Revolution Health & Wellness

Lipoprotein(a) – Lp(a)

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Lipoprotein(a) – Lp(a)

What is Lp(a)

Lipoprotein(a) [Lp(a)] is a highly heterogeneous molecule, consisting of a low-density lipoprotein (LDL) with a highly glycosylated apolipoprotein(a) [apo(a)] molecule covalently linked to the apolipoprotein B moiety of LDL via a single disulfate bond.

Apo(a) has approximately 80% structural homology with plasminogen but does not contain the active site for fibrin cleavage.1 Lp(a) has been associated with atherogenesis and promotion of thrombosis.2-5 One proposed mechanism for Lp(a)’s atherogenicity is competition for binding sites with plasminogen during fibrin clot formation and the resulting inhibition of fibrinolysis.1

Lp(a) does not bind to the LDL receptor, therefore circulating Lp(a) levels are more a reflection of synthesis rate rather than clearance.6

The liver is better able to secrete the smaller apo(a) isoforms than the larger ones. The MW of the apo(a) molecule depends on how many kringle repeats are present in the KIV-2 domain; the fewer the number of KIV-2 repeats, the lower the MW and the higher the hepatic secretion rate. So paradoxically, even though small isoforms have a lower MW than the larger isoforms (which have more KIV-2 repeats), serum Lp(a) particle counts [Lp(a)-P] will usually be higher in patients with the smaller, lower MW isoforms compared to those whose Lp(a) mass [or apo(a) mass] derives from the larger, higher MW isoforms.2

Lp(a) is Genetic

Plasma Lp(a) levels remain relatively stable over an individual’s lifetime, primarily determined by variation in the Lp(a) gene (LPA) on chromosome 6q23, which encodes the apo(a) protein, and influences its production rate and isoform size.3,9 In fact, KIV-2 copy number variation and apo(a) isoform size explain ~30-50% of variation in Lp(a) concentrations across multiethnic populations.10,11 However, individuals without Lp(a) or with very low Lp(a) levels seem to be healthy.12.13 Thus plasma Lp(a) is certainly not vital, at least under normal environmental conditions.

In the clinical laboratory, immunologic methods are generally used to quantify Lp(a) protein mass. Difficulties in standardizing Lp(a) mass measurement arise from the variability in signals produced by different reagents due to the size polymorphisms (repeats of kringle type IV-2) of apo(a).

For this reason, some elevations of Lp(a) mass are associated with low levels of Lp(a)-C. Large, high molecular weight (MW) apo(a) isoforms have large numbers of KIV-2 repeats. Assays insensitive to isoform size are not yet widely available, which presents a challenge for standardization of Lp(a) measurement in plasma. Most assays cannot directly measure molar concentrations (particle numbers) of Lp(a), instead reporting estimates obtained by converting milligrams to moles using an average, not the exact apo(a) MW unique to a given patient.

Since most people are heterozygous for large and small isoforms, Lp(a) mass measurements reflect the sum of the MW of both small and large apo(a) isoforms. Due to its greater hepatic release, the vast majority of apo(a) molecules in most individuals with elevated Lp(a) mass are of low MW. Therefore, the major limitation in relying on Lp(a) mass concentration testing is that Lp(a) mass does not always correlate with Lp(a)-P and cardiovascular (CV) risk is more likely related to the number of Lp(a) particles than it is Lp(a) mass.14

There is evidence that measuring Lp(a)-C would be a better correlate with Lp(a)-P than Lp(a) mass.15 As this method measures only the cholesterol contained in the Lp(a) particles and is thus not influenced by the relative size of the apo(a) molecule, it may provide a more specific assessment of cardiovascular risk than Lp(a) mass measurement. For this reason, some elevations of Lp(a) mass are associated with low levels of Lp(a)-C. However, the ability to measure Lp(a)-P directly now circumvents this issue and provides the most accurate measure of plasma Lp(a) concentration. A recent study demonstrated that at normal TG levels, Lp(a)-P correlated with Lp(a)-C; however, at high TG levels, this association was lost with the majority of the variance of Lp(a)-P related to HDL lipidation, VLDL, and TG. These results imply that Lp(a) metabolism is related to receptors and lipases primarily interacting with HDL and TG-rich lipoproteins.16

Reference ranges for Lp(a)-P as assessed by this novel, high precision assay, are as follows:

  • Optimal: < 75 nmol/L
  • Intermediate risk: 75-125 nmol/L
  • High risk: > 125 nmol/L

Clinical Interpretation

In epidemiological trials, the small, low MW isoforms of apo(a) or Lp(a) are associated with higher cardiovascular risk and considered more atherogenic than the larger high MW isoforms.5 This is likely related to Lp(a) particle number. If a patient does secrete the larger, higher MW isoforms rather than small isoforms, Lp(a) mass will be high but CV risk may be lower than suggested by the apo(a) mass measurement; i.e., there will be discordance between Lp(a)-P and Lp(a) mass. This is one shortcoming of Lp(a) mass concentration testing. Increased plasma levels of Lp(a) have been estimated to confer a 1.5- to 3.0-fold increased risk for coronary artery disease (CAD) in many but not all studies.17-29 Recently a high correlation was demonstrated between Lp(a) and oxidized LDL, suggesting that the atherogenicity of Lp(a) lipoprotein may be mediated in part by associated proinflammatory, oxidized phospholipids.29

The Mayo Clinic conducted a four-year study on 504 angiography patients and looked at the hazard ratio for angiographic CAD in a multivariat analysis. Lp(a)-C, but not Lp(a) mass, was shown to be an independent predictor of angiographic CAD and subsequent cardiovascular events in patients referred for coronary angiography.15

