Novel Parameters to Improve Quantification of Repolarization Reserve and Arrhythmogenesis Using a Dofetilide Challenge

Abstract

<h3>Background</h3> In the canine complete AV block (AVB) model with bradycardia, inducibility of drug-induced torsades de pointes (TdP) is usually the primary outcome parameter, whereas short-term variability (STV) of the left ventricular monophasic action potential duration (LV MAPD) is used as primary surrogate parameter. The dichotomous parameter inducibility is cumbersome because it requires ≥3 TdP episodes and does not take into account (multiple) ectopic beats or severity of TdP episodes. In this study, we introduce arrhythmia score (AS) and T25, using dofetilide (D) to improve quantification of repolarization reserve. <h3>Methods</h3> Experiments performed under general anesthesia in unremodeled, acute AVB dogs (aAVB, n=13) and 3 groups of AVB dogs with chronic bradycardia but differences in remodeling due to alterations in chronic activation pattern were analyzed: spontaneous idioventricular rhythm (IVR, n=19), more physiologic high-septal pacing (HSP, n=10), and right ventricular apex pacing (RVA, n=8). AS was calculated as 1 + mean number of beats of the 3 most severe arrhythmias after D (0.025 mg/kg/5 min), with scores of 50, 75, and 100, for 1, 2, and ≥3 cardioversions, respectively. T25 was defined as the time required to obtain 25-ms increase of LV MAPD after D. <h3>Results</h3> For groups aAVB, IVR, HSP and RVA, TdP inducibility was 0%, 74% (<i>P</i> <.001 vs aAVB), 30%, and 75% (<i>P</i> <.01 vs aAVB), respectively, with a similar pattern in AS: 3.8 ± 6.5 (mean ± SD), 41 ± 28 (<i>P</i> <.001 vs aAVB), 14 ± 22 (<i>P</i> <.05 vs IVR), and 28 ± 24. Serial analysis in aAVB dogs revealed that AS was increased by D (from 1.3 ± 0.4 to 4.3 ± 7.4; n=10; <i>P</i> <.05), although 3 or more TdPs were not induced in any dog. T25 values were 2.1 ± 0.4 minutes 1.4 ± 0.4 minutes (<i>P</i> <.001 vs aAVB), 1.9 ± 0.4 minutes (<i>P</i> <.01 vs IVR), and 1.5 ± 0.3 minutes (<i>P</i> <.01 vs aAVB), respectively. Unexpectedly, STV before or after D was not significantly higher in any group vs aAVB. "Predicting" inducibility after pooling all data (n = 50) yielded areas under the receiver operating characteristics curves of 0.995 for AS and 0.792 for T25, and best cutoff values of 7.7 minutes and 1.6 minutes, respectively. <h3>Conclusions</h3> In anesthetized AVB dogs, AS is not inferior to inducibility and seems to be more detailed. T25 is a good surrogate for the arrhythmogenic outcome and is superior to STV.