High-rate pacing reduces variability of repolarization and prevents repolarization-dependent arrhythmias in dogs with chronic AV block.

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 microg/kg/5 minutes) 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(2) = 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.

Proarrhythmic electrical remodelling is associated with increased beat-to-beat variability of repolarisation.

OBJECTIVE: Acquired long-QT syndrome in combination with increased beat-to-beat variability of repolarisation duration (BVR) is associated with lethal torsades de pointes arrhythmias (TdP) in dogs with remodelled heart after atrioventricular block (AVB). We evaluated the relative contributions of bradycardia and ventricular remodelling to proarrhythmic BVR with and without pharmacological I(Kr) block in order to identify the individual at risk. METHODS: Three groups of dogs were used: sinus rhythm dogs (n = 12), dogs with acute AVB (n = 8), and dogs with >3 weeks chronic AVB (n = 27). Under anaesthesia, ECG and monophasic action potential duration (MAPD) were measured. Local BVR was quantified as short-term variability from 30 consecutive left ventricular MAPD (STV = summation absolute value(D(n(i)-D(n+1))/[30 x square root of 2])). All dogs received dofetilide iv. RESULTS: The slower ventricular rate acutely after AVB affected neither QTc nor STV (288+/-18 to 293+/-38 ms and 0.7+/-0.1 to 0.7+/-0.1 ms, respectively; P = NS for both), whereas ventricular remodelling increased both (to 376+/-46 and 2.3+/-0.6 ms, respectively; P < 0.05 for both). Neither dogs in sinus rhythm nor acute AVB showed any TdP, whereas dofetilide induced TdP in 74% of the chronic-AVB dogs. Dofetilide increased the QTc interval in all groups (19-24%; P < 0.05 for all groups), whereas STV was elevated in chronic-AVB dogs only (to 4.2+/-1.5 ms; P < 0.05) and further confined to inducible chronic-AVB dogs (5.0+/-0.8 versus 1.9+/-0.4 ms for resistant dogs; P < 0.05). Variability of the idioventricular rate was increased directly after AVB and did not influence BVR. CONCLUSIONS: Under drug-free circumstances, a persistent high BVR in chronic-AVB dogs is remodelling dependent rather than a direct consequence of bradycardia acutely after AVB. Variability of this slower rate does not influence BVR. Dofetilide causes a transient increase in BVR only in proarrhythmic dogs. Thus, BVR may aid the identification of the TdP-susceptible patient.