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Cardiovascular Research 2001 49(1):94-102; doi:10.1016/S0008-6363(00)00235-2
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Copyright © 2000, European Society of Cardiology

Altered response to ibutilide in a heart failure model

Sumeet S. Chugh*, Susan B. Johnson and Douglas L. Packer

Division of Cardiovascular Disease, Department of Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN, USA

* Corresponding author. Cardiology Division, UHN-62 Oregon Health Sciences University 3181 SW Sam Jackson Park Road, Portland, OR 97201, USA. Tel.: +1-503-494-8750; fax: +1-503-494-8550 chughs{at}ohsu.edu

Received 31 May 2000; accepted 15 September 2000


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 5 Conclusions
 References
 
Objective: Despite the frequent use of anti-arrhythmic drugs in the general population, the electrophysiologic effects of these agents have not been elucidated in congestive heart failure (CHF). Methods: To examine the impact of left ventricular dysfunction on actions of type III anti-arrhythmic drugs, we evaluated the actions of ibutilide in a canine model of pacing-induced dilated cardiomyopathy. Following ablation of the atrioventricular node, effects on action potential duration at 90% (APD90) were compared in vivo, between eight CHF animals and seven controls. Monophasic action potential recordings were obtained from right and left ventricular endocardium/epicardium during and after three doses of ibutilide (0.01, 0.02 and 0.05 mg/kg), at pacing cycle lengths of 300–1000 ms. Results: APD90 prolongation with ibutilide (0.01 mg/kg) was significantly greater in CHF vs. controls (P = 0.0026, ANOVA). However, plasma ibutilide levels at this dose, were not significantly different between the two groups. In CHF, maximal effects were observed at the lowest dose, whereas effects were gradual and dose-dependent in controls. With ibutilide administration (0.01 mg/kg), an increased dispersion of left–right ventricular APD90 was observed in CHF, but not in controls (P = 0.03). A trend was observed, for increased incidence of non-sustained polymorphic ventricular tachycardia in CHF. Conclusions: In the presence of CHF, the actions of ibutilide are altered significantly. These findings may reflect altered tissue effects, as a consequence of myocardial electrical remodeling in CHF.

KEYWORDS Antiarrhythmic agents; Heart failure; K-channel; Remodeling; Ventricular arrhythmias


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 5 Conclusions
 References
 
The syndrome of CHF results in the alteration of fundamental cardiac electrophysiologic properties [1–4]. At the cellular level, prolongation of the action potential duration is a consistent finding in animal models as well as human subjects [3,5,6]. This may be due to substantial reductions in the Ca2+-independent transient outward K+ current (Ito), the inward rectifying K+ current (IK1) as well as the slow component of the delayed rectifier K+ current (IKs) [3,6–8]. The role of augmentation in the inward Ca2+ current is less clear [9].

The impact of these fundamental electrophysiologic changes on antiarrhythmic drug action is also unclear. It is possible that the effectiveness of an antiarrhythmic drug could be enhanced in this electrophysiologically remodeled setting. Conversely, the additive effects of underlying physiology and drug action could heighten proarrhythmic risk. Although the increased prevalence of clinical proarrhythmia in subjects with CHF has been well-documented [10–17], there is a lack of studies investigating the fundamental mechanisms of antiarrhythmic drugs in this condition. To attain a better understanding of class III antiarrhythmic drug action in the presence of pre-existing abnormalities of repolarization, we compared the effects of ibutilide in dilated dysfunctional ventricles and normal ventricles, in vivo.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 5 Conclusions
 References
 
