Effects of a heat shock protein inducer on the atrial fibrillation substrate caused by acute atrial ischaemia

• Published in: Cardiovascular research 2008-04, Vol.78 (1), p.63-70
• Main Authors: Sakabe, Masao, Shiroshita-Takeshita, Akiko, Maguy, Ange, Brundel, Bianca J.J.M., Fujiki, Akira, Inoue, Hiroshi, Nattel, Stanley
• Format: Article
• Language: English
• Subjects: Action Potentials; Administration, Oral; Animals; Anti-Arrhythmia Agents - administration & dosage; Anti-Arrhythmia Agents - pharmacology; Antiarrhythmic agents; Antiarythmic agents; Arrhythmia; Atrial Fibrillation - etiology; Atrial Fibrillation - metabolism; Atrial Fibrillation - prevention & control; Biological and medical sciences; Cardiac dysrhythmias; Cardiology. Vascular system; Cardiovascular system; Disease Models, Animal; Diterpenes - administration & dosage; Diterpenes - pharmacology; Dogs; Heart; Heart Atria - metabolism; Heat-Shock Proteins - metabolism; HSP70 Heat-Shock Proteins - metabolism; Ischaemia; Medical sciences; Myocardial Ischemia - complications; Myocardial Ischemia - drug therapy; Myocardial Ischemia - metabolism; Myocardium - metabolism; Pharmacology. Drug treatments; Time Factors; Up-Regulation
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvn019

Aims Heat shock proteins (HSPs) are a set of endogenous cytoprotective factors activated by various pathological conditions. This study addressed the effects of geranylgeranylacetone (GGA), an orally active HSP inducer, on the atrial fibrillation (AF) substrate associated with acute atrial ischaemia (AI). Methods and results Four groups of mongrel dogs were studied: (1) a group subjected to AI without GGA (AI-CTL, n = 13 dogs); (2) dogs that underwent AI after GGA pretreatment (120 mg/kg/day; AI-GGA, n = 12); (3) dogs receiving GGA pretreatment without AI (n = 5); (4) control dogs for tissue sampling (n = 5). Isolated right AI was produced by occluding a right atrial (RA) coronary-artery branch. AI reduced ischaemic-zone conduction velocity (CV, from 94 ± 3 to 46 ± 5 cm/s; P < 0.01) and increased maximum local phase delays (P95, from 1.6 ± 0.1 to 4.6 ± 0.6 ms/mm; P < 0.01), conduction heterogeneity index (CHI, from 0.7 ± 0.1 to 2.9 ± 0.5; P < 0.01), and the mean duration of burst pacing-induced AF (DAF, from 44 ± 18 to 890 ± 323 s; P < 0.01) in AI-CTL dogs. GGA pretreatment attenuated ischaemia-induced conduction abnormalities (CV, 77 ± 8 cm/s; P95, 2.1 ± 0.4 ms/mm; CHI, 1.1 ± 0.2; all P < 0.01 vs. AI-CTL) and DAF (328 ± 249 s; P < 0.01) in AI-GGA dogs. GGA treatment alone, without ischaemia, did not alter DAF or conduction indices. AI slightly prolonged atrial refractory period, an effect also prevented by GGA. GGA significantly increased HSP70 protein expression in RA tissues of ischaemic hearts. Conclusions GGA prevents ischaemia-induced atrial conduction abnormalities and suppresses ischaemia-related AF. These results suggest that HSP induction might be a useful new anti-AF intervention for patients with coronary artery disease.