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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3774_Библиотеки_им_академика_М_И_Перельмана
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Uptake of modied lipoprotein particles in the subintimal compartment is benecial initially as it sequesters potentially damaging lipoprotein particles. However,
when this increased lipoprotein uptake is paired together with an impaired efux
capacity, intracellular capacity of cholesterol surpasses the capacity of macrophages
to handle it. As cholesterol starts accumulating, macrophages become enlarged with
cholesterol and cholesterol esters residing within lipid droplets in the cytoplasm,
resulting in the appearance of a foam cell. This negates the “protective role” of
macrophages. Over time, the progressive accumulation of lipids inside foam cells
causes endoplasmic reticulum stress leading to ROS production which triggers an
apoptotic cascade. This leads to the release of proinammatory cytokines which
further promote atherosclerosis as more immune cells inltrate the plaque as an
attempt to rescue. This type of inammatory amplication represents an innate
immune response due to the non-dependence on antigenic stimulation.
Plaque growth and stability are inuenced by accumulation and removal of macrophages and foam cells, and the production of pro- (“M1”) and anti-inammatory (“M2”)
cytokines, chemokines, ROS, and matrix degrading enzymes [27]. Murine modelling of
atherosclerosis has suggested that macrophages accumulate primarily by monocyte
recruitment in early plaque, and by local proliferation as plaque progresses [28].
It is also important to note that even though the role of macrophages in foam cell
formation is reasonably established, the contribution of circulating monocytes is
less well understood. Circulating monocytes also express the same SRs as macrophages (albeit at lower levels) and can potentially accumulate lipids prior to their
migration to the arterial intima and differentiation into macrophages [25].
S. Fernando et al.
2.4.5 Lymphocyte Responses
The adaptive immune system which is usually activated in the presence of pathogens, also recognises modied LDL and other inammatory cytokines released during plaque progression and directs immune cells to the site. While macrophages
comprise the vast majority of immune cells in atherosclerotic lesions, T and B lymphocytes have also been found to migrate into the atherosclerotic aortic wall in an
L-selectin-dependent manner similar to that of monocytes, discussed earlier
(Fig.2.4) [29, 30]. This migration initially occurs as an abortive attempt to remove
or sequester abnormal lipid which is generally perceived as a danger signal.
Lymphocyte responses in plaque progression and the advances in the eld of
adaptive immunity in atherogenesis have been studied extensively. In brief, T lymphocytes participate in the formation of atherosclerotic lesions as early in the atherosclerotic process as monocytes. Several leukocyte adhesion molecules such as
VCAM-1 and ICAM-1 also initiate T cell recruitment. T lymphocytes can exhibit
functional diversity where T-helper type 1 (Th1) lymphocytes appear to accelerate
atherosclerosis and regulatory T cells (T-regs) limit the disease process [31]. Th1
lymphocytes secrete inammatory cytokines, such as interferon-γ (IFN-γ), TNF- α/β and IL-2 which activate macrophages, endothelial cells and SMCs leading to
local inammation [22, 30–32], whereas T-regs through the secretion of TGF-β and
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Fig. 2.4 Innate immunity and adaptive immunity. A simplied diagram of innate and adaptive
immunity pathways operating during atherosclerosis. PAMPS pathogen-associated molecular
patterns
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IL-10 are believed to dampen this process [2, 33]. The balance between different T
cell subsets is therefore an important determinant of plaque progression.
B cells also populate the lesion area, where they mostly assist with the mitigation
of the disease [2, 34], as seen by B1 cells which produce natural antibody protection
against atherosclerosis. However, several studies have reported that B2 cells might
aggravate plaque progression [2].
