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Cardiovascular Research 1998 40(1):56-63; doi:10.1016/S0008-6363(98)00137-0
© 1998 by European Society of Cardiology
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Copyright © 1998, European Society of Cardiology

Antifibrillatory efficacy of ersentilide, a novel β-adrenergic and Ikr blocker, in conscious dogs with a healed myocardial infarction

Philip B. Adamsona,b,c,*, Emilio Vanolib,c,d,e, Stephen S. Hullb, Robert D. Foremanb and Peter J. Schwartzb,d,e

aW.K. Warren Medical Research Institute, Oklahoma City OK 73190, USA
bDepartment of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City OK 73190, USA
cCardiology Section of the Department of Internal Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City OK 73190, USA
dDipartimento di Cardiologia, Università di Pavia, IRCCS Policlinico S. Matteo, Pavia, Italy
eCentro di Fisiologia Clinica e Ipertensione, IRCCS Ospedale Maggiore, Università di Milano, Milano, Italy

* Corresponding author. University of Oklahoma, Health Sciences Center, Dept. of Physiology, P.O. Box 26901, BMSB 653, Oklahoma City OK 73190, USA. Tel.: +1 (405) 271 2226; Fax: +1 (405) 271 3181; E-mail: philip-adamson @uokhsc.edu

Received 3 February 1998; accepted 26 March 1998


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objectives: IKr blockade is ineffective in preventing ventricular fibrillation elicited by the interaction between acute myocardial ischemia and elevated sympathetic activity. This depends in part on the fact that adrenergic activation offsets more than 50% of the action potential prolonging effect of IKr blockade, and thus impairs its primary mechanism of action. This study examined the antifibrillatory effect of ersentilide (CK-3579), a novel antiarrhythmic agent which combines blockade of the rapid component of the delayed rectifier potassium channel (IKr) with relatively weak β-adrenergic blockade, in a conscious canine model of lethal arrhythmias. Methods: Ersentilide was tested in 19 dogs with a healed myocardial infarction (MI) undergoing two minutes of circumflex artery occlusion (CAO) during sub-maximal treadmill exercise. Epicardial monophasic action potential duration was measured before and after ersentilide in 8 anesthetized open chest dogs at baseline and during stimulation of the left stellate ganglion at constant paced heart rate. Results: In the control tests 13 of the 19 dogs had ventricular fibrillation (VF) during the exercise and ischemia test, 6 did not. During a subsequent exercise test, ersentilide prevented VF in 85% (11 of 13) of the high risk animals and showed no proarrhythmic effects in the 6 dogs without arrhythmias in the initial test. Ersentilide lowered heart rate at all levels of exercise and during acute myocardial ischemia. The antifibrillatory effect was maintained in 3 of 4 dogs in which heart rate was kept at control levels by atrial pacing. Ersentilide prolonged left ventricular monophasic action potential duration by 30% (from 179±6 ms to 233±5 ms, p<0.001) at a 360 ms cycle length and completely prevented its shortening during sympathetic stimulation. Conclusions: The combination of IKr and weak β-adrenergic blockade, using ersentilide, represents a very effective and safe antiarrhythmic intervention able to overcome the limitations present in drugs devoid of any antiadrenergic effect. Such a combination may be very useful in the management of post-myocardial infarction patients at high arrhythmic risk.

KEYWORDS Sudden death; K-channel; Autonomic nervous system; Myocardial infarction; Antiarrhythmic agents


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
The negative [1, 2]and neutral [3, 4]results of recent clinical trials after myocardial infarction (MI) underscore the need for development of new antiarrhythmic compounds not only effective in preventing lethal arrhythmias but also well tolerated and devoid of proarrhythmia. Partially encouraging results were obtained with amiodarone in two prospective multicenter trials, the European Myocardial Infarct Amiodarone Trial (EMIAT,3) and the Canadian Amiodarone Myocardial Infarction Trial (CAMIAT,4). In these two trials, amiodarone did not reduce cardiac mortality, but did significantly reduce the incidence of arrhythmic deaths.

