Abstract 1237: Heat Shock Protein Induction Attenuates Atrial Remodeling and Atrial Fibrillation Promotion in Dogs with Ventricular Tachycardiomyopathy
Both atrial tachycardia (AT) and heart failure (HF) cause AF-promoting remodeling, but with different pathophysiologies. Heat shock proteins (HSPs) are induced by a variety of stressors and may have an autoprotective function. We have shown that HSP induction protects against AT remodeling, but the effect of HSP induction on HF-induced atrial structural remodeling is unknown and was the object of this study.
Methods: Dogs were subjected to ventricular tachypacing (VTP, 240 bpm × 2 wks) to induce HF in the absence (VTP-only, N=7) and presence of the HSP inducer geranylgeranylacetone (GGA, 120 mg/kg/day, N=5), starting 3 days prior to VTP and continued throughout the study period. Electrophysiological (including 240 electrode mapping) and histological analyses were obtained and compared to non-paced controls (NP, N=7). To study potential mechanisms, we assessed MAP kinase (p38 and JNK) phosphorylation (Western blot), an early event in HF remodeling, after 24 hr VTP.
Results: Mean duration of burst-pacing induced AF (DAF) was increased by 2 wk VTP (1016±284 s in VTP-only vs 24±9 s NP, p<0.01). VTP-induced DAF increase was prevented by GGA (48±19 s, p<0.01 vs VTP-only). Left ventricular end diastolic pressure (LVEDP), left (LAP) and right atrial pressure (RAP) increased in VTP-only dogs (12±2, 11±1, 10±1 mmHg vs 5±1, 5±1, 5±1 mm Hg in NP respectively, p<0.01 for each): filling pressure changes were attenuated by GGA (LVEDP: 8±1, LAP: 7±0, RAP: 5±0 mmHg, p<0.01 vs VTP-only). HF-induced conduction abnormalities (conduction heterogeneity index 0.9±0.1 in NP; 1.6±0.1 in VTP-only, p<0.01) were suppressed by GGA (0.8±0.0, p<0.01 vs VTP-only). Atrial interstitial fibrosis induced by HF (fibrous tissue content 3±1% in NP vs 19±1% VTP-only, p<0.01) was markedly attenuated by GGA (5±2%, p<0.01 vs VTP-only). Phosphorylated p38 and JNK increases due to 24 hr VTP (from 0.8±0.2 to 1.5±0.4 and 0.7±0.1 to 1.5±0.2, respectively) were markedly attenuated by GGA (0.8±0.1, 0.8±0.1, respectively).
Conclusions: HSP induction prevents HF-related atrial structural remodeling and AF promotion, possibly by suppressing underlying MAP kinase phosphorylation.
These results support the notion that HSP enhancement may be an interesting novel therapeutic approach for AF prevention.