ANTI-ARRHYTHMICS
Electrophysiological and antiarrhythmic effects of the novel antiarrhythmic agent AZD7009: a comparison with azimilide and AVE0118 in the acutely dilated right atrium of the rabbit in vitro
AstraZeneca R&D Mölndal, Integrative Pharmacology, Pepparedsleden 1, S-431 83 Mölndal, Sweden
Manuscript submitted 7 December 2005. Accepted after revision 29 March 2006.
* Corresponding author. Tel: +46 317761682; fax: +46 317763766. E-mail address: leif.g.carlsson{at}astrazeneca.com
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Abstract |
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Aims To compare the electrophysiological and antiarrhythmic effects of AZD7009, azimilide, and AVE0118 in the acutely dilated rabbit atria in vitro.
Methods and results In the isolated Langendorf-perfused rabbit heart, the atrial effective refractory period (AERP) and the inducibility of atrial fibrillation (AF) were measured at increasing concentrations of AZD7009 (0.1–3 µM), azimilide (0.1–3 µM), and AVE0118 (0.3–10 µM). In separate groups of atria, termination of sustained AF was assessed. In non-dilated atria, the AERP was 82±1.3 ms (mean±SEM) and AF could not be induced. Dilation significantly reduced the AERP to 49±1.0 ms (P<0.001) and 92% of the atria became inducible. Perfusion with AZD7009, azimilide, and AVE0118 concentration-dependently increased the AERP and reduced the AF inducibility. At the highest concentrations of AZD7009, azimilide, and AVE0118, AERP and AF inducibility changed from 50±4.5 to 136±6.6 ms and 80 to 0% (both P<0.001) from 51±3.0 to 105±9.9 ms (P<0.001) and 80 to 0% (P<0.01) and from 46±2.8 to 85±6.0 ms and 90 to 0% (both P<0.001). Restoration of sinus rhythm was seen in 6/6, 5/6, and 5/6 hearts perfused with AZD7009, azimilide, and AVE0118, respectively.
Conclusion In the dilated rabbit atria, AZD7009, azimilide, and AVE0118 concentration-dependently increased AERP, effectively prevented AF induction, and rapidly restored sinus rhythm.
Key Words: Atrial fibrillation, Antiarrhythmic agents, Atrial dilation, Refractoriness
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Introduction |
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Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia; and with the ageing of the population it is emerging as a major public health concern. AF is often associated with atrial enlargement and clinical studies have shown a causal relationship between atrial size and AF development.1
,2 Furthermore, atrial dimension is considered an important predictor of successful termination of AF and maintenance of sinus rhythm.3 In animal studies, acute and chronic atrial enlargement have been found to augment the vulnerability to AF.4–7 Dilation of the atrium increases the atrial surface and reversibly attenuates the atrial effective refractory period (AERP) and according to the multiple wavelet theory, the enlargement may harbour an increased number of coexisting wavelets, which conjointly with a shortened refractory period may promote the initiation and perpetuation of AF.5,8,9
AZD7009 is a novel antiarrhythmic agent currently under clinical investigation for treatment of AF. Experimental studies in animals and in man have demonstrated that AZD7009 can be characterized as a compound that influences atrial electrophysiology predominantly, has a high antiarrhythmic efficacy, and a low proarrhythmic potential.10–12 Observations from cellular electrophysiological studies suggest that AZD7009 exerts its action through a mixed potassium- and sodium-channel blockade.13,14 The aim of the present study was to examine the electrophysiological and antiarrhythmic properties of AZD7009, azimilide, and AVE0118 in the dilated rabbit atria in vitro, an established model of AF in which increased atrial stretch results in a significant increase in AF vulnerability closely correlated with shortening of the AERP and local conduction disturbances.5,15,16 Azimilide and AVE0118, two antiarrhythmic agents under clinical development for management of AF, but with partly different mechanisms of action when compared with those of AZD7009, were included in this study.17–19
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Methods |
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All experiments were carried out in accordance with the Declaration of Helsinki and were approved by the Local Ethics Committee for animal experiments at the University of Gothenburg, Gothenburg, Sweden.
