Directed graph mapping shows rotors maintain non-terminating and focal sources maintain self-terminating Torsade de Pointes in canine model.

Torsade de Pointes is a polymorphic ventricular tachycardia which is as yet incompletely understood. While the onset of a TdP episode is generally accepted to be caused by triggered activity, the mechanisms for the perpetuation is still under debate. In this study, we analysed data from 54 TdP episodes divided over 5 dogs (4 female, 1 male) with chronic atrioventricular block. Previous research on this dataset showed both reentry and triggered activity to perpetuate the arrhythmia. 13 of those TdP episodes showed reentry as part of the driving mechanism of perpetuating the episode. The remaining 41 episodes were purely ectopic. Reentry was the main mechanism in long-lasting episodes (>14 beats), while focal sources were responsible for maintaining shorter episodes. Building on these results, we re-analysed the data using directed graph mapping This program uses principles from network theory and a combination of positional data and local activation times to identify reentry loops and focal sources within the data. The results of this study are twofold. First, concerning reentry loops, we found that on average non-terminating (NT) episodes (≥10 s) show significantly more simultaneous reentry loops than self-terminating (ST) TdP (<10 s). Non-terminating episodes have on average 2.72 ± 1.48 simultaneous loops, compared to an average of 1.33 ± 0.66 for self-terminating episodes. In addition, each NT episode showed a presence of (bi-)ventricular loops between 10.10% and 69.62% of their total reentry duration. Compared to the ST episodes, only 1 in 4 episodes (25%) showed (bi-)ventricular reentry, lasting only 7.12% of its total reentry duration. This suggests that while focal beats trigger TdP, macro-reentry and multiple simultaneous localized reentries are the major drivers of long-lasting episodes. Second, using heatmaps, we found focal sources to occur in preferred locations, instead of being distributed randomly. This may have implications on treatment if such focal origins can be disabled reliably.

Chronically altered ventricular activation causes pro-arrhythmic cardiac electrical remodelling in the chronic AV block dog model.

AIMS: Altered ventricular activation (AVA) causes intraventricular mechanical dyssynchrony (MD) and impedes contraction, promoting pro-arrhythmic electrical remodelling in the chronic atrioventricular block (CAVB) dog. We aimed to study arrhythmogenic and electromechanical outcomes of different degrees of AVA. METHODS AND RESULTS: Following atrioventricular block, AVA was established through idioventricular rhythm (IVR; n = 29), right ventricular apex (RVA; n = 12) pacing or biventricular pacing [cardiac resynchronization therapy (CRT); n = 10]. After ≥3 weeks of bradycardic remodelling, Torsade de Pointes arrhythmia (TdP) inducibility, defined as ≥3 TdP/10 min, was tested with specific IKr-blocker dofetilide (25 µg/kg/5 min). Mechanical dyssynchrony was assessed by echocardiography as time-to-peak (TTP) of left ventricular (LV) free-wall minus septum (ΔTTP). Electrical intraventricular dyssynchrony was assessed as slope of regression line correlating intraventricular LV activation time (AT) and activation recovery interval (ARI). Under sinus rhythm, contraction occurred synchronous (ΔTTP: -8.6 ± 28.9 ms), and latest activated regions seemingly had slightly longer repolarization (AT-ARI slope: -0.4). Acute AV block increased MD in all groups, but following ≥3 weeks of remodelling IVR animals became significantly more TdP inducible (19/29 IVR vs. 5/12 RVA and 2/10 CRT, both P < 0.05 vs. IVR). After chronic AVA, intraventricular MD was lowest in CRT animals (ΔTTP: -8.5 ± 31.2 vs. 55.80 ± 20.0 and 82.7 ± 106.2 ms in CRT, IVR, and RVA, respectively, P < 0.05 RVA vs. CRT). Although dofetilide steepened negative AT-ARI slope in all groups, this heterogeneity in dofetilide-induced ARI prolongation seemed least pronounced in CRT animals (slope to -0.8, -3.2 and -4.5 in CRT, IVR and RVA, respectively). CONCLUSION: Severity of intraventricular MD affects the extent of electrical remodelling and pro-arrhythmic outcome in the CAVB dog model.

Interplay between temporal and spatial dispersion of repolarization in the initiation and perpetuation of torsades de pointes in the chronic atrioventricular block dog.

