Metabolomics implicate eicosanoids in severe functional mitral regurgitation

Abstract

Aims: Secondary, or functional, mitral regurgitation (FMR) was recently recognized as a separate clinical entity, complicating heart failure with reduced ejection fraction (HFrEF) and entailing particularly poor outcome. Currently, there is a lack of targeted therapies for FMR due to the fact that pathomechanisms leading to FMR progression are incompletely understood. In this study, we sought to perform metabolomic profiling of HFrEF patients with severe FMR, comparing results to patients with no or mild FMR.

Methods and results: Targeted plasma metabolomics and untargeted eicosanoid analyses were performed in samples drawn from HFrEF patients (n = 80) on optimal guideline-directed medical therapy. Specifically, 17 eicosanoids and 188 metabolites were analysed. Forty-seven patients (58.8%) had severe FMR, and 33 patients (41.2%) had no or non-severe FMR. Comparison of eicosanoid levels between groups, accounting for age, body mass index, and sex, revealed significant up-regulation of six eicosanoids (11,12-EET, 13(R)-HODE, 12(S)-HETE, 8,9-DiHETrE, metPGJ2, and 20-HDoHE) in severe FMR patients. Metabolites did not differ significantly. In patients with severe FMR, but not in those without severe FMR, levels of 8,9-DiHETrE above a cut-off specified by receiver-operating characteristic analysis independently predicted all-cause mortality after a median follow-up of 43 [interquartile range 38, 48] months [hazard ratio 12.488 (95% confidence interval 3.835-40.666), P < 0.0001].

Conclusions: We report the up-regulation of various eicosanoids in patients with severe FMR, with 8,9-DiHETrE appearing to predict mortality. Our observations may serve as a nucleus for further investigations into the causes and consequences of metabolic derangements in this important valvular abnormality.

Keywords: Eicosanoids; Functional mitral regurgitation; Heart failure; Metabolomics.

Figure 1

Levels of eicosanoids in patients with no or mild vs. severe functional mitral regurgitation (FMR). Eicosanoids were measured in plasma from patients with or without severe FMR using metabolomic analysis. Out of a total of 17 measured eicosanoids, six were different between the groups, with a false discovery rate (FDR) of below 0.1. (A) 11,12‐EET, (B) 13(R)‐HODE, (C) 12(S)‐HETE, (D) 8,9‐DiHETrE, (E) metPGJ2, and (F) 20‐HDoHE.

Figure 2

Correlation between eicosanoid 8,9‐DiHETrE and N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) in patients with severe functional mitral regurgitation (FMR). Correlations were calculated using Spearman's coefficient. (A) Severe FMR and (B) no/mild FMR; alpha‐level 0.05.

Figure 3

Influence of 8,9‐DiHETrE on outcome in patients with severe functional mitral regurgitation (FMR). All‐cause mortality of patients suffering from severe FMR. The Kaplan–Meier curves stratify by levels of 8,9‐DiHETrE. A cut‐off of −6.05 was identified using receiver‐operating characteristic (ROC) analysis. Censored patients are not shown. Multivariable Cox regression, alpha‐level 0.05. CI, confidence interval; HR, hazard ratio.