Isolated Langendorff-perfused heart preparation
Seventy-one male New Zealand White rabbits were anaesthetized with sodium pentobarbital (60–70 mg/kg i.v.) and injected with 1000 IE heparin. The thorax was opened by a midsternal incision, and the heart and the lungs were rapidly excised and placed in cold (10°C) Tyrode's perfusion fluid. The aorta was then cannulated and the heart perfused at a constant pressure of 60 mmHg with Tyrode's solution (37°C) containing (in millimolar): NaCl, 120; NaHCO3, 25; KCl, 4; CaCl2; 1.8, MgSO4, 0.5; Na2HPO4, 1.8; glucose, 9; pyruvic acid, 2; and ethylenediaminetetraacetic acid, 0.026. The solution was saturated with a mixture of 95% O2 and 5% CO2 resulting in a pH of 7.4. Subsequently, the superior and inferior caval veins were cannulated, the pulmonary artery and the pulmonary veins sutured, and the lungs removed. Hence, the coronary perfusate draining from the coronary sinus into the right atrium could only escape through a polyethylene tube positioned in the inferior caval vein. The height of the outflow tract of the cannula could rapidly be adjusted to vary the right intra-atrial pressure. In the present series of experiments, the right intra-atrial pressure was increased from 0 to 10 cm H2O to dilate the atrium, as earlier studies have shown that dilation above that level did not result in further changes in refractoriness, repolarization, or AF inducibility.5 A polyethylene tube connected to a custom-made pressure transducer was inserted into the superior caval vein to record the right intra-atrial pressure. During the experiment, the heart was immersed in warm Tyrode's solution to maintain the temperature at 37°C.
Electrophysiological and antiarrhythmic evaluation
Right atrial epicardial stimulation was carried out by means of a custom-made bipolar suction electrode attached to the midatrial wall and a custom-made computerized constant-current stimulator delivering pulses of 1 ms duration (1.2x threshold). A similar electrode was used to record atrial electrograms from the right atrial appendage. The AERP was measured during atrial pacing at a basic cycle length of 200 ms. After a 10-beat train (S1–S1), a single premature stimulus (S2) was introduced. Starting well within the refractory period, the S1–S2 coupling interval was incremented in steps of 2 ms. The AERP was defined as the longest S1–S2 interval that failed to capture the atrium. The vulnerability of the atrium to fibrillate was quantified by measurement of the induction of AF by single early premature stimuli. AF was defined as a rapid irregular rhythm lasting for >2 s.
Experimental protocols
The concentration-dependent effects of AZD7009 (n=10), azimilide (n=10), and AVE0118 (n=10) on the AERP were assessed at 0 and 10 cm H2O. After baseline measurements (undertaken in duplicate 10 min apart) at an intra-atrial pressure of 0 cm H2O, the pressure was increased to 10 cm H2O and 5 min later the measurements were repeated. Subsequently, the atria were deflated to 0 cm H2O and the lowest concentration of the test drug under evaluation was added to the perfusion solution. After 10 min, a new measurement was carried out, the intra-atrial pressure increased for 5 min and the measurement repeated. The sequence was then repeated throughout the entire concentration range examined (0.1, 0.3, 1, and 3 µM for AZD7009 and azimilide and 0.3, 1, 3, and 10 µM for AVE0118, respectively). Pilot studies indicated that at concentrations of AZD7009 and azimilide above 3 µM, it was not possible to achieve atrial capture during atrial stimulation. Hence, concentrations of AZD7009 and azimilide above 3 µM were not explored. Owing to poor solubility of AVE0118, concentrations above 10 µM could not be tested. Hearts perfused with Tyrode's solution only were run in parallel as time-matched controls (n=10). In case AF was induced (only seen at an elevated intra-atrial pressure), the arrhythmia was allowed to last for 30 s maximum, where after, the pressure was reduced to 0 cm H2O (which always restored sinus rhythm).
