Abstract 1944: Dysregulated Mitochondrial Biogenesis Promotes Failure of the Hypertrophied Infant Right Ventricle
Background: RV failure due to chronic pressure load is a major problem in congenital heart disease. Physiologic load (e.g. growth, exercise) increases production of functional mitochondria (biogenesis) and oxidative capacity. We hypothesized that RV pressure load leads to early disruption of the coordinated nuclear and mitochondrial mitochondrial gene responses required for biogenesis, thereby promoting progression to RV failure.
Methods and Results: Newborn rabbits underwent pulmonary artery banding. RVH and RV function were monitored (RV:body weight ratio, serial echocardiography, and RV P-V curves). Three groups were identified (N = 4 – 6 each): age-matched control, compensated RVH, and RV failure. Mitochondrial O2 consumption (polarography), electron transport complex activities (spectrophotometry), RV mitochondrial number and ultrastructure (electron microscopy), and nuclear and mitochondrial genes encoding mitochondrial biogenesis and energy metabolism programs (Northern blot and RT-PCR) were measured. Within 6 weeks of compensated hypertrophy (when RV mass was continuing to increase and RV function, mitochondrial number, and mitochondrial structure were preserved), significant reductions (P < 0.05) in expression of genes encoding nuclear receptor coactivator PPARγ-1α (PGC-1α), mitochondrial transcription factor A (mtTFA), and nuclear respiratory factor (NRF-2) were observed; these were followed by marked reductions (P < 0.01) in mitochondrial number, State 3 respiration, and complex I activity as hypertrophy progressed. Subsequently, RV function progressively declined, accompanied by marked mitochondrial swelling, abnormal mitochondrial ultrastructure (20–91% of mitochondria) and onset of significant RV myocyte apoptosis.
Conclusion: Successful adaptation to infant RV pressure load requires sustained mitochondrial biogenesis. Loss of this mechanism , which is regulated and coordinated in large part by PPAR, PGC-1α, mtTFA, and NRF, underlies the transition to failure. Stimulating these pathways to promote mitochondrial biogenesis may allow sustained compensation to abnormal loading of the infant RV.