Long-Chain Acylcarnitines and Monounsaturated Fatty Acids Discriminate Heart Failure Patients According to Pulmonary Hypertension Status

Abstract

Defects in fatty acid (FA) utilization have been well described in group 1 pulmonary hypertension (PH) and in heart failure (HF), yet poorly studied in group 2 PH. This study was to assess whether the metabolomic profile of patients with pulmonary hypertension (PH) due HF, classified as group 2 PH, differs from those without PH. We conducted a proof-of-principle cross-sectional analysis of 60 patients with chronic HF with reduced ejection fraction and 72 healthy controls in which the circulating level of 71 energy-related metabolites was measured using various methods. Echocardiography was used to classify HF patients as noPH-HF (n = 27; mean pulmonary artery pressure [mPAP] 21 mmHg) and PH-HF (n = 33; mPAP 35 mmHg). The profile of circulating metabolites among groups was compared using principal component analysis (PCA), analysis of covariance (ANCOVA), and Pearson’s correlation tests. Patients with noPH-HF and PH-HF were aged 64 ± 11 and 68 ± 10 years, respectively, with baseline left ventricular ejection fractions of 27 ± 7% and 26 ± 7%. Principal component analysis segregated groups, more markedly for PH-HF, with long-chain acylcarnitines, acetylcarnitine, and monounsaturated FA carrying the highest loading scores. After adjustment for age, sex, kidney function, insulin resistance, and N-terminal pro-brain natriuretic peptide (NT-proBNP), 5/15 and 8/15 lipid-related metabolite levels were significantly different from controls in noPH-HF and PH-HF subjects, respectively. All metabolites for which circulating levels interacted between group and NT-proBNP significantly correlated with NT-proBNP in HF-PH, but none with HF-noPH. FA-related metabolites were differently affected in HF with or without PH, and may convey adverse outcomes given their distinct correlation with NT-proBNP in the setting of PH.

Relationship of Acylcarnitines to Myocardial Ischemic Remodeling and Clinical Manifestations in Chronic Heart Failure

“…It is probable that these features lead to more rapid metabolic remodeling of myocardium of the above parts against the background of greater myocardial stress than in LV and, as a result, accumulation of underoxidized medium-and long-chain ACs. This is confirmed not only by studies in which we evaluated the relationship of this AC fraction with remodeling of myocardium of RA and RV on the background of pre-and postcapillary pulmonary hypertension [35,36], but also by a clear correlation of this fraction with the increase of pulmonary artery pressure in our work.…”

Metabolomics in Pulmonary Hypertension—A Useful Tool to Provide Insights into the Dark Side of a Tricky Pathology

“…PH triggered by heart failure (Group 2) is characterized by the overexpression of long-chain acylcarnitines, acetylcarnitine, and monounsaturated fatty acids. A statistically significant correlation with N-terminal pro-brain natriuretic peptide, a biomarker capable of predicting the outcome of cardiac insufficiency, was detected as well [26]. A metabolomic study was carried out with the aim of looking for different blood metabolites whose levels are different in PH subjects in comparison with healthy controls and among patients with different forms of PH linked to left heart disease (Group 2).…”