associated with a high incidence of sudden death. Abnormal cardiac repolarization is a potential risk factor for sudden death in this population. RTT patients may have prolonged corrected QT (QTc) on electrocardiogram (ECG) that is a sensitive marker of torsades des pointes. However, other repolarization markers such as T wave morphology, the time it takes the T wave to return to baseline from peak amplitude (Tpeak - Tend), and heart rate corrected JTpeak have not been studied. Hypothesis: Rett syndrome patients have abnormal cardiac repolarization. Methods: Retrospective T wave analysis was performed using QT Guard software. T wave morphology and heterogeneity parameters of RTT patients were compared to ECGs of age and sex matched healthy controls. A composite T wave morphology score was calculated from individual feature of flatness, notching, and asymmetry; a higher score means more abnormal morphology. Heterogeneity of repolarization was represented by the principal component analysis ratio 2 (PCA-2). Results: 57 Rett patients (260 ECG) and 121 controls (134 ECG) were studied. The RTT group had longer QTc (p = 0.001) along with more abnormal T-wave morphology scores and heterogeneity parameters when compared to controls (Tables 1, 2). RTT patients without long QTc also had more abnormal morphology scores than controls (p = 0.001). Conclusion: Cardiac repolarization is diffusely abnormal in RTT even in the absence of long QTc. T wave morphology analysis may be used to detect and monitor abnormal cardiac repolarization in RTT in clinical practice.

Towards a better understanding of QT interval variability

The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guideline E14 recommends ‘Thorough QT Study’ as a standard assessment of drug-induced QT interval prolongation. At the same time, the value of drug-induced QTc prolongation as a surrogate marker for risk of life-threatening polymorphic ventricular tachycardia known as torsades des pointes remains controversial. Beat-to-beat variability of QT interval was recently proposed as an alternative metric. The following review addresses mechanisms of beat-to-beat QT variability, methods of QT interval variability measurements, and its prognostic value in clinical studies.

Effects of early afterdepolarizations on reentry in cardiac tissue: a simulation study

Early afterdepolarizations (EADs) are classically generated at slow heart rates when repolarization reserve is reduced by genetic diseases or drugs. However, EADs may also occur at rapid heart rates if repolarization reserve is sufficiently reduced. In this setting, spontaneous diastolic sarcoplasmic reticulum (SR) Ca release can facilitate cellular EAD formation by augmenting inward currents during the action potential plateau, allowing reactivation of the window L-type Ca current to reverse repolarization. Here, we investigated the effects of spontaneous SR Ca release-induced EADs on reentrant wave propagation in simulated one-, two-, and three-dimensional homogeneous cardiac tissue using a version of the Luo-Rudy dynamic ventricular action potential model modified to increase the likelihood of these EADs. We found: 1) during reentry, nonuniformity in spontaneous SR Ca release related to subtle differences in excitation history throughout the tissue created adjacent regions with and without EADs. This allowed EADs to initiate new wavefronts propagating into repolarized tissue; 2) EAD-generated wavefronts could propagate in either the original or opposite direction, as a single new wave or two new waves, depending on the refractoriness of tissue bordering the EAD region; 3) by suddenly prolonging local refractoriness, EADs caused rapid rotor displacement, shifting the electrical axis; and 4) rapid rotor displacement promoted self-termination by collision with tissue borders, but persistent EADs could regenerate single or multiple focal excitations that reinitiated reentry. These findings may explain many features of Torsades des pointes, such as perpetuation by focal excitations, rapidly changing electrical axis, frequent self-termination, and occasional degeneration to fibrillation.