Primer: Atherosclerosis

PRIMER
Atherosclerosis
Peter Libby1*, Julie E. Buring2, Lina Badimon3, Göran K. Hansson4, John Deanfield5,
Márcio Sommer Bittencourt6,7,8, Lale Tokgözoğlu9 and Eldrin F. Lewis1
Abstract | Atherosclerosis, the formation of fibrofatty lesions in the artery wall, causes much
morbidity and mortality worldwide, including most myocardial infarctions and many strokes,
as well as disabling peripheral artery disease. Development of atherosclerotic lesions probably
requires low-density lipoprotein, a particle that carries cholesterol through the blood. Other risk
factors for atherosclerosis and its thrombotic complications include hypertension, cigarette
smoking and diabetes mellitus. Increasing evidence also points to a role of the immune system,
as emerging risk factors include inflammation and clonal haematopoiesis. Studies of the cell and
molecular biology of atherogenesis have provided considerable insight into the mechanisms that
link all these risk factors to atheroma development and the clinical manifestations of this disease.
An array of diagnostic techniques, both invasive (such as selective coronary arteriography)
and noninvasive (such as blood biomarkers, stress testing, CT and nuclear scanning), permit
assessment of cardiovascular disease risk and targeting of therapies. An expanding
armamentarium of therapies that can modify risk factors and confer clinical benefit is available;
however, we face considerable challenge in providing equitable access to these treatments and
in maximizing adherence. Yet, the clinical application of the fruits of research has advanced
preventive strategies, enhanced clinical outcomes in affected individuals, and improved their
quality of life. Rapidly accelerating knowledge and continued research promise to provide further
progress in combating this common chronic disease.
Atherosclerosis refers to the accumulation of fatty ulceration and gangrene that can jeopardize limb viabil
and/or fibrous material in the innermost layer of arter ity. Atherosclerosis remains a major killer, and has now
ies, the intima. The term atherosclerosis derives from the spread globally. This Primer proposes not to mire the
Greek word for ‘gruel’ or ‘porridge’, reflecting the appear reader in the details of the pathogenetic pathways that
ance of the lipid material found in the core of the typi preoccupy the authors in their research work. Rather, it
cal atherosclerotic plaque (or atheroma). With time, the aims to convey the fundamentals of the current concepts
atherosclerotic plaque can become more fibrous and of the epidemiology, pathophysiology, risk assessment
accumulate calcium mineral. Advanced atherosclerotic and management of atherosclerotic CVD. Each of these
plaques can encroach upon the arterial lumen, impeding topics has witnessed major advances in recent years. Too
blood flow and leading to tissue ischaemia. Atheromata many individuals still die of the acute complications of
that do not produce a flow-limiting obstruction can atherosclerosis out of hospital, despite the improvements
disrupt and provoke the formation of a thrombus in prevention. Yet, if a patient presents to the health-care
that can occlude the lumen providing a second route, system with an acute manifestation of atherosclerosis,
usually more acute, to ischaemia. Atherosclerotic cardio with our current interventions and management strat
vascular disease (CVD) remains a leading cause of vas egies, they overwhelmingly survive. This progress in
cular disease worldwide. When it affects the heart’s cardiovascular medicine represents a sterling example
own circulation, it can cause acute coronary syndromes of how the clinical application of scientific discoveries
including myocardial infarction or chronic conditions can yield benefits for patients.
such as stable angina pectoris (chest pain or discomfort Despite these successes, much remains to be done
caused by insufficient perfusion of the heart muscle). in applying what we know already more effectively and
Atherosclerosis causes many ischaemic strokes and equitably in practice. We must also challenge ourselves
transient cerebral ischaemic attacks. It can lead to the to confront the remaining unacceptable burden of resid
*e-mail: plibby@
bwh.harvard.edu formation of aneurysms including those that form ual risk. In addition to celebrating our advances, we need
https://doi.org/10.1038/ in the abdominal aorta. When it affects the periph to continue to strive to stem the worldwide epidemic of
s41572-019-0106-z eral arteries, it can cause intermittent claudication, CVD. Although most patients survive acute coronary

NATURE REvIEWS | DIseAse PRImeRs | Article citation ID: (2019) 5:56 1
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Author addresses treatment of high LDL-C increased significantly, from

28.4% in 1999–2002 to 48.1% in 2005–2008. In addition,
1
Department of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard the prevalence of individuals achieving a degree of LDL
Medical School, Boston, MA, USA. lowering more than doubled during the study period,
2
Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, MA, USA.
from 14.6% to 33.2%3.
3
Centre d’Investigació Cardiovascular CSIC-ICCC, Hospital de la Santa Creu i Sant Pau,
Barcelona, Spain. Globally, >75% of deaths from CVD occur in low-
4
Center for Molecular Medicine, Karolinska Universitetssjukhuset, Stockholm, Sweden. income and middle-income countries1. In these coun
5
Institute of Cardiovascular Sciences, University College London, London, UK. tries, individuals with CVD have limited access to
6
Center for Clinical and Epidemiological Research, University Hospital, University of effective and equitable health-care services, a limitation
São Paulo, São Paulo, Brazil. that can delay CVD detection until late in the disease
7
Faculdade Israelita de Ciencias da Saude Albert Einstein, São Paulo, Brazil. course and increase premature mortality from CVD
8
DASA, São Paulo, Brazil. and other non-communicable diseases. CVD leads
9
Hacettepe University, Ankara, Turkey. to 18% of disability-adjusted life years lost in high-
income countries, and 10% in low-income and middle-
syndromes, they can be left with impaired cardiac func income countries, placing a heavy burden on the
tion that sets the stage for heart failure, a growing epi economies of developing countries4.
demic. This Primer provides a road map for the reader Although ischaemic heart disease remains the lead
to understand where we are today, and where we should ing cause of premature adult mortality worldwide, since
set our sights for the future. the 1950s advances in cardiovascular health have led to
striking declines in mortality in both men and women
Epidemiology from heart disease and stroke. Yet, these improvements
CVDs, which include coronary heart disease, hyperten do not apply evenly across all populations. For example,
sion and stroke, collectively comprise the number one in the UK, a high-income country, CVD mortality in
cause of death globally1,2 (Fig. 1). Heart disease (most men of 35–69 years of age decreased from 22% in 1950
commonly due to atherosclerotic disease of the coro to 6% in 20105. However, the Global Burden of Disease
nary arteries) and stroke are the two leading causes of 2010 study estimated that this decrease has not occurred
death in the world; in the USA, heart disease is the first consistently in low-income and middle-income coun
cause of death, and stroke the fifth2. Over 17 million tries4,6. Although mortality from stroke has declined,
people died from CVD in 2015, representing 31% deaths from heart disease have dropped less consistently,
of all global deaths1. Of these, an estimated 7.4 mil with some countries, especially in Eastern Europe and
lion occurred owing to coronary heart disease and Asia, reporting increases in mortality4.
6.7 million to stroke. In the USA, among individuals of Overall declines in cases of heart disease and stroke
>20 years of age, 37.4% of men and 35.9% of women probably arise from a number of factors, including
have some form of CVD, with men representing 50.6% changes in behavioural risk factors due to population-
of deaths from CVD2. Of the men with CVD, 37.7% are based or individual interventions, or both. Risk factors
non-Hispanic white, 46.0% black and 31.3% Hispanic; include tobacco use, unhealthy diet, obesity, physical
in women, these figures are 35.1%, 47.7% and 33.3%, inactivity, hyperlipidaemia, hypertension and high
respectively2. According to data from the US National alcohol use. Exposure to risk factors has a cumula
Health and Nutrition Examination Survey, the overall tive effect throughout life (discussed in detail in the
population prevalence of high low-density lipoprotein Prevention section below). The increasing epidemic of
cholesterol (LDL-C) did not change substantially from obesity, especially in low-income and middle-income
1999–2002 (34.5%) to 2005–2008 (33.5%). However, countries, remains a particular threat to a continued
decline in CVD4. In 2016, the WHO and the US Centers
for Disease Control and Prevention launched Global
20
Hearts, a new initiative to reduce the global threat of
Global deaths in 2016 (%)
18
16 CVD by 2025, especially in developing countries7. This
14
12
programme will elevate efforts for CVD prevention and
10 control by promoting population-level interventions to
8 reduce risk factors, including reducing tobacco use and
6
4 dietary salt intake, and strengthening CVD management
2 in primary health care.
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Fig. 1 | The contribution of cardiovascular diseases to the global burden of death
in 2016. These data convey the importance of atherosclerotic cardiovascular disease
worldwide. Of note, many stroke deaths may not result directly from atherosclerotic Initiation of atherosclerosis
disease but from hypertension, a highly prevalent cardiovascular risk factor. Similarly , LDL cholesterol. LDL particles cause atherosclerosis.
not all cases of cardiomyopathy result from ischaemic damage, and some cases of These spheroidal packets of lipids rich in cholesterol,
atrial fibrillation may not be associated with atherosclerosis. Data from the Global enveloped in a phospholipid coating with apolipo
Burden of Disease. protein B snaking through their equatorial region,
2 | Article citation ID: (2019) 5:56 www.nature.com/nrdp

