NMR-Based Metabolomic Analysis of Plasma in Patients with Adult Congenital Heart Disease and Associated Pulmonary Arterial Hypertension: A Pilot Study

Abstract

Patients with unrepaired congenital heart disease (CHD) are prone to pulmonary arterial hypertension (PAH). The ovine pulmonary arterial smooth muscle cells exposed to increased pulmonary blood flow (PBF) exhibited hyperproliferation and metabolic alterations, but the metabolic disorders of patients with CHD and associated PAH (PAH-CHD) have not yet been fully understood. Adult CHD patients were prospectively included and divided into the PAH-CHD group (n = 24) and CHD group (n = 38), while healthy adults were included as healthy control (HC) group (n = 29). Plasma from each subject was prepared for nuclear magnetic resonance (NMR) detection. 1H-NMR spectra were acquired using 850 MHz NMR spectrometer. A total of 28 metabolites were identified from the NMR spectra and their relative concentrations were calculated and analyzed by multivariate and univariate statistical analyses and metabolic pathway analysis. Receiver operating characteristic (ROC) curve analysis and correlation analysis were performed to identify potential biomarkers and assess their roles in clinical assessment. Multivariate statistical analysis showed that the metabolic profile of PAH-CHD was altered relative to CHD or HC, while that of CHD was altered relative to HC. The identified characteristic metabolites were alanine, glucose, glycine, threonine and lactate, and the areas under the ROC curves (AUCs) were 0.769, 0.808, 0.711, 0.842 and 0.817, respectively. Multivariate ROC curve analysis showed AUCs ranging from 0.895 to 0.955 for the combination of these characteristic metabolites. The correlation analysis indicated that lactate and threonine were significantly correlated with mean pulmonary arterial pressure, pulmonary vascular resistance and N-terminal pro-B-type natriuretic peptide. The increased PBF could trigger global metabolic alterations in patients with CHD, which were more severe in patients with PAH-CHD. The characteristic metabolites have the potential to be biomarkers of PAH-CHD, which could be used for its noninvasive diagnosis, severity and prognosis assessment, thereby improving the management of PAH-CHD.