Overview

Lipoprotein(a) (Lp[a]) is an atherogenic lipoprotein that consists of LDL-C (ie, cholesterol, phospholipids, and apolipoprotein B-100) linked covalently by a disulfide bond to apolipoprotein(a). Apolipoprotein(a) is homologous to plasminogen, a proenzyme promoting clot lysis. Unlike plasminogen, apolipoprotein(a) promotes thrombosis by competitive inhibition of plasminogen. Lp(a) binds to endothelial cells, monocytes, and macrophages. It is believed to provide the link between thrombosis and atherosclerosis.

The level of Lp(a) is unrelated to the level of other lipoproteins or apolipoproteins. Lp(a) levels are genetically determined. The actual level is a function of synthesis in the liver rather than of degradation or catabolism. Lp(a) levels are decreased in chronic liver disease and increased in end-stage renal disease, hypothyroidism, and acromegaly. Both testosterone and estrogen decrease Lp(a) levels. Furthermore, Lp(a) is an acute-phase reactant, increasing after an acute event.

Population studies have shown a skewed distribution among white and Asian populations. African Americans have a normal distribution of Lp(a) levels; however, plasma levels are 2-4 times higher than in whites. Lp(a) does not appear to convey the same risk of coronary artery disease (CAD) as among whites. Increased levels of Lp(a) have been associated with increased risk of CAD among South Asians.

Risks of Lp(a)

The literature on the risk of Lp(a) is not always concordant. However, a meta-analysis of 27 prospective studies with a mean follow-up period of 10 years showed that patients with Lp(a) levels in the upper tertile had a 70% increased risk of coronary heart disease (CHD).

Using a nested case-control design, the Lipid Research Clinics Coronary Primary Prevention Trial reported that an elevated Lp(a) level was an independent risk factor for CHD during a follow-up period of 7-10 years. In contrast, in the Physicians’ Health Study, using a nested case-control design, Lp(a) levels did not predict future myocardial infarction after 60 months.

The Framingham Heart Study reported an 11.4% prevalence of Lp(a) levels greater than 30 mg/dL in the cohort population. Lp(a) was an independent risk factor for CHD events among men aged 55 years or younger. The attributable risk of 9.3% was similar to a total cholesterol level of 240 mg/dL or higher (10.3%) or an HDL-C level of less than 35 mg/dL (10.3%).

In a Swedish study of 1216 patients with established coronary disease, an Lp(a) level of 30 mg/dL or greater was present in 30% of the population and found to be an independent predictor of death over a mean follow-up period of 6.7 years. Other predictors of death included a high fibrinogen level, a low antithrombin III level, depressed left ventricular function, and a high coronary obstruction score.

To assess the predictive role of Lp(a) in the Cardiovascular Health Study, 3972 ambulatory men and women aged 65 years or older who were free of cardiovascular disease were monitored for 7.4 years. For men only, elevated levels of Lp(a) were associated with a 2.92 times increased risk of stroke, a 2.09 times increased risk of death due to vascular diseases, and a 1.60 times increased risk of all-cause mortality.

Children who have an Lp(a) level of 30 mg/dL or greater are more likely to have a parental history of heart attack or angina before age 50 years.

The Familial Atherosclerosis Treatment Study examined 146 men aged 62 years or younger with known CAD and apolipoprotein B levels of 125 mg/dL or higher. Baseline coronary disease severity, its progression, and events over a 2.5-year period were best correlated with Lp(a) levels. However, once LDL-C levels were lowered, Lp(a) was not as predictive for atherogenic outcomes.

In the Prospective Cardiovascular Münster Study, men with Lp(a) levels of 20 mg/dL or greater were shown to have 2.7 times more cardiovascular events over a 10-year period compared to men with lower levels. The risk was magnified in concert with other risk factors, including a high LDL-C, low HDL-C, and hypertension.

Elevated levels of Lp(a) are associated with other risks as well:

• Saphenous vein graft stenosis after coronary bypass surgery is related to Lp(a). With a level of 31.6 mg/dL, 92% of patients developed vein graft stenosis.
• An elevated Lp(a) level has been shown to be a risk factor for venous thromboembolism.
• An interaction between elevated levels of Lp(a) and factor V Leiden, protein C deficiency, antithrombin deficiency, and hyperhomocystinemia seems to exist.
• Lp(a) levels of greater than 30 mg/dL are associated with an increased risk of atherosclerotic cardiovascular disease.

Clinical guidelines

Rather than being viewed as a major risk factor, Lp(a) is considered an “emerging” risk factor for cardiovascular disease by the Adult Treatment Panel (ATP) III; thus, routine measurement is not advocated. The ATP III recognized that a high Lp(a) level could count as a second risk factor, justifying a lower goal for LDL-C levels, although that was considered a controversial approach.

Recommendations for assessment of Lp(a)

Measurement of Lp(a) levels should be reserved for persons with a strong family history of premature CAD and those with genetic causes of hypercholesterolemia. Consider measuring levels in patients with a normal lipid profile and established CAD.

Lp(a) is not stable at room temperature; thus, an analysis should be immediately performed or centrifuged and frozen for later determination. Measurement of Lp(a) is performed using immunologic methods, and assays for measurement of Lp(a) levels are variable. Since accurate methodology is not available in most clinical chemistry laboratories, samples must generally be sent to special laboratories.

In general, dietary interventions and exercise are ineffective in reducing Lp(a) levels. However, increased fish, almond, and red wine consumption appears to be modestly effective. Statins have been reported to have variable effects on Lp(a). Nicotinic acid in doses of 3-4 g daily can also lower Lp(a) levels as much as 30%. However, whether niacin reduces the associated risks is unknown. Both tamoxifen and estrogen lower Lp(a) levels. LDL apheresis is considered the most effective means to lower Lp(a) levels as much as 50%.

References

Ariyo AA, Thach C, Tracy R. Lp(a) lipoprotein, vascular disease, and mortality in the elderly. N Engl J Med. 2003;349(22):2108-2115.

Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies. Circulation. 2000;102(10):1082-1085.

Kostner KM, Kostner GM. Lipoprotein(a): still an enigma? Curr Opin Lipidol. 2002;13(4):391-396.

Koschinsky ML, Marcovina SM. Structure-function relationships in apolipoprotein(a): insights into lipoprotein(a) assembly and pathogenicity. Curr Opin Lipidol. 2004;15(2):167-174.

Lippi G, Guidi G. Lipoprotein(a): an emerging cardiovascular risk factor. Crit Rev Clin Lab Sci. 2003;40(1):1-42.

Marcovina SM, Koschinsky ML, Albers JJ, Skarlatos S. Report of the National Heart, Lung, and Blood Institute Workshop on Lipoprotein(a) and Cardiovascular Disease: recent advances and future directions. Clin Chem. 2003;49(11):1785-1796.

Obisesan TO, Aliyu MH, Adediran AS, et al. Correlates of serum lipoprotein (A) in children and adolescents in the United States. The third National Health Nutrition and Examination Survey (NHANES-III). Lipids Health Dis. 2004;3(1):29.

Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106(25):3143-3421.