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. 2010 Dec 17;3(6):327–332. doi: 10.1111/j.1752-8062.2010.00238.x

Enigmatic Role of Lipoprotein(a) in Cardiovascular Disease

Erdembileg Anuurad 1, Byambaa Enkhmaa 1, Lars Berglund 1
PMCID: PMC3075492  NIHMSID: NIHMS253407  PMID: 21167011

Abstract

Lipoprotein (a), [Lp(a)] has many properties in common with low‐density lipoprotein, (LDL) but contains a unique protein apolipoprotein(a), linked to apolipoprotein B‐100 by a single disulfide bond. There is a substantial size heterogeneity of apo(a), and generally smaller apo(a) sizes tend to correspond to higher plasma Lp(a) levels, but this relation is far from linear, underscoring the importance to assess allele‐specific apo(a) levels. The presence of apo(a), a highly charged, carbohydrate‐rich, hydrophilic protein may obscure key features of the LDL moiety and offer opportunities for binding to vessel wall elements. Recently, interest in Lp(a) has increased because studies over the past decade have confirmed and more robustly demonstrated a risk factor role of Lp(a) for cardiovascular disease. In particular, levels of Lp(a) carried in particles with smaller size apo(a) isoforms are associated with coronary artery disease (CAD). Other studies suggest that proinflammatory conditions may modulate risk factor properties of Lp(a). Further, Lp(a) may act as a preferential acceptor for proinflammatory oxidized phospholipids transferred from tissues or from other lipoproteins. However, at present only a limited number of agents (e.g., nicotinic acid and estrogen) has proven efficacy in lowering Lp(a) levels. Although Lp(a) has not been definitely established as a cardiovascular risk factor and no guidelines presently recommend intervention, Lp(a)‐lowering therapy might offer benefits in subgroups of patients with high Lp(a) levels. Clin Trans Sci 2010; Volume 3: 327–332

Keywords: lipoprotein(a), apo(a) size, allele‐specific apo(a) levels, risk factors, ethnicity

Introduction

Lipoprotein(a), [Lp(a)], is a complex lipoprotein particle with many properties in common with low‐density lipoprotein (LDL). As LDL, the Lp(a) particle has one molecule of apolipoprotein B‐100 (apo B‐100) and a cholesteryl ester‐rich lipid core surrounded by a phospholipid and free cholesterol surface layer. In addition, Lp(a) contains a unique glycoprotein, apo(a), linked to apoB through a single disulfide bond. 1 , 2 , 3 , 4 In contrast to apoB, apo(a) is highly hydrophilic with a high carbohydrate content. Apo(a) is structurally heterogeneous, dominated by a variable number of copies of a loop structure, a so‐called kringle (K) domain, analogous to a corresponding structure in plasminogen, kringle 4, K4. The apo(a) gene codes for 10 different types of K4 domains, referred to as K4 type 1 through 10. K4 types 1 and 3–10 are present as single copies, whereas K4 type 2 (KIV2) is present as multiple copies, varying in number from three to more than 40 copies. 5 , 6 , 7 , 8 , 9 This variation in copy number of KIV2 results in a pronounced interindividual heterogeneity of the apo(a) protein, detected as circulating apo(a) isoforms with a molecular weight ranging from 300 to 800 kDa. Generally, there is an inverse relation between apo(a) size and Lp(a) levels—smaller isoforms with fewer KIV2 repeats tend to correspond to higher plasma Lp(a) levels, but this relation is far from linear.

