Chronic Atrioventricular Block Research Articles

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.

Electropharmacological Characterization of Licorice Using the Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Sheets and the Chronic Atrioventricular Block Dogs.

Licorice has been traditionally prescribed for palpitation, whereas its overdose has caused lethal arrhythmias including torsade de pointes. Licorice contains glycyrrhizic acid of ≥ 2% (w/w), which is hydrolyzed to glycyrrhetinic acid (GRA) in the intestine. Since their cardiac electropharmacological properties are not fully understood, we assessed them to ask mechanism of licorice-induced torsade de pointes. GRA at 0.1, 1 and 10μg/mL was cumulatively applied to the human induced pluripotent stem cell-derived cardiomyocytes sheets (n = 6). GRA shortened spontaneous activation interval and repolarization period, and decreased maximum contraction velocity, indicating Ca2+ channel blockade. It prolonged effective refractory period and post-repolarization refractoriness with a steep frequency-dependency, whereas it delayed conduction with a modest use-dependency, resembling lidocaine in the mode of Na+ channel-blocking action. Meanwhile, Kanzoto containing a decoction of licorice alone in a dose of 2 or 6g/body/day was orally administered to the conscious chronic atrioventricular block dogs for 3days (n = 4). Kanzoto prolonged QT interval with increasing its temporal dispersion, suggesting K+ channel suppression, and slightly decreased the plasma K+ concentration without inducing torsade de pointes. Moreover, it significantly suppressed atrial and idioventricular rates, leading to sinus arrest along with the onset of ventricular fibrillation in one animal, possibly due to Na+ channel blockade. These results indicate that electropharmacological profile of licorice can be explained by Na+, Ca2+ and K+ channels blockade, which may be associated with low torsadogenic risk, but might contribute to the onset of other types of lethal ventricular arrhythmias.

IKs Activator ML277 Mildly Affects Repolarization and Arrhythmic Outcome in the CAVB Dog Model

Long QT syndrome type 1 with affected IKs is associated with a high risk for developing Torsade de Pointes (TdP) arrhythmias and eventually sudden cardiac death. Therefore, it is of high interest to explore drugs that target IKs as antiarrhythmics. We examined the antiarrhythmic effect of IKs channel activator ML277 in the chronic atrioventricular block (CAVB) dog model. TdP arrhythmia sensitivity was tested in anesthetized mongrel dogs (n = 7) with CAVB in series: (1) induction experiment at 4 ± 2 weeks CAVB: TdP arrhythmias were induced with our standardized protocol using dofetilide (0.025 mg/kg), and (2) prevention experiment at 10 ± 2 weeks CAVB: the antiarrhythmic effect of ML277 (0.6-1.0 mg/kg) was tested by infusion for 5 min preceding dofetilide. ML277: (1) temporarily prevented repolarization prolongation induced by dofetilide (QTc: 538 ± 65 ms at induction vs. 393 ± 18 ms at prevention, p < 0.05), (2) delayed the occurrence of the first arrhythmic event upon dofetilide (from 129 ± 28 s to 180 ± 51 s, p < 0.05), and (3) decreased the arrhythmic outcome with a significant reduction in the number of TdP arrhythmias, TdP score, arrhythmia score and total arrhythmic events (from 669 ± 132 to 401 ± 228, p < 0.05). IKs channel activation by ML277 temporarily suppressed QT interval prolongation, delayed the occurrence of the first arrhythmic event and reduced the arrhythmic outcome in the CAVB dog model.

Characterization of pathological remodeling in the chronic atrioventricular block cynomolgus monkey heart.

