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A Double-Blind Placebo-Controlled Evaluation of the Human Electrophysiologic Effects of Zatebradine, a Sinus Node Inhibitor

Chiamvimonvat, Vera; Newman, David; Tang, Anthony*; Green, Martin*; Mitchell, Jan; Wulffhart, Zaev; Dorian, Paul

Journal of Cardiovascular Pharmacology: October 1998 - Volume 32 - Issue 4 - p 516-520
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The purpose of this study was to evaluate the electrophysiologic effects of zatebradine, a sinus node inhibitor, in human subjects. Patients without structural heart disease were randomized to receive intravenous zatebradine (23 patients) or placebo (12 patients). Electrophysiologic measures were obtained at baseline and repeated at 40 and 70 min after drug administration. In the placebo group, there were no significant changes in any parameter over time. After zatebradine, sinus node function changed significantly at 40 min, with no further change at 70 min; sinus cycle length was prolonged by 16 and 17% (p < 0.001), and corrected sinus node recovery time was prolonged by 30 and 22% (p = 0.008). Similarly, atrioventricular node function changed significantly at 40 min, with no further change at 70 min; atrio-His interval was prolonged by 15 and 15% (p = 0.02), atrioventricular node effective refractory period was prolonged by 12 and 11% (p = 0.01), and Wenckebach cycle length was prolonged by 15 and 11% (p = 0.002). Atrial refractoriness, His-Purkinje conduction, ventricular refractoriness, and action-potential duration were not affected by zatebradine. Zatebradine, a sinus node inhibitor, alters the conduction and refractory properties of the human atrioventricular node, in addition to the expected effect on sinus node function.

From the Divisions of Cardiology, Departments of Medicine, St. Michael's Hospital, University of Toronto, Toronto; and *University of Ottawa Heart Institute, Ottawa, Ontario, Canada

Received May 20, 1997; revision accepted February 26, 1998.

Address correspondence and reprint requests to Dr. P. Dorian at St. Michael's Hospital, 30 Bond St., 7F, Toronto, Ontario, Canada M5B 1W8.

Heart rate reduction is an integral mechanism of action contributing to the therapeutic benefit of several classes of cardioactive drugs. The benefits of heart rate-reducing agents likely include reduction in sudden death (1,2), ventricular arrhythmias (3,4), infarct size (5,6), and reinfarction (1,2), in addition to an antiischemic action (7,8). Pharmacologically, a decrease in heart rate can be modulated through several mechanisms, including indirectly via action on the autonomic nervous system or directly via action on the pacemaker cells of the sinus node. The terms "sinus node inhibitors" and "specific bradycardic agents" have been used to describe a new class of compounds that act through the latter mechanism directly to decrease the sinus rate without other effects, at physiologic doses (9).

Zatebradine (UL-FS 49 CL; 1,3,4,5-tetrahydro-7,8-dimethoxy-3-(3-{[2-(3,4-dimethoxyphenyl)ethyl]methyl-limino}propyl)-2H-3-benzazepin-2-one hydrochloride) is one of the most selective and efficacious of these compounds (10). Although its precise mechanism of action is still uncertain, several studies suggest that it acts mainly as a selective blocker of the hyperpolarization-activated pacemaker current (If) in a use-dependent manner, with lesser effects on the slow inward Ca2+ current and the delayed rectifier K+ current (11-15). Zatebradine reduces heart rate by a direct effect on the rate of diastolic phase 4 depolarization in sinus nodal cells with little effect on inotropism, lusitropism, or vasomotion, both in animal models (16-18) and in humans (19-21). It blocks the increase in heart rate caused by β-stimulation in a noncompetitive manner, without influencing the positive inotropic effect (22,23).

With its pharmacologic profile, which is different from that of other heart rate-reducing agents, zatebradine may offer a new therapeutic modality, especially in the treatment of angina pectoris. Although its action is thought to be limited only to the sinus node, its precise electrophysiologic properties in humans have not been characterized. The aim of our investigation therefore was to study the electrophysiologic effects of zatebradine in normal human subjects.