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T cell How excessive LDL-C causes atherosclerosis

LDL particle Classic Macrophage
Endothelial cell remains unsettled. Many decades of research have
monocyte supported the concept that oxidized LDL particles can
promote atherogenesis17,18. Pathways that can lead to
Macrophage modification of LDL particles include formation of
foam cell reactive oxygen species in the intima due to metal ion
Adhesion
molecule catalysis (the Fenton reaction), among other sources.
Intima Internal elastic membrane The expression of high-capacity scavenger receptors for
LDL particles does not drop when cellular cholesterol
Blood vessel Smooth
muscle cells content rises, as does the expression of the high-affinity
Media LDL receptor. Thus, these scavenger receptors permit
Nerve
overloading of macrophages with cholesteryl ester,
Adventitia Mast cell External elastic membrane generating foam cells, a hallmark of the early atheroscle
rotic lesion. Most schemata of the initiation of athero
Fig. 2 | Initiation and progression of atherosclerosis. The normal artery wall has a tri- sclerosis posit a causal role for oxidized LDL particles
laminar structure. The outermost layer, the adventitia, contains nerve endings, mast cells, as ligands for the scavenger receptors that facilitate
and vasa vasorum, microvessels that nourish the outer layer of the media. The tunica media foam cell formation (Fig. 2). Constituents of oxidized
consists of quiescent smooth muscle cells and a well-organized extracellular matrix LDL particles may induce inflammation and furnish
comprising elastin, collagen and other macromolecules. The atherosclerotic plaque forms neo-epitopes that stimulate humoral and adaptive
in the innermost layer, the intima. In the early stage of lesion initiation, low-density immunity19.
lipoprotein (LDL) particles accumulate in the intima, where protected from plasma
Despite the wealth of experimental data that support
antioxidants, they can undergo oxidative and other modifications that can render them
pro-inflammatory and immunogenic. Classic monocytes that exhibit a pro-inflammatory
this sequence of events, we still lack rigorous proof that
palette of functions then enter the intima. Monocytes circulate in the bloodstream and oxidized LDL particles initiate human atherosclerosis20.
can bind to adhesion molecules expressed by activated endothelial cells. Chemoattractant Perhaps therapeutic interventions that target oxidative
cytokines, known as chemokines, can promote the migration of the bound monocytes into pathways are initiated too late in the process, but to date
the artery wall. Once in the intima, monocytes can mature into macrophages, and attain no antioxidant vitamin has forestalled atherosclerotic
characteristics associated with the reparative or less pro-inflammatory monocyte/ events in a suitably powered clinical trial. A lipid-
macrophage population. These cells express scavenger receptors that permit them to bind soluble antioxidant that effectively blocks LDL particle
lipoprotein particles and become foam cells. T lymphocytes, although numerically less oxidation, succinobucol, did not reduce cardiovascular
abundant than monocytes, also enter the intima, and regulate functions of the innate events in a large-scale clinical study21. Moreover, labora
immune cells as well as the endothelial and smooth muscle cells. Smooth muscle cells in
tory studies suggest that native rather than oxidized LDL
the tunica media can migrate into the intima in response to mediators elaborated by the
accumulating leukocytes. The smooth muscle cell chemoattractant platelet-derived particles stimulate T cell responses thought to partici
growth factor arising from macrophages and deposited by activated platelets at sites of pate in atherogenesis22. Thus, although the ‘oxidized LDL
endothelial breaches or intraplaque haemorrhage probably participates in this directed particle hypothesis’ rests on solid experimental evidence,
migration of medial smooth muscle cells into the intima. its relevance to human atherosclerosis remains conjec
tural and, from a clinical perspective, has not yielded an
actionable therapy. Nonetheless, strong human genetic
transport water-insoluble cholesterol through the blood. evidence, results of observational epidemiological stud
Atherosclerosis probably would not occur in the absence ies, and pharmacological interventions establish LDL-C
of LDL-C concentrations in excess of physiological needs as an indubitable causal factor and therapeutic target in
(on the order of 10–20 mg/dL)8. Phylogenetic, compar atherosclerosis (reviewed in detail in ref.14).
ative population studies and pharmacological interven LDL-C can deposit in the arterial wall owing to
tion investigations suggest that LDL-C concentrations in impaired barrier function of the endothelium and is
the 20–30 mg/dL range (about 0.5–0.8 mmol/L) suffice retained within the intimal layer by extracellular matrix
for good health8–11. Hence, despite recent secular trends macromolecules23. An alternative pathway in atherogen
towards lowering cholesterol levels, the concentrations esis mediated by aggregated LDL particles has received
of blood cholesterol prevalent in most contemporary less attention. When LDL particles accumulate in the
human societies exceed by far the biological needs of subendothelial space, they can bind to intimal proteo
the organism, and permit the development of athero glycans and form aggregates. These collections can then
sclerosis12,13. The cumulative exposure of an artery to enter smooth muscle cells through receptors of the LDL
LDL-C over years remains a principal determinant receptor-related protein (LRP) superfamily. Cells can
of disease initiation and progression14. The observa accumulate cholesterol in this manner as LRP superfam
tion that patients with familial hypercholesterolaemia ily members, like scavenger receptors, evade the usual
achieve this cumulative LDL-C burden threshold at homeostatic mechanisms that reduce expression of the
early ages and develop premature atherosclerotic CVD classic LDL receptor under conditions of cholesterol suf
supports a causal role of LDL in atherosclerosis15. On ficiency. These smooth muscle cells and macrophages
the other hand, individuals with proprotein convertase can become engorged with lipid and contribute to lesion
subtilisin/kexin type 9 (PCSK9) loss-of-function muta progression24.
tions have life-long low LDL-C concentrations due to
reduced catabolism of the LDL receptors, and show a HDL cholesterol, triglycerides, and lipoprotein(a).
greater reduction of coronary events than that afforded High-density lipoprotein cholesterol (HDL-C) concen
by statin treatment alone16. trations consistently associate inversely with the risk

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of atherosclerotic events in observational epidemio The endothelium. Alterations in the endothelial mono
logical studies. Yet, current human genetic evidence layer, which provides the interface between blood and
does not support a protective role for HDL-C against the arterial intima, the site of atheroma initiation,
atherosclerosis25. Moreover, numerous therapies that occur early during atherogenesis. Exposure to athero
raise HDL-C have failed to improve cardiovascular out genic risk factors, including those considered above,
comes. The disparity with the observational data may interferes with the production of endogenous vaso
be because HDL-C tracks inversely with triglyceride dilators, such as nitric oxide, by endothelial cells37.
concentrations26. Substantial human genetic evidence Consumption of a cholesterol-containing diet can acti
now supports a causal role for triglyceride-rich lipopro vate the expression of adhesion molecules, such as vas
teins in atherosclerosis27. In contrast to HDL, convincing cular cell adhesion protein 1, that bind blood leukocytes
human genetic evidence supports the strong observa to the endothelial surface, and of chemoattractants
tional relationship between lipoprotein(a) (Lp(a)) and that promote entry of the bound leukocytes into the
atherosclerotic risk28. intima38,39.
The local haemodynamic environment also affects
Inflammation. Other risk factors implicated causally endothelial functions. Changes to the blood flow are
in atherogenesis include hypertension, tobacco use and sensed by flow-dependent ion channels or surface
the components of the metabolic syndrome cluster, structures, such as members of the integrin family
which include elevated blood pressure, visceral adipos of transmembrane proteins. Downstream transcrip
ity, insulin resistance and high blood concentrations of tional mechanisms that transduce the effects of flow
triglyceride-rich lipoproteins, and ultimately can lead to into altered gene expression include Krüppel-like fac
full-blown diabetes mellitus. As in the case of LDL-C, tor 2 (ref.40). Such abnormal flow patterns disturb the
however, the mechanisms that link these risk factors physiological homeostatic atheroprotective functions
to atherogenesis remain incompletely elucidated. But of the endothelium, reversing tonic vasodilatation,
many if not all of these risk factors also participate in the anti-thrombotic and anti-inflammatory properties, and
activation of inflammatory pathways. Inflammation in mechanisms that resist thrombus formation and per
turn can alter the function of the cells of the artery wall sistence41. Atherosclerotic plaques tend to form at sites
in a manner that drives atherosclerosis. For example, of flow disturbance, whereas sites in the arterial tree
angiotensin II, which participates in the pathogenesis where laminar shear stress predominates generally resist
of hypertension, can also unleash inflammatory path atheroma formation42. Thus, exposure to risk factors
ways such as those governed by the master transcrip for atherosclerosis, or their downstream mediators, in
tional regulator nuclear factor-κB (NF-κB) pathway29. the context of disturbed flow perturbs the homeostatic
Similarly, recent experimental work implicates adaptive properties of the endothelial monolayer and promotes
T cell immunity in the pathogenesis of hypertension, some of the initial steps in atherogenesis.
providing a common pathogenetic pathway for elevated
blood pressure and atherosclerosis30. Tobacco use can Progression of atherosclerosis
elicit an inflammatory response in the airways and alve Once established, atherosclerotic plaques progress by
oli. Visceral adipose tissue, a common concomitant of continued accumulation of lipid and lipid-engorged
insulin resistance and type 2 diabetes mellitus, contains cells. For many years, most researchers considered
inflammatory cells and elaborates multiple mediators of macrophages derived from blood monocytes as the pre
inflammation31,32. These extravascular sites of inflam cursors of lipid-laden foam cells in atheromata. Recent
mation can affect distant artery walls, as they release experimental data suggest that metaplasia of smooth
soluble inflammatory mediators such as cytokines that muscle cells may also give rise to foam cells resembling
can activate cells in the intima33,34. Biomarkers of inflam macrophages43. The human intima contains resident
mation, notably C-reactive protein (CRP; measured with smooth muscle cells, particularly at sites where athero
a highly sensitive assay, hsCRP), prospectively predict mata tend to develop. Migration of smooth muscle cells
cardiovascular risk and rise in tandem with many estab from the media into the intima can contribute to the
lished cardiovascular risk factors35. A rich experimen accumulation of smooth muscle cells in the growing
tal basis has established a role for adaptive immunity atherosclerotic plaque. These cells can proliferate over
in atherogenesis as well. Human atherosclerotic lesions the years and elaborate extracellular matrix macromol
contain T lymphocytes and display markers of adaptive ecules that comprise much of the bulk of an established
immune activation22. Some T cell subtypes (for exam atherosclerotic plaque43.
ple, type 1 T helper (TH1) cells) promote experimental
atherosclerosis, whereas others (for example, regu Extracellular matrix of the atherosclerotic plaque. The
latory T (Treg) cells) seem to mitigate atherogenesis20,36. extracellular matrix of atherosclerotic plaques contains
A strong body of laboratory work, mostly conducted in interstitial collagen, elastin, proteoglycans and glyco
mice, has rigorously demonstrated a causal role for vari saminoglycans. Many of these extracellular matrix
ous arms of adaptive immunity in modulating experi macromolecules can entrap lipoproteins and promote
mental atherosclerosis22,36. These findings, along with lipid accumulation within the intima. Inflammatory
study of human atherosclerotic plaques and biomarker leukocytes not only arrive in the intima by infiltration
investigations in human populations, provide support but can also proliferate within the lesion44. Various
for the contribution of inflammation and immunity in retention factors such as semaphorins can retard
atherosclerosis. the egress of these leukocytes and contribute to their

