کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2953578 | 1577502 | 2006 | 8 صفحه PDF | دانلود رایگان |
ObjectivesA pressure overload model was developed to simulate aortic stenosis and assess caspase activity during the transition to heart failure.BackgroundCardiomyocyte apoptosis is implicated in the pathogenesis of heart failure, and caspase activation is central to this pathophysiological process.MethodsA total of 10 sheep were banded with variable aortic constriction devices, progressively inflated to increase left ventricular (LV) afterload. Serial LV endomyocardial biopsy samples were obtained to measure caspase activity and presence of apoptosis.ResultsOver the first 3 to 4 weeks, hypertrophy developed in the sheep (LV mass index 90.8 ± 4.9 g/m2vs. 44.0 ± 3.0 g/m2, p < 0.01), followed by gradual dilatation of the left ventricle (diastolic LV internal diameter 4.23 ± 0.08 cm vs. 3.39 ± 0.07 cm, p < 0.01). Ventricular function remained stable until 7 to 8 weeks after banding, when there was significant deterioration (fractional shortening 18.3 ± 2.4% vs. 46.9 ± 2.6%, p < 0.01), associated with clinical heart failure. Serial LV endomyocardial biopsy samples were obtained at each echocardiographically defined stage (LV hypertrophy, LV dilation, and LV failure). Activity of caspases-3, -8, and -9 (measured by specific fluorogenic peptide substrates and immunohistochemistry) increased progressively, particularly with the onset of myocardial dysfunction (caspase-3 7.92 ± 1.19 vs. 1.00 ± 0.15, caspase-8 1.94 ± 0.21 vs. 1.00 ± 0.04, caspase-9 5.87 ± 0.97 vs. 1.00 ± 0.18 relative fluorescent units, p < 0.05). No evidence of deoxyribonucleic acid (DNA) fragmentation, however, was identified by immunohistochemical assays.ConclusionsActivation of cardiomyocyte caspase enzymes occurs during the transition to heart failure, without completion of apoptotic DNA fragmentation. Increased activity of caspase-8 and -9 suggests both mitochondrial and death-receptor mediated pathways are involved in this pathological process. Further knowledge of these pathways may stimulate development of apoptosis-based strategies for slowing progression of heart failure in aortic stenosis patients.
Journal: Journal of the American College of Cardiology - Volume 48, Issue 7, 3 October 2006, Pages 1451–1458