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METHODS

The study used a randomized, double-blind, placebo-controlled design, performed at two tertiary care centers. Patients with no structural heart disease who were undergoing follow-up electrophysiologic study after successful radiofrequency ablation for supraventricular tachyarrhythmias were eligible for the study. Exclusion criteria were evidence of sinus node disease (sinus bradycardia <50 beats/min, sinus pause >2.5 s, history of tachyarrhythmia/bradyarrhythmia), heart block greater than first degree, QT prolongation >480 ms, QRS prolongation >120 ms, and His-Purkinje conduction (HV interval) >65 ms at baseline electrophysiologic study. Patients had not received β-blockers, calcium channel blockers, antiarrhythmic drugs, digoxin, tricyclic antidepressants, or neuroleptic drugs within 5 half-lives at the time of the study. The studies were approved by the institutional research ethics committees at both participating sites, and all patients gave written informed consent.

Patients were randomized in a 2:1 ratio to receive either intravenous zatebradine (Boehringer Ingleheim Pharmaceuticals, Inc.), 5 mg over 5 min, followed by 5 mg over 45 min, a physiologically active dose that was previously validated to have clinically relevant effects (17) or intravenous saline in equal volume in a double-blind design. Electrophysiologic measures were performed at baseline and repeated at 40 and 70 min after the onset of drug administration.

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Electrophysiologic measures

Electrophysiologic studies were performed in a standard manner. Venous catheters were inserted in the femoral vein, and quadripolar electrode catheters were positioned in the high right atrium, His bundle region, and right ventricular apex. All pacing was performed at twice diastolic threshold by using a constant-current stimulus of 2-ms pulse width. A contact action-potential recording electrode was used for ventricular monophasic action-potential recordings (EP Technologies, Mountain View, CA, U.S.A.). Femoral arterial blood pressure was continuously monitored throughout the study.

Measures of sinus node function included mean sinus cycle length averaged over 10 beats and sinus node recovery time, corrected for mean cycle length, measured as the longest interval from the last paced atrial beat to the first sinus beat, after a sudden cessation after 30 s of atrial pacing. Pacing was performed at cycle lengths of 800, 700, 600, 500, 400, and 350 ms (unless limited by sinus rate). Measures of atrioventricular (AV) node function included AV nodal effective refractory period measured as the longest. A1-A2 interval with block proximal to the His bundle by using single atrial extrastimuli during atrial pacing at cycle length of 600 ms for 8 beats and 10-ms decrements until refractoriness, with a 2-s intertrain pause; atrio-His (AH) interval during atrial paced cycle length of 600 ms; and Wenckebach cycle length measured as the longest interval associated with Wenckebach periodicity during continuous atrial pacing beginning at cycle length of 600 ms and decrementing by 10 ms every 6 beats without a pause. Atrial effective refractory period was measured by using single atrial extrastimuli during atrial pacing at cycle length of 600 ms for eight beats and 10-ms decrements until refractoriness, with a 2-s intertrain pause. His-Purkinje conduction (HV interval) was measured during atrial paced cycle length of 600 ms. Measures of ventricular refractoriness included ventricular effective refractory period measured by using single ventricular extrastimuli during ventricular pacing at cycle length of 600 ms for eight beats and 10-ms decrements until refractoriness, with a 3-s intertrain pause; and ventricular monophasic action-potential duration measured as the time from onset to 90% depolarization from the plateau, after 30 s of continuous pacing at a cycle length of 600 ms. The error for repeated ventricular monophasic action-potential duration measures is ±3%.

Patients were monitored for adverse events for ≥24 h and were contacted by telephone at 7 days.

All data were analyzed by using two-way analysis of variance for repeated measures, comparing between zatebradine and placebo at all three time points. All results are expressed as means ± SEM; p < 0.05 was considered statistically significant.

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RESULTS

Thirty-five patients were entered into the study: 23 patients received zatebradine, and 12 patients received placebo. Baseline characteristics were not significantly different between the zatebradine and placebo groups with respect to age (45 ± 16 years vs. 45 ± 9 years; mean ± SD) and sex distribution (male/female = 13:10 vs. 8:4). All baseline electrophysiologic measures and blood pressures were similar between the treatment groups (Tables 1 and 2)

