Background— Noninvasive imaging of cardiac activation before ablation of the arrhythmogenic substrate can reduce electrophysiological procedure duration and help choosing between an endocardial or epicardial approach. A noninvasive imaging technique was evaluated that estimates both endocardial and epicardial activation from body surface potential maps. We performed a study in isolated and in situ pig hearts, estimating activation from body surface potential maps during sinus rhythm and localizing endocardial and epicardial stimulation sites. Methods and Results— From 3 Langendorff-perfused pig hearts, 180 intramural unipolar electrograms were recorded during sinus rhythm and ectopic activation, together with pseudo–body surface potential map ECGs in 2 of them. From 4 other anesthetized pigs, 64-lead body surface potential maps were recorded during sinus rhythm and ventricular stimulation from 27 endocardial and epicardial sites. The ventricular activation pattern was computed from the recorded QRS complexes. For both Langendorff-perfused hearts, the calculated epicardial and endocardial activation patterns showed good qualitative correspondence to the patterns obtained with needle electrodes. Absolute timing difference for sinus rhythm was 10±5 and 11±8 ms respectively, and for ectopic activation 6±5 and 7±6 ms, respectively. Calculated activation for the in situ hearts in sinus rhythm was similar to patterns recorded in Langendorff-perfused hearts. During stimulation, the distance between the stimulation site and calculated site of earliest activation was 18 (15–27) mm, and 23 of 27 stimulation sites were correctly mapped to either endocardium or epicardium. Conclusions— Noninvasive activation imaging is able to determine earliest ventricular activation and discriminate endocardial from epicardial origin of activation with clinically relevant accuracy.

Background: Beat-to-beat variability in ventricular repolarization (BVR) associates with increased arrhythmic risk. Proarrhythmic remodeling in the dog with chronic AV-block (CAVB) compromises repolarization reserve and associates with increased BVR, which further increases upon dofetilide infusion and correlates with Torsade de Pointes (TdP) arrhythmias. It was hypothesized that these pro-arrhythmia-associated increases in BVR are induced by beat to-beat variability in preload.Methods and Results: Left ventricular monophasic action potential duration (LVMAPD) was recorded in acute (AAVB) and CAVB dogs, before and after dofetilide infusion. BVR was quantified as short-term variability of LVMAPD. The PQ-interval was controlled by pacing: either a constant or an alternating preload pattern was established, verified by PV-loop. The effect of the stretch-activated channel blocker, streptomycin, on BVR was evaluated in a second CAVB group. At alternating preload only, BVR was increased after proarrhythmic remodeling (0.45 +/- 0.14ms AAVB vs. 2.2 +/- 1.1 ms CAVB, P<0.01). At CAVB, but not at AAVB, dofetilide induced significant proarrhythmia. Preload variability augmented the dofetilide-induced BVR increase at CAVB (+1.5 +/- 0.8ms vs. +0.9 +/- 0.9ms, P=0.058). In the second group, the increase in baseline BVR by alternating preload (0.3 +/- 0.03 ms to 1.0 +/- 0.8ms, P<0.01) was abolished by streptomycin (0.5 +/- 0.2ms, P<0.05).Conclusions: In CAVB dogs, the inverse relation between BVR and repolarization reserve originates from an augmented sensitivity of ventricular repolarization to beat-to-beat preload changes. Stretch-activated channels appear to be involved in the mechanism of BVR.

BACKGROUND AND PURPOSE:The electromechanical window (EMW), the interval between the end of the T-wave and the end of the left ventricular pressure (LVP) curve, has recently been proposed as a predictor of risk of Torsade de Pointes (TdP) in healthy animals, whereby a negative EMW (mechanical relaxation earlier than repolarization) after drug administration indicates an increased TdP risk. The aims of this study were to assess (i) the effect of the ventricular remodelling in the canine chronic, complete atrioventricular block (CAVB) model on EMW; (ii) the effect of the I(Kr) -blocker dofetilide on EMW; and (iii) the correlation of EMW with TdP inducibility. EXPERIMENTAL APPROACH:Our 11 year database of experiments of CAVB in dogs under general anaesthesia was reviewed and experiments included if ECG and LVP were recorded simultaneously at spontaneous rhythm. In total, 89 experiments in 44 dogs were appropriate and were analysed. KEY RESULTS:During normally conducted sinus rhythm or acute atrioventricular block, EMW was positive. During CAVB, EMW was decreased to negative values. Dofetilide further reduced EMW before inducing repetitive TdP in 82% of the experiments. However, subclassification into inducible and non-inducible dogs revealed no difference in EMW. Analysis of the components of EMW revealed that the observed changes in EMW were solely caused by QT prolongation. CONCLUSIONS AND IMPLICATIONS:In the canine CAVB model, ventricular remodelling and I(Kr) block by dofetilide are associated with negative EMW values, but this reflects QT prolongation, and implies that the EMW lacks specificity to predict dofetilide-induced TdP.