Another clinically successful antiarrhythmic compound that shares some electrophysiologic properties with amiodarone is D,L-sotalol. D,L-sotalol reduced mortality in a British trial without reaching statistical significance possibly because the study was underpowered [5]. An excess mortality associated with D,L-sotalol in the early phase after MI, potentially related to the relatively high dose, did complicate the interpretation of the results of this study but the overall 18% reduction in mortality suggested potential benefit by the drug. In another, more recent study, D,L-sotalol appeared more effective than other antiarrhythmic compounds [6], but the trial design generated concerns that prevented generalization of the results [7].

The impact of these relatively encouraging results with amiodarone and D,L-sotalol is significantly hampered by their side effects [3, 4, 8]. Almost 40% of patients randomized to amiodarone discontinued therapy [3]. The use of D,L-sotalol is similarly limited by substantial side-effects due to its strong β-blocking properties [8]. In an attempt to overcome these limitations, two recent trials examined the antiarrhythmic efficacy of drugs designed to possess the electrophysiologic property deemed to be responsible for the success of amiodarone and D,L-sotalol, i.e. prolongation of repolarization. SWORD (Survival With ORal D-sotalol), used D-sotalol to selectively block the rapid component of the delayed rectifier potassium channel, IKr but was terminated early due to an increase in mortality in the actively treated group [2]. DIAMOND (Danish Investigations of Arrhythmia and Mortality ON Dofetilide) [9]used another IKr blocker, dofetilide, in post-MI patients, but without any effect on cardiac mortality (reported at the American Heart Association annual scientific meeting, 1997). While these trials do not exclude the possibility that prolongation of repolarization may be a reasonable approach to the prevention of arrhythmic death after MI, they suggest that an effective strategy to reduce post-MI mortality cannot be based on a single mechanism of antiarrhythmic action [10, 11].

Contrary to other pre-clinical animal data [12], we reported that D-sotalol did not prevent ventricular fibrillation (VF) elicited by the interaction between elevated sympathetic activity and transient myocardial ischemia in the presence of a healed MI [13]. In the same preparation also dofetilide is ineffective [14]. One possible mechanism for the lack of effect of D-sotalol and dofetilide is that they prolong repolarization by blocking IKr, but leave unopposed the catecholamine-sensitive slow component of IK, IKs [15]. The risk for lethal arrhythmias is greatly enhanced by elevated sympathetic activity and the consequent increase in heart rate [16, 17]. In this setting IKs activation must be taken in to account when prolongation of repolarization by IKr blockade is the dominant antiarrhythmic intervention.

The present study was designed to assess the efficacy of ersentilide (CK-3579), a new IKr blocker with less potent β-blocking properties than D,L-sotalol [18, 19]in preventing ventricular fibrillation due to acute myocardial ischemia and elevated sympathetic activity.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
2.1 Surgical preparation
The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the USD National Institutes of Health (NIH Publication No. 85-23, revised 1996).

The characteristics of the canine model used in this study have been described in detail elsewhere [20, 21]. Briefly, after induction of surgical anesthesia, a left 4th intercostal space thoracotomy was performed to expose the heart and great vessels. A catheter was secured in the descending aorta to chronically measure arterial blood pressure. The heart was exposed, a Doppler flow probe was placed around the circumflex coronary artery and a pneumatic vascular occluder was implanted distally. The left anterior descending coronary artery was permanently ligated immediately proximal to the first major diagonal branch after a 20 minute critical stenosis [20, 21]. All instrumentation leads were exteriorized on the dorsum of the neck. Each animal received immediate post-operative short-term analgesia (pentazocine lactate, 1 mg/kg, i.m.) followed by a longer acting analgesic (nalbuphine HCl, 0.5 mg/kg, i.m.). Thirty days were allowed for recovery from surgery and the MI before any testing was started.

