Journal of Lipids

Journal of Lipids / 2020 / Article

Review Article | Open Access

Volume 2020 |Article ID 3491764 | 26 pages | https://doi.org/10.1155/2020/3491764

Lipoprotein(a) the Insurgent: A New Insight into the Structure, Function, Metabolism, Pathogenicity, and Medications Affecting Lipoprotein(a) Molecule

Academic Editor: Xian-Cheng Jiang
Received26 Jun 2019
Accepted17 Aug 2019
Published01 Feb 2020

Abstract

Lipoprotein(a) [Lp(a)], aka “Lp little a”, was discovered in the 1960s in the lab of the Norwegian physician Kåre Berg. Since then, we have greatly improved our knowledge of lipids and cardiovascular disease (CVD). Lp(a) is an enigmatic class of lipoprotein that is exclusively formed in the liver and comprises two main components, a single copy of apolipoprotein (apo) B-100 (apo-B100) tethered to a single copy of a protein denoted as apolipoprotein(a) apo(a). Plasma levels of Lp(a) increase soon after birth to a steady concentration within a few months of life. In adults, Lp(a) levels range widely from <2 to 2500 mg/L. Evidence that elevated Lp(a) levels >300 mg/L contribute to CVD is significant. The improvement of isoform-independent assays, together with the insight from epidemiologic studies, meta-analyses, genome-wide association studies, and Mendelian randomization studies, has established Lp(a) as the single most common independent genetically inherited causal risk factor for CVD. This breakthrough elevated Lp(a) from a biomarker of atherosclerotic risk to a target of therapy. With the emergence of promising second-generation antisense therapy, we hope that we can answer the question of whether Lp(a) is ready for prime-time clinic use. In this review, we present an update on the metabolism, pathophysiology, and current/future medical interventions for high levels of Lp(a).

1. Introduction

Atherosclerosis is a chronic inflammatory lipid-fueled disease of the arteries that is initiated very early in childhood and mediated by innate and adaptive immune responses. Atherosclerosis is characterized by progressive accumulation of lipids, necrotic cell debris, and extracellular matrix proteins in the vessel wall and eventually results in partial or total vessel occlusion or thrombosis due to rupture or erosion of the atherosclerotic plaque. Atherosclerosis reveals itself clinically later in life and is influenced by genetic, environmental, behavioral, and dietary risk factors [13]. The main risk factors for atherosclerosis include hypercholesterolemia, diabetes, cigarette smoking, and hypertension. Hypercholesterolemia, for instance, increases the permeability of the vessel walls and initiates the pathogenesis of the disease [4]. The Framingham study showed that low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C) are the major independent predictors of future atherosclerotic events [4]. The need to pinpoint further causal risk factors and thus prospective targets for future interventions is evident [5] by the fact that atherosclerosis is the still the principal cause of cardiovascular disease (CVD) death worldwide despite the decline in mortality rate due to advances in its diagnosis, treatment, prevention, and rehabilitation [6, 7]. Currently, lipoprotein(a) [Lp(a)], aka “Lp little a”, is considered a likely candidate and independent strong predictor of atherosclerosis.

Lp(a) was first discovered by the Norwegian physician Kåre Berg almost six decades ago [8]. It is an enigmatic class of lipoprotein particles found in plasma and is assumed to be a genetic variant of LDL [9]. The Lp(a) protein moiety comprises two components, a single copy of apolipoprotein (apo) B-100 (apo-B100) tethered to a single copy of a protein denoted as apolipoprotein(a) [apo(a)]. Apo(a) is a polymorphic glycoprotein and carbohydrate-rich moiety whose mRNA is expressed almost entirely in the liver [10]. Lp(a) also has a lipoprotein unit that is essentially identical to LDL both in make-up and in its physical and chemical characteristics [11]. Because Lp(a) and LDL are metabolically distinct due to the presence of apo(a), the special properties of Lp(a), including its mass and density heterogeneity, are virtually totally produced by apo(a) [11]. The discovery that apo(a) has homology with plasminogen (PLG), a substantial enzyme in fibrinolysis, suggested a theoretical association between Lp(a) and thrombosis [12]. The gene controlling the plasma Lp(a) concentration is the LPA gene, which evolved through replication and modification of the kringle (K) domains of the PLG gene. In contrast to LDL-C, which follows a normal Gaussian distribution in the population, Lp(a) levels skew toward lower values in most populations studied to date [13], with most individuals with low Lp(a) levels and a tail of individuals who display high Lp(a) levels and corresponding prominent CVD risk [14]. Ethnicity powerfully impacts Lp(a) plasma concentrations: Caucasians tend to have the lowest Lp(a) levels, and African Americans have the highest [14]. However, it has become clear that the risk of developing coronary artery disease (CAD) in Caucasians is more than two times higher in individuals with increased Lp(a) levels [15, 16]. Several Mendelian randomization studies and meta-analyses have shown undoubted proof that elevated Lp(a) plasma concentrations are correlated with an amplified risk of myocardial infarction, stroke, and aortic valve stenosis [17]. Notwithstanding extensive investigations, the causal mechanisms behind how Lp(a) giving rise to atherosclerotic vascular diseases are still partly understood [18]. In this review, we present an update on the metabolism, pathophysiology and current/future medical interventions for high Lp(a) levels.

2. Lp(a) Molecule

2.1. Structure of Lp(a) Molecule

Lp(a) has multiple components (see Figure 1(a)) and mainly resembles and consists of an LDL-C molecule. Similar to LDL, Lp(a) has a hydrophilic apo-B100 component located around a lipid core of cholesteryl esters (CEs) and triacylglycerols with many phospholipids and unesterified cholesterol at its surface [19]. According to Siekmeier et al. [20], “corresponding to the physical resemblance to LDL, both lipoproteins are very indistinguishable to each other with respect to their structure” [21] (see Figure 1(b)). However, Lp(a) is distinguished from LDL-C by its hydrophilic highly glycosylated apo(a) portion (the PLG-like pathogenic component of Lp(a)) [17]. In fact, the presence of apo(a) distinguishes Lp(a) from all other lipoprotein classes [22]. Apo(a) is covalently connected to apo-B100 via a single disulfide thioester bond through cysteine residues located in both proteins [18, 23], and these residues represent 88% of the total protein mass in Lp(a) [24]. Apo(a) is the key component of Lp(a) and evolved from the PLG gene superfamily a very long time ago through duplication and remodeling. Apo(a) existence imparts distinctive synthetic, catabolic, and functional characteristics along with a huge size heterogeneity [1719, 23]. In addition to apo(a) and apo-B100, a recent proteomic study has shown that Lp(a) has 33 more proteins associated with its surface that might be involved in lipid metabolism processes, inflammatory response, and coagulation processes [25].

2.2. Similarity to Plasminogen

The protease zymogen PLG acts like a proenzyme that is transformed to the fibrinolytic enzyme plasmin by a ternary multicomponent protein that is associated with tissue PLG activator (tPA), PLG, and fibrin either endogenously or iatrogenically [17]. A previous examination of an apo(a) cDNA from a human hepatocyte library revealed that apo(a) has outstanding physical similarities with PLG [12, 19]. Apo(a) and PLG share high amino acid sequence similarity in several regions, including the protease domain and the Danish pastry-like structure referred to Kringles (K) type 4 (K4) and type 5 (K5) [19, 23]. Each kringle contains six conserved cysteine residues that form three disulfide bonds to provide the characteristic triple loop structure of the kringles [22]. These loop-like structures are also present in other coagulation factors, such as PLG, prothrombin, urokinase, and tissue-type PLG activators [8]. In contrast, PLG also has three more Kringles (K1 to K3) (see Figure 1(a)). Unlike PLG, apo(a) contains 10 subtypes of K4 (KIV1 to KIV10); KIV1 and KIV3 to KIV10 have a single copy, and KIV2 has repeated copies. Each KIV repeat contains three internal disulfide bonds, one N-linked bond, and six potential O-linked glycosylation sites [26]. It is noteworthy that apo(a) has an inactive serine protease-like domain that cannot be activated by tPA and urokinase PLG activator (uPA) to become an active plasmin even though it has an intact Ser-His-Asp triad [27, 28]. This characteristic may suggest that Lp(a) can hamper the physiologic properties of PLG in the fibrinolytic cascade [27]. This characteristic may suggest that Lp(a) can hamper the physiologic properties of PLG in the fibrinolytic cascade [27].

2.3. The Functions of Specific Kringles

The kringles on apo(a) serve critical functions (e.g., KIV10 is responsible for the important lysine-binding properties of Lp(a)). Several other kringles play critical pathobiological roles, such as KIV(6-7), which interact with scavenger receptors on foam cells [29]. This interaction results in the secretion of proinflammatory cytokines, such as interleukin (IL)-1, IL-6, and matrix metalloproteinases (MMPs), which can amplify the local inflammatory response and stimulate vascular smooth muscle cell (VSMC) proliferation and initial migration toward the atherosclerotic lesion [13, 29, 30]. Moreover, KIV(7-8) are essential for Lp(a) formation due to the weak lysine binding sites (LBS) among these Kringles [29]. LBS are critical in the creation of the noncovalent apo(a)-LDL complex by allowing the free cysteine in KIV9 to form a covalent disulfide bridge to the apo-B100 component of LDL. The presence of strong LBS within these Kringles, particularly in KIV10, significantly enhances the capacity of Lp(a) to attach to and remain in vessel wall cells and fibrin and may thus be crucial to the atherothrombotic nature of Lp(a) [29].

2.4. The Influence of the LPA Gene on Size and Concentration

Inheritance of the Lp(a) molecule is dominant and was initially described as a dichotomous and qualitative (Lp+, Lp−) genetic trait [8]. However, it soon became apparent that the genetic variation is related to the levels of Lp(a) in the sera of different individuals (quantitative) rather than to the simple presence or absence of the Lp(a) molecule (qualitative) [31, 32]. The gene that retains 90% of the control of apo(a) levels [33] is the LPA gene, which is located at positions 26 and 27 on the long arm of chromosome 6 (6q26-27) [23]. In fact, the LPA gene is one of the most potent monogenetic risk factors for CAD regardless of race [17]. No other quantitative trait is as influenced by sequence differences at a single locus as is Lp(a) [33]. This gene is accountable for the substantial size heterogeneity of apo(a) isoforms [34], which is associated with the variable number of copies (repeats) of kringle KIV2, ranging from 2 to more than 50 repeats with substantial size polymorphism (200–800 kilodaltons) [35] (see Figure 2).

The largest apo(a) isoform described so far has 52–54 KIV repeats [36]. This size variability is a unique phenomenon, as other lipoproteins usually have constant masses [17]. Up to 80% of individuals carry two different size alleles of apo(a), each inherited from one parent [34]. Thus, individuals may have two large, two small, or mixed-size apo(a) molecules. Generally, within individuals, the smaller isoform contributes more to net apo(a) production and concentration than does the larger isoform [17, 34]. Consequently, apo(a) isoform size is inversely related to Lp(a) density and plasma concentration [19, 37, 38]. This relationship might occur because small apo(a) size results in easy secretion by the liver, which leads to higher Lp(a) concentration and increases the cardiovascular risk and vice versa [39].

3. Metabolism of Lipoprotein(a)

3.1. Synthesis of Lipoprotein(a)

Lp(a) synthesis occurs exclusively in the liver, and the LPA gene mainly influences Lp(a) production [18, 37, 40]. Many studies have confirmed that diet and environmental factors have minimal to no impact on Lp(a) [17]. According to Hobbs and White [33], the rate of apo(a) secretion is determined by different stages inside the hepatocyte: first, the transcription of the apo(a) gene and apo(a) mRNA stability stage; second, apo(a) translation, which is believed to have a dominant influence on the production rate; third, extensive posttranslation modifications, including the formation of three disulfide bonds and the addition of an N-linked glycan, which is essential for folding [26], of apo(a) kringles in the endoplasmic reticulum (ER) [33] and subsequent transport out of the ER [33]; fourth, transport to the Golgi complex, where N-linked and O-linked glycans are further processed [33]; fifth, Golgi-specific addition and modification of apo(a) carbohydrates [41]; and sixth, transport to the cell surface [42]. Many in vivostudies suggest that the third step is the most important step in the production of apo(a) [10, 43]. White and colleagues [43] have demonstrated using baboon liver cells that this inverted association could be accounted for by differences in the rate and the extent to which apo(a) isoform chains were processed through the ER. Specifically, these researchers verified that small apo(a) chains more completely and swiftly exit the ER than do large apo(a) chains [10].

3.2. Assembly of Lipoprotein(a)

Assembly is a two-step procedure. First, to promote, mediate, and reinforce the association between the two apo components of Lp(a), the apo(a)-cysteines (Cys-4057) located at KIV3–7 are positioned close to the only free cysteine (Cys-3734) in apo-B100 via a noncovalent interaction [36, 44]. Second, a covalent disulfide bridge is established between KIV9 of apo(a) and apo-B100 of the LDL component [44]. The site of assembly is controversial. The main theory is that assembly occurs either on the surface of the liver cells or in the space of Disse [45, 46]. White and Lanford [43] used primary cultures of baboon liver cells to analyze the stages of Lp(a) biogenesis. Their study proved that the Lp(a) association was extracellular because it was inhibited when anti-apo(a) serum was present in the culture medium [43]. In contrast, according to Frank et al. [47], mixing recombinants of apo(a) with LDL-C in vitro and incubating the mixture for a few minutes leads to the formation of an intact Lp(a) particle that is entirely similar to the native Lp(a). The latter theory leads to the assumption that assembly may occur in either the plasma or the interstitial space [44, 47, 48]. It is worth noting that although apo(a) is predominantly attached to LDL, 2–5% apo(a) is free and present in the plasma [49].

The new secreted apo(a) is associated with a recently produced apoB-containing TG-abundant molecule to form Lp(a) with very-low-density lipoprotein (VLDL) properties (see Figure 3), which can correspondingly be transformed into a cholesterol-abundant unit with LDL properties [43, 46]. Additionally, the linkage could directly occur with a molecule with LDL properties. In the bloodstream, the TG-abundant Lp(a) molecule is swiftly subjected to lipolysis by lipoprotein lipase to form a TG-remnant Lp(a) molecule that is directly catabolized, allowing apo(a) to be recycled [50] to the recently secreted apo(a) pool by the liver [46]. The recycled apo(a) then associates with an additional newly synthesized TG-abundant LDL molecule or is finally eliminated from the plasma by the liver or perhaps by the kidney [46]. TG synthesis may also be critical for the synthesis of apo(a) by hepatoma cells [51]. Understanding whether apo(a) binds to LDL within liver cells before or after secretion to the plasma and which apo-B100 containing lipoprotein is involved in Lp(a) assembly should be the focus of future studies to develop new Lp(a)-lowering therapies.

4. Catabolism

Lp(a) clearance is still one of the most fundamental targets of therapies to treat elevated plasma Lp(a). Unfortunately, little is known about the dominant sites and processes accountable for the removal of Lp(a) from circulation: scientists debate between the liver and kidneys as the dominant clearance sites. The spleen and the muscles may also play a modest role in the clearance process [36]. Numerous evidence from in vivo studies suggests that the variations in Lp(a) size and plasma concentration are related to apo(a) production rate and size [52] rather than on its very slow clearance rate [13, 26, 30, 31]. According to Diffenderfer and colleagues [46], apo(a) requires twice the residency time (11 days) required by apo-B100 (4 days), supporting the notion that the apo(a) and apo-B100 components of Lp(a) in circulation are not removed from the bloodstream as a unit in humans.

4.1. The Liver

The unique duality of the Lp(a) molecule’s structure allows Lp(a) to be recognized by multiple LDL and PLG receptors. It was initially thought that LDL receptor (LDLR) in the liver is responsible for the degradation of Lp(a). However, there is evidence that LDLR has minimal or no effect on Lp(a) catabolism [20]. Many kinetic studies have reported that Lp(a) has a longer circulating time than does LDL-C due to the small affinity of Lp(a) for LDLR [17, 20]. This low affinity occurs because the apo(a) component interferes with the positioning of the LDLR [17]. Second, many clinical studies have reported that increasing LDLR expression by using statins rather than proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors does not lower Lp(a) levels; however, PCSK9 inhibitor does [17, 53]. Other receptors, such as Megalin, gp330 receptor [53], macrophage scavenger receptor-BI [54], lipoprotein receptor (LRP-1) [55], VLDL receptor [46], and galactose-specific asialoglycoprotein receptor (ASGPR) [56] show affinity for Lp(a) and may be involved in Lp(a) internalization and clearance (see Figure 3).

The most novel clearance mechanism was presented recently by Sharma and colleagues [50] and involves PLG receptors PlgRKT and proteolytic cleavage and recycling of apo(a) Apparently, PlgRKT is responsible for the uptake and internalization of both circulating Lp(a) and apo(a) to the Rab5+ early endosome. Then, these researchers determined that the apo(a) component of Lp(a) is trafficked to the Golgi network and released via the Rab11+ endosome, which subsequently promotes the re-excretion of apo(a) to circulation and the trafficking of the LDL component to the lysosome for degradation [50]. This mechanism suggests that Lp(a) has a longer plasma residence time in circulation than does LDL [17] and support the theory that the liver is the final clearance organ for apo(a) if this component is not reassembled back into Lp(a) [50].

4.2. The Kidneys

Several in vivo studies have reported that the kidney plays a valuable role in Lp(a) metabolism [57, 58]. An important report has shown that Lp(a) levels are elevated and its clearance rate is lower in patients with end-stage renal disease undergoing hemodialysis. Urinary apo(a) levels significantly decrease once the glomerular filtration rate becomes <70 mL/min [59, 60]. Another important study used an in vivo approach by measuring Lp(a) plasma concentrations simultaneously in the ascending aorta and renal vein of one hundred patients undergoing coronary angiography or coronary angioplasty [61]. Lp(a) concentrations changed remarkably between the two vessels even after correcting for hemoconcentration, corresponding to a mean arteriovenous difference of −9% in the arterial concentration [61]. These results suggest that the atherogenic Lp(a) molecules are taken up by the kidney from renal circulation [61]. In familial hypercholesterolemia (FH) patients, LDL apheresis lessened plasma Lp(a) concentrations by up to 75% with an associated abrupt 45% decrease in urinary apo(a) [62]. The kidneys share with the liver some of the important receptors that show affinity for Lp(a) uptake, e.g., PlgRKT, Megalin, gp330 receptor, and VLDL receptor [46].

5. Physiological Functions of Lp(a)

5.1. The Role of Lp(a) in Angiogenesis and Tumor Growth

Several studies have reported that Lp(a) plays a significant role in angiogenesis and tumor growth [63–65]. The similarity between Lp(a) and PLG may decrease the activation of the proteases, which is mandatory for the activation of MMPs and the subsequent activation of angiogenesis [63]. An animal study conducted by Kim et al. [64] reported that Lp(a) plays a significant role in angiogenesis and tumor growth. These researchers demonstrated that recombined kringle fragments derived from apo(a), called rhLK68, significantly inhibit angiogenesis and angiogenesis-dependent tumor growth, but interfere with basic fibroblast growth factor (bFGF)-stimulated/mitogen-activated protein kinase (MAPK) signaling pathway in endothelial cells [64]. Furthermore, another study proved that apo(a) and its components present in the urine are favorably efficient inhibitors in tube forming assays, in vitro surrogate tests for angiogenesis [65]. On the other hand, other studies reported centenarians who did not suffer from CVD, suggesting that Lp(a) may also play a protective role against cancers [34, 66, 67].

