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

• Published in: Circulation (New York, N.Y.) Vol. 99; no. 15; pp. 1959 - 1964
• Main Authors: ZAMBON, A, HOKANSON, J. E, BROWN, B. G, BRUNZELL, J. D
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 20-04-1999; American Heart Association, Inc
• Subjects: Aged; Anticholesteremic Agents - administration & dosage; Anticholesteremic Agents - therapeutic use; Apolipoproteins B - blood; Biological and medical sciences; Cardiology. Vascular system; Centrifugation, Density Gradient; Chemical Phenomena; Chemistry, Physical; Cholesterol, LDL - metabolism; Colestipol - administration & dosage; Colestipol - therapeutic use; Combined Modality Therapy; Coronary Artery Disease - diet therapy; Coronary Artery Disease - drug therapy; Coronary Artery Disease - enzymology; Coronary Artery Disease - genetics; Coronary Artery Disease - physiopathology; Coronary heart disease; Drug Therapy, Combination; Heart; Humans; Hypolipidemic Agents - administration & dosage; Hypolipidemic Agents - therapeutic use; Lipase - metabolism; Lipids - blood; Lipolysis; Lipoproteins - blood; Liver - enzymology; Lovastatin - administration & dosage; Lovastatin - therapeutic use; Male; Medical sciences; Middle Aged; Niacin - administration & dosage; Niacin - therapeutic use; Human; Enzyme; Pathogenesis; Liver; Buoyancy; Triacylglycerol lipase; Cardiovascular disease; Esterases; Coronary heart disease; Carboxylic ester hydrolases; Lipoprotein LDL; Risk factor; Hydrolases
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.99.15.1959

Small, dense LDL particles are associated with coronary artery disease (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 study examines the relationship among LDL density, hepatic lipase (HL), and CAD progression, identifying a new biological mechanism for the favorable effects of lipid-altering therapy.
Eighty-eight of the subjects in FATS with documented coronary disease, apolipoprotein B levels >/=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 colestipol in those with elevated LDL cholesterol levels. Plasma hepatic lipase (HL), lipoprotein lipase, and LDL density were measured when subjects were and were not receiving lipid-lowering therapy. LDL buoyancy increased with lovastatin-colestipol therapy (7.7%; P<0.01) and niacin-colestipol therapy (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, respectively). Changes in LDL buoyancy and HL activity were associated with changes in disease severity (P<0.001). In a multivariate analysis, an increase in LDL buoyancy was most strongly associated with CAD regression, accounting for 37% of the variance of change in coronary stenosis (P<0.01), followed by reduction in apolipoprotein Bl (5% of variance; P<0.05).
These studies support the hypothesis that therapy-associated changes in HL alter LDL density, which favorably influences CAD progression. This is a new and potentially clinically relevant mechanism linking lipid-altering therapy to CAD improvement.