Autonomic modulation and antiarrhythmic therapy in a model of long QT syndrome type 3
Identifieur interne : 000A28 ( Istex/Corpus ); précédent : 000A27; suivant : 000A29Autonomic modulation and antiarrhythmic therapy in a model of long QT syndrome type 3
Auteurs : Larissa Fabritz ; Dierk Damke ; Markus Emmerich ; Susann G. Kaufmann ; Kathrin Theis ; Andreas Blana ; Lisa Fortmller ; Sandra Laakmann ; Sven Hermann ; Elena Aleynichenko ; Johannes Steinfurt ; Daniela Volkery ; Burkhard Riemann ; Uwe Kirchhefer ; Michael R. Franz ; Gnter Breithardt ; Edward Carmeliet ; Michael Schfers ; Sebastian K. G. Maier ; Peter Carmeliet ; Paulus KirchhofSource :
- Cardiovascular Research [ 0008-6363 ] ; 2010-07-01.
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). -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 (KPQ) 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. -Adrenoceptor stimulation suppressed arrhythmias, shortened rate-corrected action potential duration, increased rate, and minimized difference in late sodium current between genotypes. -Adrenoceptor density was reduced in LQT3 hearts. Acute -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. -Adrenoceptor density is reduced, and -adrenoceptor blockade does not prevent arrhythmias. Sodium channel blockade and -adrenoceptor stimulation suppress arrhythmias by shortening repolarization and minimizing difference in late sodium current.
Url:
DOI: 10.1093/cvr/cvq029
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Franz</name><affiliation><mods:affiliation>Departments of Pharmacology and Cardiology, Georgetown University and VA Medical Center, Washington, DC, USA</mods:affiliation></affiliation></author><author><name sortKey="Breithardt, Gnter" sort="Breithardt, Gnter" uniqKey="Breithardt G" first="Gnter" last="Breithardt">Gnter Breithardt</name><affiliation><mods:affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</mods:affiliation></affiliation></author><author><name sortKey="Carmeliet, Edward" sort="Carmeliet, Edward" uniqKey="Carmeliet E" first="Edward" last="Carmeliet">Edward Carmeliet</name><affiliation><mods:affiliation>Vesalius Research CenterVIB, Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Schfers, Michael" sort="Schfers, Michael" uniqKey="Schfers M" first="Michael" last="Schfers">Michael Schfers</name><affiliation><mods:affiliation>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>European Institute of Molecular Imaging, University of Mnster, Mnster, Germany</mods:affiliation></affiliation></author><author><name sortKey="Maier, Sebastian K G" sort="Maier, Sebastian K G" uniqKey="Maier S" first="Sebastian K. G." last="Maier">Sebastian K. G. Maier</name><affiliation><mods:affiliation>Medizinische Klinik und Poliklinik I, Universittsklinikum Wrzburg, Wrzburg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Carmeliet, Peter" sort="Carmeliet, Peter" uniqKey="Carmeliet P" first="Peter" last="Carmeliet">Peter Carmeliet</name><affiliation><mods:affiliation>Vesalius Research CenterVIB, Leuven, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Vesalius Research CenterKU Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Kirchhof, Paulus" sort="Kirchhof, Paulus" uniqKey="Kirchhof P" first="Paulus" last="Kirchhof">Paulus Kirchhof</name><affiliation><mods:affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:D965F6E081BB39FDCDFBA7D999ACAB684772C515</idno><date when="2010" year="2010">2010</date><idno type="doi">10.1093/cvr/cvq029</idno><idno type="url">https://api.istex.fr/document/D965F6E081BB39FDCDFBA7D999ACAB684772C515/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">000A28</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">Autonomic modulation and antiarrhythmic therapy in a model of long QT syndrome type 3</title><author><name sortKey="Fabritz, Larissa" sort="Fabritz, Larissa" uniqKey="Fabritz L" first="Larissa" last="Fabritz">Larissa Fabritz</name><affiliation><mods:affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: fabritzl@uni-muenster.de</mods:affiliation></affiliation></author><author><name sortKey="Damke, Dierk" sort="Damke, Dierk" uniqKey="Damke D" first="Dierk" last="Damke">Dierk Damke</name><affiliation><mods:affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</mods:affiliation></affiliation></author><author><name sortKey="Emmerich, Markus" sort="Emmerich, Markus" uniqKey="Emmerich M" first="Markus" last="Emmerich">Markus Emmerich</name><affiliation><mods:affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</mods:affiliation></affiliation></author><author><name sortKey="Kaufmann, Susann G" sort="Kaufmann, Susann G" uniqKey="Kaufmann S" first="Susann G." last="Kaufmann">Susann G. Kaufmann</name><affiliation><mods:affiliation>Medizinische Klinik und Poliklinik I, Universittsklinikum Wrzburg, Wrzburg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Theis, Kathrin" sort="Theis, Kathrin" uniqKey="Theis K" first="Kathrin" last="Theis">Kathrin