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LDL Particle Number and Size

Measurement as a strategy for CAD prevention

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Heart disease continues to be the leading cause of death among men and women in the United States.1 In 2010, an estimated 785,000 people experienced a new cardiac event, and another 470,000 had a recurrent event.2

For too many people, sudden death is the first sign of heart disease.3 Considering that coronary artery disease (CAD) is often preventable with screening and intervention, this lack of awareness is unacceptable. All healthcare providers should work to prevent CAD by screening patients for risk factors such as hypertension, dyslipidemia, obesity, diabetes, family history of CAD, sedentary lifestyle, high-fat and high-cholesterol diet, and nicotine addiction.

Lipid Management

Lipid management is an important aspect of managing patients in primary care and specialty settings, and it is a powerful strategy in CAD recognition and prevention. Lipid management is no longer limited to treating total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels. Cross-sectional and prospective studies have determined that LDL particle number is a better evaluator of risk than LDL cholesterol level (LDL-C).3

A consensus report released in 2008 by the American Diabetes Association (ADA) and the American College of Cardiology (ACC) states that LDL particle number is a stronger predictor of cardiovascular risk than non-HDL cholesterol and LDL-C.3 With regard to LDL particle size, some studies have determined that it is significantly associated with cardiovascular risk, but others have not documented a strong link. The ADA-ACC report says that small LDL particles are more atherogenic than large LDL particles, and that more research about the direct effects of particle size is needed.3

The ADA-ACC report recommends evaluating LDL particle number and size and states that these two variables can be managed in a primary care setting.3 Nuclear magnetic resonance (NMR), which produces a digital representation of the molecules in a blood sample, can document LDL particle number and size.

Nuclear Magnetic Resonance

NMR measures the number and size of lipoprotein particles. LDL particles carrying cholesterol in the bloodstream travel into artery walls where the cholesterol is deposited and forms plaque.4 This plaque can obstruct blood flow through the coronary arteries and cause a myocardial infarction (MI). When a high number of LDL particles transport cholesterol, a large amount of plaque can be deposited into the lining of the arteries. A high number of LDL particles is associated with a higher risk of heart disease.5

Archive Image4

(Click image to view larger photo.)

NMR also can assess LDL particle size. Approximately 30% to 60% of LDL particle size is determined by genetics, and the remainder is a result of environmental influences such as diet, physical activity, obesity and insulin resistance and hyperinsulinemia.6 Smaller LDL particles have increased atherogenicity.7 Small LDL particles (known as pattern B) can be described as dense "BBs" in the arteries. They can damage artery walls and promote inflammation, which increases the risk for cholesterol deposits to form plaque buildup. Large LDL particles (known as pattern A) are less dense and less atherogenic. They have a harder time penetrating the lining of the arteries and thus contribute less to plaque buildup. Large particles can be described as "cotton balls" (light and buoyant). A high number of large particles is associated with increased cardiac risk.5

As of late 2011, NMR was available in one patented technology method, the NMR LipoProfile. This testing is priced around $100 to $120,8 which is slightly more than the price of a regular lipid panel. Many insurance companies cover the cost of NMR, including Medicare.8

Pharmacotherapy

First-line therapy for abnormal lipids usually includes 3-hydroxy-3- methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, better known as statins. Statins partially inhibit HMG-CoA reductase,9 which is responsible for the synthesis of cholesterol. Statins reduce the amount of cholesterol produced by the liver. As cholesterol is reduced, fewer LDL particles are needed for transport.

Medications used to increase LDL particle size include extended-release niacin and fibric acid derivatives. Extended-release niacin decreases hepatic LDL production, which in turn reduces the number of LDL particles.9 It also improves HDL by minimizing the breakdown of apolipoprotein A1.9 Extended-release niacin is the most potent medication available for raising HDL.9 It is also effective in lowering LDL and triglycerides and increasing LDL particle size. Fibric acid derivatives such as fenofibrate are mainly used to reduce triglycerides and increase LDL particle size; they have a modest effect on HDL-C and LDL-C.9 Fibric acid derivatives activate lipoprotein lipase, which enhances the degradation of triglyceride-rich lipoproteins.9

Case Example

Mr. S, age 47, presents to the cardiology clinic for evaluation of CAD risk. He has a family history of premature CAD: His father died suddenly as a result of an MI at age 49, and his mother died after an MI at age 60. His brother, who is 2 years younger, recently experienced an MI and subsequently underwent five-vessel coronary artery bypass grafting.

Mr. S has not experienced any symptoms of angina, but he is concerned about his heart health due to his family history. Other risk factors present include hypertension treated with amlodipine and hydrochlorothiazide, obesity (body mass index 32) and hyperlipidemia treated with pravastatin for the past 5 years. Mr. S is a nonsmoker who works in an office setting. He exercises by walking for about 30 minutes three to four times per week. He does not follow a particular diet.

A recent coronary calcium score of 537 places Mr. S in the 99th percentile for cardiac event risk among men his age. A coronary calcium score is calculated using a noninvasive CT scan that shows the extent of calcified plaque in the coronary arteries.10 A lipid panel shows that Mr. S has a total cholesterol level of 165 mg/dL, triglycerides of 32 mg/dL, HDL-C of 50 mg/dL, and LDL-C of 109 mg/dL.

Archive Image4

(Click image to view larger photo.)