We studied time course of pathological remodeling occurring in the cynomolgus monkey hearts against persistent atrioventricular block condition (n = 10). The atrioventricular block induced the ventricular and atrial dilation followed by the ventricular hypertrophy. Interstitial fibrosis in the ventricle was also observed along with gradual increases in the plasma angiotensin II and aldosterone concentrations. These adaptations were associated with the changes in gene expression profiling reflecting fibrosis and hypertrophy. Atrioventricular block reduced the ventricular rate and cardiac output, but the ejection fraction and stroke volume increased, whereas the cardiac output was gradually restored to its basal level. Systolic/diastolic blood pressure after the atrioventricular block was kept equal to or lower than that before the block, according with lack of increase in the plasma catecholamine levels. Chronic atrioventricular block gradually prolonged the QRS width and JT interval, leading to the QT interval prolongation in conscious state. 10mg/kg of dl-sotalol hydrochloride induced torsade de pointes (TdP) in 6 out of 10 animals by 15months. Animals showing longer QTcF under anesthesia after the atrioventricular block developed dl-sotalol-induced TdP earlier. No marked difference was observed in pharmacokinetics of dl-sotalol between 1 and 7months after the atrioventricular block. Each TdP spontaneously terminated, reflecting a monkey's relatively small "effective size of the heart (=∛(left ventricular weight)/wavelength of reentry)". These fundamental knowledge will help better utilize the chronic atrioventricular block monkeys as an in vivo proarrhythmia model for detecting drug-induced TdP.

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

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. 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). Severity of intraventricular MD affects the extent of electrical remodelling and pro-arrhythmic outcome in the CAVB dog model.

Validation of Risk-Stratification Method for the Chronic Atrioventricular Block Cynomolgus Monkey Model and Its Mechanistic Interpretation Using 6 Drugs With Pharmacologically Distinct Profile.

Validation of risk-stratification method for the chronic atrioventricular block cynomolgus monkey model and its mechanistic interpretation was performed using 6 pharmacologically distinct drugs. The following drugs were orally administered in conscious state, astemizole: 1, 5, and 10 mg/kg (n = 6); haloperidol: 1, 10, and 30 mg/kg (n = 5); amiodarone: 30 mg/kg (n = 4); famotidine: 10 mg/kg (n = 4); levofloxacin: 100 mg/kg (n = 4); and tolterodine: 0.2, 1, and 4.5 mg/kg (n = 4). Astemizole of 5 and 10 mg/kg significantly prolonged ΔΔQTcF, whereas no significant change was observed by the others. Torsade de pointes (TdP) was induced by astemizole of 5 and 10 mg/kg in 3/6 and 6/6, and by haloperidol of 10 and 30 mg/kg in 1/5 and 1/5, respectively, which was not observed in the others. Torsadogenic risk of the drugs was quantified using the criteria for the monkey model specified in our previous study. Namely, high-risk drugs induced TdP at ≤ 3 times of their maximum clinical daily dose. Intermediate-risk drugs did not induce TdP at this dose range, but induced it at higher doses. Low/no-risk drugs never induced TdP at any dose tested. The magnitude of risk was intermediate for astemizole and haloperidol, and low/no risk for the others. The prespecified, risk-stratification method for the monkey model may solve the issue existing between nonclinical models and patients with labile repolarization, which can reinforce the regulatory decision-making and labeling at time of marketing application of nondouble-negative drug candidate (hERG assay positive and/or in vivo QT study positive).

Dg-mapping as a tool to determine the spatial distribution of the focal sources and the number of reentries during torsade de pointes in the cavb dog model

