Europace Advance Access originally published online on September 21, 2007
Europace 2007 9(11):1099-1104; doi:10.1093/europace/eum196
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EXPERIMENTAL STUDIES
Comparative effects of acute vs. chronic oral amiodarone treatment during acute myocardial infarction in rats
1 Department of Cardiology, University of Ioannina, 1 Stavrou Niarxou Avenue, 45110 Ioannina, Greece; 2 Department of Child Health, University of Ioannina, 1 Stavrou Niarxou Avenue, 45110 Ioannina, Greece; 3 Department of Pharmacology, University of Athens, Goudi, Athens, Greece; 4 Department of Nuclear Medicine, University of Ioannina, 1 Stavrou Niarxou Avenue, 45110 Ioannina, Greece
Manuscript submitted 6 July 2007. Accepted after revision 13 August 2007.
* Corresponding author. Tel: +30 2651097227; fax: +30 2651097053. E-mail address: thkolet{at}cc.uoi.gr
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Abstract |
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Aims: This study investigated whether chronic and acute amiodarone treatment has differential effects on ventricular arrhythmogenesis during acute myocardial infarction in rats.
Methods and results: Forty-six rats were randomly allocated into vehicle, chronic oral amiodarone (30 mg/kg daily for 2 weeks), or acute amiodarone (a single dose, 100 mg/kg). Five additional rats were sham-operated. Myocardial infarction was generated by left coronary artery ligation 2 weeks after chronic treatment. Amiodarone was administered acutely 5 min post-ligation. The electrocardiogram was recorded for 24 h, using an implanted telemetry transmitter. Episodes of ventricular tachyarrhythmias and mortality rates were analysed. Serum catecholamines and infarct size were measured 24 h post-ligation. No differences were found in infarct size. Compared with controls (22.7 ± 10.9), there was a similar reduction in the number of tachyarrhythmia episodes after either chronic (2.6 ± 1.6, P = 0.0011) or acute (3.6 ± 1.7, P = 0.031) amiodarone administration. Norepinephrine levels were lower only after chronic treatment. Mortality in both amiodarone treatment arms was exclusively due to bradyarrhythmia secondary to cardiac failure, whereas mortality in controls was mainly attributed to tachyarrhythmic death.
Conclusions: A rapid antiarrhythmic effect was observed after acute amiodarone administration in the rat. Norepinephrine levels decreased after chronic treatment and may be associated with bradyarrhythmic mortality.
Key Words: Myocardial infarction, Ventricular tachyarrhythmias, Amiodarone, Loading dosage, Catecholamines, Mortality
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Introduction |
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Amiodarone is one of the most effective antiarrhythmic compounds that are currently available.1
This agent has a wide spectrum of actions and is effective in the treatment of ventricular tachyarrhythmias. However, amiodarone is associated with a slow onset of action,2 thus large loading doses are required before clinical efficacy can be established.1–3
During acute myocardial infarction (MI), amiodarone decreases the incidence of ventricular tachycardia (VT) and ventricular fibrillation (VF).1–4 Intravenous amiodarone accelerates the onset of action5 and this route of administration is favoured during acute MI. However, coronary and peripheral vasodilation are common, confounding its antiarrhythmic actions.4–6 Moreover, intravenous amiodarone is associated with negative inotropic effects, requiring haemodynamic monitoring in patients with depressed left ventricular function.6 Oral amiodarone may overcome these limitations, but its pharmacokinetics are complex and not well understood.7,8 As a result, the optimal loading dosage required to achieve a rapid onset of action is unclear and a variety of regimes have been reported.1–3
Experimental studies using oral loading doses prior to MI indicated that amiodarone decreases the incidence of VT/VF in anaesthetized animals during the immediate post-infarction period.9–11 These results were extended in a previous study from our group, in which oral amiodarone treatment (30 mg/kg for 2 weeks) decreased VT/VF during the 24 h period post-MI in the conscious, untethered rat.12 However, the pre-treatment used in these studies9–12 limits the clinical relevance during acute MI. Moreover, in our previous study,12 the decrease in VT/VF was not translated into a survival benefit due to an excess bradycardia in treated animals.
The purpose of this study was to assess the safety and efficacy of a single, large, oral amiodarone dosing regimen administered immediately after MI generation. As in our previous study,12 we used the conscious rat model that permits the study of VT/VF for extended periods of time, without the confounding effects of anaesthesia. We aimed to compare the effects of chronic vs. acute amiodarone treatment on the infarct size and on the incidence of VT/VF occurring during the 24 h period post-MI. To provide further insight into possible antiarrhythmic mechanisms, plasma catecholamine levels were measured 24 h post-MI.
