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Atherosclerosis Compendium

Circulation Research Compendium on Atherosclerosis

Atherosclerosis: Successes, Surprises, and Future Challenges
Epidemiology of Atherosclerosis and the Potential to Reduce the Global Burden of Atherothrombotic Disease
Triglyceride-Rich Lipoproteins and Atherosclerotic Cardiovascular Disease: New Insights From Epidemiology, Genetics, and Biology
Genetics of Coronary Artery Disease
Surprises From Genetic Analyses of Lipid Risk Factors for Atherosclerosis
From Loci to Biology: Functional Genomics of Genome-Wide Association for Coronary Disease
Are Genetic Tests for Atherosclerosis Ready for Routine Clinical Use?
Endothelial Cell Dysfunction and the Pathobiology of Atherosclerosis
Macrophages and Dendritic Cells: Partners in Atherogenesis
Macrophage Phenotype and Function in Different Stages of Atherosclerosis
Adaptive Response of T and B Cells in Atherosclerosis
Microdomains, Inflammation, and Atherosclerosis
Vascular Smooth Muscle Cells in Atherosclerosis
MicroRNA Regulation of Atherosclerosis
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The Success Story of LDL Cholesterol Lowering

From Lipids to Inflammation: New Approaches to Reducing Atherosclerotic Risk
Imaging Atherosclerosis
Peter Libby, Karin E. Bornfeldt, and Alan R. Tall, Editors

Epidemiology of Atherosclerosis and the Potential to Reduce

the Global Burden of Atherothrombotic Disease
William Herrington,* Ben Lacey,* Paul Sherliker, Jane Armitage, Sarah Lewington

Abstract: Atherosclerosis is a leading cause of vascular disease worldwide. Its major clinical manifestations include
ischemic heart disease, ischemic stroke, and peripheral arterial disease. In high-income countries, there have
been dramatic declines in the incidence and mortality from ischemic heart disease and ischemic stroke since the
middle of the 20th century. For example, in the United Kingdom, the probability of death from vascular disease
in middle-aged men (3569 years) has decreased from 22% in 1950 to 6% in 2010. Most low- and middle-income
countries have also reported declines in mortality from stroke over the last few decades, but mortality trends
from ischemic heart disease have been more varied, with some countries reporting declines and others reporting
increases (particularly those in Eastern Europe and Asia). Many major modifiable risk factors for atherosclerosis
have been identified, and the causal relevance of several risk factors is now well established (including, but not
limited to, smoking, adiposity, blood pressure, blood cholesterol, and diabetes mellitus). Widespread changes in
health behaviors and use of treatments for these risk factors are responsible for some of the dramatic declines in
vascular mortality in high-income countries. In order that these declines continue and are mirrored in less wealthy
nations, increased efforts are needed to tackle these major risk factors, particularly smoking and the emerging
obesity epidemic.(Circ Res. 2016;118:535-546. DOI: 10.1161/CIRCRESAHA.115.307611.)
Key Words: atherosclerosis coronary epidemiology peripheral stroke

Original received September 12, 2015; revision received November 4, 2015; accepted November 6, 2015.
From the Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, Oxford OX3 7LF, UK.
*These authors share joint contribution.
These authors share joint contribution.
Correspondence to Jane Armitage, Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health,
Richard Doll Bldg, Old Rd Campus, Roosevelt Dr, Oxford OX3 7LF, UK. E-mail jane.armitage@ctsu.ox.ac.uk
2016 American Heart Association, Inc.
Circulation Research is available at http://circres.ahajournals.org DOI: 10.1161/CIRCRESAHA.115.307611

536Circulation ResearchFebruary 19, 2016

mortality rates for both IHD and stroke have declined between
Nonstandard Abbreviations and Acronyms
1990 and 2010, with steeper declines for developed than for
ARIC Atherosclerosis Risk In Communities developing countries (Figure2).4 Nevertheless, IHD remains
BMI body mass index the leading cause of premature adult mortality worldwide.5
CI confidence interval
CKD chronic kidney disease Global Burden of IHD
DPP Diabetes Prevention Program The Global Burden of Disease 2010 Study described the
GRACE Global Registry of Acute Coronary Events IHD mortality rates (age-standardized to the World Health
HDL high-density lipoprotein Organisation standard population6) for 21 world regions.2 In
HR hazard ratio 2010, the highest mortality rates were reported for Eastern
IHD ischemic heart disease
Europe (434 per 100000 per year in men, 235 in women),
which included Russia; Central Asia (400 in men, 225 in
LDL low-density lipoprotein
women); Central Europe (201 in men, 117 in women); and
Lp(a)/LPA lipoprotein (a)
North Africa/Middle East (189 in men, 123 in women). The
MI myocardial infarction
lowest rates were for the high-income Asia Pacific region (46
MR Mendelian randomization
in men, 27 in women) and Eastern Sub-Saharan Africa (60
MRFIT Multiple Risk Factor Intervention Trial
in men, 47 in women). The equivalent rates for the United
NHANES National Health and Nutrition Examination Survey
States were 122 in men and 78 in women.4 In this study, an
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NSTEMI nonST-segmentelevation MI analysis of the global incidence of myocardial infarction (MI)