Researchers in The Copenhagen City Heart Study observed a stepwise increase in risk of myocardial infarction (MI) with increasing levels of Lp(a) in both genders, with no evidence of a threshold effect. The study also found that extreme Lp(a) levels > 95th percentile predict a three to four-fold increase in risk of MI and absolute 10-year risks of 20% and 35% in high-risk women and men.30,31 A systematic review by Erquo et al. (2010) showed that there is a two-fold difference in the risk for myocardial infarction and stroke between Caucasian subjects with low MW (~40%) versus high MW apo(a) phenotypes (~60%) – differentiated by a cut-off of approximately 22 KIV-2 repeats.5 Data from a recent population study of 8,720 Danish individuals suggests that either extreme Lp(a) levels or risk genotypes in LPA can substantially improve risk prediction for myocardial infarction and coronary heart disease (CHD).32

Lp(a) may contribute to the development of MI and ischemic heart disease (IHD) by two different mechanisms: the LDL particle component may promote atherosclerosis, whereas the plasminogen-like apo(a) particle may interfere with fibrinolysis and increase the risk of thrombosis.1-3 Lp(a) can enter into and leave the arterial wall by mechanisms similar to LDL, but Lp(a) appears to accumulate more at the sites of arterial injury and can enter atherosclerotic plaques.33,34 Results from in vitro and animal studies implicate Lp(a) in foam cell formation, smooth-muscle cell proliferation, and plaque inflammation and instability.4,34-35 Lp(a) has also been shown to bind proinflammatory, oxidized phospholipids recently associated with CAD.8 Mechanisms by which Lp(a) may contribute to thrombus formation include activation of tissue factor pathway inhibitor, thus promoting coagulation and attenuation of fibrinolysis through inhibition of plasminogen activation.4,35

Numerous studies have documented the relationship between high plasma Lp(a) concentrations and a variety of cardiovascular disorders, including peripheral vascular disease, cerebrovascular disease, premature coronary disease, vein graft restenosis, and retinal arterial occlusion.18-28,38-41,31 High Lp(a) predicts risk of early atherosclerosis, similar to high LDL, but in advanced atherosclerosis, Lp(a) is an independent risk factor. One large study of older Americans, in particular, demonstrated that elevated levels of Lp(a) lipoprotein independently predict an increased risk of stroke, death from vascular disease, and death from all causes in men.42 There may be a relationship between Lp(a) mass and LDL-C, as some epidemiologic studies have suggested the risk of Lp(a) is worse or even limited to those with high LDL-C. Other trials have shown that Lp(a) greatly increases cardiovascular event risk in patients with elevated LDL-C or low HDL-C.43,44 Baseline Lp(a) as an independent risk factor for combined cardiovascular events is reportedly higher in women [although one large study showed that to be true only in women with very high apo(a) mass plus high LDL-C] and patients with a history of peripheral vascular disease.45 A 2010 European consensus statement declared, “Elevated Lp(a) levels associate robustly and specifically with increased cardiovascular disease (CVD) risk. The association is continuous in shape, without a threshold, and does not depend on high levels of LDL-C or non-HDL-cholesterol, or on the levels or presence of other CV risk factors.”31 Recent findings in the EPIC-Norfolk Study also report an association of Lp(a) risk and both coronary and peripheral artery disease that was not modified by LDL-C levels.46 Moreover, and refuting earlier work, increasing quintiles of Lp(a) in an updated Atherosclerosis Risk in Communities (ARIC) Study were just as predictive of future CVD in the African-American population as in Caucasians.47

Treatment Considerations

There are to date no level 1 evidence trials which demonstrate that lowering Lp(a) level will reduce cardiovascular benefit. One problem is that drugs that may lower Lp(a) also lower apoB, and/or beneficially modulate other lipid/lipoprotein fractions, making it impossible to predict which lipoprotein changes underlie the improvement in cardiovascular risk. Reduction in Lp(a) by hormone replacement therapy in one study (a weak post-hoc analysis) or plasma apheresis has been shown to reduce cardiovascular events in post-menopausal women and limit restenosis following angioplasty.39,48 Niacin is the most potent Lp(a)-lowering drug available (30-40% in a dose- dependent fashion) but there is no outcome data yet for patients thus treated.31 Knowledge that Lp(a) mass is elevated allows the physician to better assess risk and perhaps set more aggressive LDL goals. One might, after statin therapy, which does not reduce Lp(a), select a therapy that, in addition to other effects, may reduce Lp(a) and hopefully, cardiovascular events. In terms of medications, statin, statin/ezetimibe, or statin/bile acid sequestrant therapy may not decrease Lp(a) levels, but by lowering apoB, LDL-P and LDL-C may modify the cardiovascular risk associated with Lp(a)7,31; niacin, although difficult to tolerate in the high doses needed to decrease Lp(a), does decrease Lp(a) levels and would provide additional apoB reduction while increasing HDL- C.31,42,49,50 European Atherosclerosis Society (EAS) guidelines recommend 1-3 g niacin daily for the treatment of elevated Lp(a) levels.31 Plasma concentrations of Lp(a) can increase in post-menopausal women and estrogen replacement therapy will reduce them.33 However, data concerning the relationship between hormone therapy (HT) and Lp(a) levels are conflicting and controversial, in part because HT use in women with CVD is itself controversial and because studies that show decreases in Lp(a) levels with HT use have rarely been powered to assess the impact on CVD.33,50-53 It is not indicated for the sole purpose of CVD risk reduction in primary or secondary prevention. Brown et al. (2010) recently provided a state of the art discussion on the nuances of treating patients with high Lp(a).54


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