INTRODUCTION
The clinical interest in Lp(a) is largely derived from its role as a cardiovascular risk factor. Although not considered an established risk factor, Lp(a) levels have been associated with cardiovascular disease in numerous studies.
Recently Lp(a) serum levels were found to be associated with the severity of aortic atherosclerosis, especially in abdominal aorta, as well as coronary atherosclerosis and is involved in the development of atherothrombosis and activation of acute inflammation, exerting a proatherogenic and hypofibrinolytic effect. Lp(a) even plays a critical role in the proinflammatory reaction and can be considered as a common joint among different metabolic systems.
Lipoprotein(a) as a potential causal genetic risk factor of cardiovascular disease: a rationale for increased efforts to understand its pathophysiology and develop targeted therapies, 2012
GENETICS
The LPA gene evolved from the Plasminogen (PLG) gene during primate evolution about 40 million years ago and is only present in Old World monkeys and primates (including humans). PLG contains five types of K domains (KI–KV) and a protease domain. The PLG gene has been duplicated and extensively remodeled during the evolution of the human LPA gene, and KI, KII and KIII have been lost whereas KV has been retained in single copy and KIV has expanded and diversified by mutation into 10 different types (KIV types 1–10). One of these, the KIV-2 domain exists in multiple copies. The number of copies is variable, ranging from two to >40 in one allele. Therefore, few individuals have two alleles of identical copy number in their genomes. The resulting polymorphism represents a rare type of copy number variation (CNV), and heterozygosity is >95% in most populations; thus, this CNV is very informative in terms of genetic heritability.
The resulting size polymorphism of apo(a) can be determined by immunoblotting from plasma. This not only allows an indirect estimate of the number of KIV-2 repeats but also provides information on the amount of apo(a) contributed by each allele: the fewer the repeats in the apolipoprotein(a) gene, the higher the plasma levels of Lp(a).
Lipoprotein(a): resurrected by genetics, 2012
STRUCTURE
Lipoprotein(a) is a plasma lipoprotein consisting of an LDL-like particle to which apolipoprotein(a) is covalently linked (disulfide bond). The LDL-like moiety is composed of a central core of cholesteryl esters (CE) and triglycerides (TG) surrounded by phospholipids (PL), free cholesterol (FC), and a single molecule of apolipoprotein B (apoB100).
METABOLISM
Apolipoprotein(a) is synthesized exclusively by the liver. The site of assembly with apoB in LDL is still debated but may include the secretory pathway of the hepatocyte, the hepatocyte plasma membrane, the space of Disse or the plasma compartment. Enzymatic activity, catalyzing disulphide bond formation between apoB in LDL and apo(a), has been identified and the assembly of Lp(a) most likely occurs at the hepatocyte surface or in plasma and proceeds in two steps: first, apo (a) docks to LDL, and then a disulphide bond is formed between KIV-9 of apo(a) and apoB of LDL.
Differences in Lp(a) plasma levels are caused by differences in the synthetic rate for isoforms of different size. Variation in Lp(a) concentrations amongst individuals with isoforms of identical size is also determined by the rate of Lp(a) production rather than by differences in the catalytic rate and this suggests that KIV-2 repeat number, as well as the sequence variation, affects the synthetic rate.
In contrast to the site of synthesis, it is unclear how and where Lp(a) is removed from plasma. Although binding to several members of the LDL receptor (LDLR) family including VLDLR/megalin and the LDLR itself has been demonstrated , it is unknown whether or to which extend these LDLRs function as Lp(a) receptors in vivo. Binding to the LDLR was not confirmed in several studies, but a ‘hitchhiking-like process’ whereby Lp(a) attached to LDL is removed by the LDLR pathway has been proposed . The observations that Lp(a) level is elevated in patients with familial hypercholesterolaemia (FH) caused by LDLR mutations, provide indirect evidence that the LDLR may be involved in vivo. On the other hand, statins, which cause an upregulation of LDLR, markedly decrease levels of LDL cholesterol (LDL-C) but not Lp(a). The findings of an arteriovenous difference in Lp(a) concentrations in the renal circulation, of apo(a) fragments in urine and of disturbed Lp(a) metabolism in kidney disease have suggested a major role of the kidney in Lp(a) catabolism.
Median and mean Lp(a) concentrations differ by up to fourfold between ethnic groups. Populations of sub-Saharan African descent have the highest reported levels whereas concentrations in Europeans are much lower.