2.4.6 Smooth Muscle Cell Migration andFibrous
Cap Formation
SMCs are largely responsible for the transition of atherosclerotic plaque from the
fatty streak stage to the brous atheromatous plaque stage. In the normal arterial
wall, SMCs express a differentiated phenotype and are surrounded by a basal lamina consisting of type IV collagen. They are normally contractile and do not divide
or migrate. However, in atherosclerosis, lipoproteins, foam cells, activated endothelial cells and Th1 lymphocytes release inammatory cytokines and proteolytic signals which degrade this supporting framework and initiate SMC migration into the
arterial intima. This process starts with downregulation of genes responsible for
SMC differentiation, such as smooth muscle α-actin (Acta2) and smooth muscle
myosin heavy chain (Myh11). At the same time the release of platelet- derived
growth factor (PDGF) and TGF-β by macrophages and endothelial cells stimulates
SMC migration across the internal elastic lamina into the subendothelial space, giving SMCs a ‘synthetic’ phenotype (Fig.2.5) [35]. In the intima, foam cells release
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Fig. 2.5 Formation of atherosclerotic plaque. (1) LDL enters the subintima. (2) LDL becomes
modied. (3) Monocytes which are circulating in blood become attached to the adhesion molecules
expressed on the endothelial surface. (4) Monocytes differentiate into macrophages in the subintima.
(5) Macrophages uptake the modied LDL particles and become foam cells. (6) SMCs migrate into
the intima and proliferate. (7) SMCs also take up modied LDL particles and form foam cells. (8)
Foam cells undergo apoptosis and start forming the necrotic core. (9) Thin brous cap is formed
S. Fernando et al.
an array of cytokines, namely TNF-α, IL-1, TGF-β and broblast growth factor
(FGF) which stimulate SMC proliferation as well as the synthesis and secretion of
new extracellular matrix proteins, proteoglycans and other proteins which are
thought to be benecial for arterial remodelling and plaque stabilisation [36–38].
These cytokines also provoke activation of other leukocytes and promote further
cytokine release, thus reinforcing a positive feedback loop to maintain inammation
in the atherosclerotic lesion.
On the other hand, SMCs also play an important role in stabilising atherosclerotic plaques as they are responsible for the production of brillar collagens (type I
and type III collagens), which leads to the formation of a brous cap on top of the
plaque. This brous cap is vital in separating plaque’s thrombogenic core from
mediators of coagulation that circulate in the blood. The thickness and collagen
content of the brous cap are important determinants of plaque stability. Plaques
most at risk of rupture are dened as plaques with a brous cap less than 65μm
thick, also referred to as TCFA, as previously mentioned.
2.4.7 Macrophage Apoptosis andNecrotic Core Formation
Macrophage apoptosis (programmed cell death) occurs during all stages of plaque
progression. The induction of this process likely involves chronic, cumulative stimuli
over time rather than a single acute catastrophic stimulus. These take the form of; (1)
oxidative stress; (2) high concentrations of pro-inammatory cytokines, such as
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TNF-α; (3) accumulation of unesteried cholesterol, oxysterols and modied LDL;
(4) activation of Fas death pathway via Fas ligand and (5) endoplasmic reticulum stress.
In early lesions, the engorged foam cells become unstable over time and eventually undergo apoptosis. Studies in early atherosclerotic models have found an
inverse relationship between macrophage apoptosis and lesion size, where increased
macrophage apoptosis in early lesions was associated with decreased lesion size
[39–41]. This is due to the rapid removal of apoptotic remnants by efferocytosis (see
Glossary), leading to suppression of the pro-inammatory responses. The overall
effect is a reduction in lesion cellularity and size.
However, in advanced lesions the apoptotic macrophages are not cleared efciently by efferocytosis. As a result, apoptotic macrophages accumulate and undergo
secondary necrosis and their lipid-rich cargo is deposited in the tissue where it provokes further inammation [42, 43]. Studies have reported observing apoptotic
macrophages and SMCs in focal areas surrounding the necrotic core. The presence
of free apoptotic remnants in advanced lesions that are not associated with phagocytic cells, indicates that impaired efferocytosis contributes to the growth of the
necrotic core [44, 45].
The chemical composition of the necrotic core suggests that sources of lipids are
also major contributors to its formation, which includes direct accumulation of cholesterol esters from LDL, free cholesterol and cholesterol crystal formation. It is not
known why only some lesions develop necrotic cores while others do not. If there is
no necrotic core present, there is typically no overlying brous cap to rupture.
However, larger necrotic cores pose a greater risk of rupture than smaller ones.
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2.4.8 Calcication
Vascular calcication occurs in the intima as well as the media of the vessel wall.
