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Pathophysiology ofAtherosclerosis
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45
Further Reading
Galkina E, Kadl A, Sanders J, Varughese D, Sarembock IJ, Ley K.Lymphocyte recruitment into
the aortic wall before and during development of atherosclerosis is partially L-selectin depen-
dent. J Exp Med. 2006;203:1273–82.
Hansson GK. Inammation, atherosclerosis, and coronary artery disease. N Engl J Med.
2005;352:1685–95.
Kolaczkowska E, Kubes P.Neutrophil recruitment and function in health and inammation. Nat
Rev Immunol. 2013;13:159–75.
Moore KJ, Sheedy FJ, Fisher EA.Macrophages in atherosclerosis: a dynamic balance. Nat Rev
Immunol. 2013;13:709–21.
Ridker PM, Stampfer MJ, Rifai N.Novel risk factors for systemic atherosclerosis: a comparison of
C-reactive protein, brinogen, homocysteine, lipoprotein(a), and standard cholesterol screen-
ing as predictors of peripheral arterial disease. JAMA. 2001;285:2481–5.
Robbins CS, Hilgendorf I, Weber GF, Theurl I, Iwamoto Y, Figueiredo JL, etal. Local proliferation
dominates lesional macrophage accumulation in atherosclerosis. Nat Med. 2013;19:1166–72.
Tabas I. Macrophage death and defective inammation resolution in atherosclerosis. Nat Rev
Immunol. 2010;10:36–46.
Chapter 3
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Mechanisms oftheVulnerable
Atherosclerotic Plaque andImaging
KhizarRana, StephenJ.Nicholls, andJohanW.Verjans
Key Learning Points
Plaque rupture and thrombosis are responsible for approximately 2 out of 3 of
•
acute ischaemic syndromes. Plaque erosion is distinct from plaque rupture, is less
well understood, and accounts for the majority of remaining non- rupture events.
• Vulnerable plaque features that predispose to plaque rupture include thin-cap
broatheromas, larger plaque volume, larger lipid-rich necrotic core, neovascu-
larization, intraplaque haemorrhage and spotty microcalcication.
• Imaging modalities including ultrasound, CT and magnetic resonance imaging
(MRI) have shown capability and value in detecting various vulnerable plaque
features noninvasively.
• Positron emission tomography (PET) scans can be used to image the biology of
plaque processes such as inammation and calcication that are implicated in
atherosclerosis and plaque rupture.
• Intravascular imaging, though invasive, offers superior spatial resolution to char-
acterise plaques beyond that which can be achieved with non-invasive modalities.
K. Rana
South Australian Health and Medical Research Institute, Adelaide, SA, Australia
University of Adelaide, SA, Australia
S. J. Nicholls
Monash Heart, Monash University, Melbourne, VIC, Australia
J. W. Verjans (
South Australian Health and Medical Research Institute, Adelaide, SA, Australia
University of Adelaide, SA, Australia
Royal Adelaide Hospital, Adelaide, SA, Australia
e-mail: Johan.Verjans@SAHMRI.com
R. Fitridge (ed.), Mechanisms of Vascular Disease,
https://doi.org/10.1007/978-3-030-43683-4_3
*)
47© Springer Nature Switzerland AG 2020
48
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K. Rana et al.
3.1 Introduction
Atherosclerotic disease is the leading cause of death worldwide [1]. Acute plaque
thrombosis and subsequent occlusion of vessels is the mechanism underlying the
acute-ischaemic syndromes. Acute plaque thrombosis can be secondary to (1)
plaque rupture, (2) plaque erosions or (3) calcied nodules.
3.2 Plaque Rupture
Plaque rupture is dened as a disruption in the brous cap leading to a thrombosis
that communicates with the necrotic core and is usually occlusive (Fig. 3.1).
Plaque rupture is responsible for the vast majority (70–80%) of acute-ischaemic
syndromes [2, 3]. Various plaque morphological features are known risk factors
for a plaque rupture. These include thin-cap broatheromas, larger volume
plaques, larger lipid- rich necrotic core, neovascularization, intraplaque haemorrhage and spotty microcalcication. These plaque morphological features will be
discussed below.
3.2.1 Thin Cap Fibroatheromas
Atherosclerotic plaques with thin brous caps are more likely to rupture and expose
the thrombogenic plaque core to the blood. An autopsy study of sudden cardiovascular deaths found that 95% of ruptured plaques had a brous cap thickness of less
than 65μm and this lead to the term thin-cap broatheromas (TCFAs) being introduced to describe such lesions [4, 5]. TCFAs are the likely precursors of the majority of fatal coronary plaque ruptures [6] (Fig.3.1).
Fibrous cap thinning probably occurs due to two concurrent mechanisms; (1)
decreased matrix production by smooth muscle cells (SMCs) and (2) increased
matrix breakdown by inltrating macrophages that secrete proteolytic enzymes
such as matrix metalloproteinases (MMPs). Decreased production of collagen
occurs due to the depletion of smooth muscle cells as a result of apoptosis [7, 8].
Additionally, in-vitro studies have shown that interferon-gamma released from activated T-cells can inhibit SMC collagen gene expression [9] and reduce the expression of an enzyme (lysyl oxidase) necessary for the crosslinking of collagen bres
[10]. Increased matrix breakdown is thought to result from the release of proteolytic
enzymes such as matrix metalloproteinases, plasminogen activators and cathepsins
by macrophage foam cells. The matrix metalloproteinases are released as latent
zymogens which are subsequently activated by plasmin from macrophages, chymase from degranulating mast cells and trypsin [11]. Thus, thinning of the brous
cap occurs probably due to the pro-inammatory actions of inltrating macrophages
and activated T-cells.