In four groups of six atria each, the ability of AZD7009 (3 µM), azimilide (3 µM), or AVE0118 (3 and 10 µM) to terminate AF lasting for 5 min was examined. Seven time-matched control atria were allowed to fibrillate for 15 min without intervention. AF was induced in the dilated state (10 cm H2O) as described earlier. In the atria destined for an attempt to terminate the AF by any of the three drugs, perfusion with AZD7009, azimilide, or AVE0118 lasting for 10 min maximum was commenced after 5 min of sustained AF. During these experiments, the atrial electrogram was continuously recorded for assessment of drug-related influences on AF cycle length (AFCL) and Rényi entropy as a measure of signal complexity. For measurement of AFCL, the procedure described by Botteron and Smith20 was used to pre-process the atrial electrograms. In short, digitized (1 kHz) atrial electrogram recordings were first band-pass filtered at 40–250 Hz using a third order Butterworth filter. The absolute value of the output from this filtering was then low-pass filtered at 20 Hz using a similar third-order filter, thus producing a signal proportional to the amplitude of the high-frequency components of the electrogram and one that contains the temporal information of the atrial activation process. For analysis of the AFCL, a threshold algorithm was used whose parameters were typically adjusted to recognize 10–20% of the maximal atrial activation wave amplitude occurring at >20 ms after the last wave. To obtain a quantitative measure of signal complexity and disorder, the third order Rényi entropy was estimated.21–23 The Rényi entropy was then estimated from the time-frequency distribution (Morlet scalogram) of the signal.22 Signal pre-processing, construction of time-frequency distributions, and threshold analysis were undertaken using software from Ixellence GmbH, Wildau, Germany (Dataplore). Rényi entropies were estimated using the Matlab time-frequency toolbox (available freely at www.gdr-isis.org/Applications/tftb/iutsn.univ-nantes.fr/auger/tftb.html).
AZD7009, azimilide dihydrochloride, and AVE0118 were synthesized by AstraZeneca R&D, Mölndal, Sweden. Stock solutions of AZD7009 and azimilide were prepared by dissolving the drug substance in an equimolar amount of 0.1 M tartaric acid and distilled water and in distilled water, respectively. A 1 mM stock solution of AVE0118 was prepared by dissolving the drug in 0.25 mL DMSO, 1.25 mL PEG400, and 8.5 mL distilled water. The stock solutions were prepared fresh on the day of use, kept at room temperature, and diluted with Tyrode's solution to the desired concentration.
Statistical analysis
The AERPs in the undilated and in the dilated atria and the duration of the AF episode induced in the dilated atria were analysed in a mixed effect ANOVA with fixed factors for concentration and treatment and random for atria. The estimated change from pre-drug measurement (baseline) to each drug concentration level was calculated for the three drugs and adjusted for the corresponding change in the time-matched control group. Hochberg's method was used as the multiple-testing adjustment for the comparisons of the different concentrations for each variable and substance, in order to protect the experiment-wise alpha error rate at 0.05.24 For the inducibility of AF, the proportion of non-response for each drug concentration was compared with the corresponding proportion of non-response in the time-matched control group measured at the corresponding time. Cochran–Mantel–Haenszel test, stratified by pre-concentration response, was used.25 Statistical analysis of data generated in the study on conversion efficacy (i.e. conversion rate, AFCL, and Rényi entropy) was undertaken by means of Fisher exact probability test and Student's t-test as appropriate. The statistical analysis was performed using the statistical software SAS© (version 8.2, SAS Institute Inc., Cary, NC, USA).
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Concentration-dependent effects of AZD7009, azimilide, and AVE0118 on AERP in the undilated and dilated atria
Dilation of the atria by a pressure of 10 cm H2O was associated with a marked reduction in AERP in all groups of atria. Hence, at baseline (i.e. pre-drug) the AERP decreased from 82±1.3 to 49±1.0 ms (P<0.001, n=71). The effects of increasing concentrations of AZD7009, azimilide, and AVE0118 and of time (in the time-matched control atria) on AERP in the undilated and the dilated atria, respectively, are presented in Table 1. In the time-matched control group, the AERP remained fairly stable over the study period (i.e. 60 min). Figures 1–3 illustrate the adjusted (for changes seen in the control atria) estimated changes in AERP in the atria perfused with increasing concentrations of AZD7009, azimilide, or AVE0118. All drugs caused a concentration-dependent and statistically significant increase in the AERP in the undilated as well as in the dilated atria. Of the three drugs, AZD7009 appeared to be the most potent followed by azimilide and AVE0118. Quantitatively, the absolute change tended to be more pronounced in the dilated atria than in the undilated atria and in relative terms this was definitively the case. Hence, in the undilated and the dilated atria, respectively, 3 µM AZD7009, azimilide, or AVE0118 increased the AERP by 65±3.6 and 90±5.6 ms (P<0.01 vs. undilated atria), by 44±9.5 and 53±8.2 ms (P=ns) and by 29±6.0 and 38±5.4 ms (P=ns). Despite the fact that AVE0118 was explored at higher concentrations than AZD7009 and azimilide, the increase in AERP was smaller. During superfusion with the highest concentration of AVE0118 (10 µM), 1 µM AZD7009 was added to the perfusate, which further increased the AERP from 110±5.2 to 153±7.7 ms and from 85±6.0 to 131±8.1 ms in the undilated (P<0.001, n=8) and in the dilated atria (P<0.001, n=7), respectively.
