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29/9/2020 Pathogenesis of atherosclerosis - UpToDate
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Patogenia de la aterosclerosis
Autor: Xue-Qiao Zhao, MD, FACC
Editores de sección: Juan Carlos Kaski, DSc, MD, DM (Hons), FRCP, FESC, FACC, FAHA, Peter Libby, MD
Editor adjunto: Gordon M. Saperia, MD
Todos los temas se actualizan a medida que se dispone de nueva evidencia y se completa nuestro proceso de
revisión por pares .
Revisión de la literatura vigente hasta: agosto de 2020. | Este tema se actualizó por última vez: 01 de junio de
2020.
INTRODUCCIÓN
La aterosclerosis es un proceso patológico que causa enfermedad de las arterias coronarias,

cerebrales y periféricas y de la aorta [ 1,2 ]. Las formas de arteriopatías aceleradas, como la
reestenosis después de una intervención coronaria percutánea con colocación de stents y la
vasculopatía por trasplante coronario, difieren en la patogenia y se analizan por separado. (Ver
"Reestenosis del stent intracoronario" y "Trasplante de corazón en adultos: patogenia y factores
de riesgo de la vasculopatía del aloinjerto cardíaco" ).
EPIDEMIOLOGÍA
La aterosclerosis puede comenzar en la infancia con el desarrollo de vetas grasas ( tabla 1 ). Las
lesiones de la aterosclerosis avanzan con el envejecimiento [ 3-5 ]. Los siguientes puntos
demuestran la frecuencia de aterosclerosis en las poblaciones occidentales y su progresión con la
edad:
● En un estudio de autopsia de 2876 hombres y mujeres de 15 a 34 años que murieron por

causas no cardíacas, todos los individuos tenían estrías de grasa aórtica [ 6 ].
● En otro estudio de autopsia de 760 jóvenes (de 15 a 34 años) víctimas de accidentes,

suicidios u homicidios, se observaron ateromas coronarios avanzados en el 2 y el 0 por
ciento de los hombres y mujeres de 15 a 19 años, y en el 20 y el 8 por ciento de los hombres
y mujeres de 30 a 34 años [ 5 ].
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● En un estudio de 260 parches aórticos perirrenales recolectados durante el trasplante de

órganos, las primeras tres décadas de vida se caracterizaron por engrosamiento de la íntima
y xantomas. La cuarta, quinta y sexta décadas se caracterizaron por placas más complicadas
de engrosamiento de la íntima patológico, fibroateromas tempranos y tardíos con tapas
fibrosas delgadas, placas rotas, rotura cicatrizada y placas fibróticas calcificadas [ 7 ].
● Con la ecografía intracoronaria, uno de cada seis adolescentes estadounidenses tiene un

engrosamiento de la íntima anormal [ 4 ].
HISTOLOGÍA
Rayas grasas - La primera fase de la aterosclerosis histológicamente ocurre como un

