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


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.
Sakabe
Masao
M
Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, 5000 Belanger St. E., Montreal, Quebec, Canada H1T 1C8.
Shiroshita-Takeshita
Akiko
A
Maguy
Ange
A
Brundel
Bianca J J M
BJ
Fujiki
Akira
A
Inoue
Hiroshi
H
Nattel
Stanley
S
D000200:Action Potentials; D000284:Administration, Oral; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001281:Atrial Fibrillation / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D004224:Diterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D004285:Dogs; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006325:Heart Atria / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation
D000889:Anti-Arrhythmia Agents; D004224:Diterpenes; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C031049:geranylgeranylacetone