5.2. Acute-Phase Reactant

Many studies have reported that Lp(a) levels increase in patients with acute pathologies, such as myocardial infarction, inflammatory bowel disease, and gallbladder fistula [21, 68–70]. One study exposed nine subjects with plasma Lp(a) concentrations between 64 and 177 mg/L to a single intravenous infusion of bisphosphonates previously liquefied in 250 mL of saline; these subjects showed a substantial increase in Lp(a), ESR, and CRP two days after intervention [71]. Moreover, Ramharack et al. [72] reported that modulation of Lp(a) by cytokines resulted in some significant changes in Lp(a) concentration in primary monkey hepatocytes. In this study, treatment with IL-6, the primary mediator of acute-phase responses, resulted in a marked two- to fourfold increase in Lp(a) concentration and mRNA expression in hepatocyte culture. Therefore, the inflammatory status should always be considered when interpreting Lp(a) assays results [21, 71, 72].

5.3. Binding and Carrying of Oxidized Phospholipids and LP-PLA2

Oxidized phospholipids (OxPLs) play a fundamental role in the early stages of atherosclerosis; they elicit robust proinflammatory responses in murine macrophages and monocytes and are capable of stimulating proinflammatory genes, leading to vascular inflammation [73]. Several studies have reported that OxPLs usually form on oxidizing LDL-C and apoptotic cell membranes and are released into circulation afterward [7476]. However, another important study suggested that Lp(a) and OxPLs would associate at the hepatocyte level and not in circulation [77]. Evidence from several studies has shown that Lp(a) has a unique protective physiological function, which is binding, carrying, and promoting the clearance of OxPLs [74, 75]. This occurs through the formation of a covalent bond between the KIV of the apo(a) fragment of Lp(a) and OxPLs [78].

5.4. Wound Healing

Wound healing is achieved by multiple complex processes. Many investigators have reported the positive role of Lp(a) in wound healing [20, 21, 79]. Yano et al. [79] measured the presence of Lp(a) in tissue during healing. They observed markedly positive staining of Lp(a) in healing tissues, especially in the fibrous cap surface, endothelial cells of small vessels, and the extracellular space [79], in the second stage of wound healing. Based on this evidence and given that Lp(a) levels are genetically determined and do not change due to diet or environmental factors, Lp(a) might be a considerable source of cholesterol for use in tissue regeneration and repair.

5.5. Fibrinolysis

Apo(a) isoforms share substantial structural and functional homology with PLG, the principal component of the fibrinolytic pathway, which is converted to plasmin for fibrinolysis [63]. This homology allows apo(a) to compete with PLG for fibrin affinity sites, as small apo(a) isoforms have a higher affinity for fibrin than do large apo(a) isoforms [80]. Additionally, Lp(a) stimulates the synthesis of PLG activator inhibitor-1 (PAI-1) to inhibit tPA and urinary-type (u-PA) PLG activators and consequently regulate PLG activation to plasmin [81]. These data shed light on the potential physiological role of Lp(a) in fibrinolysis, by which Lp(a) could give the injured tissue enough time to heal and regenerate.

6. The Pathogenicity of Lp(a)

Since the discovery of Lp(a), many basic scientists and clinicians have dedicated their work to explaining the hidden mechanisms that lead Lp(a) to cause atherosclerosis. The duality and uniqueness of Lp(a), which make Lp(a) homologous to both LDL-C and PLG, most likely underlie the different but related atherosclerosis mechanism theories. Most importantly, Lp(a) transmits all of the harmful atherogenic characteristics of LDL units, incorporating their tendency to oxidize before and after entry into the subintimal layer of the vessel walls and creating extremely proinflammatory oxidized Lp(a) [OxLp(a)] [17]. In fact, basic medical scientists and clinicians consider Lp(a) far more dangerous than LDL due to the presence of an apo(a) component within Lp(a). In this part of the review, we will discuss the different theories of how Lp(a) causes atherosclerosis. These different theories are summarized in Figure 4.

6.1. The Entry of Lp(a) into the Vascular Wall

Numerous in vivo kinetic studies have shown that radiolabeled human Lp(a) enters the intima at a similar rate as does LDL-C in normal and atherosclerotic vessels [82], similar to other lipoproteins, through modest molecular filtering without any receptors [83]. However, this entry depends on lipoprotein plasma concentrations, lipoprotein unit size, blood pressure, vessel wall permeability and Lp(a) residence time [82]. LDL-C entry into and accumulation in weak but normal vessels begin when LDL-C reaches a certain threshold as low as 60 mg/dL [84]. Lp(a), on the other hand, is present in dysfunctional atherosclerotic but not normal vessel walls, and these cells exhibit proinflammatory attributes, which suggests that Lp(a) plays a role later in the atherosclerotic process after lesions have developed [33]. For instance, Nielsen et al. [85] showed that balloon injury of the thoracic aorta of rabbits leads to accelerated accumulation of radiolabeled Lp(a) in comparison to radiolabeled LDL-C in the balloon-injured intimal wall [85]. Additionally, the loss rate of Lp(a) decreased more than that of LDL-C in atherosclerotic vessels [86]. However, this information does not explain why Lp(a) preferentially traps and accumulates at greater rates than does LDL-C. Recently, many researchers have suggested that this phenomenon occurs due to the long residency time for Lp(a) causes atherosclerosis.These different the long residency time for Lp(a) in comparison to that for LDL-C [83]. This long residency might be due to the enhanced and selective binding capacity of the abundant LBS in the apo(a) fragment of Lp(a) to the matrix intima and small blood clots (fibrin and glycosaminoglycan) in the injured vascular wall [83]. Additionally, this residency might be due to the recycling effect of apo(a) [50]. In fact, the presence of the LBS of Lp(a) was shown to be associated with potent focal deposition of Lp(a) in the vascular endothelial wall [87]. The mutation affecting the LBS of Lp(a) of KIV10 decreases the affinity of Lp(a) to the endothelial wall [88]. Indeed, this information reflects the importance of the role of apo(a) LBS in atherosclerosis pathogenicity. Additionally, under inflammation, leukocytes enhance the persistence and localization of Lp(a) by releasing a polypeptide named defensing [89]. Finally, in a recent study, scavenger receptor class B type 1 (SR-B1) was shown to transport LDL across the endothelial cell monolayer and thereby governed the transcytosis of LDL by the help of DOCK 4 and the buildup of LDL by artery wall macrophages [90]. This study will shed light on the role of SR-B1 on Lp(a) recruitment molecules to the endothelial wall.

6.2. Pro-Inflammatory and Proatherogenic Effects of Lp(a)

Although there are abundant data confirming that inflammation could elevate plasma Lp(a) concentrations, data have surfaced indicating that the presence of Lp(a), particularly its apo(a) fragment, causes vascular inflammation [18, 70, 73, 74, 91]. After Lp(a) enters the vessel’s walls, it undergoes some oxidation and modification processes. This oxidative effect occurs as a repercussion of existing in an aerobic environment. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and myeloperoxidase (MPO) play a vital role in the oxidation of Lp(a) by producing reactive oxygen species (ROS). The contact of lipoproteins with lipoxygenase (LPO) or ROS such as superoxide anion and hydrogen peroxide produces miscellaneous OxPL types that commence and augment the inflammatory response [92]. The oxidation and modification processes of Lp(a) influence its atherogenic characteristics by altering their catabolism to alter the catabolic rate, vessel wall retention, uptake by macrophages, and foam cell formation [93]. One of the significant modifications caused by oxidation is the alteration of receptor identification [94]. Thus, receptors no longer have the ability to identify the oxidized lipoproteins [94]. Subsequently, OxLp(a) triggers a sequence of pro-inflammatory events leading to the development and progression of atherosclerosis [73, 95]. OxLp(a) is then trapped within the intimal layer of the injured vessel, leading to its degradation by lipoprotein lipase, which liberates free fatty acids and monoacylglycerols, resulting in even more local inflammation [73]. It is worth mentioning that the diacylated and triacylated lipoproteins can be identified by Toll-like receptors (TLR-4) and pattern-recognition receptors (PPRs), which usually respond to attacking microorganisms and activate the inflammatory response [73, 9698].

6.2.1. Role of the Oxidized Phospholipids

One of the key constituents found both in the lipid phase and covalently bound to OxLp(a) in atherosclerotic lesion is OxPLs. However, atherosclerotic lesions are not the only locations where OxPLs are formed. Apoptosis of various cell types has been shown to be associated with OxPLs generated by NADPH oxidase for clearance by macrophages [96]. Thus, apoptotic cells are another source of OxPLs and may contribute to even more vessel inflammation and atherosclerosis [74, 75, 96]. A wealth of data from papers published in the last decade have documented the regulatory effect of phosphocholine (PC)-containing OxPLs on endothelial cell and macrophage function [18, 49, 51, 53, 75, 78, 99]. Moreover, abundant evidence has suggested that proinflammatory OxPLs are crucial contributors to the early stages of atherogenesis, such as adhesion molecule expression and immune system activation [100]. Additionally, OxPLs might play an important role in the late stages of atherogenesis, such as platelet aggregation and plaque disruption [100]. Furthermore, exposure of endothelial cells to OxPLs likewise reduces their production of nitric oxide, a crucial arbitrator of vascular wall relaxation [100]. Although OxPLs have some protective effects, such as the activation of prostaglandin E2 production and heme oxygenase 1 (HO-1) formation, OxPLs strongly accumulate under high concentrations of atherosclerotic lesions, which led us to conclude that the OxPL molecule is an atherosclerosis promotor [96, 99]. In 2008, Bergmark et al. [75] showed that among all apo-B100-containing lipoproteins, only Lp(a) preferentially scavenges and carries OxPLs for clearance through a covalent bond with PC-containing OxPLs in humans. This might be because Lp(a) contains the Lp-PLA2 enzyme, which is responsible for the cleavage of OxPL for degradation and platelet activating factor (PAF) catabolism [29]. Unfortunately, this protective effect is inversely related to Lp(a) size [29]. This information led us to believe that the potential protective effect when Lp(a) exceeds its normal concentration may become harmful and promote the pro-inflammatory atherogenic impact of OxPLs by delivering it to the injured vessels.

6.3. The Proposed Mechanisms of Endothelial Dysfunction, Inflammation and Atherosclerosis
6.3.1. Endothelial Permeability and Adhesion Molecule Expression

The OxPLs from the apo(a) fragment of OxLp(a) build up in the vascular wall and activate various cell types to express a specific set of proteins that may be involved in the inflammatory reaction through several signaling pathways in endothelial cells and macrophages [96]. The high concentration of OxPLs delivered under high levels of OxLp(a) and apo(a) make the endothelial cell monolayer permeable due to the activation of the Src kinase pathway, which phosphorylates vascular endothelial cadherin (VE-cadherin) (an essential protein for barrier function) [101]. VE-cadherin phosphorylation leads to disassociation of β-catenin and paxillin and thus disrupts the cell-cell junction complexes [101]. Another mechanism by which OxLp(a) with OxPLs disrupts the endothelial monolayer involves vascular endothelial growth factor receptor 2 (VEGFR2) activation. VEGFR2 activation subsequently leads to increased Rho/Rho kinase activation, which triggers the activation of myosin light chain (MLC) phosphorylation by Ca2+/calmodulin-activated MLC kinase (MLCK) [102] and inactivation of MLC phosphatase by direct phosphorylation of its 130-kDa regulatory subunit (MYPT1) [103]. This mechanism leads to the stimulation of actomyosin contractility, eventual endothelial cell retraction and the creation of openings between endothelial cells [104]. Additionally, OxPLs mediate occludin expression and phosphorylation in vascular endothelial cells, which lead to decreased tight junction interactions, increased permeability of the endothelial cells [105], and increased accumulation of additional Lp(a). Adhesion molecules play a major role in this mechanism. The interaction of OxPLs with the E-type prostaglandin receptor (EP2) causes an increase in cyclic AMP (cAMP) [106]. Subsequently, cAMP increases R-Ras activation by inhibiting H-Ras activation [106]. This step leads to the stimulation of phosphoinositide 3 kinase (PI3K), which subsequently leads to α5β1 stimulation on endothelial cells [107]. This causes the buildup of the connecting segment 1 (CS-1) fibronectin, an essential adhesion molecule associated with OxPL, on the apical surface of endothelial cells that binds the attracted monocytes [107]. It is worth mentioning that the association between OxPLs and vascular cell adhesion molecule-1 (VCAM-1) is modest and not detected in large vessels [108]. Indeed, other studies have reported that there is a calcium-dependent interaction of Lp(a) with cultured human coronary artery endothelial cells that does not appear to involve any of the apo(a) LBS that induce efficient surface expression of VCAM-1 and E-selectin adhesion molecules [109]. Moreover, several lines of evidence have shown that OxLp(a) could increase the expression of P-selectin and intercellular adhesion molecule-1 (ICAM-1) in cultured human umbilical vein endothelial cells and suggest its important role in atherogenesis [110, 111].

6.3.2. Cytokine Production

IL-8 and chemoattractant molecule 1 (MCP-1) are the chemokines that are responsible for facilitating and guiding the monocyte diapedeses between endothelial cells to infiltrate into the tunica intima or innermost layer of the vascular arterial wall [112]. OxPLs could rapidly induce OxPL MAPK phosphatase 1 (MKP1), thereby stimulating the production of MCP-1 [113]. OxPLs also activate metalloproteinases such as disintegrin and metalloproteinase 10 (ADAM 10) and disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4), which present on the endothelial cell surface [114]. This metalloproteinase activation leads to activation of heparin-binding EGF-like growth factor (HBEGF), which attaches to epidermal growth factor receptor (EGFR) to induce IL-8 synthesis [99, 114]. OxPLs also activate the 15-Lox1–15(S)-HETE axis, which leads to the production of ROS and thereby activates EGFR. EGFR then stimulates signal transducer and activator of transcription 3 (STAT3) phosphorylation through the activation of Src kinase, which eventually leads to MCP-1 expression and production [115]. Additionally, OxPLs elevate cytosolic calcium (Ca2+) levels, which are considered an initiator of many signaling pathways. Including the activation of peroxisome proliferator-activated receptor α (PPAR α), which eventually leads to the expression of IL-8 and MCP-1 [116118]. OxPLs could also activate the VEGFR2 pathway, leading to IL-8 and MCP-1 production. In contrast, Lp(a) and its pathogenic fragment apo(a) may independently induce chemoattraction for monocyte cells through a cGMP-dependent pathway [119] and by binding and carrying MCP-1 from the circulation to the vascular wall and may mediate chemoattraction [120]. Finally, Sotiriou et al. [121] reported that apo(a) interaction with β2-integrin Mac-1 promotes the adhesion of monocytes and their transendothelial migration in a Mac-1-dependent manner, especially in the presence of homocysteine.

According to Lee et al. [99], following the entry of monocytes into the intimal wall, the newly resident monocytes differentiate into several phenotypes of macrophages in the nascent atheroma. This differentiation occurs due to the activation of TLR-2, TLR-4, CD36, and PAF by OxPLs. The first phenotype of the newly differentiated macrophages is chemokine-producing M1 macrophage. It secretes additional MCP-1, macrophage inhibitor protein-2 (MIP-2), IL-1 beta (IL-1β), IL-12, inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNFα) and regulated upon activation, normal T-cell expressed, and secreted (RANTES) [91, 99, 122]. The Mox phenotype, which is characterized by antioxidant Nrf2-dependent gene expression may play a role in atherosclerosis [122]. Macrophages could also differentiate into dendritic cells that are not fully functional due to OxPL epigenetic mechanisms [123]. Lastly, the foam cell phenotype is formed by the activation of CD36. CD36 acts as a scavenger receptor and signaling mediator [124]. The foam cell signaling pathway triggers tyrosine protein kinase Lyn/Fyn followed by the stimulation of Vav group proteins, which are cytoplasmic guanine nucleotide exchange factors (GEFs) [99]. Interaction of Vav proteins with dynamin-2/PLC γ generates Ca2+ flux. Increased Ca2+ concentration leads to OxLp(a) internalization and foam cell formation [125] (which are hallmarks of early atherosclerotic lesions) [112].

6.3.3. Vascular Smooth Muscles

One of the key features of an advanced atherosclerotic lesion is pathological vascular wall remodeling [126]. Vascular wall remodeling involves VSMC phenotypic switching and endothelial barrier dysfunction. Alexander et al. [127] defined phenotypic switching “as a switch between a contractile to a synthetic state (macrophage-like) through repression of the SMC-selective contractile/cytoskeletal proteins that mark differentiated SMCs and concomitant increases in proliferation, migration, and matrix synthesis.” The VSMC differentiation marker includes smooth muscle (SM) actin α, SM myosin heavy chain, myocardin, and other components [127]. The goal of vascular SM remodeling in atherogenesis is to shield the foam cells that assemble under the endothelium and to promote the formation of a stable plaque with a thick fibrous cap, thereby protecting against plaque rupture and thrombosis [112, 128]. However, if the atherogenic stimuli persevere over the years, as they often do, the reparative response may become harmful, narrow the vascular lumen, reduce blood flow, and result in eventual ischemia [129].

Numerous previous studies have verified that human Lp(a), apo(a), and OxPLs promote the phenotypic switching, proliferation, and migration of VSMCs in atherosclerotic lesions [130]. OxPLs have been shown to increase MCP-1, IL-1β, and TNFα production via macrophage foam cells, which leads to an increase in the inflammatory state of VSMCs by promoting the production of IL-6 and multiple MMPs [109, 126]. IL-1β also modulates the VSMC phenotype to a distinct inflammatory phenotype through nuclear factor light-chain-enhancer of activated B cells (NF-ҡB)-dependent mechanisms [127]. Another mechanism by which OxLp(a), native Lp(a), and OxPLs mediate VSMC phenotypic switching involves the phosphorylation of extracellular signal-regulated kinase (ERK) [131], which leads to the activation of ETS-like transcription factor 1 (Elk-1), eventually repressing the SM α-actin gene and SM heavy chain marker [132]. Additionally, OxPLs might suppress the SM α-actin gene through Krüppel-like factor 4 (Klf4), which is involved in most phenotypic switching pathways [133] and eventually binds to histone deacetylases (HDACs), inhibiting the transcription of actin [132134]. Furthermore, several studies have shown that apo(a) inhibits transforming growth factor-β (TGF-β), which is a cytokine involved in the maintenance of normal endothelial and SMC phenotypes and functions [135].

Numerous pathways increase VSMC replication due to exposure to OxPLs and their constituents. Komai et al. [131] showed that Ox-Lp(a) significantly stimulated the growth of human VSMCs in a dose-dependent manner. Moreover, according to Zhao et al. [136], the upregulation of platelet-derived growth factor (PDGF-BB) by the native Lp(a) and especially OxLp(a) may be one of the most principal mechanisms accounting for the migration and proliferation of VSMCs and narrowing of the vasculature in atherosclerosis [136]. Another study was able to show that increased atherosclerosis in transgenic rabbits is associated with VSMC proliferation possibly related to impaired fibrinolytic activity by which Lp(a) build-up may inhibit plasmin and stimulate PAI-1 [130]. OxLp(a) and its OxPLs constituent may also promote VSMC proliferation through the phosphorylation of connexin 43 (Cx43) [137] and activation of galactosyltransferase-2 (GALT2) to produce lactosylceramide (LacCer) and eventually increase c-fos and proliferating cell nuclear antigen (PCNA) [99]. Regarding VSMC migration, the inhibition of TGF-β production due to the build-up of Lp(a) molecules reduces the inhibition of VSMC migration from media to the intima and thereby contributes to atherogenesis [138]. Finally, Ox-Lp(a) may promote VSMC migration through the expression of many extracellular matrix membrane proteins. Most importantly, type IIIV collagen causes OxPLs to activate SP-1 to activate the Klf4 pathway, eventually leading to the migration of VSMCs [139].

