Augmented Cardiac Mitochondrial Capacity in High Aerobic Capacity “Disease Resistant” Phenotype at Rest is Lost Following Ischemia Reperfusion

Rationale Ischemic heart disease is a major cause of morbidity. Regular active exercise is therapeutic, but up to 70% of individual exercise capacity is due to an intrinsic genetic component. Intrinsic capacity can be studied using high (HCR) and low (LCR) aerobic running capacity rat strains. The phenotypes differ by more than 5 fold in sedentary average running distance and time. The HCR rats have been characterized as “disease resistant”, while the LCRs are characterized as “disease prone”. A consistent characteristic of the LCR is reduced metabolic capacity in several tissues, but metabolic capacity in cardiac tissue is not well studied in these phenotypes, particularly following the metabolic stress of ischemia and reperfusion. Methods 32 HCR and LCR rats were obtained from the parent colony at the University of Toledo, housed under sedentary conditions, and fed normal chow. LCR and HCR animals were randomly assigned to either control (C, n = 8 each) or ischemia reperfusion (IR, n = 8 each). On each study day, one HCR/LCR pair was anesthetized and hearts were rapidly excised. In IR animals, the hearts were immediately flushed with iced hyperkalemic, hyperosmotic, cardioplegia solution, and subjected to cold global ischemic arrest (80 min). Following arrest, the hearts underwent warm reperfusion (120 min) using a Langendorff style perfusion system. Following reperfusion, the heart was weighed and the LV was isolated. A mid ventricular ring was obtained to estimate infarction size (TTC), and part of the remaining tissue (~150 mg) was transferred to homogenation buffer on ice. Isolated mitochondria (MITO) samples were prepared and used to determine respiratory capacity under different metabolic conditions (OROBOROS). MITO from control animals were obtained and prepared in similar fashion, but immediately following anesthesia and heart removal, and without IR. Citrate synthase activity was measured in each sample. Results In the control rats, HCR MITO showed respiratory rates 32% higher at rest and more than 40% higher under maximally stimulated conditions, compared to LCR MITO (both p < 0.05). After IR, resting MITO respiratory rates were decreased to about 10% in both strains, and the augmented capacity in HCRs was absent. Maximally stimulated rates also were decreased more than 50% from control, and were no longer different between phenotypes. Infarct size was not significantly different between HCR and LCR (49.2% ± 5.6 vs. 53.7% ± 4.9), nor was average coronary flow during reperfusion. Conclusion Cardiac mitochondria from HCR were significantly higher in control conditions with each substrate tested. After IR insult, the cardiac mitochondrial respiratory rates were similar between phenotypes, as was infract size. Relatively, the loss of respiratory capacity was actually greater in HCR than LCR. Together, these data could suggest limits in the extent to which the HCR phenotype might be “protective” against acute tissue stressors. The extent to which any of these deficits could be “rescued” by an active exercise component is unknown.