INTRODUCTION — Atherosclerosis is a pathologic process that causes disease of the coronary, cerebral, and peripheral arteries and the aorta [1,2]. Forms of accelerated arteriopathies, such as restenosis following percutaneous coronary intervention with stenting and coronary transplant vasculopathy differ in pathogenesis and are discussed separately. (See "Intracoronary stent restenosis" and "Heart transplantation in adults: Cardiac allograft vasculopathy pathogenesis and risk factors".)
EPIDEMIOLOGY — Atherosclerosis can begin in childhood with the development of fatty streaks (table 1). The lesions of atherosclerosis advance with aging [3,4]. The following points demonstrate the frequency of atherosclerosis in Western populations and its progression with age:
●In an autopsy study of 2876 men and women aged 15 to 34 years who died of non-cardiac causes, all individuals had aortic fatty streaks [5].
●In another autopsy study of 760 young (age 15 to 34 years) victims of accidents, suicides, or homicides, advanced coronary atheromata were seen in 2 and 0 percent of men and women aged 15 to 19, and 20 and 8 percent of men and women aged 30 to 34 [4].
●In a study of 260 peri-renal aortic patches collected during organ transplantation, the first three decades of life were characterized by intimal thickening and xanthomas. The fourth, fifth, and sixth decades were characterized by more complicated plaques of pathological intimal thickening, early and late fibroatheromas with thin fibrous caps, ruptured plaques, healed rupture, and fibrotic calcified plaques [6].
●Using intracoronary ultrasound, one in six United States teenagers have abnormal intimal thickening [3].
HISTOLOGY
Fatty streaks — The first phase in atherosclerosis histologically occurs as focal thickening of the intima with accumulation of lipid-laden macrophages (foam cells) and extracellular matrix (table 1 and figure 1) [7]. Smooth muscle cells can also populate the intima, some of which may arise from hematopoietic stem cells [8], migrate, and proliferate. Lipids accumulate early in fatty streak formation yielding both intracellular lipid and extracellular deposits, which produce the fatty streak. Biglycan, a small dermatan sulfate proteoglycan detected in the intima of atherosclerotic coronary artery segments, can bind and trap lipoproteins, including very low density lipoproteins and low density lipoprotein [9]. The fatty streak can also contain T lymphocytes. (See 'Inflammation' below.) Foam cells constitute the hallmark of the early atheroma.
As these lesions expand, more smooth muscle cells accumulate in the intima. The smooth muscle cells within the deep layer of the fatty streak can undergo apoptosis, which associates with further macrophage accumulation and microvesicles that can calcify, perhaps contributing to the transition of fatty streaks into atherosclerotic plaques (table 1) [10].
Fibrous cap — Fibrous cap atheromas are defined as plaques with a well-defined lipid core covered by a fibrous cap, which may be relatively acellular (made of dense collagen) or may be rich in smooth cells. (See "Mechanisms of acute coronary syndromes related to atherosclerosis".)
Vasa vasorum — The vasa vasorum form a network of micro-vessels that originates primarily from the adventitial layer of large arteries. These vessels supply oxygen and nutrients to the outer layers of the arterial wall [11]. As atherosclerotic plaques develop and expand, they acquire their own microvascular network, extending from the adventitia through the media and into the thickened intima [12]. These thin-walled vessels are prone to disruption, leading to hemorrhage within the substance of the plaque and contributing to the progression of coronary atherosclerosis [13].
Fibrous plaque — The fibrous plaque evolves from the fatty streak via accumulation of connective tissue with an increased number of smooth muscle cells filled with lipids and often a deeper extracellular lipid pool.
Advanced lesions — More advanced lesions often contain a necrotic lipid-rich core, and eventually calcified regions (table 1) [14].
Atheroma formation associates with coronary artery remodeling (figure 2) [15]. Positive remodeling involves expansion of the plaque and external elastic membrane area due to a compensatory increase in local vessel size, while negative remodeling refers to a smaller external elastic membrane area at the lesion site due to the local shrinkage of vessel size (image 1A-B).