Pronounced beat-to-beat variability in cardiac repolarization duration (BVR) is associated with increased arrhythmic risk in patients, animal models and isolated cardiomyocytes. However, the mechanisms linking an enhanced BVR to arrhythmogenicity is unknown and may differ between single cells and the intact heart, since cellular coupling is known to attenuate repolarization variability and suppress early afterdepolarizations. We hypothesized that in dogs with chronic AV-block (CAVB) and reduced repolarization strength, beat-to-beat variability in preload, only present in the intact heart, is required to increase BVR. Methods: Endocardial left ventricular monophasic action potential duration (LVMAPD80) was recorded in acute (AAVB, n=6) and CAVB dogs (n=7), before and after a challenge with the IKr blocker dofetilide. We used atrial and ventricular stimulation to provide either a constant or an alternating preload pattern, which was verified by PV-loop determined mechanical parameters. The effect of the stretch activated channel blocker streptomycin on baseline BVR and arrhythmic response to dofetilide was evaluated in a second CAVB group (n=9). Short-term variability of LVMAPD was used to quantify BVR. Arrhythmic outcome was quantified by combining the number of ectopic beats, episodes of TdP and defibrillations into a single arrhythmia score (AS). Results: Pro-arrhythmic remodeling (>3weeks AV-block) increased BVR during alternating preload, (0.45±0.14 AAVB vs 2.2±1.1 ms CAVB, p<0.01), while no change in BVR was seen at constant preload (0.35±0.12 AAVB vs 0.32±0.14 ms CAVB, NS). At AAVB, reduction of repolarization reserve by dofetilide did not induce TdP (AS 1[1-2], median[IQR]), but was pro-arrhythmic in CAVB (AS 27[9-62], p<0.05 vs AAVB). Variation of preload did not alter arrhythmic outcome at CAVB (AS 16[7-37] constant vs 47[2-57] alternating, NS), but was present in BVR determined prior to arrhythmias (2.5±1.4 constant vs 5.9±4.5 ms alternating, p=0.08). In the second group, the increase in BVR at baseline by alternating preload (0.3±0.03 vs 1.0±0.8 ms , p<0.01) was almost abolished by streptomycin (0.5±0.2 ms alternating, p<0.05 vs baseline alternating, NS vs baseline constant). Furthermore, arrhythmia score after dofetilide was reduced after streptomycin pre-treatment (AS 4[2-13], p=0.05). Conclusions: In the anesthetized CAVB dog BVR is a marker of pro-arrhythmic remodeling and critically reduced repolarization reserve, and originates from altered response to changes in preload. There is involvement of stretch activated channels both in the mechanisms of BVR and of drug-induced arrhythmia.

Introduction: Non-invasive mapping of cardiac activation before ablation of arrhythmic foci can reduce EP procedure duration. A novel non-invasive activation mapping technique was developed that estimates both endocardial and epicardial activation times from body surface electrograms. To evaluate the clinical applicability of this technique, we performed an experimental in-vivo validation study by non-invasively localizing various endo- and epicardial stimulation sites. Methods: Three male pigs (62-65 kg) were sedated and catheterized (endocardial and epicardial access). A 64 lead body surface map was recorded during cardiac stimulation from various endocardial and epicardial sites. Stimulation electrode positions were determined with fluoroscopy images recorded in three different directions. A detailed volume conductor model was derived from computer tomography images recorded immediately prior to the procedure. We used the equivalent double layer source model located on the endo- and epicardial ventricular surface, its local strength proportional to the estimated transmembrane potential of the myocardial tissue underneath. Results: A total of 127 beats, stimulated from 11 endocardial and 9 epicardial sites were analyzed. Median distance between stimulus site and estimated location of first activation was 17 mm (16, 20 and 16 mm resp.). The stimulation surface (endo- or epicardial) was identified correctly for 82% of the analyzed beats. Example of estimated activation time Example of estimated activation time Conclusion: Our non-invasive activation mapping technique was able to discriminate endocardial from epicardial foci of activation with clinically relevant accuracy. This can be used to support the choice of the initial approach (endocardial or epicardial) prior to ablation procedures.

