Evidence for a new pathophysiological mechanism for coronary artery disease regression - Hepatic lipase-mediated changes in LDL density

Background-Small, dense LDL particles are associated with coronary artery d isease (CAD) and predict angiographic changes in response to lipid-lowering therapy. Intensive lipid-lowering therapy in the Familial Atherosclerosis Treatment Study (FATS) resulted in significant improvement in CAD. This stu dy examines the relationship among LDL density, hepatic lipase (HL), and CA D progression, identifying a new biological mechanism for the favorable eff ects of lipid-altering therapy. Methods and Results-Eighty-eight of the subjects in FATS with documented co ronary disease, apolipoprotein B levels greater than or equal to 125 mg/dL, and family history of CAD were selected for this study. They were randomly assigned to receive lovastatin (40 mg/d) and colestipol (30 g/d), niacin ( 4 g/d) and colestipol, or conventional therapy with placebo alone or with c olestipol in those with elevated LDL cholesterol levels. Plasma hepatic lip ase (HL), lipoprotein lipase, and LDL density were measured when subjects w ere and were not receiving lipid-lowering therapy. LDL buoyancy increased w ith lovastatin-colestipol therapy (7.7%; P<0.01) and niacin-colestipol ther apy (10.3%; P<0.01), whereas HL decreased in both groups (-14% [P<0.01] and -17% [P<0.01] with lovastatin-colestipol and niacin-colestipol, respective ly). Changes in LDL buoyancy and HL activity were associated with changes i n disease severity (P<0.001). In a multivariate analysis, an increase in LD L buoyancy was most strongly associated with CAD regression, accounting for 37% of the variance of change in coronary stenosis (P<0.01), followed by r eduction in apolipoprotein B1 (5% of variance; P<0.05). Conclusions-These studies support the hypothesis that therapy-associated ch anges in HL alter LDL density, which favorably influences CAD progression. This is a new and potentially clinically relevant mechanism linking lipid-a ltering therapy to CAD improvement.