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Low-Density Cholesterol Subfractions: Not all LDL-C Particles are Created Equal


Kerri Penno
Contributing Editor

Medical conventions are challenged every day. Already in the new year, the effectiveness of cold medicine and the gold standard in breast cancer treatment have been challenged. Standards in cholesterol testing are the latest casualty of medical innovation.

For years, cholesterol has been measured by a simple panel of high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C); good and bad cholesterol. In the past couple of decades, the National Cholesterol Education Program (NCEP) recommendations have evolved from the total cholesterol test to a fasting lipoprotein profilecomprised of total cholesterol, HDL-C, LDL-C and triglycerides.

These guidelines have operated under the assumption that high levels of LDL-C are essentially harmful; LDL-C has been associated with coronary heart disease (CHD), coronary artery disease (CAD), metabolic syndrome and atherosclerosis. However, studies on cholesterol testing effectiveness have long shown that the guidelines may not be universally effective at identifying a patients risk of cardiac events. In 1988, a study on cholesterol lipids and CAD noted that 75 percent of patients who suffer myocardial infarctions have normal levels of HDL-C and LDL-C (Castelli, Can J Cardiol 1988 4A:5A). These insufficiencies have led to the revision of the guidelines and additional studies to measure risk factors.

The NCEP recently released The Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III), reiterating and expanding on the aforementioned guidelines. ATP III identified LDL-C as the primary target of cholesterol-lowering therapy.

Recent studies, however, show that not all LDL-C particles are created equal. Two patients with similar LDL-C levels may, in fact, have a different makeup of LDL-C particles, rendering one more at risk for conditions such as CHD. The concentrations and sizes of the particles (LDL-C, small LDL, large HDL and large very-low-density lipoproteins) are better indicators of risk than the traditional lipid panel (Kraus et al, N Engl J Med 2002; 347:1483-92).

While a standard LDL-C panel may place a patient in the at-risk range for CAD, the breakdown of LDL subfractions may show that the patient is in fact, not at risk preventing overtreatment. In other cases, for patients that fall outside the traditional risk range, or near the border, an LDL particle breakdown may show that they in fact are at risk of CAD, due to an unhealthy distribution of particles. Accordingly, a number of tests have been developed that focus on lipid particle size and density.

The Lipoprint (Quantimetrix) was designed to do just that. The test uses a gel electrophoresis method to examine lipoprotein subfractions, including 12 cholesterol parameters. The Lipoprint identifies small, dense atherogenic particles that indicate a higher risk of metabolic syndrome and coronary events. Each patient receives a color-coded graphical representation of their particle breakdown and subsequent risk. The NMR LipoProfile (LipoScience, Inc.) also measures LDL particle size and distribution, by nuclear magnetic resonance spectroscopy blood test. The LipoProfile identifies the average size of LDL particles (in units of nanomoles of particles per liter), linking a greater distribution of small particles with the greatest risk for developing CHD and Type 2 Diabetes Mellitus. Patients with a high distribution of large LDL particles are at a lesser, but still significant risk for CHD. The VAP (Atherotech) also measures LDL particle size and density, in addition to hereditary risk factor and remnant lipoprotein, giving a more accurate depiction of the patients risk for CAD, CHD and metabolic syndrome.

Other analyses physically se parate and break down lipoproteins. The SPIFE Lipoprotein analyzer (Helena Laboratories) offers lipoprotein phenotypingseparating lipoproteins into alpha, pre-beta and beta lipoproteins, as well as chylomicrons.

Beyond identifying risk, a patients lipoprotein distribution also can serve as a better indicator of treatment efficacy than the traditional lipid panel. Treatment efficiency varies with subfraction makeup as well. After implementing lifestyle and diet changes, the NCEP recommends the following drug treatments to lower LDL-C and raise HDL-C; HMG CoA reductase inhibitors (statins), bile acid sequestrants, nicotinic acids and Fibric acids. All of these treatments also lower triglyceride levels, with the exception of bile acid sequestrants. New evidence illustrates that small LDL particle concentration can be substantially reduced by statin combination therapy. Obtaining a clear breakdown of lipoprotein particle size and concentration can offer better, more individualized treatment methods than drugs designed to lower overall cholesterol levels.

In fact, if treatment with an LDL-lowering drug (statins are the primary drug of choice) is unsuccessful, the NCEP recommends combining treatments, and referring the patient to a lipid specialist if this tactic proves unsuccessful. As cholesterol testing evolves, new guidelines, studies and common practice are moving toward more specific, specialized testing that identifies each patients true risk, and offers more appropriate, effective, individualized treatment solutions.
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