Ventricular arrhythmias, consisting of single ectopic beats (sEB), multiple EB (mEB), and torsades de pointes (TdP, defined as ≥5 beats with QRS vector twisting around isoelectric line) can be induced in the anesthetized chronic atrioventricular block (CAVB) dog by dofetilide (IKr blocker). The interplay between temporal dispersion of repolarization, quantified as short-term variability (STV), and spatial dispersion of repolarization (SDR) in the initiation and perpetuation of these arrhythmias remains unclear. Five inducible (≥3 TdPs/10 min) CAVB dogs underwent one mapping experiment and were observed for 10 min from the start of dofetilide infusion (0.025 mg/kg, 5 min). An intracardiac decapolar electrogram (EGM) catheter and 30 intramural cardiac needles in the left ventricle (LV) were introduced. STVARI was derived from 31 consecutive activation recovery intervals (ARIs) on the intracardiac EGM, using the formula: [Formula: see text]. The mean SDR3D in the LV was determined as the three-dimensional repolarization time differences between the intramural cardiac needles. Moments of measurement included baseline (BL) and after dofetilide infusion before first 1) sEB (occurrence at 100 ± 35 s), 2) mEB (224 ± 96 s), and 3) non-self-terminating TdP (454 ± 298 s). STVARI increased from 2.15 ± 0.32 ms at BL to 3.73 ± 0.99 ms* before the first sEB and remained increased without further significant progression to mEB (4.41 ± 0.45 ms*) and TdP (5.07 ± 0.84 ms*) (*P < 0.05 compared with BL). SDR3D did not change from 31 ± 11 ms at BL to 43 ± 13 ms before sEB but increased significantly before mEB (68 ± 7 ms*) and to TdP (86 ± 9 ms*+) (+P < 0.05 compared with sEB). An increase in STV contributes to the initiation of sEB, whereas an increase in SDR is important for the perpetuation of non-self-terminating TdPs.NEW & NOTEWORTHY This study compared two well-established electrophysiological parameters, being temporal and spatial dispersion of repolarization, and provided new insights into their interplay in the arrhythmogenesis of torsades de pointes arrhythmias. Although it confirmed that an increase in temporal dispersion of repolarization contributes to the initiation of single ectopic beats, it showed that an increase in spatial dispersion of repolarization is important for the perpetuation of non-self-terminating torsades de pointes arrhythmias.

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

INTRODUCTION: Torsade de pointes arrhythmias (TdP) in the chronic atrioventricular block (CAVB) dog model result from proarrhythmic factors, which trigger TdP and/or reinforce the arrhythmic substrate. This study investigated electrophysiological and arrhythmogenic consequences of severe bradycardia for TdP. METHODS: Dofetilide (25 µg/kg per 5 min) was administered to eight anesthetized, idioventricular rhythm (IVR) remodeled CAVB dogs in two serial experiments: once under 60 beats per minute (bpm), right ventricular apex paced (RVA60) conditions, once under more bradycardic IVR conditions. Recordings included surface electrocardiogram and short-term variability (STV) of repolarization from endocardial unipolar electrograms. TdP inducibility (three or more episodes within 10 min after start of dofetilide) and arrhythmic activity scores (AS) were established. Mapping experiments in 10 additional dogs determined the effect of lowering rate on STV and spatial dispersion of repolarization (SDR) in baseline. RESULTS: IVR-tested animals had longer baseline RR-interval (1,403 ± 271 ms) and repolarization intervals than RVA60 animals. Dofetilide increased STV similarly under both rhythm strategies. Nevertheless, TdP inducibility and AS were higher under IVR conditions (6/8 and 37 ± 27 vs. 1/8 and 8 ± 12 in RVA60, respectively, both p < 0.05). Mapping: Pacing from high (128 ± 10 bpm) to middle (88 ± 10 bpm) to experimental rate (61 ± 3 bpm) increased all electrophysiological parameters, including interventricular dispersion, due to steeper left ventricular restitution curves, and intraventricular SDR: maximal cubic dispersion from 60 ± 14 (high) to 69 ± 17 (middle) to 84 ± 22 ms (p < 0.05 vs. high and middle rate). CONCLUSION: In CAVB dogs, severe bradycardia increases the probability and severity of arrhythmic events by heterogeneously causing electrophysiological instability, which is mainly reflected in an increased spatial, and to a lesser extent temporal, dispersion of repolarization.

Evaluation of a Fully Automatic Measurement of Short-Term Variability of Repolarization on Intracardiac Electrograms in the Chronic Atrioventricular Block Dog.

