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Lipoprotein classification, metabolism, and role in atherosclerosis

Lipoprotein classification, metabolism, and role in atherosclerosis
Literature review current through: Jan 2024.
This topic last updated: Oct 23, 2023.

INTRODUCTION — Lipids, such as cholesterol and triglycerides, are insoluble in plasma. Circulating lipid is carried in lipoproteins that transport the lipid to various tissues for energy utilization, lipid deposition, steroid hormone production, and bile acid formation. The lipoprotein consists of esterified and unesterified cholesterol, triglycerides, phospholipids, and proteins referred to as apolipoproteins (apo).

The classification of lipoproteins, the function of the different apolipoproteins that they contain, the pathways of lipid metabolism, and how lipoprotein disorders can promote the development of atherosclerosis will be reviewed here.

APOLIPOPROTEINS — Each class of lipoprotein particle discussed below (see 'Classification' below) contains protein that is referred to as apolipoprotein. Understanding the major functions of the different apolipoproteins is important clinically, because variants in their structure or alterations in their metabolism can lead to abnormalities in lipid handling [1]. (See "HDL cholesterol: Clinical aspects of abnormal values" and "Lipoprotein(a)" and "Hypertriglyceridemia in adults: Management" and "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia" and "Measurement of blood lipids and lipoproteins".)

A-I – Structural protein for high-density lipoprotein (HDL); ligand for ABCA1 (ATP Binding Cassette) transporter, activator of lecithin-cholesterol acyltransferase (LCAT).

A-II – Structural protein for HDL; activator of hepatic lipase.

A-IV – Activator of lipoprotein lipase (LPL) and LCAT.

B-100 – Structural protein for very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), LDL, and lipoprotein(a) (Lp(a)); ligand for the LDL receptor; required for assembly and secretion of VLDL.

B-48 – Truncated form of B-100 that contains 48 percent of B-100; required for assembly and secretion of chylomicrons; does not bind to LDL receptor.

C-I – Activator of LCAT.

C-II – Essential cofactor for LPL.

C-III – Interferes with apoE-mediated clearance of triglyceride-enriched lipoproteins and remnants by cellular receptors, particularly in the liver [2]; inhibits triglyceride hydrolysis by LPL and hepatic lipase [3]; and has multiple proatherogenic effects on the arterial wall, including interfering with normal endothelial function [4,5].

D – May be a cofactor for cholesteryl ester transfer protein.

E – Ligand for hepatic chylomicron and VLDL remnant receptor, leading to clearance of these lipoproteins from the circulation; ligand for LDL receptor. There are three different apoE alleles in humans: E-2, which has cysteine residues at positions 112 and 158; E-3, which occurs in over 60 to 80 percent of studied populations (in Europe, Africa, Asia, and the United States [6]) and has cysteine at position 112 and arginine at position 158; and E-4, which has arginine residues at positions 112 and 158 [7]. These alleles encode for a combination of apoE isoforms that are inherited in a codominant fashion. Compared with apoE-3, apoE-2 has reduced affinity and apoE-4 has enhanced affinity for the LDL (apoB/E) receptor. These isoforms are important clinically because apoE-2 is associated with familial dysbetalipoproteinemia (due to less efficient clearance of VLDL and chylomicrons) and apoE-4 is associated with an increased risk of hypercholesterolemia and coronary heart disease (CHD). (See "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia", section on 'Polygenic hypercholesterolemia' and "Hypertriglyceridemia in adults: Approach to evaluation", section on 'Etiology'.)

Apo(a) – Structural protein for Lp(a); inhibitor of plasminogen activation on Lp(a).

The assembly and secretion of apoB-containing lipoproteins in the liver and intestines is dependent upon microsomal triglyceride transfer protein, which transfers lipids to apoB-100 for hepatically synthesized lipoproteins and to apoB-48 for intestinally synthesized lipoproteins. A study identified apoB and microsomal transfer protein gene expression in human myocytes, strongly suggesting that the heart synthesizes and secretes apoB-containing lipoproteins [8]. This may represent a pathway of "reverse triglyceride transport" by which the cardiac myocytes can unload surplus fatty acids not required for fuel.

CLASSIFICATION — The six major lipoproteins particles are chylomicrons and chylomicron remnants, VLDL, intermediate-density lipoprotein (IDL), LDL, HDL, and lipoprotein(a) (Lp(a)). All six lipoproteins carry cholesterol and triglycerides to varying degrees. These particles have been classified based on their physicochemical characteristics (eg, size, density) and apolipoprotein composition. LDL and HDL have been divided into subclasses.

Triglyceride-rich lipoproteins — The term triglyceride-rich lipoproteins (TGRL) includes chylomicrons and VLDL. In the bloodstream, TGRLs undergo lipolysis, resulting in delipidated particles that contain proportionally more cholesterol and less triglyceride. These triglyceride-rich remnant particles comprise chylomicron remnants and VLDL remnants. Chylomicrons are rapidly cleared from the circulation but may accumulate under circumstances of impaired lipolysis resulting in chylomicron remnant particles. Large VLDL particles are the precursor of hepatically derived TGRL remnants that encompass the aggregate of VLDL and IDL, all of which have differing physiochemical properties.

Small dense LDL is an end-product of large VLDL lipolysis, but data suggest that these particles may also be directly secreted. High levels of small dense LDL may be genetically determined and independent of VLDL hydrolysis [9]. The role of TGRL in atherosclerosis is discussed below. (See 'Triglyceride-rich lipoprotein remnants and cardiovascular disease' below.)

There is no easy way to measure the cholesterol content of TGRL and TGRL remnants. Accurate measurement of TGRLs is technically challenging due to the dynamic catabolism that alters the lipid and apolipoprotein composition of chylomicrons and VLDL. With lipolysis, the TGRLs become smaller in size, depleted in triglycerides, and enriched in cholesterol while maintaining one apoB per particle. Although chylomicrons carry apoB-48, a truncated form of apoB-100, the chylomicron precursor and remnants often overlap in size and density, limiting this measure. VLDL and VLDL remnants contain apoB-100, but apoB-100 is present on LDL and Lp(a), and thus cannot be used to measure VLDL remnants. Limitations of analytical approaches for the accurate measurement of TGRLs have been discussed in reviews [10,11].

Conventionally, remnant cholesterol is estimated mathematically as the sum of chylomicron, VLDL, and IDL cholesterol, using the formula remnant cholesterol = total cholesterol – HDL cholesterol – LDL cholesterol. Use of this equation is limited when the cholesterol content in LDL is not measured directly [12]. (See "Measurement of blood lipids and lipoproteins", section on 'Direct measurement'.)

Chylomicrons and chylomicron remnants — Chylomicrons are very large particles that carry dietary lipid. They are formed in the intestine and migrate into the circulation, where they are metabolized into smaller and denser remnants called IDL (see 'Intermediate-density lipoprotein' below). They are associated with a variety of apolipoproteins, including A-I, A-II, A-IV, B-48, C-I, C-II, C-III, and E. They are formed in the intestinal tract and absorbed into the blood stream.

