Elevated LDL-C Level and Cardiovascular Disease

Overview

Low-density lipoprotein (LDL) particles are the major plasma carriers of cholesterol. Therefore, the serum cholesterol measurement usually reflects the low-density lipoprotein cholesterol (LDL-C) concentration, except in patients with excessive very low-density lipoprotein (VLDL) and chylomicron particles manifesting as high serum triglyceride levels. Elevated LDL-C concentrations may be the consequence of elevated LDL production or decreased LDL breakdown. Diets high in saturated fat, trans fat, and cholesterol appear to cause a reduction in LDL receptors in the liver, thus retarding LDL catabolism.

While the liver itself may secrete some LDL, whether increased direct hepatic LDL output is a factor in elevated LDL states is unknown. Overproduction of VLDL can obviously lead to increased LDL levels because VLDL is converted to LDL; however, many patients with elevated VLDL (triglyceride) levels have reduced LDL concentrations due to accelerated VLDL metabolism. Some patients with mixed dyslipidemias probably have nonfamilial hypercholesterolemia, manifesting as elevated LDL-C concentrations, and insulin resistance, manifesting as low high-density lipoprotein cholesterol (HDL-C) levels, high triglyceride values, or both.

It is becoming clear that LDL-C is a major, if not the only, culprit in the pathogenesis of cardiovascular atherosclerotic disease. The cascade of atherosclerosis may be initiated and/or perpetuated by LDL-C’s susceptibility to oxidation, change in particle size, or defective processing by the scavenger cells (and hence altered clearance).

Lowering the LDL level is therefore a logical step in the management of dyslipidemia. All major primary and secondary prevention trials involving 3 different statins (ie, lovastatin, pravastatin, simvastatin) demonstrate a well-recognized linear relation between the LDL-C level and the coronary event rate.

To better understand the role of LDL-C in cardiovascular disease, please review the following sections of this newsletter: LDL-C Receptor, LDL-C Recommendations, Past Studies, and Current Studies and Future Targets of Therapy.

LDL-C Receptor

The LDL receptor binds apolipoprotein B-100 and apolipoprotein E. After LDL binds to the receptor, the following sequence normally ensues:

1. The receptor is internalized by hepatocytes and dissociates from LDL, returning to the cell surface in a cycle that takes 10 minutes to complete.

2. LDL is degraded within lysosomes, and free cholesterol is released to the cytosol.

3. Intracellular cholesterol inhibits 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase), thereby interfering with cholesterol synthesis.

4. Intracellular cholesterol increases the storage of excess cholesterol by promoting its esterification.

5. Intracellular cholesterol inhibits LDL-receptor synthesis and prevents further internalization and accumulation of cholesterol.

6. If LDL receptors are absent or abnormal, the aforementioned feedback mechanism does not occur, thereby causing uncontrolled synthesis of cholesterol within the liver.

7. The gene for the LDL receptor, which is autosomal dominant, is located on the short arm of chromosome 19.

8. Since the discovery of the LDL-receptor gene (LDLR gene), more than 900 mutations have been identified as having meaningful influence on receptor function.

Clinical Trials

Past Studies

At least 8 studies have demonstrated better cardiovascular outcomes when LDL-C was closer to or less than 100 mg/dL. These include the Post–Coronary Artery Bypass Graft (POST-CABG) Trial, the Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT), the Atorvastatin Versus Revascularization Treatment (AVERT) study, the Effects of Atorvastatin Versus Simvastatin on Atherosclerosis Progression (ASAP) study, the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) trial, and the Reversal of Atherosclerosis With Aggressive Lipid Lowering (REVERSAL) Using Pravastatin or Atorvastatin study.

The Lescol Intervention Prevention Study (LIPS) demonstrated that lowering LDL-C from average levels is beneficial when fluvastatin is used as the statin of intervention. The concept that “lower LDL is better” got a boost from the results of the Heart Protection Study (HPS). Since this study showed benefits of statin therapy even in patients with LDL-C levels below 100 mg/dL, simvastatin was approved by the US Food and Drug Administration for all high-risk patients, regardless of the baseline LDL-C level (initiating dose, 40 mg).

Current Studies and Future Targets of Therapy

The following large-scale trials are under way to study the clinical benefits of lowering LDL-C concentration even further (by ~75 mg/dL): Treating to New Targets (TNT), using atorvastatin; Study of Effectiveness of Additional Reduction in Cholesterol on Homocysteine (SEARCH), using simvastatin; Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL), using simvastatin; Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER); and Aggressive Lipid-Lowering Initiation Abates New Cardiac Events (ALLIANCE).

Other potential emerging targets of therapy include a total cholesterol/HDL ratio of less than 4, rather than non–HDL-C level, as recommended by the NCEP ATP III panel. Another evaluated ratio target is the apolipoprotein B/apolipoprotein A-1 ratio, which is claimed to be a better event risk predictor than the LDL-C level. Apolipoprotein B measurements may be most useful in patients with elevated triglyceride levels. Other candidates include homocysteine, intracellular adhesion molecule-1, phospholipase A2, and myeloperoxidase. The high-sensitivity C-reactive protein (hs-CRP) has received significant press and is claimed to predict cardiovascular events better than small, dense LDL.

References

Ballantyne CM. Achieving greater reductions in cardiovascular risk: lessons from statin therapy on risk measures and risk reduction. Am Heart J. 2004;148:3S-8.

Goldstein JL, Brown MS: Molecular medicine. The cholesterol quartet. Science. 2001 May 18;292(5520):1310-2.

Goldstein JL, Brown MS: Regulation of low-density lipoprotein receptors: implications for pathogenesis and therapy of hypercholesterolemia and atherosclerosis. Circulation. 1987 Sep;76(3):504-7.

Goldstein JL, Hobbs HH, Brown, MS: Familial Hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY:McGraw-Hill;2001:2863-913.

Grundy S, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the national cholesterol education program adult treatment panel III guidelines. J Am Coll Cardiol. 2004;44:720-732.

LaRossa JC, Gotto AM. Past, present and future standards for management of dyslipidemia. Am J Med. 2004;116(6A):3S-8S.