PAD peripheral arterial disease described a similar geographical distribution to IHD mortality,
RR relative risk with the highest rates for 2010 in Eastern Europe (410 in men,
SBP systolic blood pressure 199 in women) and Central Asia (341 in men, 189 in women)
STEMI ST-segmentelevation MI and lowest rates in the high-income Asia Pacific region (107 in
TOAST Trial of Org 10172 in Acute Stroke Treatment men, 51 in women) and East Asia (133 in men, 79 in women).7
Long-term studies of trends in MI incidence are mostly lim-
ited to national registries of hospitalized events or subnational
studies of hospitalized and out-of-hospital events, conducted
What Is Atherosclerosis? mainly in high-income countries. Assessment of temporal
Atherosclerosis is a chronic arterial disease and a major cause trends in incidence over the last 20 years has also been com-
of vascular death. Fatty streaks in arterial walls gradually de- plicated by the introduction of increasingly sensitive cardiac
velop into atheroma and characteristic plaques. The acute rup- biomarkers and changes to the definitions for MI.810 However,
ture of these atheromatous plaques causes local thrombosis, a recent review of 8 community-based incidence studies in 6
leading to partial or total occlusion of the affected artery.1 The European countries (Finland, Italy, Germany, France, Spain,
clinical consequences of these plaques depend on their site and Estonia), which accounted for the increased use of these
and the degree and speed of vessel occlusion. The disease has biomarkers over time, described a decline in acute MI attack
a latency of many years and frequently coexists in >1 vascular rates (defined as incidence and recurrence combined) between
bed. Its major clinical manifestations include ischemic heart
disease (IHD), ischemic stroke, and peripheral arterial disease
(PAD). The global distribution and an overview of the major
determinants of these manifestations are described later.

Vascular Mortality Trends 1950 to 2010

There have been dramatic declines in both IHD and stroke
mortality rates in most high-income countries since the
middle of the 20th century. In the United Kingdom, for ex-
ample, vascular mortality rates for middle-aged men (aged
3569 years) have decreased from 700 per 100000 per year
in 1950 to <200 by 2010 and for middle-aged women, from
450 in 1950 to <100 by 2010 (Figure1). In men, these de-
clines accelerated in the 1980s. For men and women consid-
ered together, the 35-year vascular mortality risk from age 35
years (ie, the risk of a vascular death before age 69 years) was
16% in 1980 and 4% in 2010. Most low- and middle-income
countries have also reported declines in mortality from stroke
over the last few decades but mortality trends from IHD have
been more varied, with some countries reporting declines and
Figure 1. United Kingdom 1950 to 2010 vascular mortality
others reporting increases (particularly in some countries in
rates at ages 35 to 69, by sex. Source: WHO mortality and UN
Eastern Europe and Asia).2,3 The Global Burden of Disease population estimates. *Mean of annual rates in the 7 component
2010 Study estimated that overall, the global age-standardized 5-year age groups.
Herrington et al Epidemiology of Atherosclerosis 537

1985 and 2010 in all populations.11 The annual reduction in registry of patients presenting with acute coronary syndrome
rates over this period at age 35 to 74 years for these countries to 184 hospitals in 25 mostly high-income countries) reported
combined was 4.0% (95% confidence interval [CI] 3.7%4.4%) that for patients recruited from 2001 to 2007, 30% had ST-
for men and 4.2% (3.6%4.8%) for women (ie, nearly a 70% segmentelevation MI (STEMI; the subtype of MI with the
reduction in MI rates over 25 years), with some regional varia- worst short-term prognosis16), 31% had nonST-segmentele-
tion. These MI rate decreases are similar to those described in vation MI (NSTEMI), 26% had unstable angina, and 12% had
studies in the United States and the United Kingdom.1214 In the other cardiac or noncardiac diagnoses (ie, the ratio of MIs that
United States, the 4 communities of the Atherosclerosis Risk were STEMI:NSTEMI was 50:50; median age 65 years).17 A
In Communities (ARIC) Study, with a combined population national registry of patients presenting to hospitals in England
of just under 400000 adults aged 35 to 74 years, reported an and Wales in 2013/14 with acute coronary syndromes reported
average fall in incidence (first hospitalized MI or IHD death) a somewhat higher proportion of MI patients with NSTEMI
from 1987 to 2008 of 4.3% per year in men and 3.8% per year (61%) versus STEMI (39%).18 The proportion of patients
in women; incidence was higher, and the decline in rates less with NSTEMI was noted to increase with age (mean age at
steep, in African Americans compared with White Americans event 69 years) and was slightly higher in women than men. A
for both sexes.15 A nationwide study in England from 2002 to large community-based study in the United States (the Kaiser
2010 reported that rates of hospital admissions or death from Permanente study) described similar findings to the United
acute MI decreased by 4.8% per year in men and 4.5% in wom- Kingdom: 67% of patients hospitalized for MI between 1999
en.13 This study estimated that around half the decrease in IHD and 2008 had NSTEMI and 33% had STEMI (mean age 69
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mortality in England over this period could be attributed to a years).14 Several long-term incidence studies in the West have
decline in acute MI events, and just under half was attributable described temporal trends in the incidence of NSTEMI and
to a decline in the case fatality. STEMI, with most reporting steep declines in the incidence of
Over the last 2 decades, there has been a change in the STEMI over the last 20 years and less steep declines (and oc-
type of MI presentation in high-income countries. The Global casionally increases)19 in the incidence of NSTEMI (perhaps
Registry of Acute Coronary Events (GRACE) Study (a large the result of increased diagnostic sensitivity).14,15 Over the
same period (20012011), and in contrast to the West, China
experienced a rapid rise in hospitalization for STEMI (3.5 per
100000 per year in 2001 to 15.4 per 100000 in 2011).20
There is limited evidence worldwide on the incidence of an-
gina,21,22 but good data on prevalence. The 2011 UK prevalence
of angina estimated from primary care data varied with age
from <1% at age 45 to 54 years in both men and women to 9%
in men and 5% in women at age 65 to 74 years.21 In the 2009
to 2012 US National Health and Nutrition Examination Survey
(NHANES), the prevalence of self-reported physician diagno-
sis of angina was 2% at age 40 to 64 years in both men and
women and 8% in men and 5% in women at age 65 years.23