engrosamiento focal de la íntima con acumulación de macrófagos cargados de lípidos (células
espumosas) y matriz extracelular ( tabla 1 y figura 1 ) [ 8 ]. Las células del músculo liso también
pueden poblar la íntima, algunas de las cuales pueden surgir de células madre hematopoyéticas [
9 ], migrar y proliferar. Los lípidos se acumulan temprano en la formación de la veta grasa,
produciendo depósitos tanto intracelulares como extracelulares, que producen la veta grasa. El
biglicano, un pequeño proteoglicano de dermatán sulfato detectado en la íntima de los segmentos
de la arteria coronaria aterosclerótica, puede unirse y atrapar lipoproteínas, incluidas las
lipoproteínas de muy baja densidad y las lipoproteínas de baja densidad [10 ]. La veta grasa
también puede contener linfocitos T. (Consulte "Inflamación" a continuación). Las células
espumosas constituyen el sello distintivo del ateroma temprano.
A medida que estas lesiones se expanden, se acumulan más células de músculo liso en la íntima.
Las células del músculo liso dentro de la capa profunda de la estría grasa pueden sufrir
apoptosis, que se asocia con una mayor acumulación de macrófagos y microvesículas que
pueden calcificarse, contribuyendo quizás a la transición de las estrías grasas en placas
ateroscleróticas ( tabla 1 ) [ 11 ].
Fibrosa tapa - ateromas capa fibrosa se definen como placas con un núcleo lipídico bien
definida cubierta por una capa fibrosa, que pueden ser relativamente acelular (hechas de
colágeno denso) o puede ser rico en células lisas. (Ver "Mecanismos de los síndromes coronarios
agudos relacionados con la aterosclerosis" ).
Vasa vasorum : los vasa vasorum forman una red de microvasos que se origina principalmente
en la capa adventicia de las grandes arterias. Estos vasos suministran oxígeno y nutrientes a las
capas externas de la pared arterial [ 12 ]. A medida que las placas ateroscleróticas se desarrollan
y se expanden, adquieren su propia red microvascular, que se extiende desde la adventicia a
través de la media hasta la íntima engrosada [ 13 ]. Estos vasos de paredes delgadas son
propensos a romperse, lo que lleva a una hemorragia dentro de la sustancia de la placa y
contribuye a la progresión de la aterosclerosis coronaria [ 14,15 ].
Fibrosa placa - Los evoluciona placa fibrosa de la estría grasa a través de la acumulación de
tejido conjuntivo con un mayor número de células de músculo liso llenos de lípidos y a menudo
una piscina de lípidos más profundo extracelular.
Lesiones avanzadas - Las lesiones más avanzadas a menudo contienen un núcleo rico en
lípidos necrótico, y finalmente regiones calcificadas ( tabla 1 ) [ 3 ].
La formación de ateroma se asocia con la remodelación de las arterias coronarias ( figura 2 ) [ 16

]. La remodelación positiva implica la expansión de la placa y el área de la membrana elástica
externa debido a un aumento compensatorio en el tamaño del vaso local, mientras que la
remodelación negativa se refiere a un área de la membrana elástica externa más pequeña en el
sitio de la lesión debido a la contracción local del tamaño de los vasos ( imagen 1A-B ).
La remodelación positiva actúa como un mecanismo compensatorio en la enfermedad arterial

coronaria temprana, evitando la pérdida luminal a pesar de la acumulación de placa. Sin
embargo, la remodelación arterial como consecuencia de la formación y expansión de la placa se
asocia con una fisiología arterial anormal, así como con el desarrollo de síntomas clínicos [ 16 ].
Se observa remodelación positiva con placas complejas e inestables en pacientes que presentan
angina inestable; por el contrario, la remodelación negativa se asocia con placas obstructivas en
pacientes con angina estable [ 17 ]. (Ver "Mecanismos de los síndromes coronarios agudos
relacionados con la aterosclerosis" ).
Hemorragia intraplaca - hemorragia intraplaca se debe principalmente a la neovascularización

de placa y aumento de la permeabilidad de neovasos [ 18,19 ], es una característica común de
las lesiones ateroscleróticas avanzadas, y un elemento crítico que conduce a progresión
acelerada placa [ 20-23 ], inestabilidad de la placa [ 24-26 ], y eventos vasculares isquémicos [
27-30 ].
PATOGÉNESIS
Múltiples factores contribuyen a la patogenia de la aterosclerosis, incluida la disfunción endotelial,