Abstract Funding Acknowledgements Type of funding sources: None. Background Torsade de Pointes (TdP) is a ventricular tachycardia that is still incompletely understood. While the origin of the arrhythmia is generally accepted to be caused by triggered activity, the perpetuation of such an episode is still under debate. Purpose We compare the difference in reentrant activity between self- and non-terminating(ST and NT) TdP episodes. In addition, we analyzed the distribution of the triggered activity for preferred locations. Methods A total of 5 dogs with Chronic Atrioventricular Block developed 54 episodes of TdP. These episodes were examined for reentry loops and focal sources. First, to detect loops, we used Directed Graph Mapping, a novel mapping technique based on principles from network theory. Subsequently, the number of simultaneous loops and the presence of (bi-)ventricular reentry was compared between the ST and NT groups. Second, focal sources were accumulated into heatmaps. The distribution of sources was compared to a randomly distributed model for the detection of preferred locations. Results Concerning reentry, during the time at which loops are present, a typical ST episode shows an average of 1.33(±0.66) reentry loops present at one time compared to an average of 2.72(±1.48) for a typical NT episode. Looking at the (bi-)ventricular reentry, only 1 of the 4 ST episodes (25%) shows the presence of this type of reentry and only 7.12 % of the total reentry duration, while all 9 NT episodes (100%) develop (bi-)ventricular reentry to a greater degree than in the one ST episode (Between 10.10% and 69.62% of their total reentry duration). Regarding the triggered activity, we see locations in the heatmaps containing up to 23% of all detected focal sources in the entire system. Compared to a random distribution of focal sources, the chances to get as many sources in one location as shown in the data are close to 0%. Conclusion Reentry in NT TdP differentiates itself from the reentry in ST cases on the basis of the number of simultaneous loops in the system and the presence of (bi-)ventricular reentry. Triggered activity in CAVB dogs occurs at preferred locations in the ventricles. Therefore, ablating these preferred regions could be a possible strategy to prevent TdP.

Electropharmacological analyses of licorice using the human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) sheets and the chronic atrioventricular block dogs

Electropharmacological analyses of licorice using the human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) sheets and the chronic atrioventricular block dogs

TASK-1阻害薬doxapramの電気薬理学的作用および抗心房細動作用の解析：イソフルラン麻酔正常犬および慢性房室ブロック犬での検討

TASK-1阻害薬doxapramの電気薬理学的作用および抗心房細動作用の解析：イソフルラン麻酔正常犬および慢性房室ブロック犬での検討

Simultaneous analyses of hemodynamic and electrophysiological effects of oseltamivir along with its pharmacokinetic profile using the canine paroxysmal atrial fibrillation model

Since information of antiviral drug oseltamivir on the anti-atrial fibrillation (AF) property is still limited, we assessed it using the canine paroxysmal AF model. Oseltamivir in doses of 3 and 30 mg/kg/10 min was intravenously infused to the isoflurane-anesthetized, chronic atrioventricular block dogs (n = 6) with monitoring hemodynamic and electrophysiological variables, in which AF was induced by 10 s of burst pacing on atrial septum. Oseltamivir decreased AF incidence and AF duration, and prolonged AF cycle length in a dose-dependent manner. The low and high doses attained the peak plasma drug concentrations of 9.7 and 96.5 μg/mL, which were approximately 100 and 1000 times greater than those observed in human clinical cases, respectively. The low dose of oseltamivir decreased mean blood pressure without altering sinoatrial or idioventricular rate, whereas its high dose reduced each of them. Oseltamivir delayed inter-atrial conduction in dose- and frequency-dependent manners, whereas it prolonged atrial effective refractory period in dose-dependent but frequency-independent manners. The high dose prolonged ventricular effective refractory period, which was not detected with the low dose. These findings can be used for repurposing oseltamivir as an anti-AF drug candidate.

Etiology of chronic atrioventricular block in young adults in a public university hospital in India

In young adults, chronic atrioventricular (AV) block has scant systematic documentation in India. This prospective study included patients 18–40 years old, presenting with AV block without a reversible cause. There were 27 patients, aged 32 +/- 6.3 years, with 16 males. All patients had complete AV block with a narrow QRS escape rhythm (rate 40.5 ± 6.5 beats/min). Three patients were ANA positive and of these, 2 patients were anti ds DNA positive. The ESR and CRP levels were mildly elevated in 12 and 8 patients respectively. The rest of the tests were unremarkable. Despite performing multiple tests, the etiology remained idiopathic in most.

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.

