Overview of established risk factors for

cardiovascular disease
Author: Peter WF Wilson, MD
Section Editors: Joann G Elmore, MD, MPH, Christopher P Cannon, MD
Deputy Editors: Jane Givens, MD, MSCE, Nisha Parikh, MD, MPH

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2023. | This topic last updated: Jan 11, 2023.

INTRODUCTION

Cardiovascular disease (CVD) is common in the general population worldwide,

affecting the majority of adults past the age of 60 years. In 2012 and 2013, CVD
was estimated to result in 17.3 million deaths worldwide on an annual basis [1-3].
The 2019 Heart Disease and Stroke Statistics update of the American Heart
Association (AHA) reported that 48 percent of persons ≥20 years of age in the
United States have CVD (which includes coronary heart disease [CHD] [4], heart
failure, stroke, and hypertension) [4]. The reported prevalence increases with age
for both males and females.

As a diagnostic category, CVD includes four major areas:

● CHD, manifested by myocardial infarction (MI), angina pectoris, and coronary

death
● Cerebrovascular disease, manifested by stroke and transient ischemic attack
● Peripheral artery disease, manifested by intermittent claudication
● Aortic atherosclerosis and thoracic or abdominal aortic aneurysm

An overview of the established risk factors for CVD is presented here. An overview
of the possible emerging CVD risk factors, data supporting the importance of the
individual risk factors (eg, hyperlipidemia, hypertension, smoking), coronary risk
factors of particular importance in women and in young patients, and estimation
of coronary risk in an individual patient are discussed elsewhere. (See "Overview of
possible risk factors for cardiovascular disease" and "Low-density lipoprotein
cholesterol-lowering therapy in the primary prevention of cardiovascular disease"
and "Overview of hypertension in adults", section on 'Treatment' and "Overview of
atherosclerotic cardiovascular risk factors in females" and "Coronary artery
disease and myocardial infarction in young people" and "Atherosclerotic
cardiovascular disease risk assessment for primary prevention in adults: Our
approach" and "Cardiovascular disease risk assessment for primary prevention:
Risk calculators".)

EPIDEMIOLOGY

Lifetime risk of overall cardiovascular disease (CVD) approaches 50 percent for

persons age 30 years without known CVD [5]. Coronary heart disease (CHD)
accounts for approximately one-third to one-half of the total cases of CVD, with
ischemic heart disease as the number-one cause of death in adults from both low-,
middle-, and high-income countries [4,6]. The lifetime risk of CHD was illustrated in
a study of 7733 participants, age 40 to 94, in the Framingham Heart Study who
were initially free of CHD [7]. The lifetime risk for individuals at age 40 was 49
percent in men and 32 percent in women. Even those who were free from CHD at
age 70 had a non-trivial lifetime risk of developing CHD (35 and 24 percent in
males and females, respectively). Similar findings have been reported in a meta-
analysis of 18 cohorts involving over 250,000 adults [8]. (See "Atherosclerotic
cardiovascular disease risk assessment for primary prevention in adults: Our
approach", section on 'Lifetime risk'.)

Autopsy data have documented the early onset of atherosclerosis, beginning in

the second and third decades of life, although the prevalence of anatomic CHD has
decreased over time. In an analysis of 3832 autopsies performed on United States
military personnel (98 percent male, mean age 26 years) who died of combat or
unintentional injuries between October 2001 and August 2011, the prevalence of
any coronary atherosclerosis was 8.5 percent [9]. This represents a marked decline
in the prevalence of autopsy-documented CHD compared with the rates seen
 during the Korean War in the 1950s (77 percent) and the Vietnam War in the 1960s
(45 percent) [9].

