wenxin keli and atrial fibrillation

Anthor:Masonic Medical Research Laboratory, Utica, New York 13501, USA

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 (APD(90)) 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 I(Na) 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 I(Na)-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 0.4-1% in the general population and greater than 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 to up to15 million in North America alone by 2050, largely due to aging of the population.

Despite significant progress in radiofrequency and cryoablation therapy, antiarrhythmic drugs (AADs) 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 ultra-rapid 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 sodium channels of atrial and ventricular cells.3 A number of experimental studies have demonstrated the ability of sodium channel blockers like ranolazine, amiodarone and dronedarone to produce atrial-selective electrophysiological effects capable of effectively suppressing AF with minimal effects in the ventricle.3-10

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 comprised 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.

Methods
Coronary-perfused canine right atrial preparations were used to study the effects of Wenxin Keli on electrophysiology of atrial and right ventricular parameters and on termination and induction of AF.

Effect of Wenxin Keli on acetylcholine (ACh)-induced AF

In the presence of 1 μM ACh, persistent AF is induced in 100% of coronary-perfused atrial preparations. We tested the ability of Wenxin Keli to terminate AF and prevent its re-induction in two separate series of experiments. In the first set, ACh was added to the perfusate 30-60 min after the start of Wenxin Keli (5 g/L) and followed by attempts to induce arrhythmias electrically (these experiments were performed in 6 preparations in which electrophysiological parameters were measured first). In the second set, Wenxin Keli was added to the perfusate during ACh-mediated persistent AF (on the 5-6th minutes after the start of the arrhythmia). In cases in which the drug successfully terminated AF, we attempted to re-induce AF with electrical stimulation.

Effect of Wenxin Keli on INa in HEK293 Cells

HEK 293 cells stably expressing WT-SCN5A and transiently transfected with WT-SCN1B using fugene were used to study the effect of Wenxin Keli on INa characteristics.

Statistics
Statistical analysis was performed using paired, unpaired t test as well as one way repeated measures or multiple comparison analysis of variance (ANOVA) followed by Bonferroni’s test, as appropriate. All data are expressed as mean±SD. p<0.05 will be considered significant.

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 safe and effective management of AF. The mechanism(s) of atrial selectivity of Wenxin Keli to inhibit INa appear to be unique and requires further study.

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