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Concentration-dependent effects of AZD7009, azimilide, and AVE0118 on AF inducibility and AF duration in the dilated atria
Induction of AF by introducing a premature stimulus was attempted in all atria studied, both in the undilated and in the dilated state. At baseline (i.e. pre-drug), AF was never induced in the undilated atria but in 65/71 (92%) of the dilated atria (Figure 4). Furthermore, in the fibrillating atria, deflation (to 0 cm H2O) always resulted in a prompt restoration of sinus rhythm. In the time-matched control atria, the inducibility varied between 80 and 60% over the experimental period (i.e. 60 min) (Figure 5) and the AERP remained fairly unchanged (Table 1). In addition, the AFCL did not alter during this period of repeated AF induction (55±3.3 ms at baseline and 54±3.7 ms after 60 min of perfusion, P=ns).
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Perfusion with AZD7009, azimilide, and AVE0118 in atria dilated to 10 cm H2O was associated with a concentration-dependent reduction in AF inducibility (Figure 5). At the highest concentration assessed (3 µM for AZD7009 and azimilide and 10 µM for AVE0118), all drugs rendered induction of AF impossible. Of the three drugs examined, AZD7009 appeared to be the most effective in terms of reducing inducibility.
An AF episode induced during the assessment of the concentration-efficacy relationship for AF inducibility was allowed to last for 30 s maximum (see Methods), whereupon the atrium was deflated, sinus rhythm restored, and perfusion with the next higher concentration of the test drug commenced. If the AF episode lasted for 30 s that duration was used for the calculation of the mean AF duration at each concentration of test drug. Hence, the duration of episodes lasting between 
2 and 
30 s was eligible for the calculation of the mean AF duration. From these experiments it was obvious that all drugs concentration-dependently shortened the duration of the induced AF episodes, whereas it remained constant in the time-matched control atria (Table 2).
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Termination of AF and influence on AFCL and Rényi entropy by AZD7009, azimilide, and AVE0118 in the dilated rabbit atria
In separate groups of 32 dilated atria (10 cm H2O), the intention was to examine the ability of AZD7009 (3 µM), azimilide (3 µM), or AVE0118 (3 and 10 µM) to terminate AF lasting for 5 min. The drugs were administered until sinus rhythm was restored or for 10 min maximum (n=6 within each drug-treated group). The time-matched control atria (n=7) were followed for 15 min after the induction of AF. Atrial electrograms for subsequent analysis of AFCL and signal complexity (Rényi entropy) were continuously recorded throughout these experiments (see Methods). Entropy is a classical measure of disorder and information content and the Renyi entropy exploits the time-frequency distribution of a signal.21
,23 Organized signals (i.e. small number of components in the time-frequency distribution) give rise to small entropy values, whereas the diffuse time-frequency distribution of complex signals gives large entropy values. In the fibrillating time-matched control atria (n=7), the AFCL and the Rényi entropy remained constant during the 15 min study period (Figures 6 and 7) and none of the atria spontaneously converted to sinus rhythm. Hence, after 5 and 15 min of AF, the AFCL was 63±2.6 and 63±2.4 ms and the Rényi entropy 1.5±0.04 and 1.5±0.05 bits, respectively (both P=ns). Perfusion with AZD7009 or azimilide was associated with AF termination in 6/6 (P=0.0012 vs. control atria) and in 5/6 (P=0.0093) of the atria after 3.1±0.36 and 7.0±0.98 min of drug perfusion. In 1/6 (P=ns) and 5/6 (P=0.0093) of the atria perfused with AVE0118 (3 and 10 µM) sinus rhythm was restored after 7.8 and 5.9±1.03 min of perfusion. Furthermore, before the AF termination, the AFCL increased from 64±1.9 to 87±4.7 ms (P<0.01), from 61±2.2 to 74±4.0 ms (P<0.05), and from 62±2.8 to 69±3.2 ms (P=0.07) in atria perfused with AZD7009, azimilide, and AVE0118, respectively (Figure 6). In accordance, the Rényi entropy was reduced imminent to the AF termination [from 1.4±0.04 to 1.2±0.03 bits (P<0.01), from 1.5±0.03 to 1.3±0.03 bits (P<0.01), and from 1.5±0.06 to 1.3±0.06 bits (P<0.05), Figure 7]. After restoration of sinus rhythm, the Rényi entropy further fell to 0.8±0.06 bits (AZD7009), 0.9±0.04 bits (azimilide), and 0.8±0.16 bits (AVE0118), respectively.