Despite increases in longevity and decreases in age-specific death rates from CVD,
CHD, and stroke since 1975, CVD and its related complications remain highly
prevalent and expensive to treat [4,10-14]. In one cohort of over 1.9 million
persons age 30 years or older free of known baseline CVD who were followed for a
median of six years, the majority of initial CVD presentations were neither
myocardial infarction (MI) nor stroke [15]. These presentations, which included
angina ( table 1), heart failure, peripheral arterial disease, transient ischemic
attack, and abdominal aortic aneurysm, along with some less common
manifestations, represented 66 percent of the initial CVD presentations.

While CVD remains the leading cause of death in most developed countries,
mortality from acute MI appears to have decreased by as much as 50 percent in
the 1990s and 2000s. Among 49 countries in Europe and northern Asia, over four
million persons die annually from CHD [16]. In the United States, approximately
1.5 million persons suffer a heart attack or stroke annually, resulting in over
250,000 deaths [17,18].

Along with the improvements in mortality associated with the initial CVD event, the
prevalence of CVD is rapidly increasing in resource-limited countries as well [19-
21]. Between 1990 and 2010, it is estimated that the global burden of CHD
increased by 29 percent due to increases in therapy and longevity along with
global population growth [22]. Additionally, 2010 data showed significant regional
variation in CHD mortality, with the largest number of CHD deaths seen in South
Asia but the highest rates of CHD mortality seen in Eastern Europe and Central
Asia [23]. In a study of 156,424 persons from 17 countries (3 high-income, 10
middle-income, 4 low-income), the INTERHEART risk score (for assessing risk
factors) was highest in high-income countries and lowest in low-income countries
[24]. However, CVD events and mortality appeared inversely related to the
INTERHEART score, with significantly lower rates of CVD events and mortality in
high-income countries compared with middle- and low-income countries, a finding
which is purportedly due to greater risk factor modification in high-income
countries.
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 Many risk factors for CVD are modifiable by specific preventive measures. In the
worldwide INTERHEART study of patients from 52 countries, nine potentially
modifiable factors accounted for over 90 percent of the population-attributable
risk of a first MI. Smoking, dyslipidemia, hypertension, diabetes, abdominal
obesity, and psychosocial factors were associated with greater risk, and daily
consumption of fruits and vegetables and regular alcohol consumption were
associated with lower risk [25].

NONCORONARY ATHEROSCLEROTIC DISEASE

Some patients without known coronary heart disease (CHD) have a risk of
subsequent cardiovascular events that is comparable to that of patients with
established CHD [26]. Noncoronary atherosclerotic arterial disease, a diffuse
condition that involves the entire arterial circulation, includes patients with carotid
artery disease, peripheral artery disease, or abdominal aortic aneurysm. The
presence of clinical atherosclerosis in one vascular territory generally indicates an
increased likelihood that it exists elsewhere, since the risk factors are generally the
same.

Concurrent risk factors should be treated aggressively in such patients. (See

"Management of asymptomatic abdominal aortic aneurysm", section on
'Introduction' and "Management of asymptomatic extracranial carotid
atherosclerotic disease", section on 'Intensive medical therapy and follow-up' and
"Management of claudication due to peripheral artery disease", section on 'Risk
for progression and risk modification'.)

PREVALENCE OF CARDIOVASCULAR DISEASE RISK FACTORS

Many individuals in the general population have one or more risk factors for
coronary heart disease (CHD), and over 90 percent of CHD events occur in
individuals with at least one risk factor [25,27,28]. The five leading modifiable risk
factors (hypercholesterolemia, diabetes, hypertension, obesity, and smoking) are
estimated to be responsible for more than half of cardiovascular mortality [29]. On
the other hand, the absence of major risk factors predicts a much lower risk of
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 CHD [28].

