title: Propranolol prevents life-threatening arrhythmias in LQT3 transgenic mice: implications for the clinical management of LQT3 patients.
abstract: BACKGROUND
  The efficacy of beta-blockers for treatment of patients with long QT syndrome type 3 (LQT3) has been repeatedly questioned, and it has been suggested that they might be detrimental for this genetic subgroup of patients with long QT syndrome (LQTS). The disquieting consequence has been that cardiologists confronted with LQT3 patients often do not even attempt pharmacologic therapy and implant cardioverter-defibrillators as first-choice treatment. However, the most recent clinical data indicate high efficacy of beta-blocker therapy in LQT3 patients.
  
  
  OBJECTIVE
  The purpose of this study was to test the antiarrhythmic efficacy of beta-blockers in an established experimental model for LQT3.
  
  
  METHODS
  After phenotypic validation of 65 ∆KPQ-SCN5A knock-in transgenic (TG) mice compared to 32 wild-type (WT) mice, we tested the effect of the arrhythmogenic cholinergic muscarinic agonist carbachol in 19 WT and 39 TG anesthetized mice, with and without pretreatment with propranolol given intraperitoneally.
  
  
  RESULTS
  At the same heart rates, TG mice had a markedly longer QT interval than WT mice. Whereas carbachol had minor arrhythmic effects in the WT mice, it produced ventricular tachycardia (VT) and ventricular fibrillation (VF) in 55% of 20 TG mice. By contrast, in none of 19 TG mice pretreated with propranolol did VT/VF occur after carbachol injection.
  
  
  CONCLUSIONS
  These experimental data indicate that, contrary to previous reports, beta-blockade effectively prevents VT/VF in a validated LQT3 model. Together with the most recent clinical data, these findings indicate that there is no reason for not initiating protective therapy with beta-blockers in LQT3 patients.
authors.affiliation: IRCCS Istituto Auxologico Italiano, Laboratory of Cardiovascular Genetics, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Calvillo
authors.affiliation: Fondazione IRCCS Policlinico S. Matteo, Department of Cardiology, Pavia, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Spazzolini
authors.affiliation: Fondazione IRCCS Policlinico S. Matteo, Department of Cardiology, Pavia, Italy; Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Vullo
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Insolia
authors.affiliation: IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin, Milan, Italy; Department of Molecular Medicine, University of Pavia, Pavia, Italy; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Lia
authors.initials: L
authors.lastname: Crotti
authors.affiliation: IRCCS Istituto Auxologico Italiano, Laboratory of Cardiovascular Genetics, Milan, Italy; Department of Molecular Medicine, University of Pavia, Pavia, Italy; IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin, Milan, Italy; Cardiovascular Genetics Laboratory, Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, University of Cape Town, Cape Town, South Africa; Department of Medicine, University of Stellenbosch, Stellenbosch, South Africa; Department of Family and Community Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia. Electronic address: peter.schwartz@unipv.it.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Schwartz
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage; D000818:Animals; D000075224:Cardiac Conduction System Disease; D016757:Death, Sudden, Cardiac / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004562:Electrocardiography / Q000187:drug effects*; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D007274:Injections, Intraperitoneal; D008133:Long QT Syndrome / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D011433:Propranolol / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D000319:Adrenergic beta-Antagonists; D011433:Propranolol
keywords: Beta-blocker; HR; ICD; IP; LQT3; LQTS; Long QT syndrome type 3; Sudden death; TG; Transgenic mice; VF; VPB; VT; WT; heart rate; implantable cardioverter-defibrillator; intraperitoneal; long QT syndrome; long QT syndrome type 3; transgenic; ventricular fibrillation; ventricular premature beat; ventricular tachycardia; wild type