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| Despite Successful CABG in a Swine Model of Myocardial Hibernation, Maximal Oxygen Consumption and Mitochondrial Proteomic Expression Remain Depressed | ||||||||||||||||||
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Rosemary F. Kelly1, Elizabeth A. Ziemba1, Jesus A. Cabrera1, Melanie Crampton2, Lorraine B. Anderson1, Edward O. McFalls2, Herbert B. Ward1; 1Cardiothoracic Surgery, University of Minnesota, Minneapolis, MN; 2Cardiology, VA Medical Center, Minneapolis, MN Objective: Hibernating myocardium may not become normal following successful coronary artery bypass grafting (CABG), potentially because of altered expression of mitochondrial proteins in chronically ischemic, viable tissue. This inability to support electron flow through the electron transport chain (ETC) may lead to insufficient oxygen consumption during high work states, which potentially may have a negative impact on oxygen expenditure and contraction. In a swine model of hibernating myocardium, we hypothesized that persistent myocardial wall motion abnormality in revascularized myocardium by off-pump CABG is due to persistently depressed expression of key mitochondrial proteins involved with the ETC. Methods: In a novel animal model, seven pigs were instrumented at age 4 weeks with a constrictor around the proximal left anterior descending (LAD) artery. By 12 weeks, a severe stenosis was demonstrated by multi-detector computer tomography (MDCT) along with a anteroseptal wall motion abnormality by 2D ECHO. Using off-pump CABG, the left internal mammary artery (LIMA) was grafted to the mid-LAD and pigs recovered for 4 weeks. During the terminal study, regional blood flows were determined by colored microspheres at baseline and during stress with dobutamine infusion (40 μg/kg/min-iv). Following sacrifice, mitochondria were isolated from myocardial regions and protein expression from the ETC was determined, using proteomic analysis with iTRAQ. Results: Prior to sacrifice, repeat MDCT showed a widely patent LIMA to the LAD and 2D ECHO demonstrated improved but mildly reduced regional function in the LAD region. TTC staining confirmed the absence of necrosis. As shown in the Table, regional myocardial blood flow (MBF) was lower in the LAD region during the high work state at a time that the graft was widely patent. Essential mitochondrial proteins for ATP production within the ETC, including NADH dehydrogenase, ATP synthase, and cytochrome c oxidase were >40% lower in the LAD region compared with remote regions. Conclusion: In successfully revascularized hibernating myocardium, resting regional function does not normalize and MBF at a high work state are lower than remote regions. Critical proteins within the mitochondria remain depressed despite successful CABG, and may explain an inability of myocytes to maximize oxygen utilization. Persistent mitochondrial adaptations to chronic ischemia despite CABG may provide insight into failure of complete recovery in hibernating myocardial tissue. Myocardial Blood Flow (MBF) and Mitochondrial Protein Expression Post-Revascularization
MBF (ml/min/g); †p<0.05 versus remote (Student's t-test) Back to 2010 Annual Meeting Back to Program Outline Back to Main Program |
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