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Methods |
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The study was conducted in 53 female rats of similar age and weight (20 ± 1 weeks, 200–250 g, respectively). The animals were housed in individual cages, under optimal laboratory conditions (controlled humidity, temperature and light/dark cycles), and were given water and standard rat chow ad libitum. Animal care and procedures were in accordance with the recommendations in the Declaration of Helsinki, as well as with national and international legislation on animal research. The study protocol was approved by the local state authority.
Study protocol
The animals were randomized into a chronic treatment arm and an acute treatment arm. Simple randomization was performed using a custom lottery draw. In the chronic treatment arm, the rats were further randomized into a 2 week oral treatment of either amiodarone or vehicle. In the acute treatment arm, the animals were further randomized into a single oral administration of either amiodarone or vehicle. Five additional rats were sham-operated. After MI generation, continuous electrocardiographic (ECG) recordings were performed for 24 h, followed by catecholamine measurements and infarct size calculation. The study groups are depicted in Figure 1, and the study protocol is shown in Figure 2.
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Drug administration
Amiodarone was administered orally by gavage. Before each administration, a fresh solution was prepared in 0.6% methylcellulose to obtain the necessary drug concentration in 3 mL of the solution. The control groups received 0.6% methylcellulose alone. In the chronic treatment arm, amiodarone (30 mg/kg) was administered once daily for 2 weeks. In the acute treatment arm, a single dose (100 mg/kg) of amiodarone was administered 5 min after MI induction.
Implantation of telemetry transmitter
One day prior to MI generation, a continuous ECG telemetry transmitter (Dataquest, Data Sciences International, Transoma Medical, Arden Hills, MN, USA) was implanted in the abdominal cavity, using a previously described method,13 after slight modification in our laboratory.12 The animals were intubated and mechanically ventilated (Model 7025, Ugo Basile, Comerio, VA, Italy) and anaesthetized with 2% isoflurane. The transmitter was secured in the abdominal cavity and the leads were tunnelled under the skin. The rats were housed in individual cages placed on a receiver that continuously captured the signal, independent of animal activity. The ECG signal was displayed with the use of a computer program (A.R.T. 2.2, Dataquest, Data Sciences International, Transoma Medical, Arden Hills, MN, USA) and was stored for analysis.
Generation of acute myocardial infarction and blood sample collection
Coronary artery ligation was performed, as described previously,14 by an operator blinded to treatment assignment. The left coronary artery was encircled and ligated using a 6-0 suture, placed between the pulmonary artery cone and the left atrial appendage; following these anatomical landmarks ensures generation of similar infarct size in all experiments. In sham-operated animals, the coronary artery was encircled but not ligated. The incision was sutured and the remaining air was aspirated from the thorax, allowing the resumption of spontaneous respiration. A six-lead ECG was obtained and ST-segment elevation confirmed the induced MI. Upon cessation of anaesthesia, the animals regained consciousness within 2–3 min. No resuscitation attempts were allowed at any time during the study.
Twenty-four hours after MI generation, the survivors were re-anaesthetized and the internal jugular vein was exposed. Blood was collected by venous puncture, centrifuged immediately, and the serum was stored at –20°C. The rats were subsequently sacrificed using a lethal dose of potassium chloride and the heart was harvested for measurement of infarct size.
Infarct size
The heart was excised, frozen (in –20°C for 1 h), hand-cut in five 2 mm slices, incubated (in triphenyltetrazolium chloride for 15 min at 37°C), and fixed (in 10% formalin for 20 min), as previously described.15 The slices were scanned (Scanjet 4570c/5500c, Hewlett-Packard, Palo Alto, CA, USA) and the areas of infarcted and non-infarcted myocardium were measured (Image Tool, University of Texas, San Antonio, Texas, USA) from both sides of each slice and averaged. The measured areas were multiplied by the slice thickness and values were summed. Infarct size was defined as the ratio between the infarcted and the total left ventricular volume.
Measurement of catecholamine serum levels
Serum levels of epinephrine and norepinephrine were measured 24 h post-ligation using 125I radioimmunoassay kits purchased from the national representative of BioSource Europe S.A., Nivelles, Belgium.
Heart rate
Heart rate (HR) was measured from continuous 2 min ECG recordings, from which non-sinus beats were excluded. The mean value of these RR intervals was used to determine HR for each time point. Heart rate was calculated at baseline, at the 5th, 30th, and 60th min post-MI and hourly thereafter.