The frequency and predictive value of five major risk factors (blood pressure, low-
density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, glucose
intolerance, and smoking) was evaluated in 35- to 74-year-old White non-Hispanic
individuals without CHD in the Framingham Heart Study and the Third National
Health and Nutrition Examination Survey (NHANES III) ( table 2) [27]. The
frequency of "borderline" risk factors (defined as systolic pressure 120 to 139
mmHg, diastolic pressure 80 to 89 mmHg, LDL cholesterol 100 to 159 mg/dL [2.6
to 4.1 mmol/L], HDL cholesterol 40 to 59 mg/dL [1.0 to 1.5 mmol/L], impaired
fasting glucose without overt diabetes, and a past history of smoking) was also
assessed in the same cohorts ( table 3) [27]. The following estimates were noted:

● More than 90 percent of CHD events occurred in individuals with at least one
risk factor, and approximately 8 percent occurred in individuals who had only
borderline levels of multiple risk factors. Few events occurred in patients with
no elevated or borderline risk factors. (See "Atherosclerotic cardiovascular
disease risk assessment for primary prevention in adults: Our approach",
section on 'Lifetime risk'.)

● In NHANES III, approximately 60 percent of men and 50 percent of women

had one to two elevated risk factors, and 26 percent of men and 41 percent
of women had at least one borderline risk factor. The complete absence of
any elevated or borderline risk factor was rare (0 to 0.4 percent) except for
women between the ages of 35 to 44 (8.9 percent) or 45 to 54 (3.7 percent).

The increase in risk when multiple risk factors are present has been noted in
several studies in both Western and Asian populations [27,30-32]. As examples:

● In a cohort study of 20,000 adults in Chicago with 22 years of follow-up, when

two or all three major risk factors (serum cholesterol ≥200 mg/dL [≥5.2
mmol/L], elevated systolic and diastolic blood pressure [≥120/80 mmHg], and
cigarette smoking) were present, both males and females had a marked
increase in the relative risk of CHD (5.5 and 5.7, respectively), cardiovascular
disease (CVD; 4.1 and 4.5), and all-cause mortality (3.2 and 2.3) [31].

● In a cohort study of 380,000 individuals from Asia, Australia, and New

:
 Zealand, patients in the higher categories of both total cholesterol (≥240
mg/dL [6.25 mmol/L]) and systolic pressure (≥160 mmHg) had a sevenfold
increase in CHD and an eightfold increase in stroke compared with patients
in the lowest category of both total cholesterol (less than 183 mg/dL [4.75
mmol/L]) and systolic pressure (less than 130 mmHg) [32]. Estimates of CVD
risk factors across Asia in the early 21st century have generally shown
decreases in systolic blood pressure and blood cholesterol in high-income
countries but increases in other countries, while there has also been a
significant increase in the prevalence of diabetes in most Asian countries
[33].

ESTABLISHED RISK FACTORS FOR ATHEROSCLEROTIC CVD

General principles — Atherosclerosis is responsible for almost all cases of

coronary heart disease (CHD). This insidious process begins with fatty streaks that
are first seen in adolescence; these lesions progress into plaques in early
adulthood, and culminate in thrombotic occlusions and coronary events in middle
age and later life. (See "Pathogenesis of atherosclerosis".)

A variety of factors, often acting in concert, are associated with an increased risk
for atherosclerotic plaques in coronary arteries and other arterial beds
( figure 1) [34]. Risk factor assessment is useful in adults to guide therapy for
dyslipidemia, hypertension, and diabetes, and multivariate formulations can be
used to help estimate risk for coronary disease events [35,36]. (See
"Atherosclerotic cardiovascular disease risk assessment for primary prevention in
adults: Our approach".)

As an example, a 12-year follow-up of 14,786 Finnish males and females, age 25 to

64, found that the incidence of CHD was threefold higher in men than women and
mortality was fivefold higher [37]. The relative difference in CHD risk between the
sexes was largest among the youngest subjects (25 to 49 years), but the absolute
difference was largest in the older age group due to a higher prevalence (60 to 64
years). Almost half of the difference in CHD risk between males and females was
associated with the sex differences in cardiovascular risk factors, particularly the
high-density lipoprotein (HDL)/total cholesterol ratio and smoking. Differences in
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 serum total cholesterol, blood pressure, body mass index, and prevalence of
diabetes accounted for approximately one-third of the age-related increase in CHD
prevalence in men and 50 to 60 percent in women.

