title: Insights into sick sinus syndrome from an inducible mouse model.
abstract: OBJECTIVE
  Sick sinus syndrome is a generalized abnormality of cardiac impulse formation and is responsible for a large proportion of pacemaker implantations. Although the exact aetiology is not known, it is widely accepted that age-dependent degenerative fibrosis of nodal tissue is the most common cause. Despite its importance, an animal model for sick sinus syndrome is lacking. We attempted to generate a mouse model phenocopying the pathohistological changes as well as the characteristic arrhythmic manifestations of this syndrome.
  
  
  RESULTS
  We crossed two genetically engineered mouse lines, ROSA-eGFP-DTA and HCN4-KiT-Cre, to achieve an inducible deletion of cells specifically in the cardiac pacemaking and conduction system. This deletion resulted in a degenerative fibrosis of nodal tissue, which accurately reflects the pathohistological findings in human sick sinus syndrome. The extent of the sino-atrial fibrosis could be controlled by varying the dosage of the inducing substance, tamoxifen. A high-dose protocol resulted in the complete ablation of all sino-atrial cells as demonstrated by histochemical analysis and quantitative reverse transcriptase-polymerase chain reaction. The animals developed a variety of arrhythmias, including progressive bradycardia, sinus pauses, supraventricular and ventricular tachycardia and chronotropic incompetence. Remarkably, the complete destruction of the primary pacemaker centre resulted in only a small increase in mortality.
  
  
  CONCLUSIONS
  This study describes the generation and analysis of an inducible mouse model which closely reflects the pathophysiological characteristics of sick sinus syndrome. The model, with the ability to control the extent of nodal cell ablation and fibrosis, offers new insights into sick sinus syndrome and other cardiac conduction diseases.
authors.affiliation: Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany. herrmann@pharmakologie.uni-erlangen.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Herrmann
authors.forename: Larissa
authors.initials: L
authors.lastname: Fabritz
authors.forename: Beate
authors.initials: B
authors.lastname: Layh
authors.forename: Paulus
authors.initials: P
authors.lastname: Kirchhof
authors.forename: Andreas
authors.initials: A
authors.lastname: Ludwig
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D001683:Biological Clocks; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics; D004167:Diphtheria Toxin / Q000235:genetics; D004195:Disease Models, Animal; D004562:Electrocardiography; D005355:Fibrosis; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics; D006339:Heart Rate; D019426:Integrases / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics; D011506:Proteins / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D022661:RNA, Untranslated; D012804:Sick Sinus Syndrome / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D012849:Sinoatrial Node / Q000473:pathology / Q000503:physiopathology*; D013686:Telemetry; D013997:Time Factors
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; D004167:Diphtheria Toxin; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D010446:Peptide Fragments; D011506:Proteins; D022661:RNA, Untranslated; C029795:diphtheria toxin fragment A; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D019009:Proto-Oncogene Proteins c-kit; C045073:Cre recombinase; D019426:Integrases