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xi
Contributors
Yousif Ahmad, MD
Research Fellow
University of Birmingham Centre for
Cardiovascular Sciences
City Hospital
Birmingham, United Kingdom
Mark J. Alberts, MD, FAHA,
FANA
Vice-Chair of Clinical Affairs
Professor of Neurology
Department of Neurology and
Neurotherapeutics
UT Southwestern Medical Center
Dallas, Texas
Amjad AlMahameed, MD, MPH
Clinical Instructor, Interventional
Cardiology
Division of Cardiovascular Medicine
Beth Israel Deaconess Medical Center
Harvard Medical School
Boston, Massachusetts
George Bakris, MD
Director, ASH Comprehensive
Hypertension Center
Professor, Department of Medicine
The University of Chicago Medicine
Chicago, Illinois
Roger S. Blumenthal, MD
Director, Johns Hopkins Ciccarone
Center for the Prevention of
Heart Disease
Professor of Medicine
Johns Hopkins University School of
Medicine
Baltimore, Maryland
Alexandros Briasoulis, MD
Clinical Fellow in Hypertension
ASH Comprehensive Hypertension
Center, Department of Medicine
The University of Chicago Medicine
Chicago, IL
Patrick Collier, MB, PhD
Clinical Fellow, Advanced Multi-
modality Cardiac Imaging
Robert and Suzanne Tomsich
Department of Cardiovascular
Medicine
Cleveland Clinic
Cleveland, Ohio
Flavio de Souza Brito, MD
Clinical Research Fellow
Division of Cardiology
Duke University Medical Center
Duke Clinical Research Institute
Durham, North Carolina
Basem Elbarouni, MD
Division of Cardiology
Department of Medicine
University of Toronto
Toronto, Ontario
Brian Griffi n, MD, FACC
The John and Rosemary Brown
Endowed Chair
Section Head of Cardiovascular
Imaging
Robert and Suzanne Tomsich
Department of Cardiovascular
Medicine
Cleveland Clinic
Cleveland, Ohio
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xii
CONTRIBUTORS
Sangeeta Kashyap, MD
Assistant Professor of Medicine
Cleveland Clinic Lerner College of
Medicine
Department of Endocrinology,
Diabetes and Metabolism
Cleveland Clinic
Cleveland, Ohio
Gregory Y. H. Lip, MD
Consultant Cardiologist and
Professor of Cardiovascular
Medicine
Director, Haemostasis, Thrombosis
& Vascular Biology Unit
University of Birmingham Centre for
Cardiovascular Sciences
City Hospital
Birmingham, United Kingdom
Renato D. Lopes, MD,
MHS, PhD
Associate Professor of Medicine
Division of Cardiology
Duke University Medical Center
Duke Clinical Research Institute
Durham, North Carolina
Seth S. Martin, MD
Cardiology Fellow
Johns Hopkins Ciccarone Center for
the Prevention of Heart Disease
Johns Hopkins University School of
Medicine
Baltimore, Maryland
Michelle L. O’Donoghue,
MD, MPH
Associate Physician, Cardiovascular
Division
Brigham and Women’s Hospital
Assistant Professor of Medicine
Harvard Medical School
Boston, Massachusetts
Chintan Patel, MD, MPH
Resident, Internal Medicine, St. Agnes
Hospital , Baltimore, Maryland
Johns Hopkins Ciccarone Center for
the Prevention of Heart Disease
Baltimore, Maryland
Matthew T. Roe, MD, MHS
Associate Professor of Medicine
Division of Cardiology
Duke University Medical Center
Duke Clinical Research Institute
Durham, North Carolina
Amy Sarma, MD
Resident, Internal Medicine
Department of Medicine
Brigham and Women’s Hospital
Boston, Massachusetts
Andrew T. Yan, MD
Associate Professor
Division of Cardiology
Department of Medicine
St. Michael’s Hospital University
of Toronto
Toronto, Ontario
Kathleen Yip, BS
Cleveland Clinic Lerner College of
Medicine
Cleveland, Ohio
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11
Chapter 1
Atherothrombosis
Basem Elbarouni and Andrew T. Yan
Introduction
Atherosclerosis is a systemic disease affecting large- and medium-sized arter-
ies, characterized by focal or diffuse luminal narrowing due to the deposition
of lipid and fi brous material (plaque) in the vessel walls. Plaque formation,
originally thought to refl ect merely a cholesterol storage disorder, is medi-
ated through complex pathways, with endothelial dysfunction and systemic
infl ammation playing major roles.