6.3.4. Cell Death

In advanced atherosclerotic lesions, macrophages and VSMCs die by programmed cell death (apoptosis) or necrosis. This cellular suicide leads to yet another enigmatic feature of atherosclerotic lesions in that the disintegration of these cells leads to the development of a weakening lipid-rich central pool and delicate and rupture-prone fibrous cap [123, 129]. OxPLs containing OxLp(a) and apo(a) largely contribute to cell death. They trigger ER-stressed macrophages mainly through the activation of CD36, TLR-2, and TLR-6, which subsequently activate the ERK/MAPK pathway [140]. OxPLs containing Ox-PL(a) are also more potent than oxidized LDL in the generation of ROS and thereby induce apoptosis [141]. ROS generation requires the activation of NADPH oxidase 2 (NOX2) through the activation yet again of the ERK/MAPK pathway [99]. Furthermore, OxLp(a) and its OxPLs may compromise the integrity of the mitochondria to activate the intrinsic apoptotic caspase cascade, thereby inducing macrophage apoptosis [142]. Regarding VSMCs, the results from Loidl and colleagues [128] indicate that activated acid sphingomyelinase is the central mediator in the OxPL-triggered signaling pathway, ultimately leading to apoptosis of VSMCs and causing little but remarkable inflammation [143]. This pathway includes the activation of ceramide to phosphorylate JNK and P38 MAPKs, which have been shown to activate caspase 3 and programmed cell death [99, 143].

Afterward, ROS generated due to the build-up of Ox-Lp(a) molecules also activate macrophage autophagy by two direct and indirect pathways. The indirect pathway is mediated by adenosine diphosphate-ribose polymerase-1 (PARP-1), liver kinase B1 (LKB1), adenosine monophosphate-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR) signaling pathway. The direct pathway is mediated by LKB1-AMPK-mTOR signaling [144]. Both signaling pathways eventually lead to decreased mTOR activity via decreased phosphorylation of p70S6K and 4EBP1, which can spark macrophage autophagy [144]. Finally, apoptotic cells release phosphatidylserine-containing OxPLs, which stimulate the macrophage uptake of apoptotic cells and may stimulate angiogenesis. At this point, plaques rupture may occur at their shoulder area and is characterized by decreased VSMCs, a thin fibrous cap, a huge necrotic center, and increased macrophage infiltration into the cap.

6.4. Pro-Thrombotic Effect

Following damage to the vessel wall, platelets become triggered and initiate thrombus formation. Fibrin cross-links and stabilizes the clot and then undergoes several fibrinolysis processes [70]. Fibrinolysis is a vastly controlled and restricted process leading to the suspension of fibrin clots and renovation of vascular endothelium [145]. Adsorption of tPA and PLG to the exterior of fibrin permits the creation of plasmin and thus its degradation [27, 145]. In fact, PLG binding to fibrin alters the protein from a closed to an open conformation [27]. This binding leads to the development of carboxyl-terminal lysine residues, which promote positive feedback in the fibrinolytic cascade [95]. Additionally, it mediates plasmin-mediated alteration of native Glu1-PLG to Lys77-PLG by cleavage of a 76-amino-acid preactivation peptide [95] and thus becomes an improved substrate for tPA [27]. Thereby, plasmin is responsible for the degradation of the fibrin molecules within clots. The specific cell surface receptors for PLG are articulated by a wide variety of cells with great density in EC and aid in promoting fibrinolysis and native PLG proteolysis [146, 147]. In fact, they play a major role in accelerating PLG activation and protecting plasmin from inhibition [146]. Moreover, tPA binds to the PLG receptor (annexin 2) at a separate site close to the PLG binding site, leading to a more efficient generation of plasmin.

The structural homology and the abundance of PLG receptors have led to theories about the relationship between Lp(a) and thrombosis. In fact, as mentioned above, Lp(a) may interfere with the PLG activation ternary complex and lead to competitive interference with PLG and the enhancement of tissue factor (TF) pathways. Moreover, OxPLs may play a vital role in thrombosis. It is worth noting that atherosclerosis and its subsequent thrombosis are mechanistically interlinked. Therefore, further studies are needed to determine whether the direct pro-coagulant antifibrinolytic effect of Lp(a) plays a significant role in increasing the risk for atherothrombotic events. Lp(a) is believed to promote thrombosis by a number of separate but related mechanisms.

6.4.1. Platelet Responsiveness

Platelets are activated on the surface of the injured vascular wall once they are exposed to collagen, leading to the production of dense granules to activate additional new platelets in a positive feedback loop [70]. Aggregation of the platelets then occurs when the αIIbβ3 domain of the platelets binds to the attracted fibrinogen molecules, after which clot formation is initiated [148]. Several lines of evidence have associated Lp(a) with enhanced platelet response [149, 150]. One study suggests that the enhanced responses of platelets may involve protease-activated receptor-1 thrombin receptor [149]. Another study suggests that Lp(a) blocks PAF-induced platelet activation in a nonspecific manner[150]. The blocking of αIIbβ3 activation and fibrinogen attachment to the activated platelets may denote the major mechanism by which Lp(a) blocks PAF-induced platelet aggregation [150]. Moreover, OxLp(a) and OxPLs may be involved in platelet hypersensitivity via the CD36-dependent pathway in a mechanism similar to foam cell formation [151].

6.4.2. Inhibition of Plasminogen Activation and Plasmin Generation

Many reports have revealed that Lp(a), through its kringles, attaches to fibrin to form the quaternary complex [70] and block new PLG binding and activation at PLG binding sites on fibrin, fibrinogen, and cell surfaces [152]. In fact, Lp(a) may attach to carboxyl-terminal lysine residues of fibrin and consequently interfere with fibrinolysis, as apo(a) in Lp(a) has no catalytic activity [145]. KIV5–9 and kringle V play a critical role in this mechanism [153]. Lp(a) also inhibits PLG activation by the bacterial activator streptokinase [152]. Moreover, other in vitro and in vivo studies have reported that Lp(a) and its apo(a) component inhibit the generation of plasmin on the endothelial cell surface with and without interference and tPA binding attenuation [152, 154]. One of the most robust theories behind this phenomenon is that Lp(a) increases the expression of PAI-1, which by definition inhibits the availability of tPA. An important report has shown that PAI-1 inhibits tPA in a protein kinase-C-dependent mechanism [70, 155]. Another report showed that Lp(a) also associates with other prothrombotic proteins, including α2-macroglobulin (A2M) (a plasmin inhibitor) and SERPINA1, a tPA inhibitor [25]. Thus, decreased PLG binding and activation on the cell surface may decrease fibrin degradation and create an antifibrinolytic effect. Finally, the antifibrinolytic effect mainly depends on the size of apo(a) polymorphs [95]; the smaller the apo(a) isoforms are, the higher the antifibrinolytic effect is [156].

6.4.3. Effect of Lp(a) on Tissue Factor

TF, which acts as a transmembrane receptor for factor VII/VIIa (FVII/VIIa), is the key cellular motivator of the coagulation protease cascade leading to the triggering of thrombin [157, 158]. It is constitutively expressed by VSMCs, pericytes, and adventitial fibroblasts within the vessel wall and cells surrounding blood vessels [157]. The endothelium physically splits this compelling “activator” from its circulating ligand FVII/FVIIa and blocks inappropriate initiation of the clotting cascade [157]. Damage to the endothelial barrier leads to exposure of extravascular TF and swift initiation of the clotting cascade [157]. Several lines of evidence have shown that Lp(a) increases the expression of TF and inhibits the potent inhibitory effect of TF pathway inhibitor (TFPI), which eventually lead to thrombosis [159].

6.4.4. Role of OxLp(a) & OxPLs

Microarray studies demonstrated that OxPL exposure of HAEC from 150 donors controlled the quantities of main thrombogenic molecules [99]. OxPLs drastically downregulated thrombomodulin expression by 40% while upregulating TF and Serpin B2 expression by 70% [99]. The postulated mechanism begins with an elevation of OxPLs, which increases cAMP and cytosolic Ca2+ levels. Cytosolic Ca2+ release plays a vital role in many signaling pathways. Increased Ca2+ levels activate the calcineurin and nuclear factor of activated T cells (NFAT) pathway, which leads to a shift in and attachment of NFAT to the TF promoter [160]. Moreover, OxPLs activate protein kinase C (PKC), which activates the early growth response protein 1 (EGR-1) pathway [160]. The latter is a transcription factor that usually associates with genes that mediate inflammation and thrombosis. The induction of EGR-1 is mediated by the metenkephalin/extracellular signal-related kinase 1/2 (MEK/ERK) cascade. EGR-1 and NFAT activation eventually leads to upregulation of TF [160].

6.4.5. Effect of Lp(a) on Tissue Factor Pathway Inhibitor

TFPI is a protease inhibitor with three tandem Kunitz-type blocking domains (K1, K2, and, K3) that blocks the TF coagulation cascade [161]. Thus, TFPI strongly blocks the initial steps of the extrinsic coagulation pathway [95]. TFPI is present on endothelial cells, activated monocytes, and platelets [95]. Lp(a) and OxPLs inhibit the activity of isolated TFPI, which augments unopposed TF effects. The mechanism underlying its inhibitory activity is direct binding to the active TFPI inhibitor domains with much higher affinity than PLG and inactivation of TFPI activity in the presence or absence of physiologic concentrations of PLG [159].

7. Factors that Influence Lp(a) Levels in the Blood

Primarily, the Lp(a) plasma levels are genetically determined. Nonetheless, several factors may increase or decrease the Lp(a) bloodstream levels, as reviewed [36, 63, 162]. For example, chronic liver as well as kidney diseases are associated with plasma Lp(a) levels [58, 61, 80, 163165]. Moreover, as mentioned above, elevated Lp(a) concentrations are an acute phase reactant, for example, following an inflammatory stimulus, pregnancy, myocardial infarction and other situations [162, 166]. These augmented Lp(a) levels stabilize subsequently when the trigger signal of the acute phase withdraws [162, 166]. Several studies have examined the relationships between Lp(a) concentration and chronic ethanol consumption. Ethanol has a powerful influence and decrease bloodstream Lp(a) levels up to 60% [63] in dose-dependent manner independent of the size distribution of apo(a) isoforms [167]. Tobacco smoking reduces plasma Lp(a) by up to 20% [168, 169] although tobacco smoking is one of the major risk factors for CVD, increasing plasma TG and lowering HDL-C [170].

Several underlying diseases and the therapeutic administration of hormones affect Lp(a) plasma levels, partly due to changes occurring in other lipoproteins. For instance, the administration of hormones such as adrenocorticotrophic hormone (ACTH) has a strong effect on Lp(a) levels, decreasing them up to 40% [63]. Moreover, there are divergent effects of growth hormone (HGH) and IGF on plasma Lp(a) levels [63]. Though HGH significantly increases Lp(a) levels by up to 120%, IGF-I decreases Lp(a) concentrations by up to 60% [171]. Insulin inconsistently affects Lp(a) levels [172, 173]. Moreover, male and female sexual steroids affect many parameters of fat metabolism [174]. Anabolic sterols considerably decrease Lp(a) levels up to 70% [175]. Lastly, Lp(a) levels increase one- to twofold or more during the gestational period and normalize after delivery, during the puerperium period [176]. Other factors influencing Lp(a) levels are summarized in Table 1.


Increase Lp(a) levels
Apo(a) geneUp to 90%
Acute phaseUp to two-fold increase in Lp(a) concentrations. Concentrations normalize after the triggering signal for the acute phase withdraws. The highest upsurge is reported approximately 6–8 days after the acute event [162, 166]
Renal diseaseRenal insufficiency and nephrotic syndrome increase Lp(a) levels up to three-fold [58, 61, 163]
Diabetes mellitusThe increase in Lp(a) levels in diabetic patients mainly relates to the stage of kidney disease [172, 173]
HypothyroidismIncrease in Lp(a) concentrations was reported [198]
PregnancyUp to two- to threefold increase during pregnancy, with highest Lp(a) levels increase seen at the 20th week [176]
HGHIncreases Lp(a) by up to 120% [171]

Decrease Lp(a) levels
Cholestatic liver diseasesUp to 90%. May be due to impairment of Lp(a) production and/or assembly
Alcohol consumptionChronic consumption may reduce plasma Lp(a) in a dose-dependent manner and up to 60% [167, 178]
IGF-1Was found to decrease Lp(a) levels by 60% [171]
Anabolic steroidsUp to 70% reported (N/R) [45, 175]
TestosteroneOnly few reported up to 40% reduction [179]
ACTHYield reductions of up to 30–40% [63]
TamoxifenAnti-estrogen drug that decreases Lp(a) by 35%
Ca+2 antagonistsLess than 10% reduction [180]
EstrogensUp to 37% reported in postmenopausal women receiving HRT (N/R) [45]
ProgesteroneLow percentage reported
TiboloneAgonist of type I steroid hormone receptor, Leads to 35% reduction
RaloxifeneEstrogen receptor modulator, leads to 35% reduction
Cigarette smokingLowers plasma Lp(a) levels by 10–20% [168, 169]
CancerTumors of many origins reported up to cause a two-fold increase [34, 66, 67]
ObesityThere is an inverse relationship between weight plasma Lp(a) concentration and obesity [63]
DietMajority of the reports have shown no to minimum reduction[181]; however, a defined plant-based diet [182] and fish oils were found to reduce plasma Lp(a) by 10% [180]

(N/R): not recommended for clinical use. This table was adapted from [36, 63, 162].

8. Lp(a) Measurement

8.1. Isoform-Dependent vs. Isoform-Independent

There are many structural characteristics of Lp(a), which, along with the covalent bond of apo(a) with apo-B100, make it peculiar. Additionally, there are strong structural similarities between apo(a) and PLG. Most importantly, the high particle size heterogeneity is associated with the variability in KIV2 repeats. This peculiar structure results in substantial limitations and challenges to standardizing immunological assays, determining appropriate calibrators and selecting reference material, activities that are crucial for analyzing and comparing the results of different studies [19]. There are two categories of immunological assays used to measure Lp(a) levels. The first category of immunological assays is “isoform-dependent,” representing the entire protein mass of Lp(a), reported in milligrams per (deciliter/liter) [183]. The molecular mass of the apo(a) protein mainly depends on the number of KIV motif repeats, with an extremely wide range of 200–800 kilodaltons [39]. There are many concerns related to measuring Lp(a) mass because most antibodies are polyclonal and cross-react with several KIV2 repeats. These assays would thus overestimate Lp(a) concentrations in patients with large apo(a) isoforms and underestimate Lp(a) concentrations in patients with small apo(a) isoforms [17]. Thus, the impact of the heterogeneity of Lp(a) mass may lead to underestimation of the relationship between Lp(a) concentration and CVS risk assessment. The other category is “isoform-independent,” an assay that recognizes a unique nonrepeating kringle IV (type 9), and it is reported in units of nanomoles per liter (nmol/L) [11]. Use of the isoform-independent immunological assays is considered the gold standard by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) and approved by the World Health Organization (WHO) to measure Lp(a) because in these assays, apo(a) size will not affect the final results [184]. It is worth noting that most previous research used the mass-dependent mg/dL instead of nmol/L. Moreover, many scientists have used a mean conversion factor of 2.4 (2.4 nmol/L to 1 mg/dL or 10 mg/L) to convert mass-based concentrations (mg/dL or mg/L) of Lp(a) to molar concentrations (nmol/L) [185]. However, the Lp(a) conversion factor, unlike the conversion factors for any analyte with a defined molecular mass, is inaccurate because it ignores the size heterogeneity of apo(a) and should be re-evaluated for accuracy [186]. Moreover, Lp(a) should be preferably measured in freshly isolated plasma, although most laboratories worldwide use frozen samples, which may lead to inaccurate results [11]. As the efficacy of various new Lp(a)-lowering therapies is currently under intense investigation, it is clear that great consideration must be given to the assay that is used to measure plasma Lp(a) levels to have an accurate, reproducible, dependable, and standardized quantitation of Lp(a).

8.2. Important Considerations
8.2.1. Friedewald Formula

We use this formula commonly in clinical practice to calculate LDL-C. LDL-C = TC−(HDL-C + TG/5), where TG/5 represents the cholesterol in VLDL, provided that the plasma TG levels are <4.5 mmol/L and that type III dyslipoproteinemia is not present [187]. HDL-C is quantified in the plasma supernatant after the apo-B100-containing lipoproteins are precipitated by a polyanion that precisely interacts with the apo-B100 of both Lp(a) and LDL [187]. Thus, the Friedewald formula overestimates the LDL-C value, which is, in fact, the value LDL-C + Lp(a)-C. This is very crucial because elevated Lp(a) levels increase LDL-C thanks to the Friedewald formula and may contribute to the diagnosis of certain diseases, such as FH, which depend clinically on a specific LDL-C threshold.

9. Screening

Plasma Lp(a) levels increase soon between after birth until the 7th postnatal day [188] and reach a constant concentration within a few months of life [189]. In adults, Lp(a) levels range widely, from <2 up to 2500 mg/L [190]. It used to be thought that there were no differences in Lp(a) levels associated with gender. However, many studies suggest females are more prone to elevated Lp(a) levels than are males [191193] and that they are especially prone during pregnancy [176]. According to a study of the general population of Copenhagen, the distribution of Lp(a) levels is positively skewed to the left, with a tail toward the highest levels [194] that represents 20% of the general population [195]. Moreover, one of the most distinctive features regarding Lp(a) is that there are significant differences in plasma Lp(a) levels between different populations and ethnic groups [34]. Lp(a) levels are the lowest in Caucasian patients and highest in patients of African ethnicity. Most studies suggest that the Lp(a) cut-off point for CVD should be equal to or above 500 mg/L, which represents the 80th percentile of the general population distribution for Lp(a); this value can be rationally proposed to clinicians as an indicator of augmented risk for CVD [19]. Nevertheless, due to the nonexistence of firmly established race-specific clinical cut-off points for Lp(a) levels in populations other than those of Caucasians, clinicians should exercise their best judgment in the risk assessment of different ethnic groups [19].

Screening for increases in Lp(a) levels in the general population is still not recommended [11]. Because the majority of circulating Lp(a) molecules are genetically determined with little effect from diet and environment [196] and because plasma concentrations do not vary considerably around a preset baseline over a lifespan (<10%) in any individual, it is logical that this measurement is required only once for screening or diagnostic purposes [196]. Moreover, because Lp(a) level screening is a cost-effective test, it could rationally be added to the lipid profile for first-time patients [17]. Nordestgaard and colleagues [194] recommend that Lp(a) be measured in patients with FH, a strong family history of CVD, a personal history of premature CVD, recurrent CVD despite statin treatment, and an inadequate response to statins. Moreover, Lp(a) should be measured in patients with a ≥5% 10-year risk of fatal CVD according to the European guidelines [197] or ≥10% 10-year risk per US guidelines, as well as in patients with a 10–19% Framingham risk according to 2012 Canadian Cardiovascular Society recommendations [180]. Finally, consideration of repeat measurement is indicated only in individuals treated for high Lp(a) levels [198] (Table 2).