Background: Short-term variability (STV) of repolarization of the monophasic action potential duration (MAPD) or activation recovery interval (ARI) on the intracardiac electrogram (EGM) increases abruptly prior to the occurrence of ventricular arrhythmias in the chronic AV-block (CAVB) dog model. Therefore, this parameter might be suitable for continuous monitoring of imminent arrhythmias using the EGM stored on an implanted device. However, 24/7 monitoring would require automatic STVARI measurement by the device. Objective: To evaluate a newly developed automatic measurement of STVARI for prediction of dofetilide-induced torsade de pointes (TdP) arrhythmias in the CAVB-dog. Methods: Two retrospective analyses were done on data from recently performed dog experiments. (1) In seven anesthetized CAVB-dogs, the new automatic STVARI method was compared with the gold standard STVMAPD at baseline and after dofetilide administration (0.025 mg/kg in 5 min). (2) The predictive value of the automatic method was compared to currently used STVARI methods, i.e., slope method and fiducial segment averaging (FSA) method, in 11 inducible (≥3 TdP arrhythmias) and 10 non-inducible CAVB-dogs. Results: (1) The automatic measurement of STVARI had good correlation with STVMAPD (r 2 = 0.89; p < 0.001). Bland-Altman analysis showed a small bias of 0.06 ms with limits of agreement between -0.63 and 0.76 ms. (2) STVARI of all three methods was significantly different between inducible and non-inducible dogs after dofetilide. The automatic method showed the highest predictive performance with an area under the ROC-curve of 0.93, compared to 0.85 and 0.87 of the slope and FSA methods, respectively. With a threshold of STV set at 1.69 ms, STVARI measured with the automatic method had a sensitivity of 0.91 and specificity of 0.90 in differentiating inducible from non-inducible subjects. Conclusion: We developed a fully-automatic method for measurement of STVARI on the intracardiac EGM that can accurately predict the occurrence of ventricular arrhythmias in the CAVB-dog. Future integration of this method into implantable devices could provide the opportunity for 24/7 monitoring of arrhythmic risk.

Repeating noninvasive risk stratification improves prediction of outcome in ICD patients.

BACKGROUND: Noninvasive risk stratification aims to detect abnormalities in the pathophysiological mechanisms underlying ventricular arrhythmias. We studied the predictive value of repeating risk stratification in patients with an implantable cardioverter-defibrillator (ICD). METHODS: The EUTrigTreat clinical study was a prospective multicenter trial including ischemic and nonischemic cardiomyopathies and arrhythmogenic heart disease. Left ventricular ejection fraction ≤40% (LVEF), premature ventricular complexes >400/24 hr (PVC), non-negative microvolt T-wave alternans (MTWA), and abnormal heart rate turbulence (HRT) were considered high risk. Tests were repeated within 12 months after inclusion. Adjusted Cox regression analysis was performed for mortality and appropriate ICD shocks. RESULTS: In total, 635 patients had analyzable baseline data with a median follow-up of 4.4 years. Worsening of LVEF was associated with increased mortality (HR 3.59, 95% CI 1.17-11.04), as was consistent abnormal HRT (HR 8.34, 95%CI 1.06-65.54). HRT improvement was associated with improved survival when compared to consistent abnormal HRT (HR 0.10, 95%CI 0.01-0.82). For appropriate ICD shocks, a non-negative MTWA test or high PVC count at any moment was associated with increased arrhythmic risk independent of the evolution of test results (worsening: HR 3.76 (95%CI 1.43-9.88) and HR 2.50 (95%CI 1.15-5.46); improvement: HR 2.80 (95%CI 1.03-7.61) and HR 2.45 (95%CI 1.07-5.62); consistent: HR 2.47 (95%CI 0.95-6.45) and HR 2.40 (95%CI 1.33-4.33), respectively). LVEF improvement was associated with a lower arrhythmic risk (HR 0.34, 95%CI 0.12-0.94). CONCLUSIONS: Repeating LVEF and HRT improved the prediction of mortality, whereas stratification of ventricular arrhythmias may be improved by repeating LVEF measurements, MTWA and ECG Holter monitoring.

Pro-Arrhythmic Ventricular Remodeling Is Associated With Increased Respiratory and Low-Frequency Oscillations of Monophasic Action Potential Duration in the Chronic Atrioventricular Block Dog Model.