Arrhythmia analysis
The ECG tracings were displayed and analysed offline by two operators blinded to treatment assignment. We report the number and duration of VT and VF episodes, according to the guidelines provided by the Lambeth Conventions for determination of experimental arrhythmias.16 Ventricular tachycardia was defined as 4 or more consecutive premature ventricular contractions (PVCs) and VF was defined as a signal with indistinguishable QRS deflections. In the present study, we report VT and VF collectively. We used two previously validated methods for arrhythmia analysis.13,17
In the first method, the number of VT/VF episodes was compared in the three groups.13 Since the incidence of VT/VF varies greatly over time,18 we report the hourly distribution of VT/VF episodes. Differences in mortality may confound the results, hence the number of VT/VF episodes was normalized to survival time (i.e. the time at risk of tachyarrhythmia occurrence), as previously suggested.13
In the second method, we calculated the arrhythmia score,17 which quantifies VT/VF on the basis of the number of episodes, duration, and outcome. A score of 2 was given for one spontaneously reverting VT/VF episode and 3 for two or more episodes, with a total duration of <60 s. A score of 4 was given for episodes lasting 60–119 s, 5 for VT/VF lasting >119 s, 6 for fatal VT/VF starting <15 min post-ligation, 7 for fatal VT/VF starting 4–14 min, 8 for fatal VT/VF 1–3 min, and 9 for fatal VT/VF starting <1 min post-ligation. The arrhythmia score was calculated for four post-ligation time periods, namely 0–6, 6–12, 12–18, and 18–24 h. This method also accounts for differences in mortality rates and timing, by giving a score of 9 for the time period(s) following death.
Twenty-four hour mortality
Tachyarrhythmic death was due to ventricular asystole, immediately preceded by VT/VF. Bradyarrhythmic death due to cardiac failure was defined as a phase of morbidity, associated with a gradual increase in sinus HR, followed by an abrupt onset of complete atrioventricular block. In the rat model, this mode of death is generally considered representative of death due to heart failure.12,13,19,20
Statistical analysis
All values are given as mean ± standard error of the mean. Differences in continuous variables were compared using one-way analysis of variance, followed by Duncan’s multi-range test. The continuous variables describing the arrhythmia frequencies were not normally distributed and were compared using the Kruskal–Wallis analysis of variance. In the case of a significant variance, further comparisons were made using the non-parametric Mann–Whitney U test. Pair-wise comparisons between categorical variables were made with Fisher’s two-tailed exact test. Statistical significance was defined at an alpha level of 0.05.
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Animal study population
Forty-eight Wistar rats, weighing 219 ± 2 g, formed the initial animal study population. Of these, 26 were randomized to the chronic treatment arm and received amiodarone (n = 13) or vehicle (n = 13). The acute treatment arm group consisted of 22 rats that received a single oral dose of amiodarone (n = 11) or vehicle (n= 11). Death due to excessive bleeding occurred during telemetry transmitter implantation (n = 1) and during MI generation (n = 1). Thus, the final study population consisted of 46 animals, of which 13 rats (225 ± 2 g) received chronic amiodarone, 12 rats (220 ± 3 g) chronic vehicle, 10 rats (214 ± 3 g) a single amiodarone dosage and 11 rats (217±5 g) a single vehicle dosage. Five additional rats (229 ± 2 g) were sham-operated. This sample size gives an
90% power to detect a 50% reduction in the number of VT/VF episodes. As expected, comparison between the two control groups in the acute and chronic treatment arms revealed no differences in any variable. Therefore, for presentation purposes, we report the results from the two active treatment groups and a single control group.
Heart rate
A statistical variance (F = 22.0, P < 0.0001) was present in baseline HR that was due to significantly (P < 0.0001) lower HR in the chronic amiodarone group, compared with both other groups. Heart rate increased significantly (F = 5.2, P < 0.0001) after MI induction in all groups. An increase was also present in sham-operated animals (F = 3.5, P < 0.0001), probably attributable to the procedure, with sinus HR returning to baseline values after the second hour of recording. Although there was a trend towards higher HR in the chronic amiodarone group, no significant differences were found between groups (Figure 3).
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Infarct size
Mean infarct size was 42.1 ± 2.0% in the chronic amiodarone group, 45.7 ± 1.2% in the acute amiodarone group, and 42.4 ± 1.6% in controls. No significant differences were found between groups (F = 1.2, P = 0.30).
