Rationale:: Spontaneous Ca ²⁺ release (SCR) from the sarcoplasmic reticulum can cause delayed afterdepolarizations and triggered activity, contributing to arrhythmogenesis during β-adrenergic stimulation. Excessive beat-to-beat variability of repolarization duration (BVR) is a proarrhythmic marker. Previous research has shown that BVR is increased during intense β-adrenergic stimulation, leading to SCR. Objective:: We aimed to determine ionic mechanisms controlling BVR under these conditions. Methods and Results:: Membrane potentials and cell shortening or Ca ²⁺ transients were recorded from isolated canine left ventricular myocytes in the presence of isoproterenol. Action-potential (AP) durations after delayed afterdepolarizations were significantly prolonged. Addition of slowly activating delayed rectifier K ⁺ current (I _Ks ) blockade led to further AP prolongation after SCR, and this strongly correlated with exaggerated BVR. Suppressing SCR via inhibition of ryanodine receptors, Ca2+/calmodulin-dependent protein kinase II inhibition, or by using Mg ²⁺ or flecainide eliminated delayed afterdepolarizations and decreased BVR independent of effects on AP duration. Computational analyses and voltage-clamp experiments measuring L-type Ca ²⁺ current (I _CaL ) with and without previous SCR indicated that I _CaL was increased during Ca ²⁺ -induced Ca ²⁺ release after SCR, and this contributes to AP prolongation. Prolongation of QT, T _peak -T _end intervals, and left ventricular monophasic AP duration of beats after aftercontractions occurred before torsades de pointes in an in vivo dog model of drug-induced long-QT1 syndrome. Conclusions:: SCR contributes to increased BVR by interspersed prolongation of AP duration, which is exacerbated during I _Ks blockade. Attenuation of Ca ²⁺ -induced Ca ²⁺ release by SCR underlies AP prolongation via increased I _CaL. These data provide novel insights into arrhythmogenic mechanisms during β-adrenergic stimulation besides triggered activity and illustrate the importance of I _Ks function in preventing excessive BVR.

Beat-to-beat variability of repolarization duration (BVR) is an intrinsic characteristic of cardiac function and a better marker of proarrhythmia than repolarization prolongation alone. The ionic mechanisms underlying baseline BVR in physiological conditions, its rate dependence, and the factors contributing to increased BVR in pathologies remain incompletely understood. Here, we employed computer modeling to provide novel insights into the subcellular mechanisms of BVR under physiological conditions and during simulated drug-induced repolarization prolongation, mimicking long-QT syndromes type 1, 2, and 3. We developed stochastic implementations of 13 major ionic currents and fluxes in a model of canine ventricular-myocyte electrophysiology. Combined stochastic gating of these components resulted in short- and long-term variability, consistent with experimental data from isolated canine ventricular myocytes. The model indicated that the magnitude of stochastic fluctuations is rate dependent due to the rate dependence of action-potential (AP) duration (APD). This process (the “active” component) and the intrinsic nonlinear relationship between membrane current and APD (“intrinsic component”) contribute to the rate dependence of BVR. We identified a major role in physiological BVR for stochastic gating of the persistent Na⁺ current (I_Na) and rapidly activating delayed-rectifier K⁺ current (I_Kr). Inhibition of I_Kr or augmentation of I_Na significantly increased BVR, whereas subsequent β-adrenergic receptor stimulation reduced it, similar to experimental findings in isolated myocytes. In contrast, β-adrenergic stimulation increased BVR in simulated long-QT syndrome type 1. In addition to stochastic channel gating, AP morphology, APD, and beat-to-beat variations in Ca²⁺ were found to modulate single-cell BVR. Cell-to-cell coupling decreased BVR and this was more pronounced when a model cell with increased BVR was coupled to a model cell with normal BVR. In conclusion, our results provide new insights into the ionic mechanisms underlying BVR and suggest that BVR reflects multiple potentially proarrhythmic parameters, including increased ion-channel stochasticity, prolonged APD, and abnormal Ca²⁺ handling. Every heartbeat has an electrical recovery (repolarization) interval that varies in duration from beat to beat. Excessive beat-to-beat variability of repolarization duration has been shown to be a risk marker of potentially fatal heart-rhythm disorders, but the contributing subcellular mechanisms remain incompletely understood. Computational models have greatly enhanced our understanding of several basic electrophysiological mechanisms. We developed a detailed computer model of the ventricular myocyte that can simulate beat-to-beat changes in repolarization duration by taking into account stochastic changes in the opening and closing of individual ion channels responsible for all main ion currents. The model accurately reproduced experimental data from isolated myocytes under both physiological and pathological conditions. Using the model, we identified several mechanisms contributing to repolarization variability, including stochastic gating of ion channels, duration and morphology of the repolarization phase, and intracellular calcium handling, thereby providing insights into its basis as a proarrhythmic marker. Our computer model provides a detailed framework to study the dynamics of cardiac electrophysiology and arrhythmias.

Prolonged and dispersed left-ventricular (LV) contraction is present in patients with long-QT syndrome (LQTS). Electrical and mechanical abnormalities appear most pronounced in symptomatic individuals. We focus on the ‘electromechanical window’ (EMW; duration of LV-mechanical systole minus QT interval) in patients with genotyped LQTS. Profound EMW negativity heralds torsades de pointes in animal models of drug-induced LQTS. We included 244 LQTS patients from three centres, of whom 97 had experienced arrhythmic events. Seventy-six matched healthy individuals served as controls. QT interval was subtracted from the duration of Q-onset to aortic-valve closure (QAoC) midline assessed non-invasively by continuous-wave echocardiography, measured in the same beat. Electromechanical window was positive in controls but negative in LQTS patients (22 ± 19 vs. −43 ± 46 ms; P < 0.0001), being even more negative in symptomatic than event-free patients (−67 ± 42 vs. −27 ± 41 ms; P < 0.0001). QT, QTc, and QAoC were longer in LQTS subjects (451 ± 57, 465 ± 50, and 408 ± 37 ms, P < 0.0001). Electromechanical window was a better discriminator of patients with previous arrhythmic events than resting QTc (AUC 0.77 (95% CI, 0.71–0.83) and 0.71 (95% CI, 0.65–0.78); P = 0.03). In multivariate analysis, EMW predicted arrhythmic events independently of QTc (odds ratio 1.25; 95% CI, 1.11–1.40; P = 0.001). Adding EMW to QTc for risk assessment led to a net reclassification improvement of 13.3% (P = 0.03). No EMW differences were found between the three major LQTS genotypes. Patients with genotype-positive LQTS express EMW negativity, which is most pronounced in patients with documented arrhythmic events.

Electrical activity at the level of the heart muscle can be noninvasively reconstructed from body-surface electrocardiograms (ECGs) and patient-specific torso-heart geometry. This modality, coined electrocardiographic imaging, could fill the gap between the noninvasive (low-resolution) 12-lead ECG and invasive (high-resolution) electrophysiology studies. Much progress has been made to establish electrocardiographic imaging, and clinical studies appear with increasing frequency. However, many assumptions and model choices are involved in its execution, and only limited validation has been performed. In this article, we will discuss the technical details, clinical applications and current limitations of commonly used methods in electrocardiographic imaging. It is important for clinicians to realise the influence of certain assumptions and model choices for correct and careful interpretation of the results. This, in combination with more extensive validation, will allow for exploitation of the full potential of noninvasive electrocardiographic imaging as a powerful clinical tool to expedite diagnosis, guide therapy and improve risk stratification.