In addition to beat-to-beat fluctuations, action potential duration (APD) oscillates at (1) a respiratory frequency and (2) a low frequency (LF) (<0.1 Hz), probably caused by bursts of sympathetic nervous system discharge. This study investigates whether ventricular remodeling in the chronic AV block (CAVB) dog alters these oscillations of APD and whether this has consequences for arrhythmogenesis. We performed a retrospective analysis of 39 dog experiments in sinus rhythm (SR), acute AV block (AAVB), and after 2 weeks of chronic AV block. Spectral analysis of left ventricular monophasic action potential duration (LV MAPD) was done to quantify respiratory frequency (RF) power and LF power. Dofetilide (0.025 mg/kg in 5 min) was infused to test for inducibility of Torsade de Pointes (TdP) arrhythmias. RF power was significantly increased at CAVB compared to AAVB and SR (log[RF] of -1.13 ± 1.62 at CAVB vs. log[RF] of -2.82 ± 1.24 and -3.29 ± 1.29 at SR and AAVB, respectively, p < 0.001). LF power was already significantly increased at AAVB and increased even further at CAVB (-3.91 ± 0.70 at SR vs. -2.52 ± 0.85 at AAVB and -1.14 ± 1.62 at CAVB, p < 0.001). In addition, LF power was significantly larger in inducible CAVB dogs (log[LF] -0.6 ± 1.54 in inducible dogs vs. -2.56 ± 0.43 in non-inducible dogs, p < 0.001). In conclusion, ventricular remodeling in the CAVB dog results in augmentation of respiratory and low-frequency (LF) oscillations of LV MAPD. Furthermore, TdP-inducible CAVB dogs show increased LF power.

Data on differential multivariable risk prediction of appropriate shock vs. competing mortality.

This data article features supplementary figures and tables related to the article "Differential Multivariable risk prediction of appropriate shock vs. competing mortality - a prospective cohort study to estimate benefits from implantable cardioverter defibrillator therapy" (Bergau et al., 2018) [1]. The figures show the clinical study CONSORT graph (data that show the number of patients not-analyzable as well as a distribution of patients by outcomes) and the correlation scatter plot for risk scores of appropriate shock vs. mortality (data that show the calculated score values of the two scores plotted against each other). The tables show the results for the univariate Cox regressions for prediction of mortality and appropriate shock. For further information, please see Bergau et al. (2018) [1].

Differential multivariable risk prediction of appropriate shock versus competing mortality - A prospective cohort study to estimate benefits from ICD therapy.

BACKGROUND AND OBJECTIVE: We prospectively investigated combinations of risk stratifiers including multiple EP diagnostics in a cohort study of ICD patients. METHODS: For 672 enrolled patients, we collected history, LVEF, EP study and T-wave alternans testing, 24-h Holter, NT-proBNP, and the eGFR. All-cause mortality and first appropriate ICD shock were predefined endpoints. RESULTS: The 635 patients included in the final analyses were 63 ±â€¯13 years old, 81% were male, LVEF averaged 40 ±â€¯14%, 20% were inducible at EP study, 63% had a primary prophylactic ICD. During follow-up over 4.3 ±â€¯1.5 years, 108 patients died (4.0% per year), and appropriate shock therapy occurred in n = 96 (3.9% per year). In multivariate regression, age (p < 0.001), LVEF (p < 0.001), NYHA functional class (p = 0.007), eGFR (p = 0.024), a history of atrial fibrillation (p = 0.011), and NT-pro-BNP (p = 0.002) were predictors of mortality. LVEF (p = 0.002), inducibility at EP study (p = 0.007), and secondary prophylaxis (p = 0.002) were identified as independent predictors of appropriate shocks. A high annualized risk of shocks of about 10% per year was prevalent in the upper quintile of the shock score. In contrast, a low annual risk of shocks (1.8% per year) was found in the lower two quintiles of the shock score. The lower two quintiles of the mortality score featured an annual mortality <0.6%. CONCLUSIONS: In a prospective ICD patient cohort, a very good approximation of mortality versus arrhythmic risk was possible using a multivariable diagnostic strategy. EP stimulation is the best test to assess risk of arrhythmias resulting in ICD shocks.

Selective late sodium current inhibitor GS-458967 suppresses Torsades de Pointes by mostly affecting perpetuation but not initiation of the arrhythmia.