Positive remodeling acts as a compensatory mechanism in early coronary artery disease, preventing luminal loss despite plaque accumulation. However, arterial remodeling consequent to plaque formation and expansion is associated with abnormal arterial physiology as well as the development of clinical symptoms [15]. Positive remodeling is seen with complex, unstable plaques in patients presenting with unstable angina; in contrast, negative remodeling is associated with obstructive plaques in patients with stable angina [16]. (See "Mechanisms of acute coronary syndromes related to atherosclerosis".)
Intraplaque hemorrhage — Intraplaque hemorrhage mainly results from plaque neovascularization and increased neovessel permeability [17,18], is a common feature of advanced atherosclerotic lesions, and a critical element leading to accelerated plaque progression [19-22], plaque instability [23-25], and ischemic vascular events [26-29].
Cholesterol crystals — Cholesterol crystals (CCs) are taken up by macrophages and other cell types, which subsequently alter cellular function and survival [30]. The effect and impact of external CCs on various cell types have also been studied in neutrophils and endothelial cells. The presence of CCs has been implicated in the activation of the complement system and in coagulation events.
PATHOGENESIS — Multiple factors contribute to the pathogenesis of atherosclerosis, including endothelial dysfunction, dyslipidemia, inflammatory, and immunologic factors, plaque rupture, and smoking. (See "Overview of established risk factors for cardiovascular disease" and "Cardiovascular risk of smoking and benefits of smoking cessation".)
Endothelial dysfunction — The endothelium forms an active biologic interface between the blood and all other tissues. The single layer of continuous endothelium lining arteries forms a unique thromboresistant layer between blood and potentially thrombogenic subendothelial tissues. The endothelium also modulates tone, growth, hemostasis, and inflammation throughout the circulatory system. Endothelial vasodilator dysfunction is an initial step in atherosclerosis and is felt to be caused principally by loss of endothelium-derived nitric oxide [31]. This issue is discussed in detail separately and will only briefly be reviewed here. (See "Coronary endothelial dysfunction: Clinical aspects".)
Endothelial dysfunction is associated with many of the traditional risk factors for atherosclerosis, including hypercholesterolemia, diabetes, hypertension, cigarette smoking. In particular, endothelial dysfunction is induced by oxidized low density lipoprotein (LDL) and in some respects can be considered as a final common pathway (table 2). It can be improved with correction of hyperlipidemia by diet or by therapy with a statin (HMG-coenzyme A reductase inhibitor), which increases the bioavailability of nitric oxide [32,33], with angiotensin converting enzyme inhibitors [34], or with high doses of antioxidants such as vitamin C or flavonoids contained in red wine and purple grape juice [35,36]. However, clinical benefits of these therapies have only been demonstrated convincingly for statins. (See "Coronary endothelial dysfunction: Clinical aspects" and "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease".)
Inflammation — Evidence of inflammation in atherosclerotic lesions has been noted from the earliest histologic observations and inflammation is central to understanding the pathogenesis of atherosclerosis [37-40]. Macrophages that have taken up oxidized LDL release a variety of inflammatory substances, cytokines, and growth factors [41,42]. Among the many molecules that have been implicated are: monocyte chemotactic protein (MCP)-1 [43,44]; intercellular adhesion molecule (ICAM)-1 [43]; macrophage and granulocyte-macrophage colony stimulating factors [45,46]; CD40 ligand ; interleukin (IL)-1, IL-3, IL-6, IL-8, and IL-18 [47-49]; and tumor necrosis factor alpha [50-52]. The role of IL-6 is discussed separately. (See "Overview of established risk factors for cardiovascular disease", section on 'Interleukin-6'.)
Evidence supporting the importance of inflammation in the pathogenesis of atherosclerosis comes from the observation that markers of increased or decreased systemic inflammation associated with the risk of atherosclerosis. Furthermore, the Cankanumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) has demonstrated that inhibition of interleukin-1 beta with canakinumab substantially lowered the inflammatory biomarkers hsCRP and IL-6 without changing atherogenic lipids in patients with a prior myocardial infarction. The risk of a composite of cardiovascular death, nonfatal myocardial infarction, and non-fatal stroke fell by 15 percent (p = 0.021) with canakinumab 150 mg subcutaneous injection every three months [53]. Some of these markers are discussed in the next sections.