Short-term variability of repolarization is equally modulated by atrial and (bi)ventricular high rate pacing in patients with an indication for an implantable cardioverter defibrillator

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Dutch Heart Foundation Background An increase in temporal dispersion of repolarization, quantified as short-term variability of the QT-interval (STV-QT), precedes ventricular arrhythmias and has therefore been proposed as a marker for monitoring of imminent arrhythmic risk. A reversal of an increased STV by high rate pacing at 100 bpm was anti-arrhythmic in the chronic atrioventricular block dog model susceptible to Torsade de Pointes arrhythmias upon challenge with an IKr-blocker. The objective of the current study was to investigate the physiological modulation of STV by pacing in patients with an indication for an implantable cardioverter defibrillator (ICD), and to compare atrial and ventricular pacing. Methods ECG recordings were obtained with a sampling frequency of 1200 Hz in 10 dual chamber ICD patients and 10 patients with cardiac resynchronization therapy with defibrillation function (CRT-D) during the implantation or replacement. One-minute recordings were made during sinus rhythm (SR), and during pacing at 80 and 100 beats per minute (bpm) from the atrium (AAI), atrium and right ventricle (DDD RVp), and during atrio-biventricular pacing (DDD BiVp). The QT-interval was determined offline with fiducial segment averaging at one minute of each pacing rate, and 31 consecutive beats were used to calculate STV-QT with the following formula: ∑|D(n + 1)-Dn |/(N×√2), where D represents the determinant of repolarization (in this case the QT interval), and N represents the number of beats taken into account minus 1. Results In the patients overall, STV-QT decreased from 1.27 ± 0.38 ms in SR (±58 bpm) to 0.86 ± 0.26 ms* during AAI80, and to 0.68 ± 0.22 ms*† during AAI100 (*p &amp;lt; 0.05 compared to SR, †p &amp;lt; 0.05 compared to 80 bpm). The same decrease was seen during DDD80 RVp (0.81 ± 0.28 ms*) and during DDD100 RVp (0.66 ± 0.22 ms*†) (fig. 1). Additionally, DDD BiVp decreased STV-QT to 0.78 ± 0.20 ms* at 80 bpm and to 0.62 ± 0.19 ms* at 100 bpm in CRT-D patients (fig. 2). Conclusion Pacing at 80 and 100 bpm decreases STV-QT compared to sinus rhythm both in dual chamber ICD patients and CRT-D patients. The modulation of STV-QT is similar during atrial, and atrio- right ventricular and atrio-biventricular pacing. Abstract Figure. Modulation of STV-QT by AAI and DDD RVp

The canine chronic atrioventricular block model in cardiovascular preclinical drug research.

Ventricular cardiac arrhythmia is a life threating condition arising from abnormal functioning of many factors in concert. Animal models mirroring human electrophysiology are essential to predict and understand the rare pro‐ and anti‐arrhythmic effects of drugs. This is very well accomplished by the canine chronic atrioventricular block (CAVB) model. Here we summarize canine models for cardiovascular research, and describe the development of the CAVB model from its beginning. Understanding of the structural, contractile and electrical remodelling processes following atrioventricular (AV) block provides insight in the many factors contributing to drug‐induced arrhythmia. We also review all safety pharmacology studies, efficacy and mechanistic studies on anti‐arrhythmic drugs in CAVB dogs. Finally, we compare pros and cons with other in vivo preclinical animal models. In view of the tremendous amount of data obtained over the last 100 years from the CAVB dog model, it can be considered as man's best friend in preclinical drug research.LINKED ARTICLESThis article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc

Translational Studies on Anti-Atrial Fibrillatory Action of Oseltamivir by its in vivo and in vitro Electropharmacological Analyses.