Background 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. Methods 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. Results For groups aAVB, IVR, HSP and RVA, TdP inducibility was 0%, 74% (P <.001 vs aAVB), 30%, and 75% (P <.01 vs aAVB), respectively, with a similar pattern in AS: 3.8 ± 6.5 (mean ± SD), 41 ± 28 (P <.001 vs aAVB), 14 ± 22 (P <.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; P <.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 (P <.001 vs aAVB), 1.9 ± 0.4 minutes (P <.01 vs IVR), and 1.5 ± 0.3 minutes (P <.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. Conclusions 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. 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. 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. For groups aAVB, IVR, HSP and RVA, TdP inducibility was 0%, 74% (P <.001 vs aAVB), 30%, and 75% (P <.01 vs aAVB), respectively, with a similar pattern in AS: 3.8 ± 6.5 (mean ± SD), 41 ± 28 (P <.001 vs aAVB), 14 ± 22 (P <.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; P <.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 (P <.001 vs aAVB), 1.9 ± 0.4 minutes (P <.01 vs IVR), and 1.5 ± 0.3 minutes (P <.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. 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.

BACKGROUND Repolarization variability is considered to predict sudden cardiac death. T-wave alternans (TWA) has been the subject of exhaustive research, whereas beat-to-beat variability of repolarization (BVR) is a new parameter that possibly predicts proarrhythmia. How these parameters interact has not been tested.OBJECTIVE The purpose of this study was to compare TWA and BVR as predictors of proarrhythmic substrate early after myocardial infarction (MI).METHODS In nine pigs, MI was induced by 1-hour occlusion of the left anterior descending coronary artery. Cardiac magnetic resonance imaging was performed at day 21. Six sham pigs served as control. Spectral TWA was tested during right atrial pacing before induction of MI and after 21 days. BVR was calculated from 60 consecutive QT intervals.RESULTS Magnetic resonance imaging showed transmural MI. TWA was negative in all pigs at clinical threshold rate and equally present in MI versus sham pigs at higher rates (170 bpm: 55% vs 50% positive TWA). In MI pigs, BVR of QT intervals increased significantly during acute ischemia (2.44 +/- 0.43 ms vs 3.55 +/- 0.41 ms, P < .01) and even more on day 21 (5.80 +/- 1.12 ms), but it differed significantly from sham (2.14 +/- 0.54 ms, P < .01). A clinical ventricular tachycardia induction protocol was positive in 2 of 8 MI pigs and in none of 6 shams.CONCLUSION In early remodeling after MI, BVR at intrinsic heart rate was a consistent phenomenon, whereas TWA during atrial pacing or baseline QT-interval changes were not. TWA and BVR could reflect different post-MI remodeling processes. BVR may be a new technique for predicting a potentially proarrhythmic substrate in the early postinfarction period.

INTRODUCTION:A number of predisposing factors have been suggested to be contributing to drug-induced torsade de pointes (TdP) arrhythmias: short-long-short (SLS) sequence, bradycardia, timing of drug administration, anaesthesia, ventricular remodelling, and altered ventricular activation due to ventricular ectopic beats (SLS) or idioventricular rhythm (IVR). Chronic atrio-ventricular (AV)-block (CAVB) dogs are susceptible to dofetilide-induced TdP.METHODS AND RESULTS:In 32 anaesthetized animals, the relevance of ventricular remodelling for TdP susceptibility was studied by dofetilide [0.025 mg/kg/5 min intravenously (iv)] during bradycardia in the presence (CAVB, n= 18) or absence [acute atrio-ventricular block (AVB), n= 32] of ventricular remodelling. In sub-protocols, the possible pro-arrhythmic effects of timing of dofetilide administration: prior to (n= 11), or after creation of AVB (n= 9) and relevance of SLS pacing (n= 17) was investigated during IVR. Dofetilide was also given after AVB when the activation of the ventricles was normal: pacing (1000 ms) from the high septum (n= 7) or abnormal but fixed from the left ventricular apex (n= 5). Torsade de pointes inducibility was defined as reproducible (≥ 3 times) occurrence. In acute AV block (AAVB), dofetilide did not induce TdP spontaneously (0 of 32), whereas TdP was seen in 10 out of 18 serially tested dogs in CAVB (P< 0.001). The other factors: timing of dofetilide (0 of 11 vs. 0 of 9), SLS pacing (0 of 17 vs. 1 of 17), or ventricular activation (0 of 7 vs. 0 of 5) did not increase TdP susceptibility. Beat-to-beat variability of repolarization increased after ventricular remodelling and was highest prior to TdP induction.CONCLUSION:In AAVB dogs, TdP is not spontaneously seen, whereas it is present in CAVB. This implies that ventricular remodelling is a prerequisite for TdP induction in this model.