These two processes occur independently of each other. Intimal calcication develops as a result of lipid accumulation and inammation in atherosclerosis, whereas
medial calcication arises mainly in patients with chronic kidney disease and type
2 diabetes mellitus [46]. Vascular intimal calcication is primarily the process of
bio-mineralisation where insoluble calcium deposits in the form of calcium salts
and is considered an active process where multiple mechanisms exist [47, 48]. It is
believed that SMCs obtain osteogenic properties and calcify analogous to bone formation [17]. Extracellular vesicles are also thought to calcify when calcium phosphates appear inside them, and this leads to the formation of hydroxyapatite crystals,
again akin to bone formation. Another popular theory for the mechanistic basis of
intimal calcication is that apoptotic cells which arise from SMC and macrophage
death also undergo calcication in the extracellular milieu where the same hydroxyapatite crystal formation occurs [49, 50]. It is also believed that these processes of
calcication are stimulated by the loss of inhibitors of calcication which are usually present in the normal arterial wall such as Matrix Gla-Protein (MGP), osteopontin (OPN), fetuin and pyrophosphates [17].
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Arterial calcication progresses with age and its extent generally correlates with
plaque burden. The location and structure of calcication are the most important
determinants of the hazards associated with it. Pathologically, largely calcied atheromatous lesions are much stiffer than more cellular lesions and are less likely to
be associated with plaque rupture. It follows that gross calcication may in fact
provide stability to plaques. Conversely, it has been reported that non-homogenous
calcication, also known as spotty calcication or micro-calcication, is associated
with high-risk, rupture-prone plaques due to the substantial stress it imposes on the
overlying brous cap. Thus, depending on the degree and nature of calcication in
atherosclerosis, it can either be a stabilising force for plaque or alternatively cause
penetrating perturbations which can lead to a reduction in lesion stability [51, 52].
Statins have been shown to increase calcication and collagen production by vascular SMCs [53–55], and this is thought to increase the biomechanical stability of
plaques which makes them less prone to rupture and thrombotic complications [55].
S. Fernando et al.
2.4.9 Neovascularisation andIntraplaque Haemorrhage
With progression of atherosclerotic lesions, the arterial wall thickness increases. It
has been suggested that when this wall thickness exceeds 100μm, oxygen supply to
the plaque site becomes restricted. As a compensatory mechanism, hypoxia- inducible
factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and other angiogenic
modulators are secreted. Together these factors promote neovascularisation (including angiogenesis) [56]. Neovessels originate from the adventitial vasa vasorum and
grow into the base of the progressing atherosclerotic lesion. This provides an alternative route for oxygen and nutrients to enter the plaque site. These plaque neovessels
are also leaky and express cellular adhesion molecules, favouring local extravasation
of red blood cells, plasma proteins, circulating monocytes and other inammatory
cells which further contribute to the growth and destabilisation of the plaque.
Neovascularisation has been found to be present in 50% of coronary atherectomy
samples from patients with unstable angina, compared to 10% from patients with
stable angina, suggesting a possible role in plaque instability. This could be due to
the neovascularisation within the plaque leading to extravasation of red blood cells
and inammatory mediators causing intraplaque haemorrhage. Once red blood cells
are leaked into the plaque, cholesterol from their cell membrane becomes incorporated into the lipid core, increasing its volume [57].
2.4.10 Fibrous Cap Degradation andPlaque Rupture
The brous cap is located between the vascular lumen and the necrotic core.
Plaques tend to rupture where the brous cap is at its thinnest and most inltrated
by macrophages and foam cells. In eccentric plaques, the weakest spot is usually
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in the shoulder region or the cap margin, whereas the thinnest caps (≤65μm)
known as TCFAs are most prone to rupture [8, 18].
Thinning of the brous cap occurs due to its degradation. This brous cap degradation is hypothesised to occur due to two mechanisms [1]. The rst mechanism
involves the gradual loss of SMCs from the brous cap which are the main source
of collagen synthesis. This results in thinning of the brous cap, thus contributing to
plaque vulnerability. Secondly, inltrating macrophages and foam cell formation,
and subsequently their apoptosis lead to the continuous release of MMPs that
degrade the collagen-rich matrix of the brous cap [58, 59]. The time taken for the
brous cap to be degraded is not known. Further studies are needed to determine
whether this evolves over decades or more acutely. Nevertheless, broatheromas
have been commonly observed in patients as young as 30years of age where acute
coronary syndrome is very rare [60, 61]. This suggests that the thinning of the
brous cap may take at least a few years to evolve [1].