Theis</name><affiliation><mods:affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</mods:affiliation></affiliation></author><author><name sortKey="Blana, Andreas" sort="Blana, Andreas" uniqKey="Blana A" first="Andreas" last="Blana">Andreas Blana</name><affiliation><mods:affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</mods:affiliation></affiliation></author><author><name sortKey="Fortmller, Lisa" sort="Fortmller, Lisa" uniqKey="Fortmller L" first="Lisa" last="Fortmller">Lisa Fortmller</name><affiliation><mods:affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</mods:affiliation></affiliation></author><author><name sortKey="Laakmann, Sandra" sort="Laakmann, Sandra" uniqKey="Laakmann S" first="Sandra" last="Laakmann">Sandra Laakmann</name><affiliation><mods:affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</mods:affiliation></affiliation></author><author><name sortKey="Hermann, Sven" sort="Hermann, Sven" uniqKey="Hermann S" first="Sven" last="Hermann">Sven Hermann</name><affiliation><mods:affiliation>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>European Institute of Molecular Imaging, University of Mnster, Mnster, Germany</mods:affiliation></affiliation></author><author><name sortKey="Aleynichenko, Elena" sort="Aleynichenko, Elena" uniqKey="Aleynichenko E" first="Elena" last="Aleynichenko">Elena Aleynichenko</name><affiliation><mods:affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</mods:affiliation></affiliation></author><author><name sortKey="Steinfurt, Johannes" sort="Steinfurt, Johannes" uniqKey="Steinfurt J" first="Johannes" last="Steinfurt">Johannes Steinfurt</name><affiliation><mods:affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</mods:affiliation></affiliation></author><author><name sortKey="Volkery, Daniela" sort="Volkery, Daniela" uniqKey="Volkery D" first="Daniela" last="Volkery">Daniela Volkery</name><affiliation><mods:affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</mods:affiliation></affiliation></author><author><name sortKey="Riemann, Burkhard" sort="Riemann, Burkhard" uniqKey="Riemann B" first="Burkhard" last="Riemann">Burkhard Riemann</name><affiliation><mods:affiliation>Department of Nuclear Medicine, University Hospital Mnster, Mnster, Germany</mods:affiliation></affiliation></author><author><name sortKey="Kirchhefer, Uwe" sort="Kirchhefer, Uwe" uniqKey="Kirchhefer U" first="Uwe" last="Kirchhefer">Uwe Kirchhefer</name><affiliation><mods:affiliation>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute of Pharmacology and Toxicology, University Hospital Mnster, Mnster, Germany</mods:affiliation></affiliation></author><author><name sortKey="Franz, Michael R" sort="Franz, Michael R" uniqKey="Franz M" first="Michael R." last="Franz">Michael R. Franz</name><affiliation><mods:affiliation>Departments of Pharmacology and Cardiology, Georgetown University and VA Medical Center, Washington, DC, USA</mods:affiliation></affiliation></author><author><name sortKey="Breithardt, Gnter" sort="Breithardt, Gnter" uniqKey="Breithardt G" first="Gnter" last="Breithardt">Gnter Breithardt</name><affiliation><mods:affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</mods:affiliation></affiliation></author><author><name sortKey="Carmeliet, Edward" sort="Carmeliet, Edward" uniqKey="Carmeliet E" first="Edward" last="Carmeliet">Edward Carmeliet</name><affiliation><mods:affiliation>Vesalius Research CenterVIB, Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Schfers, Michael" sort="Schfers, Michael" uniqKey="Schfers M" first="Michael" last="Schfers">Michael Schfers</name><affiliation><mods:affiliation>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>European Institute of Molecular Imaging, University of Mnster, Mnster, Germany</mods:affiliation></affiliation></author><author><name sortKey="Maier, Sebastian K G" sort="Maier, Sebastian K G" uniqKey="Maier S" first="Sebastian K. G." last="Maier">Sebastian K. G. Maier</name><affiliation><mods:affiliation>Medizinische Klinik und Poliklinik I, Universittsklinikum Wrzburg, Wrzburg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Carmeliet, Peter" sort="Carmeliet, Peter" uniqKey="Carmeliet P" first="Peter" last="Carmeliet">Peter Carmeliet</name><affiliation><mods:affiliation>Vesalius Research CenterVIB, Leuven, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>Vesalius Research CenterKU Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Kirchhof, Paulus" sort="Kirchhof, Paulus" uniqKey="Kirchhof P" first="Paulus" last="Kirchhof">Paulus Kirchhof</name><affiliation><mods:affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Cardiovascular Research</title><idno type="ISSN">0008-6363</idno><idno type="eISSN">1755-3245</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2010-07-01">2010-07-01</date><biblScope unit="volume">87</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="60">60</biblScope><biblScope unit="page" to="72">72</biblScope></imprint><idno type="ISSN">0008-6363</idno></series><idno type="istex">D965F6E081BB39FDCDFBA7D999ACAB684772C515</idno><idno