Global Burden of Ischemic Stroke

The Global Burden of Disease 2010 Study also reported the
mortality from ischemic stroke in different regions of the
world.3 Age-standardized to the World Health Organisation
standard population, the region with the highest median coun-
try-specific mortality was Eastern Europe (96 per 100000
per year), followed by the Oceanic islands (63) and Central
Europe (62). The lowest mortality rates were reported for high-
income North America (19), Australasia (19), and Andean
Latin America (21). At a country level, the age-standardized
mortality ranged from 9 per 100000 per year in Qatar to 138
in Russia.
Like IHD, ischemic stroke incidence (fatal or not) in-
creases with age. For example, the Oxford Vascular Study,
a community-based study in the United Kingdom, reported
that the incidence of ischemic stroke in 2002 to 2005 in-
creased from 35 per 100000 per year at age 35 to 44 years
to 952 at age 75 to 84 years.24 On the whole, studies report
Figure 2. Developed and developing countries 1990 to 2010 slightly higher age-specific incidence of (and mortality
ischemic heart disease and stroke mortality rates at ages 35
to 69, by sex. Source: Global Burden of Disease Study 20134; from) ischemic stroke in men than women.25,26 In the United
*Mean of annual rates in the 7 component 5-year age groups. States, there is also variation in ischemic stroke incidence by
538Circulation ResearchFebruary 19, 2016

ethnicity, with higher rates in African Americans compared Overview of Modifiable Causes of
with white Americans.27 Atherosclerosis
Age-standardized to the World Health Organisation stan- Many modifiable risk factors for atherosclerosis have been
dard population, the Global Burden of Disease 2010 Study identified by large prospective observational studies, and the
estimated that the incidence of ischemic stroke in the United causal relevance of several risk factors is now well established.
States for 2010 was 143 per 100000 person-years, somewhat Widespread changes in health behaviors and use of treatments
higher than in the United Kingdom with 85, but an 18% de- for these risk factors are responsible for some of the dramatic
crease in incidence since 1990. Similar proportional reduc- declines in vascular mortality rates in high-income countries
tions were reported for other high-income countries.28 Studies over the last 60 years.41,42 The relevance of cigarette smoking,
of temporal trends in most low- and middle-income coun- blood pressure, blood lipids, diabetes mellitus, chronic kidney
tries have not been feasible because the use of computed disease (CKD), and adiposity to atherothrombotic risk is de-
tomography and magnetic resonance imaging scanners (to scribed below.
differentiate stroke subtypes) is not widespread.
Ischemic stroke can be divided into subtypes according Smoking and Atherosclerosis
to the site of the causal lesion.2932 The Trial of Org 10172 in During the first few decades of the 20th century, the consump-
Acute Stroke Treatment (TOAST) criteria is commonly used tion of manufactured cigarettes increased greatly,43 whereas
and has the following categories: large vessel, small vessel, the hazards of smoking remained largely unsuspected. It was
cardioembolic, stroke of other determined cause, and stroke only around the middle of the 20th century that several case
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of indeterminate cause.29 Atherosclerosis is the major underly- control studies of lung cancer were published in Western
ing pathophysiological mechanism in large vessel disease and Europe4447 and North America,48 leading to the conclusion in
may also be responsible for a large proportion of ischemic 1950 that smoking was a cause, and an important cause of
strokes with indeterminate cause (eg, there is evidence that lung cancer. This discovery led to a UK prospective obser-
aortic atherosclerotic plaques may be a source of thrombus vational study among 35000 British doctors, which began in
formation and embolism).33 In the late 1990s, the Rochester 1951,49 and two US prospective studies which began in 1959
Epidemiology Project (a community-based stroke incidence and 1982, each with over one million participants.50,51 Men
study in Minnesota) reported that 16% of strokes were large born in the United Kingdom and United States were select-
vessel, 16% were small vessel, 29% were cardioembolic, 3% ed because these were the first major populations in which
were other determined cause, and 36% were indeterminate cigarette consumption from a young age was substantial.
cause (mean age at event 76 years).34 Broadly similar propor- Consequently, these studies provided the best evidence on the
tions have been reported by other studies in the United States 31,35 relevance of smoking to many causes of deaths due both to
and Europe,36 but reliable data from low- and middle-income their large size and because by the end of the 20th century, the
countries are limited. smoking epidemic had matured so that in old age, those who
still smoked had generally been regularly smoking substantial
Global Burden of PAD numbers of cigarettes throughout their adult life.
Compared with IHD and stroke, PAD (which includes arte- The 50-year follow-up of the British Doctors study con-
rial disease of the lower extremity, renal, mesenteric, and firmed that smoking caused more deaths by other diseases than
abdominal aortic territories) is a relatively rare cause of mor- by lung cancer and that half of all smokers would eventually
tality, accounting for only 1% to 2% of cardiovascular deaths be killed by their habit. For example, there was a relative risk
globally in 2013.5 However, lower extremity PAD is a com- (RR) of 1.6 for IHD mortality for current smokers compared
mon cause of morbidity, which may result in reduced mobil- with never smokers (age-standardized mortality of 1001 per
ity, intermittent claudication, critical limb ischemia, and acute 100000 men per year versus 619; Table 1) and 1.6 for stroke
limb ischemia.37,38 A recent meta-analysis estimated the global mortality (432 versus 275),52 with hazards higher among those
prevalence of lower extremity PAD (using an ankle-brachial who smoked more cigarettes. Importantly, these data also
systolic blood pressure [SBP] index threshold of 0.9) from 34 demonstrated that one-third of the absolute excess mortality
population-based studies conducted between 1997 and 2011.38 among cigarette smokers was because of IHD or cerebrovas-
In high-income countries, the average age-specific prevalence cular disease, and even more importantly, that smoking ces-
ranged from 5% at age 40 to 49 years to 13% at age 70 to 79 sation prevents most of this excess mortality. Quitting at age
years (irrespective of sex). In low- and middle-income coun- 50 halved the risk of death, and quitting by age 30 avoided
tries, the age-specific prevalences were similar in women to almost all of it.
high-income countries but were somewhat lower in men: 6% at Only recently has it been possible to observe directly
age 40 to 49 years and 12% at age 70 to 79 years in women and the full effects of smoking on premature mortality among
3% at age 40 to 49 years to 9% at age 70 to 79 years in men. In women because in both the United Kingdom and the United
the 1999 to 2000 NHANES, the US prevalence of PAD (ankle- States, the smoking epidemic in women began later, with
brachial SBP index <0.9) ranged from 1% at age 40 to 49 years women born around 1940 becoming the first generation
to 15% at age 70 years, with no evidence of variation by sex.39 in which many smoked substantial numbers of cigarettes
Prevalence studies of intermittent claudication have tended to throughout adult life. The Million Women Study of 1.3
find higher rates in men than women, but this difference is less million UK women aged 50 to 65 years recruited between
apparent in studies using ankle-brachial SBP index.40 1996 and 2001 and followed for 12 years, demonstrated that
Herrington et al Epidemiology of Atherosclerosis 539