1
Atherothrombosis is characterized by acute
disruption of atherosclerotic plaque leading to superimposed thrombus forma-
tion. This leads to acute narrowing or occlusion of the arterial lumen, causing
acute reduction or cessation of blood fl ow to the supplied organ. Clinical mani-
festations can also result from distal embolization of the newly formed throm-
bus (e.g., stroke due to carotid artery atherothrombosis). Clinical syndromes
of atherothrombosis vary depending on the vascular tree involved (Fig. 1.1). In
particular, vascular beds at risk include the coronary arteries, cerebrovascular
circulation, and peripheral circulation.
The acute coronary syndrome (ACS) is the most common clinical manifes-
tation of atherothrombosis. The spectrum of ACS, including unstable angina,
non-ST-elevation myocardial infarction, ST-elevation myocardial infarction, and
sudden cardiac death, depends on the degree of lumen occlusion and the myo-
cardium at risk.
2
Atherothrombosis is also a major cause of ischemic strokes
and transient ischemic attacks (TIAs). The affected vessel could be either
intracranial, with clinical manifestations secondary to acute artery occlusion, or
extracranial, with symptoms occurring due to distal embolization of the newly
formed thrombus. Atherothrombosis in the peripheral circulation is also a
major cause of acute limb ischemia, defi ned as a sudden decrease in limb perfu-
sion potentially threatening limb viability.
3
Pathophysiology
Atherosclerosis is a lifelong pathological process that primarily affects the
intimal layer of large and medium-sized arteries. Early pathological changes,
including intimal thickening and fatty streaks, can be seen as early as in child-
hood.
4
As lesions progress with age, fi brous atheromatous plaques form that
can lead to narrowing of the vascular lumen, causing a gradual decline in blood
fl ow to supplied organs. For example, lesions in the coronary circulation can
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2
CHAPTER 1 Atherothrombosis
cause stable angina, while disease in the peripheral circulation can lead to clau-
dication. Vulnerable plaques, also called thin-cap atheromas, are lesions with
a high risk of acute disruption. Histologically, they consist of a large necrotic
lipid core separated from the vessel lumen by a thin fi brous cap. The fi brous
cap has a paucity of smooth muscle cells and is heavily infi ltrated by mac-
rophages (Fig. 1.2).
5
Atherothrombosis occurs when plaque disruption occurs, leading to
superimposed acute thrombus formation. Histologically, the most common
form of atherothrombosis is plaque rupture, in which there is disruption of
the fi brous cap, leading to direct contact between the intraluminal blood
and the lipid-rich core, triggering the clotting cascade and leading to throm-
bus formation (Fig. 1.3). The second most common form of atherothrom-
bosis is plaque erosion, in which there is thrombus formation over a fi brous
cap with no histological evidence of plaque rupture.
6
Calcifi ed nodules are
Stroke
Abdominal aortic
aneurysm
Acute coronary
syndromes:
Stable coronary
artery disease
Atrial Fibrillation
Angioplasty
Bare metal stent
Drug eluting stent
Coronary bypass
surgery
• ST-elevation myocardial
infarction
• Non-ST-elevation
myocardial infarction
• Unstable angina
Transient ischemic attack
Intracranial stenosis
Renal artery stenosis
Renal artery stenting
Peripheral arterial disease
Acute limb ischemia
Claudication
Amputation
Endovascular stenting
Peripheral bypass
Abnormal ankle brachial
index
Carotid artery stenosis
Carotid endarterectomy
Carotid stenting
Figure 1.1 Major clinical manifestations of atherothrombosis. (From Meadows TA,
Bhatt DL. Clinical aspects of platelet inhibitors and thrombus formation. Circ Res
2007; 100 (9):1261–1275.)
