Incremental prognostic value of lipoprotein(a) and oxidized LDL for long-term major adverse cardiovascular events in patients with stable coronary artery disease: A prospective cohort study

Background: Lipoprotein(a) [Lp(a)] and oxidized lowdensity lipoprotein (oxLDL) are established risk factors for atherosclerosis, but their independent and incremental predictive value for major adverse cardiovascular events (MACE) relative to emerging biomarkers such as Galectin-3 and growth differentiation factor-15 (GDF-15) remains to be clarified in contemporary cohorts of patients with stable coronary artery disease (CAD). Methods: In this prospective cohort study, 1,450 patients with stable CAD were enrolled. Baseline plasma levels of Lp(a), oxLDL, Galectin-3, GDF-15, and high-sensitivity C-reactive protein (hs-CRP) were measured. The primary endpoint was MACE, defined as a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Multivariable Cox proportional hazards models were used to assess the independent predictive value of each biomarker, and C-statistics, continuous net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were used to evaluate incremental risk prediction. Median follow-up was [X] months. Results: During follow-up, 289 patients (19.9%) experienced a MACE. After adjustment for traditional risk factors, Lp(a) >50 mg/dL (HR 1.68, 95% CI 1.31-2.15, p<0.001) and oxLDL in the highest tertile (HR 1.55, 95% CI 1.19-2.02, p=0.001) remained independent predictors of MACE, as did GDF-15 (HR per 1-SD increase 1.41, 95% CI 1.22-1.63, p<0.001). Galectin-3 and hsCRP were not independently associated with MACE after full adjustment. Addition of Lp(a) and oxLDL to a baseline clinical model improved the C-statistic from 0.71 to 0.76 (p=0.01), with significant improvements in continuous NRI and IDI. Patients with elevated Lp(a) and oxLDL had a substantially higher risk than those with normal levels of both markers (HR 2.45, 95% CI 1.88-3.19, p<0.001). Conclusions: In patients with stable CAD, Lp(a) and oxLDL onclusions: are robust, independent predictors of long-term MACE and add prognostic value beyond traditional risk factors and other novel biomarkers. The combination of elevated Lp(a) and oxLDL identifies a very high-risk phenotype, suggesting a possible additive or synergistic contribution to residual cardiovascular risk.