2.1 Pacemaker implantation
This study was approved by the Mayo Foundation Institutional Animal Care and Use Committee and followed the guidelines of the National Institutes of Health Guide for Care and Use of Laboratory Animals [18]. Fifteen adult mongrel dogs of either sex were studied. In eight animals, dilated cardiomyopathy was induced by rapid pacing [5,19]. Under ECG monitoring, Nembutal anesthesia (30 mg/kg i.v.) was administered and mechanical ventilation was initiated. Clindamycin (300 mg s.q.) and Flocillin (2 ml i.m.) were also given prophylactically. Following a procedure described by Zhu et al. [5], a left thoracotomy was performed, allowing placement of a 53-cm epicardial screw-in lead at the LV apex. The lead was tunneled to a modified pulse generator secured in an infrascapular subcutaneous pocket, which was programmed to VVI mode (30 bpm). Postoperatively, animals were treated with butorphanol (0.2–0.4 mg/kg) as needed for pain. Following a 3–4-day recovery period, pacing at 250 bpm was initiated. Animals were examined daily, with periodic electrocardiographic monitoring to ensure appropriate pacemaker capture. Transthoracic echocardiography was performed prior to and weekly after surgery, while the dogs were unrestrained. To avoid an extra surgical procedure, the control group of seven dogs did not undergo pacemaker implantation.

2.2 Open-chest study
All animals underwent a final open-chest evaluation. A re-study was undertaken in CHF animals when ejection fraction was less than 30% or signs/symptoms of severe CHF were apparent. Animals were studied in the supine position after anesthesia induction with Nembutal (5–10 mg/kg i.v.) to maintain a deep level of anesthesia. After intubation, mechanical ventilation was initiated with supplemental oxygen at 4 l/min.

Cardiac hemodynamics were measured in the closed-chest state using a 7-Fr balloon tipped catheter in the pulmonary artery and a 5-Fr pigtail in the LV. After median sternotomy, the chest wall was retracted and the heart supported in a pericardial cradle. Atrioventricular (AV) node ablation was performed using a technique described by Steiner et al. [20]. The left ventricle (LV) was paced from the apex using the chronic indwelling pacing lead in CHF animals and a new pacing electrode in the same location in controls. Two custom-made 12x12 mm silastic conforming plaques, each with 12 pairs of recording electrodes (2 mm inter-pair spacing, three pairs per arm, arranged in a ‘cross’ configuration around a central pacing electrode) were sutured to the epicardial surface of the basal portion of the right ventricle (RV) and the LV apex. Plaques were positioned with two electrode arms parallel and two transverse to the epicardial fiber orientation. Recorded electrograms were digitally converted and displayed on a 48-channel cardiac mapping system (Prucka Engineering) for subsequent analysis. Myocardial temperature was monitored at the cardiac apex. Serial monitoring of blood gases and electrolytes ensured maintenance of physiological conditions. Body temperature was maintained at 37°C with a water circulating heating pad and overhead lamps.

2.2.1 Monophasic action potential recordings
Epicardial and endocardial monophasic action potentials (MAPs) were recorded from the vicinity of the two epicardial plaques. For endocardial recordings, a MAP contact electrode catheter was introduced into the RV from an external jugular vein cutdown, and via a common carotid artery cutdown for LV recordings. Epicardial MAP recordings were acquired using a table-mounted, spring-loaded cantilever system [21]. A stable MAP configuration and diastolic segment over the course of the experiment was required for data analysis. Criteria for inclusion of MAP recordings for analysis were prespecified and included amplitude of at least 10 mV, constant baseline potential and smooth phase 3 contour. The onset of the action potential was defined as the earliest point of abrupt rise of phase zero, and the point of 90% recovery (APD90) referenced to the maximum amplitude of the plateau phase of the action potential. Typically, measurements from three consecutive action potentials were averaged for analysis [5,21,22].

2.2.2 Effect of heart rate on cardiac repolarization
The rate-dependence of repolarization was assessed during LV pacing (pulse width 2.0 ms, amplitude twice diastolic threshold) at cycle lengths of 1000, 600, 500, 400 and 300 ms without interim pause. To eliminate virtual cathode effects, coaxial bipolar pacing was performed from the center of the silastic plaques. APD90 was measured after at least 20 s of pacing at any cycle length.