2.2 Risk for ventricular fibrillation
To evaluate the risk for lethal arrhythmias, each dog underwent a submaximal exercise stress test on a motor-driven treadmill [20]. Dogs ran for approximately 12 to 15 min while the workload was progressively increased every 3 min (3 mph at 0% grade, 4 mph at 0% grade, 4 mph at 4% grade, 4 mph at 8% grade, and 4 mph at 12% grade) until heart rate reached approximately 220 bpm representing 75% of the theoretical maximum heart rate for a dog. When the target heart rate was achieved, the circumflex vascular occluder was inflated for 2 min: the animals continued to run during the first minute and exercise was stopped during the second minute of ischemia. Dogs developing VF during the two minutes of myocardial ischemia were defibrillated and labeled susceptible or high risk for VF. The remaining animals did not develop sustained ventricular arrhythmias and were labeled resistant, or low risk for VF. This protocol has consistently been associated with a >90% reproducibility of risk status [22].

2.3 Antiarrhythmic efficacy
Thirteen dogs, which developed VF during their initial exercise and myocardial ischemia test, were allowed 4 days of recovery before further testing was performed. The dogs repeated the exercise and myocardial ischemia test 30 minutes after administration of ersentilide (1 mg/kg, i.v.). The workloads for each exercise and ischemia test were the same. All animals protected by ersentilide then underwent another exercise and ischemia test after 7 days of drug washout to confirm reproducibility of VF. In two animals, reproducibility of VF was documented by two consecutive exercise and ischemia tests before administration of ersentilide. Early in the protocol the unexpected finding of an apparent long-term effect of ersentilide led to an extension of reproducibility testing in six dogs which were tested every 7 days following ersentilide administration up to 21 days. Since heart rate was lower after ersentilide administration, four of the protected animals ran another exercise and ischemia test after a second dose of ersentilide, but with atrial pacing at rates equivalent to the no-drug run.

The potential proarrhythmic risk with ersentilide was evaluated in 6 dogs resistant to VF. These animals repeated the exercise and myocardial ischemia test at the same workload, 30 min after administration of ersentilide (1 mg/kg, i.v.) and the incidence of ventricular arrhythmias was monitored.

2.4 Effects on monophasic action potential and ventricular contractility
Eight dogs prepared for the arrhythmia study were also used to examine the effect of ersentilide on ventricular monophasic action potential (MAP) according to a protocol already described [23]. Animals were anesthetized with thiopental sodium followed by alpha-chloralose (80 mg/kg with 10–20 mg/kg, i.v. supplements as needed) and mechanically ventilated after endotracheal intubation. A left thoracotomy was performed in the fourth intercostal space, the heart was exposed and the left stellate ganglion was prepared for electrical stimulation. Epicardial MAPs were recorded from the left ventricular lateral wall by means of silver–silver chloride electrodes (EP Technology). The signal was considered acceptable for analysis if its amplitude exceeded 10 mV. Data were collected during atrial pacing at 360, 330 and 300 ms cycle lengths. The atria were paced at each cycle length for 2 min to obtain stable baseline recordings followed by 20 second stimulations of the left stellate ganglion (15 Hz, 2–4 mA, 3 ms pulse duration). Sympathetic stimulation was considered satisfactory if systolic blood pressure increased by at least 20–30 mmHg. Ten minutes were allowed for recovery between each pacing session. Monophasic action potential was measured at 90% of repolarization before and after administration of ersentilide (1 mg/kg, i.v.). Concomitant to MAP evaluations, left ventricular dP/dt was determined using an intraventricular pressure measurement with a Millar pressure transducer placed in the left ventricular apex. All dP/dt recordings were made at a stable cycle length of 360 ms.

2.5 Isoproterenol dose response curves
Peak heart rate responses to increasing doses of isoproterenol were evaluated in control conditions, after administration of propranolol (1 mg/kg, i.v.) and, on another day, after ersentilide (1 mg/kg, i.v.) in 13 animals. Isoproterenol dose response curves were also evaluated in five dogs before and after administration of D,L-sotalol (8 mg/kg, i.v.). These doses were chosen because they were effective in preventing ventricular fibrillation in the canine model of sudden death used here [13], as well as in another experimental preparations [24]. The animals were first acclimated to the recording environment by repeated exposure to the laboratory. When the dogs were determined to be calm, based on heart rate and behavioral evaluation, i.v. boluses of isoproterenol were administered in doses from 0.01 to 1 µg/kg during continuous recording of the transthoracic ECG. Repeated isoproterenol dose response curves were evaluated approximately every 4–6 days after the administration of ersentilide in three animals in which ersentilide appeared to have produced prolonged antifibrillatory effect.

