Decoding the Heart Failure Peptidome

BACKGROUND: Peptides such as angiotensin II and brain natriuretic peptide are pivotal in diagnosing and treating heart failure (HF). However, unbiased systematic studies of the peptidome in patients with HF are lacking. Deciphering the plasma peptidome might significantly improve the diagnosis, prognostication, and treatment of patients with HF. METHODS: To systematically explore the low molecular peptidome, we conducted a cross-sectional mass spectrometry analysis from 486 patients with HF and 98 age-matched non-HF controls. We quantified 21 694 unique peptides in plasma, which were ranked according to (1) the relative upregulation in HF versus controls, (2) pattern similarity to bioactive peptides by an adapted machine learning method, and (3) association with clinical outcome. RESULTS: We observed 1924 differentially expressed peptides between patients with HF and non-HF controls. Among high-ranking peptides in patients with HF were angiotensin-related peptides (eg, angiotensin 1-9), propeptides from GIP (gastric inhibitory polypeptide), osteocalcin and cholecystokinin, and peptides mapping to the extracellular part of the natriuretic peptide clearance receptor and integrin alpha-7. Among the regulated peptides, 141 were scored in the top 5% by our machine learning approach, and 65 peptides herein were independently associated with clinical outcome. A hierarchical clustering analysis of patients with HF revealed 3 major patient clusters based on the peptide signature. The patient cluster with the lowest survival probability exhibited a specific peptide degradation pattern with a higher proportion of peptides linked to the acute phase response and increased inflammation. CONCLUSIONS: This study uniquely identifies peptides according to their regulation and likelihood of being a bioactive peptide in patients with HF compared with non-HF controls. The study provides crucial peptide-level information to complement protein-based methodologies. The most promising peptides were related to the renin-angiotensin system, natriuretic peptides, and cardiometabolic regulation. The stepwise ranking highlights the HF peptide signal important for outcome and provides a rich resource for additional exploration.