Very low-density lipoprotein — VLDL particles are assembled in the liver and, to a minor extent, in the intestine [13]. These particles carry endogenous triglycerides and, to a lesser degree, cholesterol. In the circulation, they are metabolized to smaller, denser VLDL remnants. The major apolipoproteins associated with VLDL are B-100, C-I, C-II, C-III, and E.

Intermediate-density lipoprotein — IDL particles carry cholesterol esters and triglycerides. They are associated with apolipoproteins B-100, C-III, and E.

Low-density lipoprotein — LDL particles carry cholesterol esters and are associated with apolipoproteins B-100 and C-III.

High-density lipoprotein — HDL particles carry cholesterol esters. These particles are associated with apolipoproteins A-I, A-II, C-I, C-II, C-III, D, and E.

HDL particles can be subcategorized into subclasses based on physicochemical properties (table 1) [14-16]. However, the relevance of these subclasses to understanding HDL’s role in atherosclerosis is still quite uncertain.

The HDL2 density range is predominantly comprised of apoA-I HDL particles (very large [HDL-VL], large [HDL-L], medium [HDL-M]) and the HDL3 density range is predominantly comprised of particles containing apoA-I and apoA-II (small [HDL-S], very small [HDL-VS]). Another method used to quantify HDL particle size is nuclear magnetic resonance (NMR) spectroscopy [16,17]. With this technique, 47 HDL subclasses have been characterized. For simplicity, large HDL particles are those between 8.8 nm and 13 nm, and small HDL particles are 7.3 nm to 8.2 nm. Large HDL particles correspond to the gradient gel electrophoresis (GGE) HDL subclass designations HDL2b (HDL-M) and 2a (HDL-VL, HDL-L), and small HDL particles correspond to the GGE designations HDL 3b (HDL-S) and 3c (HDL-VS). The NMR approach also provides a measure of total HDL particle concentration [16], which has been shown to be more strongly associated with carotid intima media thickness, a surrogate measure of atherosclerosis, and ischemic cardiovascular events than HDL cholesterol [18]. Ion mobility is a newer method that quantifies HDL particle concentration [19]. A further modification of the ion mobility method that minimizes HDL aggregates provides more accurate separation of HDL particle concentration [20].

Lipoprotein(a) — Lp(a) is discussed in detail elsewhere. (See "Lipoprotein(a)".)

DYSLIPIDEMIA — One definition of dyslipidemia is total cholesterol, LDL-cholesterol (LDL-C), triglyceride, or lipoprotein(a) levels above the 90th percentile or HDL-cholesterol (HDL-C) or apoA-I levels below the 10th percentile for the general population (table 2). However, many if not most clinical laboratories do not use these 90th and 10th percentile definitions for what is high or low. Rather, they use lipoprotein levels that have been shown to be epidemiologically associated with lower risk and so may be considered desirable levels rather than normal levels, as conventionally defined for most lab tests.

The prevalence of dyslipidemia varies with the population being studied. The prevalence is highest in patients with premature CHD, which can be defined as occurring before 55 to 60 years of age in men and before 65 years in women. In this setting, the prevalence of dyslipidemia is as high as 75 to 85 percent compared with approximately 40 to 48 percent in age-matched controls without CHD (figure 1) [21,22].

The disturbance in lipoprotein metabolism is often familial. In one study, for example, 54 percent of all patients with premature CHD (and 70 percent of those with a lipid abnormality) had a familial disorder [21]. In the great majority of patients, inheritance is polygenic, and the expression of dyslipidemia is strongly influenced by factors such as obesity (particularly central obesity/visceral adiposity) and the saturated fat and cholesterol content of the diet. In nations with low rates of obesity and where saturated fat intake is low, both the incidence of CHD and the prevalence of dyslipidemia are low compared with North America and Europe. This polygenic type of dyslipidemia is the major source of atherosclerotic cardiovascular disease.

There is a less common, but important, group of familial disorders that are monogenic. These require few or no nongenetic factors for their expression and carry a high risk of CHD at a young age, which argues for their identification as early as possible. The clinical syndrome of familial hypercholesterolemia is the leading clinical phenotype resulting from monogenic, usually dominantly inherited defects in LDL catabolism.

Clinical classification of dyslipidemias — The major classes of dyslipidemia were historically first classified according to the Fredrickson phenotype in the 1960s [23]. This classification was based on knowledge derived from phenotyping the lipoproteins that were present in abnormally high quantities. As greater molecular understanding of the defects involved in lipid metabolism has emerged, especially characterization of the genetic defects producing those changes, the Fredrickson classification has become less widely utilized. It is, however, a potentially useful tool for describing the phenotype of the lipid disorder a patient has. A variety of defects, some of which are familial, can produce these disorders (table 3).

Fredrickson phenotype I (familial chylomicronemia syndrome, mixed disorder chylomicronemia syndrome) – Serum concentration of chylomicrons is elevated; triglycerides concentrations are elevated to >99th percentile.

Fredrickson phenotype IIa (hypercholesterolemia) – Serum concentration of LDL-C is elevated; the total cholesterol concentration is >90th percentile.

Fredrickson phenotype IIb (familial combined hyperlipidemia) – Serum concentrations of LDL-C and VLDL-C are elevated; total cholesterol and/or triglycerides may be ≥90th percentile and apoB ≥90th percentile.

Fredrickson phenotype III (familial dysbetalipoproteinemia) – Serum concentrations of VLDL remnants and chylomicrons are elevated; total cholesterol and triglycerides are >90th percentile.

Fredrickson phenotype IV (hypertriglyceridemia) – Serum concentrations of VLDL are elevated; total cholesterol may be >90th percentile and may also see triglyceride concentrations >90th percentile or low HDL.

Fredrickson phenotype V (mixed dyslipidemia) – Elevated serum concentrations of chylomicrons and VLDL; triglycerides are >99th percentile.

EXOGENOUS PATHWAY OF LIPID METABOLISM — Lipoprotein metabolism can be divided into exogenous and endogenous pathways. The exogenous pathway starts with the intestinal absorption of dietary cholesterol and fatty acids (figure 2). The mechanisms regulating the amount of dietary cholesterol that is absorbed are unknown. Sitosterolemia is a rare autosomal recessive disorder associated with hyperabsorption of cholesterol and plant sterols from the intestine [24]. These genes involved are expressed primarily in the liver and intestine and are upregulated by cholesterol feeding; they may normally cooperate to limit intestinal sterol absorption [25].