2.3 Study protocol
Following closed-chest hemodynamic evaluation, sternotomy and AV node ablation, baseline assessment of MAP duration was made and measurements of refractoriness undertaken. Thereafter, ibutilide was administered cumulatively in three doses, 0.01, 0.02 and 0.05 mg/kg i.v., each as a 10-min infusion. The first two doses were specifically selected to simulate the clinical routine for administration of ibutilide in human subjects. At 10 min following each ibutilide infusion, measurements of MAP duration were repeated. Measurements were completed within 30 min of each dose. Plasma ibutilide levels (Pharmacia & Upjohn) were obtained at baseline, 10 and 40 min after each dose. Occurrence of spontaneous or induced ventricular arrhythmia was noted, as were the duration and configuration of the action potential both preceding and during arrhythmia episodes.

2.4 Statistical analysis
Students unpaired t-test was used to compare measures of left ventricular function between the two groups. Two-way repeated measures analysis of variance (ANOVA) methods were employed to analyze the differences between control and CHF groups, as well as between baseline and each subsequent intervention in either group. A paired t-test was used to compare APD90 at different cycle lengths in either group. Plasma ibutilide levels were analyzed in a similar fashion, using two-way repeated measures (ANOVA) for group effects and paired t-test for control vs. CHF at individual sampling periods. P values less than 0.05 were considered significant.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 5 Conclusions
 References
 
3.1 Evidence of LV dysfunction in CHF
At a mean pacing duration of 29±4 days, dogs in the pacing group developed significant LV dysfunction as indicated by a decrease in the echocardiographic ejection fraction to 27±5 vs. 59±3% seen in the control group (Table 1). This was accompanied by an increase in the left ventricular end-diastolic dimension to 47±5 vs. 33±4 mm in control animals (P<0.001). Left ventricular end-diastolic pressure was four-fold higher in the CHF group (28±7 vs. 7±1 mmHg, P<0.001). Changes in right atrial and pulmonary artery pressures were also indicative of significantly reduced LV function in the CHF group (Table 1).


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  		Table 1 Comparison of hemodynamic parameters

 
3.2 Evidence of repolarization abnormalities in CHF
Rapid pacing in the CHF group had significant effects on APD90. Mean APD90 was significantly longer in the CHF animals compared to controls at all pacing cycle lengths (P<0.05, ANOVA). At baseline, control vs. CHF APD90 values were 169±13 vs. 178±7, 181±12 vs. 194±9, 190±13 vs. 205±11, 194±16 vs. 211±13 and 197±16 vs. 211±14 ms at cycle lengths 300, 400, 500, 600 and 1000 ms, respectively (mean±S.D.). In addition, there was a trend for greater prolongation in APD90 with increasing cycle length in CHF vs. controls (P = 0.19, ANOVA).

3.3 Comparison of ibutilide effects in CHF vs. controls
Ibutilide increased action potential duration in both groups. Representative tracings for effects of ibutilide on the MAP in one control and one CHF animal are shown in Fig. 1. However, at the lowest ibutilide dose, effects were significantly greater in CHF animals compared to controls at all pacing cycle lengths (ibutilide 0.01 mg/kg, P = 0.0026 ANOVA). As mean APD90 at baseline was greater in CHF, these data are expressed as percent APD90 increase (Fig. 2). These effects on APD90 were observed at both right and left ventricular recording sites. In controls mean APD90 increased by 2 and 11% in LV and RV, respectively. In CHF animals, an average APD90 increase of 18 and 19% was observed at LV and RV sites, respectively. With ibutilide 0.02 mg/kg, these trends were not statistically significant. At the highest dose of ibutilide (0.05 mg/kg), no differences in values of APD90 could be detected between control and CHF animals (Fig. 3).


Figure 1
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  		Fig. 1 Examples of actual action potential recordings showing ibutilide effects on APD90 in a control animal (a) and a CHF animal (b). The numbers 1, 2 and 3 represent baseline, 0.01 mg/kg and 0.02 mg i.v. ibutilide, respectively. All recordings are from RV epicardium, at pacing cycle length 600 ms. APD20, APD50 and APD90 represent action potential duration at 20, 50 and 90%, respectively.

 

Figure 2
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  		Fig. 2 Significantly greater APD90 prolongation in CHF (ibutilide 0.01 mg/kg; *, P = 0.0026 ANOVA) at all cycle lengths. As CHF APD90 values were greater at baseline, APD90 prolongation is expressed as percentage APD90 increase. APD90 values are averaged from all cardiac locations.