Lp(a) should be measured once in all subjects at intermediate or high risk of CVD/CHD who present with one of the following:
 (i) Premature CVD
 (ii) Recurrent CVD despite statin treatment
 (iii) Familial hypercholesterolemia
 (iv) Strong family history of premature CVD and/or elevated Lp(a) ≥500 mg/L
 (v) Recurrent CVD despite optimal lipid-lowering treatment
 (vi) ≥5% 10-year risk of fetal CVD according to European guidelines
 (vii) ≥10% 10-year risk of fetal CVD according to US guidelines
 (viii) 10–19% Framingham risk according to the 2012 Canadian Cardiovascular Society recommendations
Repeat measurement is only necessary if treatment for high Lp(a) levels is initiated in order to evaluate therapeutic response

This table was adopted from [194].

10. Interventions

10.1. Diet and Physical Exercise

A healthy diet and regular exercise are recommended for the prevention of coronary artery disease because these practices improve the lipid profile as well as the Framingham risk score [181]. However, their effects on Lp(a) concentration are completely different. The majority of cross-sectional and interventional studies support the empirical evidence that serum Lp(a) concentration is regulated independently of diet, other lipoprotein classes, and long-term or acute rigorous physical exercise [13, 181], despite these activities producing a favorably improved lipid profile [13, 199]. Conversely, a recent study has shown that a plant-based diet substantially decreased inflammatory biomarkers and atherogenic lipoproteins, including Lp(a) [182].

Although lifestyle factors may not directly impact Lp(a) levels themselves, the synergistic multiplier effect of high LDL and Lp(a) concentrations together should be carefully considered. Indeed, studies have shown that in patients with elevated Lp(a) and LDL-C levels, CVD risk is magnified compared to that in patients with only high LDL-C [183, 200, 201]. Therefore, reducing LDL-C (e.g., via diet) and elevating HDL-C (e.g., via exercise) levels in the bloodstream must be greatly recommended to lessen the synergistic multiplier risk and should always be the core pillar of high Lp(a) CVD preventive care [13, 201].

10.2. Medication
10.2.1. Lipid Treatment Essentials

(1) HMG-CoA Reductase Inhibitors. While 3-hydroxy-3-methyl–glutaryl-coenzyme A (HMG-CoA) reductase inhibitor (aka “statin”) intervention is essential in atherosclerosis, the effect of statins on Lp(a) is controversial. It has been assumed that statins slightly reduce or have no effect on Lp(a) concentrations because the LDLR may play either no role or an inconsequential role in Lp(a) clearance. In fact, in patients with FH, statins have been shown to reduce Lp(a) levels by 17–22% [180, 202]. However, recent data from the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study showed that HMG-CoA reductase inhibitors tended to increase Lp(a) levels by 10–20% [17, 203]. This result could be why some subjects do not usually respond to decreased LDL-C levels by statins, as most of their cholesterol is on Lp(a) molecules rather than LDL molecules [204] and Lp(a) can surge with statin treatment [17] (Table 3).


MechanismApproved and investigational therapeutic drugs to lower LDL & Lp(a)

AgentStatusIs it specific for Lp(a)?LDL∆%Lp(a)∆%CommentRef

Reduce production of new LDL/Lp(a)StatinsApprovedNo19–49↓0 –20↑The effect of statins on Lp(a) is controversial. However, statins lower LDL-C and risk of CVD events[17, 203, 205]
NiacinApprovedNoUp to 45↓30–40↓Does not reduce CV risk. However, EAS recommends the use of niacin to achieve an Lp(a) concentration less than 500 mg/L[206, 207]
IONIS-APO(a)-LRx (AKCEA-APO(a)-LRx)InvestigationalYes39–92↓Most promising agent, which is an ASO that specifically targets apo(a) mRNA[17, 208, 209]
AMG 890InvestigationalYes90%↓siRNA directed to apo(a) mRNA to block mRNA translation. This lowering was shown in primates[210]
MipomersenApprovedNo21–40↓20–33↓ApoB ASO, which decreases LDL synthesis. For patients with HoFH[17, 183, 211, 212]
LomitapideApprovedNo19–51↓15–17↓Decreases VLDL production via MTTP inhibition. Approved for patients with HoFH[212, 213]
CETP inhibitorsStoppedNo14–26↓36–39↓Increases levels of HDL-C and reduces levels of LDL-C[205, 214–216]
AspirinApprovedNo10–80↓Aspirin reduces apo(a) by suppression of apo(a) gene transcription[207, 217]
Increase LDLR expression for LDL/ Lp(a) uptakeEvolocumabApprovedNo39–75↓30↓PCSK9 inhibition leads to the recycling of LDLR back to hepatocyte surface for LDL/Lp(a) molecule uptake[218–221]
AlirocumabApprovedNo29–73 ↓30↓Same as above agent[218, 219, 222]
InclisiranInvestigationalNoUp to 60↓25.6↓siRNA directed to PCSK9 mRNA, leading to significant and constant blocking of the production of PCSK9 protein[223, 224]
Physical elimination of Lp(a) moleculesApheresisApprovedNo80↓68–75↓Remove all apo-B100-containing particles in a single session. Most effective—expensive with limited access to facilities[183, 225]
Lp(a)-apheresisInformation not availableYes70–80↓Remove Lp(a) only in a single session by immunoadsorption[226, 227]

10.2.2. Reducing the Production of Novel Lp(a)

(1) IONIS-APO(a)-LRx (AKCEA-APO(a)-LRx). IONIS-APO(a)-LRx is a second-generation antisense oligonucleotide (ASO) designed to reduce the synthesis of apo(a) in the liver [17]. IONIS-APO(a)-LRx is a chemically modified oligonucleotide (typically 16–20 nucleotides) [228] targeting hepatic mRNA in the nucleus and in the cytoplasm if mRNA is present in this compartment to lower plasma concentrations of apoB-containing lipoproteins, including Lp(a) [17]. ASOs bind to plasma proteins and enter the liver, where they accumulate intracellularly. Then, ASOs selectively bind mRNAs coding for apo(a) proteins and often cause degradation at Watson–Crick hybridization [228]. Once attached, ASOs can act via a number of mechanisms, but the most common mechanism is the recruitment of RNase H1, an enzyme that degrades apo(a) mRNA in a DNA-RNA-like duplex. The activation of RNase H1 eventually reduces plasma concentrations of the apo(a) protein or through translational arrest blocks the ribosome [208, 209, 229]. The other mechanisms include the initiation of RNA cleavage through catalytically active ribozymes and RNA interference induced by small interfering RNA (siRNA) molecules [230].

In a recent randomized, double-blind, placebo-controlled, phase I study, 47 healthy individuals aged 18–65 years with Lp(a) levels of 25 nmol/L (100 mg/L) or more were randomized to receive one single dose of IONIS-APO(a) at different concentrations (50–400 mg), six consecutive doses at different concentrations or placebo [209]. The multiple-dose treatment produced a substantial dose-dependent reduction in Lp(a) levels from baseline to the end of the fifth week (100 mg: 39.6%, 200 mg: 59.0%, 300 mg: 77.8% vs. placebo) [209]. OxPL-apo[a] and OxPL-apoB levels were also significantly lower at week five [209]. In a phase II trial, 64 participants with high Lp(a) levels were randomly assigned treatments (100 mg, 200 mg, and 300 mg once a week for four weeks each) or injections of saline placebo (once a week for 12 weeks). At day 85/99, participants had mean Lp(a) reductions between 66.8% and 71.6% [208]. Furthermore, this drug significantly decreased the inflammatory properties of monocytes, which, as mentioned before, originate and hasten CVD, in addition to plasma LDL-C [208]. IONIS-APO(a)-LRx also contains an N-acetyl-galactosamine (GalNac3)-conjugated that is selectively taken up by hepatocytes, with a mean reduction up to 99% reduction of Lp(a) in some patients [17]. These trials showed that IONIS-APO(a)-LRx is a tolerable, potent, and promising selective Lp(a)-lowering drug. It remains to be seen whether IONIS-APO(a)-LRx will reduce CVD events related to high Lp(a). Also, It remains to be seen whether newer drugs such as AMG 890 [210] have better efficacy and reduce CVD events significantly.

(2) Mipomersen. To date, only mipomersen, a second-generation ASO against the coding region of human apoB mRNA (nucleotides 3249–3269), has been approved by the US FDA as an adjunct to diet and statins for lowering LDL-C, apoB, total cholesterol, and nonHDL-C for the treatment of homozygous FH (HoFH) [211]. Mipomersen also has also significantly decreased Lp(a) concentrations [183, 212]. In four phase III trials, 382 participants receiving maximally tolerated lipid-lowering treatment were randomly allocated to weekly administration of 200 mf of the ASO mipomersen or placebo for 26 weeks [211]. The median percent decrease in Lp(a) concentration at 28 weeks was significantly greater in the mipomersen group than in the Placebo group (−26.4% [IQR: −42.8, −5.4] versus 0.0% [IQR: −10.7, 15.3]; ) [211]. However, mipomersen did not affect the production of apo(a), which continued to be released into the plasma as “free” apo(a) [17]. Similar to lomitapide, hepatotoxicity has been observed with mipomersen, and therefore, mipomersen has only been approved for patients with HoFH.

(3) Lomitapide. Lomitapide is an inhibitor or blocker of microsomal TG transfer protein (MTTP), which is an ER-associated protein [212]. It plays a central role in the biosynthesis of lipoproteins by mediating the allocation of neutral lipids (CE and TG) to the new apo-B100 and apo-B48 polypeptides [212], thus promoting the association of VLDL in the liver and chylomicrons in the intestine [212]. Thus, lomitapide does not depend on the functionality of LDL receptors. Lomitapide combined with a low-fat diet and statins substantially and stably lowers LDL-C by 50% in adult patients with HoFH [213]. In an open-label, phase III study, 29 subjects with HoFH were enrolled to receive lomitapide for 78 weeks [213]. The median dose of lomitapide was 40 mg per day [213]. The drug produced a 15% reduction in Lp(a) concentration at 56 weeks [213]. However, by the end of the study, there was no statistically significant difference in Lp(a) concentration from the baseline [213].

(4) Niacin. Niacin is considered a broad spectrum hypolipidemic agent [231]. It has an antilipolytic effect, reducing the mobilization of free fatty acids from the adipose tissue to the liver and reducing the trafficking of free fatty acids, which significantly decreases the concentrations of all apo-B—containing lipoproteins from chylomicrons to Lp(a) [206, 232]. Niacin also stimulates the degradation of apoB-containing lipoproteins and decreases TG synthesis by inhibiting diacylglycerol acyltransferase-2 [23], an enzyme that catalyzes the final reaction involved in TG production as well as selective inhibition of apoA-I uptake without affecting de novo production [205], which eventually increases HDL-C concentrations [205, 231]. A therapeutic dose of niacin is associated with LDL-C and Lp(a) reduction by approximately 45% [205] and 20–30%, respectively, as shown in a meta-analysis of 14 randomized placebo-controlled clinical trials including 9,013 subjects [206], but with detrimental adverse effects. Unfortunately, niacin intervention has not been shown to reduce cardiovascular risk in recent clinical trials [233]. However, in Europe, the use of niacin at a dose of 1–3 g/day in high-risk patients after suitable LDL-cholesterol reduction is recommended by the European Atherosclerosis Society (EAS) to achieve a Lp(a) concentration <500 mg/L [183]. Finally, it must be noted that clinical research trials on niacin lack reliability with respect to patient assortment, drug dosage, intervention interval, and techniques used for quantifying Lp(a) [234].

(5) Cholesterylester Transfer Protein (CETP) Inhibitors. CETP mediates the exchange of cholesterol esters and TGs of LDL-c and HDL-c. Blocking this transfer with CETP inhibitors increases HDL-C levels and reduces t LDL-C levels [216]. In a study that evaluated the effects of the CETP inhibitor anacetrapib on lipid levels and its safety when administered as single therapy or in ad-on therapy with statins in Japanese patients, intervention as single therapy or coadministered with statins significantly decreased Lp(a) and LDL-C levels and increased HDL-C levels [215]. In a randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of anacetrapib in 1623 patients with CHD, intervention consistently decreased Lp(a) levels by 38.8% from baseline levels [214]. While CETP inhibitors might significantly improve the lipid profile, no data are available because research activities have been stopped [186].

(6) Aspirin. Aspirin is mainly used for its antithrombotic effect. In 2002, a study evaluated the effect of aspirin treatment on serum concentrations of Lp(a). Japanese with high Lp(a) patients () were recruited and received aspirin (81 mg/day). Aspirin decreased serum Lp(a) levels to ~80% of the baseline values in patients with high Lp(a) levels (>300 mg/L) [217]. Aspirin may reduce apo(a) production in human liver cells by suppressing apo(a) gene transcription [207].

10.2.3. LDL Receptor Removal or Uptake

(1) PCSK9 Inhibitors. PCSK9 is a protein involved in regulating LDLR recycling, and it was discovered when investigators found gain-of-function genetic alterations in PCSK9 protein in patients with FH [218]. PCSK9 inhibitors such as evolocumab and alirocumab are fully human monoclonal antibodies that attach to the PCSK9 protein and obstruct its contact with the LDLR, resulting in boosted receptor recycling and LDL clearance [235]. These drugs have been shown to reduce LDL-C by up to 60–70% [221]. Trials that have observed lipid profiles in patients treated with PCSK9 inhibitors showed reproducible and constant reductions in Lp(a) levels [14]. However, it is unclear whether the Lp(a)-lowering effect could be expected in the early clinical trials. An analysis of data pooled from 1359 patients enrolled in 4 phase II trials assessed the effects of evolocumab on Lp(a) levels. Significant dose-related decreases in Lp(a) levels compared to those under placebo treatment were reported [220]. Evolocumab therapy for 12 weeks significantly decreased Lp(a) levels by 29.5% (95% CI: 23.3%, 35.7%) and 24.5% (95% CI: 20.4%, 28.7%) when given at 140 mg and 420 mg dosed every two and four weeks, respectively [220]. In a pooled data analysis from 3 double-blind, randomized, placebo-controlled, phase II trials, alirocumab at 150 mg every two weeks significantly decreased Lp(a) levels in patients with hypercholesterolemia [222] from baseline levels compared with those under placebo treatment (30.3% vs. 0.3%, ) [222].

(2) Inclisiran. Inclisiran is a long-acting siRNA therapeutic agent that reduces the synthesis of PCSK9 protein, a target for the lowering of LDL-C [223]. The inclisiran molecule follows the ordinary pathway of mRNA interference and PCSK9 silencing via RNA interference [236]. In transgenic mice expressing human PCSK9, inclisiran decreased PCSK9 mRNA concentrations up to 70% concomitant with up to a 60% decrease in plasma cholesterol concentrations [236]. In a randomized, single blind, placebo-controlled phase I trial in patients with LDL-C levels ≥100 mg/dL and fasting TG levels of <400 mg/dL, doses of 300 mg or more significantly lowered levels of PCSK9, LDL-C, and Lp(a) by 74.5%, 50%, and 48.1%, respectively, for at least six months [223]. In a phase II, double-blind, placebo-controlled, multiple-ascending-dose trial of inclisiran vs. placebo, 501 patients at high risk for CVD and with LDL-C levels >2.5 mmol/L, or >1.8 mmol/L were enrolled in the study [224]. The experimental group that received 200 mg of inclisiran at baseline and after 90 days experienced a persistent decrease in LDL-C and Lp(a) levels by 52.6% and 25.6%, respectively, at 180 days compared with the values at baseline [224].

10.3. Apheresis

Extracorporeal elimination with apheresis is the most effective, well-tolerated, and approved treatment for lowering Lp(a) levels [237, 238]. This process removes all apoB-containing lipoproteins (specifically LDL-C and Lp(a)) from the blood using antibody-coupled columns, precipitation, and complex creation at low pH. Double filtration and direct absorption have been confirmed to lower plasma LDL-c and Lp(a) levels by up to 80% [63]. A longitudinal cohort trial that evaluated the efficiency of lipid apheresis therapy on Lp(a) concentrations and major adverse coronary events (MACEs) reported a median reduction in Lp(a) levels of 73% compared with medical treatment alone [239]. Additionally, the study revealed that a combination of lipid-lowering treatments, such as statins, ezetimibe, and nicotinic acid with apheresis, reduced major adverse cardiac events up to 88% over a 10-year follow-up period [183, 240]. In a prospective observational multicenter study including 170 participants with Lp(a)-HLP and progressive CVD, comparable results were stated; single apheresis treatment decrease Lp(a) levels by 68.1%, and therapy over a period of 5 years significantly decreased the yearly CVD occurrence rates [241]. Other important benefits of apheresis include lowering the markers of vascular inflammation and improving blood rheology [242]. In addition to removing Lp(a) mass, lipoprotein apheresis reduces the activities of OxPLs and lipoprotein-associated phospholipase A2, which are bound to Lp(a) [225]. One of the significant drawbacks of apheresis is the rapid rebound of Lp(a) levels to those at the baseline within two weeks of intervention, thus requiring repeated, expensive, weekly sessions with limited access to treatment [183].

11. Conclusion

Elevated Lp(a) concentration is dominantly inherited and was first described in the 1960s as a qualitative (Lp+, Lp−) genetic trait [8]. However, we now know that elevated Lp(a) concentration is a quantitative genetic trait influenced mainly by the LPA gene located on chromosome 6 (6q26–27) [23]. This gene is responsible for the inverse relationship between Lp(a) size, which may vary within and among individuals, and Lp(a) plasma concentration. This size heterogeneity is a unique phenomenon among lipoproteins, which usually have constant masses. The similarity of the two main parts of Lp(a) to the LDL and PLG molecules strongly enhances its atherogenicity. OxPLs play a key role in the pathogenesis of Lp(a) and may significantly contribute to the atherogenicity of Lp(a) and its association with increased risk for CVD. Individuals with low Lp(a) levels do not express any physical or metabolic abnormalities. However, numerous studies have shown that individuals with elevated Lp(a) concentrations > 300 mg/L are at increased risk of atherosclerosis, especially if LDL levels are high. Lp(a) measurement and interpretation have many challenges. For instance, the size variation in the apo(a) moiety of Lp(a) leads to overestimation or underestimation of Lp(a) concentrations. The development of isoform-independent assays has helped to significantly improve Lp(a) measurements. Another important challenge is the contribution of Lp(a) cholesterol to LDL-C when using the Friedewald formula, which may require a mathematical correction before any interpretation is made [170].

Reducing LDL levels through healthy diet and exercise or even through extensive statin treatment does not significantly influence the reduction in Lp(a) levels. However, these interventions should be vigorously implemented in the lifestyles of patients with high Lp(a) levels. Indeed, studies have shown that the risk of CVD in patients with high Lp(a) levels is dramatically reduced by lowering LDL-C. There is no approved drug on the market that directly reduces Lp(a) levels. Many of the multiple-effect lipid-lowering treatments decrease Lp(a) levels without a clear clinical outcome. IONIS ASOs are the only known investigational drugs that block the formation of apo(a) directly and dramatically lower Lp(a) levels. Extracorporeal elimination with apheresis is the most effective, well-tolerated, and approved treatment for lowering Lp(a) to date. However, apheresis has significant drawbacks. For instance, the Lp(a) levels rebound every two weeks. Thus, this costly and limited treatment has to be repeated every so often.