Based upon the absolute, relative, and attributable risks imposed by the various
risk factors, concepts of "normal" have evolved from usual or average to more
optimal values associated with long-term freedom from disease. As a result,
optimal blood pressure, blood glucose, and lipid values have been revised
downward in the past 20 years [38-40].

Some authors have asserted that approximately one-half of all patients suffering a
manifestation of CHD have no established risk factors other than age and sex, a
claim that has contributed to efforts to identify other markers of cardiovascular
risk [41,42]. However, the accuracy of this assertion has been challenged by the
results of several analyses suggesting the prevalence of major risk factors in
patients with CHD to be higher than 75 percent [43-45]:

● In an observational study from the National Registry of Myocardial Infarction

that enrolled more than 540,000 patients between 1994 and 2006 who
presented with a first myocardial infarction (MI) with no prior cardiovascular
disease, 86 percent had one of five major risk factors (hypertension,
smoking, dyslipidemia, diabetes mellitus, or family history of CHD) [45].
Among the nearly 51,000 patients who died prior to hospital discharge, there
was a significant inverse relationship between the risk of death and the
number of major risk factors present, with patients having 0 to 2 risk factors
significantly more like to die compared with persons with all five risk factors
(adjusted odds ratio [OR] of death for zero risk factors 1.54, 95% CI 1.23-1.94).

● A report based upon data from three observational studies (the Framingham
Heart Study, the Multiple Risk Factor Intervention Trial [MRFIT], and the
Chicago Heart Association Detection Project in Industry) included more than
380,000 subjects, 21,000 of whom died of CHD [43]. Major CHD risk factors
were defined as total cholesterol ≥240 mg/dL (≥6.22 mmol/L), systolic blood
pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, smoking, and
diabetes. Study subjects were stratified by age and sex. Among subjects
dying of CHD, exposure to at least one risk factor ranged from 87 percent (for
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 men aged 40 to 59 in the MRFIT trial) to 100 percent (for women aged 18 to
39 years in the Framingham Heart Study).

● Another report, based upon 14 randomized clinical trials of CHD, included

more than 120,000 subjects with ST elevation MI, non-ST elevation acute
coronary syndrome, or percutaneous coronary intervention [44]. Risk factors
were defined by information collected at the time of study enrollment,
including smoking, diabetes, hypertension, and hyperlipidemia. At least one
of these four risk factors was present in 85 percent of women and 81 percent
of men. When stratified by age, the lowest prevalence of at least one risk
factor was seen among subjects >75 years old (77 percent of women and 65
percent of men).

Several metrics for risk factors have been associated with greater cardiovascular
disease (CVD) risk: mean levels, median levels, time spent at a high risk factor level,
and increased variability in a specific metric over time. This has been reported for
the risk factors blood pressure, cholesterol levels, and body weight, among others
[46-50]. Patients who are not very compliant with their treatments often have
greater variability in risk factor measurements, and measurement error is often
much greater at high values. Compounding the issue for heart disease is that very
low-weight persons may experience greater risk for recurrent heart disease.

Risk factor prevalence — An exact estimate of the prevalence of CVD risk factors
remains elusive, but the prevalence of identified risk factors has changed over
time with increased awareness and changes in diet and lifestyle. A comparison of
results from sequential reports from the National Health and Nutrition
Examination Survey (NHANES) has shown that the prevalence of obesity (body
mass index [BMI] ≥30 kg/m2) increased dramatically in the United States between
1960 and 2000 (15 to 30 percent) [51]. Not surprisingly, there was an associated
increase in diagnosed diabetes (1.8 to 5.0 percent) that was most prominent in
obese subjects (2.9 to 10.1 percent). (See 'Obesity' below.)