Number and duration of ventricular tachycardia/ventricular fibrillation episodes
Apart from occasional PVCs, no VT/VF was recorded in sham-operated animals. In the remaining animals, a statistical variance was present (H = 6.5, P = 0.038) in the total number of VT/VF episodes, which was more pronounced (H = 11.4, P = 0.0032) when normalized for survival time. This variance was due to significantly fewer episodes (per hour alive) in either the chronic amiodarone group (2.6 ± 1.6, two-sided P = 0.0011) or the acute amiodarone group (3.6 ± 1.7, two-sided P = 0.031), compared with controls (22.7 ± 10.9). The hourly distribution of VT/VF episodes is shown in Figure 4. No significant differences were found between the two treatment arms (two-sided P = 0.48). In addition, no significant variance (H = 0.78, P = 0.67) was found in the mean duration of each episode in the three groups; values were 19.4 ± 8.7 s in the chronic amiodarone group, 29.4 ± 9.8 s in the acute amiodarone group, and 22.4 ± 4.4 s in controls.
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Arrhythmia score
A statistical variance was present in the arrhythmia score during the entire observation period, owing to significantly lower score in either the chronic or the acute amiodarone groups compared with controls (Table 1).
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Serum catecholamine levels
A variance (F = 4.0, P = 0.0151) was present in epinephrine plasma levels 24 h post-ligation, owing to lower values in sham-operated animals. However, values in both treatment arms did not differ from values in control animals. A more prominent statistical variance (F = 19.5, P < 0.0001) was found in norepinephrine plasma levels 24 h post-ligation, owing to significantly lower values in the chronic amiodarone group compared with either the acute amiodarone or the control groups (Table 2).
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Twenty-four hour mortality
Total mortality was 30.7% in the chronic amiodarone treatment arm, 10.0% in the acute amiodarone treatment arm, and 47.8% in controls. The variance in total 24 h mortality indicated only a trend towards statistical significance (H = 4.4, P = 0.10). Pair-wise comparisons revealed no difference between chronic amiodarone and controls, but a trend (P = 0.054) towards a lower 24 h mortality in the acute amiodarone group than in controls. No cases of sinus arrest were recorded. Mortality in both amiodarone treatment arms was exclusively due to bradyarrhythmia secondary to complete atrioventricular block, generally thought as representative of cardiac failure mortality.12
,13,19,20 All bradyarrhythmic deaths were preceded by sinus tachycardia and clinical signs of morbidity, followed by an abrupt onset of complete atrioventricular block and ventricular asystole. Thus, 24 h mortality in both amiodarone treatment arms was attributed to cardiac failure, whereas 24 h mortality in controls was mainly attributed to tachyarrhythmic death, as shown in Figure 5.
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Discussion |
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Amiodarone is effective in suppressing VT/VF during acute MI, but delayed onset of action after oral dosing remains a concern.2
,21 Pre-treatment with amiodarone is not clinically feasible and may increase mortality due to cardiac failure.12 In the present study, we compared chronic pre-treatment with an acute amiodarone dosing regimen in the conscious rat model of MI. This model is suitable for the study of ischaemic arrhythmias, as the rat displays a high frequency of VT/VF post-ligation, with a time course resembling that observed in humans post-MI.13,18–20 In the rat model, the significance of PVCs, doublets or triplets, is debated,13 hence such count was omitted. Moreover, separating VF from VT is difficult,12,13 therefore in the present study, VT and VF are reported collectively.
Antiarrhythmic efficacy of acute and chronic amiodarone treatment
We report a comparable antiarrhythmic efficacy of acute and chronic amiodarone administration. Compared with controls, both treatment regimens decreased the number of VT/VF episodes by 85%. However, it should be noted that the dosages used in the present study were high, compared with those used clinically. A rather surprising finding of the present study was the fast onset of action after a single, large, oral dose of amiodarone. This inference is based on the very low incidence of VT/VF during the first hour post-ligation in acutely treated rats when compared with controls. This observation is important because several studies in rats12,13,18–20 have indicated that this time period is highly arrhythmogenic.