type="DOI">10.1093/cvr/cvq029</idno><idno type="ArticleID">cvq029</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0008-6363</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="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). -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 (KPQ) 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. -Adrenoceptor stimulation suppressed arrhythmias, shortened rate-corrected action potential duration, increased rate, and minimized difference in late sodium current between genotypes. -Adrenoceptor density was reduced in LQT3 hearts. Acute -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. -Adrenoceptor density is reduced, and -adrenoceptor blockade does not prevent arrhythmias. Sodium channel blockade and -adrenoceptor stimulation suppress arrhythmias by shortening repolarization and minimizing difference in late sodium current.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Larissa Fabritz</name><affiliations><json:string>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</json:string><json:string>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</json:string><json:string>E-mail: fabritzl@uni-muenster.de</json:string></affiliations></json:item><json:item><name>Dierk Damke</name><affiliations><json:string>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</json:string></affiliations></json:item><json:item><name>Markus Emmerich</name><affiliations><json:string>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</json:string></affiliations></json:item><json:item><name>Susann G. Kaufmann</name><affiliations><json:string>Medizinische Klinik und Poliklinik I, Universittsklinikum Wrzburg, Wrzburg, Germany</json:string></affiliations></json:item><json:item><name>Kathrin Theis</name><affiliations><json:string>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</json:string></affiliations></json:item><json:item><name>Andreas Blana</name><affiliations><json:string>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</json:string></affiliations></json:item><json:item><name>Lisa Fortmller</name><affiliations><json:string>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</json:string><json:string>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</json:string></affiliations></json:item><json:item><name>Sandra Laakmann</name><affiliations><json:string>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</json:string><json:string>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</json:string></affiliations></json:item><json:item><name>Sven Hermann</name><affiliations><json:string>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</json:string><json:string>European Institute of Molecular Imaging, University of Mnster, Mnster, Germany</json:string></affiliations></json:item><json:item><name>Elena Aleynichenko</name><affiliations><json:string>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</json:string></affiliations></json:item><json:item><name>Johannes Steinfurt</name><affiliations><json:string>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</json:string></affiliations></json:item><json:item><name>Daniela Volkery</name><affiliations><json:string>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</json:string></affiliations></json:item><json:item><name>Burkhard Riemann</name><affiliations><json:string>Department of Nuclear Medicine, University Hospital Mnster, Mnster, Germany</json:string></affiliations></json:item><json:item><name>Uwe Kirchhefer</name><affiliations><json:string>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</json:string><json:string>Institute of Pharmacology and Toxicology, University Hospital Mnster, Mnster, Germany</json:string></affiliations></json:item><json:item><name>Michael R. Franz</name><affiliations><json:string>Departments of Pharmacology and Cardiology, Georgetown University and VA Medical Center, Washington, DC, USA</json:string></affiliations></json:item><json:item><name>Gnter Breithardt</name><affiliations><json:string>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</json:string></affiliations></json:item><json:item><name>Edward Carmeliet</name><affiliations><json:string>Vesalius Research CenterVIB, Leuven, Belgium</json:string></affiliations></json:item><json:item><name>Michael Schfers</name><affiliations><json:string>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</json:string><json:string>European Institute of Molecular Imaging, University of Mnster, Mnster, Germany</json:string></affiliations></json:item><json:item><name>Sebastian K.G. Maier</name><affiliations><json:string>Medizinische Klinik und Poliklinik I, Universittsklinikum Wrzburg, Wrzburg, Germany</json:string></affiliations></json:item><json:item><name>Peter Carmeliet</name><affiliations><json:string>Vesalius Research CenterVIB, Leuven, Belgium</json:string><json:string>Vesalius Research CenterKU Leuven, Belgium</json:string></affiliations></json:item><json:item><name>Paulus