Within the intestinal cell, free fatty acids combine with glycerol to form triglycerides, and cholesterol is esterified by acyl-coenzyme A:cholesterol acyltransferase (ACAT) to form cholesterol esters. The important role of ACAT was established in an animal model of ACAT deficiency, which found complete resistance to diet-induced hypercholesterolemia due to lack of cholesterol ester synthesis and reduced capacity to absorb cholesterol [26]. Despite this, clinical trials have found that ACAT inhibitors may worsen atherosclerosis [27,28]. Triglycerides and cholesterol are assembled intracellularly as chylomicrons. The main apolipoprotein is B-48, but C-II and E are acquired as the chylomicrons enter the circulation. ApoB-48 permits lipid binding to the chylomicron but does not bind to the low-density lipoprotein receptor, thereby preventing premature clearance of chylomicrons from the circulation before they are acted upon by lipoprotein lipase (LPL).

ApoC-II is a cofactor for LPL that makes the chylomicrons progressively smaller, primarily by hydrolyzing the core triglycerides and releasing free fatty acids. The free fatty acids are then used as an energy source, converted to triglyceride, or stored in adipose tissue. The end-products of chylomicron metabolism are chylomicron remnants that are cleared from the circulation by hepatic chylomicron remnant receptors, for which apoE is a high-affinity ligand. The chylomicron remnants contain a smaller core of lipids that is enveloped by excess surface components. These surface constituents are transferred from the chylomicron remnant for the formation of HDL.

ENDOGENOUS PATHWAY OF LIPID METABOLISM — The endogenous pathway of lipid metabolism begins with the synthesis of VLDL by the liver (figure 3). VLDL particles contain a core of triglycerides (60 percent by mass) and cholesterol esters (20 percent by mass). Microsomal triglyceride transfer protein (MTP) is an intracellular lipid-transfer protein found in the endoplasmic reticulum. It is essential for the transfer of the lipid molecules (principally triglycerides) onto apoB-100 in the liver [29,30]. The surface apolipoproteins for VLDL are noted above. They include apoC-II, which acts as a cofactor for LPL; apoC-III, which inhibits this enzyme; and apoB-100 and E, which serve as ligands for the apoB/E (LDL) receptor [1]. In the absence of functional MTP, VLDL is not secreted into the circulation. Abetalipoproteinemia is a rare genetic disorder in which MTP is absent.

The triglyceride core of nascent VLDL particles is hydrolyzed by LPL. During lipolysis, the core of the VLDL particle is reduced, generating VLDL remnant particles (also called intermediate-density lipoprotein [IDL]) that are depleted of triglycerides via a process similar to the generation of chylomicron remnants. Some of the excess surface components in the remnant particle, including phospholipid, unesterified cholesterol, and apolipoproteins A, C, and E, are transferred to HDL.

LPL requires the binding of a protein that is expressed on capillary endothelial cells, called GPIHBP1 (glycosylphosphatidylinositol-anchored HDL binding protein 1), for full activity in the capillary lumen. Its mode of action is to shuttle LPL from the interstitial side of endothelial cells to the capillary side. In the capillary lumen, LPL hydrolyzes triglycerides contained in the core of chylomicrons and VLDL; it also facilitates cholesterol transfer from these lipoproteins to HDL (figure 3 and figure 4B). The hydrolysis of triglycerides releases free fatty acids that are then used as an energy source, converted to triglyceride, or stored in adipose tissue. The metabolic regulation of fasting and postprandial triglyceride and HDL concentrations is modulated by lipoprotein ligands and the combined actions of LPL, hepatic lipase, and cholesteryl ester transfer protein (CETP) (figure 3 and figure 4B) [31-33]. Both inherited and acquired disorders of triglyceride metabolism have been identified [34]. (See "Hypertriglyceridemia in adults: Approach to evaluation", section on 'Etiology'.)

Patients with a deficiency GPIHBP1 have low levels of active LPL, impaired intravascular hydrolysis of triglycerides, and severe hypertriglyceridemia (with chylomicronemia). Missense mutations of GPIHBP1 have been identified as have monoclonal autoantibodies to GPIHBP1 [35].

VLDL remnants can either be cleared from the circulation by the apoB/E (LDL) or the remnant receptors, or remodeled by hepatic lipase to form LDL particles. There are four common sequence polymorphisms in the hepatic lipase gene promoter; the most frequent is a C to T substitution [36]. The presence of a C allele is associated with higher hepatic lipase activity; smaller, denser, and more atherogenic LDL particles; and, inversely, with lower levels of HDL-C [37].

Low-density lipoprotein — LDL particles contain a core of cholesterol esters, lesser amounts of triglyceride, and contain one apoB-100, which is the ligand for binding to the apoB/E (LDL) receptor. LDL can be internalized by hepatic and nonhepatic tissues. Hepatic LDL-C can be converted to bile acids and secreted into the intestinal lumen. LDL-C internalized by nonhepatic tissues can be used for hormone production, cell membrane synthesis, or stored in the esterified form.

The internalization of LDL is regulated by cellular cholesterol requirements via negative feedback control of apoB/E (LDL) receptor expression [38]. Cells in positive cholesterol balance, for example, suppress apoB/E (LDL) receptor expression. On the other hand, decreased activity of HMG CoA reductase, the enzyme that controls the rate of de novo cholesterol synthesis by the cell, leads sequentially to a fall in cell cholesterol, increased expression of apoB/E (LDL) receptors, enhanced uptake of cholesterol from the circulation, and a reduction in the plasma cholesterol concentration.

Chemically-modified LDL, such as oxidized LDL, can also enter macrophages and some other tissues through the unregulated scavenger receptor. This pathway can result in excess accumulation of intracellular cholesterol and the formation of foam cells, which contribute to the formation of atheromatous plaques. (See 'Lipoproteins and atherosclerosis' below.)

The importance of the LDL receptor in the regulation of cholesterol metabolism has been demonstrated in both experimental animals and humans. Knockout of the LDL receptor in transgenic mice leads to a substantial elevation in total cholesterol levels, a defect that can be reversed by restoring the LDL receptor gene [39]. In humans, familial hypercholesterolemia is often associated with a defect in the LDL receptor [40]. (See "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia".)

High-density lipoprotein — The formation and metabolism of HDL particles involves the following steps (figure 4A-B) [1,4,41]:

Hepatic and intestinal synthesis of small nascent HDL particles composed of phospholipid and apolipoproteins.

Procurement of surface components (phospholipids, cholesterol, and apolipoproteins) from triglyceride-depleted chylomicron and VLDL remnants.

Acquisition of free (unesterified) cholesterol from tissue sites (such as the liver and macrophages in the arterial wall) and other lipoproteins; the initial HDL particles contain relatively little cholesterol.

HDL particles are thought to participate in cholesterol metabolism in the following way:

Nascent HDL particles (cholesterol-absent and phospholipid-depleted) promote the transfer of intracellular cholesterol to the cell membrane [41], in the peripheral tissues, through the action of a protein known as ABCA1 [42,43]. ABCA1 expression on the cell surface is induced by cholesterol loading and reduced after the cholesterol has been removed by apolipoproteins [44]. Mutations in the gene encoding for ABCA1 are associated with low serum HDL-C concentrations in familial HDL deficiency and Tangier disease. ApoA-I (see 'Apolipoproteins' above) on the surface of HDL plays a central role in this process by signaling a transduction protein to mobilize cholesterol esters from intracellular pools. (See "HDL cholesterol: Clinical aspects of abnormal values", section on 'Inherited causes'.)