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Fibrous cap thinning

Increased collagen
SMC death breakdown
(MMPs)
Impaired LDL particle
collagen synthesis Macrophage
(IFNγ) foam cell Defective
efferocytosis
SMC Macrophage
division division
Macrophage Monocyte
SMC Necrotic death
core
Intima Internal elastic membrane

Macrophage–SMC
metaplasia
Media
Adventitia External elastic membrane
Fig. 3 | The progression of atherosclerotic lesions: cellular birth and death. During the evolution of the atherosclerotic
plaque, the resident and recruited smooth muscle cells (SMCs) produce extracellular matrix molecules (such as interstitial
collagen and elastin, as well as proteoglycans and glycosaminoglycans) that contribute to the thickening of the intimal
layer. However, T cell mediators such as IFNγ can impair the ability of the SMC to synthesize interstitial collagen and
thereby dampen the ability of these cells to repair and maintain the fibrous cap that overlies the necrotic core. Furthermore,
activated macrophages show increased production of enzymes of the matrix metalloproteinases (MMPs) family that
degrade the interstitial collagen that lends strength to the fibrous cap. Thinning and structural weakening of the fibrous
cap increase the susceptibility of the plaque to rupture. SMCs and macrophages in the evolving lesion can divide. SMCs
and the mononuclear phagocytes can also interchange through a process of metaplasia. As the lesion advances, SMCs and
macrophages can undergo cell death including by apoptosis. The debris from dead and dying cells accumulates, forming
the necrotic, lipid-rich core of the atheroma. Impaired efferocytosis (clearance of dead cells) can contribute to the formation
of the necrotic core. LDL , low-density lipoprotein.
persistent presence in the atherosclerotic plaque45,46. Clonal haematopoiesis of indeterminate potential.

Although macrophages predominate numerically, T Recent evidence supports a causal role of myeloid cells
lymphocytes also localize within lesions and may have that bear mutations associated with the development
either positive or negative effects on many aspects of of myelodysplastic syndromes and acute myelogenous
atherosclerotic plaque growth and evolution. TH1 cells leukaemia in experimental atherogenesis and as a novel
typically elaborate IFNγ that can promote atheroscle important risk factor for human atherosclerosis54,55. With
rosis, whereas TH2 cells can produce anti-inflammatory age, somatic mutations in bone marrow haematopoie
cytokines such as IL-10, and Treg cells secrete trans tic stem cells that confer a proliferative advantage can
forming growth factor β that can limit inflammation give rise to clones of myeloid cells in peripheral blood.
and smooth muscle cell proliferation and promote Mutations in only a handful of genes (for example,
interstitial collagen synthesis36,47. Furthermore, athero DNMT3A, TET2, ASXL1 and JAK2) can generate these
sclerotic plaque components drain from the lesions and clones, and over 10% of septuagenarians harbour such
reach adjacent lymph nodes, where they may serve as clones in the circulation54,55. As most persons who have
antigens for T and B cells. Other atherosclerotic plaque such clones of mutant myeloid cells will never develop
components, such as locally produced cytokines, can leukaemia, this condition is called clonal haematopoie
modulate immune responses in these lymph nodes48. sis of indeterminate potential (CHIP). Individuals with
In advanced disease, tertiary lymphoid structures CHIP develop acute leukaemia at a rate of 0.5–1% per
(ectopic lymphoid aggregates that form in diseased year, a transition that is associated with accumulation
tissue) may develop adjacent to large arteries. In these of successive mutations in the same clone. Carriers of
structures, B cells differentiating to plasma cells pro CHIP have a much higher mortality than attributable to
duce large amounts of antibodies against LDL particle haematological malignancy. CVDs, including the com
components49. plications of atherosclerosis, account for much of the
Macrophages and smooth muscle cells can undergo excess mortality in people who have CHIP. Several of the
programmed cell death forming the nidus of a lipid-rich genes mutated in CHIP alter methylation of DNA, and
or necrotic core of the advancing atheroma50,51 (Fig. 3). seem to alter the expression of inflammatory genes such
Impaired clearance of dead cells, known as defective as IL1B via epigenetic regulation. Mutations in JAK2
efferocytosis, can also contribute to the formation of (encoding the tyrosine-protein kinase JAK2) can sen
the necrotic core52,53. sitize leukocytes to form neutrophil extracellular traps

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(NETs) that can promote thrombosis (see below)56. As of plaques, and may promote a tendency to rupture and
the cardiovascular risk associated with CHIP does not provoke thrombosis59. Larger accumulations of calcium
depend on traditional CVD-associated risk factors, the may associate with lower probability of triggering a
pursuit of the mechanisms that connect CVD with CHIP thrombotic event60. PET imaging with Na18F may pro
promises to shed new light on pathways that promote vide a window on calcification in human atherosclerotic
atherosclerosis and its complications57. plaques and promises to provide a new tool for research
Altogether, these findings provide further support for into the pathophysiology of calcification in human
links between leukocytes and atherosclerosis. Some evi atherosclerosis61.
dence supports the presence of virtually every subtype of
leukocyte in the evolving atheroma, although cells with Complications of atherosclerosis
the functional properties of macrophages and various During much of the disease course of the atherosclerotic
subtypes of T lymphocytes probably predominate in plaque, the lesions expand outward radially, in an ablu
defining the properties of atherosclerotic plaques that minal (away from the lumen) direction, preserving the
give rise to complications47. calibre of the arterial lumen. Some of the remodelling
of the arterial wall that accompanies lesion progression
Calcification. During their evolution, many atheroscle may result from the production by smooth muscle cells
rotic plaques develop regions of calcification. Far from of proteinases specialized in degrading constituents of
a passive degenerative process, the accumulation of cal the arterial extracellular matrix, such as matrix metallo
cium mineral in atheromata arises from dysregulation of proteinase 3 (MMP3, also known as stromelysin 1)62,63.
deposition and impaired clearance58. Much of the miner Eventually, the growing atherosclerotic plaque begins
alization process in atherosclerotic plaques recapitulates to encroach upon the arterial lumen, and can lead to
biological processes in bone formation. Microscopic or the formation of flow-limiting lesions. (Fig. 4). The con
spotty calcification associates with mechanical instability sequent impairment of coronary arterial perfusion,
Thrombosis due to
ruptured fibrous cap
Tunica adventitia Thrombus
Tunica media
Lumen
Tunica intima
Fibrous cap
Lipid core Healing, fibrosis, stenosis,

calcification, buried cap
Thrombosis due to
superficial erosion
?
Thrombus Buried Tunica

fibrous intima
cap
Fibrous plaque Lipid core
Fig. 4 | Atheroma complication: disruption and healing. The fracture of the fibrous cap of the atherosclerotic plaque
permits blood coagulation components to access to the core of the plaque. Pro-coagulant substances such as tissue factor
can trigger thrombosis, which can cause occlusion of the vessel and lead to an acute ischaemic event. Many mural thrombi
may not totally occlude the vessel or may undergo lysis due to endogenous fibrinolytic defences. The resorbing thrombus,
a source of transforming growth factor-β (TGFβ) and platelet-derived growth factor elaborated by activated platelets,
can stimulate smooth muscle cell migration and extracellular matrix production. These processes lead to increased lesion
volume and eventual encroachment upon the arterial lumen. Pathological studies of advanced human atherosclerotic
plaques showed ‘buried caps’ that provide evidence for prior rupture and healing. Plaques that lack a well-defined lipid
core and have abundant rather than sparse extracellular matrix can provoke coronary thrombi due to a process known
as superficial erosion. The clots associated with superficial erosion have characteristics of platelet-rich ‘white’ thrombi;
by contrast, ‘red’ thrombi are rich in fibrin and trapped erythrocytes and associate with plaque rupture184.