Kirchhof</name><affiliations><json:string>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</json:string><json:string>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Long QT syndrome 3</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Antiarrhythmic therapy</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Basic mechanisms of arrhythmias</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Murine model</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Telemetry ECG</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Stress</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Autoradiography</value></json:item></subject><articleId><json:string>cvq029</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><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). -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 (KPQ) 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. -Adrenoceptor stimulation suppressed arrhythmias, shortened rate-corrected action potential duration, increased rate, and minimized difference in late sodium current between genotypes. -Adrenoceptor density was reduced in LQT3 hearts. Acute -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. -Adrenoceptor density is reduced, and -adrenoceptor blockade does not prevent arrhythmias. Sodium channel blockade and -adrenoceptor stimulation suppress arrhythmias by shortening repolarization and minimizing difference in late sodium current.</abstract><qualityIndicators><score>8.868</score><pdfVersion>1.5</pdfVersion><pdfPageSize>595.276 x 793.701 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>7</keywordCount><abstractCharCount>1807</abstractCharCount><pdfWordCount>6402</pdfWordCount><pdfCharCount>42939</pdfCharCount><pdfPageCount>13</pdfPageCount><abstractWordCount>239</abstractWordCount></qualityIndicators><title>Autonomic modulation and antiarrhythmic therapy in a model of long QT syndrome type 3</title><genre><json:string>research-article</json:string></genre><host><volume>87</volume><publisherId><json:string>cardiovascres</json:string></publisherId><pages><last>72</last><first>60</first></pages><issn><json:string>0008-6363</json:string></issn><issue>1</issue><genre><json:string>journal</json:string></genre><language><json:string>unknown</json:string></language><eissn><json:string>1755-3245</json:string></eissn><title>Cardiovascular Research</title></host><categories><wos><json:string>CARDIAC & CARDIOVASCULAR SYSTEMS</json:string></wos></categories><publicationDate>2010</publicationDate><copyrightDate>2010</copyrightDate><doi><json:string>10.1093/cvr/cvq029</json:string></doi><id>D965F6E081BB39FDCDFBA7D999ACAB684772C515</id><score>0.26681775</score><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/D965F6E081BB39FDCDFBA7D999ACAB684772C515/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/D965F6E081BB39FDCDFBA7D999ACAB684772C515/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/D965F6E081BB39FDCDFBA7D999ACAB684772C515/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a">Autonomic modulation and antiarrhythmic therapy in a model of long QT syndrome type 3</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Oxford University Press</publisher><availability><p>Published on behalf of the European Society of Cardiology. All rights reserved. The Author 2010. For permissions please email: journals.permissionsoxfordjournals.org.</p></availability><date>2010-01-28</date></publicationStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Autonomic modulation and antiarrhythmic therapy in a model of long QT syndrome type 3</title><author xml:id="author-1"><persName><forename type="first">Larissa</forename><surname>Fabritz</surname></persName><email>fabritzl@uni-muenster.de</email><affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</affiliation><affiliation>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</affiliation></author><author xml:id="author-2"><persName><forename type="first">Dierk</forename><surname>Damke</surname></persName><affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</affiliation></author><author xml:id="author-3"><persName><forename type="first">Markus</forename><surname>Emmerich</surname></persName><affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</affiliation></author><author xml:id="author-4"><persName><forename type="first">Susann G.