 

Figure 3
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  		Fig. 3 Comparison of ibutilide dose response at CL 600 ms. With increasing ibutilide dose, mean APD90 values were greater in CHF vs. controls until 0.05 mg/kg i.v. At this dose there was no significant difference in APD90 for CHF vs. controls. *, P<0.05 ANOVA, CHF vs. controls. APD90 values are averaged from all cardiac locations.

 
While ibutilide effects were dose-dependent in controls (Fig. 4a), near maximal prolongation was achieved in CHF with the first dose (Fig. 4b). Subsequent doses of ibutilide did not result in further prolongation of the action potential duration in the CHF group (Fig. 4b).


Figure 4
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  		Fig. 4 Dose-related effects of ibutilide. (a) Controls — effects were dose-dependent. *, P<0.05 for CL 300 vs. 600 ms at 0.02 mg/kg i.v. ANOVA P<0.005 for baseline vs. 0.01 mg/kg; ANOVA P<0.005 for 0.02 vs. 0.05 mg/kg. (b) CHF — effects were independent of dose, with the lowest dose producing maximal effects. ANOVA P<0.005 for baseline vs. 0.01 mg/kg; P = NS for 0.01 mg/kg vs. 0.02 or 0.05 mg/kg. APD90 values are averaged from all cardiac locations.

 
3.4 Rate dependence of actions of ibutilide
Trends for more pronounced effects on APD90 were observed at slower heart rates (CL 600 vs. 300 ms) in both CHF and control animals (Fig. 4a and b). However, statistical significance for this trend was achieved only in control animals (dose 0.02 mg/kg; P<0.05). While CHF animals exhibited numerically greater increases in APD90 at cycle length 600 vs. 300 ms at all doses, these differences were not statistically significant.

3.5 Ibutilide effects on dispersion of action potential duration
At baseline, there were no significant differences between left and right ventricular or epicardial and endocardial APD90 values in either group. With ibutilide administration (0.01 mg/kg), the difference between left and right ventricular APD90 was significantly increased in CHF but not in controls (P = 0.03, Table 2). Significant differences were not observed at other doses. Differences in endocardial–epicardial APD90 dispersion between the two groups were not statistically significant at any dose (Table 2).


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  		Table 2 Ibutilide effects on dispersion of repolarization

 
3.6 Occurrence of ventricular arrhythmia with ibutilide infusion
Both polymorphic (3–4 beats) and monomorphic (3–20 beats) non-sustained ventricular tachycardia (VT) occurred during ibutilide infusion. Polymorphic VT was observed in three CHF and one control animal (P = 0.34), while monomorphic VT was noted in four animals in each group. MAP recordings identified certain distinct characteristics of these tachycardias. Prior to ibutilide administration, no oscillations of the action potential or premature ventricular depolarizations were observed in either group. However, in four animals (three CHF and one control) prominent oscillations in late phase 3 of the action potential were observed with ibutilide administration. Some of these oscillations reached threshold and resulted in premature MAPs. Such oscillations and premature action potentials initiated all episodes of polymorphic VT (Fig. 5a). On multiple occasions, phase 3 transients resulted in single premature depolarizations (Fig. 5b). In contrast, initiation of monomorphic VT always occurred during the diastolic interval, after completion of repolarization. All ventricular arrhythmias were more likely to occur during, rather than following ibutilide infusion, but were unrelated to ibutilide dose or plasma levels. Tachycardia occurrence in a specific animal could not be explained on the basis of differences in left-ventricular function, APD90 dispersion or extent of ibutilide-induced APD90 prolongation.


Figure 5
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  		Fig. 5 Surface ECG with simultaneous monophasic action potential recordings during ibutilide infusion. (a) (Polymorphic VT) is from a study in a CHF animal. (b) (Isolated premature ventricular complexes) from a control animal. Catheter position is RV endo (endocardial).

