Abstract 1251: Lipophilic Index of Fatty Acid Fluidity in Erythrocyte and Plasma and Risk of Coronary Heart Disease

Multiple lines of evidence suggest that fatty acid (FA) binding affinity, viscosity, and cellular membrane fluidity together may play important roles in cardiovascular pathophysiology. Conventional classifications also incompletely capture the wide heterogeneity of diverse FAs. Via a novel etiologic paradigm, we investigate the Lipophilic Index (LI) and risk of coronary heart disease (CHD). Prospective nested case-control study in a cohort of 32,826 U.S. women who provided baseline blood in 1989 –1990. During 6-years follow-up, 166 incident CHD cases were matched with 327 controls. Assaying full FA profiles via gas chromatography, 43 FAs were identified in plasma and erythrocytes. We developed a novel FA risk index based on molecular properties of fat lipophilicity, constructed upon FA melting points, and parameterized via individual weighted summation of melting points; the LI was constructed upon 32 unique FAs with official melting points. Among controls, mean (SD) lipophilicity was 16.8°C (2.48) for Plasma-LI and 17.1°C (1.5) for Erythrocyte-LI, r=0.54. In prospective analyses, increasing Plasma-LI and Erythrocyte-LI were strongly associated with greater risk of CHD in both crude and multivariable models: RR=3.56 (95%CI: 1.48 – 8.67, P-trend=0.001) for Plasma-LI, and RR=3.80 (1.12–12.9, P-trend=0.03) for Erythrocyte-LI, comparing extreme quintiles. Individuals with higher LI also exhibited adverse lipid profiles, hyperglycemia, hypertension, and endothelial dysfunction. Notably, higher Plasma-LI was associated with having low HDL<40mg/dl (OR per-SD=2.71, 1.91–3.84; P<0.0001), elevated triglycerides>=150mg/dl (OR=3.89, 2.83–5.35; P<0.0001), hypertension (OR=1.34, 1.07–1.66; P=0.009), elevated HbA1c>=6% (OR=1.50, 1.17–1.91; P=0.001), and highest quintile of E-selectin (OR=1.92, 1.47–2.50; P<0.0001). LI trends with CHD risk also persisted after adjustment for these metabolic risk factors, plus trans and total fat intakes. The Lipophilic Index of plasma and erythrocyte fatty acids is strongly associated with adverse metabolic profiles and higher risk of CHD development. Findings support a novel mechanism that fatty acid lipophilicity is important in CHD pathogenesis.