Ranolazine Safely Decreases Ventricular and Atrial Fibrillation in Timothy Syndrome (LQT8) DIPAK P. SHAH, M.D., JOSE L. BAEZ-ESCUDERO, M.D., IAN L. WEISBERG, M.D., JOHN F. BESHAI, M.D., and MARTIN C. BURKE, D.O. From the Department of Medicine, Section of Cardiology, University of Chicago, Chicago, Illinois Long QT eight (LQT8), otherwise known as Timothy syndrome (TS), is a genetic disorder causing hyper- activation of the L-type calcium channel Cav 1.2. This calcium load and the resultant increase in the QT interval provide the substrate for ventricular arrhythmias. We previously presented a case in a patient with TS who had a profound decrease in his burden of ventricular arrhythmias after institution of an L-type calcium channel blocker. Although this patient’s arrhythmia burden had decreased, he displayed an increasing burden of atrial fibrillation and still had bouts of ventricular fibrillation requiring defibrillator therapy. Basic research has recently shown that ranolazine, a multipotent ion-channel blocker, may be of benefit in patients with LQT8 syndrome. This case report details the decrease of atrial fibrillation and ventricular fibrillation events in our LQT8 patient with the addition of ranolazine. (PACE 2012; 35:e62–e64) electrophysiology—clinical, long QT , pharmacology Timothy syndrome (TS), characterized as the eighth long QT syndrome (LQT8), is a genetic disorder noted as a de novo mutation of G406R on exon 8A causing hyperactivation (reduced inactivation) of the L-type calcium channel Cav 1.2. 1,3,4 Although TS is classically associated with syndactyly, TS 2 is the variant form that has been described in two patients without the webbed phenotype. 2 TS 1 and 2 patients display a prolonged QT interval and the propensity for severe ventricular arrhythmias. LQT8 patients have abnormalities with calcium loading, are more prone to torsades de pointes (TdP) displaying early after depolarizations, delayed after depolariza- tions (DADs), and increased transmural dispersion of repolarization (TDR). 4 Previously we reported that verapamil, an L-type calcium channel antagonist, reduced the burden of ventricular arrhythmias in a TS 2 patient who was genotyped with a Cav 1.2 mu- tation. 3 The ventricular arrhythmias and internal cardioverter defibrillator (ICD) shocks decreased significantly when precalcium and postcalcium channel blocker ICD logs were reviewed. However, we continued to still note that our patient required occasional ICD therapy for ventricular fibrillation. Also, his burden of symptomatic Address for reprints: Martin C. Burke, D.O., Univer- sity of Chicago Hospitals, 5758 South Maryland Avenue, MC 9024, Chicago, IL 60637. Fax: 773-702-4666; e-mail: mburke@medicine.bsd.uchicago.edu Received May 26, 2010; revised June 29, 2010; accepted July 14, 2010. doi: 10.1111/j.1540-8159.2010.02913.x (palpitations) atrial fibrillation events increased. 3 The patient’s clinical improvement on verapamil was made possible by understanding the genetic channelopathy. Recent data have suggested that ranolazine, a multipotent ion-channel blocker first studied as an antianginal, may be of benefit in patients with LQT8 syndrome despite its black box contraindication in LQT patients. 4 Ranolazine has been shown to inhibit IKr, late INa, late ICa, peak ICa, and INa-Ca and decrease TDR. 5,6 There has been concern that with its inhibition of IKr, QT prolongation and proarrhythmia would be a risk, especially in congenital LQT patients. Other reports have communicated that ranolazine has safely and effectively decreased the burden of atrial fibrillation, mainly through a mechanism of potent use dependent block of peak INa. 7 We tested the addition of ranolazine in a TS 2 patient to control his ventricular fibrillation and decrease his burden of atrial fibrillation. Case Report The patient is a 26-year-old man with TS 2, a variant of LQT8, who presents with sporadic ventricular tachyarrhythmias and recurrent per- sistent atrial fibrillation. The patient’s genotype and clinical phenotype has previously been reported to respond favorably to verapamil in the treatment of his ventricular tachyarrhythmias. 3 His atrial fibrillation had been responding to periodic cardioversion and maintenance therapy with verapamil SR 240 mg daily and long-acting metoprolol 150 mg daily. Vaughn-Williams class I and III antiarrhythmic medications were avoided due to the severe prolongation of the patient’s QTc and history of severe, frequent episodes of C 2010, The Authors. Journal compilation C 2012 Wiley Periodicals, Inc. e62 March 2012 PACE, Vol. 35