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CHAPTER 1 Atherothrombosis
Pathologic intimal
thickening
Fibrous cap atheroma
NC
EL
Figure 1.2 Pathological intimal thickening versus atheroma. EL, elastic lamina; NC,
necrotic core. (From Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons
from sudden coronary death: a comprehensive morphological classifi cation scheme for
atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000; 20 (5):1262–1275.)
Erosion
Rupture Calcified nodule
Figure 1.3 Atherosclerotic lesions with luminal thrombi. FC, fi brous cap; NC necrotic
core; Th, thrombus. (From Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM.
Lessons from sudden coronary death: a comprehensive morphological classifi cation
scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000; 20 (5):1262–1275.)
the least common cause of atherothrombosis. These lesions are formed
mainly of calcifi ed nodules with little or no lipid core. The calcifi ed nodule
erodes into the lumen and comes into contact with the bloodstream, causing
thrombosis.
7
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CHAPTER 1 Atherothrombosis
Epidemiology
Since the early 20th century, rising living standards, along with unprecedented
advances in medical knowledge and health care, including improved prevention
and treatment of infectious disease, have led to a signifi cant increase in life
expectancy. For example, life expectancy at birth has increased globally from
46 years in 1950 to 68 years in 2009.
8,9
This has led to a signifi cant global change
in the causes of death, with a shift from predominantly infectious diseases and
nutritional defi ciencies to chronic non-communicable diseases, such as cardio-
vascular disease and cancer. This shift has been dubbed the “epidemiologic
transition.”
9
Different societies can be considered to be at different stages of
this transition: developed countries are at an advanced stage of this transition,
while developing countries are undergoing the early stages of this transition.
10
As a consequence of this shift, cardiovascular disease, including atherothrom-
bosis, is the most common cause of death globally.
In developed countries, atherothrombosis is a major cause of morbidity and
mortality. For example, in the United States, the prevalence of coronary heart
disease (CHD) among the adult population is estimated at 7 percent, with close
to half (3.1 percent) of these patients having suffered a myocardial infarction.
The prevalence of stroke among the same population is 3 percent. Each year,
an estimated 785,000 Americans will have a new ACS, while 470,000 will have a
recurrent attack. An estimated 795,000 people will experience a new or recur-
rent stroke.
11
Projections show that by 2030 an additional 8 million people could
have CHD, a 16.6 percent increase in prevalence from 2010.
12
In 2008, CHD
caused 1 of every 6 deaths, while stroke caused 1 in 18 deaths.
11
Peripheral
artery disease (PAD) affects an estimated 12 to 20 percent of Americans more
than 65 years of age.
13
Despite the high prevalence and incidence of atherosclerosis, there has been
a signifi cant decline in mortality rates attributable to CHD. In the Framingham
Heart Study, there was a 59 percent decline in CHD deaths from 1950–1969
to 1990–1999. This decline is true for both sudden and non-sudden cardiac
death.
14
This trend in declining mortality has continued over the last decade,
with a 36 percent decline in the rates of death attributable to cardiovascular
disease from 1998 to 2008. Globally, similar declines in cardiovascular and cere-
brovascular mortality were seen in industrialized countries, including Canada,
Australia, Japan, and Western Europe.
15
This decline in mortality is probably
due to a combination of improvements in early and long-term management
strategies for patients with atherothrombosis, and the reduction and improved
control of atherothrombosis risk factors.
16
This could be considered akin to a
later stage of the epidemiologic transition, in which adoption of healthier life-
style habits, better control of risk factors, and improved secondary prevention
lead to a reduction in mortality rates.
Cardiovascular disease is also a major health burden in developing coun-
tries. In 2004, approximately 80 percent of the 16.7 million deaths attributed to
cardiovascular disease occurred in low- and middle-income countries.
17
These
countries could be considered at earlier stages of the epidemiologic transition,
where increasing life expectancy and “westernization” of lifestyle habits, includ-
ing decreasing physical activity, urbanization, dietary changes, and increasing
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CHAPTER 1 Atherothrombosis
rates of tobacco use combine, leading to an epidemic of cardiovascular disease.
Unfortunately, contrary to the trends seen in industrialized countries, the mor-
tality rates from cardiovascular disease in developing countries continue to rise.
