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Background: Pacing at higher rates is known to suppress torsade de pointes (TdP) arrhythmias. Nevertheless, exact application and mechanism need further clarification. In the anesthetized canine chronic atrioventricular block model, ventricular remodeling is responsible for a high and reproducible incidence of TdP upon a challenge with dofetilide.Objective: We used this model to investigate by what mechanism accelerated pacing averts TdP and what repolarization parameter could be used to guide temporary accelerated pacing (TAP).Methods: Ten dogs with repetitive TdP after administration of dofetilide when paced at 60 beats/min were selected. In a serial experiment, TAP was initiated at 100 beats/min after the first ectopic beat. Electrocardiogram and right and left ventricular (LV) monophasic action potential durations (MAPDs) were recorded. In a subset, vertical dispersion was determined with a duodecapolar catheter. Temporal dispersion was quantified as short-term variability (STV). Arrhythmias were quantified with the arrhythmia score.Results: The increase in repolarization parameters observed after administration of dofetilide was counteracted by TAP (eg, LV MAPD from 381 ± 94 ms back to 310 ± 17 ms; P < .05). Temporal dispersion (STVLVMAPD) increased from 0.69 ± 0.37 to 2.59 ± 0.96 ms (P < .05) after administration of dofetilide and back to 1.15 ± 0.54 ms (P < .05) with TAP. This was accompanied by suppression of recurrent TdP in 7 of 10 dogs (P < .05) and a trend toward reduction in vertical (spatial) dispersion from 56 ± 25 to 31 ± 4 ms (P = .06). In those dogs, seconds after capture of TAP, almost all ectopy disappeared, causing a decrease in arrhythmia score from 21 ± 12 to 4 ± 3 (P < .05).Conclusion: TAP is effective in averting TdP by decreasing spatial and temporal measures of repolarization. Increase in temporal dispersion (STV) can guide TAP. [ABSTRACT FROM AUTHOR]

Introduction: High-rate pacing may have an inhibitory effect on the initiation of Torsade de Pointes arrhythmias (TdP). However, permanent pacing is only indicated in high-risk patients. We performed a proof of concept study into automatic overdrive pacing for prevention of drug-induced TdP, using short-term variability of repolarization (STV) as a feedback parameter of arrhythmic risk. Methods and Results: The minimal signal sampling frequency required for measuring STV was determined through computer simulation. Arrhythmogenic response to dofetilide (25 μg/kg/5minutes) was tested at two different paced heart rates (60-65 bpm vs 100-110 bpm) in 7 dogs with chronic atrioventricular block, while recording right and left ventricular (LV) monophasic action potential (MAP) and LV electrogram (EGM). Simulations showed a sampling frequency of 500 Hz is sufficient to capture relevant STV values. High-rate pacing prevented dofetilide-induced TdP seen at the low rate (low: 6/7 vs high: 1/7). At the low rate, STV from LV MAP duration increased before occurrence of spontaneous, ectopic activity and TdP (1.7 ± 0.6-3.0 ± 1.8 ms, P < 0.05), but at the high-rate STV did not change significantly (0.9 ± 0.2-1.5 ± 1.4 ms, NS). Regression analysis showed a close relation between STV calculated from LV MAP and from LV EGM (R= 0.71). Conclusions: High-rate pacing increases repolarization reserve in dogs with chronic atrioventricular block, preventing dofetilide-induced TdP. Changes in repolarization reserve are reflected in values of STV. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1384-1391, December 2010) [ABSTRACT FROM AUTHOR]

The anesthetized chronic AV-blocked dog (cAVB) and methoxamine-sensitized rabbit model are widely used to determine pro-arrhythmic properties of drugs. In general, both models show similar results. However, conflicting data have also been reported; K201 and AZD1305 induced Torsade de Pointes (TdP) exclusively in cAVB dogs. Vernakalant, an antiarrhythmic drug that blocks several ion channels has been approved only in Europe. Its propensity to induce repolarization-dependent TdP arrhythmias has been evaluated solely in the methoxamine-sensitized rabbits. We therefore assessed the proarrhythmic potential of vernakalant in the cAVB dog model. Vernakalant was evaluated in 10 mongrel dogs (sinus rhythm (SR) 2mg/kg; chronic AV block (cAVB) 2+3mg/kg). The same dogs were challenged with dofetilide (25μg/kg) to evaluate TdP inducibility. During the serial experiments the animals were paced from the right ventricular apex (60beats/min). Short-term variability of repolarization (STV) was quantified for proarrhythmic risk. In SR (n=8) vernakalant prolonged QT (265±11 to 311±18ms P<0.01⁎⁎) but not PQ or QRS. In cAVB (n=8), 2mg/kg vernakalant prolonged QT (391±43 to 519±73ms⁎⁎) and QRS (103±24 to 108±23ms⁎⁎). After a 30min lag-time, 3mg/kg vernakalant (n=4) increased QT to a lesser extent (413±34 to 454±27ms⁎⁎) while maintaining QRS prolongation (114±18 to 122±20ms⁎⁎). Neither dose increased STV or caused arrhythmias. Dofetilide prolonged QT (398±51 to 615±71ms⁎⁎), increased STV (1.0±0.4 to 2.2±1.0ms P<0.05⁎) and induced TdP arrhythmias in 6/8⁎ cAVB dogs. Vernakalant did not induce arrhythmias in the cAVB dog model. Higher dosages (3mg/kg) did not prolong repolarization further whereas negative inotropic effects were starting to become apparent precluding further increases in dose. [ABSTRACT FROM AUTHOR]