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particularly when myocardial oxygen demands increase thrombi through promotion of fibrinolysis. Endothelial
owing to physical effort, can produce ischaemia and the dysfunction, as occurs in the presence of atherosclerotic
symptoms of angina pectoris. risk factors or more acutely during inflammatory acti
vation (for example, due to pro-inflammatory cytokines
Plaque rupture. Rupture of atherosclerotic plaques is or pathogen-associated factors, such as bacterial endo
the most common trigger of acute thrombosis of coro toxins), can impair these normal homeostatic pro
nary arteries that causes myocardial infarction64,65. perties. Under these circumstances, endothelial cells
Atherosclerotic plaques that have ruptured often have produce tissue factor, a potent procoagulant molecule,
large lipid cores covered by a thin fibrous cap (<60 µm). and plasminogen activator inhibitor 1, a key endogenous
Lesions with these characteristics have often been inhibitor of fibrinolysis74.
termed ‘vulnerable plaques’65. By contrast, plaques with
limited lipid accumulation and thicker fibrous caps are Plaque erosion. Effective anti-atherosclerotic therapy,
often referred to as ‘stable plaques’. This classification including measures described below (for example, lipid-
oversimplifies considerably the complexity of the mech lowering therapy, treatment of hypertension and smok
anisms of atherosclerotic plaque destabilization66,67, yet ing cessation), has shifted the substrate of the thrombotic
has provided a framework for much thought regarding complications of atherosclerosis. Atherosclerotic plaques
the pathophysiology of acute coronary syndromes for have become less inflamed and lipid-laden, and more
several decades. fibrous, and, therefore, probably less liable to rupture
Defects in the extracellular matrix that overlies the due to fissure of the fibrous cap than in the past67,75.
lipid core of the atherosclerotic plaque can lead to Under these circumstances, another mechanism of
the formation of an overlying fibrous cap, and a fissure thrombotic complications of atheroma may account for
can form in this structure. Inflammatory processes can an increasing proportion of acute coronary syndromes.
impede synthesis of interstitial collagen by smooth mus This alternative thrombotic mechanism, called plaque
cle cells in the atherosclerotic plaque, impairing the abi erosion, seems to arise from lesions with a quite distinct
lity of these cells to maintain the skeleton of the fibrous morphology from the typical ruptured plaque (Fig. 4).
cap68,69. Activated inflammatory cells can also elaborate The lesions complicated by erosion tend to have a rich
interstitial collagenases specialized in degrading the key extracellular matrix without a thin, friable fibrous cap,
structural components of the fibrous cap of the lesion70. few inflammatory leukocytes, and little lipid76. The
Rupture of an atherosclerotic plaque exposes the con mechanisms of plaque erosion have undergone sub
tents of the interior of the plaque to the blood compart stantially less exploration than those of plaque rupture.
ment. Thrombogenic material in the plaque core, notably Yet, emerging evidence suggests that innate immune
tissue factor produced by macrophages and smooth activation involving engagement of pattern-recognition
muscle cells, can trigger thrombosis, the ultimate and receptors, such as Toll-like receptor 2, and the partici
most dreaded complication of atherosclerosis. pation of polymorphonuclear leukocytes as amplifiers
Together with locally impaired homeostatic function of the local thrombotic process may contribute to this
of the luminal endothelium, persistent and occlusive mode of plaque complication77,78. Indeed, NETs may
thrombi can provoke ischaemic insults such as acute propagate thrombosis during acute coronary syndromes,
coronary syndromes and stroke. Thrombus formation particularly those caused by intimal erosion77.
can also contribute to critical ischaemia of the lower
extremities and complicate peripheral artery disease. Diagnosis, screening and prevention
Arterial thrombi that complicate atherosclerotic plaques Clinical presentation
arise from thrombin-mediated generation of fibrin from Atherosclerosis is a diffuse, slowly progressing disease
fibrinogen. Thrombin also activates platelet aggrega that can affect several arterial beds79 (Fig. 5). Because of
tion, a process that contributes to clot formation. Recent this slow progression, most cases remain asymptomatic
work has implicated NETs in vascular clotting71. NETs for decades. When symptoms do arise, they usually
consist of strands of DNA that bind leukocyte granular relate to a reduction in blood flow caused by the lumi
enzymes and proteins such as tissue factor adsorbed from nal stenosis (narrowing) or to thrombotic obstruction.
blood and are elaborated by neutrophils that undergo Ischaemia due to stenotic, flow-limiting lesions can
a specialized form of cell death known as NETosis. occur under conditions of increased myocardial oxy
Thus, blood clots contain fibrin strands, clumps of activ gen demand, for example during physical exertion, and
ated platelets, and NETs that can propagate thrombus cause symptoms of angina pectoris. Acute thrombotic
formation and amplify intimal injury72,73. occlusion that interrupts myocardial oxygen supply typ
Under physiological conditions, the arterial ically results from disruption of atherosclerotic plaques,
endothelium possesses numerous properties that as described above64.
prevent clot formation and promote thrombolysis41. The clinical presentation of atherosclerosis can be
Thrombomodulin and heparan sulfate proteoglycans on acute or chronic and varies substantially, depending on
the endothelial surface and production of nitric oxide the vascular territory involved (Fig. 5). In some arteries,
and prostacyclin by the endothelial cells contribute to such as renal arteries, the most common presentation is
the anticoagulant and antithrombotic properties of the a chronic, long-developing syndrome (for example, pro
normal endothelial monolayer. Furthermore, the expres gressive renovascular hypertension and/or worsening
sion of urokinase-type plasminogen activator and tissue- renal function secondary to renal artery stenosis). In other
type plasminogen activator combats the persistence of vascular territories, atherosclerosis most commonly

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Carotid arteries and cerebral Coronary arteries

arteries
• Acute coronary syndromes
• Stroke (unstable angina and
• Transient ischaemic attack (TIA) myocardial infarction)
• Recurrent TIAs • Stable angina

• Vascular dementia • Silent ischaemia
Thoracic aorta Abdominal aorta
• Aortic rupture • Aortic occlusion (rare)

• Aortic dissection
• Aortic aneurysm
Renal arteries
Peripheral arteries (aortoiliac,
• Renal artery occlusion (rare) common or superficial femoral
arteries; popliteal, tibial or
• Worsening renal function peroneal arteries)
• Renovascular hypertension
• Acute peripheral arterial
occlusion
Superior and inferior mesenteric
arteries • Chronic limb ischaemia
• Intermittent claudication
• Acute mesenteric ischaemia
• Chronic mesenteric ischaemia Acute presentation

• Abdominal angina
Chronic presentation
Fig. 5 | Clinical manifestations of atherosclerosis. Atherosclerosis is a systemic disease that may involve multiple
vessels. Consequently , the clinical manifestations vary widely according to the vascular territory involved. Despite the
systemic nature of many risk factors such as hypercholesterolaemia, hypertension, diabetes mellitus and smoking,
atherosclerosis tends to involve primarily specific regions of the arterial tree. Arterial areas subjected to either disturbed
flow or low shear stress have particular susceptibility to atheroma formation41. These conditions prevail at branch points in
the arterial tree.
manifests with acute and sudden presentations, such extent, severity, location and plaque characteristics of
as acute ischaemic stroke due to atherosclerosis. In the the atherosclerotic disease (as assessed by the aforemen
coronary arteries, both acute coronary syndromes and tioned imaging methods) determine additional medi
chronic presentations (that is, stable angina pectoris) cal, catheter-based or surgical interventions to reduce
commonly arise. ischaemic symptoms or risk of acute events.
The definitive diagnosis of the clinical syndromes
caused by atherosclerosis usually depends on imaging Clinical significance
tests for direct visualization of atherosclerosis or the Since the initial demonstration by invasive angiography
documentation of target organ ischaemia (Table 1). Each of the association between ischaemic symptoms and
imaging method addresses a specific clinical scenario. narrowing of the arterial lumen, the degree of luminal
Whereas ultrasonography and CT angiography are stenosis assesses the clinical significance of atheroscle
typically used for non-invasive investigation of athero rosis. Classic studies suggest that thresholds of 50% to
sclerosis in various vascular territories, other more 75% luminal narrowing associate with physiological
invasive procedures, such as invasive angiography, intra limitations in coronary flow at stress and at rest81. Thus,
vascular ultrasonography or optical coherence tomo patients usually start experiencing symptoms initially
graphy, serve mainly to guide interventional therapies. under conditions of increased oxygen demand such
Technologies such as PET and MRI tend to be restricted as physical or emotional stress, when stenosis exceeds
to use in research on the evaluation of atherosclerosis. a threshold of 50–75%81 (Fig. 6). Until recently, these
Multiple guidelines from various jurisdictions address results traditionally helped to define the clinically sig
appropriate use of cardiovascular imaging modalities80. nificant atherosclerotic plaque82. More recently, studies
Once a definitive diagnosis of clinically significant have used fractional flow reserve (FFR) to assess the
(see below) atherosclerosis is established, risk strati severity of atherosclerotic disease in the coronary arter
fication of the atherosclerotic disease informs man ies. This method evaluates the intra-coronary pressure
agement. Although most individuals with clinically to determine if a luminal reduction is limiting flow, by
significant atherosclerosis require medical management comparing the pressure upstream and downstream of
with lipid-lowering medication (for example, statins) the lesion after administration of a vasodilator such as
and aggressive management of other risk factors, the adenosine to augment flow. FFR measurements have

