A new method is proposed to evaluate the dynamics of QT interval adaptation in response to heart rate (HR) changes. The method considers weighted averages of RR intervals (RR) preceding each cardiac beat to express RR interval history accounting for the influence on repolarization duration. A global optimization algorithm is used to determine the weight distribution leading to the lowest regression residual when curve fitting the [QT, RR1 data using a patient-specific regression model. From the optimum weight distribution, a memory lag L90 is estimated, expressing the delay in the QT adaptation to HR changes. On average, RR intervals of the past 150 beats (approximately 2.5 min) are required to model the QT response accurately. From a clinical point of view, the interval of the initial tens of seconds to one minute seems to be most important in the majority of cases. A measure of the optimum regression residual (r(opt)) has been calculated, discriminating between post-myocardial infarction patients at high and low risk of arrhythmic death while on treatment with amiodarone. A similar discrimination has been achieved with a variable expressing the character of QT lag behind the RR interval dynamics.

AimsHuman atrial electrophysiology exhibits high inter-subject variability in both sinus rhythm (SR) and chronic atrial fibrillation (cAF) patients. Variability is however rarely investigated in experimental and theoretical electrophysiological studies, thus hampering the understanding of its underlying causes but also its implications in explaining differences in the response to disease and treatment. In our study, we aim at investigating the ability of populations of human atrial cell models to capture the inter-subject variability in action potential (AP) recorded in 363 patients both under SR and cAF conditions.Methods and ResultsHuman AP recordings in atrial trabeculae (n = 469) from SR and cAF patients were used to calibrate populations of computational SR and cAF atrial AP models. Three populations of over 2000 sampled models were generated, based on three different human atrial AP models. Experimental calibration selected populations of AP models yielding AP with morphology and duration in range with experimental recordings. Populations using the three original models can mimic variability in experimental AP in both SR and cAF, with median conductance values in SR for most ionic currents deviating less than 30% from their original peak values. All cAF populations show similar variations in GK1, GKur and Gto, consistent with AF-related remodeling as reported in experiments. In all SR and cAF model populations, inter-subject variability in IK1 and INaK underlies variability in APD90, variability in IKur, ICaL and INaK modulates variability in APD50 and combined variability in Ito and IKur determines variability in APD20. The large variability in human atrial AP triangulation is mostly determined by IK1 and either INaK or INaCa depending on the model.ConclusionExperimentally-calibrated human atrial AP models populations mimic AP variability in SR and cAF patient recordings, and identify potential ionic determinants of inter-subject variability in human atrial AP duration and morphology in SR versus cAF.

Background--Congenital long QT syndrome type 2 (abnormal hERG potassium channel) patients can develop flat, asymmetric, and notched T waves. Similar observations have been made with a limited number of hERG-blocking drugs. However, it is not known how additional calcium or late sodium block, that can decrease torsade risk, affects T wave morphology.Methods and Results--Twenty-two healthy subjects received a single dose of a pure hERG blocker (dofetilide) and 3 drugs that also block calcium or sodium (quinidine, ranolazine, and verapamil) as part of a 5-period, placebo-controlled cross-over trial. At predose and 15 time-points post-dose, ECGs and plasma drug concentration were assessed. Patch clamp experiments were performed to assess block of hERG, calcium (L-type) and late sodium currents for each drug. Pure hERG block (dofetilide) and strong hERG block with lesser calcium and late sodium block (quinidine) caused substantial T wave morphology changes (P<0.001). Strong late sodium current and hERG block (ranolazine) still caused T wave morphology changes (P<0.01). Strong calcium and hERG block (verapamil) did not cause T wave morphology changes. At equivalent QTc prolongation, multichannel blockers (quinidine and ranolazine) caused equal or greater T wave morphology changes compared with pure hERG block (dofetilide).Conclusions--T wave morphology changes are directly related to amount of hERG block; however, with quinidine and ranolazine, multichannel block did not prevent T wave morphology changes. A combined approach of assessing multiple ion channels, along with ECG intervals and T wave morphology may provide the greatest insight into drug-ion channel interactions and torsade de pointes risk. Long QT syndrome patients are at increased risk for torsade de pointes, a potentially fatal ventricular arrhythmia.2 Conventionally, physicians and drug regulators have focused solely on the QT interval in assessing risk for torsade; however, more information may be present in the electrocardiogram (ECG). Moss and colleagues 3 identified different T wave patterns associated with the 3 major congenital long QT syndrome types. LQT1 patients (decreased IKs current) have early onset broad-based T waves, LQT2 patients (decreased hERG potassium current, IKr) have low amplitude, bifid or notched T waves, and LQT3 patients (increased late sodium current, INa late ) have long isoelectric ST segments with lateappearing, normal morphology T waves. In the 1990s, there was recognition of an epidemic of druginduced QT prolongation and torsade de pointes resulting in many drugs being withdrawn from the market. 4 It was also recognized that nearly all drugs that increased torsade risk blocked the hERG potassium channel. 5 This resulted in all new drugs being required to be screened for their ability to block the hERG potassium channel and prolong QT in Thorough QT studies. 6,7 However, the extreme focus on hERG and QT has There are multiple examples of drugs on the market that block the hERG channel (an outward potassium current), but ...