Extensive Dysregulation of Phenylalanine Metabolism Is Associated With Stress Hyperphenylalaninemia and 30-Day Death in Critically Ill Patients With Acute Decompensated Heart Failure

Abstract

Background: Stress hyperphenylalaninemia predicts elevated mortality rates in patients with acute decompensated heart failure (ADHF). This study investigated the metabolic pathways underlying this association and identified a unique metabolic phenotype underlying the association between stress hyperphenylalaninemia and adverse outcomes in ADHF.

Methods and results: This was a retrospective cohort study. We enrolled 120 patients with ADHF in an intensive care unit (60 with a phenylalanine level ≥112 μM, 60 with a phenylalanine level <112 μM), and 30 controls. Plasma phenylalanine-derived metabolites were measured, and participants were evaluated for 30-day death. Patients with ADHF had extensive activations of the alternative pathways for metabolizing phenylalanine, leading to the levels of phenylalanine-derived downstream metabolites 1.5 to 6.1 times higher in patients with ADHF than in the controls (all P<0.001). Extensive dysregulation of these alternative pathways significantly increased phenylalanine levels and contributed to a distinct metabolic phenotype, characterized by increased phenylalanine, tyrosine, homogentisic acid, and succinylacetone levels but decreased benzoic acid and 3,4-dihydroxyphenylalanine levels. Throughout the 30-day follow-up period, 47 (39.2%) patients died. This distinct metabolic phenotype was associated with an increased mortality rate (odds ratio, 1.59 [95% CI, 1.27-1.99]; P<0.001). A multivariable analysis confirmed the independent association of this metabolic phenotype, in addition to phenylalanine and tyrosine levels, with 30-day death.

Conclusions: In patients with ADHF, extensive dysregulation of the alternative pathways for metabolizing phenylalanine was correlated with stress hyperphenylalaninemia and a distinct metabolic phenotype on the phenylalanine-tyrosine-homogentisic acid-succinylacetone axis. Both stress hyperphenylalaninemia and metabolic dysregulation on this axis were associated with poor outcomes.

Keywords: death; heart failure; intensive care unit; metabolism; phenylalanine.

Figure 1. Diagram of metabolic pathways of phenylalanine associated with 30‐day death.

Upregulated and downregulated metabolites are indicated in red and blue, respectively. DOPA indicates 3,4‐dihydroxyphenylalanine; and TCA, tricarboxylic acid.

Figure 2. Prognostic value of phenylalanine, tyrosine, and downstream metabolites.

A, Receiver operating characteristic curve illustrates the predictive performance of benzoic acid, DOPA, homogentisic acid, succinylacetone, and the collective metabolic score derived from these 4 metabolites for all patients. B, Receiver operating characteristic curve depicts the predictive performance of phenylalanine, tyrosine, and metabolic score. DOPA indicates 3,4‐dihydroxyphenylalanine; PHE, phenylalanine; and TYR, tyrosine.