Elsevier

Heart Rhythm

Volume 9, Issue 1, January 2012, Pages 125-131
Heart Rhythm

Experimental
Atrial-selective inhibition of sodium-channel current by Wenxin Keli is effective in suppressing atrial fibrillation

https://doi.org/10.1016/j.hrthm.2011.08.027Get rights and content

Background

Wenxin Keli is a Chinese herb extract reported to be of benefit in the treatment of cardiac arrhythmias, cardiac inflammation, and heart failure.

Methods and Results

We evaluated the electrophysiologic effects of Wenxin Keli in isolated canine arterially perfused right atrial preparations with a rim of right ventricular tissue (n = 11). Transmembrane action potentials and a pseudoelectrocardiogram were simultaneously recorded. Acetylcholine (1 μM) was used to induce atrial fibrillation (AF) and to test the anti-AF potential of Wenxin Keli (5 g/L). Wenxin Keli produced preferential abbreviation of action potential duration measured at 90% repolarization (APD90) in atria, but caused atrial-selective prolongation of the effective refractory period, due to the development of postrepolarization refractoriness. The maximum rate of rise of the action potential upstroke was preferentially reduced in atria. The diastolic threshold of excitation increased in both atria and ventricles, but much more in atria. The duration of the “P wave” (index of atrial conduction time) was prolonged to a much greater extent than the duration of the “QRS complex” (index of ventricular conduction time). Wenxin Keli significantly reduced INa and shifted steady-state inactivation to more negative potentials in HEK293 cells stably expressing SCN5A. Wenxin Keli prevented the induction of persistent AF in 100% atria (6/6) and, in another experimental series, was found to terminate persistent acetylcholine-mediated AF in 100% of atria (3/3).

Conclusion

Wenxin Keli produces atrial-selective depression of INa-dependent parameters in canine isolated coronary-perfused preparations via a unique mechanism and is effective in suppressing AF and preventing its induction, with minimal effects on the ventricular electrophysiology.

Introduction

Effective and safe treatment of atrial fibrillation (AF) remains a major unmet medical need, and the problem is growing as the prevalence of AF continues to increase with the aging of the population. AF is the most prevalent sustained clinical arrhythmia associated with increased morbidity and mortality. Its prevalence is 0.4% to 1% in the general population and >8% in individuals >80 years of age. An estimated 2.5 million individuals in North America and 4.5 million in Europe are affected by AF. These numbers are projected to increase up to 15 million in North America alone by 2050, largely because of the aging of the population.

Despite significant progress in radiofrequency and cryoablation therapy, antiarrhythmic drugs remain first-line therapy for rhythm control of AF.1 However, the effectiveness and/or safety of agents available for the treatment of AF is less than optimal. Currently available pharmacologic strategies for the rhythm control of AF include (1) sodium-channel blockers, such as propafenone and flecainide; (2) potassium-channel blockers (largely IKr), such as sotalol and dofetilide; and (3) mixed ion-channel blockers, such as amiodarone and dronedarone.

The development of safe and effective drugs for the management of AF remains a high priority.1 A major disadvantage of most of the drugs in current use is the risk of induction of ventricular arrhythmias. This risk can be reduced with the use of agents that selectively affect atrial electrophysiological parameters. Inhibition of the ultrarapid delayed rectifier potassium current (IKur) present in atria, but not in the ventricles, is an example of an atrial-selective approach that has attracted much of the focus of the pharmaceutical industry in recent years.2 Recent studies have introduced the concept of atrial-selective block of peak sodium-channel current as a novel approach for the management of AF, taking advantage of the electrophysiological distinctions between the sodium channels of atrial and ventricular cells.3 A number of experimental studies have demonstrated the ability of sodium-channel blockers such as ranolazine, amiodarone, and dronedarone to produce atrial-selective electrophysiological effects capable of effectively suppressing AF with minimal effects in the ventricle.3, 4, 5, 6, 7, 8, 9, 10

Wenxin Keli is a Chinese herb extract reported to be of benefit in the treatment of cardiac arrhythmias, cardiac inflammation, and heart failure. The extract is composed of 5 components: Nardostachys chinensis Batal extract (NcBe), Codonopsis, Notoginseng, amber, and Rhizoma Polygonati.

The present study was designed to evaluate the electrophysiologic effects and antiarrhythmic potential of Wenxin Keli in isolated canine arterially perfused right atrial and ventricular preparations. We demonstrate an effect of Wenxin Keli to produce atrial-selective depression of INa-dependent parameters and to be effective in suppressing AF and preventing its induction, with minimal effects on ventricular electrophysiology.

Section snippets

Methods

Coronary-perfused canine right atrial preparations were used to study the effects of Wenxin Keli on the electrophysiology of atrial and right ventricular parameters and on the termination and induction of AF. Detailed methods are provided in the supplementary material available online.

Electrophysiological effects of Wenxin Keli in atria and ventricles

Wenxin Keli preferentially abbreviated the action potential (AP) duration (APD) measured at 90% repolarization (APD90) in atria but caused atrial-selective prolongation of the effective refractory period (ERP) (Figure 1, Figure 2). ERP prolongation in atria was rate dependent, that is, greater at a cycle length (CL) of 300 vs 500 ms. This was due to the development of rate-dependent postrepolarization refractoriness (PRR) selectively in atria (Figure 2). At CLs of 300 and 500 ms, Wenxin Keli

Discussion

AF is a growing clinical problem associated with increased morbidity and mortality. Pharmacological agents remain first-line therapy for rhythm control management of AF.1 Agents that can effectively suppress AF and prevent its recurrence without substantial risk of adverse actions are highly desirable. The search for new anti-AF agents has largely been focused on the delineation of atrial-specific or -selective targets/agents in order to avoid or reduce the risk of induction of ventricular

Conclusions

Our data suggest that Wenxin Keli possesses potent anti-AF properties owing to its ability to depress sodium-channel–dependent parameters. The atrial selectivity of this action of the drug likely contributes to its usefulness for the safe and effective management of AF. The mechanism(s) of atrial selectivity of Wenxin Keli to inhibit INa appears to be unique and requires further study.

Acknowledgments

We gratefully acknowledge the expert technical assistance of Judy Hefferon and Robert Goodrow.

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    This study was supported by grants from Buchang Group, Xi'An, China; NIH grant HL-47687 (CA); and the New York State and Florida Masons. Dr Antzelevitch received research support from Buchang Group, Xi'An, China.

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