 
3.7 Plasma levels of ibutilide
As a group, peak plasma ibutilide levels were higher in CHF animals vs. controls [P(group)=0.023, Fig. 6]. However, at the individual sampling periods, there were no significant differences between plasma ibutilide levels in control and CHF animals.


Figure 6
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  		Fig. 6 Comparison of plasma ibutilide levels. As a group, plasma ibutilide levels were greater in CHF than in controls. However, there were no significant differences between CHF and control animals at any individual sampling period. ANOVA (group) P = 0.023; *, P = NS (control vs. CHF for each sampling period).

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
5 Conclusions
 References
 
In the present study, we observed augmented effects of ibutilide on cardiac repolarization, in the setting of canine dilated cardiomyopathy. In addition, in CHF animals, near-maximal effects on action potential duration were noted with the lowest dose of ibutilide. However, in controls, the response to ibutilide was dose-dependent, with greater action potential prolongation at higher doses. These differences in drug action could not be explained on the basis of plasma ibutilide levels. Both groups attained a common maximal limit for action potential prolongation. Increased dispersion of repolarization with ibutilide was observed in CHF, but not in controls. We also noted inverse rate-dependence of ibutilide effects in both groups, and a trend toward increased occurrence of polymorphic ventricular tachycardia in CHF animals.

CHF is accompanied by the occurrence of significant cardiac repolarization abnormalities [3,8,23]. Thus far, their impact on anti-arrhythmic drug action in CHF has been unclear. The rationale for the use of ibutilide as an anti-arrhythmic drug is action potential prolongation, mediated either by blocking the rapidly activating component of the delayed rectifier [24], or increasing a slow inward plateau Na+ current [25]. In CHF, well-described potassium channel abnormalities limit the availability of repolarizing currents, thereby resulting in action potential prolongation [17]. Further prolongation of repolarization by ibutilide could add to the altered electrophysiologic milieu of CHF. In contrast to controls, ibutilide effects on the APD90 in CHF were significantly greater at the lowest, clinically relevant dose. In addition, near maximal effects were observed at the lowest dose and subsequent dose increases were not additive. Thus the limit of repolarization reserve may have been attained at the 0.01 mg/kg dose due to a paucity of recruitable repolarization currents. The common maximal value of action potential duration achieved during ibutilide infusion in both control and CHF groups, suggests there exists a limit for prolongation of repolarization due to a specific drug mechanism.

A recent study examined proarrhythmic effects of ibutilide in a canine model of cardiomyopathy [26]. Both in methodology and design, this study is dissimilar to the present one. The authors used a new model where AV block was created prior to pacing for 2–3 weeks, which renders it a model of AV block and heart failure. In addition, the majority of effects were observed at 0.04 and 0.08 mg/kg i.v. of ibutilide, which reflect drug toxicity, not proarrhythmia. Also, plasma ibutilide levels were not measured, limiting the ability to evaluate effects at the tissue level. In the present study, AV block was created at the time of the terminal study, exclusively to evaluate ibutilide effects during bradycardia. We observed differential effects with ibutilide which were of the greatest magnitude with the first dose (0.01 mg/kg) especially administered to reflect the prescribed clinical dose of ibutilide in patients. Also, our conclusions regarding altered effects at the myocardial level are based on similar plasma levels between control and CHF, at the first initial dose of ibutilide.

Ibutilide infusions resulted in both polymorphic and monomorphic non-sustained ventricular tachycardia. It is likely that the episodes of polymorphic tachycardia represent non-sustained torsades de pointes. The exact mechanism of drug-related torsades de pointes is unclear, although there is substantial evidence for early afterdepolarizations as an important focal trigger for this arrhythmia [27]. Such early afterdepolarizations have been described in a rabbit model of proarrhythmia during administration of toxic doses of ibutilide [28]. In a canine model of AV block and ventricular hypertrophy, early afterdepolarizations were observed to be dose-dependent, with highest incidence at a dose of 0.08 mg/kg i.v. [29]. In the present study, the initiating beat of polymorphic VT consistently arose from phase 3 of the action potential. Preceding action potential complexes revealed sub-threshold transients in the smooth contour of phase 3, consistent with early after-depolarizations. While the exact location of this process could not be determined in the present study, involvement of both Purkinje and M cells has been reported [30,31]. Similar to the canine AV model [29], but unlike the rabbit proarrhythmia model [28], we observed the greatest effect of ibutilide at the slowest heart rates. This ‘reverse rate-dependence’ is a feature of anti-arrhythmic agents blocking the delayed rectifier potassium current [32] and may increase the risk of proarrhythmia at lower heart rates. These findings may further explain the clinical experience with ibutilide, which suggests an increased incidence of torsades de pointes in patients with CHF and an inverse relationship with heart rate [12,16].

