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      The Use Of Oral Ranolazine To Convert New Or Paroxysmal Atrial Fibrillation: A Review Of Experience With Implications For Possible "Pill In The Pocket" Approach To Atrial Fibrillation

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          Abstract

          Background

          Atrial fibrillation (AF) is the most common arrhythmia requiring treatment. High dose oral anti-arrhythmics may cardiovert some paroxysmal AF. This "pill in pocket" approach has allowed patients to treat themselves on an as needed basis. Pro-arrhythmic concerns have limited the usefulness of this approach to patients without structural heart disease. Ranolazine is an anti-anginal agent, which inhibits abnormal late Na+ channel currents in cardiomyocytes and decreases sodium-calcium overload. Ranolazine is a potent inhibitor of after-depolarizations, which have been implicated in the initiation and propagation of AF. Because ranolazine has no known pro-arrhythmic effects, it could be useful as a safe "pill in the pocket" agent if it were effective in converting AF. We describe our experience using oral ranolazine to convert new or paroxysmal AF.

          Methods

          2000 mg of ranolazine were administered to 18 patients with new (11 patients) or paroxysmal (7 patients) AF of at least 3, but not greater than 48 hours duration. Most patients (14) were in the hospital at the time ranolazine was administered. Age, sex, echocardiographic data, associated health conditions and structural heart disease were recorded. Successful conversion was defined as restoring sinus rhythm within 6 hours of ranolazine administration.

          Results

          All but 1 patient had some form of structural heart disease and all but 2 patients had left atrial enlargement. Thirteen of 18 patients converted to sinus rhythm. No pro-arrhythmic effects, hemodynamic instability, adverse rate effects, or perceived intolerance (other than constipation) were noted. The 72% conversion rate was comparable to other reported "pill in the pocket" protocols.

          Conclusions

          High dose oral ranolazine shows utility as a possible safe agent to convert new or paroxysmal AF. Lack of blinded controls and small numbers limits the power of this observation.

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          Most cited references29

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          Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications.

          The prevalence of atrial fibrillation (AF) is related to age. Anticoagulation is highly effective in preventing stroke in patients with AF, but the risk of hemorrhage may be increased in older patients. We reviewed the available epidemiologic data to define the age and sex distribution of people with AF. From four large recent population-based surveys, we estimated the overall age- and gender-specific prevalence of AF. These estimates were applied to the recent US census data to calculate the number of men and women with AF in each age group. There are an estimated 2.2 million people in the United States with AF, with a median age of about 75 years. The prevalence of AF is 2.3% in people older than 40 years and 5.9% in those older than 65 years. Approximately 70% of individuals with AF are between 65 and 85 years of age. The absolute number of men and women with AF is about equal. After age 75 years, about 60% of the people with AF are women. In contrast to people with AF in the general population, patients with AF in recent anticoagulation trials had a mean age of 69 years, and only 20% were older than 75 years. The risks and benefits of antithrombotic therapy in older individuals are important considerations in stroke prevention in AF.
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            Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties.

            Ranolazine is a novel antianginal agent capable of producing antiischemic effects at plasma concentrations of 2 to 6 micromol/L without reducing heart rate or blood pressure. The present study examines its electrophysiological effects in isolated canine ventricular myocytes, tissues, and arterially perfused left ventricular wedge preparations. Transmembrane action potentials (APs) from epicardial and midmyocardial (M) regions and a pseudo-ECG were recorded simultaneously from wedge preparations. APs were also recorded from epicardial and M tissues. Whole-cell currents were recorded from epicardial and M myocytes. Ranolazine inhibited I(Kr) (IC50=11.5 micromol/L), late I(Na), late I(Ca), peak I(Ca), and I(Na-Ca) (IC50=5.9, 50, 296, and 91 micromol/L, respectively) and I(Ks) (17% at 30 micromol/L), but caused little or no inhibition of I(to) or I(K1). In tissues and wedge preparations, ranolazine produced a concentration-dependent prolongation of AP duration of epicardial but abbreviation of that of M cells, leading to reduction or no change in transmural dispersion of repolarization (TDR). At [K+]o=4 mmol/L, 10 micromol/L ranolazine prolonged QT interval by 20 ms but did not increase TDR. Extrasystolic activity and spontaneous torsade de pointes (TdP) were never observed, and stimulation-induced TdP could not be induced at any concentration of ranolazine, either in normal or low [K+]o. Ranolazine (5 to 20 micromol/L) suppressed early afterdepolarizations (EADs) and reduced the increase in TDR induced by the selective I(Kr) blocker d-sotalol. Ranolazine produces ion channel effects similar to those observed after chronic amiodarone (reduced I(Kr), I(Ks), late I(Na), and I(Ca)). The actions of ranolazine to suppress EADs and reduce TDR suggest that, in addition to its antianginal actions, the drug may possess antiarrhythmic activity.
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              Triggered firing in pulmonary veins initiated by in vitro autonomic nerve stimulation.