Table 1. Selected Mortality Rates Among 34439 Men Born 1851 to 1930 and Observed 1951 to 2001 in the
British Doctors Study, by Current, Former, and Never Smokers
Age-Standardized Mortality Rate per 100000 Men
Cigarette Smokers Current (Cigarettes/d)
No of Deaths
Cause of Death (% of All Deaths) Never Former Current 114 1524 25
Lung cancer 1052 (4%) 17 68 249 131 233 417
COPD 640 (3%) 11 64 156 104 141 261
Ischemic heart disease 7628 (30%) 619 761 1001 910 1007 1111
Stroke 3307 (13%) 275 318 432 376 435 523
Other vascular disease 3052 (12%) 228 283 415 337 440 533
All cause (no of deaths) 25346 1938 (2917) 2415 (5354) 3540 (4680) 2934 (1450) 3479 (1725) 4534 (1505)
COPD indicates chronic obstructive pulmonary disease. Annual mortality rates are indirectly standardized for 5-year age group and time
period to the person-years distribution of the whole cohort. Other causes of death not shown. Created using data from Doll R et al.52

compared with never-smokers, current smokers (who had excretion =4.9 [standard deviation 1.7] grams per day).56
smoked on average 15 cigarettes a day since the age of 19) Outdoor temperature, in the absence of central heating, also
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were at 4 increased risk of IHD mortality (RR 4.5, 95% CI has been shown to be a strong determinant of blood pressure.57
4.24.8; 4458 deaths) and 3 increased risk of stroke mor- The first quantitative evidence for a link between hyper-
tality (RR 3.1, 95% CI 2.83.3; 2986 deaths).53 Other stud- tension and cardiovascular disease came from a report by the
ies have suggested that smoking increases the relative risk Actuarial Society of America in 1925.58 During the 1950s,
for PAD more than the relative risk for IHD.54 Consistent more evidence accumulated that hypertension increased the
with these findings was a 6 increased risk of a death at- risk of death, particularly from cardiovascular diseases,59,60 and
tributed to aortic aneurysm (RR 6.3, 95% CI 5.27.7; 494 in 1988, the Multiple Risk Factor Intervention Trial (MRFIT)
deaths) or intestinal ischemia (RR 5.6, 95% CI 4.37.3; 274 study of 360000 US men demonstrated a graded relationship
deaths) among women smokers in the Million Women Study. between mortality and blood pressure, with no evidence of a
As among men, much of these excess risks were avoided by threshold down to an SBP of at least 120 mmHg.61 This find-
quitting at around age 40 years (and most by stopping ear- ing was corroborated in 1990 in an overview involving 420000
lier; Figure 3).53 participants from 9 prospective observational studies, which
demonstrated a continuous relationship between diastolic
Blood Pressure and Atherosclerosis blood pressure and both IHD and stroke down to at least 70
The principal determinants of high blood pressure seem to be mmHg.62 This study was the first study to account for random
age (SBP increases by 7 mmHg per decade of adult life), error in blood pressure measurement, which had previously
general adiposity (SBP increases by 8 mmHg per 5 kg/m2 led to a systematic underestimation of the strength of any re-
increase in body mass index [BMI]),55 and salt intake (SBP lationship between blood pressure and disease risk (known as
increases by 1.7 mmHg per gram of ingested sodium per day: the regression dilution bias). In 2002, the Prospective Studies
average global sodium intake estimated from urinary sodium Collaboration reported a meta-analysis involving one million