2.6 Statistical analysis
Chi square analysis with Bonferroni correction was used to compare changes in the incidence of VF. One-way ANOVA for repeated measures was used to compare the effects of ersentilide on heart rate, blood pressure, MAP, and dP/dt. Significance was determined at p<0.05. Data are reported in the text as mean±standard deviation.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
As shown in Fig. 1, 76 mongrel dogs entered the study and 34 (45%) died either in the very early phase after coronary artery ligation (n=17, 22.5%) or within the following week (n=17, 22.5%). Four dogs were lost to the protocol due to instrumentation failure. Thirty-eight dogs underwent the exercise and myocardial ischemia test to evaluate risk for VF 30 days after myocardial infarction. Thirteen (34%) of these 38 dogs developed VF during exercise and transient myocardial ischemia (susceptible). The remaining animals (n=25) had no sustained ventricular arrhythmias (resistant). Subsequently, all 13 susceptible dogs were treated with ersentilide and the exercise test was repeated to determine the drug's antifibrillatory efficacy. Six of the resistant animals underwent another exercise test after ersentilide to test the potential proarrhythmic effect of the drug.


Figure 1
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  		Fig. 1 Flowchart of the study (see text for detail).

 
3.1 Effect on heart rate and on risk for ventricular fibrillation
Ersentilide prevented VF in 11 of the 13 (85%, p<0.05) susceptible dogs (Fig. 2). This protection was associated with a reduction in heart rate during exercise as shown in Fig. 3. Ersentilide decreased resting heart rate from 113±30 bpm to 97±18 bpm (–14%, p<0.05) and heart rate reduction was seen at every level of exercise (p<0.01, Fig. 3). Immediately before coronary artery occlusion, heart rate was 220±25 bpm in the no drug test and 202±22 bpm with ersentilide. The antiadrenergic effect of ersentilide became particularly evident during acute myocardial ischemia. After 15 s of myocardial ischemia heart rate increased by 15% to 253±25 bpm during the no drug test compared with an increase of only 3% to 209±22 bpm after ersentilide. Overall, almost 80% of the neurally mediated increase in heart rate during acute ischemia was blocked by ersentilide. As a result, heart rate after ersentilide was 17% lower compared with the no drug test (p<0.001). In addition to these effects on heart rate, ersentilide prolonged the resting QTc interval by 9.6% from 260±7 msec to 285±3 msec (p<0.05) in 10 dogs.


Figure 2
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  		Fig. 2 Incidence of ventricular fibrillation (VF, y axis) during control, no drug conditions (left bar), and after 1 mg/kg i.v. of ersentilide (right bar) in 13 conscious dogs during exercise and myocardial ischemia, 30–45 days following myocardial infarction.

 

Figure 3
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  		Fig. 3 Heart rates during exercise (top panel) and acute myocardial ischemia (bottom panel) in 13 dogs 30–45 days after myocardial infarction during no drug conditions (closed square) and after 1 mg/kg i.v. ersentilide (closed circles).

 
To determine if the heart rate reduction was the sole mechanism of the protection seen, four of the protected dogs underwent another exercise test following a second bolus of ersentilide while the exercise heart rates were maintained with atrial pacing at the same levels observed in the pre-drug tests. Ersentilide prevented VF in three of the four dogs tested with atrial pacing (p<0.05) indicating a significant drug effect independent of heart rate reduction. However, although the results of the pacing experiments are statistically significant, caution must be applied in interpreting the results due to the small number of animals tested.