Role of Lp(a) in Atherosclerotic Cardiovascular Disease

Since Lp(a) was first described approximately 40 years ago, interest in this entity is largely derived from its putative role as a cardiovascular risk factor. 10 , 11 , 12 On balance, many studies have reported that plasma levels of Lp(a) are associated with cardiovascular disease. 10 , 11 , 12 However, results from some early studies have yielded conflicting results, ranging from a strong positive association between Lp(a) and CAD, to no association at all. 13 Many case‐control studies, in which patients with established CAD were compared with matched controls, have shown a significant association between an elevated concentration of Lp(a) and CAD. 14 , 15 , 16 , 17 , 18 , 19 These studies included survivors of myocardial infarction, 14 , 16 patients with symptoms of angina, 19 and patients with angiographically diagnosed coronary disease. 15 , 20 However, these types of studies have been criticized due to the possibility of selection bias. In addition, a retrospective case‐control design cannot distinguish whether Lp(a) is in the causative pathway or whether Lp(a) levels are increased secondary to cardiovascular disease. Prospective studies offer possibilities to assess more direct evidence for Lp(a) as a risk factor, 21 , 22 , 23 , 24 , 25 and many such studies undertaken so far provide support for the notion that elevated plasma Lp(a) concentration is a predictor of CAD. For example, Danesh and colleagues reported a meta‐analysis of 27 prospective studies on 5,436 CAD cases observed during a mean follow‐up time of 10 years, 26 and demonstrated that subjects in the general population with an Lp(a) concentration in the top third are at 70% increased risk of CAD compared with those of in the bottom third. In a prospective cohort study consisting of 1,216 patients undergoing coronary angiography, Glader et al., showed that Lp(a) levels greater than 30 mg/dL independently predicted mortality in patients with established CAD. 20 The authors concluded that an Lp(a) level exceeding this threshold indicates a poor further prognosis and that Lp(a) may help to identify patients in need of secondary prevention. In the large‐scale prospective Reykjavik Study (n= 18,569), involving 2,047 patients with first event of myocardial infarction or death from coronary heart disease (CHD), there was an independent and continuous association of Lp(a) levels with risk of future CHD. 27 Further, the odds ratio (OR) of elevated Lp(a) for CHD remained unaltered after adjustment for established risk factors and the ratio was comparable to that of C‐reactive protein (CRP) and triglycerides. 27 In addition, a recent collaborative analysis of individual data from 36 prospective studies, involving more than 126,000 participants, demonstrated a continuous association of circulating Lp(a) concentrations with risk of CHD and stroke independent of traditional risk factors. 28

As the argument for Lp(a) as a risk factor gets stronger, it is of interest to assess where the risk reside, as the atherogenic properties of Lp(a) could be caused by risk associated with the LDL moiety, with the apo(a) moiety, or from their combination in Lp(a). First, as a carrier of a LDL moiety, with an apo B‐100 molecule, it seems likely that Lp(a) can be classified as a proatherogenic LDL. In support of this, Lp(a) has been detected in the vessel wall, where it appear to be retained more avidly than LDL. 29 , 30 Second, based on the similarity between apo(a) and plasminogen, a prothrombotic role of Lp(a) interfering with the physiological role of plasminogen has been suggested. 31 In support of this, recent studies have demonstrated that Lp(a) can provoke the formation of acute thrombosis—the second stage of atherothrombosis. 32 , 33 , 34 Third, the presence of apo(a), a large, carbohydrate‐rich, hydrophilic protein, may obscure key features of the LDL moiety in interaction with factors in the vessel wall. This might be due to interference with established LDL‐clearing pathways, due to the close distance between apo(a) and LDL receptor binding sites in apoB. Further, presence of highly charged hydrophilic carbohydrate structures might offer opportunities for interaction with vessel wall elements. Fourth, Tsimikas et al. have demonstrated that proinflammatory, oxidized phospholipids are preferentially bound to kringle V in apo(a). 35 , 36 These results suggest that Lp(a) may act as a preferential acceptor that tightly binds oxidized phospholipids transferred from tissues or from other lipoproteins. 35 , 37 This could imply that the potential physiological role of Lp(a) may be to bind and detoxify deleterious oxidized lipids, preventing an increased uptake in the vessel wall of other lipoproteins, primarily LDL, containing this factor. In this regard, when present at low levels, Lp(a) may serve a protective function participating in the transfer and degradation of oxidized phospholipids. On the other hand, when the Lp(a) levels are elevated, the presence of oxidized phospholipids in Lp(a) may be proatherogenic, potentially being taken up by the extracellular matrix of the artery wall. 38 , 39 , 40 Altogether, there are several possible factors that could contribute to an atherogenic role of Lp(a) and further studies are needed to verify or refuse these possibilities.

