Pathogenesis of atherosclerosis

Author: Xue-Qiao Zhao, MD, FACC

Section Editors: Juan Carlos Kaski, DSc, MD, DM (Hons), FRCP, FESC, FACC, FAHA, Peter Libby, MD
Deputy Editor: Gordon M Saperia, MD, FACC
Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Oct 2016. | This topic last updated: May 17, 2016.
INTRODUCTION Atherosclerosis is a pathologic process that causes disease of the coronary, cerebral,
and peripheral arteries [1,2]. The basic aspects of the pathogenesis of atherosclerosis will be reviewed here.
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 "Pathogenesis of and risk factors for cardiac allograft vasculopathy".)
EPIDEMIOLOGY Atherosclerosis begins in childhood with the development of fatty streaks (table 1). The
advanced lesions of atherosclerosis occur with increasing frequency with aging [3-5]. 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 [6].
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 [5].
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 [7].
Using intracoronary ultrasound, one in six United States teenagers have abnormal intimal thickening [4].
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) [8].
Smooth muscle cells can also populate the intima, some of which may arise from hematopoietic stem cells
[9], 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 [10]. 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 are susceptible to apoptosis, which is associated with further macrophage
accumulation and microvesicles that can calcify, perhaps contributing to the transition of fatty streaks into
atherosclerotic plaques (table 1) [11].
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
"Pathology and pathogenesis of the vulnerable plaque".)
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 [12]. As atherosclerotic plaques develop and expand, they acquire their own microvascular network
(vasa vasorum), extending from the adventitia through the media and into the thickened intima [13]. 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 [14,15].
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 develop a microvasculature from both the luminal and medial
aspects, and often contain a necrotic lipid-rich core, and eventually calcified regions (table 1) [3].
Atheroma formation associates with coronary artery remodeling (figure 2) [16]. Positive remodeling is defined
as 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 has been felt to be 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 [16]. 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 [17]. (See "The role of the vulnerable plaque in acute coronary syndromes".)
PATHOGENESIS Multiple factors contribute to the pathogenesis of atherosclerosis, including endothelial
dysfunction, dyslipidemia, inflammatory, and immunologic factors, plaque rupture, and smoking. (See
"Overview of the risk equivalents and 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 endotheliumderived nitric oxide [18]. This issue is discussed in detail separately and will only briefly be reviewed here.
(See "Coronary artery 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) [19]. 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 [20,21], with
angiotensin converting enzyme inhibitors [22], or with high doses of antioxidants such as vitamin C or
flavonoids contained in red wine and purple grape juice [23,24]. However, clinical benefits of these therapies
have only been demonstrated convincingly for statins. (See "Coronary artery endothelial dysfunction: Clinical
aspects" and "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease" and
"Nutritional antioxidants in 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 [2528]. Macrophages that have been modified by oxidized LDL release a variety of inflammatory substances,
cytokines, and growth factors [29,30]. Among the many molecules that have been implicated are: monocyte
chemotactic protein (MCP)-1 [31,32]; intercellular adhesion molecule (ICAM)-1 [31]; macrophage and
granulocyte-macrophage colony stimulating factors [33,34]; soluble CD40 ligand ; interleukin (IL)-1, IL-3, IL-6,
IL-8, and IL-18 [35-37]; and tumor necrosis factor alpha [38-40]. The role of IL-6 is discussed separately. (See
"Overview of the risk equivalents and established risk factors for cardiovascular disease", section on
'Interleukin-6'.)
Perhaps the best 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. Some of these markers are discussed in the next sections.
Serum CRP The best studied of these markers is the acute phase reactant C-reactive protein (CRP).
Although CRP is consistently associated with atherosclerotic cardiovascular disease, genetic data do not
support its function as a causal risk factor. The role of CRP 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 [41] did not show
improved outcomes. (See "Prevention of cardiovascular disease events in those with established disease or
at high risk", section on 'Therapies without well established benefit'.)
Cytokines Cytokines may participate in the pathogenesis of atherosclerosis [42]. Mediators such as
interleukin-1 or tumor necrosis factor-alpha have a multitude of atherogenic effects. They enhance the
expression of cell surface molecules such as ICAM-1, VCAM-1, CD40, CD40L, 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 "The role of the vulnerable
plaque in acute coronary syndromes".)
Leukocyte activation Leukocyte (circulating monocytes, and to a lesser extent T lymphocytes)
recruitment is seen early in the atherosclerotic lesion, providing some evidence of the role of systemic
