Each VLDL particle contains apolipoproteins from the C and E family and one molecule of apo B-100 per particle. VLDL is the way the liver exports excess triglycerides derived from plasma-free fatty acids and chylomicron remnants. As triglycerides are removed from the peripheral adipose and muscle tissue, two additional atherogenic lipoprotein particles are formed, VLDL remnants and IDLs.

Intermediate-density lipoproteins are the product of VLDL and chylomicron metabolism. IDLs are cholesterol-rich VLDLs and chylomicron remnants that are either cleared by the liver or metabolized by hepatic lipase into LDL, which retains apo B.

Low-density lipoproteins are the products of VLDL and IDL metabolism and the most cholesterol-rich and atherogenic of all lipoprotein particles. LDL binds to specific LDL receptors on the surface of each cell, and such binding facilitates transfer of the remaining cholesterol to these cells, where it can be stored for future use to make such chemical products as cell membranes, steroid hormones, and bile acids. About 70 % of these receptors are located within the liver, which clears the majority of LDL particles, while the rest are taken up by non-hepatic scavenger receptors. The number of LDL receptors is regulated by the intracellular concentration of cholesterol within each cell. When the intracellular cholesterol content of the cells is low, LDL receptor synthesis is upregulated, receptor numbers increase, and the LDL concentration of circulating plasma diminishes. On the other hand, when intracellular cholesterol is increased, LDL receptor synthesis is downregulated, receptor numbers diminish, and LDL within the circulation rises. When plasma LDL is present in excess, atherosclerosis results in proportion to the degree of circulating LDL [1–3].

There are two forms of LDL: large (buoyant) and small, dense LDL. Small, dense LDL (sdLDLD) is rich in cholesterol esters and particularly atherogenic. The increased atherogenicity of small, dense LDL derives from less efficient hepatic LDL receptor binding, leading to prolonged circulation and exposure to the endothelium and increased oxidation.

High-density lipoproteins are initially cholesterol-free lipoproteins that are synthesized in both enterocytes and the liver as lipid-poor discoid particles. HDL’s overall role is to obtain cholesterol from peripheral tissues and other lipoproteins and transport it to where it is needed most, to other cells, other lipoproteins, and the liver (for clearance). This process is known as “reverse cholesterol transport” and plays an important role in the antiatherogenic properties of the HDL particle.

LDL cholesterol has been shown to be among the most predictive lipoprotein fractions for determining carotid atherosclerosis and stroke, being directly proportional to its concentration over a wide range of values. The majority of evidence derives from large statin trials to lower LDL cholesterol that showed reductions in carotid atherosclerosis progression, a need for carotid intervention, and cerebrovascular events, mainly the Heart Protection Study and SPARCL [10–12].

In addition, LDL fractions are intensively investigated as potentially more accurate predictors of carotid artery disease, mainly oxLDL and sdLDL. Clinical studies have shown an increase in plasma and plaque levels of oxLDL in patients with symptomatic carotid plaques compared to asymptomatic ones [13, 14]. Even more, baseline oxLDL levels may predict carotid disease progression in asymptomatic subjects, independent of other cardiovascular risk factors [15]. Regarding sdLDL, several lines of evidence suggest that it could be more atherogenic than the large (buoyant) particles of LDL and a more accurate predictor of carotid atherosclerosis compared to the traditionally measured LDL [16–21]. Many authors advocate that both plasma oxLDL and sdLDL assessments can be used as biomarkers for carotid disease progression, providing a link between lipoprotein disorders and inflammation [13–15, 18–21].

Although LDL cholesterol is widely accepted as the major risk factor for the development and progression of atherosclerosis, its measurements generally include IDL. The Monitored Atherosclerosis Regression Study (MARS) provided further evidence for the role of these lipoproteins in the progression of carotid atherosclerosis and supported the suggestion that the risk of atherosclerosis attributable to LDL may be the result of the IDL included within the traditional LDL measurements [22, 23]. A later study on patients with carotid artery disease (stenosis >50 %) showed that fasting and postprandial triglyceride-rich lipoproteins (mainly VLDL and IDL) are elevated compared to controls and correlate to echo-lucent, rupture-prone carotid plaques [24].

