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Cited by 263Lipoproteins and Cardiovascular HealthLipid metabolism and disordersCholesterol and Lipid Metabolism

Evidence for a New Pathophysiological Mechanism for Coronary Artery Disease Regression: Hepatic Lipase–Mediated Changes in LDL Density

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Zambon, Alberto, Hokanson, John E., Brown, B. Greg, Brunzell, John D.·1999·Circulation
DOI 10.1161/01.cir.99.15.1959
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Abstract

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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Crossref · 10.1161/01.cir.99.15.1959

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  • Several prospective studies suggest that circulating levels of small, dense LDL particles are better predictors of coronary atherosclerosis, carotid atherosclerosis, and response to therapy than are levels of large, buoyant LDL particles.

    “Several prospective studies suggest that circulating levels of small, dense LDL particles are better predictors of coronary atherosclerosis, carotid atherosclerosis, and response to therapy than are levels of large, buoyant LDL particles (28,(31)(32)(33).”

    From Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline (2012) · cites this paper as [28]

    The Abstract reports prospective associations between LDL size or density and coronary artery disease, and says patients with small, dense LDL responded better to therapy than those with large, buoyant LDL. The Results link changes in LDL buoyancy to changes in coronary stenosis. The cited paper does not address carotid atherosclerosis, so it does not support that part of the claim. Page numbers are unavailable in our copy. (LLM, conf=0.87)

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  • Hepatic lipase and cholesterol ester transfer protein contribute to remodeling of LDL and HDL particles, and which has the predominant effect depends on the triglyceride content of VLDL.

    “Hepatic lipase and cholesterol ester transfer protein contribute to the remodeling processes; whether hepatic lipase or cholesterol ester transfer protein has the predominant effect on the size and density of LDL and HDL particles depends on the triglyceride content of very low-density lipoproteins (VLDL) (27,28).”

    From Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline (2012) · cites this paper as [28]

    The Discussion (page not provided) says hepatic lipase acts on large, buoyant LDL and converts larger HDL₂ particles to smaller HDL₃ particles, supporting its role in remodeling. It does not say that cholesteryl ester transfer protein contributes to this process or that VLDL triglyceride content determines which has the predominant effect. (LLM, conf=0.86)

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1 of the 54 references couldn’t be matched to a known paper.

Research works printed but not linked: 6

  1. Lamarche B, Tchernof A, Moorjani S, Cantin B, Dagenais GR, Lupien PJ, Despres J-P. Small, dense low-density lipoprotein particles as pre- dictor of the risk of ischemic heart disease in men. Circulation. 1997;95: 69 -75.
  2. Chung BH, Segrest JP, Ray MJ, Brunzell JD, Hokanson JE, Krauss RM, Beaudrie K, Cone JT. Single vertical spin density gradient ultracentrifu- gation. In: Segrest JP, Albers JJ, eds. Methods in Enzymology, Plasma Lipoproteins: Preparation, Structure, and Molecular Biology. Orlando, Fla: Academic Press; 1986:181-209.
  3. Armitage P. Statistical Methods in Medical Research. Oxford, UK: Blackwell Scientific Publications; 1971:314.
  4. Austin MA, King M-C, Vranizan K, Krauss RM. The atherogenic lipoprotein phenotype (ALP): a proposed genetic marker for coronary heart disease risk. Circulation. 1990;82:495-506.
  5. Kinnunen PHJ, Virtanen JA, Vainio P. Lipoprotein lipase and hepatic endothelial lipase: their roles in plasma lipoprotein metabolism. Ath- eroscler Rev. 1983;11:65-105.
  6. Brunzell JD, Deeb SS. Lipoprotein lipase, apo CII and hepatic lipase deficiency. In: Scriver CR , Beudet AL , Sly WS , Valle D, Vogelstein B, Childs B, eds. The Metabolic and Molecular Basis of Inherited Disease. 8th ed. New York, NY: McGraw-Hill. In press.

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Authors
Zambon, A., Hokanson, J. E., Brown, B. G., & Brunzell, J. D.
Affiliations
University of Washington (US)
ORCID
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
1999-04-20
Volume
99
Issue
15
Pages
1959-1964
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
DOI
10.1161/01.cir.99.15.1959
OpenAlex
W1999551921
Cited by
263
References
54
Citations by year
2022: 3 · 2021: 1 · 2019: 1 · 2018: 2 · 2017: 1 · 2016: 3 · 2015: 5 · 2014: 4 · 2013: 8 · 2012: 6
FWCI
22.45
Type
journal article
Language
en
Open access
Locations
  • Circulation (publishedVersion)
  • PubMed (publishedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion, other-oa)
Funders
  • American Heart Association
  • National Institutes of Health (5r01hl019451-14, DK35816, 1r01hl042419-01)
  • National Heart, Lung, and Blood Institute (HL-42419, P01HL030086, HL3-0086, HL19451)
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
hepatic lipase, lipid-lowering therapy, lovastatin, nicotinic acid, colestipol, apolipoprotein B, coronary artery stenosis, lipoprotein lipase
MeSH terms
Aged, Anticholesteremic Agents, Hypolipidemic Agents, Apolipoproteins B, Centrifugation, Density Gradient, Chemistry, Physical, Colestipol, Combined Modality Therapy, Coronary Artery Disease, Drug Therapy, Combination, Humans, Lipase, Lipids, Lipolysis, Lipoproteins, Cholesterol, LDL, Liver, Lovastatin, Male, Middle Aged, Niacin, Chemical Phenomena

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