dislipidemia, factores inflamatorios e inmunológicos, rotura de placa y tabaquismo. (Consulte
"Descripción general de los factores de riesgo establecidos de enfermedad cardiovascular" y
"Riesgo cardiovascular de fumar y beneficios de dejar de fumar" ).
Disfunción endotelial : el endotelio forma una interfaz biológica activa entre la sangre y todos
los demás tejidos. La capa única de endotelio continuo que recubre las arterias forma una capa
tromborresistente única entre la sangre y los tejidos subendoteliales potencialmente
trombogénicos. El endotelio también modula el tono, el crecimiento, la hemostasia y la
inflamación en todo el sistema circulatorio. La disfunción vasodilatadora endotelial es un paso
inicial en la aterosclerosis y se cree que es causada principalmente por la pérdida de óxido nítrico
derivado del endotelio [ 31 ]. Este tema se analiza en detalle por separado y solo se revisará
brevemente aquí. (Ver "Disfunción endotelial coronaria: aspectos clínicos" .)
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) [32]. 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 [33,34], with angiotensin converting enzyme inhibitors
[35], or with high doses of antioxidants such as vitamin C or flavonoids contained in red wine and
purple grape juice [36,37]. 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" and
"Nutritional antioxidants in atherosclerotic cardiovascular 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 [38-41]. Macrophages that have taken up oxidized LDL release a variety of
inflammatory substances, cytokines, and growth factors [42,43]. Among the many molecules that
have been implicated are: monocyte chemotactic protein (MCP)-1 [44,45]; intercellular adhesion
molecule (ICAM)-1 [44]; macrophage and granulocyte-macrophage colony stimulating factors
[46,47]; CD40 ligand ; interleukin (IL)-1, IL-3, IL-6, IL-8, and IL-18 [48-50]; and tumor necrosis
factor alpha [51-53]. 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 Cankinumab 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 [54]. 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 [55,56], 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 [54,57]. 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 [58] did not show improved outcomes. (See "Overview of the prevention of
cardiovascular disease events in those with established disease (secondary prevention) or at high
risk", section on 'Therapies with uncertain or no benefit'.)
Cytokines — Cytokines may participate in the pathogenesis of atherosclerosis [59]. Mediators

such as interleukin-1 or tumor necrosis factor-alpha have a multitude of atherogenic effects. Basic
science studies [60-62] 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 [63,64]. 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 [65]. 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
[66]. 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 [67].
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
[68]. 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 [69]. 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 [70]. PAPP-A can be produced by
osteoblasts, fibroblasts, endothelial, vascular smooth muscle cells, and monocytes/macrophages
[71-75], and has been identified in vulnerable coronary plaques but not in stable ones [76-78].
Dyslipidemia — Lipid abnormalities play a critical role in the development of atherosclerosis

[43,79-85]. 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 [79,85] are particularly important risk factors for atherosclerosis
(algorithm 1) [80].
● Cholesterol accumulates in the lipid-laden macrophages (foam cells), and in the lipid core, of
atherosclerotic plaque [86]. 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 [87,88]. Macrophage uptake of
LDL cholesterol may initially be an adaptive response, which prevents LDL-induced
endothelial injury [89]. However, cholesterol accumulation in foam cells leads to mitochondrial
dysfunction, apoptosis, and necrosis, with resultant release of cellular proteases,
inflammatory cytokines, and prothrombotic molecules [89]. 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 [90,91]. (See "Management of low density lipoprotein cholesterol (LDL-C) in
the secondary prevention of cardiovascular disease", section on 'Benefits of LDL-C lowering'
and "Management of elevated low density lipoprotein-cholesterol (LDL-C) in primary
prevention of cardiovascular disease", section on 'Rationale for LDL-C lowering in primary
prevention'.)
● 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 [92]. However, cardiovascular disease event reduction from increasing HDL-
cholesterol has not been established, particularly in patients with well-controlled LDL-
cholesterol levels [93-95]. A Mendelian randomization study showed that raised plasma HDL-
cholesterol levels through some genetic mechanisms are not associated with lower risk of MI
[96]. Studies showed that HDL-cholesterol efflux had a close relationship with clinical
atherosclerosis [97] and CV events [98]. 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 [99,100]. (See
"Hypertriglyceridemia".)
● Oxidized lipoproteins including LDL [43], HDL [101], remnant lipoproteins [102], and
phospholipid [103] 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 [104,105]. In addition, antibodies to oxidized LDL
have been found in human atherosclerotic plaques and in the plasma of patients with
atherosclerosis [106,107]. 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 [108,109].
Additional functions of Lp(a) include initiation of signaling pathways in macrophages [110] and
vascular endothelial cells [111,112], 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 [113]. Lp(a) associates with increased residual
cardiovascular event risk in JUPITER [112] and AIM-HIGH [114], 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 [115-117]. It can increase arterial wall tension,
potentially leading to disturbed repair processes and aneurysm formation [2].
Smoking — Cigarette smoking is another major risk factor [115-117] and it impacts all phases of
atherosclerosis from endothelial dysfunction to acute clinical events, the latter being largely
thrombotic [118]. The following observations have been made:
● In humans, cigarette smoke exposure impairs endothelium-dependent vasodilation, perhaps