Serum high sensitivity CRP (hsCRP) — hsCRP is one of the downstream inflammatory markers. It consistently associates with the increased risk of atherosclerotic cardiovascular disease independent of cholesterol level [54,55], although genetic data do not support its function as a causal risk factor. It has been considered as a useful marker to identify individuals with increased vascular inflammation [53,56]. The role of C-reactive protein in cardiovascular disease is discussed in detail separately. (See "C-reactive protein in cardiovascular disease".)
Lp-PLA2 — Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a macrophage-secreted enzyme that may perpetuate plaque inflammation and whose elevated levels predict a 40 to 400 percent (averaging about 100 percent) increased risk of myocardial infarction (MI) and stroke in population studies fully adjusted for other cardiovascular disease risk factors. Clinical trials with an inhibitor of Lp-PLA2 [57] did not show improved outcomes. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Therapies with uncertain or no benefit'.)
Cytokines — Cytokines may participate in the pathogenesis of atherosclerosis [58]. Mediators such as interleukin-1 or tumor necrosis factor-alpha have a multitude of atherogenic effects. Basic science studies [59-61] have identified that the proinflammatory cytokine interleukin-1ß plays multiple roles in the development of atherosclerotic plaque and the favorable effects of inhibiting interleukin-1ß signaling in animals with experimental atherosclerosis [62,63]. The cytokines enhance the expression of cell surface molecules such as ICAM-1, VCAM-1, CD40, and selectins on endothelial cells, smooth muscle cells, and macrophages. Pro-inflammatory cytokines can also induce cell proliferation, contribute to the production of reactive oxygen species, stimulate matrix metalloproteinases, and induce tissue factor expression. Other cytokines, such as interleukin-4 and interleukin-10, are antiatherogenic. Still others, such as interferon-gamma, can promote experimental atherogenesis. (See "Mechanisms of acute coronary syndromes related to atherosclerosis".)
Leukocyte activation — Leukocytes infiltrate and accumulate in the atherosclerotic lesion, providing evidence for the role of local inflammation [64]. Inflammatory cells, including macrophages and T-lymphocytes, have often been found at the immediate site of intimal rupture or erosion of a thrombosed coronary artery in patients who died of acute myocardial infarction [65]. A systemic evaluation of immune/inflammatory cells in 114 aortic atherosclerotic specimens has described the inflammatory footprint in plaque instability:
●Scattered CD4 and CD8 cells with a T memory subtype were found in normal aorta, early, nonprogressive lesions.
●The total number of T cells increased in progressive lesions.
●A further increase in medial and adventitial T cells was found upon progression to vulnerable lesions.
●Formation of adventitial lymphoid-like structures containing B cells and plasma cells, a process accompanied by transient expression of CXCL13, was identified at this critical stage of progression to vulnerable lesions.
●A dramatic decrease of T-cell subsets, disappearance of lymphoid-like structures, and loss of CXCL13 expression were characterized among post-ruptured lesions [66].
Evidence in support of systemic inflammation comes from a study in which the inflammatory mRNA profile of circulating leukocytes was tested in 524 men with a prior MI and 628 controls [67]. The patients, compared to controls, had mRNA profiles showing increased levels of many inflammatory mRNAs.
Toll-like receptor 4 — Further evidence for the role of inflammation comes from study of polymorphisms in the toll-like receptor 4 gene that confer differences in the inflammatory response to Gram negative pathogens and perhaps other ligands [68]. A particular polymorphism of this gene, Asp299Gly, presents in 7 percent of an Italian population, diminishes receptor cycling, and is associated with diminished inflammatory response to Gram-negative pathogens.
Carriers of the Asp299Gly polymorphism, compared to patients with only wild-type alleles, have reduced circulating levels of a variety of inflammatory markers, including CRP, adhesion molecules, and IL-6, and a reduced incidence of carotid atherosclerosis (odds ratio 0.54) as detected by ultrasonography. They have an increased rate of serious bacterial infections.