3.2 Isoproterenol dose-response
The β-blocking activity of ersentilide was compared with that of propranolol and D,L- sotalol using the heart rate response to increasing i.v. bolus doses of isoproterenol while the animals were resting quietly. Fig. 4 illustrates the relative β-blocking potency of the three drugs tested. Ersentilide was well over one order of magnitude less effective in β-adrenoceptor blockade compared to propranolol or D,L-sotalol. Specifically, the heart rate response to 1.0 mcg/kg of isoproterenol was 219±10 bpm in control condition, 183±9 bpm after ersentilide, (–16%, p<0.05) and 102±4 bpm after propranolol (–55%, p<0.01, Fig. 4). At the dose tested here the β-blocking effect of D,L-sotalol was comparable to that of propranolol. Isoproterenol at the dose of 1.0 mcg/kg increased heart rate up to 225±8 bpm with no drug and to 94±9 bpm after D,L-sotalol (–58%, p<0.01, Fig. 4).


Figure 4
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  		Fig. 4 Heart rate response to graded doses of isoproterenol before (triangles), after ersentilide (1 mg/kg, i.v., squares) and propranolol (1 mg/kg, i.v., circles) in 13 dogs 30 days after myocardial infarction. In another group of five dogs, 30 days after myocardial infarction D,L-sotalol (8 mg/kg i.v. diamonds) was also tested.

 
3.3 Monophasic action potential duration
Ersentilide prolonged MAP duration by 30% (from 179±6 to 233±5 ms, p<0.001) during pacing at a cycle length of 360 ms (see an example in Fig. 5). At this cycle length left stellate ganglion stimulation reduced MAP duration by 11% (p<0.01) before drug administration, but MAP duration was shortened only by 4% during sympathetic stimulation (p=NS) after ersentilide (Figs. 5 and 6Go). Ersentilide prolonged MAP duration by 20% (from 175±13 to 210±17 ms, p<0.001) at a paced cycle length of 330 ms and 21% at a cycle length of 300 ms (from 162±15 to 196±14 ms, p<0.001). Left stellate stimulation after ersentilide administration reduced MAP duration by 9% at a paced cycle length of 330 ms and by 4% at a paced cycle length of 300 ms. Overall, only 12 to 25% of MAP duration prolonging effect of ersentilide was lost during sympathetic stimulation, depending on the cycle length examined.


Figure 5
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  		Fig. 5 Monophasic action potential duration lengthening demonstrated during control, no drug conditions (tracing A), after 1 mg/kg i.v. of ersentilide (tracing B) and during left stellate ganglion stimulation after ersentilide (tracing C) in the same dog.

 

Figure 6
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  		Fig. 6 Changes in monophasic action potential duration as percent change from baseline during left stellate ganglion stimulation (LSGS; left bar), after ersentilide administration (1 mg/kg, i.v.; middle bar) and during LSGS following ersentilide administration (right bar).

 
3.4 Left ventricular dP/dt max
Ersentilide had no effect on resting dP/dt max (3418±243 vs 3861±268 mmHg/s, p=NS). However, ersentilide significantly blunted the positive inotropic effect of left stellate ganglion stimulation (5030±1090 vs 11 578±1194 mmHg/s, p<0.01).

3.5 Proarrhythmia
None of the six resistant dogs tested after ersentilide administration appeared to have an increase in arrhythmias at rest. Furthermore, during exercise and acute myocardial ischemia none of these dogs had VF, non-sustained ventricular tachycardia or an increase in PVCs.

3.6 Long-term antiarrhythmic effect
An unexpected long-term persistence of the antiarrhythmic effect after a single i.v. dose was found in 8 of the 11 dogs initially protected by ersentilide. Seven of these animals were monitored for susceptibility with a repeated exercise and ischemia test once a week for a total of 21 days following the first exposure to the drug. By 21 days, three of the seven dogs again developed VF but four of them still remained protected. The isoproterenol dose response curves in three of these animals demonstrated persistent β-blocking activity over this time period (Fig. 7).


Figure 7
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  		Fig. 7 Illustration of the prolonged β-adrenergic effect of one bolus injection of ersentilide (1 mg/kg, i.v.) on heart rate (top panel) in a representative dog. The bottom panel demonstrates the antifibrillatory effect of one bolus injection of ersentilide initially preventing ventricular fibrillation in 11 of the 13 susceptible dogs (Day 0). Seven of the protected animals were re-tested weekly. By day 21, 6 of the original 13 dogs had recurrence of VF. This was associated with a return to baseline of the isoproterenol heart rate stimulation response.

