Abstract 452: Residual Dysfunction After Revascularization of Hibernating Myocardium is Independent of Fibrosis and Secondary to Myocyte Loss and Persistent Regional Reductions in Mitochondrial Oxidative Enzymes.
Background - While function improves after percutaneous revascularization (PCI) of hibernating myocardium (HM), it infrequently normalizes and mechanisms responsible for persistent dysfunction are unknown. We hypothesized that residual dysfunction is independent of irreversible injury and related to myocyte loss and persistent metabolic remodeling.
Methods - Pigs (n=6) were instrumented with a silastic LAD stenosis (1.5 mm) to reduce flow reserve and produce HM over 3 months. Studies were performed before and 1 month after LAD PCI. Differential protein expression in subendocardial samples was assessed with fluorescent 2D DIGE, with candidate proteins identified by mass spectrometry. Relative changes were compared to normals and nonrevascularized pigs with HM. Regional myocyte loss was assessed by histology.
Results - One month post-PCI, LAD wall-thickening increased from 3.8 ± 0.3 to 5.7 ± 0.7 mm (p<0.05) but remained depressed compared to remote myocardium (7.9 ± 0.6 mm, p<0.05) and normal pigs. While flow reserve increased after PCI, resting subendocardial LAD flow remained depressed (1.2 ± 0.1 vs. 1.5 ± 0.1 ml/min/g in remote, p<0.05) without infarction (TTC) or increased fibrosis. Despite amelioration of ischemia, metabolic proteins involved with oxidative metabolism and the electron transport chain were downregulated in HM, and remained so after PCI (Table⇓). In contrast, stress and structural proteins upregulated in HM normalized. Histology revealed persistently reduced LAD myocyte nuclear density despite PCI (LAD 1172 ± 153 vs. 2014 ± 64 nuclei/mm2 in remote, p<0.05).
Conclusions - Persistent dysfunction in HM occurs without infarction and is associated with persistent reductions in regional myocyte loss and enzymes associated with oxidative metabolism. Thus, intrinsic cellular adaptations that downregulate metabolic protein expression and energy utilization in response to chronic repetitive ischemia do not normalize 1 month after PCI.