One common variant of this gene, R219K, is associated with higher HDL-C and lower triglyceride concentrations; carriers of this variant have a reduced severity of coronary disease, a slower progression of disease, and fewer coronary events [45]. Other genetic variations in the ABCA1 gene may also contribute to determining HDL-C concentrations in the general population [46,47].

After acquisition of free cholesterol by the HDL particle, the cholesterol is esterified to cholesterol esters by lecithin:cholesterol acyl transferase (LCAT), a plasma enzyme that is activated primarily by apoA-I. By a similar mechanism, HDL can act as an acceptor for cholesterol released during lipolysis of triglyceride-containing lipoproteins.

Lipid transfer proteins, such as cholesteryl ester transfer protein (CETP) (see 'Cholesteryl ester transfer protein' below), facilitate movement of the cholesterol esters to apoB-containing lipoproteins (VLDL, IDL, and LDL). This cholesterol can then be delivered to the tissues for steroid synthesis or storage or to the liver for the conversion intro bile acids. (See 'Low-density lipoprotein' above.)

Cholesteryl ester transfer protein — The role of CETP in lipoprotein metabolism is complex, and the impact of CETP (figure 4A-B) on cardiovascular disease is not well understood [48].

Circulating CETP mediates the transfer of cholesteryl esters from HDL particles to the TGRLs LDL and VLDL; at the same time, triglycerides are transferred in the opposite direction. In this process, HDL-C is decreased, the cholesterol content in VLDL is increased, and LDL particles become smaller and denser. Intracellular CETP in both the periphery and the liver appears to promote cholesterol removal from peripheral cells and uptake by the liver.

The impact of circulating CETP on the risk of cardiovascular disease has been evaluated in a number of clinical studies. The prognostic role of CETP remains uncertain and may vary with triglyceride concentrations. The following studies demonstrate the potential relationship between CETP and CHD risk:

A nested case-control study found that higher CETP levels were associated with an increased risk of CHD, particularly among adults with higher triglyceride levels [49]. CETP was also directly associated with LDL-C concentrations and inversely associated with HDL-C concentrations. This is a potentially important observation since some have suggested that the association between CETP and CHD is attenuated after adjusting for HDL-C and LDL-C concentrations [50].

A second nested case-control study concluded that in men with low triglyceride levels, a higher CETP concentration was associated with a decreased risk of CHD [51].

Polymorphisms affecting the activity of CETP, such as an isoleucine for valine substitution at codon 405 (I405V) are common. In a study from Denmark, for example, 43 percent of people studied were heterozygous for I405V and 11 percent were homozygous for I405V [52]. Polymorphisms such as I405V that reduce the activity of CETP typically increase plasma HDL-C concentrations, although this has not been found consistently in all studies [53-55].

Studies that have looked at individuals with other polymorphisms that increase rather than decrease CETP activity have had conflicting results about the effect on risk of CHD. At least one CETP inhibitor has been associated with an increase in cardiovascular risk. (See "HDL cholesterol: Clinical aspects of abnormal values", section on 'Inherited causes' and "HDL cholesterol: Clinical aspects of abnormal values", section on 'CETP inhibition'.)

The potential cardiovascular effect of CETP inhibition is discussed separately. (See "HDL cholesterol: Clinical aspects of abnormal values", section on 'CETP inhibition'.)

Lipoprotein(a) — Lipoprotein(a) or Lp(a) is a specialized form of LDL that is assembled intrahepatically from apo(a) and LDL [56,57]. Apo(a) links to apoB-100 on the surface of LDL by disulfide bridges. The formation of apo(a):apoB complexes requires an LDL particle of a certain morphology and composition. The structural integrity of LDL, and therefore Lp(a) formation, are modulated by LCAT [56]. The apo(a) chain contains five domains known as kringles [25]. The fourth kringle contains regions that are homologous with the fibrin-binding domains of plasminogen. Through this structural similarity to plasminogen, apo(a) interferes with fibrinolysis by competing with plasminogen binding to plasminogen receptors, fibrinogen, and fibrin. However, impaired fibrinolysis has not been observed in an ex vivo study with Lp(a) [58].

Lp(a) can also bind to macrophages via a high-affinity receptor, possibly promoting foam cell formation and localization of Lp(a) at atherosclerotic plaques [59]. The full discussion of the potential role of Lp(a) in the development of atherosclerosis is found elsewhere. (See "Lipoprotein(a)".)

LIPOPROTEINS AND ATHEROSCLEROSIS — Elevated concentrations of apoB-containing lipoproteins are a major predisposing factor to atherosclerosis.

In its simplest description, the process of atherosclerosis is accelerated by abnormally high levels of cholesterol within the arterial wall. The excess cholesterol causes an activation of macrophages and smooth muscle cells that leads to a chronic inflammatory response in the intima of the artery wall. Although triglycerides are well metabolized (degraded), even in excess, by macrophages and smooth muscle cells, it is possible that released toxic free fatty acids induce inflammation [60].

Cholesterol is carried in all lipoproteins and, with the exception of HDL, all have been associated with an increase in the risk of cardiovascular disease events. In the aggregate they have been referred to as atherogenic lipoproteins. Measurement of the cholesterol component of these particles is technically challenging.

Historically, significant attention has been paid to high levels of cholesterol carried within LDL and VLDL. The success of statin therapy is attributed to its ability to lower circulating levels of cholesterol carried in LDL particles. Statins, and other effective LDL-C lowering therapies, may not effectively lower the cholesterol contributed by triglyceride-rich lipoproteins (TGRL). The result is that even in the presence of a normal level of LDL-C, residual risk exists if total cholesterol remains elevated due to TGRL. (See 'Triglyceride-rich lipoproteins' above.)

Although hypertriglyceridemia is a risk factor for future atherosclerotic events, causality has not been established (see "Hypertriglyceridemia in adults: Approach to evaluation", section on 'Potential mechanisms'). Reasons include the association between other lipoproteins and other conditions associated with increased cardiovascular risk, such as disorders of insulin resistance. Due to delayed clearance of TGRL on VLDL particles that carry apoC-III or reduced LPL activity, which is common in insulin resistance, the VLDL remnants may enter the vessel wall or be converted to small LDL particles. Small LDL particles have conformational changes in apoB that impair the efficiency of LDL receptor-mediated clearance, thereby allowing these particles to circulate for a longer duration where they become susceptible to oxidation, glycation, and glyco-oxidation. High concentrations of chylomicron remnants or VLDL particles result in lower levels of HDL-C, a process that results from cholesteryl ester transfer protein-mediated lipid exchange between TGRL and the cholesterol cargo of HDL particles. Triglyceride-enriched HDL particles have reduced macrophage cholesterol efflux capacity.