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
This study demonstrates the efficacy of ersentilide in preventing lethal arrhythmias due to acute myocardial ischemia and increased sympathetic activity. The main concept brought to focus is that a drug with one order of magnitude less β-blocking activity than propranolol or D,L-sotalol sufficiently antagonized the effect of sympathetic activation on action potential prolongation induced by IKr blockade. Maintenance of IKr blockade during elevated sympathetic activity resulted in excellent antifibrillatory efficacy. These results have implications for patients at high risk for sudden death after myocardial infarction who might not tolerate drugs with strong β-blocking activity.

4.1 The experimental model for sudden cardiac death and the antifibrillatory effect of ersentilide
The chronic canine model used in the present investigation allows the study of lethal arrhythmias resulting from the combination of acute myocardial ischemia, in the presence of a healed myocardial infarction, associated with high sympathetic activity due to exercise and ischemia-dependent autonomic reflexes [20]. This model has already provided several insights for the understanding of the autonomic mechanisms involved in lethal arrhythmias and has largely generated the background for the use of markers such as baroreflex sensitivity and heart rate variability in risk stratification after MI [21]. The clinical impact of these markers has been definitively proven in the recent prospective study ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) [25].

A critical aspect of this experimental preparation is the possibility to study, by internal control analysis, influences of autonomic activation on antiarrhythmic drug efficacy. Recurrence of acute myocardial ischemia associated with elevated sympathetic activity is one of the most important circumstances in which sudden death may occur. This hypothesis is supported by the growing evidence that patients with impaired autonomic balance resulting in sympathetic dominance and/or depressed cardiac vagal activity have a higher risk of cardiac mortality in the first year after MI [25]. The present study represents a rational step in the evaluation of a drug that, like ersentilide, has the potential for preventing sudden arrhythmic death. Ersentilide prevented electrophysiologically induced ventricular tachycardia as well as ischemia-dependent ventricular fibrillation in another model of sudden death [26]in which, however, also D-sotalol [12]and dofetilide [27]were effective but then failed in large clinical trials.

Among the many interventions studied in more than 250 susceptible dogs with this preparation [22]ersentilide, unlike D-sotalol or dofetilide, appears to be one of the most effective pharmacological means to prevent VF. The seemingly long-lasting effect of one i.v. bolus of ersentilide was intriguing, but the present study was not powered to adequately assess this unexpected effect. The persistently blunted heart rate response to isoproterenol in the three animals monitored over time also supported a long-term effect.

4.2 β-Adrenergic and potassium channel blockade and arrhythmia prevention
Blockade of the delayed rectifier potassium channel, IK, prolongs ventricular refractoriness which is the vulnerable parameter [10, 11]for reentrant arrhythmias, such as those occurring during acute myocardial ischemia [28]. The Sicilian Gambit has proposed the concept of a vulnerable parameter to describe the electrophysiogical property that, among others, is the ‘the most susceptible to alterations while manifesting a minimum of undesirable effects on the heart’ and which, when properly altered, will terminate or prevent the arrhythmia [10, 11]. Accordingly, prolongation of ventricular refractoriness may prevent reentrant arrhythmias by increasing the chances that the reentrant wavefront will encounter unexcitable tissue [10, 11]. In theory, and at first glance, antiarrhythmic therapy with compounds which block IK should have great potential for preventing sudden death arising from reentrant tachyarrhythmias. However, clinical reality is different. The first clinical trial (Survival With ORal D-sotalol, SWORD) designed to assess the effectiveness of blocking the major component of IK (IKr) using D-sotalol, reported excessive mortality in the treated group [2]. Our own experimental finding that D-sotalol was ineffective in preventing ventricular fibrillation (VF) due to the interaction between acute myocardial ischemia and elevated sympathetic activity in the presence of a healed MI [13]helped to interpret, at least in part, the results of SWORD.

