title: Autonomic modulation and antiarrhythmic therapy in a model of long QT syndrome type 3.
abstract: OBJECTIVE
  Clinical observations in patients with long QT syndrome carrying sodium channel mutations (LQT3) suggest that bradycardia caused by parasympathetic stimulation may provoke torsades de pointes (TdP). Beta-adrenoceptor blockers appear less effective in LQT3 than in other forms of the disease.
  
  
  RESULTS
  We studied effects of autonomic modulation on arrhythmias in vivo and in vitro and quantified sympathetic innervation by autoradiography in heterozygous mice with a knock-in deletion (DeltaKPQ) in the Scn5a gene coding for the cardiac sodium channel and increased late sodium current (LQT3 mice). Cholinergic stimulation by carbachol provoked bigemini and TdP in freely roaming LQT3 mice. No arrhythmias were provoked by physical stress, mental stress, isoproterenol, or atropine. In isolated, beating hearts, carbachol did not prolong action potentials per se, but caused bradycardia and rate-dependent action potential prolongation. The muscarinic inhibitor AFDX116 prevented effects of carbachol on heart rate and arrhythmias. beta-Adrenoceptor stimulation suppressed arrhythmias, shortened rate-corrected action potential duration, increased rate, and minimized difference in late sodium current between genotypes. Beta-adrenoceptor density was reduced in LQT3 hearts. Acute beta-adrenoceptor blockade by esmolol, propranolol or chronic propranolol in vivo did not suppress arrhythmias. Chronic flecainide pre-treatment prevented arrhythmias (all P < 0.05).
  
  
  CONCLUSIONS
  Cholinergic stimulation provokes arrhythmias in this model of LQT3 by triggering bradycardia. beta-Adrenoceptor density is reduced, and beta-adrenoceptor blockade does not prevent arrhythmias. Sodium channel blockade and beta-adrenoceptor stimulation suppress arrhythmias by shortening repolarization and minimizing difference in late sodium current.
authors.affiliation: Department of Cardiology and Angiology, University Hospital Münster, Albert-Schweitzer-Street 33, D-48129 Münster, Germany. fabritzl@uni-muenster.de
authors.forename: Larissa
authors.initials: L
authors.lastname: Fabritz
authors.forename: Dierk
authors.initials: D
authors.lastname: Damke
authors.forename: Markus
authors.initials: M
authors.lastname: Emmerich
authors.forename: Susann G
authors.initials: SG
authors.lastname: Kaufmann
authors.forename: Kathrin
authors.initials: K
authors.lastname: Theis
authors.forename: Andreas
authors.initials: A
authors.lastname: Blana
authors.forename: Lisa
authors.initials: L
authors.lastname: Fortmüller
authors.forename: Sandra
authors.initials: S
authors.lastname: Laakmann
authors.forename: Sven
authors.initials: S
authors.lastname: Hermann
authors.forename: Elena
authors.initials: E
authors.lastname: Aleynichenko
authors.forename: Johannes
authors.initials: J
authors.lastname: Steinfurt
authors.forename: Daniela
authors.initials: D
authors.lastname: Volkery
authors.forename: Burkhard
authors.initials: B
authors.lastname: Riemann
authors.forename: Uwe
authors.initials: U
authors.lastname: Kirchhefer
authors.forename: Michael R
authors.initials: MR
authors.lastname: Franz
authors.forename: Günter
authors.initials: G
authors.lastname: Breithardt
authors.forename: Edward
authors.initials: E
authors.lastname: Carmeliet
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfers
authors.forename: Sebastian K G
authors.initials: SK
authors.lastname: Maier
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Paulus
authors.initials: P
authors.lastname: Kirchhof
mesh_terms: D000200:Action Potentials; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001341:Autonomic Nervous System / Q000187:drug effects* / Q000503:physiopathology; D001345:Autoradiography; D001919:Bradycardia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D002217:Carbachol; D004195:Disease Models, Animal; D015536:Down-Regulation; D015716:Electrocardiography, Ambulatory; D055879:Gene Knock-In Techniques; D006321:Heart / Q000294:innervation*; D006339:Heart Rate / Q000187:drug effects*; D008133:Long QT Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D005082:Physical Exertion; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013315:Stress, Psychological / Q000150:complications; D013686:Telemetry; D013997:Time Factors; D016171:Torsades de Pointes / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D018727:Muscarinic Antagonists; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011943:Receptors, Adrenergic, beta; C568321:Scn5a protein, mouse; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D002217:Carbachol