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Discussion |
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In the present study, we used the Langendorff-perfused rabbit heart to assess the electrophysiological and the antiarrhythmic effects of AZD7009, azimilide, and AVE0118 in the dilated atria.5
Atrial dilation and atrial size are important independent risk factors for AF and predictors of successful restoration and maintenance of sinus rhythm.3 As previously shown by other groups, we found that acute dilation of the right atria of the rabbit was associated with a reduction in AERP and an increase in AF vulnerability.5,26,27 AZD7009, azimilide, and AVE0118 are all novel antiarrhythmic agents currently under clinical development for management of AF. Despite varying mechanisms of action, these agents share the property that they increase atrial refractoriness, which according to the multiple-wavelet theory, will result in a prolongation of the AF wavelength.8 An increase in the wavelength of the atrial impulse will reduce the number of wavelets that can coexist in the atria, decrease the stability of the fibrillation, and eventually terminate the arrhythmia. In addition, increasing the refractoriness will influence the vulnerability to AF by critically lengthening the wavelength to a point where AF can no longer be induced. Alternatively, and incompatible with the multiple-wavelet theory, sodium-channel blocking drugs may shorten wavelength by delaying conduction velocity at the pivot points of turning wavelets, increase average AFCL, and thus widen the temporal excitable gap.28 As a result recovery of excitability will be improved which in turn will favour fusion of wavelets eventually increasing the statistical chance of AF termination. Actually, multisite mapping studies in the canine sterile pericarditis model of AF and atrial flutter demonstrated that AZD7009 prolonged the arrhythmia cycle length by slowing conduction at a pivot point in the re-entrant circuit and arrhythmia termination was seen when the re-entrant wavefront blocked in an area of slow conduction.10
AZD7009, azimilide, and AZE0118 most likely increase atrial refractoriness through different mechanisms. Although AZD7009 exerts its effect via a mixed blockade of several repolarizing potassium currents (IKr, Ito, and IKur) and the sodium current, azimilide primarily blocks IKr, IKs, and the L-type calcium current and AVE-0118 IKur, Ito, and IKAch.13,14,17,18 Interestingly, it has been proposed that a combined blockade of IKr and Ito/IKur may act synergistically to increase AERP and improve antiarrhythmic efficacy. Hence, it was recently demonstrated that combining the Ito/IKur blocker AVE0118 with either of the selective IKr blockers ibutilide or dofetilide resulted in an increase in AERP and AF conversion rates that were considerably higher than that seen with either drug alone.29 It is thus possible that the combined ion-channel block of IKr, Ito, IKur, and INa by AZD7009 underlies the pronounced increase in the AERP seen in the present study. Interestingly, Eijsbouts et al.30 recently reported a synergistic action of atrial dilation per se and sodium channel blockade by flecainide on conduction and refractoriness in the rabbit-dilated atria and one may speculate that such a synergistic effect also exists for AZD7009. Of the three drugs examined in the present study, AZD7009 was the only one that quantitatively increased the AERP more in the dilated than in the non-dilated atrium. Potential influence on atrial conduction was not assessed in this study but AZD7009 has previously been reported strongly to influence atrial conduction time in the dog atrium in vivo.10 In addition to having an impact on antiarrhythmic efficacy, the differences in mechanisms of action between the three drugs may also influence cardiac safety. Azimilide has been shown to delay ventricular repolarization and cases of torsades de pointes have been reported in clinical trials. Although AZD7009 blocks IKr and prolongs the QT interval, animal experiments and preliminary clinical observations indicate that AZD7009 may be characterized as an agent with low proarrhythmic potential.11,12 AVE0118, targeting more atrial-specific ion channels, has been suggested to, and in animal experiments demonstrated to, be devoid of QT-prolonging effects and may thus possess a lower risk of inducing torsades de pointes.19 However, clinical evidence supporting an improved safety profile, as well as antiarrhythmic efficacy, for AVE0118 and other agents with similar mechanism of action is lacking and future studies have to show whether this approach will be a successful way towards more effective and safer treatment of AF.