One mechanism by which triglycerides may contribute to the risk of atherosclerotic events is that TGRLs increase endothelial activation, facilitate monocyte infiltration into the arterial wall, and increase activation of proinflammatory genes via AP-1 [61,62]. TGRL remnants are able to penetrate the arterial wall and may be retained preferentially. Once inside the arterial wall, their cholesterol component may directly contribute to the process of atherosclerosis [63,64]. The cholesterol content transported by TGRLs is higher than for LDL particles. In addition, the apoE ligand on VLDL remnants and IDL facilitate cholesterol uptake into macrophages.

Low-density lipoprotein — LDL particles contain cholesterol, triglycerides, phospholipids, and apolipoproteins B-100 and C-III. All LDL particles contain one copy of apoB-100, whereas 10 to 20 percent of LDL particles contain apoC-III. Thus, there is a direct relationship between apoB-100 and LDL particle number.

Elevated plasma concentrations of apoB-100-containing lipoproteins can induce the development of atherosclerosis even in the absence of other risk factors [65]. It has been proposed that the initiating event in atherogenesis is the subendothelial retention of apoB-100-containing lipoproteins via a charge-mediated interaction with proteoglycans in the extracellular matrix. Consistent with this hypothesis is the observation that mice expressing LDL with defective proteoglycan binding develop significantly less atherosclerosis than mice expressing wild-type LDL [66]. Active transcellular LDL transport, or transcytosis, into the artery wall has been found to be an important mechanism for LDL-mediated atherosclerosis. Implicated proteins, such as SRB1 in conjunction with DOCK4, help to mediate the internalization of LDL particles [67,68].

Small LDL particles penetrate the endothelial barrier 1.7-fold more than large LDL particles; these electronegative small LDL particles interact with positively charged intimal proteoglycans [69,70]. The increased retention of small LDL particles in the vessel wall allows a longer time for reactive oxygen species modification of surface phospholipids and unesterified cholesterol. In addition, the small LDL phenotype is associated with a clustering of other risk factors, including elevated levels of triglycerides, VLDL, and IDL, reduced concentrations of HDL and HDL2, and insulin resistance [71]. However, all LDL particles, regardless of their size, increase the risk of atherosclerotic cardiovascular events [72-74]. In the Women’s Health Study, the cardiovascular risk associated with small LDL particle concentration was not different from large LDL particle concentration after adjustment for the total LDL particle concentration [72]. The discussion of the clinical use of the measurement of LDL particle size is found elsewhere. (See "Measurement of blood lipids and lipoproteins", section on 'LDL cholesterol'.)

Circulating LDL also accumulates in the foam cells, but not the lipid core, of atherosclerotic plaques [75]. As noted above, circulating LDL that is not taken up by the apoB/E (LDL) receptors can also enter macrophages through unregulated scavenger receptors [38,76,77]. The most important of these receptors appears to be CD36 (also called scavenger receptor B) [78-80]. Uptake by these receptors requires chemical modification of the LDL particle by enzymatic, nonoxidative alteration [81]; oxidation, which accelerates the accumulation of cholesterol [82]; glycosylation; or glycoxidation. The oxidation process modifies a lysine amino acid on the apolipoprotein B. Oxidation of LDL can occur in any of the cells within the artery, including the endothelial cells, macrophages, smooth muscle cells, and T lymphocytes. Vitamin E can reduce the uptake of oxidized LDL by reducing expression of the CD36 receptor [83].

The oxidation of LDL results in the formation of isoprostanes, which are chemically stable, free radical catalyzed products of arachidonic acid that are structural isomers of conventional prostaglandins. They reflect lipid peroxidation and are markers of oxidant stress in hypercholesterolemia and atherosclerosis. Levels of isoprostanes are increased in atherosclerotic lesions and localize to foam cells and the extracellular matrix [84]. Asymptomatic patients with hypercholesterolemia may have increased urinary excretion of F2 isoprostanes compared to normal controls [85].

Elevated plasma concentrations of oxidized LDL are associated with CHD [57], and patients with an acute coronary syndrome have higher levels of malondialdehyde (MDA)-modified LDL than patients with stable CHD [86]. MDA-modified LDL is a type of oxidatively-modified LDL that may be produced when ischemic injury results in the release of aldehydes that substitute the lysine residues in apoB-100 [87].

The prevention of oxidative modification of lipoproteins, as with paraoxonase, is associated with less severe coronary disease [88-90]. In addition, the cholesterol-enriched macrophages (called foam cells) can rupture, releasing oxidized LDL, intracellular enzymes, and oxygen free radicals that can further damage the vessel wall. One potential strategy for preventing the development of atherosclerosis is the recombinant adenovirus-mediated gene transfer of decoy macrophage scavenger receptors that can block foam cell formation [91].

Oxidized LDL particles promote atherosclerosis via one or more of the following effects (table 4) [77,92]; however, the inflammatory and immune response of the endothelial cell to oxidized LDL is genetically determined and can be seen in an inbred mouse strain that is susceptible to diet-induced atherosclerosis, but not in a resistant strain [93]:

Oxidized LDL particles act as a chemoattractant for monocytes by increasing monocyte binding (via activation of monocyte beta-1 integrin) [94], which then develops into tissue macrophages. In addition, macrophage mobility may be reduced, thereby trapping the macrophages within the vessel wall. One study of patients with familial hypercholesterolemia undergoing selective LDL apheresis reported that hypercholesterolemia was associated with elevated levels of endothelial leukocyte adhesion molecule-1, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1, which upregulate endothelial adhesiveness [95]. The levels of these adhesion molecules were reduced after apheresis.

Chemically modified LDL particles can promote inflammatory and immune changes via cytokine release from macrophages and antibody production.

In any circumstance in which LDL-cholesterol levels are increased, due, for example, to an abnormality in the apoB/E (LDL) receptor, unregulated uptake via the scavenger pathway leads to excess accumulation of modified LDL within macrophages [38]. These cholesterol-enriched cells (called foam cells) can rupture, releasing oxidized LDL, intracellular enzymes, and oxygen free radicals that can further damage the vessel wall. Oxidized LDL induces apoptosis of vascular smooth muscle [96] and human endothelial cells via activation of a CPP32-like protease, which suggests a mechanism for the response to injury hypothesis of atherosclerosis [97].

Oxidatively-modified LDL can cause disruption of the endothelial cell surface [98] and impairs endothelial function, reducing the release of nitric oxide (NO), which is a major mediator of endothelium-dependent vasodilation [99-101]. High levels of cholesterol also increase endothelial production of oxygen free radicals, which may bind to and inactivate NO [102,103].

Treatment with lipid-lowering drugs that reduce the susceptibility of LDL to oxidation may reverse some of these changes, resulting in an improved vasomotor response to acetylcholine [100,104,105]. Endothelial function can also be improved by the administration of the NO precursor L-arginine in hypercholesterolemic rabbits [106] and, in patients with hypercholesterolemia, vitamin C, folate, and 5-methyltetrahydrofolate, the active form of folic acid; improvement occurs without changes in plasma lipids [107-109]. Vitamin C and folate may prevent the degradation of NO.

