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Published on: October 12, 2017
Evidence for a new pathophysiological mechanism for coronary artery disease regression: hepatic lipase-mediated
A Zambon1, J E Hokanson, B G Brown
1Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, Wash. 98195-6426, USA.
Insights
Lipid-lowering therapy improves coronary artery disease (CAD) by altering low-density lipoprotein (LDL) particle density. This study reveals that changes in hepatic lipase (HL) activity are key to these favorable effects on CAD progression.
Area of Science:
- Cardiovascular Medicine
- Lipid Metabolism
- Atherosclerosis Research
Background:
- Small, dense LDL particles are linked to coronary artery disease (CAD) and predict disease progression during lipid-lowering therapy.
- Intensive lipid-lowering treatment in the Familial Atherosclerosis Treatment Study (FATS) demonstrated significant CAD improvement.
- This research investigates the interplay between LDL density, hepatic lipase (HL), and CAD progression.
Purpose of the Study:
- To examine the relationship among LDL particle density, hepatic lipase (HL) activity, and coronary artery disease (CAD) progression.
- To identify a novel biological mechanism underlying the beneficial effects of lipid-altering therapies on CAD.
- To assess how different lipid-lowering regimens impact LDL density and HL activity.
Main Methods:
- Eighty-eight FATS participants with documented coronary disease were randomized to lovastatin-colestipol, niacin-colestipol, or conventional therapy.
- Plasma levels of hepatic lipase (HL) and lipoprotein lipase, along with LDL density, were measured.
- Changes in LDL buoyancy and HL activity were correlated with changes in coronary stenosis severity.
Main Results:
- Lovastatin-colestipol and niacin-colestipol therapies significantly increased LDL buoyancy (7.7% and 10.3%, respectively) and decreased HL activity (-14% and -17%, respectively).
- Changes in LDL buoyancy and HL activity were strongly associated with alterations in CAD severity (P<0.001).
- Increased LDL buoyancy was the strongest predictor of CAD regression, explaining 37% of the variance in coronary stenosis changes.
Conclusions:
- Therapy-induced alterations in hepatic lipase (HL) activity modify LDL particle density, favorably impacting CAD progression.
- This represents a new, clinically significant mechanism connecting lipid-altering therapies to improvements in coronary artery disease.
- The findings support the hypothesis that modulating HL activity is a viable strategy for managing CAD.
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.
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