</forename><surname>Kaufmann</surname></persName><affiliation>Medizinische Klinik und Poliklinik I, Universittsklinikum Wrzburg, Wrzburg, Germany</affiliation></author><author xml:id="author-5"><persName><forename type="first">Kathrin</forename><surname>Theis</surname></persName><affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</affiliation></author><author xml:id="author-6"><persName><forename type="first">Andreas</forename><surname>Blana</surname></persName><affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</affiliation></author><author xml:id="author-7"><persName><forename type="first">Lisa</forename><surname>Fortmller</surname></persName><affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</affiliation><affiliation>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</affiliation></author><author xml:id="author-8"><persName><forename type="first">Sandra</forename><surname>Laakmann</surname></persName><affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</affiliation><affiliation>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</affiliation></author><author xml:id="author-9"><persName><forename type="first">Sven</forename><surname>Hermann</surname></persName><affiliation>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</affiliation><affiliation>European Institute of Molecular Imaging, University of Mnster, Mnster, Germany</affiliation></author><author xml:id="author-10"><persName><forename type="first">Elena</forename><surname>Aleynichenko</surname></persName><affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</affiliation></author><author xml:id="author-11"><persName><forename type="first">Johannes</forename><surname>Steinfurt</surname></persName><affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</affiliation></author><author xml:id="author-12"><persName><forename type="first">Daniela</forename><surname>Volkery</surname></persName><affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</affiliation></author><author xml:id="author-13"><persName><forename type="first">Burkhard</forename><surname>Riemann</surname></persName><affiliation>Department of Nuclear Medicine, University Hospital Mnster, Mnster, Germany</affiliation></author><author xml:id="author-14"><persName><forename type="first">Uwe</forename><surname>Kirchhefer</surname></persName><affiliation>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</affiliation><affiliation>Institute of Pharmacology and Toxicology, University Hospital Mnster, Mnster, Germany</affiliation></author><author xml:id="author-15"><persName><forename type="first">Michael R.</forename><surname>Franz</surname></persName><affiliation>Departments of Pharmacology and Cardiology, Georgetown University and VA Medical Center, Washington, DC, USA</affiliation></author><author xml:id="author-16"><persName><forename type="first">Gnter</forename><surname>Breithardt</surname></persName><affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</affiliation></author><author xml:id="author-17"><persName><forename type="first">Edward</forename><surname>Carmeliet</surname></persName><affiliation>Vesalius Research CenterVIB, Leuven, Belgium</affiliation></author><author xml:id="author-18"><persName><forename type="first">Michael</forename><surname>Schfers</surname></persName><affiliation>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</affiliation><affiliation>European Institute of Molecular Imaging, University of Mnster, Mnster, Germany</affiliation></author><author xml:id="author-19"><persName><forename type="first">Sebastian K.G.</forename><surname>Maier</surname></persName><affiliation>Medizinische Klinik und Poliklinik I, Universittsklinikum Wrzburg, Wrzburg, Germany</affiliation></author><author xml:id="author-20"><persName><forename type="first">Peter</forename><surname>Carmeliet</surname></persName><affiliation>Vesalius Research CenterVIB, Leuven, Belgium</affiliation><affiliation>Vesalius Research CenterKU Leuven, Belgium</affiliation></author><author xml:id="author-21"><persName><forename type="first">Paulus</forename><surname>Kirchhof</surname></persName><affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</affiliation><affiliation>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</affiliation></author></analytic><monogr><title level="j">Cardiovascular Research</title><idno type="pISSN">0008-6363</idno><idno type="eISSN">1755-3245</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2010-07-01"></date><biblScope unit="volume">87</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="60">60</biblScope><biblScope unit="page" to="72">72</biblScope></imprint></monogr><idno type="istex">D965F6E081BB39FDCDFBA7D999ACAB684772C515</idno><idno type="DOI">10.1093/cvr/cvq029</idno><idno type="ArticleID">cvq029</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2010-01-28</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>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). -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 (KPQ) 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. -Adrenoceptor stimulation suppressed arrhythmias, shortened rate-corrected action potential duration, increased rate, and minimized difference in late sodium current between genotypes. -Adrenoceptor density was reduced in LQT3 hearts. Acute -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. -Adrenoceptor density is reduced, and -adrenoceptor blockade does not prevent arrhythmias. Sodium channel blockade and -adrenoceptor stimulation suppress arrhythmias by shortening repolarization and minimizing difference in late sodium current.