Figure 3. Nine-year relative risk for ex-smokers (n=328417) by age at stopping vs never smokers (n=619774) in the Million Women
Study. CI indicates confidence interval. Reproduced from Pirie et al53 with permission from the publisher. Copyright, Elsevier.
540Circulation ResearchFebruary 19, 2016

participants from 61 studies conducted mainly in Europe or related to differing diets across the world. Several different
North America (90%) involving 34000 IHD deaths and dietary patterns have been shown to be associated with cardio-
12000 stroke deaths. After close attention to statistical detail vascular health benefits73: these patterns vary in terms of fat
(including both correction for regression dilution bias and content affecting lipid levels, but also by other factors, such
adjustment for age at risk), a continuous log-linear associa- as intake of salt, alcohol, refined sugars, fiber, nuts, and fish
tion between both usual SBP and diastolic blood pressure and which may affect other CV risk factors.
both IHD and stroke was observed.63 The Prospective Studies Blood cholesterol (specifically low-density lipopro-
Collaboration estimated that on average, each 20 mmHg high- tein [LDL] cholesterol) is an accepted causal risk factor for
er usual SBP and 10 mmHg higher diastolic blood pressure IHD.64,74 Individual participant data from large numbers of
was associated with an approximate doubling of vascular risk, prospective observational studies from around the world
with no lower limit down to at least 115/75 mmHg (Figure 4). have been brought together in collaborative meta-analyses
Mendelian randomization (MR) experiments have suggested to quantify the relationship between various lipid measures
that these observations are causal for both IHD66 and stroke,67 (total cholesterol, high-density lipoprotein [HDL] cholesterol,
and blood pressure lowering trials have confirmed that this non-HDL cholesterol, triglycerides, and apolipoproteins) and
risk is reversible: for each 5 mmHg SBP reduction, cardiovas- risk of ischemic vascular disease.64,75,76 These meta-analyses
cular risk is reduced by 17% (hazard ratio [HR] 0.83, 95% CI demonstrated continuous positive log-linear associations
0.760.90), with little difference by antihypertensive medica- between usual blood levels of either total or non-HDL cho-
tion class.68 lesterol (a surrogate for LDL cholesterol) and the IHD risk.
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Conversely, there was a clear inverse relationship with HDL

Blood Lipids and Atherosclerosis cholesterol.64,75,76
The principal environmental determinants of blood cholesterol
levels are dietary intake of saturated fat, polyunsaturated fat, NonHDL Cholesterol and Atherosclerosis
and cholesterol,6971 although blood cholesterol concentrations The Prospective Studies Collaboration demonstrated a strong
are also affected by reduced energy intake/weight loss, genet- positive relationship for both total and non-HDL cholesterol
ic, and other factors.72 Some of the international variation in with IHD mortality that was stronger in younger adults so that
atherosclerotic disease rates as described below is, therefore, at ages 50 to 59, each 1 mmol/L (38.7 mg/dL) lower usual

Figure 4. Ischemic heart disease (IHD) and total stroke mortality rates at ages 40 to 79 vs body mass index, systolic blood
pressure, and total cholesterol floated to match average 2010 United States mortality rates. Uses relative risks from Prospective
Study Collaboration.6365 Adjusted for age at risk, smoking, study, and sex at ages 40 to 79 then multiplied by a common factor (ie,
floated) to make the inverse variance weighted average match the US 2010 annual mortality rate for ischemic heart disease and total
stroke. All analyses excluded participant with chronic disease or missing covariates at baseline, and body mass index results excluded
deaths in the first 5 years. CI indicates confidence interval.
Herrington et al Epidemiology of Atherosclerosis 541