Pregnancy-associated plasma protein-A (PAPP-A) — PAPP-A is a high molecular weight, zinc-binding metalloproteinase that is thought to degrade the proteins that maintain the integrity of the protective fibrous cap of atherosclerotic plaques [69]. PAPP-A can be produced by osteoblasts, fibroblasts, endothelial, vascular smooth muscle cells, and monocytes/macrophages [70-74], and has been identified in vulnerable coronary plaques but not in stable ones [75-77].
Dyslipidemia — Lipid abnormalities play a critical role in the development of atherosclerosis [42,78-83]. Early experiments in animals demonstrated accelerated atherosclerosis with a high cholesterol diet. Subsequent epidemiologic studies conducted in countries around the world showed an increasing incidence of atherosclerosis when serum cholesterol concentrations were above 150 mg/dL (3.9 mmol/L) (figure 3).
The role of the different lipid particles in the development of atherosclerosis is discussed elsewhere. (See "Lipoprotein classification, metabolism, and role in atherosclerosis".)
It is useful, however, to summarize the major observations.
●High levels of LDL cholesterol [83,84] are particularly important risk factors for atherosclerosis (algorithm 1) [78].
●Cholesterol accumulates in the lipid-laden macrophages (foam cells), and in the lipid core, of atherosclerotic plaque [85]. Oxidative modification of LDL facilitates macrophage uptake via unregulated macrophage scavenger receptors (among them, CD36, also called scavenger receptor B) and for accelerated accumulation of cholesterol [86,87]. Macrophage uptake of LDL cholesterol may initially be an adaptive response, which prevents LDL-induced endothelial injury [88]. However, cholesterol accumulation in foam cells leads to mitochondrial dysfunction, apoptosis, and necrosis, with resultant release of cellular proteases, inflammatory cytokines, and prothrombotic molecules [88]. A large body of the accumulative evidence in the past 50 years has demonstrated that lowering LDL-C can reduce cardiovascular events and the lower levels of LDL-C achieved are associated with a better clinical outcome [89,90]. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)
●HDL, in contrast to LDL, has putative antiatherogenic properties that include reverse cholesterol transport, maintenance of endothelial function, and protection against thrombosis. There is an inverse relationship between plasma HDL-cholesterol levels and cardiovascular risk (table 3). Values above 75 mg/dL (1.9 mmol/L) are associated with a longevity syndrome. Values above 60 mg/dL (1.5 mmol/L) count as a negative risk factor in the Framingham Risk Assessment [91]. However, cardiovascular disease event reduction from increasing HDL-cholesterol has not been established, particularly in patients with well-controlled LDL-cholesterol levels [92-94]. A Mendelian randomization study showed that raised plasma HDL-cholesterol levels through some genetic mechanisms are not associated with lower risk of MI [95]. Studies showed that HDL-cholesterol efflux had a close relationship with clinical atherosclerosis [96] and CV events [97]. These data challenge the concept that raising HDL-cholesterol levels will uniformly translate into a reduction in the risk of CV events. One explanation for the lack of benefit from therapies that raise HDL-cholesterol levels tested so far is that they may not improve the reverse cholesterol transport role of HDL. (See "HDL cholesterol: Clinical aspects of abnormal values".) Genetic studies have cast doubt on the causal relationship between low HDL levels and increased risk of atherosclerotic events. Thus, HDL may serve as a biomarker of risk, but no evidence yet shows that HDL-cholesterol is a modifiable risk factor.
●Current epidemiologic and genetic evidence support a causal role for triglyceride-rich lipoproteins, particularly those that contain apolipoprotein C3.
●An analysis in 60,608 individuals found that nonfasting remnant cholesterol, which is nonfasting total cholesterol minus HDL cholesterol and minus LDL cholesterol, associates causally with ischemic heart disease and with low-grade inflammation [98,99]. (See "Hypertriglyceridemia in adults: Management".)
