Novel Findings From a Metabolomics Study of Left Ventricular Diastolic Function: The Bogalusa Heart Study

Background Diastolic dysfunction is one important causal factor for heart failure with preserved ejection fraction, yet the metabolic signature associated with this subclinical phenotype remains unknown. Methods and Results Ultra-high-performance liquid chromatography-tandem mass spectroscopy was used to conduct untargeted metabolomic analysis of fasting serum samples in 1050 white and black participants of the BHS (Bogalusa Heart Study). After quality control, 1202 metabolites were individually tested for association with 5 echocardiographic measures of left ventricular diastolic function using multivariable-adjusted linear regression. Measures of left ventricular diastolic function included the ratio of peak early filling velocity to peak late filling velocity, ratio of peak early filling velocity to mitral annular velocity, deceleration time, isovolumic relaxation time, and left atrial maximum volume index (LAVI). Analyses adjusted for multiple cardiovascular disease risk factors and used Bonferroni-corrected alpha thresholds. Eight metabolites robustly associated with left ventricular diastolic function in the overall population and demonstrated consistent associations in white and black study participants. N-formylmethionine (B=0.05; P=1.50x10(-7)); 1-methylhistidine (B=0.05; P=1.60x10(-7)); formiminoglutamate (B=0.07; P=5.60x10(-7)); N2, N5-diacetylornithine (B=0.05; P=1.30x10(-7)); N-trimethyl 5-aminovalerate (B=0.04; P=5.10x10(-6)); 5-methylthioadenosine (B=0.04; P=1.40x10(-5)); and methionine sulfoxide (B=0.04; P=3.80x10(-6)) were significantly associated with the natural log of the ratio of peak early filling velocity to mitral annular velocity. Butyrylcarnitine (B=3.18; P=2.10x10(-6)) was significantly associated with isovolumic relaxation time. Conclusions The current study identified novel findings of metabolite associations with left ventricular diastolic function, suggesting that the serum metabolome, and its underlying biological pathways, may be implicated in heart failure with preserved ejection fraction pathogenesis.