BACKGROUND Monitoring arrhythmic risk may improve management of patients with implantable cardioverter-defibrillators (ICD) and prevent ICD shocks. Changes in repolarization duration between subsequent beats quantified as short-term variability (STV) is associated with ventricular arrhythmias in several animal models.OBJECTIVE We evaluated STV of QT from right ventricular intracardiac ICD electrograms in patients with structural heart disease and compared its predictive value with the QT variability index (QTVI).METHODS In 233 patients, STV over 60 beats for QT and RR intervals and their ratio was calculated (STVQT, STVRR, STVRatio, respectively). QTVI was derived from mean and SD of QT and heart rate. Follow-up duration was 26 +/- 15 months. Predictive value was determined for sudden arrhythmic death (SAD) defined as sudden cardiac death or fast ventricular tachycardia/fibrillation [CL < 240 ms].RESULTS In univariate analysis, STVRatio, but not STVQT or STVRR, was predictive of SAD. Hazard ratios for highest quartile STVRatio and QTVI were comparable (STVRatio: 1.9, 95% confidence interval [CI] 1.1 to 3.3, P = .038, QTVI: 2.2, 95% CI 1.2 to 3.8, P = .010). In a multivariate model, highest quartile STVRatio was predictive of SAD after adjustment for New York Heart Association class, history of ischemia, ICD indication, and use of class I antiarrhythmics (hazard ratio 1.8, 95% CI 1.0 to 3.4, P < .050). A combined criterion of highest quartile for both STVRatio and QTVI identified patients at highest risk (hazard ratio 2.4, 95% CI 1.3 to 4.3, P = .005, positive predictive value 38%, negative predictive value 82%).CONCLUSION STVRatio from ICD electrograms is predictive of SAD. Predictive value is similar for order-based STVRatio and distribution-based QTVI, but the combination of both parameters can further improve results.

Determining electrical activation of the heart in a noninvasive way is one of the challenges in cardiac electrophysiology. The ECG provides some, but limited information about the electrical status of the heart. This article describes a method to determine both endocardial and epicardial activation of the heart of an individual patient from 64 electrograms recorded from the body surface. Information obtained in this way might be helpful for the treatment of arrhythmias, to assess the effect of drugs on conduction in the heart and to assess electrical stability of the heart.

Background: Drug-induced torsade de pointes (TdP) arrhythmias can readily be induced in anesthetized dogs with remodeled hearts [chronic complete atrioventricular block (CAVB) dogs]. Similar studies in conscious CAVB dogs reveal lower TdP incidences. Regulations forced us to reconsider our anesthetic regimen, which consist of pentobarbital followed by halothane (P + H). We investigated the relevance of anesthesia for this enhanced susceptibility (part 1) and compared 3 anesthetic regimens (part 2).Methods: Part 1-Ten CAVB dogs paced from the high septum at 1000 milliseconds were challenged with dofetilide (25 mu g.kg(-1).5min(-1)) twice: once under anesthesia and once awake. Anesthesia consisted of P + H (n = 5) and thiopental maintained by isoflurane (T + I). Part 2-In CAVB dogs (n = 6) with spontaneous idioventricular rhythm, the electrophysiological and arrhythmogenic consequences of different anesthetic regimens (P + H, T + I, and P + I) were serially compared.Results: Part 1-In paced dogs, dofetilide-induced TdP was higher under anesthetized than in conscious circumstances, with the more severe outcome seen after T + I as compared with P + H or control (23): 5/5, 2/5, 0/5, and 0/5, respectively; P < 0.05. Part 2-Electrophysiologically, T accelerated idioventricular rhythm, increased QTc, and transiently induced polymorphic ventricular tachycardias in 2 of 6 dogs. This was not seen after P. At 120 minutes (end of the preparation), QTc increase was highest after T + I, intermediate with P + I, and the smallest after P + H. Dofetilide in combination with T + I induced the most severe arrhythmogenic outcome.Conclusions: Thiopental anesthesia causes arrhythmias sec, whereas anesthesia in general predisposes for drug-induced TdP in the CAVB dog. In combination with dofetilide, T + I has a more arrhythmic outcome than P + I or P + H.

