(Circulation. 1999;99:1959-1964.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Evidence for a New Pathophysiological Mechanism for Coronary Artery Disease Regression
Hepatic Lipase–Mediated Changes in LDL Density
From the Department of Medicine, Division of Metabolism, Endocrinology and Nutrition (A.Z., J.E.H., J.D.B.) and Division of Cardiology (G.B.), University of Washington, Seattle, Wash.
Correspondence to Dr Alberto Zambon, Department of Medicine, Box 356426, University of Washington, Seattle, WA 98195-6426.
Background—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.
Methods and Results—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).
Conclusions—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.
Key Words: stenosis • lipoproteins • lipids • atherosclerosis
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