Abstract
Background: Heart failure (HF) remains a leading cause of morbidity and mortality globally, necessitating the identification of reliable prognostic biomarkers to guide therapeutic interventions. Recent clinical observations have underscored phenylalanine (PHE) as a prognostic marker in HF, although the mechanisms involving inter-organ crosstalk remain understood. Methods: This study adopted a dull approach, with a retrospective analysis of 550 HF patients to establish the prognostic value of pre-discharge PHE levels and a study on the inter-organ crosstalk of PHE among 24 patients. We analyzed the correlations between PHE concentrations and clinical outcomes, alongside a comprehensive examination of PHE metabolism across the skeletal muscle, liver, heart, kidney, and lung. Results: In the clinical prognostic analysis of 550 patients hospitalized for acute decompensated HF, elevated PHE levels (≥65.6 μM) were significantly and independently associated with increased all-cause mortality during a median follow-up of 4.5 years (log rank = 36.7, p < 0.001), underscoring its value as a prognostic marker in HF. The inter-organic crosstalk study elucidated the mechanism associated with PHE elevation in patients with HF, characterized by an increase in PHE output in skeletal muscle and a decrease in hepatic and cardiac PHE uptakes. Notably, PHE concentration gradients across these organs were correlated with HF severity, such as the NYHA functional class, B-type natriuretic peptide levels, and the presence of acute HF. Conclusions: Our findings confirm the prognostic significance of PHE in patients with HF and unveil the complex metabolic interplay among key organs that contribute to PHE dysregulation. These insights not only reinforce the importance of metabolic monitoring in HF management but also open avenues for therapeutic targets.