High‐Rate Pacing Prevents Drug‐Induced Arrhythmias. 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 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. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1384‐1391, December 2010)

Summary of electrophysiological parameters and arrhythmic events in flunarizine suppression and prevention experiments Baseline 1 Dofetilide Flunarizine RR 1181 87 1291 140 1219 251QT 436 44 566 29* 435 36 $ QT C 421 49 553 40* 425 38 $ LV MAPD 355 35 492 53* 367 42 $ RV MAPD 310 32 395 68* 333 30 $ DMAPD 51 28 97 56* 48 32 $ STV LV 1.8 0.5 4.5 1.5* 1.5 0.6 $ TdP 0 011 8* 0 0 $ MEB 0 013 14* 0 0 $ SEB 1 248 58* 1 3 $ Baseline 2 Flunarizine Dofetilide RR 1239 329 1291 390 1410 462QT 422 51 380 50* 494 92* # QT C 413 51 369 41* 476 77* # LV MAPD 299 44 277 36 380 65* # RV MAPD 286 39 275 44 348 73* # DMAPD 42 27 22 16 38 42STV LV 1.5 0.6 1.0 0.5* 1.4 0.5TdP 0 00 00 0MEB 0 10 00 0SEB 3 63 56 10Maximal effects of flunarizine (5 min) in suppression experiments (upper part) and at the end of the infusion (2 min) in preventionexperiments are shown (lower part). Arrhythmias are quantified as average number of events (TdP, MEB, SEB) per 10 min, except for thepretreatment with flunarizine (lower part) where after 5 min dofetilide was added. All electrophysiological parameters are expressed in ms andarrhythmias as average number per time interval.*

Hypertrophy and heart failure are associated with an enhanced propensity for cardiac arrhythmias and a high mortality rate. Altered repolarization might play a role in the occurrence of these ventricular arrhythmias. Beat-to-beat variability of repolarization duration (BVR) has been proposed as a parameter for detection of an unstable, and less controlled repolarization process that precedes the actual tachyarrhythmia. To investigate the relevance of BVR in identifying individuals at risk for arrhythmic events, this parameter was studied in dogs with remodeled hearts and increased susceptibility to arrhythmias due to chronic complete atrioventricular block. Progression of electrical remodeling (prolongation of repolarization times), vulnerability to arrhythmias and sudden cardiac death were reflected in baseline values of BVR. Furthermore, BVR showed a strong predictive value in the screening for pro-arrhythmic effects of drugs. Thus, BVR can be used to identify 1) individuals at risk for ventricular tachycardias and 2) drugs with proarrhythmic properties.

OBJECTIVES:This study was designed to analyze the relevance of ventricular activation patterns for ventricular electrical remodeling after atrioventricular (AV) block in dogs.BACKGROUND:Bradycardia is thought to be the main contributor to ventricular electrical remodeling after complete AV block. However, an altered ventricular activation pattern or AV dyssynchrony may also contribute.METHODS:For 4 weeks, AV block dogs were either paced from the high-ventricular septum near the His bundle at lowest captured rate (n = 9, high-septal pacing [HSP]) or kept at idioventricular rate without controlled activation (n = 14, chronic AV block [CAVB]). Multiple electrocardiographic and electrophysiological parameters were measured under anesthesia at 0 and 4 weeks. Proarrhythmia was tested at 4 weeks by I(Kr) block (25 mug/kg dofetilide intravenous).RESULTS:At 0 weeks, the 2 groups were comparable, whereas after 4 weeks of similar bradycardia, QT duration at unpaced conditions had increased from 300 +/- 5 to 395 +/- 18 ms in CAVB (+32 +/- 6%) and from 307 +/- 8 ms to 357 +/- 11 ms in HSP (+17 +/- 4%; p < 0.05). Frequency dependency of repolarization was less steep in HSP compared to CAVB dogs after 4 weeks remodeling. Beat-to-beat variability of repolarization, a proarrhythmic parameter, increased only in CAVB from 0 to 4 weeks. Torsades de pointes arrhythmias were induced at 4 weeks in 44% HSP versus 78% CAVB dogs (p = 0.17). Cumulative duration of arrhythmias per inducible dog was 87 +/- 36 s in CAVB and 30 +/- 21 s in HSP (p < 0.05).CONCLUSIONS:High-septal pacing reduces the magnitude of ventricular electrical remodeling and proarrhythmia in AV block dogs, suggesting a larger role for altered ventricular activation pattern in the generation of ventricular electrical remodeling than previously assumed.