Major perturbations in plasma energy-related metabolites in HFpEF versus HFrEF

Abstract

Metabolic profiling in heart failure with reduced ejection fraction (HFrEF) patients has demonstrated that HFrEF is associated with an increased in long-chain acylcarnitine (LCAC) compounds probably due to impaired mitochondrial function. Metabolic differences between heart failure with preserved ejection fraction (HFpEF) and HFrEF have been suggested. However, only few studies have compaired circulating metabolites between HFpEF and HFrEF. The objective of our study is to compare the metabolic profile of HFpEF, HFrEF and controls. Between 2015 and 2017, we prospectively included 105 HFpEF, 44 HFrEF, and 72 controls. We performed plasma metabolomic analysis by mass spectrometry focusing on 36 energy-related metabolites, including LCAC. As expected, HFpEF patients are significantly older (76 ± 7 vs. 65 ± 12 and 63 ± 12 years), more female (57% vs. 38% and 46%) more diabetic (45% vs. 22% and 19%), have higher body mass index (29.1 ± 6.8 vs. 26.4 ± 5.1 and 25.5 ± 3.8 kg/m 2 ) and lower glomerular filtration rate (54.7 ± 20.1 vs. 58.1 ± 31.5 and 77 ± 18 ml/min/1.73 m 2 ) compared to HFrEF and controls respectively. Compared to controls, both HFpEF and HFrEF patients exhibited significantly higher levels of LCAC, although the magnitude of changes was greater in HFrEF. In contrast to HFpEF, HFrEF also showed major perturbations in 10 energy-related metabolites, including those reflecting a reduced redox ratio in cytosol (lactate/pyruvate) and mitochondria (3-hydroxybutyrate/acetoacetate); while HFpEF showed only higher levels of cysteine and pyruvate. Using a metabolomic approach, we have identified a different metabolomic signature between HFpEF and HFrEF. Changes in LCAC and energy-related metabolites suggest that mitochondrial dysfunction is more pronounced in HFrEF than HFpEF.