1H-NMR-Based Metabolic Analysis of Human Serum Reveals Novel Markers of Myocardial Energy Expenditure in Heart Failure Patients

Abstract

ObjectiveElevated myocardial energy expenditure (MEE) is related with reduced left ventricular ejection fraction, and has also been documented as an independent predictor of cardiovascular mortality. However, the serum small-molecule metabolite profiles and pathophysiological mechanisms of elevated MEE in heart failure (HF) are still lacking. Herein, we used 1H-NMR-based metabolomics analysis to screen for potential biomarkers of MEE in HF.MethodsA total of 61 subjects were enrolled, including 46 patients with heart failure and 15 age-matched controls. Venous serum samples were collected from subjects after an 8-hour fast. An INOVA 600 MHz nuclear magnetic resonance spectrometer with Carr-Purcell-Melboom-Gill (CPMG) pulse sequence was employed for the metabolomics analysis and MEE was calculated using colored Doppler echocardiography. Metabolomics data were processed using orthogonal signal correction and regression analysis was performed using the partial least squares method.ResultsThe mean MEE levels of HF patients and controls were 139.61±58.18 cal/min and 61.09±23.54 cal/min, respectively. Serum metabolomics varied with MEE changed, and 3-hydroxybutyrate, acetone and succinate were significantly elevated with the increasing MEE. Importantly, these three metabolites were independent of administration of angiotensin converting enzyme inhibitor, β-receptor blockers, diuretics and statins (P>0.05).ConclusionsThese results suggested that in patients with heart failure, MEE elevation was associated with significant changes in serum metabolomics profiles, especially the concentration of 3-hydroxybutyrate, acetone and succinate. These compounds could be used as potential serum biomarkers to study myocardial energy mechanism in HF patients.

Exhaled Acetone Concentration Is Related to Hemodynamic Severity in Patients With Non-Ischemic Chronic Heart Failure

“…As a substitute energy source, ketone bodies might be produced in the liver and utilized in the heart and other organs. 24 Although we did not show direct evidence of activation of catecholamines or insulin resistance in this study, it is plausible that neurohormonal activation in HF would lead to increased ketone body production, resulting in elevated EAC.…”

“…25, 26 Elevated blood ketone bodies would be consumed by the myocardium; that is, there is elevated energy expenditure of ketone bodies in the setting of HF. 24 In addition, impaired utilization of skeletal muscle ketone bodies because of the debilitating heart condition may contribute to the increased serum ketone body concentration used as a myocardial fuel source. 10 Thus, myocardial pressure overload, represented by high PCWP, might induce altered myocardial ketone body metabolism and augmented cardiac energy expenditure, subsequently leading to a compensatory increase in the biosynthesis of ketone bodies.…”

Cardiac Resynchronization Therapy Induces Adaptive Metabolic Transitions in the Metabolomic Profile of Heart Failure

“…The plasma levels of glycerol, linoleate, myristate, and cholesterol, which were reduced in HF patients, may indicate reduced lipid metabolism. Similarly others using different analytical platforms and patient groups found altered metabolomic profiles in heart failure and identified candidate disease biomarkers 19, 29, 49, 50 . Consistent with derangement in different metabolic pathways at a systemic level, as we observed in our study, HF patients had higher serum concentrations of phenylalanine, tyrosine, isoleucine, creatine, and lower serum levels of lactate, citrate and lysine 49 .…”

“…Consistent with derangement in different metabolic pathways at a systemic level, as we observed in our study, HF patients had higher serum concentrations of phenylalanine, tyrosine, isoleucine, creatine, and lower serum levels of lactate, citrate and lysine 49 . In patients with heart failure significant changes in serum metabolomics profiles, especially the concentration of 3-hydroxybutyrate, acetone and succinate 19 and 2-oxoglutarate and pseudouridine, 51 was demonstrated. In another study CHF patients were characterized by higher levels of lactate, alanine, creatine, proline, isoleucine, leucine and lower levels of valine, glutamine, glutamate, choline, glycine, glucose, tyrosine and histidine 50 .…”

“…The reduction of mechanical dyssynchrony within the left ventricle and subsequent improvement in left ventricular (LV) efficiency and oxygen consumption have been considered the main mechanistic benefits of CRT 14, 15 . Although the subcellular metabolic and energy systems are affected in HF 16, 17 , little is known about the effect of CRT on myocardial substrate metabolism 18, 19 .…”