title: Heat shock protein inducer modifies arrhythmogenic substrate and inhibits atrial fibrillation in the failing heart.
abstract: BACKGROUND
  Geranylgeranylacetone (GGA) has been reported up-regulating heat shock protein (HSP) expression, and protecting against atrial remodeling. This study aimed to investigate the effects of GGA on atrial electrophysiology and inducibility of atrial fibrillation (AF) in heart failure (HF) model.
  
  
  RESULTS
  HF rabbits were created 4 weeks after coronary artery ligation. Monophasic action potential recordings and multielectrode array were used to record the electrophysiological characteristics of left atrium (LA) in normal, or HF rabbits with (HF-GGA) and without (HF-control) oral administration of GGA (200 mg/kg, 24 h before experiments). The mRNA and protein expressions of ionic channels were measured by Western blot and PCR. HF-GGA LA (n = 10), similar to normal LA (n = 10) had a shorter action potential duration (APD) and effective refractory period than HF-control LA (n = 10). HF-GGA LA had less triggered activity and APD alternans (20% vs. 100%, P = 0.001), lower maxima slope of restitution curve of APD (0.94 ± 0.04 vs.1.69 ± 0.04, P < 0.001), and less inducibility of AF (50% vs. 100%, P = 0.033) than HF-control LA. HF-GGA LA had a shorter activation time and higher conduction velocity than HF-control LA. HF-GGA LA had a higher mRNA expression of Cav1.2, Nav1.5, Kir2.1, Kv1.4, Kv7.1, Kv11.1, sarcoplasmic reticulum Ca(2+)-ATPase, and higher phosphorylation of phospholamban than HF-control LA.
  
  
  CONCLUSIONS
  GGA decreases triggered activity, dispersion of APD and inducibility of AF in failing heart through induction of HSP, and modulation of ionic channels and calcium homeostasis.
authors.affiliation: Institute of Clinical Medicine and Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Shih-Lin
authors.initials: SL
authors.lastname: Chang
authors.forename: Yao-Chang
authors.initials: YC
authors.lastname: Chen
authors.forename: Chiao-Po
authors.initials: CP
authors.lastname: Hsu
authors.forename: Yu-Hsun
authors.initials: YH
authors.lastname: Kao
authors.forename: Yung-Kuo
authors.initials: YK
authors.lastname: Lin
authors.forename: Yu-Jun
authors.initials: YJ
authors.lastname: Lai
authors.forename: Hung-I
authors.initials: HI
authors.lastname: Yeh
authors.forename: Satoshi
authors.initials: S
authors.lastname: Higa
authors.forename: Shih-Ann
authors.initials: SA
authors.lastname: Chen
authors.forename: Yi-Jen
authors.initials: YJ
authors.lastname: Chen
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001281:Atrial Fibrillation / Q000503:physiopathology / Q000517:prevention & control*; D004224:Diterpenes / Q000494:pharmacology / Q000627:therapeutic use*; D006333:Heart Failure / Q000188:drug therapy*; D006360:Heat-Shock Proteins / Q000819:agonists / Q000096:biosynthesis*; D011817:Rabbits
chemical_list: D004224:Diterpenes; D006360:Heat-Shock Proteins; C031049:geranylgeranylacetone
keywords: Atrial fibrillation; GGA; Heart failure; Heat shock protein; Monophasic action potential