total cholesterol is associated with 42% lower IHD risk (HR Other Lipids and Atherosclerosis
0.58, 95% CI 0.560.61; 5561 deaths) compared with 28% The evidence for a causal role of HDL cholesterol in athero-
at ages 60 to 69 (HR 0.72, 95% CI 0.690.74; 10419 deaths) sclerosis is more equivocal. Prospective observational stud-
and 18% at ages 70 to 79 (HR 0.82, 95% CI 0.800.85; 10829 ies have shown strong inverse associations between HDL
deaths).64 However, the Prospective Studies Collaboration cholesterol and risk of IHD,64,75 which was attenuated some-
found that the association between total cholesterol and isch- what with adjustment for other lipid measures, but remained
emic stroke mortality was substantially weaker than its as- independently associated with IHD risk (HR per 0.39 mmol/L
sociation with IHD (Figure 4).64 A subsequent meta-analysis [15 mg/dL] lower HDL cholesterol =1.28, 95% CI 1.221.35;
which combined information on fatal and nonfatal ischemic 12785 events; Figure 5). However, more recent MR experi-
strokes demonstrated a positive association with non-HDL ments suggest that this association may not be causal,78 and
cholesterol (HR per 1.1 mmol/L lower non-HDL =0.89, 95% the only large randomized trial to assess a treatment that in-
CI 0.830.96; 2534 ischemic strokes; Figure 5), although this creased HDL cholesterol by 25% without any change in LDL
cholesterol (using the cholesterol-ester transfer protein inhibi-
was considerably (4) weaker than the association with IHD.75
tor dalcetrapib) was stopped early for futility.79
Twenty-one statin versus control trials, with median fol-
Observational studies also show continuous positive as-
low-up of 4.8 years, have demonstrated that LDL cholesterol
sociations between blood triglyceride concentrations and IHD
is a key cause of atherosclerosis. Each 1.0 mmol/L (38.7 mg/
risk, but these largely disappear when adjusted for other risk
dL) reduction in LDL cholesterol reduces risk of major coro- factors, including HDL and nonHDL cholesterol (Figure 5).
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nary events by a quarter (RR 0.76, 95% CI 0.730.79; 7919 This finding is consistent with triglycerides being associated
events) and ischemic stroke by about one fifth (RR 0.80, 95% with vascular risk through the cholesterol content of remnant
CI 0.740.86; 2212 strokes).74 MR experiments suggest that particles.80 Recent genetic studies also support a causal role of
life-long inherited exposure to lower LDL cholesterol may be triglyceride-mediated pathways in IHD.81
associated with 3 lower IHD risk than that estimated by the Lipoprotein(a) (Lp[a]) is an LDL cholesterol particle at-
statin trials (RR per genetic score determined 1.0 mmol/L low- tached to an apolipoprotein(a) molecule (of unknown function)
er LDL cholesterol 0.46, 95% CI 0.400.51).77 Well-powered which includes a genetically determined number of kringle IV
MR experiments of the effects of inherited lipid profiles on domains. The number of domain repeats in the LPA gene varies
ischemic stroke risk are awaited. widely within, and between, ethnic groups and encodes both

Triglyceride HDL-C Non-HDL-C

3.5 3.5 3.5

3.0 3.0 3.0

Hazard ratio and 95% CI

2.5 2.5 2.5

2.0 2.0 2.0

Ischemic heart
1.5 1.5 1.5

Adjusted for age and sex only

1.0 1.0 1.0 Further adjusted for several risk factors*

0.8 0.8 0.8

70 100 150 200 250 30 40 50 60 70 80 110 130 150 170 190 210 230
Usual triglyceride (mg/dL) Usual HDL-C (mg/dL) Usual non-HDL-C (mg/dL)

3.5 3.5 3.5

3.0 3.0 3.0

Hazard ratio and 95% CI

2.5 2.5 2.5

2.0 2.0 2.0

Ischemic stroke
1.5 1.5 1.5

1.0 1.0 1.0

0.8 0.8 0.8

70 100 150 200 250 30 40 50 60 70 80 110 130 150 170 190 210 230
Usual triglyceride (mg/dL) Usual HDL-C (mg/dL) Usual non-HDL-C (mg/dL)

Figure 5. Hazards of ischemic heart disease (n=12785) and ischemic stroke (n=2534) across quartiles of HDL and non-HDL
cholesterol. *Further adjustment included systolic blood pressure, smoking history, history of diabetes mellitus, body mass index, and
adjusted for other lipids shown. To convert mg/dL to mmol/L, divide by 38.7 for HDL and non-HDL and by 88.6 for triglycerides. HDL
indicates high-density lipoprotein cholesterol. Reproduced from Di Angelantonio et al75 with permission, the American Heart Association:
Emerging Risk Factors Collaboration.
542Circulation ResearchFebruary 19, 2016