Although a wealth of experimental11,12 and clinical3 information is available on the efficacy of amiodarone after chronic oral loading, very few data exist with respect to its actions after a single oral dose. Nagasawa et al.22 reported suppression of PVCs and VF after a single oral amiodarone (40 mg/kg) administration 2 h prior to coronary ligation in dogs. In a clinical study of 65 patients with supraventricular or ventricular arrhythmias,23 an antiarrhythmic effect was observed within hours after a single oral dose (30 mg/kg) of amiodarone. Plasma concentrations increased as early as 1 h and maximal levels were measured 6 h after administration. These findings are similar to those reported in a large paediatric population,24 but differ from those reported in adult patients, when divided doses were used.25 Our experimental data, examined together with previous clinical experience,23–25 suggest that a fast onset of action can be anticipated after oral amiodarone loading, and a single, large dose regimen should be advocated.
Sympathetic activation post-myocardial infarction and amiodarone treatment
In the present study, we report no differences in epinephrine, but significantly lower serum norepinephrine levels 24 h post-ligation in the chronic amiodarone group. These findings are in accordance with our previous results in an identical experimental setting.12 Although the class II effect of amiodarone is established,1,2 the exact mechanisms are not well understood. In addition to non-selective blockade of beta-adrenergic receptors,11 amiodarone affects intra-neuronal norepinephrine metabolism26; thus, during sympathetic activation, such as during acute MI, norepinephrine release is impaired, with consequent decreased plasma spillover.26 In our present study, norepinephrine levels in the single-dose amiodarone group were comparable with controls, indicating that these actions on norepinephrine metabolism occur only during chronic treatment.
Effects of amiodarone treatment on 24 h mortality
Whether the altered norepinephrine release after chronic amiodarone treatment is beneficial during acute MI is debatable. Our finding of comparable antiarrhythmic efficacy of acute and chronic amiodarone treatment, despite lower norepinephrine levels in the latter group, indicates that chronic sympathetic modulation is not necessary for the agent’s antiarrhythmic actions. Moreover, impaired norepinephrine release after chronic amiodarone treatment may deprive the myocardium of the required inotropic support during acute MI. This mechanism may provide an explanation for the lack of survival benefit observed in large clinical trials after chronic amiodarone treatment, mainly in patients with impaired left ventricular function.27 This hypothesis is reinforced by the findings of our present and previous12 studies, in which a trend towards increased bradyarrhythmic 24 h mortality was observed after chronic amiodarone treatment. In the rat model, this mode of death is generally considered to be secondary to heart failure.12,13,19,20 Indeed, the percentage of bradyarrhythmic death in our control rats is almost identical to that attributed to cardiac failure post-ligation in previous experimental studies.19 Furthermore, in line with previous findings from our group12 and others,13,19,20 all bradyarrhythmic deaths were preceded by sinus tachycardia and clinical signs of morbidity, indicating heart failure.
Limitations of the study
We feel that our study contributes to the current understanding of pharmacological therapy of VT/VF during acute MI. However, four limitations may be apparent. First, plasma and/or myocardial tissue levels of amiodarone were not measured. Secondly, HR variability measurement would have provided a more detailed assessment of the autonomic tone post-MI. Thirdly, the single oral dose of amiodarone in the present study (100 mg/kg) was over three times higher than that previously used in patients (30 mg/kg).23 Future studies should examine whether the antiarrhythmic efficacy of a single amiodarone administration is maintained after a more clinically applicable dosage. Lastly, although our sample size was optimal for the assessment of the antiarrhythmic effects of amiodarone, our study was underpowered to detect differences in mortality. Moreover, mortality was evaluated 24 h after ligation, and long-term assessment is lacking.
Conclusions and clinical implications
In our animal study population, a rapid suppression of ischaemic VT/VF was achieved after a single oral loading dose of amiodarone. The antiarrhythmic efficacy of acute amiodarone administration was comparable with chronic pre-treatment, with a lower incidence of cardiac failure. A single-dose regimen may prove clinically useful during emergency medical transfer of MI patients from primary care centres to tertiary hospitals with coronary care unit and cardiac catheterization facilities. Clinical studies, using a lower amiodarone dosing regimen, may be warranted to evaluate this treatment strategy.
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This research was funded, in part, by the Cardiovascular Research Institute, Ioannina and Athens, Greece (30554762 and 33867580 to M.G.A. and 33867576 to G.G.B.). We are indebted to Actelion Hellas, S.A., for their financial aid in upgrading our arrhythmia analysis software.
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Acknowledgements |
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We wish to thank Sanofi-Aventis, Montpellier, France, for providing amiodarone.
Tzihad Albouharali, MD, performed all radioimmunoassay measurements. Panagiotis Lekkas, BSc, and Anastasia Alevizatou, RN, provided valuable help during the experiments. Eleni Goga, MSc, was an excellent research coordinator.
Conflict of interest none declared.
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