              Rapid firing within pulmonary vein sleeves frequently initiates atrial fibrillation. The role of the autonomic nervous system in facilitating spontaneous firing is unknown. The purpose of this study was to determine if autonomic nerve stimulation within canine atrium and pulmonary vein sleeves initiates arrhythmia formation. Extracellular bipolar and intracellular microelectrode recordings were obtained from isolated superfused canine pulmonary veins (N = 28) and right atrium (N = 5) during local autonomic nerve stimulation. Autonomic nerve stimulation decreased pulmonary vein sleeve action potential duration (APD90 = 160 +/- 17 to 92 +/- 24 ms; P < .01) and initiated rapid (782 +/- 158 bpm) firing from early afterdepolarizations in 22 of 28 pulmonary vein preparations. The initial spontaneous beat had a coupling interval of 97 +/- 26 ms. Failure to induce arrhythmia was associated with a failure to shorten APD90 (151 +/- 18 to 142 +/- 8 ms; P = .39). Muscarinic receptor blockade (atropine: 3.2 x 10(-8) M) prevented APD90 shortening in 8 of 8 preparations and suppressed firing in 6 of 8 preparations, whereas beta1-adrenergic receptor blockade (atenolol: 3.2 x 10(-8) M) suppressed firing in 8 of 8 preparations. Suppression of the Ca transient with ryanodine (10(-5) M) completely suppressed firing in 6 of 6 preparations. Inhibition of forward Na/Ca exchange by a transient increase in [Ca+2]o completely suppressed firing in 4 of 6 preparations. The same stimulus trains produce atropine-suppressed APD90 shortening in superfused right atrial free wall but fail to produce triggered arrhythmia. The data demonstrate triggered firing within canine pulmonary veins with combined parasympathetic and sympathetic nerve stimulation. Both an enhanced Ca transient and increased Na/Ca exchange may be required for arrhythmia formation.
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                Author and article information

                Journal
                Indian Pacing Electrophysiol J
                Indian Pacing Electrophysiol J
                Indian Pacing and Electrophysiology Journal
                Indian Heart Rhythm Society
                0972-6292
                Sep-Oct 2009
                01 September 2009
                : 9
                : 5
                : 260-267
                Affiliations
                The Aspirus Heart and Vascular Institute, Cardiovascular Associates of Northern Wisconsin and The CaRE Foundation, Wausau Wisconsin USA
                Author notes
                Address for correspondence: David Kent Murdock MD, Care Foundation, 500 Wind Ridge Drive, Wausau, Wisconsin 54403. E-mail: dkmurdock@ 123456charter.net

                Funding and conflict of interest No money was received for any of the work contained in this manuscript. Dr. David Murdock and Jeff Kaliebe were investigators for the Merlin Trial. Dr. Murdock and the Care Foundation are currently working with Cardiovascular Therapeutics Inc. to develop a protocol to study post-operative atrial fibrillation.

                Authors report that a preliminary report of this material in abstract form was presented in June 2009 at the Rhythm Congress meeting in Cannes France.

                Article
                ipej090260-00
                2735158
                19763194
                9a2ab090-c95b-424c-8267-85035d7beb36
                Copyright: © 2009 Murdock et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Categories
                Original Article

                Cardiovascular Medicine
                ranolazine,anti-rhythmic agents,anti-rhythmic therapy,conversion,atrial fibrillation

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