apolipoprotein(a) isoform size and Lp(a) levels (which are in- the risk.99 CKD usually causes hypertension and is associated
versely correlated). Lp(a) has been recognized to be a risk fac- with an atherogenic dyslipidemia characterized by high tri-
tor for IHD for some time, but it has taken recent MR studies glycerides, low HDL cholesterol, and an increased proportion
to support causal hypotheses.82,83 One-in-six Europeans carry of LDL particles which are small and oxidized.100 CKD also
LPA variants which are associated with about a 50% increased causes dysregulation of calcium-phosphate metabolism (col-
chance of developing IHD.82 The relationship between Lp(a) lectively referred to as CKDmineral bone disease), and the
and stroke has been harder to elucidate, but pooling-adjusted high serum phosphate that results has been shown to increase
RRs from 6 prospective studies found that high versus low vascular risk by 10% per 0.3 mmol/L higher phosphate (HR
Lp(a) levels were associated with an increased risk of ischemic 1.10, 95% CI 1.061.13).101 Markers of CKDmineral bone
stroke.83 There is also emerging evidence linking Lp(a) to PAD disease are associated with accelerated calcification of both
risk.84 Statins have little or no effect on Lp(a) levels, but newer the vascular intima (resulting in increased amounts of calcium
lipid-modifying agents, including proprotein convertase subtil- in atherosclerotic plaques102) and the vascular media (leading
isin/kexin type 9 and cholesterol-ester transfer protein inhibi- to increased vascular stiffness),103 which helps explain why
tors, do modestly reduce levels.85,86 both atherosclerotic vascular risk and nonatherosclerotic vas-
cular disease (eg, heart failure and arrhythmias) become more
Diabetes Mellitus and Atherosclerosis common in advanced CKD.104
In 2011, diabetes mellitus (diagnosed or not) affected 14% of
the US adult population (including one third of those over the Adiposity and Atherosclerotic Risk Factors
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age of 65).87 Diabetes mellitus is a well-recognized cause of Although there has been success at reducing smoking rates in
microvascular disease in the eye and kidney, but chronic raised some parts of the world,105 globally obesity rates have been
blood glucose also promotes a combination of abnormal condi- rising for the last 3 decades. Since 1980, the prevalence of
tions, including a characteristic dyslipidemia, high blood pres- obesity (currently defined as a BMI 30 kg/m2) among US
sure, vascular inflammation, and a prothrombotic tendency,88 adults has increased from 1 in 7 to 1 in 3.106 Globally, average
which are all considered to be atherogenic. Large-scale meta- BMI has increased by 0.5 kg/m2 each decade, slightly faster
analysis of prospective observational studies recruited mainly
among women than men,107 and it is currently estimated that
from high-income countries during the second half of the 20th
600 million people (11% of adult men and 15% of adult
century quantified that diabetes mellitus increased vascular
women) are obese.108 This obesity epidemic is affecting many
mortality rates by a factor of 2 (age- and sex-adjusted HR 2.4,
high- and middle-income regions and, particularly, countries
95% CI 2.22.6; 28354 deaths).89 This hazard appeared similar
in the North, Central and South Americas, the Middle East,
when IHD, ischemic stroke, and PAD deaths were considered
Australasia, and Pacific Islands.106,108
separately.90,91 The association between high blood glucose and
Prospective observational studies, randomized trials, and
IHD was also demonstrated to start below the threshold re-
MR experiments have demonstrated that adiposity increases
quired to diagnose diabetes mellitus: compared with lower fast-
many of the modifiable atherosclerotic risk factors described
ing glucose concentrations, a glucose of 6.1 but <7 mmol/L
was associated with 17% higher risk of IHD (HR 1.17, 95% earlier, including diabetes mellitus,65,109111 high blood pres-
CI 1.081.26; 1011 deaths).90 Although initial MR experiments sure,55,65,111113 dyslipidemia,64 and CKD114 (Table 2). Obesity
associating genetic risk of type 2 diabetes mellitus to IHD risk may also affect levels of physical activity, in addition to being
were equivocal,92 more recent studies support causal asser- determined by them.116 Physical activity is inversely associ-
tions. Each genetically determined 1% increase in HbA1c is ated with both stroke117119 and IHD120122; however, the lack of
associated with about a 50% increased risk of IHD (odds ra- consistency in how activity has been defined and measured in
tio 1.53, 95% CI 1.142.05), similar in size to observational different studies means there is limited evidence on the shape
associations (although there is substantial uncertainty in both or strength of these relationships.122
these estimates).93 Meta-analysis,94,95 and extended post-trial A role for raised BMI in causing diabetes mellitus is
follow-up,96,97 of the randomized glycemic control trials also inferred from the following observations: first, the age-
suggest that these associations are, to some extent, reversible. adjusted US prevalence of diagnosed diabetes mellitus in
Aggregated results quantified that lowering HbA1c by an av- adults has doubled since 1980, increasing from 3% to 6%,109
erage of 0.9%94 reduced coronary risk by about 15% (RR for mirroring the doubling in prevalence of obesity.106 Second,
IHD death 0.85, 95% CI 0.770.93; 2318 events), whereas the prospective observational studies have demonstrated that
effects on ischemic stroke remain more uncertain.95 diabetes mellitus prevalence increases across the BMI range
(Table 2).65,110 Third, MR experiments have found that even
Kidney Disease and Atherosclerosis relatively small genetically determined increases in BMI
Reduced glomerular filtration rate defines CKD and is identi- significantly increase the chances of developing diabetes
fied in at least 5% of the US population.98 More severe CKD (ie, mellitus.111,113 Fourth, randomized evidence suggests that
lower glomerular filtration rate) is associated with increased the risk posed by adiposity is reversible: in the Diabetes
vascular risk: compared with those with normal renal func- Prevention Program (DPP) trial, allocation to a 6-month
tion, an estimated glomerular filtration rate between 45 and 60 intensive lifestyle intervention (through calorie restriction
mL/min per 1.73 m2 is associated with at least 40% increased and moderate physical activity) led to substantially great-
risk of a vascular death, and an estimated glomerular filtra- er weight loss compared with those allocated to standard
tion rate below 30 mL/min per 1.73 m2 results in at least 3 lifestyle advice and reduced the risk of developing diabetes
Herrington et al Epidemiology of Atherosclerosis 543