</p></abstract><textClass><keywords scheme="keyword"><list><head>keywords</head><item><term>Long QT syndrome 3</term></item><item><term>Antiarrhythmic therapy</term></item><item><term>Basic mechanisms of arrhythmias</term></item><item><term>Murine model</term></item><item><term>Telemetry ECG</term></item><item><term>Stress</term></item><item><term>Autoradiography</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2010-01-28">Created</change><change when="2010-07-01">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/D965F6E081BB39FDCDFBA7D999ACAB684772C515/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article"><front><journal-meta><journal-id journal-id-type="publisher-id">cardiovascres</journal-id><journal-id journal-id-type="hwp">cardiovascres</journal-id><journal-title>Cardiovascular Research</journal-title><issn pub-type="ppub">0008-6363</issn><issn pub-type="epub">1755-3245</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1093/cvr/cvq029</article-id><article-id pub-id-type="publisher-id">cvq029</article-id><article-categories><subj-group subj-group-type="heading"><subject>ORIGINAL ARTICLES</subject></subj-group></article-categories><title-group><article-title>Autonomic modulation and antiarrhythmic therapy in a model of long QT syndrome type 3</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Fabritz</surname><given-names>Larissa</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib><contrib contrib-type="author"><name><surname>Damke</surname><given-names>Dierk</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Emmerich</surname><given-names>Markus</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Kaufmann</surname><given-names>Susann G.</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Theis</surname><given-names>Kathrin</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Blana</surname><given-names>Andreas</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Fortmüller</surname><given-names>Lisa</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Laakmann</surname><given-names>Sandra</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Hermann</surname><given-names>Sven</given-names></name><xref ref-type="aff" rid="af2">2</xref><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Aleynichenko</surname><given-names>Elena</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Steinfurt</surname><given-names>Johannes</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Volkery</surname><given-names>Daniela</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Riemann</surname><given-names>Burkhard</given-names></name><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Kirchhefer</surname><given-names>Uwe</given-names></name><xref ref-type="aff" rid="af2">2</xref><xref ref-type="aff" rid="af6">6</xref></contrib><contrib contrib-type="author"><name><surname>Franz</surname><given-names>Michael R.</given-names></name><xref ref-type="aff" rid="af7">7</xref></contrib><contrib contrib-type="author"><name><surname>Breithardt</surname><given-names>Günter</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Carmeliet</surname><given-names>Edward</given-names></name><xref ref-type="aff" rid="af8">8</xref></contrib><contrib contrib-type="author"><name><surname>Schäfers</surname><given-names>Michael</given-names></name><xref ref-type="aff" rid="af2">2</xref><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Maier</surname><given-names>Sebastian K.G.</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Carmeliet</surname><given-names>Peter</given-names></name><xref ref-type="aff" rid="af8">8</xref><xref ref-type="aff" rid="af9">9</xref></contrib><contrib contrib-type="author"><name><surname>Kirchhof</surname><given-names>Paulus</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref></contrib></contrib-group><aff id="af1"><label>1</label><addr-line>Department of Cardiology and Angiology</addr-line>, <institution>University Hospital Münster</institution>, <addr-line>Albert-Schweitzer-Street 33, D-48129 Münster</addr-line>, <country>Germany</country></aff><aff id="af2"><label>2</label><institution>Interdisciplinary Center for Clinical Research Münster (IZKF Münster)</institution>, <addr-line>Münster</addr-line>, <country>Germany</country></aff><aff id="af3"><label>3</label><addr-line>Medizinische Klinik und Poliklinik I</addr-line>, <institution>Universitätsklinikum Würzburg</institution>, <addr-line>Würzburg</addr-line>, <country>Germany</country></aff><aff id="af4"><label>4</label><addr-line>European Institute of Molecular Imaging</addr-line>, <institution>University of Münster</institution>, <addr-line>Münster</addr-line>, <country>Germany</country></aff><aff id="af5"><label>5</label><addr-line>Department of Nuclear Medicine</addr-line>, <institution>University Hospital Münster</institution>, <addr-line>Münster</addr-line>, <country>Germany</country></aff><aff id="af6"><label>6</label><institution>Institute of Pharmacology and Toxicology, University Hospital Münster</institution>, <addr-line>Münster</addr-line>, <country>Germany</country></aff><aff id="af7"><label>7</label><addr-line>Departments of