Inflammatory burden, but not genetic variation, predicts attenuated LDL cholesterol reduction after ST-elevation myocardial infarction

Background Inter-individual variability in LDL cholesterol (LDL-C) reduction after ST-elevation myocardial infarction (STEMI) remains incompletely explained. Although pharmacogenetic variation has been proposed as a determinant of atorvastatin response, the role of acute inflammatory burden in the setting of STEMI is less well defined. Purpose To evaluate clinical and genetic determinants of LDL-C reduction 6 months after STEMI. Methods We studied 93 consecutive STEMI patients with lipid assessment at baseline and 6 months. Absolute LDL-C reduction (ΔLDL = LDL₆M − LDL_baseline) and achievement of ESC guideline targets were analysed. Multivariable linear and logistic regression models included baseline LDL-C, age, sex, smoking status, statin intensity, and preprocedural white blood cell count (WBC). Comprehensive genetic profiling (>300 lipid- and pharmacokinetic-related variants) was assessed using candidate gene scores, genetic burden models, unsupervised clustering, and penalized regression (Elastic Net with nested cross-validation). Results Median LDL-C reduction was −1.49 mmol/L (range −4.09 to −0.01). However, 33% of patients failed to achieve ≥30% LDL reduction, 19% showed an absolute reduction of <1.0 mmol/L, and 44% remained above 1.4 mmol/L at 6 months. Baseline LDL-C was the strongest predictor of LDL reduction (β = −0.511, p < 0.001). Importantly, preprocedural WBC independently predicted an attenuated LDL response (β = +0.069 per 1×10⁹/L increase, p < 0.001), with the model explaining 42.6% of the variability in ΔLDL (R² = 0.426). WBC consistently predicted poor response across all definitions (e.g., OR 1.16 for <30% reduction, p = 0.004). In contrast, none of the genetic approaches improved prediction beyond that provided by clinical variables (all p > 0.60). No stable genetic signature of impaired statin response was identified. Conclusion In STEMI patients, systemic inflammatory burden at presentation independently predicts attenuated LDL-C reduction at 6 months, whereas extensive genetic variation does not. These findings support a state-dependent, inflammation-modulated model of lipid-lowering response in acute coronary disease.