By contrast, a number of other major cardiovascular risk factors declined

substantially between 1960 and 2000 [51]:

● Serum total cholesterol ≥240 mg/dL (6.2 mmol/L) – 34 to 17 percent

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 ● Hypertension (blood pressure ≥140/≥90 mmHg) – 31 to 15 percent
● Smoking – 39 to 26 percent

These changes occurred in all weight groups, including obese individuals, and
were associated with increases in the use of lipid-lowering drugs and
antihypertensive medications. (See "Overweight and obesity in adults: Health
consequences", section on 'Trends in cardiovascular risk factors'.)

The presence of established risk factors is associated with CVD, and the
achievement and maintenance of good health is being emphasized in programs
from the American Heart Association (AHA) that promote seven ideal
cardiovascular health metrics (“Life’s Simple 7”), including [52]:

● Not smoking
● Being physically active
● Having a normal blood pressure
● Having a normal blood glucose level
● Having a normal total cholesterol level
● Being normal weight
● Eating a healthy diet

Numerous studies have consistently shown CVD morbidity and mortality benefits
of achieving greater numbers of ideal cardiovascular health metrics, with relative
risk reductions approaching 75 percent in persons achieving all seven metrics [53-
60]. In a 2018 systemic review and meta-analysis which included 210,443 persons
from 12 cohort studies, persons achieving between five and seven ideal
cardiovascular health metrics had the greatest reduction in incident CVD (hazard
ratio [HR] 0.28 compared with persons achieving between zero and two metrics;
95% CI 0.23-0.33), while persons achieving three and four metrics also derived a
smaller but significant benefit (HR 0.53 compared with persons achieving between
zero and two metrics; 95% CI 0.47-0.59) [61].

Risk factor prevalence in developing nations has long been unknown and/or
underrepresented in the literature. Among 46,239 Chinese adults age 20 or older
(40 percent male) recruited in 2007 and 2008 as a nationally representative cohort,
the overall prevalence of CVD was low (1.8 and 1.1 percent in males and females,
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 respectively) [62]. The prevalence of traditional CVD risk factors was much higher:

● Overweight or obese – 36.7 and 29.8 percent in males and females,

respectively
● Hypertension – 30.1 and 24.8 percent in males and females, respectively
● Dyslipidemia – 64 and 67.4 percent in males and females, respectively
● Hyperglycemia – 26.7 and 23.6 percent in males and females, respectively

After adjusting for age and sex, the odds of CVD increased with the number of risk
factors present (OR 2.4, 4.2, 4.9, and 7.2 for 1, 2, 3, and 4 or more risk factors,
respectively, compared with no risk factors) [62]. These data suggest that, in the
absence of effective lifestyle and medical interventions, there is likely to be a
significant increase in the incidence and prevalence of CVD in China in the future.

Risk factors in childhood — Cardiovascular risk factors are identifiable in

childhood and may be predictive of the subsequent development of CHD [63-65].
The identification of children with risk factors for CVD and the development of
atherosclerosis in children are discussed in detail separately. (See "Pediatric
prevention of adult cardiovascular disease: Promoting a healthy lifestyle and
identifying at-risk children" and "Overview of risk factors for development of
atherosclerosis and early cardiovascular disease in childhood".)

Age and sex — Cardiovascular risk factors promote CVD in either biological sex at
all ages but with different relative importance.

● Diabetes and a low HDL-cholesterol/total cholesterol ratio operate with

greater power in women [66,67]. (See "Prevalence of and risk factors for
coronary heart disease in patients with diabetes mellitus".)

● The incidence of an MI is increased sixfold in women and threefold in men

who smoke at least 20 cigarettes per day compared with subjects who never
smoked [68,69]. (See "Cardiovascular risk of smoking and benefits of
smoking cessation".)