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demonstrated that the relationship between luminal significance of atherosclerotic lesions. We propose a
narrowing and flow is far from linear. Other plaque practical, clinically oriented definition of atherosclerotic
characteristics such as length, eccentricity (indicated by disease, which extends generally to virtually any arterial
a plaque volume three times larger on one side than on bed affected by atherosclerosis (Fig. 5). Atherosclerosis
the other) and positive remodelling (an outward com should be considered clinically significant if it leads to
pensatory remodelling of the arterial wall to maintain a the development of documented downstream ischaemia,
lumen diameter), as well as limitations associated with has already led to an acute vascular event (for example,
estimation of luminal narrowing on invasive angiogra an acute coronary syndrome) or entails a large docu
phy, may all influence the functional consequences of mented atherosclerotic burden (for example, a coronary
any stenosis83. As a result, functional assessments such artery calcium (CAC) score, which quantifies the degree
as with FFR can help to define the clinical significance of calcification, of >200) or individual plaques that dis
of a coronary atherosclerotic lesion84. play high-risk characteristics such as high lipid con
Over the last decade, studies have also challenged the tent, compensatory enlargement or spotty calcification.
concept that luminal narrowing or downstream ischae Although overall plaque burden may not be associated
mia determines the clinical significance of atheroscle with symptoms or flow reduction, this classification has
rotic disease. Studies have shown that the risk of plaque clinical utility, as an increased risk of future cardiovas
rupture and a subsequent acute event associates more cular events should prompt consideration of changes
strongly with the propensity of an atherosclerotic plaque in clinical management. As this definition of clinically
to rupture and with systemic patient characteristics, such significant atherosclerosis includes asymptomatic dis
as inflammation, rather than the degree of focal steno ease, the identification of individuals at risk requires a
sis85. This concept has received further support from evi screening strategy.
dence that overall plaque burden (measured by CT or
by invasive angiography), irrespective of the luminal Screening
narrowing, remains the strongest anatomical predictor of Atherosclerosis meets several of the traditional Wilson’s
incident myocardial infarction or cardiovascular death. criteria88 that define a disease amenable to screening, such
The risk portended by more extensive non-obstructive as: the condition is an important health problem (that is,
disease resembles that associated with obstructive dis it has a high prevalence), treatment exists for the con
ease86,87. Thus, we need to redefine the criteria for clinical dition, there is a long latent and/or asymptomatic stage,
Table 1 | Diagnostic tests for atherosclerosis

Test Imaging characteristics Advantages Limitations Routine clinical
applications
Direct atherosclerotic plaque visualization
Ultrasonography Enables differentiation of some Non-invasive and no Can only be used in large-calibre Carotid arteries,
or Doppler plaque components radiation exposure and superficial vessels intracerebral arteries
ultrasonography required (with transcranial Doppler
ultrasonography),
abdominal aorta, lower
extremity vessels
CT angiography Enables differentiation Non-invasive Iodinated contrast agent needed; Most vascular territories
between calcified and non- radiation exposure required
calcified plaque
MRI No evaluation of plaque Non-invasive and no Limited to large-calibre vessels; Carotid artery and aorta
components radiation exposure potentially useful in selected cases
required of smaller-calibre vessels such as
coronary arteries
Intravascular Plaque tissue characterization Excellent for evaluation Invasive; radiation exposure and Selected cases of
ultrasonography by analysis of radiofrequency of plaque burden and iodinated contrast agent (for coronary artery evaluation
backscatter from the ultrasound composition catheter positioning) required;
signal: ‘virtual histology’ limited availability
Optical coherence High-resolution imaging for Excellent near-field Invasive; radiation exposure and Routine clinical
tomography plaque characteristics resolution permitting iodinated contrast agent (for application restricted
visualization of the intimal catheter positioning) required; to very selected cases of
morphology in detail limited availability and limited coronary artery evaluation
penetration, limiting the evaluation
of deeper areas of the plaque
No direct atherosclerotic plaque visualization
PET Identifies glucose uptake by Evaluates plaque Radiation exposure required; can Applications restricted to
inflammatory and other cells metabolism only be used in large-calibre vessels research
in plaques
Invasive Classic reference standard Widely available; good Invasive; radiation exposure and Most vascular territories
angiography for the evaluation of luminal visualization of the lumen iodinated contrast agent required;
stenosis does not visualize the plaque directly

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5
detection of disease, and their routine clinical use for
Maximum flow
Relative coronary artery flow/reserve
screening has its limits.

4 Resting flow To date, the role of the additional testing mentioned
above for screening and risk stratification is restricted
3 at least in part owing to the limited number of medical
Physiological limit of
nuclear stress imaging interventions that have documented benefit (for exam
ple, statins) when used in the primary prevention set
2
ting. Recent data on other lipid-lowering medications94,
anti-inflammatory drugs95 and new anti-thrombotic
1 drugs96 leading to a reduction in future CVD events
will probably spur an increase in the research on the
0
role of testing to identify suitable candidates for new
0 10 20 30 40 50 60 70 80 90 100 therapies in both the primary and secondary preven
Diameter narrowing (%) tion settings. This strategy will provide asymptomatic
patients with enough data to remain engaged in shared
Fig. 6 | Relationship between luminal diameter narrowing and relative coronary decision-making for treatment, as well as promote the
artery flow/reserve at rest and under stress conditions. Both resting and maximum use of cost-effective strategies to enable a sustainable use
coronary flows remain unchanged with stenosis of up to 50% luminal obstruction.
of health-care resources.
Above this threshold coronary flow decreases substantially with increased luminal
obstruction. The highlighted range is the limit of detection for regular SPECT stress
perfusion imaging. The maximum coronary flow was calculated as a fraction of the Prevention
resting coronary flow , and the values on the y axis are relative to the resting flow with The increasing focus on CVD prevention stems from
no stenosis. Adapted with permission from ref.81, Elsevier. an appreciation that the improved treatment of patients
cannot alone address the enormous global burden of
CVD, which experts predict will increase substantially,
and the natural history is adequately understood. Yet, the particularly in low-income and middle-income coun
policy regarding the appropriate screening strategy for tries97. New insights into the importance of lifetime risk
atherosclerosis detection and the prevention of its com management of CVD has spurred the current interest
plications remains variable across different guidelines89–91. in prevention, with an emphasis placed on young age
Despite the disagreements, virtually all guidelines recom groups, and on new opportunities derived from the dig
mend the initial evaluation of individual risk of future ital health revolution. Addressing these opportunities
CVD events based on clinically evident risk factors89,91,92. should embrace a fundamental shift in approach with
Interestingly, the individual risk scores that serve as a focus on ‘wellness maintenance’ and not just ‘disease
screening tools do not involve the actual detection of treatment’.
atherosclerosis but rather the factors discussed above
that increase the individual risk of future CVD events. Economics. The direct cost of treating CVD in the USA
For selected populations, the screening strategy currently exceeds US$300 billion per year, and predic
might incorporate a more aggressive treatment strategy tions put both direct and indirect costs to almost a tril
or use of other specific testing. For example, individu lion US dollars by 2030 (ref.98). Most countries cannot
als with familial hypercholesterolaemia merit special sustain such costs. The adoption of a healthy lifestyle
interest because of life-long exposure to high LDL-C from early life should markedly reduce the atheroscle
levels, which increase overall risk for CVD events. This rosis burden and its complications, and widespread use
genetic condition typically remains underdiagnosed and of currently recommended preventive therapies such as
undertreated. Its genetic basis supports cascade testing statins for primary prevention in at-risk individuals will
of first-degree family members of individuals with probably demonstrate high cost-effectiveness from a
familial hypercholesterolaemia. Even in those without societal perspective99.
recognized mutations, a family history of early onset of
coronary heart disease or CVD (at <60 years of age) also Effects of lifetime exposure to risk factors. Atherosclerosis
increases the risk of events. begins decades before the appearance of its clinical con
Additional tests (such as carotid ultrasonography, sequences. Several studies (first by autopsy, then using
CAC score measurement assessed by CT, and coronary in vivo imaging) show that subclinical atherosclerosis
CT angiography) can identify atherosclerosis non- increases progressively from the first decade of life,
invasively. However, current data do not support their and in the PESA cohort (asymptomatic employees in
use as the sole method of screening for atherosclerosis a Spanish bank) was present in 63% of the population
with the aim of primary prevention, though some of (71% of men and 48% of women) by 40–54 years of
the tools have robust prognostic value and can act as age79. This preclinical disease relates to levels of classic
an alternative approach to additional risk stratification CVD risk factors even in children and adolescents in a
according to most guidelines, particularly for individ cumulative manner. Exposure to risk factors during early
uals with intermediate risk for whom treatment deci life relates to incidence of future cardiovascular events100
sions are unclear93. Other tests, such as brachial artery as well as evidence of worse mid-life cognitive perfor
flow-mediated dilation and ankle–brachial index, may mance. Unhealthy behaviour begins early, and habits
provide prognostic value for risk stratification for future acquired in childhood probably persist into adulthood.
CVD events, although they do not focus on the direct The global epidemic of childhood obesity continues to

