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Lipids in Atherosclerosis: Comparison
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Please note this is a comparison between Version 2 by Camila Xu and Version 1 by Francesca Gorini.

The role of lipids is essential in any phase of the atherosclerotic process, which is considered a chronic lipid-related and inflammatory condition. The traditional lipid profile (including the evaluation of total cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein) is a well-established tool to assess the risk of atherosclerosis and as such has been widely used as a pillar of cardiovascular disease prevention and as a target of pharmacological treatments in clinical practice over the last decades.

  • atherosclerosis
  • lipids
  • non-invasive lipid indices

1. Introduction

Coronary artery disease (CAD), the main clinical manifestation of atherosclerosis, still represents the main cause of mortality and morbidity in both sexes all over the world [1]. Nonetheless, in the course of atherosclerosis, not only does ischemic heart disease develop but also cerebrovascular disease and peripheral arterial disease [2]. Moreover, it is worth noting that endovascular procedures play a very important role in the treatment of atherosclerotic diseases, but the process of restenosis limits their effectiveness and contributes to the need for re-intervention [3,4][3][4].
Long considered a degenerative disease mainly determined by a passive accumulation of lipids, atherosclerosis has been subsequently demonstrated as an inflammatory disease characterized by lipid accumulation, chronic low-grade inflammation, and endothelial dysfunction and involving oxidative modified lipoprotein infiltration, immune cell activation, and extracellular matrix changes, with evidence of lipids as key players and/or regulators of these events [5,6,7,8][5][6][7][8]. In particular, the traditional lipid profile (total cholesterol—TC, triglycerides—TG, high-density lipoprotein cholesterol—HDL, and low-density lipoprotein cholesterol—LDL) has always been considered an essential tool for the assessment of cardiovascular disease (CVD) prevention and treatment in clinical practice. However, other non-traditional lipids and indices have been proposed, some of them showing an even greater predictive role for CVD and ischemic stroke than traditional single lipid parameters [9,10][9][10].

2. Key Role of Lipids in Atherosclerosis

The two main processes involved in the pathogenesis of atherosclerosis include cholesterol deposition and chronic inflammation [11]. In particular, according to the lipid theory of atherosclerosis, lipid peroxidation and the oxidation of LDL trigger initiation and further progression of atherosclerosis [11,12][11][12]. The main transporter of cholesterol to target cells is LDL, a heterogeneous class of lipoprotein particles consisting of a hydrophobic core containing TG and cholesterol esters in a hydrophilic surface membrane of phospholipids, free cholesterol, and apolipoproteins (principally ApoB-100), the latter mediating the binding of LDL particles to specific cell-surface receptors [13,14][13][14]. Modified LDL appear to be a major causative agent in the atherosclerotic process by stimulating endothelial cells (EC) to produce inflammatory markers with consequent cytotoxic effects; inhibiting nitric oxide (NO)-induced vasodilatation; and promoting the recruitment of monocytes to the vessels, macrophage progression to foam cells, and the migration and proliferation of vascular smooth muscle cells (VSMC) [15,16,17][15][16][17] (Table 1). Although oxidized low-density lipoproteins (ox-LDL) have long been considered the only type of modified LDL crucial for atherogenesis, at least three modified LDL forms (i.e., small dense, electronegative, and desialylated LDL), have been detected in the bloodstreams of atherosclerosis patients [18,19][18][19]. These molecules act as factors able to stimulate LDL aggregation, LDL association with the extracellular matrix components, and the formation of LDL-containing immune complexes, and all of them are susceptible to oxidation by resident vascular cells [13,20,21,22][13][20][21][22]. In particular, the small dense subfraction is characterized by an enhanced atherogenicity due to its increased susceptibility to modifications and its high binding affinity to the proteoglycans contained in the intima layer of the arterial wall, and desialylated LDL exhibit enhanced uptake and a low degradation rate once internalized, while electronegative LDL show a high propensity for self-association [19,23][19][23].
Table 1. Summary of the critical molecules and events characterizing the main phases in the onset and development of the atherosclerotic plaques.
Endothelial Dysfunction Fatty Streak Fibrous Plaque Vulnerable Plaque Plaque Erosion, Rupture, Thrombosis
- Endothelial activation

- Upregulation of adhesion molecules

- Increased vascular permeability

- Monocyte and other cell recruitment and infiltration

- Impaired vasodilation (reduced NO)

- ROS and inflammatory mediators

- LDL intake/accumulation in the arterial intima		 - VSMC proliferation

- Lipid accumulation

- Foam cell development

- T lymphocyte infiltration

- Platelet aggregation

- Macrophage activation

- Inflammation		 - Deposition of extracellular connective tissue matrix

- Fibrous cap formation

- Lipid-laden foam cell core containing lipid necrotic debris and calcium

- Vascular remodeling

- Luminal narrowing

- Flow abnormalities

- Reduced oxygen supply inflammatory mediated		 - Proteolytic enzymes

(MMPs)

