BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal arrhythmia provoked by physical or emotional stress and mediated by spontaneous Ca(2+) release and delayed after-depolarizations. Beta-adrenergic blockers are the therapy of choice but fail to control arrhythmia in up to 50% of patients. OBJECTIVE: To optimize antiarrhythmic therapy in recessively inherited CPVT caused by calsequestrin (CASQ2) mutations. METHODS: Murine heart rhythm telemetry was obtained at rest, during treadmill exercise, and after injection of epinephrine. The protocol was repeated after injection of different antiarrhythmic drugs. Results were then validated in human patients. RESULTS: Adult CASQ2 mutant mice had complex ventricular arrhythmia at rest and developed bidirectional and polymorphic ventricular tachycardia on exertion. Class I antiarrhythmic agents (procainamide, lidocaine, flecainide) were ineffective in controlling arrhythmia. Propranolol and sotalol attenuated arrhythmia at rest but failed to prevent VT during sympathetic stimulation. The calcium channel blocker verapamil showed a dose-dependent protection against CPVT. Verapamil was more effective than the dihydropyridine L-type Ca(2+) channel blocker nifedipine, and its activity was markedly enhanced when combined with propranolol. Human patients homozygous for CASQ2(D307H) mutation, remaining symptomatic despite chronic β-blocker therapy, underwent exercise testing according to the Bruce protocol with continuous electrocardiogram recording. Verapamil was combined with propranolol at maximum tolerated doses. Adding verapamil attenuated ventricular arrhythmia and prolonged exercise duration in five of 11 patients. CONCLUSION: Verapamil is highly effective against catecholamine-induced arrhythmia in mice with CASQ2 mutations and may potentiate the antiarrhythmic activity of β-blockers in humans with CPVT2.
BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal arrhythmia provoked by physical or emotional stress and mediated by spontaneous Ca(2+) release and delayed after-depolarizations. Beta-adrenergic blockers are the therapy of choice but fail to control arrhythmia in up to 50% of patients. OBJECTIVE: To optimize antiarrhythmic therapy in recessively inherited CPVT caused by calsequestrin (CASQ2) mutations. METHODS:Murine heart rhythm telemetry was obtained at rest, during treadmill exercise, and after injection of epinephrine. The protocol was repeated after injection of different antiarrhythmic drugs. Results were then validated in humanpatients. RESULTS: Adult CASQ2 mutant mice had complex ventricular arrhythmia at rest and developed bidirectional and polymorphic ventricular tachycardia on exertion. Class I antiarrhythmic agents (procainamide, lidocaine, flecainide) were ineffective in controlling arrhythmia. Propranolol and sotalol attenuated arrhythmia at rest but failed to prevent VT during sympathetic stimulation. The calcium channel blocker verapamil showed a dose-dependent protection against CPVT. Verapamil was more effective than the dihydropyridine L-type Ca(2+) channel blocker nifedipine, and its activity was markedly enhanced when combined with propranolol. Humanpatients homozygous for CASQ2(D307H) mutation, remaining symptomatic despite chronic β-blocker therapy, underwent exercise testing according to the Bruce protocol with continuous electrocardiogram recording. Verapamil was combined with propranolol at maximum tolerated doses. Adding verapamil attenuated ventricular arrhythmia and prolonged exercise duration in five of 11 patients. CONCLUSION:Verapamil is highly effective against catecholamine-induced arrhythmia in mice with CASQ2 mutations and may potentiate the antiarrhythmic activity of β-blockers in humans with CPVT2.
Authors: H Lahat; M Eldar; E Levy-Nissenbaum; T Bahan; E Friedman; A Khoury; A Lorber; D L Kastner; B Goldman; E Pras Journal: Circulation Date: 2001-06-12 Impact factor: 29.690
Authors: H Swan; K Piippo; M Viitasalo; P Heikkilä; T Paavonen; K Kainulainen; J Kere; P Keto; K Kontula; L Toivonen Journal: J Am Coll Cardiol Date: 1999-12 Impact factor: 24.094
Authors: Rafael Rosso; Jonathan M Kalman; Ori Rogowski; Shmuel Diamant; Amir Birger; Simon Biner; Bernard Belhassen; Sami Viskin Journal: Heart Rhythm Date: 2007-05-24 Impact factor: 6.343
Authors: Arthur A M Wilde; Zahurul A Bhuiyan; Lia Crotti; Mario Facchini; Gaetano M De Ferrari; Thomas Paul; Chiara Ferrandi; Dave R Koolbergen; Attilio Odero; Peter J Schwartz Journal: N Engl J Med Date: 2008-05-08 Impact factor: 91.245
Authors: Efrat Kurtzwald-Josefson; Edith Hochhauser; Katia Bogachenko; Shiraz Harun-Khun; Guy Katz; Dan Aravot; Jonathan G Seidman; Christine E Seidman; Michael Eldar; Asher Shainberg; Michael Arad Journal: Heart Rhythm Date: 2014-04-21 Impact factor: 6.343
Authors: Guy Katz; Asher Shainberg; Edith Hochhauser; Efrat Kurtzwald-Josefson; Ahuva Issac; Dalia El-Ani; Dan Aravot; Arnon Afek; Jonathan G Seidman; Christine E Seidman; Michael Eldar; Michael Arad Journal: Biochem Pharmacol Date: 2013-09-23 Impact factor: 5.858
Authors: Thomas M Roston; Jeffrey M Vinocur; Kathleen R Maginot; Saira Mohammed; Jack C Salerno; Susan P Etheridge; Mitchell Cohen; Robert M Hamilton; Andreas Pflaumer; Ronald J Kanter; James E Potts; Martin J LaPage; Kathryn K Collins; Roman A Gebauer; Joel D Temple; Anjan S Batra; Christopher Erickson; Maria Miszczak-Knecht; Peter Kubuš; Yaniv Bar-Cohen; Michal Kantoch; Vincent C Thomas; Gabriele Hessling; Chris Anderson; Ming-Lon Young; Michel Cabrera Ortega; Yung R Lau; Christopher L Johnsrude; Anne Fournier; Prince J Kannankeril; Shubhayan Sanatani Journal: Circ Arrhythm Electrophysiol Date: 2015-02-24
Authors: Efrat Kurtzwald-Josefson; Edith Hochhauser; Guy Katz; Eyal Porat; Jonathan G Seidman; Christine E Seidman; Yelena Chepurko; Asher Shainberg; Michael Eldar; Michael Arad Journal: J Appl Physiol (1985) Date: 2012-10-04
Authors: Hiroshi Watanabe; Christian van der Werf; Ferran Roses-Noguer; Arnon Adler; Naokata Sumitomo; Christian Veltmann; Raphael Rosso; Zahurul A Bhuiyan; Hennie Bikker; Prince J Kannankeril; Minoru Horie; Tohru Minamino; Sami Viskin; Björn C Knollmann; Jan Till; Arthur A M Wilde Journal: Heart Rhythm Date: 2012-12-31 Impact factor: 6.343