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affect enormously population health, as does tobacco atherosclerosis, with increased carotid intima–media
use and a sedentary lifestyle in teenagers and adults. thickness or coronary artery calcification113. Estimates
Clinical studies have demonstrated that the cardiometa show that >50% of the US adult population have a
bolic changes measured in overweight and obese adults 10-year risk of <10% but a lifetime risk of ≥39%112.
already exist across the normal weight profile of chil The Joint British Societies for the prevention of cardio
dren even before puberty101. Risk factors such as blood vascular disease (JBS3) introduced a risk calculator,
pressure and lipids vary continuously across the weight adopted in the UK, that utilizes understandable metrics
spectrum of pre-pubertal children in the UK. Children such as ‘heart age’114 to encourage and engage patients.
from economically disadvantaged backgrounds may This approach has shown very promising results for
have particular vulnerability102. Studies in children have effective communication with patients and resulting
also shown that weight reduction can improve the level behavioural change115,116.
of risk factors and vascular wall function103. Managing The shared biology between CVD and other dis
childhood adiposity to delay and/or prevent atheroscle eases of ageing provides opportunities for broad health
rosis is a key public health challenge that will require gains from early risk-factor intervention. Of note, the
a broad approach, educating not only the children, but cluster of risk factors that increase the risk of CVD (for
also their families as well as managing their social and example, blood pressure, tobacco use, obesity, seden
living environments104. tary lifestyle and diabetes mellitus) also associate with
Risk-factor exposure during early life relates to inci cognitive decline and dementia117. The burden of these
dence of future CVD events100 and cognitive impair potentially modifiable risk factors from childhood and
ment. Prospective randomized clinical trials to evaluate middle age have a stronger relationship to brain func
the benefit of early control of risk factors on future CVD tion than levels in later life, supporting a similar ‘lifetime
events encounter obvious obstacles, but genetic studies exposure model’ for CVD and cognitive function118,119.
using Mendelian randomization support the potential Numerous intervention trials examining the effect of
benefit of lowering lifetime exposure to risk factors. In a lowering multiple cardiovascular risk factors on cogni
pooled analysis of 102,774 individuals who sustained tive outcomes are underway, following the FINGER trial,
14,368 events, even modestly lower levels of blood pres which showed improved cognitive performance with a
sure and LDL-C as a result of favourable genetic variants multifactorial intervention. Communication of the bene
translated to a 46% clinical event reduction105. Sustained fits of early reduction in CVD risk factors on multiple
lifestyle improvements may yield similar benefits. diseases, including future CVD and dementia, delivers a
Prospective clinical trials using risk profiles and arterial powerful message on the importance of prevention and
function tests support the concept that CVD may be supports behavioural change120.
largely preventable if lifetime exposure to risk factors can
be reduced106,107. Although the entire population would Digital health. The revolution in digital health provides
benefit from early sustained CVD risk-factor lowering, a new opportunity for CVD prevention. The public cur
achievable by lifestyle changes and reduction in environ rently demonstrates increased interest in their cardio
mental exposures, certain subgroups have a greatly vascular health, as shown with the adoption of wearable
increased risk for future CVD and, therefore, require devices that track exercise, heart rhythm, diet and sleep,
additional treatment. Examples include individuals with and the use of online risk calculators114,121. Continuous
monogenic disorders such as familial hypercholesterol monitoring of health-related parameters during normal
aemia and those with other medical conditions such as daily life reinforces positive behaviour patterns, and the
type 1 or type 2 diabetes mellitus, kidney disease and analysis of such extensive real-life data will probably sub
chronic inflammatory diseases (for example, rheuma stantially refine risk prediction models. As these tracking
toid arthritis). Periodontitis, the most common cause of devices become increasingly sophisticated, the data col
chronic systemic inflammation, has a causal relationship lected will provide epidemiological insights, refine safety
with arterial wall changes, metabolic control and future and end points in clinical trials, inform clinical care, and
CVD events108–111. change the culture of CVD prevention.
Patient engagement. Effective adherence to long-term Management

prevention strategies requires that the public and Because of the multifactorial nature of atherosclerosis,
patients be empowered to take responsibility for their its management should target all known treatable risk
cardiovascular health. Communication should focus factors. Ideally, primary prevention starts by adopting
on both risk and opportunities with emphasis on the a healthy lifestyle from childhood (primordial preven
benefits gained from early and sustained risk-factor tion), but risk-factor modification to prevent or even
lowering. Ten-year risk prediction models, which are reverse the progression of the atherosclerotic process can
used to guide treatment, have much less value for pre provide benefit at any stage of atherosclerotic disease,
vention over a lifetime. Few individuals of ≤50 years of even in the context of secondary prevention. Although
age, even with multiple modifiable risk factors, have a the reduction in cholesterol levels, blood pressure and
10-year absolute risk of >7.5%, which is the threshold tobacco use has substantially decreased CVD mortality
currently recommended for statin prescription in the in many populations122, an increase in other lifestyle-
USA112. The MESA/CARDIA studies showed that indi related risk factors such as obesity, type 2 diabetes
viduals of ≤50 years of age with a low 10-year risk but a mellitus, sedentary behaviour and psychosocial stress,
high lifetime risk already exhibit evidence of subclinical challenge these positive results123. Whereas lifestyle

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modification remains pertinent for all individuals, the the probability of CVD events to a greater extent than
use of lipid-lowering medication depends on the esti 2–5 years of pharmacological lipid-lowering therapy14.
mated risk of incident CVD events. Some studies also Thus, early intervention before CVD manifests should
recommend anti-platelet therapy after individual assess prove more effective than initiating therapy after CVD
ment of risk and benefit, though this treatment option onset135,136. The 2016 European guidelines and the 2018
remains highly debated in the literature124–126. Indeed, US cholesterol clinical practice guidelines137 recommend
current data do not support a favourable risk:benefit that treatment goals for LDL-C depend on the risk pro
balance for aspirin therapy in primary prevention127,128. If file of the patient89,137. Pharmacological treatment should
atherosclerotic disease has progressed to a stage causing start with a statin.
symptomatic ischaemia, revascularization therapy can Non-HDL-C (total cholesterol concentration minus
often relieve symptoms, and possibly increase survival, HDL concentration) represents the cholesterol in all
a conjecture currently under intense study89. atherogenic particles. Although usually concordant with
LDL-C, some discordance between LDL-C concentra
Lifestyle interventions tion and non-HDL-C concentration may exist in insulin-
Lifestyle interventions furnish the foundation of therapy, resistant states, in which non-HDL-C may better predict
have the advantage of targeting multiple risk factors, and disease than LDL-C138. Thus, having reached the desired
hold great importance to all with any stage of atheroscle LDL-C goal, non-HDL-C should serve as a secondary
rotic disease. The emphasis on diet, physical activity and target for treatment, especially in individuals with dia
abstinence from tobacco use in the prevention of athero betes mellitus. In the 2016 European guidelines, the
sclerotic disease remains essential89. A healthy diet not goals for non-HDL-C are <100 mg/dL (2.6 mmol/L) for
only influences lipid and risk-factor profile favourably very-h igh-risk patients, <130 mg/dL (3.4 mmol/L)
while decreasing obesity, but also affects gut microbiota for high-risk patients and <145 mg/dL (3.8 mmol/L) for
that may produce metabolites harmful to the vascula moderate-risk patients89. As detailed below, the 2018
ture129. Smoking cessation remains the most clinically US guidelines recommend treatment of those with
effective and cost-effective strategy for the prevention of established atherosclerosis with high-intensity or maxi
atherosclerotic disease130. Blood pressure control (with mally tolerated statin therapy, and allocation of statins
lifestyle intervention as well as medication when neces to other groups depending on risk stratum137 defined by
sary) also remains vital depending on the level of blood clinical characteristics or a risk calculator.
pressure and the risk profile of the patient131. The man Fibrates (which are weak agonists of a widely expres
agement of diabetes mellitus reduces the risk of micro sed nuclear receptor protein that regulates lipid meta
vascular complications and, with certain newer agents, bolism) lower the levels of triglyceride-rich lipoprotein
macrovascular disease, and improves cardiovascular particles, which augment atherogenesis. Yet, prospective
outcomes in these patients132. Lifestyle modifications to randomized controlled trials of fibrates in combination
reduce LDL-C and lipid levels should accompany rec with statins have not met their primary end points of
ommendations to all patients, and should accompany improving cardiovascular outcomes. In several of these
guideline-directed pharmacological therapy. studies, the subgroups with low HDL-C and high tri
glyceride levels did derive benefit from combination
Lipid-lowering pharmacological therapy therapy139. The European guidelines recommend statins
Lipid-lowering therapy remains the cornerstone of the as the first choice to reduce risk in patients with hyper
management of atherosclerotic disease. Evidence from triglyceridaemia, but suggest the consideration of the
epidemiological, genetic and Mendelian randomization use of fibrates in combination with statins to reach non-
studies and from randomized clinical trials involving HDL-C goals, especially in the high-risk patient with
>2 million participants and >20 million person-years diabetes mellitus89. The FDA has withdrawn approval of
of follow-up have shown that LDL-C acts as a causal fenofibrate in combination with statins140. Gemfibrozil
risk factor14. Thus, early control of LDL-C holds great should never be combined with statins owing to a strong
importance. Randomized clinical trials have consistently drug–drug interaction.
demonstrated that lowering LDL-C reduces the risk of
CVD events proportionate to the absolute fall in LDL-C Statins. Statins inhibit 3-hydroxy-3-methylglutaryl-
independent of other risk factors133. A substantial overall CoA reductase (HMG-CoAR), the rate-limiting enzyme
record of safety has been amassed for the use of statins, in the synthesis of cholesterol. Compelling evidence
with rare serious complications, although some individ from randomized clinical trials shows that reducing
uals do not or will not tolerate statin therapy for vari LDL-C with statins decreases CVD events. In a large
ous reasons, primarily myalgia (muscle aches)134. These meta-analysis from statin trials, treatment with a statin
findings support the current concept that lipid-lowering associated with a log-linear 22% reduction in the risk
therapy should target primarily LDL-C. of major CVD events per millimole per litre reduction
Although some differences exist in the approach to in LDL-C141. Statin prescriptions should reach the high
LDL-C lowering in various guidelines, the principles est recommended or tolerated dose to attain the treat
remain the same. The intensity of treatment reflects the ment goal. If the goal still remains unmet, combination
risk profile of the patient, defined on the basis of known therapy with a statin and a non-statin drug may prove
disease or by various risk scores in those without clinical successful.
CVD. However, Mendelian randomization analyses have On the other hand, the American College of
shown that having lifetime low cholesterol levels reduces Cardiology/American Heart Association 2018 guidelines