Table 2. Selected Studies of the Effect of Body Mass Index on Diabetes Mellitus and Blood Pressure
Study Type Study Population Exposure Result (95% confidence interval)
Diabetes mellitus
Cross-sectional observations PSC65 894576 apparently healthy Measured BMI Odds ratio for type 2 diabetes mellitus:
adults (57 studies) 1.07 (1.071.08) per +1 kg/m2
Prospective observations APCSC110 154989 adults from Asia and Measured BMI Hazard ratio for new diabetes mellitus:
Pacific regions (27 studies) 1.17 (1.141.20) per +1 kg/m2
Mendelian randomization Holmes et al113 4407 cases from 31844 14 SNP genetic risk score Odds ratio for type 2 diabetes mellitus:
(7 studies) 1.27 (1.181.36) per +1 kg/m2
Mendelian randomization ENGAGE111 20804 cases and 139543 FTO gene polymorphism Odds ratio for type 2 diabetes mellitus (ever):
controls (28 studies) 1.37 (1.231.51) per +1 kg/m2
Randomized trial DPP115 3234 adults with glucose Intensive lifestyle Odds ratio for incident diabetes mellitus:
intolerance intervention versus control 0.42 (0.340.52) per 2.2 kg/m2;
0.67 (0.610.74) per 1 kg/m2*
Blood pressure, mmHg
Cross-sectional observations Kadoorie China 512891 Chinese adults Measured BMI SBP: +1.5 (1.41.5) per +1 kg/m2
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Mendelian randomization Holmes et al113 SBP: 30136 (6 studies)/ 14 SNP genetic risk score SBP: +0.70 (0.241.16) per +1 kg/m2;
DBP: 30137 (6 studies) DBP: +0.28 (0.030.52) per +1 kg/m2
Mendelian randomization ENGAGE111 SBP: 147644 (30 studies)/ FTO gene polymorphism SBP: +0.89 (0.481.31) per +1 kg/m2;
DBP: 130380 (29 studies) DBP: +0.49 (0.190.79) per +1 kg/m2
Randomized trial AHEAD112,113 5145 overweight or obese Intensive lifestyle SBP: 1.6 (2.0 to 1.1) per 1 kg/m2;
diabetes mellitus patients intervention versus control DBP: 0.1 (0.3 to 0.2) per 1 kg/m2
AHEAD indicates Action for Health in Diabetes; APCSC, Asia-Pacific Cohort Studies Collaboration; BMI, body mass index; DBP, diastolic blood pressure; DPP, Diabetes
Prevention Program; ENGAGE, European Network for Genetic and Genomic Epidemiology; FTO, fat mass- and obesity-associated; PSC, Prospective Studies Collaboration;
SBP, systolic blood pressure; and SNP, single nucleotide polymorphism.

mellitus substantially (RR per 1 kg/m2 lower BMI estimated decreased from 22% in 1950 to 6% in 2010. Most low- and
at 0.67, 0.610.74; Table 2).115 middle-income countries have also reported declines in mortal-
In high-income countries, the causal associations between ity from stroke over the last few decades, but mortality trends
BMI and established risk factors translate into clear observa- from IHD have been more varied, with some countries report-
tional associations between high BMI and mortality from IHD ing declines and others reporting increases (particularly those
and ischemic stroke. A meta-analysis of prospective observa- in Eastern Europe and Asia). Many major modifiable risk fac-
tional studies involving 0.9 million adults has demonstrated a tors for atherosclerosis have been identified, and the causal
roughly log-linear relationship from a BMI of 25 kg/m2, with relevance of several risk factors is now well established (in-
each 1 kg/m2 increase above this level associated with about cluding, but not limited to, smoking, adiposity, blood pressure,
an 8% increase in IHD mortality (HR per 1 kg/m2 1.08, 95% blood cholesterol, and diabetes mellitus). Widespread changes
CI 1.061.09; 10783 deaths) and stroke mortality (HR per 1 in health behaviors and use of treatments for these risk factors
kg/m2 1.08, 95% CI 1.061.10; 3164 deaths; with similar re- are responsible for some of the dramatic declines in vascular
sults when major stroke subtypes were considered separate- mortality in high-income countries. In order that these declines
ly65,76) and a 9% increase in PAD risk (HR per 1 kg/m2 1.08, continue, and are mirrored in less wealthy nations, increased
95% CI 1.071.09). Applying these hazards to a uniformly efforts are needed to tackle these major risk factors, particu-
age-standardized death rate for persons aged 40 to 79 years larly smoking and the emerging obesity epidemic.
from the United States in 2010, an increase in BMI from 25
to 40 kg/m2 (ie, from ideal to 60% over ideal body weight) is Sources of Funding
estimated to increase IHD death rates by nearly 3 (from 120 CTSU, University of Oxford receives core funding from the British
to 317 per 100000 per year), with the death rates for stroke es- Heart Foundation, Medical Research Council (UK), and Cancer
timated to increase a similar amount (from 37 to 97; Figure 4). Research UK.

Conclusions Disclosures
Atherosclerosis is a leading cause of vascular disease world- None.
wide. Its major clinical manifestations include IHD, ischemic
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Epidemiology of Atherosclerosis and the Potential to Reduce the Global Burden of
Atherothrombotic Disease
William Herrington, Ben Lacey, Paul Sherliker, Jane Armitage and Sarah Lewington
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Circ Res. 2016;118:535-546

doi: 10.1161/CIRCRESAHA.115.307611
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