●Oxidized lipoproteins including LDL [42], HDL [100], remnant lipoproteins [101], and phospholipid [102] have been thought to cause disruption of the endothelial cell surface, and promote inflammatory via cytokine release from macrophages, reduced cholesterol efflux, and the development of atherosclerosis. It may also play a role in plaque instability. Levels of oxidized LDL are increased in patients with an acute coronary syndrome and are positively correlated with the severity of the syndrome [103,104]. In addition, antibodies to oxidized LDL have been found in human atherosclerotic plaques and in the plasma of patients with atherosclerosis [105,106]. Measurement of oxidized lipoproteins remains for research to better understand the pathogenesis and has not been standardized or validated as a clinically useful biomarker. Furthermore, antioxidant strategies have consistently failed to improve cardiovascular outcomes in clinical trials.
●Observational and genetic studies support a causal role for lipoprotein(a), which is LDL covalently linked to apolipoprotein (a). (See "Lipoprotein(a)".)
●The LDL moiety of Lp(a) promotes atherosclerosis, whereas the plasminogen-like apo(a) molecule may favor thrombus accumulation by interfering with fibrinolysis [107,108]. Additional functions of Lp(a) include initiation of signaling pathways in macrophages [109] and vascular endothelial cells [110,111], resulting in proatherogenic changes in cell phenotype and gene expression. Lp(a) binding to macrophages could lead to foam cell formation and localization of Lp(a) at atherosclerotic plaques [112]. Lp(a) associates with increased residual cardiovascular event risk in JUPITER [111] and AIM-HIGH [113], which suggest that Lp(a) remains a risk factor in subjects with aggressive LDL-cholesterol lowering. (See "Lipoprotein(a)".)
Hypertension — Hypertension is a major risk factor for the development of atherosclerosis, particularly in the coronary and cerebral circulations [114-116]. It can increase arterial wall tension, potentially leading to disturbed repair processes and aneurysm formation [2].
Smoking — Cigarette smoking is another major risk factor [115,116] and it impacts all phases of atherosclerosis from endothelial dysfunction to acute clinical events, the latter being largely thrombotic [117]. The following observations have been made:
●In humans, cigarette smoke exposure impairs endothelium-dependent vasodilation, perhaps through decreased nitric oxide (NO) availability [118-120].
●Cigarette smoking is associated with an increased level of multiple inflammatory markers, including C-reactive protein, interleukin-6, and tumor necrosis factor alpha in both male and female smokers [121-124].
●Cigarette smoking may decrease availability of platelet-derived NO, decrease platelet sensitivity to exogenous NO (both of which may lead to increased activation and adhesion) [125,126], increase fibrinogen levels [127,128], and decrease fibrinolysis [129].
●Cigarette smoking increases oxidative modification of LDL [130] and decreases the plasma activity of paraoxonase, an enzyme that protects against LDL oxidation [131]. The triglyceride/HDL abnormalities seen among smokers have been suggested to be related to insulin resistance [132].
Diabetes — In addition to atherogenic effects from the diabetes-related dyslipidemia (elevated triglycerides, low level of HDL cholesterol, and small/dense LDL particles), as mentioned above, many clinical and experimental studies reveal that high levels of insulin precede development of arterial diseases [133,134]. Macrophages express most insulin signaling molecules except IR substrate 1 (IRS1) and glucose transporter type 4 [135,136]. Even though insulin activates the IR/IRS2/PI3K/Akt pathway in macrophages as in other types of insulin-responsive cells, few studies have investigated the biological functions of insulin signaling in macrophages.
Atherosclerosis and type 2 diabetes share similar pathological mechanisms, including elevation in cytokines like MCP-1 and interleukin-6 (IL-6), which contribute to underlying inflammation of both [137,138]. A published study [137] evaluated if insulin affects macrophage foam cell formation and found that insulin increased the expression of CD36 and decreased ABCA-1 expression, which may promote cholesterol accumulation in human monocyte-derived macrophages. The study also showed that low concentration of adiponectin increased the phosphorylation of Akt (Ser436) by the same degree as insulin and had the same modulating effect on CD36 and ABCA-1 as insulin. Clinically, the overall risk increase conferred by type 2 diabetes is driven by accelerated progression of pre-existing atherosclerosis to clinical cardiovascular events [139].