through decreased nitric oxide (NO) availability [119-121].
● 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 [122-125].
● 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)
[126,127], increase fibrinogen levels [128,129], and decrease fibrinolysis [130].
● Cigarette smoking increases oxidative modification of LDL [131] and decreases the plasma
activity of paraoxonase, an enzyme that protects against LDL oxidation [132]. The
triglyceride/HDL abnormalities seen among smokers have been suggested to be related to
insulin resistance [133].
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 [134-140]. Macrophages express most insulin signaling molecules except IR
substrate 1 (IRS1) and glucose transporter type 4 [141,142]. 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
[143,144]. A published study [143] 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 [145].
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
[146].
Angiotensin II — Increased plasma concentrations of angiotensin II promote the development

and severity of atherosclerosis, particularly when combined with hyperlipidemia [147]. Angiotensin
II may modulate vascular smooth muscle cell proliferation and the production of extracellular
matrix [148,149].
Endothelin-1 — Endothelin-1 may contribute to the pathogenesis of atherosclerosis at all stages,

even when the plaque is clinically imperceptible [150,151]. 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 [152]. (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 [153]. 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 [151,154].
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 [155].
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 [156]. 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 [157,158].
Monocyte adhesion to endothelial cells is reduced by L-arginine, the precursor of nitric oxide [159]
and alpha tocopherol (vitamin E), and increased by androgens due in part to enhanced endothelial
cell-surface expression of VCAM-1 [160]. Antibodies that block adhesion molecules may
ameliorate elements of the inflammatory response in atherosclerotic plaques [161].
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 [162]
in a manner that impairs atheroprotective functions [42]. These changes may be mediated by
inhibition of the release of nitric oxide from the endothelial cells [163,164].
Atherosclerosis preferentially affects regions of coronary arteries that experience low shear stress
or disturbed flow [165]. In addition, low shear stress is associated with an increase in intima
medial thickness of the common carotid artery in healthy men [166].
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 [167,168]. In the hyperlipidemic ApoE knockout mouse model, mtDNA lesions
found in the aortas preceded the development of aortic plaques [169]. More mtDNA lesions and
larger plaque size were detected in the aortas of mice expressing mitochondrial mutation [169]. In
patients, association of leukocyte mtDNA with atherosclerotic plaque vulnerability was examined
in the Virtual Histology in Vulnerable Atherosclerosis (VIVA) trial [170]. 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 [170,171]. 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
https://www.uptodate.com/contents/pathogenesis-of-atherosclerosis/print?search=ATEROMA&source=search_result&selectedTitle=1~6&usag… 10/22
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 [172-174]. 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 [175].
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 [176-182] 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 [183]. (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 [184], cytomegalovirus (CMV)
[185-195], coxsackie B virus infection [196], and Helicobacter pylori [197-199]. (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 [200-
203]. 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 [204]. 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 [205-207]. Several studies have found a beneficial
effect of influenza vaccination on cardiovascular events [205,206]. 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 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 [208-210]. In a review [211] 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 [212]. 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 [213]; 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 [214]. 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
[170,171].
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".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.”
The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading
level, and they answer the four or five key questions a patient might have about a given condition.
These articles are best for patients who want a general overview and who prefer short, easy-to-
read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and
more detailed. These articles are written at the 10th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or
e-mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on “patient info” and the keyword(s) of interest.)
● Basics topic (See "Patient education: Atherosclerosis (The Basics)".)
SUMMARY
● 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.)
● 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.)
Use of UpToDate is subject to the Subscription and License Agreement.
Topic 13603 Version 19.0
GRAPHICS
Criteria for American Heart Association lesion classification system and