Oseltamivir has been shown to prolong the atrial conduction time and effective refractory period, and to suppress the onset of burst pacing-induced atrial fibrillation in vitro. To better predict its potential clinical benefit as an anti-atrial fibrillatory drug, we performed translational studies by assessing in vivo anti-atrial fibrillatory effect along with in vivo and in vitro electropharmacological analyses. Oseltamivir in intravenous doses of 3 (n = 6) and 30 mg/kg (n = 7) was administered in conscious state to the persistent atrial fibrillation model dogs to confirm its anti-atrial fibrillatory action. The model was prepared by tachypacing to the atria of chronic atrioventricular block dogs for > 6 weeks. Next, oseltamivir in doses of 0.3, 3 and 30 mg/kg was intravenously administered to the halothane-anesthetized intact dogs to analyze its in vivo electrophysiological actions (n = 4). Finally, its in vitro effects of 10–1,000 μM on IK,ACh, IKur, IKr, INa and ICaL were analyzed by using cell lines stably expressing Kir3.1/3.4, KV1.5, hERG, NaV1.5 or CaV1.2, respectively (n = 3 for IK,ACh and IKr or n = 6 for IKr, INa and ICaL). Oseltamivir in doses of 3 and 30 mg/kg terminated the atrial fibrillation in 1 out of 6 and in 6 out of 7 atrial fibrillation model dogs, respectively without inducing any lethal ventricular arrhythmia. Its 3 and 30 mg/kg delayed inter-atrial conduction in a frequency-dependent manner, whereas they prolonged atrial effective refractory period in a reverse frequency-dependent manner in the intact dogs. The current assay indicated that IC50 values for IK,ACh and IKr were 160 and 231 μM, respectively, but 1,000 µM inhibited INa, ICaL and IKur by 22, 19 and 13%, respectively. The extent of INa blockade was enhanced at faster beating rate and more depolarized resting membrane potential. Oseltamivir effectively terminated the persistent atrial fibrillation, which may be largely due to the prolongation of the atrial effective refractory period and inter-atrial conduction time induced by IK,ACh and IKr inhibitions along with INa suppression. Thus, oseltamivir can exert a powerful anti-atrial fibrillatory action through its ideal multi-channel blocking property; and oseltamivir would become a promising seed compound for developing efficacious and safe anti-atrial fibrillatory drugs.

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

IntroductionTorsade 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.MethodsDofetilide (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.ResultsIVR-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).ConclusionIn 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.

Torsadogenic Action of Cisapride, dl-Sotalol, Bepridil, and Verapamil Analyzed by the Chronic Atrioventricular Block Cynomolgus Monkeys: Comparison With That Reported in the CiPA In Silico Mechanistic Model.

In order to bridge the gap of information between the in silico model and human subjects, we evaluated torsadogenic risk of cisapride, dl-sotalol, bepridil and verapamil selected from 12 training compounds in the comprehensive in vitro proarrhythmia assay using the chronic atrioventricular block monkeys. Cisapride (0, 1, and 5 mg/kg, n = 5 for each dose), dl-sotalol (0, 1, 3, and 10 mg/kg, n = 5 for each dose), bepridil (0, 10, and 100 mg/kg, n = 4 for each dose), verapamil (0, 1.5, 15, and 75 mg/kg, n = 4 for each dose) were orally administered to the monkeys in conscious state. Five mg/kg of cisapride, 1, 3, and 10 mg/kg of dl-sotalol and 100 mg/kg of bepridil prolonged ΔΔQTcF, which was not observed by verapamil. Torsade de pointes was induced by 5 mg/kg of cisapride in 2 out of 5 animals, by 10 mg/kg of dl-sotalol in 5 out of 5 and by 100 mg/kg of bepridil in 2 out of 4, which was not induced by verapamil. These torsadogenic doses were normalized by their maximum clinical daily ones to estimate torsadogenic risk. The order of risk was dl-sotalol >bepridil ≥cisapride >verapamil in our study. Since the order was bepridil ≥dl-sotalol >cisapride >verapamil in comprehensive in vitro proarrhythmia assay (CiPA) in silico mechanistic model validation, sympathetic regulation on the heart may play a pivotal role in the onset of torsade de pointes in vivo.