Tissue factor — Tissue factor is the primary initiator of coagulation and, in advanced atherosclerosis, is found in the plaque. (See "Overview of hemostasis".) Tissue factor, as well as other factors such as enhanced platelet activity, may contribute to the development of thrombosis following plaque disruption. (See "Mechanisms of acute coronary syndromes related to atherosclerosis".) Tissue factor also plays a role in the progression of atherosclerosis via coagulation-dependent and coagulation-independent mechanisms. In one study, tissue factor overexpression increased neointimal area and plaque size by increasing mural thrombus and smooth muscle cell migration and accelerating endothelial regrowth over the plaque after rupture [140].
Angiotensin II — The renin-angiotensin-aldosterone system plays an important role in inflammatory response regulation by recruiting inflammatory cells to the injured site and stimulating the production of cytokines such as IL-6, TNF-a, and COX-2 [141]. Angiotensin II stimulates the production of reactive oxygen species [142,143] and lowers nitric oxide production [144], leading to endothelial dysfunction. Increased plasma concentrations of angiotensin II promote the development and severity of atherosclerosis, particularly when combined with hyperlipidemia [145]. Angiotensin II may modulate vascular smooth muscle cell proliferation and the production of extracellular matrix [146,147].
Endothelin-1 — Endothelin-1 may contribute to the pathogenesis of atherosclerosis at all stages, even when the plaque is clinically imperceptible [148,149]. Endothelin-1 is a potent vasoconstrictor as well as a mitogen for vascular smooth muscle cells, stimulating their migration and growth. Oxidized LDL can stimulate its production and enhance its vasoconstrictor effects [150]. (See "Pathophysiology of heart failure: Neurohumoral adaptations", section on 'Endothelin'.)
Endothelin-1 immunoreactivity is ubiquitous within the intracellular and extracellular compartments of human coronary atherosclerotic tissue and is released from these sites in response to mechanical stress [151]. In addition, endothelin-converting enzyme-1, the final enzyme for endothelin-1 production, is expressed in smooth muscle cells and macrophages of human coronary atherosclerotic lesions at all stages of development [149,152].
Adhesion molecules — Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are cell surface glycoproteins induced at endothelial sites of inflammation that mediate the adherence of leukocytes to endothelium. (See "Leukocyte-endothelial adhesion in the pathogenesis of inflammation".) A low level of ICAM-1 is expressed on normal endothelial cells and is seen in normal arterial segments, while VCAM-1 expression occurs only with inflammation and is present in the microvessels of human atherosclerotic lesions [153].
The expression of both ICAM-1 and VCAM-1 increases in atherosclerotic lesions, but VCAM-1 appears to be more important in the initiation of atherosclerosis [154]. P-selectin, a platelet and endothelial cell receptor that mediates adhesion between vascular cells, also may promote migration of inflammatory cells into early and advanced atherosclerotic lesions [155,156].
Monocyte adhesion to endothelial cells is reduced by L-arginine, the precursor of nitric oxide [157] and alpha tocopherol (vitamin E), and increased by androgens due in part to enhanced endothelial cell-surface expression of VCAM-1 [158]. Antibodies that block adhesion molecules may ameliorate elements of the inflammatory response in atherosclerotic plaques [159].
Flow characteristics — The frequent occurrence of atheroma at sites of bends, branches, and bifurcations of coronary arteries suggests that altered blood flow and low shear stress can play a role in the development of atherosclerosis. Disturbed flow can alter endothelial cell function [160] in a manner that impairs atheroprotective functions [41]. These changes may be mediated by inhibition of the release of nitric oxide from the endothelial cells [161,162].
Atherosclerosis preferentially affects regions of coronary arteries that experience low shear stress or disturbed flow [163]. In addition, low shear stress is associated with an increase in intima medial thickness of the common carotid artery in healthy men [164].