We observed significantly increased APD90 dispersion between LV and RV with the lowest clinically relevant dose of ibutilide in CHF vs. controls. Interventricular dispersion of repolarization has been implicated as a mechanism for the maintenance of torsades de pointes due to ibutilide as well as D-sotalol in the canine atrioventricular block model [29,33]. In contrast to ibutilide effects in AV block [29], in our study interventricular dispersion was not dependent on dose of ibutilide. This could be related to intrinsic differences between the models of AV block-induced hypertrophy and pacing-induced dilated cardiomyopathy. In addition, higher doses of ibutilide (up to 0.08 mg/kg i.v.) were used in the AV block model and plasma ibutilide levels were not available [29]. In general, increased dispersion of repolarization due to structural myocardial disease or extrinsic factors may play a role in the maintenance of torsades de pointes [34,35]. Functional re-entry due to increased dispersion of repolarization has also been suggested as a possible mechanism for induction of monomorphic VT [36]. Episodes of monomorphic VT were observed in both control and CHF animals in our study. This is consistent with the ibutilide clinical experience, with a 3.8% incidence of monomorphic VT in an efficacy and safety trial [16]. While the study was not designed to observe differences in arrhythmia incidence in control vs. CHF animals, non-sustained polymorphic VT was more likely to occur in CHF.

4.1 Limitations
To avoid subjecting animals to an additional procedure, the control group did not undergo sham implantation of pacemakers. However, we observed no significant differences in baseline hemodynamic and electrophysiologic parameters between these controls and sham operated animals employed in an earlier study performed in our laboratory [5]. Specifically, values in the present control group vs. previous sham-operated animals were: ejection fraction 59±3 vs. 62±3%, mean right atrial pressure 4±1 vs. 4±2 mmHg, pulmonary capillary wedge pressure 7±1 vs. 6±1 mmHg and APD90 (cycle length 300 ms) 169±13 vs. 165±20 ms (P = NS for all).

Potassium channel blockade with ibutilide may produce differential effects at varying locations, as K+ channel expression may vary in different parts of the same ventricle [37]. Thus MAP recordings at four sites may not adequately reflect changes in dispersion of repolarization. However to ensure uniformity, MAP recordings were performed at consistent locations at LV/RV endocardium and epicardium for all animals in either group.

In CHF, both volume of distribution and drug clearance of antiarrhythmic drugs may be diminished [38]. Therefore, differences in drug levels and pharmacokinetics could potentially limit interpretation of these data. However, in the CHF group, maximal effects of ibutilide were observed with the lowest dose, despite increased plasma levels with subsequent doses. In addition, there were no significant differences between control and CHF plasma levels at any individual sampling period. Thus the exaggerated effects of ibutilide in CHF animals are not explained by altered drug levels or drug handling.


   5 Conclusions
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 5 Conclusions
References
 
Ibutilide has differential effects on cardiac repolarization in canine dilated cardiomyopathy vs. control animals, at clinically relevant doses. Plasma ibutilide levels suggest that these effects may, in part, be due to CHF-related ventricular electrical remodeling. Altered effects at the level of remodeled myocardium may be an important consideration while using type III anti-arrhythmic drugs in CHF.

Time for primary review 26 days.


   Acknowledgements
 
This study was supported by the Mayo Foundation Clinical Investigator Program (Douglas L. Packer). The authors thank Pharmacia & Upjohn for their assistance in obtaining ibutilide levels.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 5 Conclusions
 References
 

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