Serum Very‐Long‐Chain Saturated Fatty Acids and the Mediating Role of Systemic Immune Inflammation in Cardiovascular Disease Risk

Very‐long‐chain saturated fatty acids (VLCSFAs) represent a distinct class of saturated fatty acids whose cardiovascular associations remain underexplored and controversial. This study investigated the associations of serum VLCSFAs—C20:0, C22:0, C23:0, and C24:0, and their sum (total VLCSFAs)—with myocardial infarction (MI), heart failure (HF), and stroke in 3456 NHANES 2011–2014 participants. Binary logistic and restricted cubic spline regression models were employed, with mediation analysis examining neutrophil‐related inflammatory markers. With the middle tertile as the reference, participants in the lowest tertile had higher odds of MI for C20:0 (OR 2.11, 95% CI: 1.30–3.43, p = 0.003) and C23:0 (OR 2.55, 95% CI: 1.54–4.22, p < 0.001); higher odds of HF for C22:0 (OR 1.77, 95% CI: 1.08–2.90, p = 0.023), C24:0 (OR 2.14, 95% CI: 1.29–3.54, p = 0.003), and total VLCSFAs (OR 2.02, 95% CI: 1.22–3.33, p = 0.006); and higher odds of stroke for C24:0 (OR 1.77, 95% CI: 1.10–2.84, p = 0.019). Conversely, the highest tertile of C24:0 was associated with lower odds of MI (OR 0.49, 95% CI: 0.28–0.89, p = 0.018), whereas the highest tertiles of the remaining VLCSFAs showed no further risk reduction. SII, NER, NHR, and NLR partially mediated the associations of C23:0, C24:0, and total VLCSFAs with HF, and NER, NHR, and NLR partially mediated that of C22:0 with HF. These findings reveal novel associations of serum VLCSFAs with MI, HF, and stroke that were most evident in the lowest tertile of serum concentrations, suggesting that VLCSFA deficiency may contribute to cardiovascular risk, partly through neutrophil‐related inflammatory pathways.