Plasma-based low-grade inflammation and endothelial dysfunction explain a small but significant proportion of the association between the n-3 polyunsaturated fatty acids and cardiovascular diseases: The Maastricht Study

BACKGROUND: n-3 polyunsaturated fatty acids (PUFAs) are linked to lower cardiovascular disease (CVD) risk, potentially via reduced low-grade inflammation (LGI). OBJECTIVE: To examine whether LGI mediates the association of n-3 PUFAs with (pre)clinical CVD, and whether LGI and endothelial dysfunction (ED) mediate the associations with clinical CVD. METHODS: H nuclear magnetic resonance (NMR; n = 3193, 50.8% men, 60 ± 8 years; EDTA plasma) and gas chromatography (GC; n = 1032, 49.6% men, 60 ± 8 years; serum). LGI was defined as the z-score of 6 plasma biomarkers. Preclinical markers of CVD comprised: ED, ankle-brachial index, carotid intima-media thickness, and carotid-femoral pulse wave velocity. CVD was self-reported as coronary heart disease, cerebrovascular disease, or peripheral artery disease. Mediations with n-3 PUFAs (exposures), LGI (mediator), and (pre)clinical CVD (outcomes), and sequential mediations with LGI and ED (mediators) and CVD (outcome) were performed. RESULTS: A total of 522 participants reported CVD. In the NMR subset, n-3 PUFAs were inversely associated with CVD and ED. n-3 PUFAs were inversely associated with LGI (β: -0.09 [-0.12, -0.05]), while LGI was positively associated with ED (β: 0.58 [0.55, 0.61]) and CVD (OR: 1.15 [1.03, 1.28]). LGI mediated the associations with CVD (