Oxidized LDL causes an increase in platelet aggregation and thromboxane release, which contributes to vasoconstriction and intravascular thrombus formation [110,111]. LDL also inhibits NO synthase activity of platelets, which in turn stimulates platelet activity and aggregation [112,113]. L-arginine supplementation attenuates platelet aggregation in humans, although the magnitude of the effect varies significantly among individual patients [114]. Oxidized LDL increases activation of redox-sensitive transcription factors nuclear factor kappa-B (NF-kappa-B) and activator protein 1 (AP-1), which in turn increase expression of a panoply of proinflammatory cytokines [92,115].

Oxidized LDL may also play a role in plaque instability [116].

Damage to the endothelium then promotes platelet adherence and the release of cytokines that stimulate smooth muscle proliferation. Thus, foam cell and platelet accumulation and smooth muscle proliferation all contribute to the formation of an atherosclerotic plaque [117].

Secretory phospholipase A2 modification of native LDL by Group V increases binding and internalization of LDL into macrophages via the putative M receptor.

Another potential mechanism by which LDL may promote atherosclerosis is by upregulation of the angiotensin II type I receptor [118]. This change may increase the functional response of vascular smooth muscle cells to angiotensin II stimulation [119]. In addition, the angiotensin II type I receptor regulates the induction of the lecithin-like oxidized LDL receptor-1 (LOX-1), an endothelial receptor for oxidized LDL that is distinct from the macrophage scavenger receptor pathway [120]. The LOX-1 receptor is important in the process of oxidized LDL-mediated monocyte adhesion to coronary artery endothelial cells [121]. Cholesterol lowering with a statin drug downregulates angiotensin II type I receptor density and reverses the elevated blood pressure response to angiotensin II [119]. (See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease".)

Intermediate-density lipoprotein (remnant lipoproteins) — Although LDL is accepted to be the major risk factor in the progression of atherosclerosis, the measurement of LDL also includes IDL. Several studies have shown that serum IDL concentrations are predictive of an increased incidence of CHD [122] and an increased incidence of coronary events in those with CHD, independently of other factors [123,124]. This relationship may be particularly strong in patients with normal total cholesterol levels and those with an elevated IDL/HDL ratio [125]. The MARS study performed analytic ultracentrifugation to determine the lipoprotein subclasses: IDL, but not VLDL or LDL, was associated with the progression of carotid artery intima-media thickness [126]. In another study, normolipidemic men with CHD and subjects with dysbetalipoproteinemia had elevated levels of IDL when compared to controls; furthermore, the increased levels of IDL were not detected with conventional lipid screening [127].

Thus, IDL may be a major determinant of the atherogenic potential of LDL. Similar to LDL, IDL is taken up by macrophages and can cause foam cell formation and can impair endothelium-dependent vasomotor function in human coronary arteries [128].

IDL also contains triglycerides and apolipoprotein C-III, each of which is associated with atherosclerotic cardiovascular disease. (See 'Apolipoprotein C-III' below and "Hypertriglyceridemia in adults: Approach to evaluation", section on 'Atherosclerotic cardiovascular disease'.)

Very low-density lipoprotein — Elevated levels of VLDL are associated with an increased risk for atherosclerotic cardiovascular disease. This relationship likely exists due to the risk associated with two of its major components: triglycerides and apoC-III. (See "Hypertriglyceridemia in adults: Approach to evaluation", section on 'Atherosclerotic cardiovascular disease'.)

One observational study found that VLDL cholesterol explained one-half of the risk of myocardial infarction from elevated apoB containing lipoproteins but VLDL triglycerides did not explain risk [60].

Apolipoprotein C-III — Elevated levels of apoC-III are associated with increased triglyceride levels and an increased risk of atherosclerotic cardiovascular disease; lower levels of apoC-III are associated with lower triglyceride levels and reduced risk [129]. These relationships are under genetic control. (See 'Apolipoproteins' above.)

Excessive apoC-III on the surface of TGRL (VLDL or LDL) may contribute to the development of atherosclerosis by at least three mechanisms:

Inhibiting the lipolysis of TGRL (including chylomicrons and VLDL) by LPL and by lessening the uptake of TGRL remnants by the liver [63,129,130]. Triglyceride levels are increased by this mechanism. The presence of apoC-III on the lipoprotein particle is thought to inhibit lipolysis by both LPL and hepatic lipase, which could in part account for the higher serum triglyceride levels.

Augmenting arterial inflammation through effects on both peripheral monocytes and endothelial cells [129].

Interfering with normal nitric oxide function in endothelial cells, perhaps through interfering with insulin signaling, and thus causing endothelial dysfunction [131].

ApoE on VLDL particles counteracts the inhibitory effects of apoC-III on VLDL-mediated hepatic uptake and the associated atherosclerotic cardiovascular risk [132].

The relationship between apoC-III, triglycerides, and cardiovascular risk was evaluated in two gene sequencing studies [63,133]. The gene most strongly associated with plasma triglyceride levels is the gene encoding for apoC-III, called APOC3 [133]. Loss of function of APOC3 (through mutation) leads to lower levels of apoC-III.

In a study of 3734 participants in the Exome Sequencing Project, four mutations in APOC3, which in the aggregate occurred in heterozygote form in approximately 1 in 150 persons, were associated with lower plasma triglyceride levels (39 percent lower than in controls; p<1 X 10-20) and apoC-III levels (46 percent lower than levels in noncarriers; p = 8 x 10-10) [133]. The risk of CHD among 498 carriers of any mutation was 40 percent lower than the risk among over 100,000 noncarriers (odds ratio 0.60, 95% CI 0.47-0.75).

In a study of 75,725 participants in two general-population studies, nonfasting triglyceride levels of less than 1.00 mmol per liter (90 mg per deciliter) had a significantly lower incidence of cardiovascular disease, as has been found in other studies [63] (see "Hypertriglyceridemia in adults: Approach to evaluation", section on 'Atherosclerotic cardiovascular disease'). Among patients heterozygous for three loss-of-function mutations in APOC3 (compared to no mutations), a mean reduction in nonfasting triglyceride levels of 44 percent (p<0.001) was observed. The cumulative incidences of ischemic vascular disease and ischemic heart disease were reduced in heterozygotes as compared with noncarriers (hazard ratio [HR] 0.59, 95% CI 0.41-0.86 and 0.64, 95% CI 0.41-0.99).

These studies do not establish either elevated levels of apoC-III (or APOC3) or triglycerides as causal of atherosclerosis, as carriers of APOC3 loss-of-function variants had higher levels of HDL-C (11 to 24 percent) and lower levels of LDL-C (3 to 4 percent). (See 'Low-density lipoprotein' above and 'High-density lipoprotein' below.)

Other potential mechanisms — In addition to triglycerides and apoC-III, other ways in which VLDL is associated with atherosclerosis include:

VLDL particles from patients with hypertriglyceridemia are enriched in apoE. This can lead to a conformational change in the VLDL particle that facilitates binding to the macrophage scavenger receptor, resulting in unregulated uptake similar to that seen with oxidized LDL [134].

