Cardiovascular Research Advance Access [Accepted Manuscript] published online on January 31, 2008
Cardiovascular Research, 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 ischemia
1 Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Canada
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, The Netherlands
Address correspondence to: Stanley Nattel, Montreal Heart Institute, 5000 Belanger St. E., Montreal, Quebec, H1T 1C8, Canada. Tel.: 514-376-3330; Fax: 514-376-1355; E-mail: stanley.nattel{at}icm-mhi.org
Aim: 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 ischemia (AI).
Methods: Four groups of mongrel dogs were studied: 1) a group subjected to atrial ischemia without GGA (AI-CTL, n=13 dogs); 2) dogs that underwent atrial ischemia after GGA pre-treatment (120 mg/kg/day, AI-GGA, n=12); 3) dogs receiving GGA pretreatment without atrial ischemia (n=5); 4) control dogs for tissue sampling (n=5). Isolated right atrial ischemia was produced by occluding a right atrial coronary-artery branch.
Results: Atrial ischemia reduced ischemic-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 ischemia-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 ischemia, did not alter DAF or conduction indices. Atrial ischemia slightly prolonged atrial refractory period, an effect also prevented by GGA. GGA significantly increased HSP70 protein expression in right atrial tissues of ischemic hearts.
Conclusion: GGA prevents ischemia-induced atrial conduction abnormalities and suppresses ischemia-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; ischemia
Time for primary review: 7
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