For example, China has witnessed a doubling of the number of deaths attrib-
uted to cardiovascular disease over the past two decades.
18
It is estimated that
disability-adjusted life years lost attributable to cardiovascular disease between
1990 and 2020 will rise by 55 percent in the developing countries, compared
to a 14.3 percent reduction in industrialized countries.
19
This indicates that the
future burden of cardiovascular disease will be shouldered mainly by emerging
economies.
Another disturbing observation is that, in developing countries, deaths due
to cardiovascular disease tend to occur a decade or two earlier than they do
in Western countries. Nearly half of cardiovascular deaths in developing coun-
tries occur before 70 years of age, compared to only a fi fth in industrialized
countries.
20
The potential impact of cardiovascular disease burden falling mainly
on society’s “breadwinners” can lead to major economic constraints at both
individual and societal levels.
Cardiovascular risk factors
Several risk factors are known to increase the risk of atherosclerosis and
atherothrombosis (Table 1.1). While the majority of studies identifying these
risk factors focus on coronary heart disease, atherosclerosis is a systemic dis-
ease, and there is general acceptance that they promote atherosclerosis in all
vascular beds. Risk factors can be divided into non-modifi able, such as age, gen-
der, and family history, and modifi able, such as smoking, diabetes, dyslipidemia,
and hypertension.
Age is a major risk factor for atherothrombosis, with the majority of heart
attacks in men occurring after the fourth decade.
21
The age-adjusted risk of
atherothrombosis is higher in men than in women, although this difference dis-
appears after the age of 75. On average, there is a 10-year delay in the onset
of atherothrombosis in women compared to men, and this difference holds
widely across the globe.
22
An interesting fi nding, however, is that modifi able risk
Table 1.1 Major Atherothrombosis Risk Factors
Non-modifi able Risk Factors
• Age
• Gender
• Family history of premature coronary artery disease
Modifi able Risk Factors
• Hypertension
• Diabetes
• Dyslipidemia
• Smoking
• Obesity
• Chronic kidney disease
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CHAPTER 1 Atherothrombosis
factors seem to operate with greater power among women. For example, the
incidence of myocardial infarction is increased six-fold in women and three-fold
in men who smoke at least 20 cigarettes per day compared to non-smokers.
23
A family history of premature cardiovascular events in a fi rst-degree rela-
tive has been shown to be associated with an increased risk of CHD, with
most cohorts showing a 40 to 60 percent increase in risk.
24,25
While variable
defi nitions of premature coronary artery disease are used in different studies, a
commonly used defi nition is CHD or sudden death in a fi rst-degree male rela-
tive younger than 55 years of age or a fi rst-degree female relative younger than
65 years of age.
26
The risk of atherothrombotic events seems to be higher when
more than one fi rst-degree relative has a positive history of premature heart
disease.
27
When assessing patients, however, it is important to note that self-
reported family history can be inaccurate, which might reduce its usefulness in
patient risk assessment.
28
Diabetes is a major risk factor for atherothrombosis. Patients with diabetes
and no prior myocardial infarction have as high a risk of cardiovascular mortal-
ity as nondiabetic patients with prior myocardial infarction.
29,30
As such, major
guidelines recommend classifying diabetes as a CHD equivalent.
26,31
Hemoglobin
A1c, which refl ects average blood glucose levels over a period of 3 months, is
a useful indicator of diabetes control and has been shown to be a predictor
of cardiovascular events.
32
When compared to conventional glucose control,
intensive lowering of blood glucose led to a signifi cant reduction in rates of
myocardial infarctions, albeit with no impact on all-cause mortality.
33
Hypertension is also a major risk factor for cardiovascular disease. In the
INTERHEART study, hypertension accounted for 18 percent of the popula-
tion-attributable risk of a fi rst myocardial infarction.
22
The association of blood
pressure levels with cardiovascular events seems to be continuous, with a pro-
gressive increase in risk with incremental increases in blood pressure above
a threshold of 115/75 mmHg.
34
In a meta-analysis of trials of blood pressure
lowering using pharmacologic strategies, a 10-mmHg systolic and a 5-mmHg
diastolic reduction in blood pressure was estimated to reduce the risk of stroke
by 38 percent and the risk of coronary disease by 16 percent, regardless of the
drug class used.