correspondence with classification of gross arterial specimens
Comments and
AHA
Criteria corresponding gross
grade
classification
0 Normal artery with or without adaptive intimal thickening; no hold Normal tissue
1 Isolated MFCs containing lipid; no extracellular lipid; variable Initial atherosclerotic lesion,
adaptive intimal thickening grossly with lipid staining sometimes visible grossly with
lipid staining
2 Numerous MFCs, often in layers, with fine particles of extracellular Fatty streak, visible grossly with
lipid; no distinct pools of extracellular lipid: variable adaptive intimal III staining
thickening
3 Numerous MFCs with ≥ pools of extracellular lipid; no well-defined Fatty plaque, raised fatty streak,
core of extracellular lipid intermediate lesion, or
transitional lesion
4 Numerous MFGs plus well-defined core of extracellular lipid, but with Atheroma, fibrous plaque, or
luminal surface covered by relatively normal intima raised lesion
5 Numerous MFCs, well-defined core or multiple cores of extracellular Fibroartherema, fibrous plaque,
lipid, plus reactive fibrotic cap, vascularization, or calcium or raised lesion
6 All of the above plus surface defect, hematoma, hemorrhage, or Complicated lesion
thrombosis
MFC: macrophage foam cell; AHA: American Heart Association.
Graphic 56922 Version 2.0
Fatty streak
Cross-section of a human coronary artery demonstrates the early atherosclerotic

changes of a fatty streak with thickening of the intima (short arrow) and a soft
lipid core (long arrow).
Courtesy of Charles E Rackley, MD.
Positive and negative arterial remodeling extremes of the

remodeling response
Longitudinal sections through vessel segments show positively and negatively remodeled
lesions. The lumen diameter is maintained with positive remodeling, while there is
significant luminal narrowing with negative remodeling.
EEM: external elastic membrane; RR: remodeling ratio (EEM area lesion/EEM area proximal
reference).
Reprinted with permission from Schoenhagen P, Ziada KM, Vince DC, et al. J Am Coll Cardiol
2001; 38:297. Copyright © 2001 American College of Cardiology.
Example of negative remodeling
Intravascular ultrasound images of the proximal reference and lesion site are
shown. The remodeling ratio (EEM area lesion/EEM area proximal reference) is
0.71.
EEM: external elastic membrane.
Reprinted with permission from: Schoenhagen P, Ziada KM, Vince DG, et al. J Am Coll
Cardiol 2001; 38:297. Copyright © 2001 American College of Cardiology.
http://www.elsevier.com/locate/jacc
http://www.sciencedirect.com
Example of positive remodeling
Intravascular ultrasound images of the proximal reference and lesion site are
shown. The remodeling ratio (EEM area lesion/EEM area proximal reference) is
1.32.
EEM: external elastic membrane.
Reprinted with permission from: Schoenhagen P, Ziada KM, Vince DC, et al. J Am Coll
Cardiol 2001; 38:297. Copyright © 2001 American College of Cardiology.
http://www.elsevier.com/locate/jacc
http://www.sciencedirect.com
Factors that cause and interventions that improve endothelial dysfunction
Factors associated with endothelial Interventions that improve endothelial

dysfunction function
Increased age L-arginine
Male sex Antioxidants
Family history of CHD Smoking cessation
Smoking Cholesterol lowering
Increased serum cholesterol ACE inhibitors
Low serum HDL-cholesterol Exercise
Hypertension Mediterranean Diet
Increased serum homocysteine
Diabetes mellitus
Obesity
High-fat meal
Association of increasing plasma cholesterol and

coronary risk
Relation between plasma cholesterol concentration and six-year coronary heart

disease risk in 361,662 men (ages 35 to 57) screened during the MRFIT study.
There is a continuous, positive, graded correlation between the plasma
cholesterol concentration and coronary risk. To convert plasma cholesterol to
mmol/L, divide by 38.5.
Data from: Stamler J, Wentworth D, Neaton JD. Is relationship between serum

cholesterol and risk of premature death from coronary heart disease continuous and
graded? Findings in 356,222 primary screenees of the Multiple Risk Factor
Intervention Trial (MRFIT). JAMA 1986; 256:2823.
Role of LDL in atherosclerosis
Schematic representation of the effects of LDL and oxidized LDL in the

pathogenesis of atherosclerosis. Other coronary risk factors, low HDL levels,
smoking, hypertension, diabetes mellitus, and estrogen deficiency also enhance
the oxidation of LDL.
HDL-C and cardiovascular risk
Multiplier for cardiovascular risk

HDL, mg/dL
Men Women
30 1.82 -
35 1.49 -
40 1.22 1.94
45 1.00 1.55
50 0.82 1.25
55 0.67 1.00
60 0.55 0.80
65 0.45 0.64
70 - 0.52
75 Longevity syndrome Longevity syndrome
Inverse relation between plasma HDL-cholesterol levels and cardiovascular risk in men and women. Multiply values by
38.5 to convert to mmol/L.
Data from Castelli WP. Am Heart J 1983; 106:1191.