Studies on the role of specific cell surface receptors in the removal of lipoprotein(a) in man, 1983
The inverse association of plasma lipoprotein(a) concentrations with apolipoprotein( a) isoform size is not due to differences in Lp(a) catabolism but to differences in production rate, 1994
LDL-mediated interaction of Lp[a] with HepG2 cells: a novel fluorescence microscopy approach, 1997
PHYSIOLOGICAL ROLE
The physiological function of Lp(a) remains unknown.
Probably, Lp(a) may provide a link between the cholesterol transport system in plasma and the fibrinolytic system and act as a modulator of the delicate balance between blood clotting and fibrinolysis. Numerous studies have tested the latter hypothesis and demonstrated, at least in vitro, that Lp(a) indeed interferes with the blood clotting/fibrinolytic cascades at several steps . The reported functions of Lp(a) include inhibition of streptokinase- and urokinase-mediated activation of PLG by the tissue-type PLG activator (t-PA), inhibition of t-PA in solution, fibrin and fibrinogen binding (throughout lysine-binding sites in KIV-8 and KIV-10), competition with PLG and t-PA binding for soluble fibrinogen, competition with PLG for binding to cellular receptors and enhancement of activity of the PLG activator inhibitor PAI-1. Lipoprotein(a)/apo(a) also interacts with several components of the extracellular matrix, including fibrin, fibronectin, tetranectin and proteoglycans, and binds to β2-glycoprotein.
In particular binding of Lp(a) to fibrin is supposed to be a mechanism to deliver cholesterol to sites of injury and wound healing. A negative side effect of this beneficial property might be deposition of cholesterol in growing atherosclerotic plaques by Lp(a) as well as inhibition of fibrinolysis at the plaque surface.
Furthermore, high Lp(a) levels impair activation of transforming growth factor-β by downregulation of plasmin generation, thereby contributing to smooth muscle cell proliferation.
An unexpected and intriguing observation is the binding of oxidized phospholipids (OxPls) to Lp(a). The binding site for OxPls has been identified in the protein moiety of Lp(a), specifically in the KV domain of apo(a). Levels of Lp(a) and OxPls in human plasma are highly correlated, suggesting that individuals with high Lp(a) levels have a higher binding capacity for OxPls and higher OxPls plasma levels; this association also results in an association between OxPl levels and cardiovascular disease (CVD). OxPls on apoB-containing lipoproteins, which reflect Lp(a), have therefore been suggested as biomarkers to predict CVD.
However, individuals without Lp(a) or with very low Lp(a) levels seem to be healthy. Thus plasma Lp(a) is certainly not vital, at least under normal environmental conditions.
Novel insights into Lp(a) physiology and pathogenicity: more questions than answers?, 2006
Lipoprotein(a) in Cardiovascular Diseases, 2013
PATHOGENESIS
There is no doubt that high Lp(a) levels increase the risk of CVD, probably because of its atherogenic and thrombogenic role.
Lp(a) may act as a proinflammatory mediator that augments the lesion formation in atherosclerotic plaques and may lead to an inflammatory process by inducing the expression of adhesion molecules on endothelial cells and the chemotaxis of monocytes. Moreover, this protein can augment the production of cytokines by vascular cells, and through the autocrine and paracrine mechanisms, the inflammatory reaction may lead to a vicious cycle resulting in lesion progression.
As the atherosclerotic plaque progresses, growth factors and cytokines secreted by macrophages and foam cells in the plaque stimulate vascular smooth muscle cell growth and interstitial collagen synthesis. Moreover, the apo(a) component of Lp(a) has been shown to enhance the expression of ICAM- 1; the expression of adhesion molecules contributes not only to initiation but also to progression of atherosclerotic plaque formation and triggering of cardiovascular events. Thus, these effects on endothelial cell function may provide mechanisms by which Lp(a) contributes to the development of atherosclerotic lesions; indeed, after transfer from plasma into the arterial intima, Lp(a) may be more avidly retained than LDL as it binds to the extracellular matrix not only through apolipoprotein(a), but also via its apolipoprotein B component, thereby contributing cholesterol to the expanding atherosclerotic plaque . The endothelial disfunction leads to reduction in nitric oxide (NO) availability and this increases oxidant excess, initiates the activation of matrix metalloproteinases MMP-2 and MMP-9 and further reduces inhibition of platelet aggregation. Moreover, Lp(a) enhances the synthesis of PAI-1 by endothelial cells, the main inhibitor of the fibrinolytic system, and reduce the activation of latent transforming growth factor-beta (TGF-beta) by displacing plasminogen from the surfaces of macrophages in atherosclerotic plaques. In the absence of activated TGF-beta, cytokines might induce smooth muscle cell proliferation and the transformation of these cells to a more atherogenic cellular phenotype.
