Background: Peptide YY (PYY) is an incretin hormone released from enteroendocrine L-cells in response to nutrient intake, similar to GLP-1. While GLP-1 and its receptor agonists modulate cardiovascular (CV) risk, the role of PYY in cardiovascular disease (CVD) remains insufficiently understood.
Methods and results: We assessed PYY concentrations in arterial (AB) and coronary-sinus (CSB) blood samples of 81 patients undergoing cardiac resynchronization therapy or electrophysiological procedures (BIO-2-HEART, NCT03323216). PYY levels were significantly lower after cardiac passage (AB 99.3 ± 5.6 pg/ml vs. CSB 97.7 ± 5.6 pg/ml; mean difference −1.6 ± 6.8 pg/ml; p = 0.036), suggesting myocardial uptake. To evaluate the relevance of circulating PYY for cardiovascular outcomes, we analyzed proteomic PYY levels (Olink Explore 3072) from 43,318 UK Biobank participants to major adverse cardiovascular events (MACE: CV death, non-fatal myocardial infarction, non-fatal stroke). Individuals in the highest PYY tertile showed a markedly increased MACE risk compared to those in the lowest tertile (age- and sex-adjusted HR 1.79 [95% CI 1.65–1.93], p < 2 × 10⁻¹⁶). This association remained significant after adjusting for LDL, hsCRP, NT-proBNP, HbA1c, eGFR and established CV risk factors (HR 1.27 [1.16–1.39], p = 2.84 × 10⁻⁷). To further investigate this relationship, we assessed genetic determinants of PYY by evaluating 201 SNPs within the PYY locus for regulatory relevance using RegulomeDB. SNP rs10853114 (C>A) emerged as the most relevant variant, explaining 13% of PYY expression variance in colon tissue (Colonomics) and showing consistent eQTL effects in colon and intestine (GTEx). Carriers of the A allele exhibited significantly lower plasma PYY levels. In an exploratory analysis, homozygous A/A carriers demonstrated a reduced incidence of MACE (p = 0.038), suggesting that genetically determined lower PYY levels may confer cardiovascular protection.
Conclusion: Integrating observational, biochemical and genetic analyses, this study suggests PYY as a potential contributor to cardiovascular risk. Elevated circulating PYY levels are associated with increased MACE, whereas genetically lower PYY expression appears protective. These findings highlight PYY as a promising biomarker and possible therapeutic target in cardiovascular disease deserving further mechanistic investigation.