Apo (a) Isoforms, Allele‐Specific Apo(a) Levels and the Risk of Cardiovascular Disease

As outlined above, due to the substantial heterogeneity in apo(a) size, and the association of smaller apo(a) sizes with higher Lp(a) levels, it is highly possible that size variation of apo(a) is associated with cardiovascular disease. This raises the issue whether the size variation of apo(a) is an independent risk factor or whether a risk factor role of apo(a) size would be confounded by higher Lp(a) levels carried by Lp(a) particles with smaller apo(a). Further, studies has demonstrated synergistic effect of smaller apo(a) isoforms with small‐dense LDL and oxidized LDL particles. 36 , 41 , 42 A number of studies have reported an association of apo(a) isoform size variation with the risk of cardiovascular disease, as plasma Lp(a) levels in subjects who carry at least one small apo(a) isoform are associated with CVD or preclinical vascular changes. 43 , 44 , 45 , 46 In studying patients with end‐stage renal disease, Kronenberg et al. demonstrated that apo(a) phenotypes of low molecular weight was a better predictor for the prevalence and the degree of carotid atherosclerosis than the plasma Lp(a) concentration. 47 Later, in the prospective Bruneck Study, the same investigators reported that apo(a) phenotypes of low molecular weight independently predicted advanced stenotic carotid atherosclerosis. 46 , 48 While an association with small isoform‐specific Lp(a) levels and cardiovascular disease has been found in men, the results are less convincing in women. 23 , 49 , 50 Furthermore, although Lp(a) levels have been reported to be increased in women with myocardial infarction, 19 a recent prospective study on cerebrovascular disease demonstrated an association between Lp(a) and stroke in men but not in women. 51 This does not necessarily conflict with an association between plasma Lp(a) levels and cardiovascular disease among women, although it could suggest that any risk carried by specific apo(a) sizes may be subject to modulation by gender‐specific factors. Further studies are needed to explore these apparent gender differences.

We have reported that the small apo(a) isoform is not always the dominant form of Lp(a)—quite frequently, the larger apo(a) molecule is present in greater amount. 52 This demonstrates a considerable variability of the contribution of apo(a) size to plasma Lp(a) levels. As the contribution of Lp(a) to atherogenic risk may depend on the constellation and relative distribution of apo(a) isoform for any given individual, use of isoform‐specific or allele‐specific apo(a) levels may be informative in assessing Lp(a) as a risk factor 45 , 49 ( Figure 1 ). Further, in addition to the interindividual variability in apo(a) size and its inverse relationship with Lp(a) levels, differences between populations have been noted. The most profound differences have been noted between Africans Americans and other populations, including Asians and Caucasians. 53 , 54 , 55 , 56 , 57 Notably, as a group, Africans have higher Lp(a) levels than Caucasians or Asians, although no substantial differences in apo(a) size distribution have been found. 52 This implies that African Americans have higher mean Lp(a) levels than Caucasians adjusting for apo(a) sizes, and this difference is particularly prominent among larger apo(a) sizes, resulting in higher allele‐specific apo(a) levels. 49 , 58

Figure 1.

Figure 1

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Lp(a) and allele‐specific apo(a) levels. In addition to a cholesterol‐rich lipid core and apoB‐100, Lp(a) particle contains one molecule of apo(a), a carbohydrate rich protein linked to apoB‐100 through a single disulfide bond. The apo(a) protein consists of repeating loop structures (Kringle (K) domains) including highly variable Type 2 K4 repeats where the number of repeats are genetically determined. In general, larger alleles with a greater number of K4 repeats correlates with lower plasma Lp(a) levels. On the other hand, smaller alleles with fewer K4 repeats are associated with higher plasma Lp(a) levels, and thus, leads to an increased risk for CVD. This is an example of the relationship between Lp(a) and allele‐specific apo(a) levels. The figure shows two scenarios, both with the same plasma Lp(a) level. In the first, an individual with a plasma Lp(a) level of 50 mg/dL, carrying two different apo(a) allele sizes—20 and 36 K4 repeats, with the smaller protein contributing 70% of the plasma level, would have an allele‐specific apo(a) level of 35 mg/dL for the larger apo(a) size, and an allele‐specific apo(a) level of 15 mg/dL corresponding to the smaller apo(a) size. In the second scenario, the proportions are inverse.

