title: Disruption of cardiac cholinergic neurons enhances susceptibility to ventricular arrhythmias.
abstract: The parasympathetic nervous system plays an important role in the pathophysiology of atrial fibrillation. Catheter ablation, a minimally invasive procedure deactivating abnormal firing cardiac tissue, is increasingly becoming the therapy of choice for atrial fibrillation. This is inevitably associated with the obliteration of cardiac cholinergic neurons. However, the impact on ventricular electrophysiology is unclear. Here we show that cardiac cholinergic neurons modulate ventricular electrophysiology. Mechanical disruption or pharmacological blockade of parasympathetic innervation shortens ventricular refractory periods, increases the incidence of ventricular arrhythmia and decreases ventricular cAMP levels in murine hearts. Immunohistochemistry confirmed ventricular cholinergic innervation, revealing parasympathetic fibres running from the atria to the ventricles parallel to sympathetic fibres. In humans, catheter ablation of atrial fibrillation, which is accompanied by accidental parasympathetic and concomitant sympathetic denervation, raises the burden of premature ventricular complexes. In summary, our results demonstrate an influence of cardiac cholinergic neurons on the regulation of ventricular function and arrhythmogenesis.
authors.affiliation: Department of Cardiology-Electrophysiology, cardiac Neuro- and Electrophysiology Research Group (cNEP), University Heart Center, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.|DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 13347 Berlin, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Jungen
authors.affiliation: Department of Cardiology-Electrophysiology, cardiac Neuro- and Electrophysiology Research Group (cNEP), University Heart Center, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.|DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 13347 Berlin, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Scherschel
authors.affiliation: Department of Cardiology-Electrophysiology, cardiac Neuro- and Electrophysiology Research Group (cNEP), University Heart Center, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Eickholt
authors.affiliation: Department of Cardiology-Electrophysiology, cardiac Neuro- and Electrophysiology Research Group (cNEP), University Heart Center, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Pawel
authors.identifier: 0000-0001-8440-654X
authors.initials: P
authors.lastname: Kuklik
authors.affiliation: Department of Cardiology-Electrophysiology, cardiac Neuro- and Electrophysiology Research Group (cNEP), University Heart Center, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.|DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 13347 Berlin, Germany.
authors.forename: Niklas
authors.initials: N
authors.lastname: Klatt
authors.affiliation: DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 13347 Berlin, Germany.|Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Nadja
authors.initials: N
authors.lastname: Bork
authors.affiliation: Department of Cardiology-Electrophysiology, cardiac Neuro- and Electrophysiology Research Group (cNEP), University Heart Center, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Salzbrunn
authors.affiliation: Department of Cardiology-Electrophysiology, cardiac Neuro- and Electrophysiology Research Group (cNEP), University Heart Center, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Fares
authors.initials: F
authors.lastname: Alken
authors.affiliation: Department of Cardiology-Electrophysiology, cardiac Neuro- and Electrophysiology Research Group (cNEP), University Heart Center, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Angendohr
authors.affiliation: Department of Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Klene
authors.affiliation: Department of Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Janos
authors.initials: J
authors.lastname: Mester
authors.affiliation: Institute of Neural and Sensory Physiology, Medical Faculty, University of Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
authors.forename: Nikolaj
authors.initials: N
authors.lastname: Klöcker
authors.affiliation: Academic Medical Center, University of Amsterdam, Department of Clinical and Experimental Cardiology, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Marieke W
authors.initials: MW
authors.lastname: Veldkamp
authors.affiliation: Institute of Anatomy and Experimental Morphology, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Schumacher
authors.affiliation: Department of Cardiology-Electrophysiology, cardiac Neuro- and Electrophysiology Research Group (cNEP), University Heart Center, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.|DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 13347 Berlin, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Willems
authors.affiliation: DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 13347 Berlin, Germany.|Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Viacheslav O
authors.initials: VO
authors.lastname: Nikolaev
authors.affiliation: Department of Cardiology-Electrophysiology, cardiac Neuro- and Electrophysiology Research Group (cNEP), University Heart Center, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.|DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 13347 Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Meyer
mesh_terms: D000368:Aged; D000818:Animals; D001281:Atrial Fibrillation / Q000503:physiopathology / Q000601:surgery*; D017115:Catheter Ablation / Q000009:adverse effects*; D059329:Cholinergic Neurons / Q000187:drug effects / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D004198:Disease Susceptibility / Q000503:physiopathology; D004452:Echocardiography; D004562:Electrocardiography; D005260:Female; D006325:Heart Atria / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006352:Heart Ventricles / Q000294:innervation* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D018377:Neurotransmitter Agents / Q000494:pharmacology; D010275:Parasympathetic Nervous System / Q000187:drug effects / Q000293:injuries / Q000503:physiopathology*; D012189:Retrospective Studies; D016276:Ventricular Function / Q000187:drug effects / Q000502:physiology
chemical_list: D018377:Neurotransmitter Agents; D000242:Cyclic AMP