- Intraplaque hemorrhage

- Thinning of the fibrous cap

- Microcalcification

- Necrotic-rich lipid core

(apoptosis and necrosis)

- Inflammatory mediators		 - Platelet aggregation

- Fibrin polymerization

- Inflammatory coagulation and proteolysis mediators

- Thrombosis

- Acute coronary syndrome
Calcific plaque

Dense calcification deposition
Abbreviations: LDL—low-density lipoprotein; MMPs—metalloproteinases; NO—nitric oxide; ROS—reactive oxygen species; VSMC—vascular smooth muscle cells.
In the initiation of the atherosclerotic process, modified lipoproteins accumulated in the intima activate the endothelium [20]. Furthermore, the reduced expression of endothelial NO synthase and superoxide dismutase, which are responsible for maintaining an effective barrier and reducing oxidative stress, respectively, affects endothelial barrier integrity and determines the retention of atherogenic LDL. Transcriptional activation of nuclear factor kappa B promotes the production of cytokines (e.g., tumor necrosis factor-alpha—TNF-α; interleukin–IL-1, IL-4, IL-6; interferon gamma—IFN-γ), which, in turn, induces the expression of monocytes and leukocyte adhesion molecules (such as vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin on the endothelial surface) and leads to the migration of monocytes and lymphocytes into the inner arterial wall [11,24,25][11][24][25]. Monocytes differentiate into macrophages [25] that internalize excess lipids derived from modified LDL, resulting in the intracellular accumulation of cholesterol esters, generation of foam cells (the hallmark of atherosclerotic lesion), and the aggregation of foam cells to form fatty streaks, the earliest grossly recognizable atherosclerotic lesions [11,22][11][22] (Table 1). Although macrophages represent the major infiltrating cells, adaptive immunity, which is modulated by T and B cells, and some effector cells such as mast cells and eosinophils play a central role in the advancement and expansion of atherosclerosis through the secretion of cytokines (IL-6, IFN-γ) and high-affinity IgA, IgE, and IgG antibodies [26]. Monocytes are also capable of differentiating into dendritic cells, a type of leukocyte that contain an elevated content of LDL-receptor 1 (LOX-1) and significantly contribute to ox-LDL uptake [27,28][27][28]. VSMC are also implicated in the development of the atherosclerotic plaque and in the transition from a fatty streak to a fibrous fatty lesion [22,29][22][29]. After their migration from the medial to the intima vascular layers, they proliferate in response to platelet-derived growth factor and basic fibroblast growth factor secreted by EC and macrophages, respectively, and produce extracellular matrix molecules such as collagen and elastin, which form the atherosclerotic plaque cap (Table 1) [22,29,30][22][29][30]. The ox-LDL–LOX-1 interaction, in addition to supporting the migration and proliferation of VSMC, may also promote their apoptosis and the release of matrix-degrading enzymes (i.e., metalloproteinases—MMPs 1 and 9) [22,27][22][27]. VSMC migration leads to the generation of the atheromatous fibrous caps that enclose a lipid-rich necrotic core, and their thickness, cellularity, matrix composition, and collagen content determine the characteristics and vulnerability of the atherosclerotic plaque (Table 1) [31]. Instead, calcification may occur in advanced plaque progression lesions, more frequently found in elderly subjects, where microcalcifications characterize a phase of the unstable plaque, while strong, dense calcification generally reflects a more stable plaque (Table 1) [31,32][31][32]. During the progression of plaque development, macrophages and T lymphocytes produce proteolytic enzymes, which may induce cup rupture, a coagulation process, and blood clot and lead to clinical events (Table 1) [33,34][33][34]. As endothelial dysfunction takes part as a critical step in atherosclerosis onset and development, it is worth mentioning that flow-mediated dilation is the most important method for endothelial dysfunction assessment in the literature as well as in clinical practice, although not without limitations (e.g., poor standardization and requirement of well-trained, experienced operators, aspects which limit reproducibility) [35,36][35][36]. Among biomarkers, in view of the pivotal role of lipids in the pathogenesis and progression of the atheromatous plaque, the traditional lipid panel (including TC, TG, HDL, and LDL) has long been identified as useful for assessing the risk factor of atherosclerosis and has been widely used as a pillar for cardiovascular (CV) disease prevention and treatment in clinical practice over the last decades [8,37,38,39][8][37][38][39]. However, other non-traditional lipids have emerged as possible alternative predictors of cardiometabolic risk in addition to traditional single or panel lipids, better reflecting the overall interaction between lipid/lipoprotein fractions [40,41,42][40][41][42].

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