BACKGROUND AND PURPOSE: Enhanced late sodium current (late INa ) in heart failure and long QT syndrome type 3 is proarrhythmic. This study investigated the antiarrhythmic effect and mode of action of the selective and potent late INa inhibitor GS-458967 (GS967) against Torsades de Pointes arrhythmias (TdP) in the chronic atrioventricular block (CAVB) dog. EXPERIMENTAL APPROACH: Electrophysiological and antiarrhythmic effects of GS967 were evaluated in isolated canine ventricular cardiomyocytes and CAVB dogs with dofetilide-induced early afterdepolarizations (EADs) and TdP, respectively. Mapping of intramural cardiac electrical activity in vivo was conducted to study effects of GS967 on spatial dispersion of repolarization. KEY RESULTS: GS967 (IC50 ~200nM) significantly shortened repolarization in canine ventricular cardiomyocytes and sinus rhythm (SR) dogs, in a concentration and dose-dependent manner. In vitro, despite addition of 1µM GS967, dofetilide-induced EADs remained present in 42% and 35% of cardiomyocytes from SR and CAVB dogs, respectively. Nonetheless, GS967 (787±265nM) completely abolished dofetilide-induced TdP in CAVB dogs (10/14 after dofetilide to 0/14 dogs after GS967), while single ectopic beats (sEB) persisted in 9 animals. In vivo mapping experiments showed that GS967 significantly reduced spatial dispersion of repolarization: cubic dispersion was significantly decreased from 237±54ms after dofetilide to 123±34ms after GS967. CONCLUSION AND IMPLICATIONS: GS967 terminated all dofetilide-induced TdP without completely suppressing EADs and sEB in vitro and in vivo, respectively. The antiarrhythmic mode of action of GS967, through the reduction of spatial dispersion of repolarization, seems to predominantly impede the perpetuation of arrhythmic events into TdP rather than their initiating trigger.

Beat-to-beat variations in activation-recovery interval derived from the right ventricular electrogram can monitor arrhythmic risk under anesthetic and awake conditions in the canine chronic atrioventricular block model.

BACKGROUND: In the chronic atrioventricular block (CAVB) dog model, beat-to-beat variation of repolarization in the left ventricle (LV) quantified as short-term variability of the left monophasic action potential duration (STVLVMAPD) increases abruptly upon challenge with a proarrhythmic drug. This increase occurs before the first ectopic beat (EB), specifically in subjects who demonstrate subsequent repetitive torsades de pointes arrhythmias (TdP). OBJECTIVE: The purpose of this study was to demonstrate that STV is feasible to monitor arrhythmic risk through use of the intracardiac electrogram (EGM) derived from the right ventricular (RV) lead from pacemakers or implantable cardioverter-defibrillators. METHODS: In 30 anaesthetized, inducible (≥3 TdP) CAVB dogs, STV between LV and RV monophasic action potential duration (STVLVMAPD and STVRVMAPD) was compared. In prospectively enrolled CAVB dogs, STV of the activation-recovery interval (ARI) derived from the RV EGM (STVRVARI) was measured before and after a challenge with dofetilide under anesthesia (2a; n = 10) and cisapride under awake conditions (2b; n = 8). RESULTS: Both STVLVMAPD and STVRVMAPD increased before the first EB (1.29 ± 0.58 ms to 3.05 ± 1.70 ms and 1.11 ± 0.53 ms to 2.18 ± 1.43 ms, respectively; P = 0.001). STVRVARI increased from 2.82 ± 0.33 ms to 3.77 ± 0.69 ms (P = .001). Inducible subjects (4/8) showed an increase in STVRVARI from 2.65 ± 0.55 ms to 3.45 ± 0.33 ms (in the first hour; P = .02) and 4.20 ± 1.33 ms (before the first EB; P = .04). CONCLUSION: Behavior of STV from the RV and LV is comparable. STVRVARI increases significantly before the occurrence of an arrhythmia in awake and anaesthetized conditions. This finding can be integrated into devices to monitor arrhythmic risk.

Torsade de pointes arrhythmias arise at the site of maximal heterogeneity of repolarization in the chronic complete atrioventricular block dog.