Abbreviations

CVD:Cardiovascular disease
GBD:Global burden disease
IHD:Ischemic heart disease
LDL-C:Low-density lipoprotein cholesterol
TG:Triglyceride
HDL-C:High-density lipoprotein-cholesterol
Lp(a):Lipoprotein(a)
Apo:Apolipoprotein
K:Kringle
CAD:Coronary artery disease
Apo-B100:Apolipoprotein-B100
CE:Cholesteryl esters
Apo(a):Apolipoprotein(a)
PLG:Plasminogen
tPA:Tissue plasminogen activator
uPA:Urokinase plasminogen activator
VSMC:Vascular smooth muscle cell
LBS:Lysine binding sites
ER:Endoplasmic reticulum
Cys:Cysteine
LDLR:LDL receptor
PCSK9:Proprotein convertase subtilisin/kexin type 9
HepG2:Human hepatoma cells G2
PlgRKT:Plasminogen receptor (KT)
MMPs:Matrix metalloproteinases
MAPK:Mitogen-activated protein kinase
bFGF:Basic fibroblast growth factor
TGF- β1:Transforming growth factor-β1
TNF-α:Tumor necrosis factor-α
OxPLs:Oxidized phospholipids
Lp-PLA2:Lipoprotein associated-phospholipase A2
PAI-1:Plasminogen activator inhibitor-1
u-PA:Urinary-type plasminogen activators
OxLp(a):Oxidized Lp(a)
OxLDL:Oxidized LDL
NADPH:Nicotinamide adenine dinucleotide phosphate
MPO:Myeloperoxidase
ROS:Reactive oxygen species
LPO:Lipoxygenase
TLR-4:Toll-like receptors 4
PPR:Pattern-recognition receptors
PAF:Platelet activating factor
VE-cadherin:Vascular endothelial cadherin
VEGFR2:Vascular endothelial growth factor receptor 2
MLC:Myosin light chain
MLCK:MLC kinase
EP2:E-type prostaglandin
cAMP:Cyclic AMP
PI3K:Phosphoinositide 3 kinase
CS-1:Connecting segment 1
VCAM-1:Vascular cell adhesion molecule-1
ICAM-1:Intercellular adhesion molecule-1
SR-B1:Scavenger receptor class B type 1
MKP1:Mitogen activated protein kinase phosphatase 1
CD36:Cluster determinant 36
EGFR:Epidermal growth factor receptor
MCP-1:Chemoattractant molecule 1
Ca+2:Calcium
PPAR α:Peroxisome proliferator-activated receptor α
MIP-2:Macrophage inhibitor protein-2
IL-1β:IL-1 beta
iNOS:Inducible nitric oxide synthase
TNFa:Tumor necrosis factor-alfa
RANTES:Regulated upon activation, normal T-cell expressed, and secreted
GEFs:Guanine nucleotide exchange factors
IL:Interleukin
MMPs:Matrix metalloproteinases
VSMC:Vascular smooth muscle
NF-κB:Nuclear factor light-chain-enhancer of activated B
ERK:Extracellular signal-regulated kinase ()
Elk-1:ETS-like transcription factor 1
Klf4:Krüppel-like factor 4
HDACs:Histone deacetylates
TGF-β:Transforming growth factor-β
PDGF-BB:Platelet-derived growth factor
Cx43:Connexin 43
GALT2:Galactosyltransferase-2
LacCer:Lactosylceramide
PCNA:Proliferating cell nuclear antigen
NOX2:NADPH oxidase 2
PARP-1:Adenosine diphosphate-ribose polymerase-1
LKB1:Liver kinase B1
AMPK:Adenosine monophosphate-activated protein kinase
mTOR:Mammalian target of rapamycin
TF:Tissue factor
TFPI:Tissue factor pathway inhibitor
NFAT:Nuclear factor of activated T cells
PKC:Protein kinase C
EGR-1:Early growth response protein 1
MEK:Metenkephalin
ERK:Extracellular signal-related kinase 1/2
IFCC:International Federation of Clinical Chemistry and Laboratory Medicine
WHO:World Health Organization
HGH:Human growth hormone
IGF-I:Insulin-like growth factor I
ACTH:Adrenocorticotrophic hormone administration
HMG-CoA:3-Hydroxy-3-methyl-glutaryl-coenzyme A 9 (statins)
ASO:Antisense oligonucleotide
siRNA:Small interfering RNA molecules
HoFH:Homozygous familial hypercholesterolemia
MTTP:Microsomal triglyceride transfers protein
CETP:Cholesterylester transfer protein.

Conflicts of Interest

The authors declare that they have no conflicts of interest regarding the publication of this paper.

Acknowledgments

We would like to express our special thanks of gratitude to Dr. Karin Humphries for her help in editing this manuscript. Finally, the support of the Saudi Arabian Cultural Bureau in Canada and University of Jeddah in Saudi Arabia to Motasim M. Jawi is gratefully acknowledged.

