title: The renin-angiotensin system promotes arrhythmogenic substrates and lethal arrhythmias in mice with non-ischaemic cardiomyopathy.
abstract: OBJECTIVE
  The progression of pathological left ventricular remodelling leads to cardiac dysfunction and contributes to the occurrence of malignant arrhythmias and sudden cardiac death. The underlying molecular mechanisms remain unclear, however. Our aim was to examine the role of the renin-angiotensin system (RAS) in the mechanism underlying arrhythmogenic cardiac remodelling using a transgenic mouse expressing a cardiac-specific dominant-negative form of neuron-restrictive silencer factor (dnNRSF-Tg). This mouse model exhibits progressive cardiac dysfunction leading to lethal arrhythmias.
  
  
  RESULTS
  Subcutaneous administration of aliskiren, a direct renin inhibitor, significantly suppressed the progression of pathological cardiac remodelling and improved survival among dnNRSF-Tg mice while reducing arrhythmogenicity. Genetic deletion of the angiotensin type 1a receptor (AT1aR) similarly suppressed cardiac remodelling and sudden death. In optical mapping analyses, spontaneous ventricular tachycardia (VT) and fibrillation (VF) initiated by breakthrough-type excitations originating from focal activation sites and maintained by functional re-entry were observed in dnNRSF-Tg hearts. Under constant pacing, dnNRSF-Tg hearts exhibited markedly slowed conduction velocity, which likely contributes to the arrhythmogenic substrate. Aliskiren treatment increased conduction velocity and reduced the incidence of sustained VT. These effects were associated with suppression of cardiac fibrosis and restoration of connexin 43 expression in dnNRSF-Tg ventricles.
  
  
  CONCLUSIONS
  Renin inhibition or genetic deletion of AT1aR suppresses pathological cardiac remodelling that leads to the generation of substrates maintaining VT/VF and reduces the occurrence of sudden death in dnNRSF-Tg mice. These findings demonstrate the significant contribution of RAS activation to the progression of arrhythmogenic substrates.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Chinatsu
authors.initials: C
authors.lastname: Yamada
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan kuwa@kuhp.kyoto-u.ac.jp.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kuwahara
authors.affiliation: Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Yamazaki
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Nishikimi
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kinoshita
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kuwabara
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Takeya
authors.initials: T
authors.lastname: Minami
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan Department of Peptide Research, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Shibata
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan Department of Peptide Research, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakao
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Kosai
authors.initials: K
authors.lastname: Cho
authors.affiliation: Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Arai
authors.affiliation: Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Haruo
authors.initials: H
authors.lastname: Honjo
authors.affiliation: Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Kaichiro
authors.initials: K
authors.lastname: Kamiya
authors.affiliation: Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kimura
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D009202:Cardiomyopathies / Q000150:complications*; D018031:Connexin 43 / Q000032:analysis; D005355:Fibrosis; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D012084:Renin-Angiotensin System / Q000502:physiology*; D020257:Ventricular Remodeling; D000092502:Renin Inhibitors
chemical_list: D018031:Connexin 43; D044140:Receptor, Angiotensin, Type 1; D000092502:Renin Inhibitors
keywords: Arrhythmia; Cardiac; Electrical remodelling; Renin–angiotensin system; Sudden