35
There is a clear relationship between serum cholesterol levels and cardio-
vascular risk, established by several epidemiologic studies.
36–38
The causal role
of cholesterol in CHD is corroborated by clinical trials that demonstrate reduc-
tion of cardiovascular death with lowering cholesterol levels.
37,39
A high level
of low-density lipoprotein (LDL) cholesterol, a fraction of total cholesterol,
is a particularly important risk factor for atherosclerosis
40
and is the primary
target of lipid-lowering strategies.
26,31
On the other hand, high-density lipopro-
tein (HDL), generally referred to as “good” cholesterol, is cardioprotective,
with HDL levels inversely related to cardiovascular events.
41,42
Unfortunately,
despite the well-documented protective effects, attempts to raise HDL with
pharmacotherapy have met with disappointing results.
43,44
Cigarette smoking is a major cause of cardiovascular disease.
45,46
The popula-
tion attributable risk of smoking in the INTERHEART study was 35 percent,
double that for hypertension. Unfortunately, active smokers, even heavy smok-
ers, seem to underestimate the cardiovascular risks of smoking.
46
Smokers who
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7
CHAPTER 1 Atherothrombosis
had a myocardial infarction should be strongly encouraged to quit, as the risk
for recurrent events decreases to 50 percent by 1 year and to nonsmoker
levels in 2 years.
47
Obesity, defi ned by a body mass index of 30 kg/m
2
or greater, is associ-
ated with a higher CHD risk.
48
It is unclear whether this association is purely
due to the higher prevalence of classic cardiovascular risk factors among obese
patients,
49
or if obesity per se is an independent risk factor for atherosclero-
sis.
50
Nevertheless, from a clinical perspective, obesity should be a trigger for
global risk factor assessment and modifi cation, and weight reduction should be
strongly encouraged for obese patients.
Chronic kidney disease has been shown in several studies to be associ-
ated with atherosclerosis.
51
While the association of end-stage renal disease
and atherothrombotic events is well established,
52
even less severe forms of
chronic kidney disease are associated with an increased risk of atherothrombo-
sis.
52
Furthermore, chronic kidney disease is associated with more severe CHD
and with higher mortality after atherothrombotic events.
53
Patients with documented atherosclerosis or prior atherothrombosis in one
vascular bed are at high risk for future atherothrombotic events and should be
managed aggressively. The presence of PAD seems to be a particularly strong
predictor of disease in other territories, and is probably a marker of advanced
systemic atherosclerosis. Furthermore, the functional limitation of patients with
PAD might mean they do not exert themselves to the point of angina, lead-
ing to delayed presentations with extensive CHD.
54
In a prospective Canadian
study of ambulatory patients at high risk for or with established atherosclerosis,
patients with PAD were at increased risk of cardiovascular events at 6 months
compared to patients without PAD (7.3 percent versus 4.1 percent, p < 0.001).
PAD remained an independent predictor in multivariable analysis (odds ratio
1.54, 95 percent confi dence interval 1.18–2.01).
55
In the ARIC study, after adjust-
ing for age and risk factors, patients with an ankle–brachial index (ABI) of less
than 0.9 were two to three times more likely to develop coronary events dur-
ing the follow-up period. This association was particularly high among patients
of African descent.
56
A meta-analysis of studies of ABI in the general population
found that the 10-year cardiovascular mortality was 18.7 percent in men with
an ABI of less than 0.9, compared to 4.4 percent in men with a normal ABI.
Furthermore, after stratifying patients according to Framingham risk category,
patients with a low ABI (less than 0.9) had twice the 10-year event rate of
patients with a normal ABI in the same Framingham risk category.
57
Polyvascular disease
Given the systemic nature of atherosclerosis, it is not surprising that a signifi -
cant portion of patients with atherosclerosis develop disease in several vascular
territories. The prevalence of polyvascular disease (atherosclerosis in more
than one vascular bed) seems to be around 15 to 30 percent of all patients
with atherothrombosis.
58,59
Furthermore, patients with polyvascular disease are
at a much higher risk of atherothrombosis events compared to patients with
single-territory disease or patients with multiple risk factors but no documented
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