Abstract P137: Metabolomic Analysis of the Early and Late Hypertrophic Heart

Abstract

The metabolic adaptations to acute myocardial pressure overload are characterized by alterations in metabolism that drive the hypertrophic response and that balance workload with energy demand. Under conditions of chronic pressure overload, it is known that substrate utilization becomes less flexible and that the heart shifts energy preference from fatty acids to glucose. Nevertheless, the metabolic changes that underlie the progression of compensated hypertrophy to heart failure are incompletely understood and attempts to correct the known metabolic defects to delay decompensation have been largely unsuccessful. To identify key changes in metabolic phenotype that could underlie progression to heart failure, we measured metabolites in a transverse aortic constriction (TAC) mouse model using an unbiased metabolomic approach. Hearts were harvested 1 d, 1 wk and 8 wks after sham or TAC operation, and metabolites were extracted from the hearts and analyzed via GC/MS and LC/MS/MS. The signal intensities of 288 named metabolites were re-scaled to median values. Welch’s t-test and two-way ANOVA were used to identify metabolites that changed significantly with pressure overload and progression to heart failure. Echocardiographic measurements showed a significant decrease in ejection fraction after 1 d (65±2% vs. 49±5%) and 8 wks (61±2% vs. 34±8%) of TAC; 1 wk of TAC showed a compensated phenotype characterized by a largely preserved ejection fraction. One day after TAC, only 1.7% of the metabolites changed significantly; however, nearly all amino acids measured were increased by 1 wk. By 8 wks, amino acids returned to near sham levels and a significant and robust decrease in phospholipid, carnitine, inositol, sterol, and fatty acid metabolites occurred. These findings demonstrate that the temporal changes in metabolic phenotype are more complex than previously thought. The preservation of pathways involved in lipid and amino acid metabolism may be important for maintaining myocardial energetics and preventing pump failure under conditions of chronic pressure overload.