● Systolic blood pressure and isolated systolic hypertension are major CHD risk
factors in males and females at all ages [40]. The Framingham study found
that the relative importance of systolic, diastolic, and pulse pressure (the
:
 difference between the systolic and diastolic blood pressures) changes with
age [70]. In patients <50 years of age, diastolic blood pressure was the
strongest predictor of CHD risk; in those 50 to 59 years of age, all three blood
pressure indices were comparable predictors of CHD risk, while in those ≥60
years of age, pulse pressure was the strongest predictor. (See 'Hypertension'
below and "Cardiovascular risks of hypertension".)

● Some risk factors, such as dyslipidemia, impaired glucose tolerance, and

elevated fibrinogen have a diminished impact with advancing age, but a
lower relative risk is offset by the high absolute risk in older adults [71,72].
Thus, all of the major risk factors continue to be relevant in older persons.

● Obesity or weight gain promotes or aggravates most of the atherogenic risk

factors and physical inactivity worsens some of them, predisposing subjects
of all ages to CHD events [73-75]. (See "Overweight and obesity in adults:
Health consequences" and "Obesity in adults: Role of physical activity and
exercise".)

Age alone also appears to contribute to the development of CVD. In a cohort of

more than 3.6 million individuals age 40 years or older who underwent self-
referred screening for CVD (ankle brachial index, carotid duplex ultrasound, and
abdominal ultrasound), the prevalence of any vascular disease increased
significantly with each decade of life [76]:

● 2 percent in 40- to 50-year-olds

● 3.5 percent in 51- to 60-year-olds
● 7.1 percent in 61- to 70-year-olds
● 13 percent in 71- to 80-year-olds
● 22.3 percent in 81- to 90-year-olds
● 32.5 percent in 91- to 100-year-olds

After adjusting for traditional risk factors, each additional decade of life was
associated with an approximate doubling of the risk of vascular disease (ORs per
decade of life were 2.14, 1.80, and 2.33 for peripheral arterial disease, carotid
stenosis, and abdominal aortic aneurysm, respectively).

Male sex alone may contribute to the risk of CHD, although the potential
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 mechanisms for such risk are not well understood. Several population studies have
identified male sex as a risk factor for higher rates of CHD and CHD-related
mortality [77-79]. Among 31,000 patients from the ONTARGET and TRANSCEND
study populations (9378 females, 22,168 males) who were followed for an average
of 56 months, females had approximately 20 percent lower risk than males for all
major cardiovascular endpoints including cardiovascular death (adjusted RR 0.83,
95% CI 0.75-0.92), MI (adjusted RR 0.78, 95% CI 0.68-0.89), and a combined
endpoint of death, MI, stroke, and heart failure hospitalization (adjusted RR 0.81,
95% CI 0.76-0.87) [79]. In premenopausal women, serious manifestations of
coronary disease, such as MI and sudden death, are relatively rare. After
menopause, the incidence and severity of coronary disease increases abruptly,
with rates three times those of women the same age who remain premenopausal
[80]. (See "Overview of atherosclerotic cardiovascular risk factors in females".)

The risk of CHD in men has been associated with variations in the Y chromosome.
Among 3233 biologically unrelated British men who underwent genotyping of
their Y chromosome, with 13 apparent ancient lineages (haplogroups) identified
based on the genotype results, those descendent from one particular haplogroup
(haplogroup I, almost entirely unique to Europeans) had significantly more CHD
than men from other haplogroups (OR 1.56, 95% CI 1.24-1.97) [81]. These results
suggest that differences in CHD risk within the male sex are associated with
inherited variations in sex chromosomes, which may contribute to the importance
of family history as a risk factor for CHD. (See 'Family history' below and "Overview
of possible risk factors for cardiovascular disease", section on 'Genetic markers'.)