3 Mechanisms oftheVulnerable Atherosclerotic Plaque andImaging
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Fig. 3.1 Gross morphology of plaque rupture, thin-cap broatheroma and stable plaque. (Left)
Plaque rupture, a disruption of the thin-brous cap (red arrow) can be seen with an overlying
thrombus (Thr) forming. The thrombus is in direct contact with the necrotic core (NC). (Middle)
Thin-cap broatheroma (TCFA). The gross features of a TCFA include a thin brous cap (white
arrows indicating the thinnest point) overlying a large haemorrhagic necrotic core. (Right) Stable
Plaque, The stable plaque is characterized by brous tissue with heavy calcications (arrows).
(Reprinted from Narula, Nakano [
105])
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3.2.2 Plaque Size andPositive Luminal Remodeling
Large plaques, which may not produce signicant vessel stenosis, are responsible
for the majority of acute plaque thromboses. This apparent anomaly can be explained
by the fact that large, vulnerable plaques are associated with positive remodeling,
whereby the degree of ow-limiting stenosis is attenuated by reactive changes in the
underlying wall [12]. Metalloproteinases, the same enzymes that are believed to play
a role in the thinning of brous caps, are believed to have an important role in the
positive remodeling response [13, 14]. In vivo ultrasound studies have shown that
large plaques and positive remodeling are associated with unstable angina whilst
negative remodeling is associated with stable angina [12, 15]. Additionally, a larger
luminal diameter, as seen in positive remodeling, is associated with a higher peak
circumferential stress on the brous cap, potentially making it more prone to rupture.
3.2.3 Lipid-Rich Necrotic Core
In early atherogenesis, diffuse intimal thickening (DIT) consisting of SMCs, elastin
and proteoglycans develops in the arterial wall. Lipoproteins then accumulate in the
intimal wall and attract macrophages that engulf the lipoproteins and secrete proteolytic enzymes, leading to the development of a lipid-rich necrotic core.
Plaque rupture is more likely to occur where the brous cap is thinnest. For
eccentric plaques, this is often at the junction of the brous cap and the adjacent
wall, known as the shoulder region [16]. Plaques with a higher cross-sectional area
of lipid-rich core have been associated with an increased risk of rupture and thrombosis in the aorta [17, 18]. A large, eccentric lipid core may cause redistribution of
circumferential stress to the vulnerable shoulder region of the brous cap, and thus
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increasing the likelihood of rupture or alternatively, an expansion of the lipid core
may erode the brous cap from below. Additionally, the lipid-rich core has a high
density of tissue factor making it highly thrombogenic when exposed to blood following plaque rupture [19].
K. Rana et al.
3.2.4 Neovascularisation andPlaque Haemorrhage
Neovascularisation is a common feature of vulnerable plaques. In the coronary circulation, the intima lacks vasa vasorum, whereas the outer media and adventitia
have a blood supply. Intimal thickening and inammation in atherosclerosis
increases the demand for oxygen above that which can be supplied by the vasa vasorum in the adventitia and hence causes hypoxia. Hypoxia and the concomitant
inammation induce the release of angiogenic factors (e.g. VEGF) that promote
angiogenesis. The sprouting vessels extend from the adventitia, through the media
and into the plaque [20]. However, these microvessels are thin-walled, lined with
discontinuous endothelium and have a lack of supporting SMCs. Disruption of
these fragile microvessels is believed to result in intraplaque haemorrhage and
extravasation of proteins and inammatory cells [21, 22].
Intraplaque haemorrhage is associated with an increase in the size of the necrotic
core, and is more frequently seen in lesions prone to rupture [23]. Clinically, studies
have shown a strong association between the presence of symptomatic carotid disease and the degree of plaque vascularity and quantity of intraplaque haemorrhage
[24, 25]. Erythrocytes have membranes rich in cholesterol. In atherosclerotic plaques,
the cholesterol in the erythrocyte membranes is liberated by an enzyme called sphingomyelinase, leading to increased cholesterol deposition in the plaque [26, 27]. Thus,
neovascularization and intraplaque haemorrhage destabilise the plaque by increasing
macrophage inltration, cholesterol deposition and expanding the necrotic core.
3.2.5 Calcication
Coronary artery calcication (CAC) is an important marker of plaque burden that
aids in cardiovascular risk stratication beyond that of the traditional risk factors
[28, 29]. Different patterns of calcication can be observed. Spotty (micro) calcication is associated with acute coronary syndromes, whereas extensive calcication
is regarded as a marker of plaque stability and is more prevalent in the stable angina
cohort [30]. Spotty calcication is further associated with other features of a vulnerable plaque including a larger total atheroma volume, brofatty plaques and positive
remodeling. Mechanistically, biomechanical studies suggest that the dense spotty
calcication on the softer brous cap can create a larger stress concentration at the
interface of the hard calcication and soft brous cap and this may lead to the sudden rupture of the brous cap [31]. Additionally, the size, shape, location, proximity
to other calcications and composition of the microcalcications may also play an
important role in determining the peak stress on the brous cap.
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