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recommend universal use of statins in all high-risk indi outcomes in high-risk patients with a baseline LDL-C of
viduals142. According to these guidelines, the following >100 mg/dL, but the development of anti-bococizumab
groups of patients should receive high-dose or moderate- antibodies in 15–20% of patients attenuated the sub
dose statin therapy: individuals with clinical athero stantial reduction in LDL-C150. Small interfering RNAs
sclerotic CVD; individuals with LDL-C >190 mg/dL; such as inclisiran provide another way to inhibit PCSK9
and individuals of 40 to 75 years of age with diabetes with impressive durability, and have entered clinical
mellitus and LDL-C in the range 70–189 mg/dL but investigation151.
without clinical atherosclerotic CVD. In adults 40 to Evidence from trials with combination therapy using
75 years of age evaluated for primary atherosclerotic ezetimibe and PCSK9 inhibitors in addition to statins
CVD prevention, a clinician–patient risk discussion show that this therapy enables the achievement of much
should precede the start of statin therapy. The risk dis lower LDL-C levels than was previously possible (from
cussion should include a review of major risk factors, 70 mg/dL to lower), and this further reduction conferred
the presence of risk-enhancing factors (such as a high greater CVD benefit152. The European Atherosclerosis
CAC score or CRP), the potential benefits of lifestyle Society/European Society of Cardiology published a
and statin therapies, the potential for adverse effects and consensus paper to help to identify patients who would
drug–drug interactions, consideration of costs of statin derive the most potential benefit from this new therapy,
therapy, and patient preferences and values in shared while also taking into account the financial constraints
decision-making. of health-care budgets, given current costs of PCSK9
All guidelines agree that statins should remain inhibition therapy153,154.
the first choice in initiating pharmacological therapy This consensus recommends consideration of treat
owing to the ample evidence supporting their efficacy. ment with a PCSK9 monoclonal antibody in very-
Depending on the type, potency and dose of statin used, high-risk patients with atherosclerotic disease or in
a 30–50% reduction in LDL-C levels may prove possible. patients with severe familial hypercholesterolaemia
Yet, achieving treatment targets can be challenging, espe without atherosclerotic CVD with substantially elevated
cially in some patient groups, for example, individuals LDL-C levels despite maximal statin−ezetimibe therapy.
with familial hypercholesterolaemia and those with sta Patients in these groups with verified statin intolerance
tin intolerance, and, therefore, may require combination also merit consideration for PCSK9 inhibition therapy.
therapy for further LDL-C reduction. A cost-effective approach to the use of PCSK9 inhibi
tor therapies targets the individuals at highest risk154.
Non-statin lipid-lowering drugs. Early clinical trials have Post-hoc analyses from trials suggest that certain sub
shown that bile-acid sequestrants also lower LDL-C groups of patients, such as those with coronary artery
and decrease CVD events. Yet, gastrointestinal adverse bypass graft surgery, multivessel atherosclerotic disease
effects, drug interactions and elevation of triglyceride and recent myocardial infarction, may derive great bene
levels limit their widespread use143. Ezetimibe inhibits fit from aggressive LDL-C lowering with combination
cholesterol absorption by enterocytes and augments therapy155.
expression of liver LDL receptors, and has proven use The use of omega-3 fatty acid supplements to pre
ful in combination therapy. Ezetimibe, when added vent CVD have yielded controversial results in the
to statins, further reduces LDL-C by 15–20%144. The past. However, a recent trial showed that among statin-
IMPROVE-IT study showed that in patients who sur treated patients with elevated triglyceride levels the risk
vived an acute coronary syndrome, adding ezetimibe to of ischaemic events, including cardiovascular death,
a statin associated with a 6.5% proportional reduction in was significantly lower among those who received 2 g of
major CVD events145. icosapent ethyl twice daily than among those who
PCSK9 binds to LDL receptors and promotes their received placebo156.
intracellular degradation, and inhibiting PCSK9 can
decrease LDL-C substantially. PCSK9 inhibitors, a Non-lipid-lowering therapy
newer class of drugs, can be used in combination with Antiplatelet drugs. Platelets play a crucial part in the
statins in selected high-risk patients. Studies with anti- pathogenesis of atherosclerosis-associated thrombotic
PCSK9 monoclonal antibodies have shown that they processes. Antiplatelet therapy does not fall under rou
can decrease LDL-C up to 60%146,147. Clinical trials have tine recommendations in primary prevention of athero
tested the fully human antibodies evolocumab and aliro sclerosis, owing to the increased risk of bleeding.
cumab as well as the humanized antibody bococizumab However, in secondary prevention settings, the benefits
in >10,000 patients. The GLAGOV study showed that, of aspirin generally exceed the bleeding hazards157,158.
on a background of statin therapy, decreasing LDL-C Inhibitors of the P2Y purinergic receptor 12 (P2Y12, an
levels with evolocumab even further could reverse coro adenosine diphosphate receptor expressed by plate
nary atherosclerosis (assessed with coronary ultra lets) further inhibit platelet aggregation. These agents
sonography)148. The FOURIER and ODYSSEY clinical should be used in addition to aspirin in acute coronary
outcome trials showed that inhibition of PCSK9 with syndromes or in the setting of percutaneous coronary
evolocumab or alirocumab in addition to statin ther intervention159. A recent study has shown that among
apy lowered LDL-C levels substantially and reduced the patients with stable atherosclerotic vascular disease,
risk of CVD events with a good safety profile over those assigned to rivaroxaban (twice daily) plus aspirin
the duration of the studies149. In the SPIRE trials, adding had better cardiovascular outcomes and more major
bococizumab to statins decreased adverse cardiovascular bleeding events than those assigned to aspirin alone96.