TABLE 1

TABLE 1

TABLE 2

TABLE 2

In the placebo group, there were no significant changes in any electrophysiologic parameters over time. After zatebradine, measures of sinus node function were significantly depressed at 40 min, with no further change at 70 min (Fig. 1 and Table 1); mean sinus cycle length was prolonged by 16 and 17% (p < 0.001), and sinus node recovery time was prolonged by 30 and 22% (p = 0.008) over baseline measures at 40 and 70 min, respectively. There was no rate-dependency effect of zatebradine on sinus node recovery time; the longest sinus node recovery time measured was not related to the atrial paced cycle length. Similarly, measures of AV node function were also significantly depressed at 40 min, with no further change at 70 mins (Fig. 2 and Table 1); AH interval was prolonged by 15 and 15% (p = 0.02), AV nodal effective refractory period was prolonged by 12 and 11% (p = 0.01), and Wenckebach cycle length was prolonged by 15 and 11% (p = 0.002), over baseline measures at 40 and 70 min, respectively. In two patients who received zatebradine, Wenckebach cycle length was prolonged to >600-ms atrial paced cycle length at 40 and 70 min. In these patients, Wenckebach cycle length and AV nodal effective refractory period was arbitrarily designated as 600 ms; AH and HV intervals (at 600 ms) could not be measured. Transient or sustained atrial arrhythmias after atrial pacing also precluded complete electrophysiologic measures in four patients in the zatebradine group and two patients in the placebo group.

FIG. 1

FIG. 1

FIG. 2

FIG. 2

Atrial refractoriness, His-Purkinje conduction, ventricular refractoriness, and action-potential duration were not affected by zatebradine (Table 2). There were no significant changes in blood pressure throughout the study in either group (Table 2).

The most commonly observed adverse effects were atrial arrhythmias, with similar incidence in the zatebradine [eight (35%) of 23] and placebo groups [five (42%) of 12]. The majority of atrial arrhythmias were nonsustained atrial fibrillation after atrial extrastimuli; two patients in the zatebradine group and one patient in the placebo group had sustained atrial fibrillation (>60 min). The incidence of transient visual symptoms, another commonly observed side effect, was also similar in the zatebradine [five (22%) of 23] and placebo groups [two (17%) of 12].

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DISCUSSION

Consistent with its postulated mechanism as a selective If channel blocker, zatebradine has significant effects on sinus node function by slowing heart rate and prolonging sinus node recovery time, without any effects on atrial and ventricular tissues or hemodynamics. The main new finding in this study is that zatebradine also significantly alters AV nodal function in humans.

The AV node has been identified as a heterogeneous structure (24) with three known electrophysiologically distinct cell types (25,26). Several ionic currents, including the If current, have been described in isolated AV nodal cells and cell clusters (27-32). However, the precise distribution and relation of these currents to AV nodal conduction and excitability is still under investigation. The finding in this study that zatebradine has a marked effect on all measured AV node functions by prolonging AH interval, AV node effective refractory period, and Wenckebach cycle length suggests that in the human AV node, If channels may be present to a greater extent than previously suggested from animal studies and may play a greater role in modulating AV node conduction and refractory properties. Alternatively, in humans, zatebradine may be affecting AV node properties through a greater action on Ca2+ or K+ currents or both than previously indicated from animal studies (14,15).

Zatebradine is under investigation as a heart rate-reducing agent that may be used in patients with contraindications to β-blockers or calcium channel blockers diltiazem or verapamil, including left ventricular dysfunction (16). In animal models of severe heart failure, zatebradine was well tolerated without any direct negative inotropic effects (33). Zatebradine may therefore have unique therapeutic roles for antianginal therapy and for control of tachycardia, such as during acute myocardial infarction, in perioperative settings, and for inotropic support (16). This study suggests it should be used with caution in patients with AV nodal conduction disturbances or in combination with drugs that impair AV nodal function.

In this placebo-controlled, double-blind study, repeated electrophysiologic measures in patients without active therapy remained unchanged in the acute setting. This is the first report of the stability and reproducibility of these parameters, measured in a blinded fashion, over the time course of an electrophysiologic study and may serve as a validation for the evaluation of drugs administered at electrophysiologic study, whose effects are compared with baseline measures of conduction or refractoriness.

In summary, zatebradine, a new class of sinus node inhibitors, alters the conduction and refractory properties of the human AV node, in addition to the expected effect on sinus node function. This finding must be considered when using this and other drugs in its class as therapeutic agents.

Acknowledgment: This study was supported by a grant in aid from Boehringer Ingleheim Pharmaceuticals, Inc. We are grateful for the secretarial assistance of Kim Brown.

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Keywords:

Zatebradine; Sinus node inhibitor; Bradycardic agent; Electrophysiology

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