AIMS: The chronic complete atrioventricular block (CAVB) dog is highly sensitive for drug-induced torsade de pointes (TdP) arrhythmias. Focal mechanisms have been suggested as trigger for TdP onset; however, its exact mechanism remains unclear. In this study, detailed mapping of the ventricles was performed to assess intraventricular heterogeneity of repolarization in relation to the initiation of TdP. METHODS AND RESULTS: In 8 CAVB animals, 56 needles, each containing 4 electrodes, were inserted in the ventricles. During right ventricular apex pacing (cycle length: 1000-1500 ms), local unipolar electrograms were recorded before and after administration of dofetilide to determine activation and repolarization times (RTs). Maximal RT differences were calculated in the left ventricle (LV) within adjacent electrodes in different orientations (transmural, vertical, and horizontal) and within a square of four needles (cubic dispersion). Dofetilide induced TdP in five out of eight animals. Right ventricle-LV was similar between inducible and non-inducible dogs at baseline (327 ± 30 vs. 345 ± 17 ms) and after dofetilide administration (525 ± 95 vs. 508 ± 15 ms). All measurements of intraventricular dispersion were not different at baseline, but this changed for horizontal (206 ± 20 vs. 142 ± 34 ms) and cubic dispersion (272 ± 29 vs. 176 ± 48 ms) after dofetilide: significantly higher values in inducible animals. Single ectopic beats and the first TdP beat arose consistently from a subendocardially located electrode terminal with the shortest RT in the region with largest RT differences. CONCLUSION: Chronic complete atrioventricular block dogs susceptible for TdP demonstrate higher RT differences. Torsade de pointes arises from a region with maximal heterogeneity of repolarization suggesting that a minimal gradient is required in order to initiate TdP.

Electrophysiological measurements that can explain and guide temporary accelerated pacing to avert (re)occurrence of torsade de pointes arrhythmias in the canine chronic atrioventricular block model.

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.

Short-Lasting Episodes of Torsade de Pointes in the Chronic Atrioventricular Block Dog Model Have a Focal Mechanism, While Longer-Lasting Episodes Are Maintained by Re-Entry.

OBJECTIVES: This study investigated the arrhythmogenic mechanisms responsible for torsade de pointes (TdP) in the chronic atrioventricular block dog model, known for its high susceptibility for TdP. BACKGROUND: The mechanism of TdP arrhythmias has been under debate for many years. Focal activity as well as re-entry have both been mentioned in the initiation and the perpetuation of TdP. METHODS: In 5 TdP-sensitive chronic atrioventricular block dogs, 56 needle electrodes were evenly distributed transmurally to record 240 unipolar local electrograms simultaneously. Nonterminating (NT) episodes were defibrillated after 10 s. Software was developed to automatically detect activation times and to create 3-dimensional visualizations of the arrhythmia. For each episode of ectopic activity (ranging from 2 beats to NT episodes), a novel methodology was created to construct directed graphs of the wave propagation and detect re-entry loops by using an iterative depth-first-search algorithm. RESULTS: Depending on the TdP definition (number of consecutive ectopic beats), we analyzed 29 to 54 TdP: 29 were longer than 5 beats. In the total group, 9 were NT and 45 were self-terminating. Initiation and termination were always based on focal activity. Re-entry becomes more important in the longer-lasting episodes (>14 beats), whereas in all NT TdP, re-entry was the last active mechanism. During re-entry, excitation fronts were constantly present in the heart, while during focal TdP, there was always a silent interval between 2 consecutive waves (142 ms) during which excitation fronts were absent. Interbeat intervals were significantly smaller for re-entry episodes-220 versus 310 ms in focal. Electrograms recorded in particular areas during NT TdP episodes had significantly smaller amplitude (0.38) than during focal episodes (0.59). CONCLUSIONS: TdP can be driven by focal activity as well as by re-entry depending on the duration of the episode. NT episodes are always maintained by re-entry, which can be identified in local unipolar electrograms by shorter interbeat intervals and smaller deflection amplitude.

Beat-to-Beat Variability in Preload Unmasks Latent Risk of Torsade de Pointes in Anesthetized Chronic Atrioventricular Block Dogs.

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±0.14 ms 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±0.8 ms vs. +0.9±0.9 ms, P=0.058). In the second group, the increase in baseline BVR by alternating preload (0.3±0.03 ms to 1.0±0.8 ms, P<0.01) was abolished by streptomycin (0.5±0.2 ms, 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. (Circ J 2016; 80: 1336-1345).

Ventricular remodelling is a prerequisite for the induction of dofetilide-induced torsade de pointes arrhythmias in the anaesthetized, complete atrio-ventricular-block dog.

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.

Anesthesia and arrhythmogenesis in the chronic atrioventricular block dog model.

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 microg x kg(-1) x 5 min(-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 (2x): 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.