LPL hydrolyzes triglycerides contained in the core of chylomicrons and VLDL (see 'Endogenous pathway of lipid metabolism' above). An Asn291Ser substitution in LPL causes impaired function of this enzyme and is associated with an increase in plasma triglycerides. Female, but not male, carriers of this mutation have a twofold increase in the risk of CHD and nonfatal cerebrovascular disease [135,136]. LPL activity is a critical enzyme in lipid homeostasis and thus is highly regulated at transcriptional, posttranscriptional, translational, and posttranslational levels. Various proteins regulate LPL, including apoC-I, apoC-II, apoC-III, apoA-V, and angiopoietin-like protein (ANGPTL) 3, 4, and 8. ANGPTL3 renders LPL more susceptible to proteolytic inactivation by proprotein convertases [33].

A different mechanism occurs in patients with hypertriglyceridemia who overproduce apoB (as in combined hyperlipidemia). These patients have a subspecies of LDL that is smaller and more dense and electronegative than LDL from patients with normal triglyceride levels [137]. Small dense LDL particles bind less avidly to the LDL receptor. This prolongs their half-life in the circulation, making these particles more susceptible to oxidative modification and to subsequent uptake by the macrophage scavenger receptors [138].

High-density lipoprotein — In epidemiologic studies, high HDL-C levels are associated with reduced risk of cardiovascular disease, but a causal role for HDL in atherosclerotic disease is controversial [139].

HDL particles, in contrast to LDL and VLDL particles, have antiatherogenic properties that include removal of cholesterol from macrophages (termed macrophage cholesterol efflux), antioxidation, protection against thrombosis, maintenance of endothelial function, and maintenance of low blood viscosity through an action on red cell deformability [4,16,41,140-143].

Much of the antiatherogenic effect of HDL is thought to be mediated by macrophage cholesterol efflux [41]. Macrophage cholesterol efflux is a process in which excess cholesterol in macrophage cells is removed. ApoA-I plays an important role (figure 4A-B) [41,144-147]. This issue is also discussed elsewhere. (See "HDL cholesterol: Clinical aspects of abnormal values", section on 'HDL particles and CVD'.)

The removal of excess cholesterol from macrophages (macrophage cholesterol efflux) and other peripheral cells is the first step in its transfer to the liver where much of it can be used for the formation and secretion of bile salts (figure 4A-B). Measures of macrophage cholesterol efflux are correlated with the incidence of cardiovascular events (see "HDL cholesterol: Clinical aspects of abnormal values", section on 'Low HDL cholesterol as an ASCVD risk factor'). The entire process is known as reverse cholesterol transport [41,148,149].

The antioxidant properties of HDL particles may be important in humans. In a group of men with CHD who were atypical in that they had high HDL-C levels (≥84 mg/dL [2.2 mmol/L]), the HDL particles were ineffective in mitigating oxidative stress and reducing ex vivo inflammatory responses compared with a control group with a similar lipid profile but without CHD [41,150].

The antioxidant properties of HDL may be due in part to the activity of HDL-associated enzymes such as paraoxonase. Paraoxonase inhibits oxidation of LDL in vitro and a genetic deletion of paraoxonase is associated with increased susceptibility of LDL to oxidation in vivo [151]. Two pieces of evidence support the antioxidant role of HDL-associated paraoxonase in humans:

Small HDL particles exhibit more antioxidant activity than large particles, due to stronger attachment of paraoxonase to these particles [152].

Higher paraoxonase activity measures were associated with both a lower prevalence of cardiovascular disease and a lower rate of future major adverse cardiac events in a prospective evaluation of 1399 patients [151].

HDL and apoA-I also inhibit the generation of calcium-induced procoagulant activity on erythrocytes via stabilization of the cell membrane [140]. This membrane-stabilizing action prevents the transbilayer diffusion of anionic lipids that is required for prothrombin activation, thereby minimizing thrombus formation.

HDL improves endothelial function by increasing eNOS production [153] and inhibiting cellular adhesion molecule expression [154].

Triglyceride-rich lipoprotein remnants and cardiovascular disease — Overproduction of TGRLs from increased production and/or impaired clearance is manifest by hypertriglyceridemia that is detected by routine lipid testing. The contribution of TGRLs to atherosclerotic cardiovascular disease derives from multitudinous evidence encompassing biological mechanisms, epidemiological observations, genomic studies, and clinical trial data.

Emerging evidence from multiple sources of evidence suggests that TGRL remnants contribute to atherosclerotic cardiovascular disease risk. An abundance of remnant lipoproteins emanating from intravascular remodeling of TGRLs, chylomicrons, and VLDL creates a proatherogenic environment that augments cardiovascular risk.

Remnant cholesterol — Nearly all epidemiological studies from 13 independent cohorts report statistically significant associations between TGRLs and incident cardiovascular disease [155].

Analyses conducted on nonfasting samples demonstrate stronger associations with cardiovascular risk than studies relying on fasting samples [10]. The largest of the prospective cohorts performed on nonfasting samples derives from three Danish studies (Copenhagen General Population Study, Copenhagen City Heart Study, Copenhagen Ischemic Heart Disease Study). This pooled analysis included 73,513 participants who were genotyped, of whom 11,984 had an ischemic event between 1976 and 2010. The adjusted risk association HR was 2.3 (1.7 to 3.1) for the highest versus lowest quintile [156]. The most recent analysis from the Copenhagen General Population Study included 102,964 participants [157]. The composite outcome measure was myocardial infarction, ischemic stroke, peripheral arterial disease, and cardiovascular death. The adjusted risk association HR for major adverse cardiovascular events was 1.99 for the highest versus lowest quartile. The risk of ischemic stroke was investigated in 102,964 individuals from the Copenhagen General Population Study who were followed for 14 years, and 9564 individuals enrolled in the Copenhagen City Heart Study during 26 years of follow-up. A high remnant cholesterol concentration (>58 mg/dL) compared with a low remnant cholesterol concentration (<19 mg/dL) was associated with a multivariate adjusted HR of 1.99 (95% CI 1.49-2.67).

The association between remnant cholesterol measured from fasting samples and cardiovascular events was investigated in 6901 older community-dwelling Spanish participants (mean age 67 years) who were at high cardiovascular risk based on a diagnosis of type 2 diabetes or three or more risk factors [158]. LDL-C was calculated by the Friedewald equation and remnant cholesterol by subtracting LDL-C and HDL-C from total cholesterol. In a multivariate adjusted Cox model, every 10 mg/dL increment in remnant cholesterol was associated with a higher risk (HR 1.21, 95% CI 1.10-1.33) of a major adverse cardiovascular outcome (myocardial infarction, stroke, or cardiovascular death) than for triglycerides (HR 1.04, 95% CI 1.02-1.06) or non-HDL-C (HR 1.05, 95% CI 1.01-1.10]). A baseline remnant cholesterol >30 mg/dL (75th percentile of the cohort) was associated with an adjusted HR of 1.83 (95% CI 1.30-2.58). Surprisingly, LDL-C was unrelated to risk.

