Key result
Progressive aortic banding drives an ~8-fold increase in LV caspase-3 during transition to heart failure.
Why the study?
Cardiomyocyte apoptosis is implicated in the pathogenesis of heart failure and caspase activation is central to this process, motivating the assessment of caspase activity during the transition to pressure overload-induced heart failure.
Does progressive pressure overload via aortic banding activate the apoptotic caspase cascade during the transition to heart failure in sheep?
Does progressive pressure overload via aortic banding activate the apoptotic caspase cascade during the transition to heart failure in sheep?
Demonstrates that both mitochondrial (caspase-9) and death-receptor (caspase-8) mediated caspase pathways are activated during the transition from pressure overload hypertrophy to heart failure without completing apoptotic DNA fragmentation, suggesting potential therapeutic targets in aortic stenosis.
Answers are grounded in this paper and cite their sources.
May implicate caspases in pressure-overload HF progression; leaves open whether inhibition alters outcomes in human aortic stenosis.
Objectives A pressure overload model was developed to simulate aortic stenosis and assess caspase activity during the transition to heart failure. Background Cardiomyocyte apoptosis is implicated in the pathogenesis of heart failure, and caspase activation is central to this pathophysiological process. Methods A 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. Results Over the first 3 to 4 weeks, hypertrophy developed in the sheep (LV mass index 90.8 +/- 4.9 g/m2 vs. 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. Conclusions Activation 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.
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Moorjani et al. (2006) studied Pressure overload-induced heart failure (simulated aortic stenosis) (n=10). Variable aortic constriction device banding vs. Baseline (pre-banding) was evaluated on Caspase-3, -8, and -9 activity and presence of apoptosis in serial LV endomyocardial biopsy samples (p=<0.05). Progressive aortic banding in sheep increased LV caspase-3 (7.92 vs 1.00), -8 (1.94 vs 1.00), and -9 (5.87 vs 1.00 RFU, p<0.05) during transition to heart failure without DNA fragmentation.
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