inflammation [43].
Further 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 [44]. 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 [45]. 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 [46]. PAPP-A, originally found in pregnant women, is produced by
syncytiotrophoblast cells, but also by osteoblasts, fibroblasts, endothelial, vascular smooth muscle cells, and
monocytes/macrophages [47-51]. Furthermore, PAPP-A has been identified in vulnerable coronary plaques
but not in stable ones [52]. Several studies have demonstrated that PAPP-A is a potentially important
biomarker of plaque instability and inflammation in patients with acute coronary syndrome [53,54].
Dyslipidemia Lipid abnormalities play a critical role in the development of atherosclerosis [30,55-61].
Early experiments in animals demonstrated accelerated atherosclerosis with a high cholesterol diet. This was
followed by epidemiologic studies conducted in countries around the world that 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 [55,61] and low levels of high density lipoprotein (HDL) cholesterol are
particularly important risk factors for atherosclerosis (algorithm 1) [56].
LDL accumulates in the cholesterol ester-enriched macrophages (foam cells), but not the lipid core, of
atherosclerotic plaque [62]. Oxidative modification of LDL is a prerequisite for macrophage uptake via
unregulated macrophage scavenger receptors (among them, CD36, also called scavenger receptor B)
and for accelerated accumulation of cholesterol [63,64]. Macrophage uptake of LDL cholesterol may
initially be an adaptive response, which prevents LDL-induced endothelial injury [65]. However,
cholesterol accumulation in foam cells leads to mitochondrial dysfunction, apoptosis, and necrosis, with
resultant release of cellular proteases, inflammatory cytokines, and prothrombotic molecules [65].
Oxidized LDL can cause disruption of the endothelial cell surface [66], promote inflammatory and
immune changes via cytokine release from macrophages and antibody production (see 'Anti-oxidized
LDL antibodies' below), and increase platelet aggregation. 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 [67,68]. Measurement of oxidized LDL has not been
standardized or validated as a clinically useful biomarker, however, and antioxidant strategies have
consistently failed to improve cardiovascular outcomes in clinical trials.
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 [69]. However, cardiovascular
disease event reduction from increasing HDL-cholesterol has not been established, particularly in
patients with well-controlled LDL-cholesterol levels [70-72]. A mendelian randomization study showed
that raised plasma HDL-cholesterol levels through some genetic mechanisms are not associated with
lower risk of MI [73]. Studies showed that HDL-cholesterol efflux had a close relationship with clinical
atherosclerosis [74] and CV events [75]. 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 reduced 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, is causally associated with ischemic heart
disease and with low-grade inflammation [76,77]. (See "Approach to the patient with
hypertriglyceridemia".)
Observational and genetic studies support a causal role for lipoprotein(a), which is LDL covalently
associated with apolipoprotein (a). Unfortunately, no currently established therapy can reduce Lp(a) and
cardiovascular events. (See "Lipoprotein(a) and cardiovascular disease".)
The role of lipoprotein(a) is rather multi-dimensional due to its structure, where the LDL-like moiety of
Lp(a) serves to promote atherosclerosis, whereas the plasminogen-like apo(a) molecule promotes
thrombosis by interfering with fibrinolysis [78,79]. Additional functions of Lp(a) include initiation of
signaling pathways in macrophages [80] and vascular endothelial cells [81,82], 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 [83]. Clinically, Lp(a) has
been considered as an emerging risk for atherosclerotic vascular disease; more importantly, Lp(a) is
associated with increased residual cardiovascular event risk in JUPITER [82] and AIM-HIGH [84], which
suggest that Lp(a) remains a risk factor in subjects with aggressive LDL-cholesterol lowering. (See
"Lipoprotein(a) and cardiovascular disease".)
Hypertension Hypertension is a major risk factor for the development of atherosclerosis, particularly in the
coronary and cerebral circulations [85-87]. It can increase arterial wall tension, potentially leading to disturbed
repair processes and aneurysm formation [2].
Smoking Cigarette smoking is another major risk factor [85-87] and it impacts all phases of
atherosclerosis from endothelial dysfunction to acute clinical events, the latter being largely thrombotic [88].
The following observations have been made:
In humans, cigarette smoke exposure impairs endothelium-dependent vasodilation, perhaps through
decreased nitric oxide (NO) availability [89-91].
Cigarette smoking is associated with an increased level of multiple inflammatory markers, including Creactive protein, interleukin-6, and tumor necrosis factor alpha in both male and female smokers [92-95].
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) [96,97], increase
fibrinogen levels [98,99], and decrease fibrinolysis [100].
Cigarette smoking increases oxidative modification of LDL [101] and decreases the plasma activity of
paraoxonase, an enzyme that protects against LDL oxidation [102]. The triglyceride/HDL abnormalities
seen among smokers have been suggested to be related to insulin resistance [103].