Family history — Family history is an independent risk factor for CHD, particularly

among younger individuals with a family history of premature disease [82-88].
There is general agreement that development of atherosclerotic CVD or death
from CVD in a first-degree relative (ie, biological parent or sibling) prior to age 55
(males) or 65 (females) denotes a significant family history, although the definition
of what constitutes a family history of premature atherosclerosis has been
somewhat variable across studies [89-91]. A wider definition of a significant family
history of CVD might also include CVD in a first-degree relative of any age (ie, not
necessarily premature) or other manifestations of atherosclerosis beyond MI or
CHD death, including stroke or transient ischemic attack, CHD requiring
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 revascularization in the absence of MI, peripheral artery disease, and abdominal
aortic aneurysm ( table 4) [91]. One study has suggested that compared with a
family history of premature CVD or a more detailed family history, asking a single
question (does any first-degree relative have CVD, at any age?) was as helpful in
identifying an increased risk of CVD [91]. (See "Coronary artery disease and
myocardial infarction in young people".)

Using data from the 2011 to 2014 NHANES survey, the 2017 AHA heart disease and
stroke statistics reported that 12.2 percent of adults have a biological parent or
sibling with heart attack or angina before age 50 years [92]. The importance of
family history has been shown in several large cohort studies (Physician's Health
Study, Women's Health Study, Reykjavik Cohort Study, Framingham Offspring
Study, INTERHEART Study, Cooper Center Longitudinal Study, Danish national
population database) that collectively followed over 163,000 patients, and all
showed that a positive family history is associated with greater risk of developing
CHD [82,83,85,86,93-96]. The risk of developing CHD in the presence of a positive
family history has ranged from 15 to 100 percent in various cohorts, with most
cohorts showing a 30 to 60 percent increase [91].

The importance of a family history of premature CVD death appears to be

magnified in families with multiple premature deaths [97-99]. Using data from the
Danish Family Relations Database (3,985,301 persons born between 1950 and
2008 followed for nearly 90 million person-years), persons from families with two
or more premature cardiovascular deaths among first-degree relatives had a
threefold greater risk of developing CVD before age 50 (incidence risk ratio 3.30,
95% CI 2.77-3.94) [97]. Similar findings have been noted among 185,810 cases of
hospitalization or death due to CHD in the Swedish Multi-Generation Registry, in
which the risk of hospitalization or death due to CHD was increased six- to
sevenfold in persons with two or three siblings with CHD [98].

Despite multiple studies showing that family history of CHD in a first-degree

relative increases one's risk of developing CHD, the incremental predictive value of
adding family history to an established risk score appears to be small, ranging
from 2 to 5 percent upward reclassification of risk [87,100]. In the EPIC-Norfolk
prospective cohort of 22,841 patients (45 percent male) aged 40 to 79 years who
were followed for a mean of 10.9 years, a family history of CHD in a first-degree
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 relative was associated with increased risk of future CHD independent of the
Framingham Risk Score (FRS) estimate (adjusted HR 1.74, 95% CI 1.56-1.95) [87].
Despite this significantly increased risk, the addition of family history to the FRS
estimate resulted in minimal reclassification of patients into different risk groups
(only 2 percent of patients deemed intermediate risk by FRS were reclassified to
high risk because of family history). (See "Cardiovascular disease risk assessment
for primary prevention: Risk calculators".)

Reliability of self-reported family history — The accuracy and reliability of a

self-reported family history may be difficult to ascertain. A 2009 report from the
National Institutes of Health reviewed the accuracy of self-reported family history
of several common disease states (asthma and allergies, diabetes mellitus, major
depression and mood disorders, stroke, CVD, and five common types of cancer)
[89]. The probability that an unaffected family member was correctly identified as
disease-free was high (90 to 95 percent), but for family members with one of the
diseases, the probability that they were correctly identified as having the disease
was generally lower and far more variable (as low as 6 percent correct identified as
having a mood disorder, up to 95 percent correct for some types of cancer).
Generally, patients more accurately identified healthy family members as being
healthy and were less accurate in correctly identifying family members with
specific diseases.