The relationship between the vulnerability of the atria to fibrillation and the atrial refractoriness (and thus the degree of stretch) is in agreement with the findings from Ravelli and Allessie5 who demonstrated that AF inducibility in the rabbit atrium was critically dependent on the refractoriness such that AF could not be induced at effective refractory periods exceeding 70 ms. Thus, in the present AF model it appears that when the AERP passes a critical level, the atria become resistant to AF induction or an ongoing AF episode will terminate. Although the maximal increase in AERP differed between the drugs assessed in the present study (AZD7009 being the most potent followed by azimilide and AVE0118), all drugs increased the AERP beyond this critical AERP level, which translated into a similar antiarrhythmic efficacy. The reduction in AF vulnerability in this model seems independent of whether the AERP increases as a result of a reduction in intra-atrial pressure or following drug-induced lengthening of the refractory period in the dilated state. It has been suggested that shortening of atrial refractoriness would favour re-entrant activity and by that entertain AF, and that the stretch-induced shortening in AERP can be completely explained by an attenuation in the duration of the action potential.5,6,31 Hence, both Ravelli and Allessie5 and Nazir and Lab6 observed a strong correlation between the degree of shortening of the monophasic action potential duration and the shortening of atrial refractoriness. The ionic mechanisms underlying the shortening of the action potential remains unknown, however, sarcolemmal stretch-activated channels (SAC) transporting monovalent and divalent cations as well as volume-sensitive chloride channels32,33 have been suggested to contribute to the shortening in AERP by dilation. On the other hand, reduction in AF vulnerability has been reported with the non-selective SAC inhibitor gadolinium and the more specific inhibitor GsMtx-4 without altering the stretch-dependence of the AERP,26,27 which may imply additional factors than AERP shortening contributing to an increased AF vulnerability during atrial stretch. For AZD7009, azimilide, and AVE0118, there are no data to suggest influence on SACs and it is most likely that the concentration-dependent increase in AERP and the reduction in AF vulnerability are consequences of the drugs' abilities to block depolarizing and repolarizing ion currents. Although the role of atrial refractoriness has been in focus as a mechanism by which atrial stretch leads to a substrate of AF, atrial conduction properties will also determine the wavelength of the atrial impulse. In a recent study by Eijsbouts et al.,16 the role of spatial heterogeneities in atrial conduction for initiation and perpetuation of AF were addressed in the dilated atria using high-density mapping. Increased atrial dilation was found to correlate with decreased conduction velocity and higher incidence of areas with slow conduction and conduction block. Hence, such spatial heterogeneities may set the stage for functional re-entry where the impulse circulates around a line of functional conduction block, often having a high wavefront curvature at the pivot points.
In the separate groups of atria used for assessing the efficacy of AZD7009, azimilide, and AVE0118 in converting sustained AF to sinus rhythm, all agents were found to be highly effective. In order to be effective, however, AVE0118 had to be administered at a higher concentration than AZD7009 and azimilide, in line with its lower potency in increasing AERP. The conversion was preceded by a progressive lengthening of the AFCL, which for AZD7009 is in line with results obtained in the canine sterile pericarditis model of AF and atrial flutter.10 During the analysis of these experiments it became apparent that not only was the AFCL prolonged, but the arrhythmia seemed more organized. Hence, we used the third order Rényi entropy in order to obtain a measure of signal complexity21–23 and to examine whether the drug-related conversion was associated with reduced complexity. The entropy, which is related to the Shannon entropy, was calculated using the time-frequency representation of the signal thus exploiting the analogy between signal energy densities and probability densities.21,23 The method implies few assumptions about the signal or the underlying process. Although alternative estimates of the complexity of global atrial fibrillatory signals have previously been used, these often refer to frequency-domain analysis (area under dominant peaks in magnitude spectra) or similarity measures and are not easily related to classical measures of signal complexity.34,35 By quantifying the drug-related changes of the Rényi entropy in the present study, it was demonstrated that all drugs progressively and significantly reduced the signal complexity of the induced atrial arrhythmia.
In conclusion, the present series of experiments has demonstrated that under conditions of increased atrial load, AZD7009, azimilide, and AVE0118 markedly increase refractoriness, effectively inhibit induction of AF, and rapidly convert AF to sinus rhythm.
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