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Anti-inflammatory drugs. The inflammatory com all known risk factors such as tobacco use, diabetes
ponent of atherosclerotic disease has gained attention mellitus, hypertension and obesity should be treated.
as a therapy target because of several clinical trials to Remnant lipoproteins, Lp(a), and inflammation also
test anti-inflammatory agents. The anti-IL-1β antibody contribute to the residual risk, and their management is
canakinumab reduces major adverse cardiovascular currently under study.
events (MACE) by 15% in patients after myocardial New developments in imaging technologies will
infarction with evidence of inflammation gauged by continue to expand and validate personalized risk-
CRP levels above the median95. In the responders who assessment and tailored treatment according to patient
achieved a reduction in CRP level greater than the and plaque characteristics in the future. Awaiting such
median reduction, MACE fell by 25%, and total and advances, we must strive to implement and encourage
cardiovascular mortality by >30%96. In an exploratory adherence to treatment following existing guidelines.
analysis, the incidence of fatal lung cancer fell by up to
77% in those treated with canakinumab160. Quality of life
Large secondary prevention studies are evaluating Health-related quality of life (HRQOL) is a key patient-
colchicine as an alternative anti-inflammatory agent161. centric outcome that represents a person’s perception of
Methotrexate in a low-dose weekly regimen did not their sense of well-being in the context of their expecta
reduce cardiovascular events in the Cardiovascular tions for health170. It links biological variables to symp
Inflammation Reduction Trial (CIRT). This treatment tom burden, functional capacity, exercise capacity and
did not, however, lower biomarkers of inflammation psychological well-being; these parameters are collec
CRP, IL-1β or IL-6162, and the participants did not have tively referred to as patient-reported outcomes171. Given
elevated CRP levels at baseline. the improved survival of patients with atherosclerosis
NSAIDs, commonly used in a variety of conditions, (and, therefore, the increased total lifetime burden
inhibit prostaglandin synthesis. Theoretically, they may of coexisting with the disease), research into HRQOL of
exert beneficial effects on vascular inflammation; how these patients has increased.
ever, their capacity to inhibit production of prostacyclin, Patients with atherosclerosis have an HRQOL
a prostaglandin that inhibits platelet aggregation, may worse than that of age-matched healthy individuals,
counterbalance such effects. Coxibs selectively inhibit yet the individual responses of these patients are quite
cyclooxygenase-2 (COX-2, also known as prostaglan variable172. Progressive atherosclerosis often leads to
din G/H synthase 2). This enzyme inhibits prostacyclin increased angina pectoris, fatigue, dyspnoea and exercise
production without interfering with production of the intolerance. Complex treatment regimens and health-
proaggregatory thromboxane A2. Inhibition of COX-2 care utilization may additionally aggravate HRQOL
might thus increase CVD events163,164. by affecting a patient’s psychological and social well-
being173, which is also impaired by anxiety due to prog
Therapeutic challenges nosis and fear of future CVD events, depression, sleep
Therapeutic challenges include nonadherence to life disturbances and adverse drug effects. The occurrence
style and lipid-lowering therapy, with most patients of acute coronary syndromes often associates with
not achieving or maintaining their goal. The benefits reduced HRQOL173. Other factors that can further impair
observed in randomized clinical trials will only apply the HRQOL of patients with atherosclerosis include com
in practice if patients adhere to treatment. Nearly half orbid conditions (for example, diabetes mellitus, peri
of patients discontinue statin use within the first year pheral artery disease and obesity), the development of
after the initial prescription, with higher discontinu heart failure, young age, female sex, poor or inadequate
ation rates after 2 years165. Discontinuation associates emotional support, belonging to a racial minority, low
with increased risk for CVD events and death166. Statin- socioeconomic status and disease severity173–175.
associated muscle symptoms, such as myalgia, remain Three types of instruments serve to measure HRQOL
the most frequent reason for nonadherence. Although in atherosclerosis: generic, disease-specific for athero
there are no objective criteria for definitive diagnosis sclerosis, and disease-specific for ancillary disease
of statin intolerance, patients who present with statin- conditions relevant to the individual. Generic instru
associated symptoms should undergo careful statin ments, such as the Short Form-36 Health Survey and
re-challenge (that is, the reintroduction of a statin after EuroQol 5D, enable comparison of the HRQOL of
suspending the treatment for ≥4 weeks, during which patients with atherosclerosis to that of other patients
time symptoms abate). Evidence shows that adherence and measurement of overall changes in health status;
to therapy remains important in high-risk patients, and importantly, the adverse effects of a drug may counter
continued statin use even after an adverse reaction is balance the improvements in atherosclerosis-related
associated with a reduced incidence of death and CVD symptoms, and the weights of both positive and neg
events167–169. ative effects depend not only on the magnitude of
Although not achieving the treatment goal is a very each effect but also on the importance given to it by
important determinant of residual risk, CVD events the patient. Common disease-specific instruments
can still occur in optimally treated patients who have include the Seattle Angina Questionnaire (SAQ)
achieved their LDL-C goal. Combination therapy could and the Myocardial Infarction Dimension Assessm
lower CVD events even further by achieving LDL-C lev ent Scale (MIDAS)176. These latter instruments more
els below guideline-recommended levels. Other risk readily respond to change and can measure efficacy of
factors besides LDL-C also contribute to residual risk and an intervention or track changes over time. Numerous

Primer
instruments can measure HRQOL associated with ancil technology or medications. For example, percutaneous
lary conditions and common disease states, including and surgical management of coronary and peripheral
functional capacity (for example, the Duke Activity atherosclerotic disease, albeit often effective, depends
Status Index (DASI))177 and depression (for example, the on increasingly complex technologies. Arrhythmias and
Patient Health Questionnaire 9 (PHQ-9))178. heart failure most often arise because of atherosclerosis.
Revascularization therapy remains the cornerstone When these conditions are advanced, their treatment
for improving HRQOL in patients with multi-vessel often also involves highly technological interventions
atherosclerotic disease. Patients who underwent percu such as pacemakers, cardiac resynchronization ther
taneous coronary intervention have better quality of life apy, and mechanical circulatory support. Physician
improvement by 1 month and fewer physical limitations and writer Lewis Thomas referred to such solutions as
than patients who received surgical revascularization179; ‘halfway technologies’.183 We have succeeded in creating
however, after ≥6 months, patients who underwent a cohort of survivors of atherosclerotic complications
surgery have greater improvements in angina pectoris who live longer, but experience considerable morbidity
and improved overall HRQOL. High-intensity interval and poor quality of life. Some of the simpler solutions to
training and moderate exercise training have similar stemming the epidemic of atherosclerosis require behav
benefits on HRQOL180. Nurse-led secondary prevention ioural or societal changes. Our ability to deploy adoption
efforts, including education and behavioural counselling of healthy diets, regular physical activity, tobacco cessa
and support, and patient-led lifestyle changes result in tion and other preventive measures has lagged behind
improvements in HRQOL181,182. Yet, understanding how our technological prowess.
individual elements of these interventions translate into We must strive on several fronts to confront the
improved outcomes remains limited. As we continue to remaining burden of atherosclerotic risk. In the lab
make progress in the management of acute and chronic oratory, we must continue to explore the fundamental
atherosclerosis, we must also develop strategies to causes of this disease, keeping our eye on the ‘moving
maximize HRQOL. target’ of the human disease, and on the limitations of
our in vitro and animal experiments. In our translational
Outlook undertakings, we must develop and test rigorously novel
The very advances in managing the complications of therapeutics that address novel pathways and address
atherosclerosis have extended life, but many individuals unmet needs rather than exhausting well-mined targets.
are left with impaired cardiac function, contributing to In our clinical practice, we should strive to implement
an epidemic of heart failure due to ischaemic cardio what we already know in an evidence-based manner,
myopathy. Beyond its human costs, the burden of heart and never permit guidelines or practice algorithms to
failure creates a major strain on health-care systems and replace our bond with individual patients and our judge
resources. We have made much progress in understand ment and experience regarding an individual’s particu
ing the mechanisms of atherosclerosis. We possess many lar circumstances, needs and preferences. As a society,
tools for treating or managing atherosclerosis and its we need to combat unhealthy lifestyles and provide
complications. Yet, the job is unfinished. We have only a healthy environment to limit the spread of CVD in
partially mastered atherosclerosis, and much remains to the future.
be done. Many of the contemporary interventions that
extend life depend highly on expensive and invasive Published online xx xx xxxx
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PRIMER

Author addresses treatment of high LDL-​C increased significantly, from

We can consider conveniently the pathogenesis of ath­

erosclerosis in three phases: initiation, progression and

2 | Article citation ID: (2019) 5:56 www.nature.com/nrdp

T cell How excessive LDL-​C causes atherosclerosis

4 | Article citation ID: (2019) 5:56 www.nature.com/nrdp

Fibrous cap thinning

Intima Internal elastic membrane

Adventitia External elastic membrane

persistent presence in the atherosclerotic plaque45,46. Clonal haematopoiesis of indeterminate potential.

Lipid core Healing, ﬁbrosis, stenosis,

Thrombus Buried Tunica

6 | Article citation ID: (2019) 5:56 www.nature.com/nrdp

Carotid arteries and cerebral Coronary arteries

• Recurrent TIAs • Stable angina

Thoracic aorta Abdominal aorta

• Aortic rupture • Aortic occlusion (rare)

• Chronic mesenteric ischaemia Acute presentation

8 | Article citation ID: (2019) 5:56 www.nature.com/nrdp

Table 1 | Diagnostic tests for atherosclerosis

screening has its limits.

10 | Article citation ID: (2019) 5:56 www.nature.com/nrdp

Patient engagement. Effective adherence to long-​term Management

12 | Article citation ID: (2019) 5:56 www.nature.com/nrdp

14 | Article citation ID: (2019) 5:56 www.nature.com/nrdp

16 | Article citation ID: (2019) 5:56 www.nature.com/nrdp

18 | Article citation ID: (2019) 5:56 www.nature.com/nrdp

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Author addresses treatment of high LDL-C increased significantly, from

We can consider conveniently the pathogenesis of ath

T cell How excessive LDL-C causes atherosclerosis

Patient engagement. Effective adherence to long-term Management