References

  1. A. C. Finney, K. Y. Stokes, C. B. Pattillo, and A. W. Orr, “Integrin signaling in atherosclerosis,” Cellular and Molecular Life Sciences, vol. 74, no. 12, pp. 2263–2282, 2017. View at: Publisher Site | Google Scholar
  2. M. Luna-Luna, A. Medina-Urrutia, G. Vargas-Alarcon, F. Coss-Rovirosa, J. Vargas-Barron, and O. Perez-Mendez, “Adipose tissue in metabolic syndrome: onset and progression of atherosclerosis,” Archives of Medical Research, vol. 46, no. 5, pp. 392–407, 2015. View at: Publisher Site | Google Scholar
  3. C. Giannini, T. de Giorgis, A. Scarinci et al., “Obese related effects of inflammatory markers and insulin resistance on increased carotid intima media thickness in pre-pubertal children,” Atherosclerosis, vol. 197, no. 1, pp. 448–456, 20081. View at: Publisher Site | Google Scholar
  4. S. C. Bergheanu, M. C. Bodde, and J. W. Jukema, “Pathophysiology and treatment of atherosclerosis,” Netherlands Heart Journal, vol. 25, no. 4, pp. 231–242, 2017. View at: Publisher Site | Google Scholar
  5. P. R. Kamstrup, “Lipoprotein (a) and ischemic heart disease—a causal association? A Review,” Atherosclerosis, vol. 211, no. 1, pp. 15–23, 2010. View at: Publisher Site | Google Scholar
  6. S. Barquera, A. Pedroza-Tobías, C. Medina et al., “Global overview of the epidemiology of atherosclerotic cardiovascular disease,” Archives of Medical Research, vol. 46, no. 5, pp. 328–338, 2015. View at: Publisher Site | Google Scholar
  7. A. Giordano, M. Peruzzi, A. G. Marullo et al., “What we learned with recent network meta-analyses on atherosclerosis prevention and treatment,” Current Atherosclerosis Reports, vol. 19, no. 2, p. 8, 2017. View at: Publisher Site | Google Scholar
  8. K. Schmidt, A. Noureen, F. Kronenberg, and G. Utermann, “Structure, function, and genetics of lipoprotein (a),” Journal of Lipid Research, vol. 57, no. 8, pp. 1339–1359, 2016. View at: Publisher Site | Google Scholar
  9. K. Berg, “A new serum type system in man—the Ld system,” Vox Sanguinis, vol. 10, no. 5, pp. 513–527, 1965. View at: Publisher Site | Google Scholar
  10. F. Nassir, D. K. Bonen, and N. O. Davidson, “Apolipoprotein (a) synthesis and secretion from hepatoma cells is coupled to triglyceride synthesis and secretion,” Journal of Biological Chemistry, vol. 273, no. 28, pp. 17793–17800, 1998. View at: Publisher Site | Google Scholar
  11. S. M. Marcovina, M. L. Koschinsky, J. J. Albers, and S. Skarlatos, “Report of the national heart, lung, and blood institute workshop on lipoprotein (a) and cardiovascular disease: recent advances and future directions,” Clinical Chemistry, vol. 49, no. 11, pp. 1785–1796, 2003. View at: Publisher Site | Google Scholar
  12. J. W. McLean, J. E. Tomlinson, W. J. Kuang et al., “cDNA sequence of human apolipoprotein (a) is homologous to plasminogen,” Nature, vol. 330, no. 6144, p. 6132, 1987. View at: Publisher Site | Google Scholar
  13. L. T. Mackinnon, L. Y. Hubinger, and F. Lepre, “Effects of physical activity and diet on lipoprotein (a),” Medicine and Science in Sports and Exercise, vol. 29, no. 11, pp. 1429–1436, 1997. View at: Publisher Site | Google Scholar
  14. P. Libby, “Lipoprotein (a): a frustrating final frontier in lipid management?” JACC: Basic to Translational Science, vol. 1, no. 6, pp. 428–431, 2016. View at: Publisher Site | Google Scholar
  15. The Emerging Risk Factors Collaboration, “Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality,” The Journal of the American Medical Association , vol. 302, no. 4, pp. 412–423, 2009. View at: Publisher Site | Google Scholar
  16. S. R. Holmer, C. Hengstenberg, H. G. Kraft et al., “Association of polymorphisms of the apolipoprotein (a) gene with lipoprotein (a) levels and myocardial infarction,” Circulation, vol. 107, no. 5, pp. 696–701, 2003. View at: Publisher Site | Google Scholar
  17. S. Tsimikas, “A test in context: lipoprotein (a): diagnosis, prognosis, controversies, and emerging therapies,” Journal of the American College of Cardiology, vol. 69, no. 6, pp. 692–711, 2017. View at: Publisher Site | Google Scholar
  18. E. Orsó and G. Schmitz, “Lipoprotein (a) and its role in inflammation, atherosclerosis and malignancies,” Clinical Research in Cardiology Supplements, vol. 12, no. 1, pp. 31–37, 2017. View at: Publisher Site | Google Scholar
  19. S. M. Marcovina and J. J. Albers, “Lipoprotein (a) measurements for clinical application,” Journal of Lipid Research, vol. 57, no. 4, pp. 526–537, 2016. View at: Publisher Site | Google Scholar
  20. R. Siekmeier, H. Scharnagl, G. M. Kostner, T. Grammer, T. Stojakovic, and W. März, “Lipoprotein (a) - structure, epidemiology, function and diagnostics of a cardiovascular risk marker,” The Open Clinical Chemistry Journal, vol. 1, pp. 79–91, 2008. View at: Publisher Site | Google Scholar
  21. G. Lippi and G. Guidi, “Lipoprotein (a): from ancestral benefit to modern pathogen?” QJM: An International Journal of Medicine, vol. 93, no. 2, pp. 75–84, 2000. View at: Publisher Site | Google Scholar
  22. S. M. Marcovina, J. J. Albers, B. Gabel, M. L. Koschinsky, and V. P. Gaur, “Effect of the number of apolipoprotein (a) kringle 4 domains on immunochemical measurements of lipoprotein (a),” Clinical Chemistry, vol. 41, no. 2, pp. 246–255, 1995. View at: Google Scholar
  23. T. A. Jacobson, “Lipoprotein (a), cardiovascular disease, and contemporary management,” Mayo Clinic Proceedings, vol. 88, no. 11, pp. 1294–1311, 2013. View at: Publisher Site | Google Scholar
  24. A. von Zychlinski, M. Williams, S. McCormick, and T. Kleffmann, “Absolute quantification of apolipoproteins and associated proteins on human plasma lipoproteins,” Journal of Proteomics, vol. 25, no. 106, pp. 181–190, 2014. View at: Publisher Site | Google Scholar
  25. A. von Zychlinski, T. Kleffmann, M. J. Williams, and S. P. McCormick, “Proteomics of lipoprotein (a) identifies a protein complement associated with response to wounding,” Journal of Proteomics, vol. 74, no. 12, pp. 2881–2891, 2011. View at: Publisher Site | Google Scholar
  26. A. L. White, B. Guerra, and R. E. Lanford, “Influence of allelic variation on apolipoprotein (a) folding in the endoplasmic reticulum,” Journal of Biological Chemistry, vol. 272, no. 8, pp. 5048–5055, 1997. View at: Publisher Site | Google Scholar
  27. M. B. Boffa and M. L. Koschinsky, “Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease?” Journal of Lipid Research, vol. 57, no. 5, pp. 745–757, 2016. View at: Publisher Site | Google Scholar
  28. A. M. Scanu and C. Edelstein, “Learning about the structure and biology of human lipoprotein [a] through dissection by enzymes of the elastase family: facts and speculations,” Journal of Lipid Research, vol. 38, no. 11, pp. 2193–2206, 1997. View at: Google Scholar
  29. A. Cai, L. Li, Y. Zhang, Y. Mo, W. Mai, and Y. Zhou, “Lipoprotein (a): a promising marker for residual cardiovascular risk assessment,” Disease Markers, vol. 35, no. 5, pp. 551–559, 2013. View at: Publisher Site | Google Scholar
  30. P. Deloukas, S. Kanoni, C. Willenborg et al., “Large-scale association analysis identifies new risk loci for coronary artery disease,” Nature Genetics, vol. 45, no. 1, p. 25, 2013. View at: Google Scholar
  31. J. S. Schultz, D. C. Shreffler, C. F. Sing, and N. R. Harvie, “The genetics of the Lp antigen: I. Its quantitation and distribution in a sample population,” Annals of Human Genetics, vol. 38, no. 1, pp. 39–46, 1974. View at: Publisher Site | Google Scholar
  32. C. EhnholmH. GaroffK. SimonsH. Aro, “Purification and quantitation of the human plasma lipoprotein carrying the Lp (a) antigen,” Biochimica et Biophysica Acta (BBA)-Protein Structure, vol. 236, no. 2, pp. 431–439, 1971. View at: Publisher Site | Google Scholar
  33. H. H. Hobbs and A. L. White, “Lipoprotein (a): intrigues and insights,” Current Opinion in Lipidology, vol. 10, no. 3, pp. 225–236, 1999. View at: Publisher Site | Google Scholar
  34. B. Enkhmaa, E. Anuurad, and L. Berglund, “Lipoprotein (a): impact by ethnicity and environmental and medical conditions,” Journal of Lipid Research, vol. 57, no. 7, pp. 1111–1125, 2016. View at: Publisher Site | Google Scholar
  35. C. Marcoux, S. Lussier-Cacan, J. Davignon, and J. S. Cohn, “Association of Lp (a) rather than integrally-bound apo (a) with triglyceride-rich lipoproteins of human subjects,” Biochimica et Biophysica Acta (BBA)-Lipids and Lipid Metabolism, vol. 1346, no. 3, pp. 261–274, 1997. View at: Publisher Site | Google Scholar
  36. K. M. Kostner, W. März, and G. M. Kostner, “When should we measure lipoprotein (a)?” European Heart Journal, vol. 34, no. 42, pp. 3268–3276, 2013. View at: Publisher Site | Google Scholar
  37. M. L. Koschinsky and M. B. Boffa, “Lipoprotein (a): an important cardiovascular risk factor and a clinical conundrum,” Endocrinology and Metabolism Clinics, vol. 43, no. 4, pp. 949–962, 2014. View at: Google Scholar
  38. A. Beheshtian, S. G. Shitole, A. Z. Segal et al., “Lipoprotein (a) level, apolipoprotein (a) size, and risk of unexplained ischemic stroke in young and middle-aged adults,” Atherosclerosis, vol. 1, no. 253, pp. 47–53, 2016. View at: Publisher Site | Google Scholar
  39. C. García-Gómez, M. Bianchi, D. de la Fuente et al., “Inflammation, lipid metabolism and cardiovascular risk in rheumatoid arthritis: a qualitative relationship?” World Journal of Orthopedics, vol. 5, no. 3, 304 pages, 2014. View at: Publisher Site | Google Scholar
  40. K. Kotani and M. Banach, “Lipoprotein (a) and inhibitors of proprotein convertase subtilisin/kexin type 9,” Journal of Thoracic Disease, vol. 9, no. 1, pp. E78–E82, 2017. View at: Publisher Site | Google Scholar
  41. S. Frank, S. Durovic, and G. M. Kostner, “Structural requirements of apo-a for the lipoprotein—a assembly,” Biochemical Journal, vol. 304, no. 1, pp. 27–30, 1994. View at: Publisher Site | Google Scholar
  42. M. Naruszewicz, E. Selinger, R. Dufour, and J. Davignon, “Probucol protects lipoprotein (a) against oxidative modification,” Metabolism, vol. 41, no. 11, pp. 1225–1228, 19921. View at: Publisher Site | Google Scholar
  43. A. L. White and R. E. Lanford, “Cell surface assembly of lipoprotein (a) in primary cultures of baboon hepatocytes,” Journal of Biological Chemistry, vol. 269, no. 46, pp. 28716–28723, 1994. View at: Google Scholar
  44. C. Brunner, H. G. Kraft, G. Utermann, and H. J. Müller, “Cys4057 of apolipoprotein (a) is essential for lipoprotein (a) assembly,” Proceedings of the National Academy of Sciences, vol. 90, no. 24, pp. 11643–11647, 1993. View at: Publisher Site | Google Scholar
  45. J. Hoover-Plow and M. Huang, “Lipoprotein (a) metabolism: potential sites for therapeutic targets,” Metabolism, vol. 62, no. 4, pp. 479–491, 2013. View at: Publisher Site | Google Scholar
  46. M. R. Diffenderfer, S. Lamon-Fava, S. M. Marcovina et al., “Distinct metabolism of apolipoproteins (a) and B-100 within plasma lipoprotein (a),” Metabolism, vol. 65, no. 4, pp. 381–390, 2016. View at: Publisher Site | Google Scholar
  47. S. Frank, K. Krasznai, S. Durovic et al., “High-level expression of various apolipoprotein (a) isoforms by “transferrinfection”: the role of kringle IV sequences in the extracellular association with low-density lipoprotein,” Biochemistry, vol. 33, no. 40, pp. 12329–12339, 1994. View at: Publisher Site | Google Scholar
  48. M. E. Frischmann, K. Ikewaki, E. Trenkwalder et al., “In vivo stable-isotope kinetic study suggests intracellular assembly of lipoprotein (a),” Atherosclerosis, vol. 225, no. 2, pp. 322–327, 2012. View at: Publisher Site | Google Scholar
  49. A. Gries, J. Nimpf, M. Nimpf, H. Wurm, and G. M. Kostner, “Free and Apo B-associated Lpa-specific protein in human serum,” Clinica Chimica Acta, vol. 164, no. 1, pp. 93–100, 1987. View at: Publisher Site | Google Scholar
  50. M. Sharma, G. M. Redpath, M. J. Williams, and S. P. McCormick, “Recycling of apolipoprotein (a) after PlgRKT-mediated endocytosis of lipoprotein (a),” Circulation Research, vol. 120, no. 7, pp. 1091–1102, 2017. View at: Publisher Site | Google Scholar
  51. C. A. Scipione, M. L. Koschinsky, and M. B. Boffa, “Lipoprotein (a) in clinical practice: new perspectives from basic and translational science,” Critical Reviews in Clinical Laboratory Sciences, vol. 55, no. 1, pp. 33–54, 2018. View at: Publisher Site | Google Scholar
  52. D. J. Rader, W. Cain, K. Ikewaki et al., “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,” The Journal of Clinical Investigation, vol. 93, no. 6, pp. 2758–2763, 1994. View at: Publisher Site | Google Scholar
  53. R. C. Maranhão, P. O. Carvalho, C. C. Strunz, and F. Pileggi, “Lipoprotein (a): structure, pathophysiology and clinical implications,” Arquivos Brasileiros de Cardiologia, vol. 103, no. 1, pp. 76–84, 2014. View at: Publisher Site | Google Scholar
  54. X. P. Yang, M. J. Amar, B. Vaisman et al., “Scavenger receptor-BI is a receptor for lipoprotein (a),” Journal of Lipid Research, vol. 54, no. 9, pp. 2450–2457, 2013. View at: Publisher Site | Google Scholar
  55. W. März, A. Beckmann, H. Scharnagl et al., “Heterogeneous lipoprotein (a) size isoforms differ by their interaction with the low density lipoprotein receptor and the low density lipoprotein receptor-related protein/α2-macroglobulin receptor,” FEBS Letters, vol. 325, no. 3, pp. 271–275, 1993. View at: Publisher Site | Google Scholar
  56. A. Hrzenjak, S. Frank, W. O. Xingde, Z. H. Yonggang, T. Van Berkel, and G. M. Kostner, “Galactose-specific asialoglycoprotein receptor is involved in lipoprotein (a) catabolism,” Biochemical Journal, vol. 376, no. 3, pp. 765–71, 2003. View at: Publisher Site | Google Scholar
  57. M. E. Frischmann, F. Kronenberg, E. Trenkwalder et al., “In vivo turnover study demonstrates diminished clearance of lipoprotein (a) in hemodialysis patients,” Kidney International, vol. 71, no. 10, pp. 1036–1043, 2007. View at: Publisher Site | Google Scholar
  58. F. Kronenberg, “Causes and consequences of lipoprotein (a) abnormalities in kidney disease,” Clinical and Experimental Nephrology, vol. 18, no. 2, pp. 234–237, 2014. View at: Publisher Site | Google Scholar
  59. B. Kollerits, M. Auinger, V. Reisig et al., “Lipoprotein (a) as a predictor of cardiovascular disease in a prospectively followed cohort of patients with type 1 diabetes,” Diabetes Care, vol. 29, no. 7, pp. 1661–1663, 2006. View at: Publisher Site | Google Scholar
  60. K. M. Kostner, S. Banyai, M. Banyai et al., “Urinary apolipoprotein (a) excretion in patients with proteinuria,” Annals of Medicine, vol. 30, no. 5, pp. 497–502, 1998. View at: Publisher Site | Google Scholar
  61. F. Kronenberg, E. Trenkwalder, A. Lingenhel et al., “Renovascular arteriovenous differences in Lp [a] plasma concentrations suggest removal of Lp [a] from the renal circulation,” Journal of Lipid Research, vol. 38, no. 9, pp. 1755–1763, 1997. View at: Google Scholar
  62. K. M. Kostner, M. Jansen, G. Maurer, and K. Derfler, “LDL-apheresis significantly reduces urinary apo (a) excretion,” European Journal of Clinical Investigation., vol. 27, no. 1, pp. 93–95, 1997 Jan. View at: Google Scholar
  63. K. M. KostnerG. M. Kostner, “Therapy of Hyper-Lp (a),” Atherosclerosis: Diet and Drugs, Springer, Berlin, Heidelberg, 2005. View at: Google Scholar
  64. J. S. Kim, J. H. Chang, H. K. Yu et al., “Inhibition of angiogenesis and angiogenesis-dependent tumor growth by the cryptic kringle fragments of human apolipoprotein (a),” Journal of Biological Chemistry, vol. 278, no. 31, pp. 29000–29008, 2003. View at: Publisher Site | Google Scholar
  65. V. Schulter, P. Koolwijk, E. Peters et al., “Impact of apolipoprotein (a) on in vitro angiogenesis,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 21, no. 3, pp. 433–438, 2001. View at: Publisher Site | Google Scholar
  66. J. Thillet, C. Doucet, J. Chapman, B. Herbeth, D. Cohen, and L. Faure-Delanef, “Elevated lipoprotein (a) levels and small apo (a) isoforms are compatible with longevity: evidence from a large population of French centenarians,” Atherosclerosis, vol. 136, no. 2, pp. 389–394, 1998. View at: Publisher Site | Google Scholar
  67. G. Pepe, V. Di Perna, F. Resta et al., “In search of a biological pattern for human longevity: impact of apo A-IV genetic polymorphisms on lipoproteins and the hyper-Lp (a) in centenarians,” Atherosclerosis, vol. 137, no. 2, pp. 407–417, 1998. View at: Publisher Site | Google Scholar
  68. O. R. Etingin, D. P. Hajjar, K. A. Hajjar, P. C. Harpel, and R. L. Nachman, “Lipoprotein (a) regulates plasminogen activator inhibitor-1 expression in endothelial cells. A potential mechanism in thrombogenesis,” Journal of Biological Chemistry, vol. 266, no. 4, pp. 2459–2465, 1991. View at: Google Scholar
  69. I. Missala, U. Kassner, and E. Steinhagen-Thiessen, “A systematic literature review of the association of lipoprotein (a) and autoimmune diseases and atherosclerosis,” International Journal of Rheumatology, vol. 2012, pp. 1–10, 2012. View at: Publisher Site | Google Scholar
  70. K. Riches and K. E. Porter, “Lipoprotein (a): cellular effects and molecular mechanisms,” Cholesterol, vol. 2012, pp. 1–10, 2012. View at: Publisher Site | Google Scholar
  71. G. Lippi, V. Braga, S. Adami, and G. Guidi, “Modification of serum apolipoprotein AI, apolipoprotein B and lipoprotein (a) levels after bisphosphonates-induced acute phase response,” Clinica Chimica Acta, vol. 271, no. 1, pp. 79–87, 1998. View at: Publisher Site | Google Scholar
  72. R. Ramharack, D. Barkalow, and M. A. Spahr, “Dominant negative effect of TGF-β1 and TNF-α on basal and IL-6–induced lipoprotein (a) and apolipoprotein (a) mRNA expression in primary monkey hepatocyte cultures,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 18, no. 6, pp. 984–990, 1998. View at: Publisher Site | Google Scholar
  73. M. Pirro, V. Bianconi, F. Paciullo, M. R. Mannarino, F. Bagaglia, and A. Sahebkar, “Lipoprotein (a) and inflammation: a dangerous duet leading to endothelial loss of integrity,” Pharmacological Research, vol. 1, no. 119, pp. 178–187, 2017. View at: Publisher Site | Google Scholar
  74. S. Tsimikas and J. L. Witztum, “The role of oxidized phospholipids in mediating lipoprotein (a) atherogenicity,” Current Opinion in Lipidology, vol. 19, no. 4, pp. 369–377, 2008. View at: Publisher Site | Google Scholar
  75. C. Bergmark, A. Dewan, A. Orsoni et al., “A novel function of lipoprotein [a] as a preferential carrier of oxidized phospholipids in human plasma,” Journal of Lipid Research, vol. 49, no. 10, pp. 2230–2239, 2008. View at: Publisher Site | Google Scholar
  76. C. J. Binder, M. K. Chang, P. X. Shaw et al., “Innate and acquired immunity in atherogenesis,” Nature Medicine, vol. 8, no. 11, pp. 1218–1226, 2002. View at: Publisher Site | Google Scholar
  77. C. Edelstein, B. Philips, D. Pfaffinger, and A. M. Scanu, “The oxidized phospholipids linked to human apolipoprotein (a) do not derive from circulating low-density lipoproteins and are probably of cellular origin,” The FASEB Journal, vol. 23, no. 3, pp. 950–956, 2009. View at: Publisher Site | Google Scholar
  78. C. Edelstein, D. Pfaffinger, J. Hinman et al., “Lysine-phosphatidylcholine adducts in kringle V impart unique immunological and potential pro-inflammatory properties to human apolipoprotein (a),” Journal of Biological Chemistry, vol. 278, no. 52, pp. 52841–52847, 2003. View at: Publisher Site | Google Scholar
  79. Y. Yano, K. Shimokawa, Y. Okada, and A. Noma, “Immunolocalization of lipoprotein (a) in wounded tissues,” Journal of Histochemistry & Cytochemistry, vol. 45, no. 4, pp. 559–568, 1997. View at: Publisher Site | Google Scholar
  80. E. Anglés-Cano, D. A. de la Peña, and S. Loyau, “Inhibition of fibrinolysis by lipoprotein(a),” Annals of the New York Academy Sciences, vol. 936, pp. 261–275, 2001. View at: Publisher Site | Google Scholar
  81. J. Loscalzo, M. Weinfeld, G. M. Fless, and A. M. Scanu, “Lipoprotein (a), fibrin binding, and plasminogen activation,” Arteriosclerosis: An Official Journal of the American Heart Association, Inc, vol. 10, no. 2, pp. 240–245, 1990. View at: Publisher Site | Google Scholar
  82. L. B. Nielsen, B. G. Nordestgaard, S. Stender, A. Niendorf, and K. Kjeldsen, “Transfer of lipoprotein (a) and LDL into aortic intima in normal and in cholesterol-fed rabbits,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 15, no. 9, pp. 1492–1502, 1995. View at: Publisher Site | Google Scholar
  83. B. G. Nordestgaard and A. Langsted, “Lipoprotein (a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology,” Journal of Lipid Research, vol. 57, no. 11, pp. 1953–1975, 2016. View at: Publisher Site | Google Scholar
  84. P. Barter, “The inflammation: lipoprotein cycle,” Atherosclerosis Supplements, vol. 6, no. 2, pp. 15–20, 2005. View at: Publisher Site | Google Scholar
  85. L. B. Nielsen, S. Stender, K. Kjeldsen, and B. G. Nordestgaard, “Specific accumulation of lipoprotein (a) in balloon-injured rabbit aorta in vivo,” Circulation Research, vol. 78, no. 4, pp. 615–626, 1996. View at: Publisher Site | Google Scholar