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, there have been many
clinical and experimental studies revealing that high levels of insulin precede development of arterial
diseases [104-110]. Macrophages express most insulin signaling molecules except IR substrate 1 (IRS1) and
glucose transporter type 4 [111,112]. Even though insulin activates the IR/IRS2/PI3K/Akt pathway in
macrophages as in other types of insulin-responsive cells, there have been few studies investigating the
biological functions of insulin signaling in macrophages. A published study [113] 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. 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 [114].
Oxidized LDL is abundant in both of these conditions and may induce secretion of these proinflammatory
cytokines in macrophages [115]. Clinically, the overall risk increase conferred by type 2 diabetes is driven by
accelerated progression of pre-existing atherosclerosis to clinical cardiovascular events; vascular risk is much
lower in diabetic patients without pre-existing significant coronary artery disease [116].
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 rupture. (See
"The role of the vulnerable plaque in acute coronary syndromes".) 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 [117].
Angiotensin II Increased plasma concentrations of angiotensin II promote the development and severity
of atherosclerosis, particularly when combined with hyperlipidemia [118]. Angiotensin II may play a role in the
modulation of vascular smooth muscle cell proliferation and the production of extracellular matrix [119,120].
(See "Actions of angiotensin II on the heart".)
Endothelin-1 Endothelin-1 may contribute to the pathogenesis of atherosclerosis at all stages, even when
the plaque is clinically imperceptible [121,122]. 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 [123]. (See "Role of endothelin in heart failure with
reduced ejection fraction".)
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 [124]. 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 [122,125].
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 [126].

The expression of both ICAM-1 and VCAM-1 are upregulated in atherosclerotic lesions, but VCAM-1 appears
to be more important in the initiation of atherosclerosis [127]. 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 [128,129].
Monocyte adhesion to endothelial cells is reduced by L-arginine, the precursor of nitric oxide [130] and alpha
tocopherol (vitamin E), and increased by androgens due in part to enhanced endothelial cell-surface
expression of VCAM-1 [131]. Antibodies that block adhesion molecules may ameliorate elements of the
inflammatory response in atherosclerotic plaques [132].
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 [133] in a manner that impairs
atheroprotective functions [29]. These changes may be mediated by stimulation of the release of nitric oxide
from the endothelial cells [134,135].
Atherosclerosis preferentially affects regions of coronary arteries that experience low shear stress or
disturbed flow [136]. In addition, low shear stress is associated with an increase in intima medial thickness of
the common carotid artery in healthy men [137].
Anti-oxidized LDL antibodies Oxidation of LDL involves the oxidation of fatty acids that produce
hydroperoxides and generate active aldehydes such as malondialdehyde [138]. Malondialdehyde can modify
the lysine residues on apolipoprotein B, which renders the molecule more attractive to the scavenger receptor
on the macrophage. The oxidized LDL, modified by oxidation or by derivatization of the lysyl residues, can
become antigenic.
Antibodies to oxidized LDL localize in human atherosclerotic plaques and in the plasma of patients with
atherosclerosis [139,140]. The titer of antibodies to oxidized LDL rise during the month after presentation with
an acute coronary syndrome and are higher than in patients with chronic coronary disease or normal
coronary arteries [68]. This issue is discussed in detail elsewhere. (See "Function and clinical applications of
immunoglobulins", section on 'Antibody specificity and cross-reactivity'.)
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 [141,142]. In the
hyperlipidemic ApoE knockout mouse model, mtDNA lesions found in the aortas preceded the development
of aortic plaques [143]. More mtDNA lesions and larger plaque size were detected in the aortas of mice
expressing mitochondrial mutation [143]. In patients, association of leukocyte mtDNA with atherosclerotic
plaque vulnerability was examined in the Virtual Histology in Vulnerable Atherosclerosis (VIVA) trial [144]. 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 [144,145]. 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 [146-148]. 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 [149].

