Cardiovascular Research Advance Access originally published online on January 31, 2008
Cardiovascular Research 2008 78(1):63-70; doi:10.1093/cvr/cvn019
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Effects of a heat shock protein inducer on the atrial fibrillation substrate caused by acute atrial ischaemia
1 Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, 5000 Belanger St. E., Montreal, Quebec, Canada H1T 1C8
2 The Second Department of Internal Medicine, University of Toyama, Toyama, Japan
3 Department of Radiation and Stress Cell Biology, Groningen University Institute for Drug Exploration (GUIDE), University Medical Center of Groningen, Groningen, The Netherlands
* Corresponding author. Tel: +1 514 376 3330; fax: +1 514 376 1355. E-mail address: stanley.nattel{at}icm-mhi.org
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.
KEYWORDS Arrhythmia; Antiarrhythmic agents; Ischaemia
Time for primary review: 7 days
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  B. J.J.M. Brundel, L. Ke, A.-J. Dijkhuis, X. Qi, A. Shiroshita-Takeshita, S. Nattel, R. H. Henning, and H. H. Kampinga Heat shock proteins as molecular targets for intervention in atrial fibrillation Cardiovasc Res, June 1, 2008; 78(3): 422 - 428. [Abstract] [Full Text] [PDF]
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