Mechanisms Associated with Poor Outcomes of Heart Failure Patients with High Plasma Level of Phenylalanine in Intensive Care Units

Phenylalanine is an essential amino acid and building block of the body, rich in muscular tissues, and is well maintained in normal blood concentration except for the inherited metabolic disease, phenylketonuria. Recently, phenylalanine gradually draws attentions in the field of heart failure (HF) based on the evidence described as follows.(1) Our metabolomics study recently published in JACC showed that elevated phenylalanine concentration was noted in patients with advanced HF. (2) For patients with acute/decompensated HF, we demonstrated that elevated phenylalanine level was associated with higher HF-related event rates independent of BNP and traditional risk factors, and represented substantial metabolism disturbance.(3) The study from PROSPER and FINRISK cohorts in Europe demonstrated that elevated phenylalanine levels predicted incident HF-related hospitalization in community cohorts at cardiovascular risk, and proposed a potential use of phenylalanine as a novel biomarker for identifying patients at early stage of HF. (4) SABRE study and British Women’s Health and Heart Study, with big community cohorts in Europe, also validated that higher serum phenylalanine level was associated with increased cardiovascular riskIn our initial study of patients in the cardiac intensive care unit, we found that patients with elevated phenylalanine had a 4.3-fold increase in mortality within one year, but why did it increase? Why is it related to death? The reason really needs to be investigated. We speculate that there are a few reasons as follows: (1) Increased tissue protein breakdown; (2) Abnormal phenylalanine metabolism; (3) Dysfunction of Co-factor for phenylalanine hydroxylase: role of tetrahydrobiopterin (BH4); and (4) relationship to Inflammation and immune. Therefore, we plan to focus on patients in the intensive care unit and explore the relevant mechanisms in depth:Study aims in 3 years:1. To increase sample size to validate the prognostic value of phenylalanine noted in our previous study (years 1 to 3)2. To investigate the causes of phenylalanine elevation, including muscle breakdown, the product of downstream phenylalanine metabolites, deficiency of BH4 and the consumption of BH4 by nitric oxide synthase (years 1 to 3).3. To investigate the immunological status in the metabolic storm defined by high phenylalanine (done by high throughput immune assessment) (years 2 and 3)4. To investigate whether multiple single nucleotide polymorphism of phenylalanine hydroxylase SNP is associated with the increase of phenylalanine (years 1 to 3)We hope to find new medical concepts by clarifying related mechanisms, and using research findings to establish indications and procedures for detecting phenylalanine, which can further identify the causes of elevation in phenylalanine. The detection platform can achieve the concept of precision medicine and fine-tune the drug intervention according to the concentration of phenylalanine to improve patient's outcomes. We have conducted preliminary research to prove that we are capable of accomplishing this task.

Project ID:PC10907-1053
External Project ID:MOST109-2314-B182-056-MY3