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Ranolazine-induced Repolarization Changes: A Case Report

Published:February 03, 2015DOI:https://doi.org/10.1016/j.amjmed.2015.01.019
      To the Editor:
      Ranolazine is a widely used antianginal and antiarrhythmic agent. Prolongation of the QTc interval and T-wave notching are well-known effects of ranolazine. To our knowledge, other electrocardiographic repolarization changes have not been described. In this report we describe reversible T-wave inversions with prolongation of the QTc interval after initial administration of ranolazine.

      Case Report

      We present the case of a 64-year-old woman with a history of coronary artery disease and prior stent placement, who presented with chest discomfort for 2 hours. Electrocardiogram (EKG) revealed sinus bradycardia with a 2-mm ST elevation in lead V2 (Figure). Troponin-T levels peaked at 0.22 ng/mL, and her maximum creatine phosphokinase level was 201 U/L. Coronary angiography revealed a patent in the left anterior descending artery, nonobstructive coronary artery disease, and akinesis of the apical diaphragmatic wall. The characteristic wall motion abnormality was consistent with Takotsubo cardiomyopathy. By Bazett's formula, her QTc interval on admission EKG was 416 ms (Figure A). Subsequently, ranolazine 500 mg was initiated as treatment of chronic angina symptoms. An EKG obtained a few hours after administration of the first dose revealed deep T-wave inversions in the inferior and lateral leads, as well as prolongation of the QTc interval (505 ms; Figure B). Subsequently, repeat measurements of creatine phosphokinase and troponin-T levels revealed a continued downward trend, and the initial apical wall motion abnormality on initial ventriculogram was not seen on echocardiogram. Instead, left ventricular wall motion was found to be normal. After discontinuation of ranolazine, the repeat EKG after 24 hours showed persistent T-wave inversions with decreased amplitudes compared with before, and her QTc interval decreased to 412 ms (similar to her admission EKG; Figure C).
      Figure thumbnail gr1
      FigureEvolution of electrocardiographic changes. (A) Electrocardiogram (EKG) 1: on admission; (B) EKG 2: after first dose of ranolazine; (C) EKG 3: 24 hours after first dose of ranolazine.

      Discussion

      Ranolazine has been shown to inhibit a number of myocardial ion channels, including the late sodium current, which is thought to be the main mechanism of its antianginal effects, as well as potassium and calcium channels.
      • Antzelevitch C.
      • Belardinelli L.
      • Zygmunt A.C.
      • et al.
      Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties.
      Prolongation of the QTc interval has been reported previously as a rare adverse event.
      • Chaitman B.R.
      • Pepine C.J.
      • Parker J.O.
      • et al.
      Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial.
      • Morrow D.A.
      • Scirica B.M.
      • Karwatowska-Prokopczuk E.
      • et al.
      Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial.
      However, multiple studies have demonstrated a low risk of associated ventricular arrhythmias. T-wave changes have been reported also, including notching and decreased T-wave amplitudes, which are thought to be a result of Ikr potassium channel inhibition.
      • Antzelevitch C.
      • Belardinelli L.
      • Zygmunt A.C.
      • et al.
      Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties.
      In the setting of normal cardiac repolarization, T-waves are usually concordant with the QRS complex. In the case of our patient, we speculate that inhibition of the Ikr potassium current and subsequent prolongation of the action potential led to a directional change of the repolarization vector, causing a negative T wave on surface EKG. To our knowledge, this is the first report of ranolazine-induced T-wave inversions. Adverse drug effects may be rare and not always apparent in clinical trials, highlighting the importance of postmarketing surveillance.

      References

        • Antzelevitch C.
        • Belardinelli L.
        • Zygmunt A.C.
        • et al.
        Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties.
        Circulation. 2004; 110: 904-910
        • Chaitman B.R.
        • Pepine C.J.
        • Parker J.O.
        • et al.
        Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial.
        JAMA. 2004; 291: 309-316
        • Morrow D.A.
        • Scirica B.M.
        • Karwatowska-Prokopczuk E.
        • et al.
        Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial.
        JAMA. 2007; 297: 1775-1783

      Linked Article

      • Electrocardiogram Changes From Ranolazine or From Takotsubo?
        The American Journal of MedicineVol. 128Issue 12
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          Kumthekar et al1 presented an interesting case of a patient with chest pain where the initial electrocardiogram (ECG) demonstrated trivial ST-segment elevation in the anterior chest leads, but a subsequent ECG showed large global T-wave inversion and marked prolongation of the QT interval. Both the clinical picture and results of cardiac catheterization were consistent with stress-induced Takotsubo cardiomyopathy.1 The authors hypothesized that the fairly substantial repolarization abnormalities were caused by a 500-mg dose of ranolazine, which was initiated for the treatment of chronic angina symptoms.
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