The exact pathways of synthesis and metabolism of Lp(a) remains to be elucidated. Studies support the concept that Lp(a) levels are primarily determined by the synthetic rate and that Lp(a) is primarily synthesized in the liver—hepatocytes synthesize apo(a) and the association with apo B‐100 particles occur at the cell surface, although some studies have suggested an intrahepatic Lp(a) formation. 59 , 60 Smaller apo(a) particles are more efficiently secreted from the hepatocytes than particles with higher molecular weight. Further, the production rate of Lp(a) is determined by the capacity of the allelic variants to escape from endoplasmic reticulum. 61 Beyond hepatic Lp(a) catabolism, there is a likely dynamic relation to LDL metabolism and apo(a) may exchange between Lp(a) and LDL particles. Thus, Schaefer et al. hypothesized that apo(a) does not remain covalently linked to a single apo B‐100 lipoprotein but that it rather reassociates at least once with another apo B‐100 particle, probably newly synthesized, during its plasma metabolism. 62 It has been shown that fractions of “free” circulating apo(a), composed of interchangeable repetitions of K‐IV type 2 structures are present. 63 As pointed out above, due to interference by apo(a), the LDL receptor pathway does not to any major extend contribute to Lp(a) clearance, although it may contribute to clearance of the core LDL‐like moiety.

Allele‐Specific Apo(a) Levels and Inflammation

It is well known that the apo(a) gene contains response elements for inflammatory factors such as Interleukin‐6 (IL‐6). 64 , 65 However, the role of Lp(a) as an acute phase reactant is controversial, and the effect of inflammation on allele‐specific apo(a) levels is largely unknown. 66 , 67 , 68 , 69 Inflammation is a complex phenomenon involving multiple cytokines and acute phase reactants, such as CRP and fibrinogen, which have commonly been used as well established and robust markers of inflammation. 70 , 71 , 72 , 73 , 74 Under extreme condition, such as sepsis, Lp(a) levels decrease along with those of other lipids, 66 however, under more moderate inflammatory conditions, both an increase or no change in Lp(a) levels have been reported. 67 , 68 , 69 A recent report demonstrated that a combination of high Lp(a) levels with a high level of either CRP or fibrinogen was associated with an increased risk for CAD. 75 Further, Tsimikas et al. have shown that Lp(a) levels increased significantly during an extended postmyocardial infarction period. 37 Taken together, these results suggest the possibility of an interaction between Lp(a) and inflammatory markers and further, that presence of inflammation might modulate risk factor properties of Lp(a).

We have shown that presence of inflammation as detected by increased levels of CRP and fibrinogen was associated with increased Lp(a) levels among African Americans.76 This increase was explained by higher allele‐specific apo(a) levels for medium apo(a) sizes (22–30 K4 repeats) in African Americans, but not in Caucasians. Our findings suggest that inflammation—associated events may selectively affect apo(a) levels representing specific apo(a) genotypes in African Americans. Further, as this segment of apo(a) sizes largely explains the interethnic differences in Lp(a) levels, our results provide a potential explanation for differences in Lp(a) levels between African Americans and Caucasians. The mechanism for an impact of inflammation on Lp(a) remains unknown. Ramharack et al. have reported that Lp(a) and apo(a) mRNA levels in primary monkey hepatocyte culture are responsive to cytokines. Thus, in vivo Lp(a) levels can be positively (IL‐6) or negatively transforming growth factor‐beta 1 and tumor necrosis factor‐alpha (TGF‐β1 and TNF‐α) regulated by physiological levels of cytokines. 64 Our finding is to our knowledge the first report on inflammation and allele‐specific apo(a) levels, and has several implications. First, it suggests that proinflammatory conditions may impact differently on Lp(a) levels in African Americans and Caucasians. Second, the effect was limited to a range of apo(a) sizes, suggesting the possibility of an interaction between an inflammatory stimulus and genetic factors. Further studies are needed to verify these results in other populations and explore whether such events may impact on the role of Lp(a) as risk factor.

