Abstract 2352: Mitochondrial Dysfunction Causes Failure of the Pressure-Loaded Infant Right Ventricle
Background: Right ventricular hypertrophy (RVH) and failure induced by chronic RV pressure overload is a major clinical problem in congenital heart disease. We assessed the role of abnormal mitochondrial function in the progression of RVH to failure.
Methods: Newborn rabbits underwent PA banding (or sham) at 7 days of age, which caused stable RV pressure load (~40 mm Hg) and development of RVH by 2 weeks; RV contractile function is preserved for ~8 weeks, followed by progressive dilation and failure. Thus, RV free wall was harvested at 4 and 8 weeks to assay mitochondrial electron transport complex activities (spectrophotometry), high energy phosphates and redox state (HPLC), expression of nuclear and mitochondrial genes (RT-PCR and Northern analysis), and mitochondrial number and ultra-structure (electron microscopy).
Results: By 4 weeks (RVH and function preserved) complex I and III activity were already significantly decreased. At 8 weeks (early failure) these losses had progressed and expanded to include complexes IV and V, as well as decreased ATP content and ATP/ADP ratio, whereas total NADH and NADH/NAD ratio increased (shift to anaerobic glycolysis). Mitochondrial complex II activity (encoded by nuclear DNA) was unchanged at any time. Reduced mRNA expression for complex I, III, IV, and V proteins, reduced mitochondrial number (biogenesis), and marked loss of normal mitochondrial ultrastructure paralleled decreases in complex activity.
Conclusion: Decreased activity and expression of mitochondrially-encoded enzymes and loss of functional mitochondria results in an RV that is “energy-starved” and in over-reduced redox state. Increased glucose flux/glycolysis is insufficient to maintain myocardial energy demands in infant RVH. Interventions that promote glycolysis and/or restore normal mitochondrial biogenesis and function are needed to prevent the transition of RV hypertrophy to failure.