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29/9/2020 Pathogenesis of atherosclerosis - UpToDate

Reimpresión oficial de UpToDate ®

La aterosclerosis es un proceso patológico que causa enfermedad de las arterias coronarias,

● En un estudio de autopsia de 2876 hombres y mujeres de 15 a 34 años que murieron por

● En otro estudio de autopsia de 760 jóvenes (de 15 a 34 años) víctimas de accidentes,

● En un estudio de 260 parches aórticos perirrenales recolectados durante el trasplante de

● Con la ecografía intracoronaria, uno de cada seis adolescentes estadounidenses tiene un

Rayas grasas - La primera fase de la aterosclerosis histológicamente ocurre como un

La formación de ateroma se asocia con la remodelación de las arterias coronarias ( figura 2 ) [ 16

La remodelación positiva actúa como un mecanismo compensatorio en la enfermedad arterial

Hemorragia intraplaca - hemorragia intraplaca se debe principalmente a la neovascularización

Múltiples factores contribuyen a la patogenia de la aterosclerosis, incluida la disfunción endotelial,

Evidence supporting the importance of inflammation in the pathogenesis of atherosclerosis comes

Lp-PLA2 — Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a macrophage-secreted

Cytokines — Cytokines may participate in the pathogenesis of atherosclerosis [59]. Mediators

Leukocyte activation — Leukocytes infiltrate and accumulate in the atherosclerotic lesion,

● The total number of T cells increased in progressive lesions.

● Formation of adventitial lymphoid-like structures containing B cells and plasma cells, a

● A dramatic decrease of T-cell subsets, disappearance of lymphoid-like structures, and loss of

Pregnancy-associated plasma protein-A (PAPP-A) — PAPP-A is a high molecular weight,

Dyslipidemia — Lipid abnormalities play a critical role in the development of atherosclerosis

It is useful, however, to summarize the major observations.

● An analysis in 60,608 individuals found that nonfasting remnant cholesterol, which is

Hypertension — Hypertension is a major risk factor for the development of atherosclerosis,

● In humans, cigarette smoke exposure impairs endothelium-dependent vasodilation, perhaps

● Cigarette smoking is associated with an increased level of multiple inflammatory markers,

● Cigarette smoking may decrease availability of platelet-derived NO, decrease platelet

Diabetes — In addition to atherogenic effects from the diabetes-related dyslipidemia (elevated

Angiotensin II — Increased plasma concentrations of angiotensin II promote the development

Endothelin-1 — Endothelin-1 may contribute to the pathogenesis of atherosclerosis at all stages,

Endothelin-1 immunoreactivity is ubiquitous within the intracellular and extracellular compartments

endothelin-1 production, is expressed in smooth muscle cells and macrophages of human

Genetic associations — The genetic influences on atherosclerosis formation, progression, and

ROLE OF PLAQUE RUPTURE AND EROSION

Atherosclerosis is generally asymptomatic until the plaque stenosis exceeds 70 or 80 percent of

INFORMATION FOR PATIENTS

● Basics topic (See "Patient education: Atherosclerosis (The Basics)".)

● Multiple factors contribute to the pathogenesis of atherosclerosis and its complications,

Use of UpToDate is subject to the Subscription and License Agreement.

Topic 13603 Version 19.0

Criteria for American Heart Association lesion classification system and

MFC: macrophage foam cell; AHA: American Heart Association.

Graphic 56922 Version 2.0

Cross-section of a human coronary artery demonstrates the early atherosclerotic

Courtesy of Charles E Rackley, MD.

Graphic 76466 Version 1.0

Positive and negative arterial remodeling extremes of the

Graphic 68786 Version 2.0

Example of negative remodeling

EEM: external elastic membrane.

Example of positive remodeling

EEM: external elastic membrane.

Factors that cause and interventions that improve endothelial dysfunction

Factors associated with endothelial Interventions that improve endothelial

Male sex Antioxidants

Family history of CHD Smoking cessation

Smoking Cholesterol lowering

Increased serum cholesterol ACE inhibitors

Low serum HDL-cholesterol Exercise