Andreia N. S. Hisi, Céline Chollet, Florence Castelli, François Fenaille, Tiphaine Vidal-Trécan, Jean-Pierre Riveline, Nicolas Venteclef, Pascal Richette, Augustin Latourte, Jean-François Gautier, Jean-Baptiste Julla, Hang-Korng Ea
Affiliation(s):
Université Paris Cité, Inserm U1132, Bioscar, Aphp - Hôpital Lariboisière, Paris, France
Introduction: Hyperuricemia (HU) is a metabolic condition associated with systemic pathologies including metabolic syndrome, hypertension, and coronary artery calcification (CAC), which reflects the burden of coronary atherosclerosis. However, the contribution of HU to CAC in patients at high risk of arterial calcification such as type 2 diabetes patients (T2Dp) remain unknown.
Objectives: To characterize in TD2p, the relationship between HU and cardiovascular risk, measured via CAC score, and to assess whether this relationship is associated with specific metabolite signatures or monocyte-driven immune profiles.
Methods: Retrospective study of a prospective DT2 patient cohort (n=3086). Patients with acute inflammation (C-Reactive Protein > 10 mg/L or Leukocyte > 12 000/mL) were excluded to ensure that observed data reflect chronic metabolic states. Agatston CAC score was used to assess cardiovascular risk. HU was defined as a serum urate level > 420 µmol/L. Metabolomics analysis was performed by ultra-high-performance liquid chromatography coupled to mass spectrometry using a validated identification framework for feature identification and discrimination. By integrating these annotations from the outset, we targeted high-confidence metabolites to drive the statistical analysis. Univariate analysis was performed using Mann-Whitney U tests to assess differential CAC score, metabolite abundance between hyperuricemic and normouricemic groups, with p-values adjusted via the Benjamini-Hochberg procedure. Multivariate exploration was conducted using Principal Component Analysis (PCA).
Results: In our cohort of 2686 DT2 patients without acute inflammation, 19% presented with hyperuricemia (HU). Compared to patients without Hu, this group exhibited a higher proportion of male (75% vs. 58%), older patients (median 64 vs. 60 years), higher BMI (29.4 vs. 28.0 kg/m2), significantly higher level of serum triglycerides (median 1.4 vs. 1.1 µmol/L) and higher CAC score (43 vs 10). Serum urate levels served as a significant differentiator of cardiovascular risk; patients with high-risk calcification (CAC > 400) presented with markedly higher serum urate levels than those in the lower-risk group (median 353 vs. 327 µmol/L, p=0.008). Immunological profiling (n=482) showed no significant correlation between HU and monocyte sub-phenotypes. In contrast, preliminary analysis using internally validated spectral libraries (n=106) revealed a significant metabolic divergence. PCA scores demonstrated a partial but distinct separation between HU and normo-uricemic profiles, while Volcano plots identified a specific set of upregulated metabolites, particularly within purine pathways.
Conclusion: In DT2p, the prevalence of HU is high and HU may contribute to cardiovascular risk via increased coronary atherosclerosis. HU is associated with modification of abundance of multiple metabolites. Whether these metabolite changes contribute to cardiovascular risk need specific studies.