Elevated plasma phenylalanine predicts mortality in critical patients with heart failure

Abstract

Aims Previous studies found a relationship between elevated phenylalanine levels and poor cardiovascular outcomes. Potential strategies are available to manipulate phenylalanine metabolism. This study investigated whether increased phenylalanine predicted mortality in critical patients with either acute heart failure (HF) or acute on chronic HF, and its correlation with inflammation and immune cytokines. Methods and results This study recruited 152 subjects, including 115 patients with HF admitted for critical conditions and 37 normal controls. We measured left ventricular ejection fraction (LVEF), plasma concentrations of phenylalanine, C-reactive protein, albumin, pre-albumin, transferrin, and pro-inflammatory and immune cytokines. Acute Physiology and Chronic Health Evaluation (APACHE II), Sequential Organ Failure Assessment (SOFA), and maximal vasoactive-inotropic scores (VIS max) were calculated. Patients were followed up until death or a maximum of 1 year. The primary endpoint was all-cause death. Of the 115 patients, 37 (32.2%) were admitted owing to acute HF, and 78 (67.8%) were admitted owing to acute on chronic HF; 64 (55.7%) had ST elevation/non-ST elevation myocardial infarction. An LVEF measured during the hospitalization of <40%, 40-50%, and ≥50% was noted in 51 (44.3%), 15 (13.1%), and 49 (42.6%) patients, respectively. During 1 year followup, 51 (44.3%) patients died. Death was associated with higher APACHE II, SOFA, and VIS max scores; higher levels of C-reactive protein and phenylalanine; higher incidence of atrial fibrillation and use of inotropic agents; lower cholesterol, albumin, pre-albumin, and transferrin levels; and significant changes in pro-inflammatory and immune cytokines. Phenylalanine levels demonstrated an area under the receiver operating characteristic curve of 0.80 for mortality, with an optimal cutoff value set at 112 μM. Phenylalanine ≥ 112 μM was associated with a higher mortality rate than was phenylalanine < 112 μM (80.5% vs. 24.3%, P < 0.001) [hazard ratio = 5.07 (2.83-9.05), P < 0.001]. The Kaplan-Meier curves revealed that phenylalanine ≥ 112 μM was associated with a lower accumulative survival rate (log rank = 36.9, P < 0.001). Higher phenylalanine levels were correlated with higher APACHE II and SOFA scores, higher C-reactive protein levels and incidence of using inotropic agents, and changes in cytokines suggestive of immunosuppression, but lower levels of pre-albumin and transferrin. Further multivariable analysis showed that phenylalanine ≥ 112 μM predicted death over 1 year independently of age, APACHE II and SOFA scores, atrial fibrillation, C-reactive protein, cholesterol, pre-albumin, transferrin, and interleukin-8 and interleukin-10. Conclusions Elevated phenylalanine levels predicted mortality in critical patients, phenotypically predominantly presenting with HF, independently of traditional prognostic factors and cytokines associated with inflammation and immunity.

Phenylalanine and COVID-19: Tracking disease severity markers

“…Moreover, Chen et al have recently reported that phenylalanine predicted mortality in critically ill patients with acute heart failure (HF) or acute on chronic HF. [32] In multivariate analysis, phenylalanine levels ≥ 112 μM predicted death over one year, regardless of age, APACHE II and SOFA scores, atrial fibrillation, C-reactive protein, cholesterol, prealbumin, transferrin, and IL-8 and IL-10. Thus, a growing body of evidence points to phenylalanine as a marker of disease severity, especially related to respiratory distress.…”

Interplay Between Gut Microbiota and Amino Acid Metabolism in Heart Failure

“…There are considerable evidence convincing the alterations of BCAA during HF, but these studies fail to explain the underlying mechanisms of how BCAA contributes to the progression of HF. Large-scale trails, to date, have been carried out to demonstrate the relationship between circulating phenylalanine concentrations and HF (34,35,37,(56)(57)(58)(59). Most of them suggest that increased phenylalanine could provide both diagnostic and prognostic value for HF.…”

“…Large-scale trails, to date, have been carried out to demonstrate the relationship between circulating phenylalanine concentrations and HF ( 34 , 35 , 37 , 56 – 59 ). Most of them suggest that increased phenylalanine could provide both diagnostic and prognostic value for HF.…”

“…Consistent with such changings, there was a paralleling increasing trend in the serum tyrosine levels ( 35 ). Phenylalanine and tyrosine participates in the biopterin cycle; accumulation of them is a signal for tetrahydrobiopterin depletion, which often causes a problem with the production of NO and leading to cardiac dysfunction ( 34 , 37 ). What is more, higher phenylalanine levels were correlated with higher C-reactive protein levels and higher pro-inflammation ( 37 ).…”

“…Phenylalanine and tyrosine participates in the biopterin cycle; accumulation of them is a signal for tetrahydrobiopterin depletion, which often causes a problem with the production of NO and leading to cardiac dysfunction ( 34 , 37 ). What is more, higher phenylalanine levels were correlated with higher C-reactive protein levels and higher pro-inflammation ( 37 ). It is an indication that HF patients with high phenylalanine levels have a more severe inflammation.…”