It is likely that the complex pathophysiological processes that occur in atherosclerosis are not determined by
a single or small number of genes. In addition, environmental factors, and their interactions with genes, likely
participate. In the general population, genetic polymorphisms of 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 [150-156] 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 [157]. (See "Inherited disorders of LDL-cholesterol metabolism".)
Infection Chronic infection may contribute to the pathogenesis of atherosclerosis. The major organisms
that have been studied are Chlamydia pneumoniae, cytomegalovirus (CMV), and Helicobacter pylori;
however, enterovirus (primarily coxsackie B virus), hepatitis A virus (HAV), and herpes simplex virus (HSV)
type 1 and type 2 have also been implicated. (See "Overview of the possible risk factors for cardiovascular
disease", section on 'Infection'.)
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.
C. pneumoniae infection C. pneumoniae has been the focus of much attention as a possible
contributor to coronary atherosclerosis [158,159]. However, large randomized trials do not support benefit
from antibiotic therapy against C. pneumoniae to reduce coronary events. (See "Chlamydia pneumoniae
infection as a potential etiologic factor in atherosclerosis".)
Cytomegalovirus infection Infection with CMV and other herpesviruses, such as HSV, has been
implicated in some but not all studies in the development of atherosclerosis, restenosis, and transplant
vasculopathy [160-165].
Serum anti-CMV antibody levels are significantly elevated in patients with coronary disease when compared
to control subjects [161,166] and in those with carotid intimal thickening (a measure of subclinical
atherosclerosis) [167]. In addition, CMV antigens, nucleic acid sequences, and DNA have been detected in
smooth muscle cells of carotid artery plaques obtained from patients undergoing endarterectomy [168].
CMV infection might promote the development of atherosclerosis by increasing the uptake of oxidized LDL in
vascular smooth muscle cells [169] and by increasing the neointimal response to vascular injury [170].
Coxsackie B virus infection A role has been postulated for the enterovirus coxsackie B virus in the
pathogenesis of coronary heart disease [171]. However, no rigorous evidence exists to support its role in
atherosclerosis.
H. pylori There is also some evidence linking H. pylori infection with atherosclerosis and premature MI
[172,173]. However, it is uncertain if this relationship is based upon the bacterium itself or its association with
other confounding factors related to atherosclerosis, primarily lower socioeconomic class, older age, and
smoking [174].
Pathogen burden 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 [175-

178]. This was illustrated in a report of 375 patients undergoing coronary angiography; antibody titers to a
number of pathogens were measured and assessment of coronary endothelial function was performed in 218
[176]. The pathogen burden, more than any single pathogen, correlated with the presence and severity of
coronary disease and was an independent predictor of endothelial dysfunction. The likelihood of
atherosclerosis was markedly increased in patients with four or five positive titers and elevated serum CRP.
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 [179].
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.
Effect of vaccination Vaccination against influenza has been evaluated for a potential benefit in
preventing cardiovascular disease [180-182]. Several studies have found a beneficial effect of influenza
vaccination on cardiovascular events [180,181]. 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 "Seasonal influenza vaccination in
adults", section on 'Older adults' and "Geriatric health maintenance", section on 'Influenza vaccine'.)
ROLE OF PLAQUE RUPTURE 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.
Acute coronary and cerebrovascular syndromes (unstable angina, myocardial infarction, sudden death, and
stroke) are typically due to rupture of plaques with less than 50 percent stenosis [183-185]. Plaque rupture
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 [186]. 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 [144,145].
The pathology and pathogenesis of the vulnerable plaque and its role in acute coronary syndromes are
discussed elsewhere. (See "Pathology and pathogenesis of the vulnerable plaque" and "The role of the
vulnerable plaque in acute coronary syndromes".)
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SUMMARY

 Although atherosclerosis is one of the most studied human diseases, an agreed upon unifying
hypothesis that fully explains its pathogenesis remains elusive.
Multiple factors contribute to the pathogenesis of atherosclerosis, including endothelial dysfunction,
inflammatory and immunologic factors, plaque rupture, 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.)
Atherosclerosis begins in childhood with the development of fatty streaks. The advanced lesions of
atherosclerosis occur with increasing frequency with aging. (See 'Epidemiology' above.)
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.)
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