Rupture of a thin cap exposes plaque components, such as the cap collagen,
apoptotic microparticles and the lipid core to thrombogenic factors in blood, which
can lead to subsequent thrombosis. The magnitude of thrombosis can be extremely
variable and in the most severe cases leads to tissue- or even life-threatening luminal
occlusion. The main determinants of thrombotic risk of plaque are explained as the
Virchow triad; (1) thrombogenicity of the exposed plaque material, (2) local blood
ow disturbances and (3) systematic thrombotic propensity [1, 10, 62].
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2.4.11 Plaque Erosion
Plaque erosion is the second most common cause of atherothrombosis behind
plaque rupture. It is best characterised in coronary atherosclerosis, where it can
cause the full spectrum of clinical manifestations of acute coronary syndrome,
including ST-segment elevation myocardial infarction (STEMI), non-ST segment
elevation myocardial infarction (NSTEMI) and sudden cardiac death [63, 64].
Although the distinct morphological features of underlying plaque in cases of erosion have not yet been fully characterised, currently recognised hallmarks are an
absent endothelium overlying a plaque which is typically scarcely calcied, with
smaller lipid core, more abundant SMCs, but fewer macrophages and less inammation than in ruptured plaques.
The mechanisms which lead to plaque erosion are still unclear. One current
hypothesis is that toll-like receptor 2 (TLR2) expressed on endothelial cells interacts with gram-positive toxins and hyaluronan, triggering apoptosis and the release
of ROS.This leads to endothelial dysfunction and local inammation which attracts
the inltration of leukocytes, particularly neutrophils. Naturally, neutrophils act to
eliminate pathogens by multiple means, both intracellular and extracellular by
phagocytosis and degranulation [65], or by releasing neutrophil extracellular traps
(NETs, see Glossary) [66]. NETs are composed of a core DNA element to which
histones, proteins (for example, lactoferrin and cathepsins) and enzymes (for
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example, myeloperoxidase and neutrophil elastase) are attached. NETs are thought
to directly kill targets by means of antimicrobial histones and proteases in a process
called NETosis [67]. Activated endothelial cells can induce NETosis. Neutrophils
and NETs directly induce endothelial dysfunction and damage to endothelial cells,
causing them to detach from the underlying internal elastic lamina basement membrane. This exposes them to thrombogenic factors in blood which leads to thrombosis [30, 68].
Compared to plaque rupture, plaque erosions are thought to convey a weaker
thrombogenic stimulus. It has been observed that fatal thrombi resulting from
plaque erosions seem to take longer to build up than those precipitated by plaque
rupture [1, 69, 70].
S. Fernando et al.
2.5 The Role ofInammation inAtherosclerosis
Inammation underpins all stages of atherosclerosis and is a major driver of
plaque complications, such as rupture or erosion, which ultimately results in
thrombosis. Circulating leukocytes, which are the mediators of host defence and
inammation localise in the earliest lesions of atherosclerosis. The normal endothelium does not generally support the binding of these leukocytes. However, in
early atherogenesis the endothelium becomes inamed and has enforced expression of leukocyte adhesion molecules (VCAM-1, ICAM-1, P selectin and E selectin) due to the pro- inammatory cytokines released by inammatory cells. These
proinammatory cytokines (e.g. MCP-1) also provide a chemotactic stimulus for
the adherent leukocytes directing their migration to the subintima. M-CSF which
is responsible for the differentiation of monocytes into macrophages is also a
major inammatory mediator which augments the expression of scavenger receptors on macrophages to increase their uptake of modied lipoproteins to form
foam cells.
Macrophages also produce the bulk of the enzymes that catabolise collagen, a
key constituent of the plaque’s brous cap. It has been reported that the overproduction of the interstitial collagenase members of the matrix metalloproteinase (MMP)
family (MMP-1, MMP-8, and MMP-13) threatens the biomechanical stability of the
plaque’s protective brous cap, predisposing to plaque rupture [14, 71].