Pharmacology and Cardiology</addr-line>, <institution>Georgetown University and VA Medical Center</institution>, <addr-line>Washington, DC</addr-line>, <country>USA</country></aff><aff id="af8"><label>8</label><addr-line>Vesalius Research Center—VIB</addr-line>, <institution>Leuven</institution>, <addr-line>Belgium</addr-line></aff><aff id="af9"><label>9</label><addr-line>Vesalius Research Center—KU Leuven, Belgium</addr-line></aff><author-notes><corresp id="cor1"><label>*</label>Corresponding author. Tel: <phone>+49 251 834 6034</phone>; fax: <fax>+49 251 834 7864</fax>, Email: <email>fabritzl@uni-muenster.de</email></corresp></author-notes><pub-date pub-type="ppub"><day>1</day><month>7</month><year>2010</year></pub-date><pub-date pub-type="epub"><day>28</day><month>1</month><year>2010</year></pub-date><volume>87</volume><issue>1</issue><fpage>60</fpage><lpage>72</lpage><history><date date-type="received"><day>29</day><month>7</month><year>2009</year></date><date date-type="rev-recd"><day>18</day><month>12</month><year>2009</year></date><date date-type="accepted"><day>22</day><month>1</month><year>2010</year></date></history><permissions><copyright-statement>Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2010. For permissions please email: journals.permissions@oxfordjournals.org.</copyright-statement><copyright-year>2010</copyright-year><license license-type="creative-commons" xlink:href="http://creativecommons.org/licenses/by-nc/2.0/uk/"><p>The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org.</p></license></permissions><abstract><sec><title>Aims</title><p>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). &bgr;-Adrenoceptor blockers appear less effective in LQT3 than in other forms of the disease.</p></sec><sec><title>Methods and results</title><p>We studied effects of autonomic modulation on arrhythmias <italic>in vivo</italic> and <italic>in vitro</italic> and quantified sympathetic innervation by autoradiography in heterozygous mice with a knock-in deletion (ΔKPQ) in the <italic>Scn5a</italic> 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 <italic>per se</italic>, but caused bradycardia and rate-dependent action potential prolongation. The muscarinic inhibitor AFDX116 prevented effects of carbachol on heart rate and arrhythmias. &bgr;-Adrenoceptor stimulation suppressed arrhythmias, shortened rate-corrected action potential duration, increased rate, and minimized difference in late sodium current between genotypes. &bgr;-Adrenoceptor density was reduced in LQT3 hearts. Acute &bgr;-adrenoceptor blockade by esmolol, propranolol or chronic propranolol <italic>in vivo</italic> did not suppress arrhythmias. Chronic flecainide pre-treatment prevented arrhythmias (all <italic>P</italic> < 0.05).</p></sec><sec><title>Conclusion</title><p>Cholinergic stimulation provokes arrhythmias in this model of LQT3 by triggering bradycardia. &bgr;-Adrenoceptor density is reduced, and &bgr;-adrenoceptor blockade does not prevent arrhythmias. Sodium channel blockade and &bgr;-adrenoceptor stimulation suppress arrhythmias by shortening repolarization and minimizing difference in late sodium current.</p></sec></abstract><kwd-group><kwd>Long QT syndrome 3</kwd><kwd>Antiarrhythmic therapy</kwd><kwd>Basic mechanisms of arrhythmias</kwd><kwd>Murine model</kwd><kwd>Telemetry ECG</kwd><kwd>Stress</kwd><kwd>Autoradiography</kwd></kwd-group><custom-meta-wrap><custom-meta><meta-name>primary-review-time</meta-name><meta-value><bold>Time for primary review: 22 days</bold></meta-value></custom-meta></custom-meta-wrap></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Autonomic modulation and antiarrhythmic therapy in a model of long QT syndrome type 3</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Autonomic modulation and antiarrhythmic therapy in a model of long QT syndrome type 3</title></titleInfo><name type="personal"><namePart type="given">Larissa</namePart><namePart type="family">Fabritz</namePart><affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</affiliation><affiliation>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</affiliation><affiliation>E-mail: fabritzl@uni-muenster.de</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Dierk</namePart><namePart type="family">Damke</namePart><affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Markus</namePart><namePart type="family">Emmerich</namePart><affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Susann G.