Mitochondrial DNA damage — The hypothesis that mitochondrial DNA (mtDNA) injury might lead to plaque development and vulnerability has been proposed and tested in experimental animal models [165,166]. In the hyperlipidemic ApoE knockout mouse model, mtDNA lesions found in the aortas preceded the development of aortic plaques [167]. More mtDNA lesions and larger plaque size were detected in the aortas of mice expressing mitochondrial mutation [167]. In patients, association of leukocyte mtDNA with atherosclerotic plaque vulnerability was examined in the Virtual Histology in Vulnerable Atherosclerosis (VIVA) trial [168]. In this study, mtDNA lesions were found to be uniquely associated with thin-cap fibroatheroma, which are associated with a high risk of cardiovascular events [168,169]. Taken together, these findings suggest a possible role of mtDNA injury in plaque progression and disruption.
Genetic associations — The genetic influences on atherosclerosis formation, progression, and atherosclerotic vascular events has attracted much attention. Two major genetic study approaches have been undertaken for a better understanding of the molecular mechanism of atherosclerosis. The first is the candidate gene approach, in which genes in known atherogenesis pathways are tested for their role in atherosclerosis in vitro, in vivo, and in association studies [170-172]. The second approach is conducting genome-wide linkage studies to find atherogenesis-regulating quantitative trait loci. This method has the potential to find new atherosclerosis genes. The availability of whole genome sequences in humans and mice, especially the abundant single nucleotide polymorphism and haplotype information, has made it possible to perform genome-wide association studies, another unbiased approach, to identify disease genes relatively quickly as compared with traditional genetic methods [173].
The complex pathophysiological processes that occur in atherosclerosis probably do not arise from a single or small number of genes. In addition, environmental factors, and their interactions with genes, likely participate. In the general population, genetic polymorphisms occur in many genes in the pathways of lipid metabolism, inflammation, and thrombogenesis.
Genetic and genomic studies have helped to identify newer therapeutic targets in atherosclerosis. For example, discovery of genetic variants of PCSK9 [174-180] in regulating LDL-C levels has led to a rapid development of PCSK9 inhibitor as a potential therapy for LDL-C lowering and reducing cardiovascular events. Furthermore, genetic manipulations in animal models will accelerate the pace of atherosclerosis research [181]. (See "PCSK9 inhibitors: Pharmacology, adverse effects, and use".)
Infection — Chronic infection may contribute to the pathogenesis of atherosclerosis. The major organisms that have been reported are Chlamydia pneumoniae [182], cytomegalovirus (CMV) [183-192], coxsackie B virus infection [193], and Helicobacter pylori [194-196]. (See "Overview of possible risk factors for cardiovascular disease", section on 'Infection'.)
In addition to individual infections, the total pathogen burden, ie, the number of pathogens to which an individual has been exposed, may be an important risk factor for atherosclerosis [197-200]. Pathogen burden with atherosclerotic lesions has been directly assessed by testing for bacterial rDNA signatures by polymerase chain reaction in specimens obtained during catheter-based atherectomy [201]. Bacterial DNA was found in all patients with a mean of 12 species per lesion; bacterial DNA was not seen in control material or any unaffected coronary arteries. It is possible that secondary colonization may accelerate disease progression.
Chronic infection could act by a number of mechanisms, including direct vascular injury and induction of a systemic inflammatory state. (See 'Inflammation' above.)
Despite the attractiveness of infection as a potential important contributing factor, clinical evidence to support its role is lacking, and antibiotic therapy does not reduce the risk of recurrent myocardial infarction.
Effect of vaccination — Vaccination against influenza has been evaluated for a potential benefit in preventing cardiovascular disease [202-204]. Several studies have found a beneficial effect of influenza vaccination on cardiovascular events [202,203]. While these studies are of interest and do document a beneficial effect of influenza vaccination in older adults, they do not establish a causative relationship between influenza infection and the pathogenesis of atherosclerosis. (See "Geriatric health maintenance", section on 'Influenza vaccine' and "Seasonal influenza vaccination in adults".)
Gut microbiota — An important contribution of gut microbiota in pathobiological processes in cardiovascular diseases has been suggested [205].