Macrophages comprise the vast majority of inammatory cells in atherosclerotic
plaques. Although in lower number, the cells of adaptive immunity, namely T lymphocytes and B lymphocytes also exist in atherosclerotic lesions [2]. Despite their
minority status, lymphocytes, particularly T lymphocytes, appear to function decisively in the regulation of inammation during atherogenesis by regulating the
innate inammatory response mediated by macrophages within plaques. The
expression of class II histocompatibility antigens by neighbouring cells has provided evidence for the functional signicance of these T cells. T lymphocytes produce IFN-γ, the inducer of class II major histocompatibility complex (MHC-II)
antigens in SMCs and macrophages.
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B cells also populate plaques. Humoral immunity appears to mitigate atherogenesis. Thus, B1 cells that give rise to natural antibody may protect against atherosclerosis. In contrast, B2 lymphocytes may aggravate atherogenesis [72]. Therefore, the
net inuence of B cell functions in atherosclerosis remains unsettled.
Even though the initial inammatory response is inherently appropriate, it eventually becomes maladaptive due to defective inammatory resolution with persistent recruitment of inammatory cells to the lesion area creating a positive feedback
loop as discussed above [21].
All these inammatory mediators contribute to an essential link between arterial
inammation and thrombosis. Recognition of this link has led to efforts to predict
future cardiovascular risk, for example through the detection of elevated levels of
inammatory biomarkers in the peripheral blood of apparently healthy men and
women. Generally, the greater the systemic inammatory response, the greater the
vascular-associated inammatory reaction will be [31].
Large scale population-based prospective studies have found increased cardiovascular risk associated with increased levels inammatory cytokines, such as IL-6,
IL-18 [73], MMP-9 [73] and TNF-α [74]; increased cell adhesion molecule expression (VCAM-1, ICAM-1, P selectin and E selection) [75–77]; elevated inammatory lipoprotein subset lipoprotein(a) [78]; and elevated downstream acute phase
reactants such as C-reactive Protein (CRP) [79–81], brinogen [78], homocysteine
[78], and serum amyloid A.
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2.6 Risk Factors
Detailed discussion of risk factors for atherosclerosis is beyond the scope of this
chapter, but the following section will provide a concise overview of genetic and
conventional risk factors and some of their notable mechanisms for mediating
atherogenesis.
2.6.1 Genetic Risk Factors
Genetic predisposition remains a major risk factor of atherosclerosis. Population
studies and in vivo animal models have conrmed several genetic variations that
inuence atherosclerotic plaque formation and progression. While there are notable
exceptions, in most affected individuals, directly causative genes responsible for
atherosclerosis remain elusive. A positive family history often reects the complexities of several genes which add incremental risk to disease progression.
Familial hypercholesterolaemia is a genetic disease in which individuals display a
two to three-fold increase in plasma cholesterol levels compared to the general population. This disease occurs due to the loss of the gene encoding for the low- density
lipoprotein receptor (LDLR) or functional defects in the LDLR protein [82–84].
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Onein every 500 individuals are heterozygous for this condition and are prone to
the development of premature atherosclerosis in early adulthood [85]. Individuals
who are homozygous for the condition have a ve to six-fold increase in their
plasma cholesterol levels, resulting in even more accelerated disease progression
andmay die from myocardial infarction before the age of 20. Familial hypercholesterolaemia represents one of the few occasions where one gene is largely responsible for atherosclerosis. Several studies of another rare genetic disorder, primary
dysbetalipoproteinaemia, also known as hyperlipoproteinaemia type III, have identied allelic variants of Apolipoprotein E (ApoE), which is involved in serum lipid
metabolism and regulation. The most common allelic variations of ApoE known
to occur in the population are E2 (60% frequency), E3 (30% frequency) and E4
(10%frequency), where E3 variants lead to an increase in plasma cholesterol levels
whereas E2 variants lead to a reduction.