As part of a risk reduction program for this patient, an NMR can be a valuable diagnostic tool. Despite being on a statin for the past 5 years and having a normal total cholesterol level, Mr. S has an abnormal calcium score and other risk factors. The NMR can provide a more detailed evaluation of the patient's cholesterol. The traditional LDL-C blood test does not accurately reflect the number and size of LDL particles.5

NMR results for Mr. S show small LDL particle size at 20.3 nm, and a borderline high LDL at 1,449 nmol/L. The goal for LDL particle number is less than 1,000 nmol/L, and the goal for LDL size is 20.6 nm or greater (pattern A).5,8,11 Appropriate pharmacotherapy would be a fibric acid derivative or extended-release niacin.

To reduce the CAD risk for Mr. S, I prescribe extended-release niacin 500 mg daily for 1 month, to be increased to 1,000 mg daily after 4 weeks and then titrated by 500 mg monthly to a goal of 2,000 mg daily. I advise Mr. S to take 325 mg noncoated aspirin 30 minutes prior to the extended-release niacin to help reduce the common side effect of flushing. This form of niacin should be taken with a meal, and spicy foods and alcohol should be avoided to minimize flushing. Liver function should be checked prior to initiating niacin and again 8 weeks after starting therapy. Liver enzymes should then be measured every 6 months to 1 year.

In addition, I recommend that the pravastatin regimen be changed to simvastatin, which is more effective in reducing the number of LDL particles. Specifically, simvastatin provides a 29% to 41% reduction in LDL-C, while pravastatin provides a 22% to 37% reduction in LDL-C, depending on dose.12

Six months after initiating extended-release niacin for Mr. S, NMR shows an LDL particle size of 21.2 nm (pattern A) and LDL particles numbering 812 nmol/L. Laboratory testing reports a total cholesterol level of 128 mg/dL, triglycerides of 48 mg/dL, HDL of 59 mg/dL, and LDL of 59 mg/dL. Mr. S and his wife are improving their dietary habits with input from a registered dietitian. He continues to exercise regularly and is tolerating the extended-release niacin without any side effects.

The Complete Picture

LDL particle number and size are better indicators of cardiovascular risk than LDL-C, so consider NMR for appropriate patients.3 Medications such as HMG-CoA reductase inhibitors can reduce LDL particle number, while extended-release niacin and fibric acid derivatives can increase LDL particle size.9 In addition to prescribing these therapies, educate patients about the importance of risk factor modification and seeing a healthcare provider regularly for further risk stratification. 

References

1. Kochanek KD, et al. Deaths: preliminary data for 2009. Natl Vital Stat Rep. 2011;59(4):1-51.

2. Lloyd-Jones D, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics - 2010 update: a report from the American Heart Association. Circulation. 2010;121(7):e46-e215.

3. Brunzell JD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol. 2008;51(15):1512-1524.

4. Thornton-Miller DA. NMR lipoprofiles: moving beyond cholesterol. Nurse Pract. 2008;33(11):30-33.

5. Cromwell WC, Otvos JD. Low-density lipoprotein particle number and risk for cardiovascular disease. Curr Atheroscler Rep. 2004;6(5):381-387.

6. Bossé Y, et al. Genetics of LDL particle heterogeneity: from genetic epidemiology to DNA-based variations. J Lipid Res. 2004;45(6):1008-1026.

7. Sacks FM, Campos H. Clinical review 163: Cardiovascular endocrinology: low-density lipoprotein size and cardiovascular disease: a reappraisal. J Clin Endocrinol Metab. 2003;88(10):4525-4532.

8. NMR LipoProfile. The weight of evidence supporting LDL-P by NMR. http://http://www.liposcience.com/userfiles/content/files/weightofevidence.pdf. Accessed Nov. 28, 2011.

9. Gotto AM Jr. Therapeutic options: pharmacologic interventions. In: Contemporary Diagnosis and Management of Lipid Disorders. 4th ed. Gotto AM Jr, ed. Newtown, PA: Handbooks in Health Care; 2008:256-356.

10. O'Rourke RA, et al. American College of Cardiology/American Heart Association Expert Consensus Document on Electron-Beam Computed Tomography for the Diagnosis and Prognosis of Coronary Artery Disease. Circulation. 2000;102(1):126-140.

11. Mora S, et al. LDL particle subclasses, LDL particle size, and carotid atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis. 2007;192(1):211-217.

12. Statin dose comparison. Pharmacist's Letter/Prescriber's Letter. 2009;25(8):250801. Available with subscription at www.pharmacistsletter.com.

Kari Gondeck is a family NP specializing in cardiology at Prevea Health in Green Bay, Wis. She has completed a disclosure statement and reports no relationships related to this article.

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Thanks for allowing comment.

You say that CAD is "often preventable." I say "sometimes" would be more accurate. This guy's risk can be reduced by maybe 20% - 25% on the program you propose. Oh, you might point out that his all-cause mortality risk is being improved much more modestly -- actually, its hard to find statistically significant proof that in primary prevention that his all-cause mortality is improved at all. Don't forget to mention side effects of the statins.

You also list high-fat and high-cholesterol diet as risk factors. Where is the reliable science supporting that? For diet, if we are going to act on suppositions, I would place my bets on eliminating wheat and grains, limiting sugar, and avoiding omega six polyunsaturated oils. Don't buy into the "healthy whole grains" nonsense. I am betting that his BMI has not improved while talking to the registered dietician.


Steve - NMR veteran February 02, 2012



After reasonble levels of LDL particles have been achieved, do you remove the statin and keep the niacin alone or does the patient need to continue the diet and exercise and multiple medications?

Paul Desilier,  PA-CJanuary 19, 2012
Cambridge, MA




     

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