Multidimensional lipid phenotyping for stratification of residual cardiovascular risk: A focus on fatty acid balance

Residual cardiovascular risk persists in stable coronary artery disease despite improved low-density lipoprotein cholesterol (LDL-C) control.

We aimed to identify lipid phenotypes using multidimensional lipid profiling and to evaluate phenotype-dependent associations of fatty acid balance and lipoprotein(a) [Lp(a)] with major adverse cardiovascular events (MACE).

This retrospective study included patients undergoing elective percutaneous coronary intervention or coronary angiography. The day after the procedure, LDL-C, triglycerides (TG), remnant-like particle cholesterol (RLP-C), fatty acids (eicosapentaenoic acid [EPA], docosahexaenoic acid [DHA], arachidonic acid [AA], dihomo-γ-linolenic acid [DGLA]), malondialdehyde-modified low-density lipoprotein (MDA-LDL), and Lp(a) were measured; clustering using lipid parameters, including EPA/AA, DHA/AA, and DGLA/AA, identified lipid phenotypes. The primary endpoint was MACE (cardiovascular death, myocardial infarction, or stroke); the secondary endpoint was ischemia-driven repeat revascularization.

Two phenotypes were identified: Cluster 1 (TG/RLP-C/MDA-LDL dominant phenotype) and Cluster 2 (higher EPA/AA lipid phenotype). During a median follow-up of 1356 days, a total of 86 MACE events occurred. Events were more frequent in Cluster 2 in unadjusted analysis (log-rank P = 0.036), but the association was attenuated after adjustment. Repeat revascularization did not differ between phenotypes. A higher EPA/AA ratio was independently associated with lower MACE risk only in Cluster 2 (HR 0.63, 95% CI 0.47-0.83; P = 0.001), with a significant interaction (likelihood ratio P = 0.012). Lp(a) showed a phenotype-specific, time-dependent association with early MACE only in Cluster 2.

Fatty acid balance may have phenotype-dependent prognostic relevance. These findings support further investigation of multidimensional lipid phenotyping in residual cardiovascular risk assessment, although they should be interpreted as exploratory.