Studies support a potential link between dietary nutrients, such as choline and carnitine (found in red meat, egg yolks, and full fat dairy foods), and their gut microbiota-dependent metabolism to trimethylamine N-oxide (TMAO), and atherosclerosis [205,206]. Prospective cohort studies have shown that increased plasma TMAO levels predict an elevated risk of major adverse cardiovascular events such as MI, stroke, or death [207-212]. High TMAO levels were found to increase the expression of proinflammatory genes including inflammatory cytokines, adhesion molecules, and chemokines [211,213-216]. These data support the notion that TMAO promotes inflammation and adds to elevated cardiovascular risk.
ROLE OF PLAQUE RUPTURE AND EROSION — Atherosclerosis is generally asymptomatic until the plaque stenosis exceeds 70 or 80 percent of the luminal diameter, which can produce a reduction in flow, as with coronary blood flow to myocardium. These stenotic lesions can produce typical symptoms of angina pectoris. Progression of atherosclerotic plaques involves two distinct processes: a chronic one that leads to luminal narrowing slowly, and an acute one that causes rapid luminal obstruction associated with plaque hemorrhage and/or luminal thrombosis.
Acute coronary and cerebrovascular syndromes (unstable angina, myocardial infarction, sudden death, and stroke) are typically due to rupture or erosion of plaques leading to thrombosis, although these plaques may have less than 50 percent stenosis [217-219]. In a review [220] of 22 autopsy studies in which 1847 coronary arteries were examined, plaque rupture was the main cause of coronary thrombosis regardless of clinical presentation (myocardial infarction: 79 percent; sudden coronary death: 65 percent), age (>60 years: 77 percent; <60 years: 64 percent; unknown: 73 percent), sex (men: 76 percent; women: 55 percent), and continent (Europe: 72 percent; United States: 68 percent; Asia 81 percent).
Plaque erosion is identified when serial sectioning of the thrombosed arterial segment fails to reveal plaque rupture [221]. Typically, the endothelium is missing at the erosion site, and the exposed intima consists predominantly of vascular smooth muscle cells and proteoglycans. Clinical studies of optical coherence tomography performed in patients presenting with acute myocardial infarction showed that the incidence of fibrous cap disruption was 73 percent, whereas plaque erosion was 23 percent and patients with plaque rupture had a higher incidence of thin cap fibroatheroma of 83 percent [222]; results were very similar to autopsy studies.
Plaque rupture or erosion may also be silent; repeated silent ruptures and thrombosis, followed by wound healing, may cause progression of atherosclerosis, with an increase in plaque burden and percent stenosis and negative arterial remodeling [223]. In studies of patients with acute coronary syndromes who underwent imaging with intravascular ultrasound (and were treated with percutaneous coronary intervention of the culprit lesion), recurrent major adverse cardiovascular events were predicted by the finding of culprit and non-culprit lesions with thin-cap fibroatheromas [168,169].
A recent review examined the mechanisms of atherosclerotic plaque healing, their role in the progression of atherosclerotic disease and in the development of acute coronary syndromes, as well as the potential therapeutic implications of the healing process [224].
The pathology and pathogenesis of the vulnerable plaque and its role in acute coronary syndromes are discussed elsewhere. (See "Mechanisms of acute coronary syndromes related to atherosclerosis".)
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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: Atherosclerosis (The Basics)".)
SUMMARY
●Multifactorial pathogenesis – Multiple factors contribute to the pathogenesis of atherosclerosis and its complications, including endothelial dysfunction, inflammatory and immunologic factors, plaque rupture or erosion, and the traditional risk factors of hypertension, diabetes, dyslipidemia, and smoking. Despite the attractiveness of infection as a potential contributing factor, clinical evidence to support its role is lacking. (See 'Pathogenesis' above.)
●Childhood origin – Atherosclerosis begins in childhood with the development of fatty streaks. The advanced lesions of atherosclerosis occur with increasing frequency with aging. (See 'Epidemiology' above.)
●Histologic stages – The histologic stages of atherosclerosis include fatty streak, fibrous cap, fibrous plaques, and advances lesions. With the availability of advanced vascular imaging techniques, the plaque histological characteristics can be identified in vivo. (See 'Histology' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Xue-Qiao Zhao, MD, FACC, who contributed to earlier versions of this topic review.
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