The analysis of the currents involved in repolarization for the choice of specific antiarrhythmic therapy [10, 11]indicates that a compound with ‘pure’ IKr blocking activity is unlikely to maintain its electrophysiologic effect in conditions frequently associated with the onset of ventricular tachyarrhythmias, such as sympathetic activation and elevated heart rate. In this setting IKs becomes the predominant repolarizing current [15]and offsets most of the electrophysiologic action of drugs like D-sotalol, which do not interfere with this component of IK. We demonstrated that D-sotalol loses most of its electrophysiologic effect when sympathetic activity is elevated [23]. However, the failure of D-sotalol and dofetilide in post-MI trials should not be viewed as evidence to abandon prolongation of repolarization as a useful mechanism to prevent lethal arrhythmias in the ischemic heart, but rather as an indication for developing new compounds with multiple and better tolerated actions.

We considered important and hypothesized that a combination drug might not need strong β-blocking activity to remain effective. In contrast to D-sotalol, the racemic compound, D,L-sotalol, initially used clinically as a potent β-blocker, prevents VF in our canine preparation [13]. This directly correlates with clinical experience with D,L-sotalol [6, 8]. However, the strong β-blocking activity of D,L-sotalol is also responsible for most side effects associated with the drug and often limits its use [8]. Certainly the most worrisome side effect is proarrhythmia with an incidence of Torsade de Pointes (TdP) ranging between 2 and 4% in D,L-sotalol treated patients [8], but other problems with β-blockade are also clinically important. Torsade de Pointes is mechanistically related to early afterdepolarizations which are favored by slow heart rates in the presence of action potential prolongation [10, 11].

Ersentilide is a benzamide derivate that concomitantly acts on β-adrenoceptors and on the rapid component of IK, IKr. When compared with other compounds, ersentilide is about 20 times more potent in blocking IKr than D,L-sotalol [18], its β-blocking activity is stereospecific for β1-adrenoceptor [18]and is about 1 order of magnitude less potent than D,L-sotalol or propranolol (Fig. 4). In our study, ersentilide prolonged repolarization as much as D- or D,L-sotalol or dofetilide, but its weak β-blocking activity was sufficient to prevent action potential shortening produced by left stellate ganglion stimulation without reducing heart rate at rest or ventricular contractility, and affecting modestly the chronotropic effect of isoproterenol.

Ersentilide did not promote the development of reentrant arrhythmias in the present model of sudden death. However, proarrhythmia associated with IK blockers tend to be pause-dependent triggered ventricular tachyarrhythmias. Because of ersentilide's weaker-blockade, the drug may be less likely to favor pause- or bradycardia-dependent arrhythmias. A balanced effect of this compound on adrenergic activity and ventricular repolarization is likely the primary mechanism of the powerful antifibrillatory effect of ersentilide.

4.3 Clinical implications
The present study demonstrated that ersentilide was effective in preventing lethal arrhythmias arising from the interaction between acute myocardial ischemia and elevated sympathetic activity in the presence of a healed myocardial infarction. The mild antiadrenergic effect of this compound may allow maintenance of appropriate prolongation of repolarization, and thus prevention of reentrant arrhythmias, in patients with signs of elevated sympathetic drive but otherwise intolerant to traditional β-blocking agent, such as D,L-sotalol.

At this time, clinically proven antiarrhythmic compounds available include D,L-sotalol and amiodarone but they are both limited by significant side effects. There is a clear need for a compound which combines the mechanisms responsible for the antiarrhythmic success of amiodarone and D,L-sotalol, yet avoiding their downside. Based on this background and on the results obtained in the present study, well-designed clinical studies aimed at testing the efficacy, safety, and tolerability of ersentilide would seem appropriate.

Time for primary review 19 days


   Acknowledgements
 
Dr. Adamson was supported by a National Research Service Award, NIH-NRSA HL08999-02. We are also very grateful for the excellent technical assistance of Tina Levison and Ian Smit. Funding for the present study was graciously provided by Helopharm, Berlin, Germany.


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

  1. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: Effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. New Engl J Med (1989) 321:406–412.[Abstract]
  2. Waldo A.L., Camm A.J., deRuyter H., et al. For the SWORD Investigators: Effect of D-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. Lancet (1996) 348:7–12.[CrossRef][Web of Science][Medline]
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