  86. L. B. Nielsen, S. Stender, M. Jauhiainen, and B. G. Nordestgaard, “Preferential influx and decreased fractional loss of lipoprotein (a) in atherosclerotic compared with nonlesioned rabbit aorta,” The Journal of Clinical Investigation, vol. 98, no. 2, pp. 563–571, 1996. View at: Publisher Site | Google Scholar
  87. S. D. Hughes, X. J. Lou, S. Ighani et al., “Lipoprotein (a) vascular accumulation in mice. In vivo analysis of the role of lysine binding sites using recombinant adenovirus,” The Journal of Clinical Investigation, vol. 100, no. 6, pp. 1493–1500, 1997. View at: Publisher Site | Google Scholar
  88. N. W. Boonmark, X. J. Lou, Z. J. Yang et al., “Modification of apolipoprotein (a) lysine binding site reduces atherosclerosis in transgenic mice,” The Journal of Clinical Investigation, vol. 100, no. 3, pp. 558–564, 1997. View at: Publisher Site | Google Scholar
  89. A. A. Higazi, E. Lavi, K. Bdeir et al., “Defensin stimulates the binding of lipoprotein (a) to human vascular endothelial and smooth muscle cells,” Blood, vol. 89, no. 12, pp. 4290–4298, 1997. View at: Google Scholar
  90. L. Huang, K. L. Chambliss, X. Gao et al., “SR-B1 drives endothelial cell LDL transcytosis via DOCK4 to promote atherosclerosis,” Nature, vol. 569, no. 7757, p. 7565, 2019. View at: Publisher Site | Google Scholar
  91. F. M. van der Valk, S. Bekkering, J. Kroon et al., “Oxidized phospholipids on lipoprotein (a) elicit arterial wall inflammation and an inflammatory monocyte response in humans,” Circulation, vol. 134, no. 8, pp. 611–624, 2016. View at: Publisher Site | Google Scholar
  92. S. Tsimikas, “In vivo markers of oxidative stress and therapeutic interventions,” The American Journal of Cardiology, vol. 101, no. 10, pp. S34–S42, 2008. View at: Publisher Site | Google Scholar
  93. M. Malaguarnera, M. Vacante, C. Russo et al., “Lipoprotein (a) in cardiovascular diseases,” BioMed Research International, vol. 2013, pp. 1–9, 2013. View at: Publisher Site | Google Scholar
  94. A. I. Papathanasiou, E. S. Lourida, L. D. Tsironis, J. A. Goudevenos, and A. D. Tselepis, “Short-and long-term elevation of autoantibody titers against oxidized LDL in patients with acute coronary syndromes: role of the lipoprotein-associated phospholipase A2 and the effect of atorvastatin treatment,” Atherosclerosis, vol. 196, no. 1, pp. 289–297, 2008. View at: Publisher Site | Google Scholar
  95. A. Deb and N. M. Caplice, “Lipoprotein (a): new insights into mechanisms of atherogenesis and thrombosis,” Clinical Cardiology, vol. 27, no. 5, pp. 258–264, 2004. View at: Publisher Site | Google Scholar
  96. N. Leitinger, “Oxidized phospholipids as modulators of inflammation in atherosclerosis,” Current Opinion in Lipidology, vol. 14, no. 5, pp. 421–430, 2003. View at: Publisher Site | Google Scholar
  97. T. Shimizu, “Inflammation-inducing factors of Mycoplasma pneumoniae,” Frontiers in Microbiology, vol. 31, no. 7, p. 414, 2016. View at: Publisher Site | Google Scholar
  98. I. Botos, D. M. Segal, and D. R. Davies, “The structural biology of Toll-like receptors,” Structure, vol. 19, no. 4, pp. 447–459, 2011. View at: Publisher Site | Google Scholar
  99. S. Lee, K. G. Birukov, C. E. Romanoski, J. R. Springstead, A. J. Lusis, and J. A. Berliner, “Role of phospholipid oxidation products in atherosclerosis,” Circulation Research, vol. 111, no. 6, pp. 778–799, 2012. View at: Publisher Site | Google Scholar
  100. S. Tsimikas, “Oxidative biomarkers in the diagnosis and prognosis of cardiovascular disease,” The American Journal of Cardiology, vol. 98, no. 11, pp. S9–S17, 2006. View at: Publisher Site | Google Scholar
  101. V. Starosta, T. Wu, A. Zimman et al., “Differential regulation of endothelial cell permeability by high and low doses of oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine,” American Journal of Respiratory Cell and Molecular Biology, vol. 46, no. 3, pp. 331–341, 2012. View at: Publisher Site | Google Scholar
  102. M. Pellegrino, E. Furmaniak-Kazmierczak, J. C. LeBlanc et al., “The apolipoprotein (a) component of lipoprotein (a) stimulates actin stress fiber formation and loss of cell-cell contact in cultured endothelial cells,” Journal of Biological Chemistry, vol. 279, no. 8, pp. 6526–6533, 2004. View at: Publisher Site | Google Scholar
  103. T. Cho, Y. Jung, and M. L. Koschinsky, “Apolipoprotein (a), through its strong lysine-binding site in KIV10, mediates increased endothelial cell contraction and permeability via a Rho/Rho kinase/MYPT1-dependent pathway,” Journal of Biological Chemistry, vol. 283, no. 45, pp. 30503–30512, 2008. View at: Publisher Site | Google Scholar
  104. O. Dubrovskyi, T. Wu, V. Starosta et al., “A Role For VEGFR2 activation in endothelial responses caused by barrier disruptive OXPAPC concentrations,” in A57 pulmonary barriers to edema formation 2012, pp. A1865–A1865, American Thoracic Society, 2012. View at: Google Scholar
  105. L. DeMaio, M. Rouhanizadeh, S. Reddy, A. Sevanian, J. Hwang, and T. K. Hsiai, “Oxidized phospholipids mediate occludin expression and phosphorylation in vascular endothelial cells,” American Journal of Physiology-Heart and Circulatory Physiology, vol. 290, no. 2, pp. H674–H683, 2006. View at: Publisher Site | Google Scholar
  106. R. Li, K. P. Mouillesseaux, D. Montoya et al., “Identification of prostaglandin E2 receptor subtype 2 as a receptor activated by OxPAPC,” Circulation Research, vol. 98, no. 5, pp. 642–650, 2006. View at: Publisher Site | Google Scholar
  107. A. L. Cole, G. Subbanagounder, S. Mukhopadhyay, J. A. Berliner, and D. K. Vora, “Oxidized phospholipid-induced endothelial cell/monocyte interaction is mediated by a cAMP-dependent R-Ras/PI3-kinase pathway,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 23, no. 8, pp. 1384–1390, 2003. View at: Publisher Site | Google Scholar
  108. K. D. O'brien, M. D. Allen, T. O. Mcdonald et al., “Vascular cell adhesion molecule-1 is expressed in human coronary atherosclerotic plaques. Implications for the mode of progression of advanced coronary atherosclerosis,” The Journal of Clinical Investigation, vol. 92, no. 2, pp. 945–951, 1993. View at: Publisher Site | Google Scholar
  109. S. Allen, S. Khan, S. P. Tam, M. Koschinsky, P. Taylor, and M. Yacoub, “Expression of adhesion molecules by Lp (a): a potential novel mechanism for its atherogenicity,” The FASEB Journal, vol. 12, no. 15, pp. 1765-1766, 1998. View at: Publisher Site | Google Scholar
  110. S.-P. Zhao and D.-Y. Xu, “Oxidized lipoprotein (a) enhanced the expression of P-selectin in cultured human umbilical vein endothelial cells,” Thrombosis Research, vol. 100, no. 6, pp. 501–510, 2000. View at: Publisher Site | Google Scholar
  111. S. Takami, S. Yamashita, S. Kihara et al., “Lipoprotein (a) enhances the expression of intercellular adhesion molecule-1 in cultured human umbilical vein endothelial cells,” Circulation, vol. 97, no. 8, pp. 721–728, 1998. View at: Publisher Site | Google Scholar
  112. P. Libby, “Inflammation in atherosclerosis,” Nature, vol. 420, no. 6917, pp. 868–874, 2002. View at: Publisher Site | Google Scholar
  113. S. Imaizumi, V. Grijalva, S. Priceman et al., “Mitogen-activated protein kinase phosphatase-1 deficiency decreases atherosclerosis in apolipoprotein E null mice by reducing monocyte chemoattractant protein-1 levels,” Molecular Genetics and Metabolism, vol. 101, no. 1, pp. 66–75, 2010. View at: Publisher Site | Google Scholar
  114. S. Lee, J. R. Springstead, B. W. Parks et al., “Metalloproteinase processing of HBEGF is a proximal event in the response of human aortic endothelial cells to oxidized phospholipids,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 32, no. 5, pp. 1246–1254, 2012. View at: Publisher Site | Google Scholar
  115. N. K. Singh, D. Wang, V. Kundumani-Sridharan, D. Van Quyen, J. Niu, and G. N. Rao, “15-Lipoxygenase-1-enhanced Src-Janus kinase 2-signal transducer and activator of transcription 3 stimulation and monocyte chemoattractant protein-1 expression require redox-sensitive activation of epidermal growth factor receptor in vascular wall remodeling,” Journal of Biological Chemistry, vol. 286, no. 25, pp. 22478–22488, 2011. View at: Publisher Site | Google Scholar
  116. P. Delerive, C. Furman, E. Teissier, J. C. Fruchart, P. Duriez, and B. Staels, “Oxidized phospholipids activate PPARα in a phospholipase A2-dependent manner,” FEBS Letters, vol. 471, no. 1, pp. 34–38, 2000. View at: Publisher Site | Google Scholar
  117. H. Lee, W. Shi, P. Tontonoz et al., “Role for peroxisome proliferator-activated receptor α in oxidized phospholipid–induced synthesis of monocyte chemotactic protein-1 and interleukin-8 by endothelial cells,” Circulation Research, vol. 87, no. 6, pp. 516–521, 2000. View at: Publisher Site | Google Scholar
  118. G. Subbanagounder, J. W. Wong, H. Lee et al., “Epoxyisoprostane and epoxycyclopentenone phospholipids regulate monocyte chemotactic protein-1 and interleukin-8 synthesis. Formation of these oxidized phospholipids in response to interleukin-1beta,” The Journal of Biological Chemistry, vol. 277, no. 9, pp. 7271–7281, 2002. View at: Publisher Site | Google Scholar
  119. T. Syrovets, J. Thillet, M. J. Chapman, and T. Simmet, “Lipoprotein (a) is a potent chemoattractant for human peripheral monocytes,” Blood, vol. 90, no. 5, pp. 2027–2036, 1997. View at: Google Scholar
  120. P. Wiesner, M. Tafelmeier, D. Chittka et al., “MCP-1 binds to oxidized LDL and is carried by lipoprotein (a) in human plasma,” Journal of Lipid Research, vol. 54, no. 7, pp. 1877–1883, 2013. View at: Publisher Site | Google Scholar
  121. S. N. Sotiriou, V. V. Orlova, N. Al-Fakhri et al., “Lipoprotein (a) in atherosclerotic plaques recruits inflammatory cells through interaction with Mac-1 integrin,” The FASEB Journal, vol. 20, no. 3, pp. 559–561, 2006. View at: Google Scholar
  122. A. Kadl, A. K. Meher, P. R. Sharma et al., “Identification of a novel macrophage phenotype that develops in response to atherogenic phospholipids via Nrf2,” Circulation Research, vol. 107, no. 6, pp. 737–746, 2010. View at: Publisher Site | Google Scholar
  123. S. Blüml, G. Zupkovitz, S. Kirchberger et al., “Epigenetic regulation of dendritic cell differentiation and function by oxidized phospholipids,” Blood, vol. 114, no. 27, pp. 5481–5489, 2009. View at: Google Scholar
  124. D. Lakshminarayan, T. K. Elajami, S. Devabhaktuni, and F. K. Welty, “Ischemic stroke in a young adult with extremely elevated lipoprotein (a): a case report and review of literature,” Journal of Clinical Lipidology, vol. 10, no. 5, pp. 1266–1271, 2016. View at: Google Scholar
  125. S. O. Rahaman, G. Zhou, and R. L. Silverstein, “Vav protein guanine nucleotide exchange factor regulates CD36 protein-mediated macrophage foam cell formation via calcium and dynamin-dependent processes,” Journal of Biological Chemistry, vol. 286, no. 41, pp. 36011–36019, 2011. View at: Publisher Site | Google Scholar
  126. M. R. Alexander and G. K. Owens, “Epigenetic control of smooth muscle cell differentiation and phenotypic switching in vascular development and disease,” Annual Review of Physiology, vol. 17, no. 74, pp. 13–40, 2012. View at: Publisher Site | Google Scholar
  127. M. R. Alexander, M. Murgai, C. W. Moehle, and G. K. Owens, “Interleukin-1β modulates smooth muscle cell phenotype to a distinct inflammatory state relative to PDGF-DD via NF-κB-dependent mechanisms,” Physiological Genomics, vol. 44, no. 7, pp. 417–429, 2012. View at: Publisher Site | Google Scholar
  128. M. R. Bennett, S. Sinha, and G. K. Owens, “Vascular smooth muscle cells in atherosclerosis,” Circulation Research, vol. 118, no. 4, pp. 692–702, 2016. View at: Publisher Site | Google Scholar
  129. E. Falk, “Pathogenesis of atherosclerosis,” Journal of the American College of Cardiology, vol. 47, no. 8, pp. C7–C12, 2006. View at: Publisher Site | Google Scholar
  130. T. Ichikawa, H. Unoki, H. Sun et al., “Lipoprotein (a) promotes smooth muscle cell proliferation and dedifferentiation in atherosclerotic lesions of human apo (a) transgenic rabbits,” The American Journal of Pathology, vol. 160, no. 1, pp. 227–236, 2002. View at: Publisher Site | Google Scholar
  131. N. Komai, R. Morishita, S. Yamada et al., “Mitogenic activity of oxidized lipoprotein (a) on human vascular smooth muscle cells,” Hypertension, vol. 40, no. 3, pp. 310–314, 2002. View at: Publisher Site | Google Scholar
  132. T. Yoshida, Q. Gan, and G. K. Owens, “Kruppel-like factor 4, Elk-1, and histone deacetylases cooperatively suppress smooth muscle cell differentiation markers in response to oxidized phospholipids,” American Journal of Physiology-Cell Physiology, vol. 295, no. 5, pp. C1175–C1182, 2008. View at: Publisher Site | Google Scholar
  133. L. S. Shankman, D. Gomez, O. A. Cherepanova et al., “KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis,” Nature Medicine, vol. 21, no. 6, pp. 628–637, 2015. View at: Publisher Site | Google Scholar
  134. N. A. Pidkovka, O. A. Cherepanova, T. Yoshida et al., “Oxidized phospholipids induce phenotypic switching of vascular smooth muscle cells in vivo and in vitro,” Circulation Research, vol. 101, no. 8, pp. 792–801, 2007. View at: Publisher Site | Google Scholar
  135. R. M. Lawn, A. D. Pearle, L. L. Kunz et al., “Feedback mechanism of focal vascular lesion formation in transgenic apolipoprotein (a) mice,” Journal of Biological Chemistry, vol. 271, no. 49, pp. 31367–31371, 1996. View at: Publisher Site | Google Scholar
  136. S. P. Zhao and D. Y. Xu, “Oxidized lipoprotein (a) increases the expression of platelet-derived growth factor-B in human umbilical vein endothelial cells,” Clinica Chimica Acta, vol. 296, no. 1–2, pp. 121–133, 2000. View at: Publisher Site | Google Scholar
  137. S. R. Johnstone, J. Ross, M. J. Rizzo et al., “Oxidized phospholipid species promote in vivo differential cx43 phosphorylation and vascular smooth muscle cell proliferation,” The American Journal of Pathology, vol. 175, no. 2, pp. 916–924, 2009. View at: Publisher Site | Google Scholar
  138. S. Kojima, P. C. Harpel, and D. B. Rifkin, “Lipoprotein (a) inhibits the generation of transforming growth factor beta: an endogenous inhibitor of smooth muscle cell migration,” The Journal of Cell Biology, vol. 113, no. 6, pp. 1439–1445, 1991. View at: Publisher Site | Google Scholar
  139. O. A. Cherepanova, N. A. Pidkovka, O. F. Sarmento et al., “Oxidized phospholipids induce type VIII collagen expression and vascular smooth muscle cell migration,” Circulation Research, vol. 104, no. 5, pp. 609–618, 2009. View at: Publisher Site | Google Scholar
  140. T. A. Seimon, M. J. Nadolski, X. Liao et al., “Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress,” Cell Metabolism, vol. 12, no. 5, pp. 467–482, 2010. View at: Publisher Site | Google Scholar
  141. K. Heermeier, R. Schneider, A. Heinloth, C. Wanner, S. Dimmeler, and J. Galle, “Oxidative stress mediates apoptosis induced by oxidized low-density lipoprotein and oxidized lipoprotein (a),” Kidney International, vol. 56, no. 4, pp. 1310–1312, 1999. View at: Publisher Site | Google Scholar
  142. R. Chen, L. Yang, and T. M. McIntyre, “Cytotoxic phospholipid oxidation products cell death from mitochondrial damage and the intrinsic caspase cascade,” Journal of Biological Chemistry, vol. 282, no. 34, pp. 24842–24850, 2007. View at: Publisher Site | Google Scholar
  143. A. Loidl, E. Sevcsik, G. Riesenhuber, H. P. Deigner, and A. Hermetter, “Oxidized phospholipids in minimally modified low density lipoprotein induce apoptotic signaling via activation of acid sphingomyelinase in arterial smooth muscle cells,” Journal of Biological Chemistry, vol. 278, no. 35, pp. 32921–32928, 2003. View at: Publisher Site | Google Scholar
  144. G. H. Li, X. L. Lin, H. Zhang et al., “Ox-Lp (a) transiently induces HUVEC autophagy via an ROS-dependent PAPR-1-LKB1–AMPK–mTOR pathway,” Atherosclerosis, vol. 243, no. 1, pp. 223–235, 2015. View at: Publisher Site | Google Scholar
  145. L. Hervio, V. Durlach, A. Girard-Globa, and E. Angles-Cano, “Multiple binding with identical linkage: a mechanism that explains the effect of lipoprotein (a) on fibrinolysis,” Biochemistry, vol. 34, no. 41, pp. 13353–13358, 1995. View at: Publisher Site | Google Scholar
  146. L. A. Miles, G. M. Fless, E. G. Levin, A. M. Scanu, and E. F. Plow, “A potential basis for the thrombotic risks associated with lipoprotein (a),” Nature, vol. 339, no. 6222, pp. 301–303, 1989. View at: Publisher Site | Google Scholar
  147. E. von Hodenberg, J. Kreuzer, M. Hautmann, T. Nordt, W. Kübler, and C. Bode, “Effects of lipoprotein (a) on success rate of thrombolytic therapy in acute myocardial infarction,” The American Journal of Cardiology, vol. 67, no. 16, pp. 1349–1353, 1991. View at: Publisher Site | Google Scholar
  148. G. Davì and C. Patrono, “Platelet activation and atherothrombosis,” New England Journal of Medicine, vol. 357, no. 24, pp. 2482–2494, 2007. View at: Publisher Site | Google Scholar
  149. M. L. Rand, W. Sangrar, M. A. Hancock et al., “Apolipoprotein (a) enhances platelet responses to the thrombin receptor–activating peptide SFLLRN,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 18, no. 9, pp. 1393–1399, 1998. View at: Publisher Site | Google Scholar
  150. L. D. Tsironis, J. V. Mitsios, H. J. Milionis, M. Elisaf, and A. D. Tselepis, “Effect of lipoprotein (a) on platelet activation induced by platelet-activating factor: role of apolipoprotein (a) and endogenous PAF-acetylhydrolase,” Cardiovascular Research, vol. 63, no. 1, pp. 130–138, 2004. View at: Publisher Site | Google Scholar
  151. K. Chen, W. Li, J. Major, S. O. Rahaman, M. Febbraio, and R. L. Silverstein, “Vav guanine nucleotide exchange factors link hyperlipidemia and a prothrombotic state,” Blood, vol. 117, no. 21, pp. 5744–5750, 2011. View at: Publisher Site | Google Scholar
  152. J. M. Edelberg, M. Gonzalez-Gronow, and S. V. Pizzo, “Lipoprotein (a) inhibition of plasminogen activation by tissue-type plasminogen activator,” Thrombosis Research, vol. 57, no. 1, pp. 155–162, 1990. View at: Publisher Site | Google Scholar
  153. N. T. Feric, M. B. Boffa, S. M. Johnston, and M. L. Koschinsky, “Apolipoprotein (a) inhibits the conversion of Glu-plasminogen to Lys-plasminogen: a novel mechanism for lipoprotein (a)-mediated inhibition of plasminogen activation,” Journal of Thrombosis and Haemostasis, vol. 6, no. 12, pp. 2113–2120, 2008. View at: Publisher Site | Google Scholar
  154. X. F. Cheng, O. Bäck, T. K. Nilsson, E. N. Lundqvist, G. Pohl, and P. Wallén, “Binding of tissue plasminogen activator to human endothelial cells. Importance of the B-chain as a ligand,” Biochemical Journal, vol. 287, no. 2, pp. 407–413, 1992. View at: Publisher Site | Google Scholar
  155. S. Ren, S. Shatadal, and G. X. Shen, “Protein kinase C-β mediates lipoprotein-induced generation of PAI-1 from vascular endothelial cells,” American Journal of Physiology-Endocrinology and Metabolism, vol. 278, no. 4, pp. E656–E662, 2000. View at: Publisher Site | Google Scholar
  156. L. Hervio, M. J. Chapman, J. Thillet, S. Loyau, and E. Angles-Cano, “Does apolipoprotein (a) heterogeneity influence lipoprotein (a) effects on fibrinolysis?” Blood, vol. 82, no. 2, pp. 392–397, 1993. View at: Google Scholar
  157. N. Mackman, “The role of tissue factor and factor VIIa in hemostasis,” Anesthesia and Analgesia, vol. 108, no. 5, pp. 1447–1452, 2009. View at: Publisher Site | Google Scholar
  158. T. A. Drake, J. H. Morrissey, and T. S. Edgington, “Selective cellular expression of tissue factor in human tissues. Implications for disorders of hemostasis and thrombosis,” The American Journal of Pathology, vol. 134, no. 5, p. 1087, 1989. View at: Google Scholar
  159. N. M. Caplice, C. Panetta, T. E. Peterson et al., “Lipoprotein (a) binds and inactivates tissue factor pathway inhibitor: a novel link between lipoproteins and thrombosis,” Blood, vol. 98, no. 10, pp. 2980-2981, 2001. View at: Publisher Site | Google Scholar
  160. V. N. Bochkov, D. Mechtcheriakova, M. Lucerna et al., “Oxidized phospholipids stimulate tissue factor expression in human endothelial cells via activation of ERK/EGR-1 and Ca++/NFAT,” Blood, vol. 99, no. 1, pp. 199–206, 2002. View at: Publisher Site | Google Scholar
  161. G. J. Broze, L. A. Warren, W. F. Novotny, D. A. Higuchi, J. J. Girard, and J. P. Miletich, “The lipoprotein-associated coagulation inhibitor that inhibits the factor VII-tissue factor complex also inhibits factor Xa: insight into its possible mechanism of action,” Blood, vol. 71, no. 2, pp. 335–343, 1988. View at: Google Scholar
  162. K. M. Kostner and G. M. Kostner, “Factors affecting plasma lipoprotein (a) levels: role of hormones and other nongenetic factors,” Seminars in Vascular Medicine, vol. 4, no. 2, pp. 211–214, 2004. View at: Publisher Site | Google Scholar
  163. H. Dieplinger, C. Lackner, F. Kronenberg et al., “Elevated plasma concentrations of lipoprotein (a) in patients with end-stage renal disease are not related to the size polymorphism of apolipoprotein (a),” The Journal of Clinical Investigation, vol. 91, no. 2, pp. 397–401, 1993. View at: Publisher Site | Google Scholar
