Autonomic modulation and antiarrhythmic therapy in a model of long QT syndrome type 3.
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.
Fabritz
Larissa
L
Department of Cardiology and Angiology, University Hospital Münster, Albert-Schweitzer-Street 33, D-48129 Münster, Germany. fabritzl@uni-muenster.de
Damke
Dierk
D
Emmerich
Markus
M
Kaufmann
Susann G
SG
Theis
Kathrin
K
Blana
Andreas
A
Fortmüller
Lisa
L
Laakmann
Sandra
S
Hermann
Sven
S
Aleynichenko
Elena
E
Steinfurt
Johannes
J
Volkery
Daniela
D
Riemann
Burkhard
B
Kirchhefer
Uwe
U
Franz
Michael R
MR
Breithardt
Günter
G
Carmeliet
Edward
E
Schäfers
Michael
M
Maier
Sebastian K G
SK
Carmeliet
Peter
P
Kirchhof
Paulus
P
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
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