Abstract 16778: Cardiac Hypertrophy in Neonates With Congenital Heart Disease Delays Maturational Changes in Cardiac Energy Metabolism via Decreased Mitochondrial Acetylation

Background: A rapid increase in fatty acid oxidation occurs in the heart following birth. However, cardiac hypertrophy, that occurs secondary to congenital heart diseases (CHDs), delays this normal maturation of fatty acid oxidation, thereby decreasing energetic capacity and increasing the susceptibility of the heart to ischemic injury during corrective surgery. Recently, increased cardiac acetylation has emerged as an important post-translational modification that increases fatty acid oxidation. We therefore examined what effect cardiac hypertrophy has on the acetylation control of fatty acid oxidation in the human neonates. Methods and Results: A total of 145 right ventricular biopsy samples were collected from neonatal patients undergoing corrective surgery for CHDs, and were stratified according to patient age (0-20 days, n=58; 21-100 days, n=41; and 101-200 days, n=46), as well as the absence (n=83) or presence (n=62) of hypertrophy (assessed by echocardiography). An increase in overall myocardial protein acetylation was seen with increasing age in non-hypertrophied hearts. In contrast, no age-dependent increase in acetylation was observed in hypertrophied hearts, in concert with an increase in mitochondrial deacetylase SIRT3, and a blunted increase in mitochondrial acetyltransferase GCN5L1. An age-dependent hyperacetylation of the fatty acid oxidation enzymes long chain acyl CoA dehydrogenase (LCAD) and β-hydroxyacyl CoA dehydrogenase (β-HAD) was observed only in non-hypertrophied hearts, which was positively correlated with their enzyme activities. Similar results were also observed in a volume-overload hypertrophy in newborn rabbits, where decreased acetylation of LCAD and β-HAD and decreased fatty acid oxidation was evident compared to non-hypertrophied rabbit hearts. Furthermore, acetylation of PGC-1α, a transcriptional regulator for mitochondrial biogenesis, decreased with age only in non-hypertrophied hearts, along with decreased expression of the nuclear acetyltransferase GCN5 and nuclear deacetylase SIRT6. Conclusions: The presence of cardiac hypertrophy in CHDs patients prevents the normal increase in myocardial acetylation following birth, resulting in a delayed maturation of fatty acid oxidation.