Treatment Possibilities

Although Lp(a) has not been established as a cardiovascular risk factor and no guidelines presently recommend intervention, 77 a growing number of studies implicate a role for Lp(a) as a cardiovascular risk factor. Our current level of understanding would suggest that Lp(a) lowering might be beneficial perhaps in subgroups of patients with high Lp(a) levels, but details on how to define such subgroups with regard to Lp(a) levels, apo(a) size, and presence of other risk factors are still lacking. Further, a target Lp(a) level has not been defined. Many well‐known lipid‐lowering drugs are ineffective in lowering Lp(a) levels. 78 Nicotinic acid, or niacin, is the only approved major hypolipidemic agent that has proven efficacy in lowering Lp(a) levels. 79 The Lp(a)‐lowering effect of niacin is graded and dose‐dependent, with a 25% decrease in Lp(a) with 2 g/day and 38% decrease with 4 g/day. 79 However, use of niacin is commonly associated with broad range of side effects such as flushing, pruritus, and hyperuricemia, and thus requires a careful pharmacological management. 80 Recently, extended‐release niacin was approved by the US Food and Drug Administration (FDA). It has shown to have fewer dose‐limiting adverse effects than regular or immediate‐release niacin. 81 Pan et al., determined Lp(a) responses to extended‐release niacin in the diabetic patients with Lp(a) levels greater than 25 mg/dL, and demonstrated a significant reduce in Lp(a) levels (from 37 ± 10 mg/dL to 23 ± 10 mg/dL, p < 0.001). 82 Dietary approaches to decrease plasma Lp(a) levels have generally been disappointing, and somewhat counterintuitive, diets rich in trans‐monounsaturated fatty acids have been shown to raise Lp(a) levels. 83 , 84 Several types of hormones have been found to affect Lp(a) levels. Androgens, such as danazol and tibolone, significantly reduce Lp(a) levels, 85 , 86 , 87 while estrogen treatment has been reported to decrease Lp(a) levels by 50%. 88 In a recent study, Danik et al. addressed the effect of hormone replacement therapy (HT) on Lp(a) and cardiovascular risk. 89 The authors showed that Lp(a) values were lower among women taking HT, and explored the effect of HT on the relationship of Lp(a) with CVD. In women not taking HT, the hazard ratio of future CVD for the highest Lp(a) quintile compared to the lowest quintile was 1.77 (p < 0.0001 for trend). In contrast, among women taking HT there were no such significant association with CVD. This observation suggests that there may be a threshold effect in the role of Lp(a) as a risk factor. It has been reported that a combination of estrogen and progestin appears to have more favorable effect in women with high initial Lp(a) levels and this effect occurs among women with known CAD. 90 Further intervention studies are needed to assess any possible therapeutic benefits of a reduction of Lp(a) levels. However, the interaction observed between LDL cholesterol and Lp(a) in some studies, as described above, suggests that an aggressive LDL‐lowering approach might be beneficial in reducing any risk associated with Lp(a). Thus, a common clinical approach in addressing high Lp(a) levels in subjects at risk for cardiovascular disease is to aggressively treat other risk factors such as high LDL cholesterol, although at present the scientific basis for this is not fully substantiated.

Conclusions

More than 45 years after the initial identification of Lp(a) by Kåre Berg, and over 20 years after the genetic sequence of apo(a) was reported by McLean et al., Lp(a) remains an enigmatic lipoprotein. Although a risk factor role of Lp(a) for cardiovascular disease has been controversial, studies during the past decade have provided robust support for a role of Lp(a) in promoting CVD. Despite its recognition as a risk factor for CVD, the atherogenic mechanism for Lp(a) is poorly understood. The substantial heterogeneity in apo(a) gene size and considerable variability in the contribution of apo(a) size to plasma Lp(a) levels post significant challenges. This underscores the importance of isoform‐specific or allele‐specific apo(a) levels, that is, the amount of Lp(a) associated with each apo(a) size allele. Further, Lp(a) particles with smaller, compared with larger, apo(a) isoforms may be a stronger risk factor for CVD. Although plasma Lp(a) levels are to a major extent regulated by genetic factors, some metabolic and environmental factors, such as diet and exercise, together with proinflammatory conditions have been shown to impact Lp(a). These alterations in Lp(a) levels may in turn enhance its proatherogenic properties and lead to increased risk for CVD ( Figure 2 ). Future population‐based and metabolic studies are warranted to understand how Lp(a) participates in the development of atherosclerosis, and how apo(a) molecular properties may modulate the Lp(a) risk factor role.

Figure 2.

Figure 2

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Regulation of plasma Lp(a) levels. Although plasma Lp(a) levels are to major extent regulated by genetic factors, some metabolic and environmental factors, such as diet and exercise, together with proinflammatory conditions can modulate risk factor properties of Lp(a). These alterations in Lp(a) may in turn enhance its proatherogenic properties and lead to increased risk for CVD.

Acknowledgments

Supported by grants HL 65938 and 62705 (PI: L Berglund) from the National Heart, Lung, and Blood Institute. This work was supported by the UC Davis Clinical and Translational Research Center (RR024146). E Anuurad is a recipient of an UC Davis Clinical and Translational Science Center K12 Award (RR024144).

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