Severe Bradycardia Increases the Incidence and Severity of Torsade de Pointes Arrhythmias by Augmenting Preexistent Spatial Dispersion of Repolarization in the CAVB Dog Model

FIGURE 1. Measurement of electrophysiological parameters and the percentage (%) increases of electrophysiological parameters following infusion of dofetilide in the serially performed IVR and RVA60 experiments. (A) Representative beats from lead II, a left ventricular (LV) intraventricular electrogram (EGM) and a right ventricular (RV) monophasic action potential (MAP) in IVR and RVA experiments. Start of activation (black dashed line) was determined at the start of the QRS complex (IVR experiments) or pacing spike (RVA experiments) in lead II. LV activation time (AT) was measured as the time between start of ventricular activation and the steepest downslope of the EGM (red dashed line), whereas LV repolarization time (RT) was measured at the steepest upslope (red dashed line). LV activation recovery interval (ARI) was measured as LV, RT – LV, AT. RV, AT was measured from the start of ventricular activation to the upstroke of the RV MAP (blue dashed line). Monophasic action potential duration (MAPD) was determined at 80% of repolarization (blue dashed line). (B) The percentage in electrophysiological parameters representing repolarization time and stability following infusion of dofetilide…

FIGURE 2. Dofetilide experiments performed under IVR or RVA60 conditions in chronic atrioventricular block dogs. Representative ECG traces (lead II and AVR) associated with MAPs recorded from the LV and RV at baseline and after dofetilide (25 μg/kg per 5 min) infusion in serial IVR (A) and RVA60 (B) experiments. Quantification of TdP-inducible CAVB dogs, AS, and average number of TdP. The circular dots represent the different experiments (C). The incidence of sEB, mEB, and TdP under IVR and RVA60 conditions (D). Values are represented as mean ± SD. AS, arrhythmia score; CAVB, chronic atrioventricular block; ECG, electrocardiogram; IVR, idioventricular rhythm; LV/RV MAP, left/right ventricular monophasic action potential; mEB, multiple ectopic beat; RVA60, right ventricular apex paced at 60 beats per minute; sEB, single ectopic beat; TdP, torsade de pointes arrhythmia. *p < 0.05 vs. IVR.

FIGURE 3. Action recovery interval (ARI) restitution curves. (A) Increasing cycle length, and thus diastolic interval (DI), caused interventricular dispersion of ARI as the repolarization duration of the left ventricle prolonged more than the right ventricle. (B) The interventricular dyssynchrony in ARI prolongation (DARI) was more pronounced in animals that were to become inducible (n = 5) when challenged with dofetilide, compared to noninducible animals (n = 5).

FIGURE 4. Bradycardia-induced increases in left ventricular intraventricular spatial dispersion of repolarization. Local repolarization times (RT) of one animal during high (130 beats/min), middle (100 beats/min), and experimental (60 beats/min) rate in the septum and LV from base (I) to apex (VI). Traces of two unipolar electrograms with their corresponding RT and their difference herein are depicted to illustrate the evolution of spatial dispersion. Colors and color gradients correspond to the absolute RT and ΔRT values, respectively, as depicted in the color bars below the cardiac maps.