Discordant fatty acid profile drives residual inflammatory risk in metabolically vulnerable patients with low atherogenic lipoprotein burden.
BACKGROUND AND AIMS Despite effective LDL-cholesterol reduction, residual cardiovascular risk persists. We investigated whether a specific fatty-acid phenotype predicts structural plaque instability and cardiovascular events independent of lipoprotein burden. METHODS This multi-cohort study integrated a clinical discovery cohort (n = 201, GC-MS profiling) with the UK Biobank validation cohort (n = 263,481, NMR profiling). Unsupervised clustering derived fatty-acid phenotypes. Structural vulnerability was assessed via optical coherence tomography (OCT) in 138 patients. The primary endpoint was MACE (cardiovascular death, non-fatal MI, stroke). RESULTS Two phenotypes emerged: Phenotype B, characterized by omega-3 depletion. Paradoxically, despite lower LDL-cholesterol (2.7 vs 3.0 mmol/L; p = 0.050) and triglycerides (1.5 vs 2.0 mmol/L; p = 0.041), Phenotype B exhibited significantly thinner fibrous caps (68.0 vs 94.2 μm; p = 0.003) and higher thin-cap fibroatheroma prevalence (49.0% vs 20.0%; p = 0.002) on OCT. In the UK Biobank, Phenotype B was associated with increased MACE risk in participants aged >60 years (HR 1.16; 95% CI 1.12-1.21; p < 0.001). In fully adjusted models, the hazard ratio was 1.12 (95% CI 1.08-1.16; p < 0.001), with 72% of excess risk mediated through glycemic, inflammatory, and adiposity pathways. CONCLUSIONS A latent fatty acid phenotype defined by omega-3 depletion and elevated omega-6/omega-3 ratio was associated with structural plaque vulnerability despite favorable atherogenic lipoprotein levels. In the UK Biobank, this phenotype was independently associated with increased MACE, most pronounced in participants aged 60 years and older. These observational findings warrant prospective validation.