</namePart><namePart type="family">Kaufmann</namePart><affiliation>Medizinische Klinik und Poliklinik I, Universittsklinikum Wrzburg, Wrzburg, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kathrin</namePart><namePart type="family">Theis</namePart><affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Andreas</namePart><namePart type="family">Blana</namePart><affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Lisa</namePart><namePart type="family">Fortmller</namePart><affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</affiliation><affiliation>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sandra</namePart><namePart type="family">Laakmann</namePart><affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</affiliation><affiliation>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sven</namePart><namePart type="family">Hermann</namePart><affiliation>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</affiliation><affiliation>European Institute of Molecular Imaging, University of Mnster, Mnster, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Elena</namePart><namePart type="family">Aleynichenko</namePart><affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Johannes</namePart><namePart type="family">Steinfurt</namePart><affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Daniela</namePart><namePart type="family">Volkery</namePart><affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Burkhard</namePart><namePart type="family">Riemann</namePart><affiliation>Department of Nuclear Medicine, University Hospital Mnster, Mnster, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Uwe</namePart><namePart type="family">Kirchhefer</namePart><affiliation>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</affiliation><affiliation>Institute of Pharmacology and Toxicology, University Hospital Mnster, Mnster, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Michael R.</namePart><namePart type="family">Franz</namePart><affiliation>Departments of Pharmacology and Cardiology, Georgetown University and VA Medical Center, Washington, DC, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Gnter</namePart><namePart type="family">Breithardt</namePart><affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Edward</namePart><namePart type="family">Carmeliet</namePart><affiliation>Vesalius Research CenterVIB, Leuven, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Michael</namePart><namePart type="family">Schfers</namePart><affiliation>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</affiliation><affiliation>European Institute of Molecular Imaging, University of Mnster, Mnster, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sebastian K.G.</namePart><namePart type="family">Maier</namePart><affiliation>Medizinische Klinik und Poliklinik I, Universittsklinikum Wrzburg, Wrzburg, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Peter</namePart><namePart type="family">Carmeliet</namePart><affiliation>Vesalius Research CenterVIB, Leuven, Belgium</affiliation><affiliation>Vesalius Research CenterKU Leuven, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Paulus</namePart><namePart type="family">Kirchhof</namePart><affiliation>Department of Cardiology and Angiology, University Hospital Mnster, Albert-Schweitzer-Street 33, D-48129 Mnster, Germany</affiliation><affiliation>Interdisciplinary Center for Clinical Research Mnster (IZKF Mnster), Mnster, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2010-07-01</dateIssued><dateCreated encoding="w3cdtf">2010-01-28</dateCreated><copyrightDate encoding="w3cdtf">2010</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><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). -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 (KPQ) 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. -Adrenoceptor stimulation suppressed arrhythmias, shortened rate-corrected action potential duration, increased rate, and minimized difference in late sodium current between genotypes. -Adrenoceptor density was reduced in LQT3 hearts. Acute -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. -Adrenoceptor density is reduced, and -adrenoceptor blockade does not prevent arrhythmias. Sodium channel blockade and -adrenoceptor stimulation suppress arrhythmias by shortening repolarization and minimizing difference in late sodium current.</abstract><subject><genre>keywords</genre><topic>Long QT syndrome 3</topic><topic>Antiarrhythmic therapy</topic><topic>Basic mechanisms of arrhythmias</topic><topic>Murine model</topic><topic>Telemetry ECG</topic><topic>Stress</topic><topic>Autoradiography</topic></subject><relatedItem type="host"><titleInfo><title>Cardiovascular Research</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">0008-6363</identifier><identifier type="eISSN">1755-3245</identifier><identifier type="PublisherID">cardiovascres</identifier><identifier type="PublisherID-hwp">cardiovascres</identifier><part><date>2010</date><detail type="volume"><caption>vol.</caption><number>87</number></detail><detail type="issue"><caption>no.</caption><number>1</number></detail><extent unit="pages"><start>60</start><end>72</end></extent></part></relatedItem><identifier type="istex">D965F6E081BB39FDCDFBA7D999ACAB684772C515</identifier><identifier type="DOI">10.1093/cvr/cvq029</identifier><identifier type="ArticleID">cvq029</identifier><accessCondition type="use and reproduction" contentType="copyright">Published on behalf of the European Society of Cardiology. 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