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Title: Autonomic modulation and antiarrhythmic therapy in a model of long QT syndrome type 3
Authors: Fabritz, Larissa
Damke, Dierk
Emmerich, Markus
Kaufmann, Susann G
Theis, Kathrin
Blana, Andreas
Fortmüller, Lisa
Laakmann, Sandra
Hermann, Sven
Aleynichenko, Elena
Steinfurt, Johannes
Volkery, Daniela
Riemann, Burkhard
Kirchhefer, Uwe
Franz, Michael R
Breithardt, Günter
Carmeliet, Edward
Schäfers, Michael
Maier, Sebastian K G
Carmeliet, Peter
Kirchhof, Paulus # ×
Issue Date: Jul-2010
Publisher: British Medical Association
Series Title: Cardiovascular Research vol:87 issue:1 pages:60-72
Abstract: AIMS: 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. METHODS AND 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). CONCLUSION: 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.
URI: 
ISSN: 0008-6363
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Vesalius Research Centre (-)
Laboratory of Angiogenesis and Vascular Metabolism (Vesalius Research Center) (+)
× corresponding author
# (joint) last author

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