  164. T. Soulat, S. Loyau, V. Baudouin et al., “Effect of individual plasma lipoprotein (a) variations in vivo on its competition with plasminogen for fibrin and cell binding: an in vitro study using plasma from children with idiopathic nephrotic syndrome,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 20, no. 2, pp. 575–584, 2000. View at: Publisher Site | Google Scholar
  165. E. A. Enas, V. Chacko, A. Senthilkumar, N. Puthumana, and V. Mohan, “Elevated lipoprotein (a)—a genetic risk factor for premature vascular disease in people with and without standard risk factors: a review,” Disease-a-Month, vol. 1, no. 52, p. 5, 2006. View at: Publisher Site | Google Scholar
  166. D. Yin, P. Shao, and Y. Liu, “Elevated lipoprotein (a) levels predict deep vein thrombosis in acute ischemic stroke patients,” Neuroreport, vol. 27, no. 1, pp. 39–44, 2016. View at: Publisher Site | Google Scholar
  167. C. Catena, M. Novello, L. Dotto, S. De Marchi, and L. A. Sechi, “Serum lipoprotein (a) concentrations and alcohol consumption in hypertension: possible relevance for cardiovascular damage,” Journal of Hypertension., vol. 21, no. 2, pp. 281–288, 2003 Feb 1. View at: Publisher Site | Google Scholar
  168. R. Siekmeier, W. März, H. Kronenberger, U. B. Seiffert, and W. Gross, “Effects of cigarette smoking on plasma lipids, apolipoproteins, and lipoprotein (a) in healthy subjects,” Clinical Chemistry, vol. 40, no. 7, pp. 1350-1351, 1994. View at: Google Scholar
  169. I. Os, A. Høieggen, A. Larsen et al., “Smoking and relation to other risk factors in postmenopausal women with coronary artery disease, with particular reference to whole blood viscosity and β-cell function,” Journal of Internal Medicine., vol. 253, no. 2, pp. 232–239, 2003 Feb. View at: Publisher Site | Google Scholar
  170. P. M. da Silva, J. S. Duarte, P. von Hafe, V. Gil, J. N. de Oliveira, and G. de Sousa, “Standardization of laboratory and lipid profile evaluation: a call for action with a special focus in 2016 ESC/EAS dyslipidaemia guidelines–Full report,” Atherosclerosis Supplements, vol. 30, no. 31, pp. e1–e12, 2018. View at: Publisher Site | Google Scholar
  171. M. R. Hammerman and S. B. Miller, “Effects of growth hormone and insulin-like growth factor I on renal growth and function,” The Journal of Pediatrics, vol. 131, no. 1, pp. S17–S19, 1997. View at: Publisher Site | Google Scholar
  172. M. Clodi, R. Oberbauer, W. Waldhäusl, G. Maurer, G. M. Kostner, and K. Kostner, “Urinary excretion of apo (a) fragments in NIDDM patients,” Diabetologia, vol. 40, no. 12, pp. 1455–1460, 1997. View at: Publisher Site | Google Scholar
  173. G. M. Kostner, “Lipoprotein (a): metabolismus und beeinflussung des plasmaspiegels,” Journal für Kardiologie-Austrian Journal of Cardiology, vol. 9, no. 7, pp. 321–324, 2002. View at: Google Scholar
  174. G. Gaeta, S. Lanero, S. Barra et al., “Sex hormones and lipoprotein (a) concentration,” Expert Opinion on Investigational Drugs, vol. 20, no. 2, pp. 221–238, 2011. View at: Publisher Site | Google Scholar
  175. M. S. Hislop, A. S. Gibson, M. I. Lambert, T. D. Noakes, and A. D. Marais, “Effects of androgen manipulation on postprandial triglyceridaemia, low-density lipoprotein particle size and lipoprotein (a) in men,” Atherosclerosis, vol. 159, no. 2, pp. 425–432, 2001. View at: Publisher Site | Google Scholar
  176. R. Zechner, G. Desoye, M. O. Schweditsch, K. P. Pfeiffer, and G. M. Kostner, “Fluctuations of plasma liproprotein-a concentrations during pregnancy and post partum,” Metabolism, vol. 35, no. 4, pp. 333–336, 1986. View at: Publisher Site | Google Scholar
  177. E. N. Pearce, “Hypothyroidism and dyslipidemia: modern concepts and approaches,” Current Cardiology Reports, vol. 6, no. 6, pp. 451–456, 2004. View at: Publisher Site | Google Scholar
  178. M. Paassilta, K. Kervinen, M. Linnaluoto, and Y. A. Kesäniemi, “Alcohol withdrawal-induced change in lipoprotein (a) association with the growth hormone/insulin-like growth factor-I (IGF-I)/IGF-binding protein-1 (IGFBP-1) axis,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 18, no. 4, pp. 650–654, 1998. View at: Publisher Site | Google Scholar
  179. A. Dionyssiou-Asteriou and M. Katimertzi, “Endogenous testosterone and serum apolipoprotein (a) levels,” Atherosclerosis, vol. 100, no. 1, pp. 123–126, 1993. View at: Publisher Site | Google Scholar
  180. R. Saeedi, M. Li, and J. Frohlich, “Lipoprotein (a): why is it important?” British Columbia Medical Journal, vol. 1, no. 56, pp. 180–182, 2014. View at: Google Scholar
  181. Y. Hirowatari, D. Manita, K. Kamachi, and A. Tanaka, “Effect of dietary modification by calorie restriction on cholesterol levels in lipoprotein (a) and other lipoprotein classes,” Annals of Clinical Biochemistry, vol. 54, no. 5, pp. 567–576, 2017. View at: Publisher Site | Google Scholar
  182. R. S. Najjar, C. E. Moore, and B. D. Montgomery, “Consumption of a defined, plant-based diet reduces lipoprotein (a), inflammation, and other atherogenic lipoproteins and particles within 4 weeks,” Clinical Cardiology, vol. 41, no. 8, pp. 1062–1068, 2018. View at: Publisher Site | Google Scholar
  183. E. Kelly and L. Hemphill, “Lipoprotein (a): a lipoprotein whose time has come,” Current Treatment Options in Cardiovascular Medicine, vol. 19, no. 7, p. 48, 2017. View at: Publisher Site | Google Scholar
  184. F. Dati, J. R. Tate, S. M. Marcovina, and A. Steinmetz, “First WHO/IFCC international reference reagent for lipoprotein (a) for immunoassay–Lp (a) SRM 2B,” Clinical Chemistry and Laboratory Medicine (CCLM), vol. 42, no. 6, pp. 670–676, 2004. View at: Publisher Site | Google Scholar
  185. J. P. McConnell, P. A. Guadagno, T. D. Dayspring et al., “Lipoprotein (a) mass: a massively misunderstood metric,” Journal of Clinical Lipidology, vol. 8, no. 6, pp. 550–553, 2014. View at: Publisher Site | Google Scholar
  186. B. Gencer, F. Kronenberg, E. S. Stroes, and F. Mach, “Lipoprotein (a): the revenant,” European Heart Journal, vol. 38, no. 20, pp. 1553–1560, 2017. View at: Publisher Site | Google Scholar
  187. A. M. Scanu, “The role of lipoprotein (a) in the pathogenesis of atherosclerotic cardiovascular disease and its utility as predictor of coronary heart disease events,” Current Cardiology Reports, vol. 3, no. 5, pp. 385–390, 2001. View at: Google Scholar
  188. C. Labeur, G. Michiels, J. Bury, D. C. Usher, and M. Rosseneu, “Lipoprotein (a) quantified by an enzyme-linked immunosorbent assay with monoclonal antibodies,” Clinical Chemistry, vol. 35, no. 7, pp. 1380–1384, 1989. View at: Google Scholar
  189. S. Tsimikas and J. L. Hall, “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,” Journal of the American College of Cardiology, vol. 60, no. 8, pp. 716–721, 2012. View at: Publisher Site | Google Scholar
  190. M. Bucci, C. Tana, M. A. Giamberardino, and F. Cipollone, “Lp (a) and cardiovascular risk: investigating the hidden side of the moon,” Nutrition, Metabolism and Cardiovascular Diseases, vol. 26, no. 11, pp. 980–986, 2016. View at: Publisher Site | Google Scholar
  191. N. Nago, K. Kayaba, J. Hiraoka et al., “Lipoprotein (a) levels in the Japanese population: influence of age and sex, and relation to atherosclerotic risk factors: the Jichi Medical School Cohort Study,” American Journal of Epidemiology, vol. 141, no. 9, pp. 815–821, 1995. View at: Publisher Site | Google Scholar
  192. A. O. Akanji, A. N. Al-Isa, and L. Thalib, “Determinants of blood levels of some thrombogenic biomarkers in healthy Arab adolescent subjects,” Clinical Chemistry and Laboratory Medicine, vol. 49, no. 10, pp. 1681–1690, 2011. View at: Publisher Site | Google Scholar
  193. J. Frohlich, M. Dobiášová, L. Adler, and M. Francis, “Gender differences in plasma levels of lipoprotein (a) in patients with angiographically proven coronary artery,” Physiological Research, vol. 53, pp. 481–486, 2004. View at: Google Scholar
  194. B. G. Nordestgaard, M. J. Chapman, K. Ray et al., “Lipoprotein (a) as a cardiovascular risk factor: current status,” European Heart Journal, vol. 31, no. 23, pp. 2844–2853, 2010. View at: Publisher Site | Google Scholar
  195. K. L. Ellis and G. F. Watts, “Is lipoprotein (a) ready for prime-time use in the clinic?” Cardiology Clinics, vol. 36, no. 2, pp. 287–298, 2018. View at: Publisher Site | Google Scholar
  196. B. G. Nordestgaard, “A test in context: lipid profile, fasting versus nonfasting,” Journal of the American College of Cardiology, vol. 70, no. 13, pp. 1637–1646, 2017. View at: Publisher Site | Google Scholar
  197. A. L. Catapano, I. Graham, G. De Backer et al., “2016 ESC/EAS guidelines for the management of dyslipidaemias: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR),” Atherosclerosis, vol. 1, no. 253, pp. 281–344, 2016. View at: Google Scholar
  198. T. J. Anderson, J. Grégoire, R. A. Hegele et al., “2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult,” Canadian Journal of Cardiology, vol. 29, no. 2, pp. 151–167, 2013. View at: Google Scholar
  199. A. H. Lichtenstein, L. M. Ausman, W. Carrasco et al., “Effects of canola, corn, and olive oils on fasting and postprandial plasma lipoproteins in humans as part of a National Cholesterol Education Program Step 2 diet,” Arteriosclerosis and Thrombosis: a Journal of Vascular Biology, vol. 13, no. 10, pp. 1533–1542, 1993. View at: Publisher Site | Google Scholar
  200. G. Luc, J. M. Bard, D. Arveiler et al., “Lipoprotein (a) as a predictor of coronary heart disease: the PRIME Study,” Atherosclerosis, vol. 163, no. 2, pp. 377–384, 2002. View at: Publisher Site | Google Scholar
  201. V. M. Maher, B. G. Brown, S. M. Marcovina, L. A. Hillger, X. Q. Zhao, and J. J. Albers, “Effects of lowering elevated LDL cholesterol on the cardiovascular risk of lipoprotein (a),” JAMA, vol. 274, no. 22, pp. 1771–1774, 1995. View at: Publisher Site | Google Scholar
  202. G. Lippi and G. Targher, “Optimal therapy for reduction of lipoprotein (a),” Journal of Clinical Pharmacy and Therapeutics, vol. 37, no. 1, pp. 1–3, 2012. View at: Publisher Site | Google Scholar
  203. C. Yeang, M. Y. Hung, Y. S. Byun et al., “Effect of therapeutic interventions on oxidized phospholipids on apolipoprotein B100 and lipoprotein (a),” Journal of Clinical Lipidology, vol. 10, no. 3, pp. 594–603, 2016. View at: Publisher Site | Google Scholar
  204. C. Yeang, J. L. Witztum, and S. Tsimikas, “‘LDL-C’= LDL-C+ Lp (a)-C: implications of achieved ultra-low LDL-C levels in the proprotein convertase subtilisin/kexin type 9 era of potent LDL-C lowering,” Current Opinion in Lipidology, vol. 26, no. 3, pp. 169–178, 2015. View at: Publisher Site | Google Scholar
  205. N. J. Woudberg, S. Pedretti, S. Lecour et al., “Pharmacological intervention to modulate HDL: what do we target?” Frontiers in Pharmacology, vol. 22, no. 8, p. 989, 2018. View at: Publisher Site | Google Scholar
  206. A. Sahebkar, Ž. Reiner, L. E. Simental-Mendía, G. Ferretti, and A. F. Cicero, “Effect of extended-release niacin on plasma lipoprotein (a) levels: a systematic review and meta-analysis of randomized placebo-controlled trials,” Metabolism, vol. 65, no. 11, pp. 1664–1678, 2016. View at: Publisher Site | Google Scholar
  207. M. Akaike, H. Azuma, A. Kagawa et al., “Effect of aspirin treatment on serum concentrations of lipoprotein (a) in patients with atherosclerotic diseases,” Clinical Chemistry, vol. 48, no. 9, pp. 1454–1459, 2002. View at: Google Scholar
  208. N. J. Viney, J. C. Van Capelleveen, R. S. Geary et al., “Antisense oligonucleotides targeting apolipoprotein (a) in people with raised lipoprotein (a): two randomised, double-blind, placebo-controlled, dose-ranging trials,” The Lancet, vol. 388, no. 10057, pp. 2239–2253, 2016. View at: Publisher Site | Google Scholar
  209. S. Tsimikas, N. J. Viney, S. G. Hughes et al., “Antisense therapy targeting apolipoprotein (a): a randomised, double-blind, placebo-controlled phase 1 study,” The Lancet, vol. 386, no. 10002, pp. 1472-1473, 2015. View at: Publisher Site | Google Scholar
  210. M. J. Borrelli, A. Youssef, M. B. Boffa, and M. L. Koschinsky, “New frontiers in Lp (a)-targeted therapies,” Trends in Pharmacological Sciences, vol. 40, no. 3, pp. 212–225, 2019. View at: Publisher Site | Google Scholar
  211. R. D. Santos, F. J. Raal, A. L. Catapano, J. L. Witztum, E. Steinhagen-Thiessen, and S. Tsimikas, “Mipomersen, an antisense oligonucleotide to apolipoprotein B-100, reduces lipoprotein (a) in various populations with hypercholesterolemia: results of 4 phase III trials,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 35, no. 3, pp. 689–699, 2015. View at: Publisher Site | Google Scholar
  212. A. Sahebkar and G. F. Watts, “New LDL-cholesterol lowering therapies: pharmacology, clinical trials, and relevance to acute coronary syndromes,” Clinical Therapeutics, vol. 35, no. 8, pp. 1082–1098, 2013. View at: Publisher Site | Google Scholar
  213. M. Cuchel, E. A. Meagher, H. du Toit Theron et al., “Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study,” The Lancet, vol. 381, no. 9860, pp. 40–46, 2013. View at: Publisher Site | Google Scholar
  214. C. P. Cannon, S. Shah, H. M. Dansky et al., “Safety of anacetrapib in patients with or at high risk for coronary heart disease,” New England Journal of Medicine, vol. 363, no. 25, pp. 2406–2415, 2010. View at: Publisher Site | Google Scholar
  215. T. Teramoto, M. Shirakawa, M. Kikuchi et al., “Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib in Japanese patients with dyslipidemia,” Atherosclerosis, vol. 230, no. 1, pp. 52–60, 2013. View at: Publisher Site | Google Scholar
  216. A. Vogt, “Lipoprotein (a)-apheresis in the light of new drug developments,” Atherosclerosis Supplements, vol. 1, no. 30, pp. 38–43, 2017. View at: Publisher Site | Google Scholar
  217. A. Kagawa, H. Azuma, M. Akaike, Y. Kanagawa, and T. Matsumoto, “Aspirin reduces apolipoprotein (a)(apo (a)) production in human hepatocytes by suppression of apo (a) gene transcription,” Journal of Biological Chemistry, vol. 274, no. 48, pp. 34111–34115, 1999. View at: Publisher Site | Google Scholar
  218. M. Abifadel, M. Varret, J. P. Rabès et al., “Mutations in PCSK9 cause autosomal dominant hypercholesterolemia,” Nature Genetics., vol. 34, no. 2, p. 154, 2003. View at: Google Scholar
  219. J. C. Cohen, E. Boerwinkle, T. H. Mosley Jr, and H. H. Hobbs, “Sequence variations in PCSK9, low LDL, and protection against coronary heart disease,” New England Journal of Medicine, vol. 354, no. 12, pp. 1264–1272, 2006. View at: Publisher Site | Google Scholar
  220. F. J. Raal, R. P. Giugliano, M. S. Sabatine et al., “Reduction in lipoprotein (a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials,” Journal of the American College of Cardiology, vol. 63, no. 13, pp. 1278–1288, 2014. View at: Publisher Site | Google Scholar
  221. M. S. Sabatine, R. P. Giugliano, S. D. Wiviott et al., “Efficacy and safety of evolocumab in reducing lipids and cardiovascular events,” New England Journal of Medicine, vol. 372, no. 16, pp. 1500–1509, 2015. View at: Publisher Site | Google Scholar
  222. D. Gaudet, D. J. Kereiakes, J. M. McKenney et al., “Effect of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 9 antibody, on lipoprotein (a) concentrations (a pooled analysis of 150 mg every two weeks dosing from phase 2 trials),” The American Journal of Cardiology., vol. 114, no. 5, pp. 711–815, 2014 Sep 1. View at: Publisher Site | Google Scholar
  223. K. Fitzgerald, S. White, A. Borodovsky et al., “A highly durable RNAi therapeutic inhibitor of PCSK9,” New England Journal of Medicine, vol. 376, no. 1, pp. 41–51, 2017. View at: Publisher Site | Google Scholar
  224. K. K. Ray, U. Landmesser, L. A. Leiter et al., “Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol,” New England Journal of Medicine, vol. 376, no. 15, pp. 1430–1440, 2017. View at: Publisher Site | Google Scholar
  225. K. Arai, A. Orsoni, Z. Mallat et al., “Acute impact of apheresis on oxidized phospholipids in patients with familial hypercholesterolemia,” Journal of Lipid Research, vol. 53, no. 8, pp. 1670–1678, 2012. View at: Publisher Site | Google Scholar
  226. S. N. Pokrovsky, A. V. Sussekov, O. I. Afanasieva, I. Y. Adamova, A. A. Lyakishev, and V. V. Kukharchuk, “Extracorporeal immunoadsorption for the specific removal of lipoprotein (a)(Lp (a) apheresis): preliminary clinical data,” Chemistry and Physics of Lipids, vol. 1, no. 67, pp. 323–330, 1994. View at: Publisher Site | Google Scholar
  227. S. N. Pokrovsky, O. I. Afanasieva, M. S. Safarova et al., “Specific Lp (a) apheresis: a tool to prove lipoprotein (a) atherogenicity,” Atherosclerosis Supplements, vol. 1, no. 30, pp. 166–173, 2017 Nov. View at: Publisher Site | Google Scholar
  228. S. T. Crooke and R. S. Geary, “Clinical pharmacological properties of mipomersen (Kynamro), a second generation antisense inhibitor of apolipoprotein B,” British Journal of Clinical Pharmacology, vol. 76, no. 2, pp. 269–276, 2013. View at: Publisher Site | Google Scholar
  229. E. Merki, M. Graham, A. Taleb et al., “Antisense oligonucleotide lowers plasma levels of apolipoprotein (a) and lipoprotein (a) in transgenic mice,” Journal of the American College of Cardiology, vol. 57, no. 15, pp. 1611–1621, 2011. View at: Publisher Site | Google Scholar
  230. J. Kurreck, “Antisense technologies: improvement through novel chemical modifications,” European Journal of Biochemistry, vol. 270, no. 8, pp. 1628–1644, 2003. View at: Publisher Site | Google Scholar
  231. L. A. Carlson, A. Hamsten, and A. Asplund, “Pronounced lowering of serum levels of lipoprotein Lp (a) in hyperlipidaemic subjects treated with nicotinic acid,” Journal of Internal Medicine, vol. 226, no. 4, pp. 271–276, 1989. View at: Publisher Site | Google Scholar
  232. A. M. Scanu and R. Bamba, “Niacin and lipoprotein (a): facts, uncertainties, and clinical considerations,” The American Journal of Cardiology, vol. 101, no. 8, pp. s44–s47, 2008. View at: Publisher Site | Google Scholar
  233. S. J. Nicholls and P. J. Psaltis, “What role for lipoprotein (a) in clinical practice?” The Lancet Diabetes & Endocrinology, vol. 5, no. 7, pp. 487–489, 2017. View at: Publisher Site | Google Scholar
  234. M. Li, R. Saeedi, S. W. Rabkin, and J. Frohlich, “Dramatic lowering of very high Lp(a) in response to niacin,” Journal of Clinical Lipidology, vol. 8, no. 4, pp. 448–450, 2014. View at: Publisher Site | Google Scholar
  235. E. Stroes, D. Colquhoun, D. Sullivan et al., “Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab,” Journal of the American College of Cardiology, vol. 63, no. 23, pp. 2541–2548, 2014. View at: Google Scholar
  236. D. Bandyopadhyay, A. Hajra, K. Ashish, A. Qureshi, and S. Ball, “New hope for hyperlipidemia management: Inclisiran,” Journal of Cardiology, vol. 71, no. 5, pp. 523-524, 2018. View at: Publisher Site | Google Scholar
  237. A. Vogt, “Hyperlipoproteinaemia (a)–apheresis and emerging therapies,” Clinical Research in Cardiology Supplements, vol. 12, no. 1, pp. 12–27, 2017. View at: Publisher Site | Google Scholar
  238. S. N. Pokrovsky, O. I. Afanasieva, and M. V. Ezhov, “Lipoprotein (a) apheresis,” Current Opinion in Lipidology, vol. 27, no. 4, pp. 351–358, 2016. View at: Publisher Site | Google Scholar
  239. B. R. Jaeger, Y. Richter, D. Nagel et al., “Longitudinal cohort study on the effectiveness of lipid apheresis treatment to reduce high lipoprotein (a) levels and prevent major adverse coronary events,” Nature Reviews Cardiology, vol. 6, no. 3, pp. 229–239, 2009. View at: Publisher Site | Google Scholar
  240. U. Kassner, T. Schlabs, A. Rosada, and E. Steinhagen-Thiessen, “Lipoprotein (a)–an independent causal risk factor for cardiovascular disease and current therapeutic options,” Atherosclerosis Supplements, vol. 1, no. 18, pp. 263–267, 2015. View at: Publisher Site | Google Scholar
  241. E. Roeseler, U. Julius, F. Heigl et al., “Lipoprotein apheresis for lipoprotein (a)-associated cardiovascular disease: prospective 5 years of follow-up and apolipoprotein (a) characterization,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 36, no. 9, pp. 2019–2027, 2016. View at: Publisher Site | Google Scholar
  242. P. M. Moriarty, “Lipoprotein apheresis: present and future uses,” Current Opinion in Lipidology, vol. 26, no. 6, pp. 544–552, 2015. View at: Google Scholar

Copyright © 2020 Motasim M. Jawi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

284 Views | 394 Downloads | 0 Citations
 PDF  Download Citation  Citation
 Download other formatsMore
 Order printed copiesOrder

We are committed to sharing findings related to COVID-19 as quickly and safely as possible. Any author submitting a COVID-19 paper should notify us at help@hindawi.com to ensure their research is fast-tracked and made available on a preprint server as soon as possible. We will be providing unlimited waivers of publication charges for accepted articles related to COVID-19.