Stress Hyperphenylalaninemia Is Associated With Mortality in Cardiac ICU: Clinical Factors, Genetic Variants, and Pteridines

Abstract

Objectives: Hyperphenylalaninemia predicts poor outcomes in patients with cardiovascular disease. However, the prognostic value and factors associated with stress hyperphenylalaninemia (SHP) were unknown in critical patients in the cardiac ICU.

Design: Prospective observational study.

Setting: Single-center, cardiac ICU in Taiwan.

Patients: Patients over 20 years old with Acute Physiology And Chronic Health Evaluation II scores greater than or equal to 15 and/or ventilatory support in the cardiac ICU.

Interventions: We measured plasma phenylalanine levels serially during patients' stays in the ICU to investigate their prognostic value for 90-day mortality. Gene array was performed to identify genetic polymorphisms associated with SHP (phenylalanine level ≥ 11.2 μmol/dL) and to develop a Genetic Risk Score (GRS). We analyzed the associations between SHP and clinical factors and genetic variants and identified the correlation between pteridines and genetic variants.

Measurements and main results: The study enrolled 497 patients. Increased phenylalanine concentration was independently associated with increased mortality risk. Patients with SHP had a higher mortality risk compared with those without SHP (log rank = 41.13; p < 0.001). SHP was associated with hepatic and renal dysfunction and with genetic polymorphisms on the pathway of tetrahydrobiopterin (BH4) synthesis (CBR1 and AKR1C3) and recycling (PCBD2). Higher GRSs were associated with lower BH4 bioavailability in response to stress ( p < 0.05). In patients without SHP at baseline, those with GRSs gretaer than or equal to 2 had a higher frequency of developing SHP during the ICU stay (31.5% vs 16.1%; p = 0.001) and a higher mortality risk ( p = 0.004) compared with those with GRSs less than 2. In patients with SHP at baseline, genetic variants did not provide additional prognostic value.

Conclusions: SHP in patients admitted to the ICU was associated with a worse prognosis. In patients without SHP, genetic polymorphisms associated with SHP measured using a GRS of greater than or equal to 2 was associated with the subsequent SHP and higher mortality risk.

Figure 1.

Prognostic value of phenotype and genotype. A, The Kaplan-Meier curves for patients with phenylalanine level at baseline (Pbase) greater than or equal to 11.2 μmol/dL versus Pbase less than 11.2 μmol/dL (left panel) and for patients with maximal phenylalanine level during the stay in the ICU (Pmax) greater than or equal to11.2 μmol/dL versus Pmax less than11.2 μmol/dL (right panel). B, Synthesis and recycling pathways of the tetrahydrobiopterin (BH4) and pteridine system. C, The Kaplan-Meier curves for patients with Genetic Risk Score (GRS) greater than or equal to 2 versus GRS less than 2 in patients with Pbase less than 11.2 μmol/dL (left panel) and in patients with Pbase greater than or equal to 11.2 μmol/dL (right panel). Red color indicates identified genetic variants. AKR = aldose reductase, BH2 = dihydrobiopterin, CBR = carbonyl reductase, DHFR = dihydrofolate reductase, DHPR = dihydropteridine reductase, GTP = guanosine triphosphate, GTPCH = GTP cyclohydrilase, PAH = phenylalanine hydroxylase, PCD = pterin-4a-carbinolamine dehydratase, PTPS = 6-pyruvoyl tetrahydropterin sunthase, qBH2 = quinonoid BH2, SR = sepiapterin reductase. 1’-OXPH4 = 6-(1’-oxo-2’-hydroxypropyl)-tetrahydropterin, 2’-OXPH4 = 6-(1’-hydroxy-2’-oxopropyl)-tetrahydropterin.

Figure 2.

Genetic polymorphisms and plasma pteridines. The concentrations of tetrahydrobiopterin (BH4) (A), dihydrobiopterin (BH2) (B), ratio of BH4 to BH2 (C), and ratio of BH4 to (BH4+BH2) (D) in patients with different genetic risk scores.