Recent genetic studies and numerous epidemiologic studies have identied lipoprotein-(a) [LP(a)] as a risk factor for atherosclerotic diseases. LPA is the gene
encoding this lipoprotein which is believed to play a role in thrombosis. Lp(a) levels
show tremendous variation due to genetic polymorphisms in the LPA gene.
Increased levels of Lp(a) are associated with increased cardiovascular risk [86].
Variants in other apo-lipoprotein genes have also been associated with altered atherosclerotic risk, for example APOB and APOA5 [87], which are involved in the
synthesis of different components that make up lipoprotein particles. These observations suggest that dysregulation of multiple aspects of lipid metabolism can
increase atherosclerotic risk. Elevated levels of homocysteine in the blood are also
known to be associated with an increased risk of atherosclerosis, likely due to the
resulting endothelial dysfunction [88, 89].
Recent genome-wide association studies (GWAS) have identied a number of
loci associated with atherosclerosis which further enhances our understanding of
the spectrum of genetic variations and promises eventual developments in the identication, prevention and treatment of atherosclerosis [90].
S. Fernando et al.
2.6.2 Traditional Risk Factors
The most common traditional risk factor for atherosclerosis is known to be high levels
of circulating cholesterol, known as hypercholesterolaemia. Observational studies have
shown that societies with high consumption of saturated fat and prevalent hypercholesterolaemia have greater mortality from coronary disease than countries with traditionally low saturated fat intake [4, 91, 92]. Accordingly, data from the Framingham heart
study and other cohorts have shown that the risk of ischaemic heart disease increases
with higher total serum cholesterol levels. The coronary risk is approximately twice as
high for a person with a total cholesterol level of 240mg/dL (6.2mmol/L) compared
with a person whose cholesterol level is 200mg/dL (5.2mmol/L).
Elevated systemic blood pressure (either systolic or diastolic) also increases the
risk of developing atherosclerosis. This risk is thought to increase gradually with
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continuous high pressures. Mechanistically, hypertension can accelerate atherosclerosis in several ways. High pressures injure the vascular endothelium which leads to
increased permeability. Cyclic circumferential strain due to hypertension stimulates
SMC production of proteoglycans [93], which retain LDL particles leading to its
modications becoming more inammatory. Angiotensin II which is released as a
vasoconstrictor that mediates hypertension can also cause oxidative stress.
Cigarette smoking increases the progression of atherosclerosis by affecting
numerous mechanisms which aggravate plaque development. Among these, smoking enhances endothelial dysfunction, increases oxidative modication of LDL,
increases oxidative stress, decreases HDL levels and increases platelet adhesiveness
which in turn increases the propensity for thrombosis [23, 32, 94].
Diabetes mellitus is another well-recognised risk factor for atherosclerosis. This
predisposition is thought to be related to an increase in non-enzymatically glycated
lipoproteins which leads to enhanced uptake of cholesterol by macrophages leading
to foam cell formation. Diabetic individuals also have impaired endothelial function
leading to the reduced bioavailability of NO which leads to increased leukocyte
adhesion and migration to the intima.
2.7 Conclusion
The pathophysiology of atherosclerosis is a complex process which is initiated in
the early days of childhood and develops over decades. It results in the accumulation of lipids in the vessel wall which narrow the arterial lumen, slowly leading to
blood ow restriction and tissue ischaemia. On the other hand, atherosclerosis can
also progress more rapidly resulting in acute atherothrombotic events that result in
sudden tissue infarction. Despite ever increasing knowledge and advances in the
eld, vascular diseases caused by atherosclerosis remain among the leading causes
of mortality and morbidity worldwide. It is undeniable that the improvements in
cardiovascular care have increased patients’ quality of life over the years. However,
it is likely that the global burden of atherosclerosis will continue to rise as populations age and as developing countries continue to adopt the ‘fast-food’ diets and
sedentary habitats of the western lifestyle. Ongoing research is tackling multiple
lines of investigation into a vast number of molecular and cellular mechanisms
involved in the pathogenesis of atherosclerosis. These ndings will continue to spur
the development of novel treatments for the disease.
References
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Res. 2014;114:1852–66.
2. Libby P, Ridker PM, Maseri A. Inammation and atherosclerosis. Circulation. 2002;105:
1135–43.
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