Atrial dilation as a substrate for atrial fibrillation in the canine complete chronic atrioventricular block model

Abstract Background Atrial fibrillation (AF) is the most common cardiac arrhythmia treated in clinical practice. Structural remodeling is characterized by atrial enlargement and contributes to the therapeutic resistance in patients with long-standing AF. Purpose To study the atrial arrhythmogenic and echocardiographic consequences induced by volume overload in the complete chronic atrioventricular block (CAVB) dog. Methods Echocardiographic and electrophysiological data was obtained in 14 anaesthetized Mongrel dogs, in acute AV-block (AAVB), after 6 weeks of CAVB (CAVB6) and CAVB10. Left atrial (LA) volume was determined with 2D echocardiography by using the biplane method. An electrocardiogram and monophasic action potentials (MAP) at the right atrial (RA) free wall were recorded. Atrial effective refractory period (AERP) was determined by continuous programmed electrical stimulation (PES) of 20 beats with a cycle length of 400 ms and an extrastimulus with decremental design until refractoriness was reached. A continuous PES protocol of 20 beats with an extrastimulus 5 ms longer than the AERP was applied for 150 seconds to trigger AF. After 5 min without arrhythmias, autonomic neuromodulation was performed by intravenous infusion (IV) of acetylcholine (1,5μg/kg/min to 6,0μg/kg/min) for 20 min followed by prompt IV infusion of isoprenaline (3μg/min) until the atrial heart rate increased by 20 bpm. PES with an extrastimulus was repeated for 150 seconds to induce AF. Results LA volume increased from 13.7±3.2 ml at AAVB to 20.5±5.9 ml* at CAVB6, and 22.7±6.0 ml* at CAVB10 (Fig. 1A). AERP was similar at AAVB, CAVB6, and CAVB10 (115.8±11.9, 117.3±11.7, and 106.8±12.1 ms respectively). Repetitive AF paroxysms of &amp;gt;10 seconds were induced in 1/14 (7%) dogs at AAVB, 1/11 (9%) at CAVB6, and 5/10 (50%)* at CAVB10 (*p&amp;lt;0.05) upon PES (Fig. 1B). Combined neuromodulation and PES did not increase the AF inducibility rate, but prolonged the longest episode of AF in the inducible dogs from 55±49 seconds to 236±202 seconds* at CAVB10 (Fig. 1C). LA volume was higher in inducible dogs 25.0±4.9 ml compared to 18.4±4.2 ml in non-inducible dogs at CAVB10. Conclusion Sustained atrial dilation forms a substrate for repetitive paroxysms of AF. Neuro-modulation prolongs AF episode duration in susceptible dogs. This animal model can be used to study structural remodeling of the atria and possible therapeutic advances in the management of AF. Figure 1 Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Amgen Research

Analysis of electropharmacological and proarrhythmic effects of donepezil using the halothane-anesthetized intact dogs and the conscious chronic atrioventricular block ones.

Donepezil, an inhibitor for acetylcholinesterase used for patients with Alzheimer's disease, has been shown to inhibit IKr, occasionally inducing torsade de pointes. In order to analyze the causal relationship between donepezil treatment and onset of lethal arrhythmias, we initially assessed electropharmacological effects of donepezil hydrochloride of 0.01, 0.1, and 1 mg/kg, i.v. over 10 min using the halothane-anesthetized intact dogs (n = 4), possibly providing subtherapeutic to supratherapeutic plasma concentrations. Although the low or middle dose did not exert any effect, the high dose transiently increased the ventricular refractoriness along with modest prolongation of the late repolarization period, indicating potential IKr inhibitory action in vivo. Moreover, the high dose induced the positive chronotropic, inotropic, and dromotropic actions along with the pressor effect and prolongation of early repolarization period, suggesting sympathicotonic condition in the central nervous system. Next, we examined proarrhythmic effects of donepezil hydrochloride of 0.1 and 1 mg/kg, i.v. over 10 min using the conscious chronic atrioventricular block dogs (n = 4). Although the low dose hardly affected the cardiovascular variables, the high dose increased the atrial and ventricular rate without significantly altering the repolarization period, possibly reflecting sympathicotonic condition. Importantly, the high dose induced non-sustained ventricular tachycardia in half of the animals. Thus, donepezil by itself did not induce torsade de pointes in vivo, which suggests that donepezil-induced sympathicotonic condition may induce Ca2+ overload, triggering the ventricular arrhythmias, but might indirectly attenuate its IKr inhibitory action, preventing excessive repolarization delay.

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 (r2 = 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.