Vasodilation is inhibited by ox-Lp(a) and the elevation of ox-Lp(a) may explain the endothelial dysfunction observed in hypertensive patients because ox- Lp(a) enhanced Lp(a)-induced PAI-1 production in vascular endothelial cells.
Accumulation of native Lp(a) may enhance the stimulation of ox-Lp(a), a more potent atherogenic lipoprotein, in the vessel wall.
Lp(a) acts on the fibrinolytic system in several ways which include the inhibition of plasminogen binding and activation, thereby impairing fibrinolytic activity and the dissolution of thrombi. High concentrations of Lp(a) might increase the risk of thrombus formation by impeding fibrinolytic mechanisms in the region of the plaque. Moreover Lp(a) inhibits plasminogen binding to the surfaces of endothelial cells and decreases the activity of fibrindependent t-PA. Furthermore Lp(a) increases plasminogen activator inhibitor activity in endothelial cells and promotes atherothrombosis. Other functions have been related to recruitment of inflammatory cells through interaction with Mac-1 integrin, angiogenesis, and wound healing.
Atherogenecity of lipoprotein(a) and oxidized low density lipoprotein: insight from in vivo studies of arterial wall influx, degradation and efflux, 1999
Lipoprotein(a) in Cardiovascular Diseases, 2013
CLINICAL USE
The clinical interest in Lp(a) is largely derived from its role as a cardiovascular risk factor. Although not considered an established risk factor, Lp(a) levels have been associated with cardiovascular disease in numerous studies.
For instance, a task force for emerging risk factor assessed the causal relationship between two Lp(a) variants (rs 10455872 and rs3798220), increased Lp(a) concentration, decreased lipoprotein size and increased risk of coronary disease. In this study the researchers confirmed that the linear dose–response relationship of the LPA variants with both the Lp(a) lipoprotein level and the risk of coronary disease provided compelling support for a causal role of an elevated plasma level of Lp(a) lipoprotein in the risk of coronary disease.
Because of this, periodical determination of Lp(a) values in subjects with coronary disease may be useful in order to predict further acute vascular events and these levels should be a marker of restenosis after percutaneous transluminal coronary angioplasty, saphenous vein bypass graft atherosclerosis, and accelerated coronary atherosclerosis of cardiac transplantation.
However it’s important to consider that although Lp(a) levels differ between ethnic groups, and thus results from one study may not be applicable to other ethnic groups, recent recommendations stated that Lp(a) screening is not warranted for primary prevention and assessment of cardiovascular risk at present, but that Lp(a) measurements can be useful in patients with a strong family history of cardiovascular disease or if risk of cardiovascular disease is considered intermediate on the basis of conventional risk factors.
There are continuous, independent, and modest associations of Lp(a) concentration with risk of CHD and stroke that appear exclusive to vascular outcomes. The Copenhagen City Heart Study (CCHS) found that extreme Lp(a) levels > 95th percentile predict a 3-to 4-fold increase in risk of myocardial infarction (MI) and absolute 10-year risks of 20% and 35% in high-risk women and men. In this study it was observed larger risk estimate for Lp(a) than most previous studies, most likely because the authors focused on extreme levels, measured levels shortly after sampling, corrected for regression dilution bias, and considered MI rather than ischemic heart disease (IHD). For the first time CCHS provided absolute 10-year risk estimates in the general population for MI and IHD as a function of Lp(a) levels stratifed for other risk factors, allowing clinicians to use extreme Lp(a) levels in risk assessment of individual patients.
Typical distributions of lipoprotein(a) levels in the general population. These graphs are based on non-fasting fresh serum samples from 3000 men and 3000 women from the Copenhagen General Population Study collected from 2003 through 2004. Green colour indicates levels below the 80th percentile, whereas red colour indicates levels above.
Genetic variants associated with Lp(a) lipoprotein level and coronary disease, 2009
Genetically elevated lipoprotein(a) and increased risk of myocardial infarction, 2009
Giulia Sbiroli e Marco Praz