The Women's Health Study evaluated the risk of incident cardiovascular disease associated with TRL cholesterol and small dense LDL that were measured using two-stage automated homogenous assays in different vascular beds [10]. This prospective, nested, case-control study included 480 cases and 496 controls. Risk associations were evaluated for the total cardiovascular disease events (eg, myocardial infarction, ischemic stroke, peripheral artery disease, and cardiovascular disease death) and individual outcomes. The composite end point increased across quartiles of TRL cholesterol and small dense LDL-C in fully adjusted models (HR 3.05, 95% CI 1.46-6.39).

VLDL cholesterol — The Copenhagen General Population Study investigated the risk of myocardial infarction in 25,480 individuals who had NMR spectroscopy-measured cholesterol and triglyceride content of VLDL, IDL, and LDL. During 11 years of follow-up, 1815 individuals had a diagnosis of myocardial infarction. For every 39 mg/dL increase in cholesterol content, the respective multivariable adjusted HR for VLDL, IDL, and LDL was 2.07 (95% CI 1.81-2.36), 5.38 (95% CI 3.73-7.75), and 1.86 (95% CI 1.62-2.14). Overall, VLDL cholesterol explained 46 percent of the risk from apoB-containing lipoproteins, and the sum of IDL and LDL explained 25 percent of the risk. In a separate analysis, remnant cholesterol explained only 10 percent (95% CI 0-24 percent) of the myocardial infarction risk. The effect of obesity on the 10-year risk of myocardial infarction in the Copenhagen General Population Study was investigated in 29,010 individuals [159]. The cholesterol content in large VLDL explained 35 percent (95% CI 23-47 percent) of the excess risk of myocardial infarction associated with a high body mass index (BMI), and cholesterol in small VLDL explained 37 percent (95% CI 26-50 percent) of the risk. The cholesterol content in large VLDL and small VLDL combined explained 40 percent (95% CI 27-53 percent) of the excess risk. In contrast, the cholesterol content in IDL was not associated with excess risk for myocardial infarction risk (1.5 percent; 95% CI -0.2 to 3.2 percent) associated with excess BMI.

Small dense LDL cholesterol — The association of small dense LDL-C with CHD events was examined in a meta-analysis of 21 studies including a total of 30,628 participants who had 5693 incident CHD events. The pooled estimate for the high versus low category of small dense LDL was 1.36 (95% CI 1.21-1.52), and 1.07 (95% CI 1.02-1.12) when analyzed by the top versus lowest quartile. The Women's Health Study investigated the association between incident cardiovascular events and the components of those end points separately. Small dense LDL was associated with a multivariable adjusted HR for myocardial infarction of 3.71 (95% CI 1.59-8.63), but not with total cardiovascular events, ischemic stroke, or peripheral arterial disease.

Evidence from observational epidemiological studies supports the contribution of TGRLs in the development of cardiovascular disease. Clinically, remnant cholesterol is estimated by an equation that has inherent limitations based on the use of estimated LDL-C versus direct LDL-C measurement. The development of biomarkers that accurately measure TGRLs in clinical practice requires continued work. When compared with remnant cholesterol, the cholesterol content in VLDL has been more strongly associated with cardiovascular risk. Other studies report positive associations between small dense LDL, the end-product of large VLDL (VLDL1), and cardiovascular events. In a prospective, nested, case-control study, small dense LDL was less predictive of cardiovascular events than a direct measurement of remnant cholesterol [156,157]. Small dense LDL was more strongly associated with the risk of myocardial infarction than either ischemic stroke or peripheral arterial disease. In an analysis of the Framingham Offspring Study, small dense LDL was the atherogenic lipoprotein parameter most strongly associated with incident atherosclerotic cardiovascular disease events (eg, myocardial infarction, angina, stroke, transient ischemic attacks, cardiovascular death, revascularization procedures). The HR for small dense LDL and atherosclerotic cardiovascular disease events was 1.42 (p<0.0001) in models that adjusted for the pooled cohort risk equation [160].

Lipoprotein(a) — Lp(a), the specialized form of LDL, is a risk factor for the development of atherosclerotic events and evidence strongly suggests that it is causative. This issue is discussed separately. (See "Lipoprotein(a)".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topic (see "Patient education: High cholesterol (The Basics)")

Beyond the Basics topic (see "Patient education: High cholesterol and lipids (Beyond the Basics)")

SUMMARY

Introduction – Lipids, such as cholesterol and triglycerides, are insoluble in plasma. Circulating lipid is carried in lipoproteins that transport the lipid to various tissues for energy utilization, lipid deposition, steroid hormone production, and bile acid formation. The lipoprotein consists of esterified and unesterified cholesterol, triglycerides, phospholipids, and protein. The protein components of the lipoprotein are known as apolipoproteins (apo) or apoproteins. The different apolipoproteins serve as cofactors for enzymes and ligands for receptors. (See 'Introduction' above.)

Lipoproteins and atherosclerosis – Abnormal lipoprotein metabolism is a major predisposing factor to atherosclerosis. It is estimated that a dyslipidemia is present in over 70 percent of patients with premature coronary heart disease (CHD). (See 'Lipoproteins and atherosclerosis' above.)

Low- and very low-density lipoprotein – Elevated plasma concentrations of apoB-100 containing lipoproteins (low-density and very low-density lipoprotein [LDL and VLDL]) can induce the development of atherosclerosis even in the absence of other risk factors. It has been proposed that the initiating event in atherogenesis is the subendothelial retention of apoB-100-containing lipoproteins. (See 'Low-density lipoprotein' above and 'Very low-density lipoprotein' above.)

Apolipoprotein C-III – The general contribution of hypertriglyceridemia to coronary risk remains uncertain; however, there are substantial data supporting the contribution of triglyceride-rich lipoprotein remnants in increasing the risk for atherosclerotic cardiovascular events. Hypertriglyceridemia tends to be associated with low high-density lipoprotein (HDL) levels; as a result, any apparent increase in CHD may be due to the reduction in HDL rather than the elevation in triglycerides. (See 'Apolipoprotein C-III' above.)

High-density lipoprotein – In epidemiologic studies, high HDL-cholesterol (HDL-C) levels are associated with reduced risk of cardiovascular disease, but a causal role for HDL in atherosclerotic disease is controversial. HDL, in contrast to LDL and VLDL, has antiatherogenic properties that include macrophage cholesterol efflux, antioxidation, protection against thrombosis, maintenance of endothelial function, and maintenance of low blood viscosity through a permissive action on red cell deformability. (See 'High-density lipoprotein' above.)

Lipoprotein(a) (lp(a)) – This is the specialized form of LDL, is a risk factor for the development of atherosclerotic events and evidence strongly suggests that it is causative. This issue is discussed separately. (See "Lipoprotein(a)".)

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Topic 4565 Version 27.0

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