HDL has been shown to have both direct and indirect antiinflammatory effects with potential antithrombotic results [25, 26]. However, the literature remains contradictory on the real protective effect of HDL against carotid atherosclerosis and stroke [27–29]. A recent systematic review of observational epidemiological studies concluded that although more evidence exists for an inverse association between HDL cholesterol levels and stroke or carotid atherosclerosis risk, further studies are needed [30].

VLDL particles and chylomicrons represent the main triglyceride carriers in the circulation. Though clearly associated with cardiovascular disease, the exact mechanisms by which triglyceride-rich lipoproteins exert their noxious effect on the vascular wall are matters of debate. It is still unclear whether it is the number of triglyceride-rich lipoprotein particles or triglyceride-rich lipoprotein cholesterol or the associated small, dense LDL and low HDL that contribute most to atherosclerosis [31–36]. A recent systematic review and meta-regression analysis of randomized trials on lipid-­modifying drugs concluded that additional studies are needed to more precisely quantify the detrimental effect of triglyceride levels on stroke risk and to establish the efficacy of triglyceride-lowering therapy in addition to LDL cholesterol reduction [37].

Lipoprotein (a) consists of an LDL particle with its apolipoprotein-a. The apo-a component is characterized by five cysteine-rich regions known as “kringles.” One of these regions is homologous with plasminogen and is thought to competitively inhibit fibrinolysis and thus predispose to thrombosis [38]. Lp(a) has been suggested as a direct promoter of atherosclerosis through various mechanisms, but the metabolic pathways of its production and clearance are not yet well characterized. Apoprotein-(a) fragments have been demonstrated to accumulate in unstable carotid plaques close to eroded and ulcerated areas, suggesting a strong correlation with atherosclerotic plaque destabilization [39]. A recent meta-analysis of observational studies on Lp(a) and cerebrovascular disease suggested that elevated Lp(a) is an independent risk factor for stroke [40].

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a member of the phospholipase A2 superfamily of enzymes that hydrolyze phospholipids. Lp-PLA2 binds mainly to circulating LDL, multiplying its atherogenic potential [41, 42].

Lp-PLA2 was initially attributed an atheroprotective role; however, recent evidence has highlighted its important role in the promotion of atherosclerosis [42].

Lp-PLA2 has been localized to human carotid plaques. Atherosclerotic plaques from symptomatic patients demonstrated greater levels of Lp-PLA2 than plaques obtained from asymptomatic patients [43, 44]. Additionally, blood levels of Lp-PLA2 have been shown to be an independent predictor of future stroke and transient ischemic events [45–48].

There is mounting evidence that serum lipid ratios may be better predictors of vascular risk than the traditional lipid measures. The Northern Manhattan Study on carotid atherosclerosis indicated that the relative levels of LDL and HDL may be more predictive than either LDL or HDL [49]. Very recently, a large-scale epidemiological study of healthy ­subjects undergoing carotid intima media measurements over an 8 year follow-up confirmed these results [50].

Ample evidence also exists on the strong association between the triglyceride: HDL cholesterol ratio (TG:HDL-C) and coronary heart disease. Respectively for carotid artery ­disease, in a retrospective analysis of more than 1,000 patients with ischemic stroke or transient ischemic attack, an elevated level of the serum TG:HDL-C ratio, but not LDL-C, was associated with large artery atherosclerotic stroke [51]. Similar results have been demonstrated for intracranial vascular disease [52]. These findings urged some authors to introduce the term “atherogenic index” [log(TG:HDL-C)]. Pathophysiologically, this index indirectly represents sdLDL [53, 54].