The reliability of a self-reported family history of CHD or of risk factors for CHD
was explored in an analysis from the Framingham Offspring Study [101]. A group
of 1628 children of study participants completed a questionnaire regarding
parental medical history. The following findings were noted:

● The predictive value of an affirmative statement was above 75 percent for

family histories of hypertension, diabetes, and hypercholesterolemia.

● For cardiac death the positive predictive value was only 66 percent for fathers
and 47 percent for mothers.

● The predictive value of a negative statement was above 90 percent for family
history of cardiac death or for diabetes, but below 60 percent for family
history of hypertension or hypercholesterolemia.
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 These findings concerning validated and self-reported family history from
Framingham suggest that there is some value in obtaining family history
information, but that self-reported information might not be accurate. They also
suggest that the additional contribution of family history to CHD risk estimation
after inclusion of other traditional risk factors is relatively modest.

Hypertension — Hypertension is a well-established risk factor for adverse

cardiovascular outcomes, including mortality from CHD and stroke [102,103]. The
lifetime risk of developing CVD is significantly higher among patients with
hypertension ( table 5). In a cohort of over 1.25 million patients aged 30 years or
older without baseline CVD, including 20 percent with baseline treated
hypertension, patients with baseline hypertension had a 63.3 percent lifetime risk
of developing CVD compared with a 46.1 percent risk for those with normal
baseline blood pressure [5]. In a separate study from the INTERHEART group,
hypertension accounted for 18 percent of the population-attributable risk of a first
MI [25]. Greater variations in blood pressure from one visit to the next may also be
associated with greater risk of CVD and mortality [104]. (See "Cardiovascular risks
of hypertension".)

The determination of what blood pressure constitutes hypertension has long been
the subject of debate, with various committees and professional societies
publishing statements or guidelines attempting to define categories of
hypertension [40,105]. An extensive discussion of the definition of hypertension
and treatment recommendations for various patient groups is presented
elsewhere. (See "Overview of hypertension in adults", section on 'Definitions' and
"Goal blood pressure in adults with hypertension".)

Although blood pressure at the time of risk assessment (current blood pressure) is
typically used in most prediction algorithms, this does not accurately reflect an
individual's past blood pressure experience. Two analyses demonstrate the
importance of inclusion of past blood pressure into risk prediction models since
the duration as well as the degree of hypertension are both risk factors. This issue
is discussed in detail elsewhere. (See "Cardiovascular risks of hypertension",
section on 'Current risk versus prior risk'.)

Ambulatory blood pressure measurements may be more predictive in patients

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 with office or white coat hypertension. (See "Out-of-office blood pressure
measurement: Ambulatory and self-measured blood pressure monitoring".)

A separate issue is the goal blood pressure in patients who already have or are at
high risk for CVD. This issue is discussed in great detail separately. (See
"Cardiovascular risks of hypertension" and "Goal blood pressure in adults with
hypertension".)

Lipids and lipoproteins — Lipids, principally cholesterol and triglycerides, are the

water insoluble compounds that require larger protein-containing complexes
called lipoproteins to transport them in blood. The protein components of the
lipoprotein are known as apolipoproteins or apoproteins. (See "Lipoprotein
classification, metabolism, and role in atherosclerosis".)

The determination of what cholesterol level constitutes dyslipidemia has long

been the subject of debate, with professional societies publishing statements or
guidelines attempting to delineate risk levels and when to consider drug therapy
for dyslipidemia [106].

The prevalence of dyslipidemia is increased in patients with premature CHD, being

as high as 75 to 85 percent compared with approximately 40 to 48 percent in age-
matched controls without CHD [84,107]. In the INTERHEART study, dyslipidemia
(defined as a raised apo B to apo A-1 ratio) accounted for 49 percent of the
population-attributable risk of a first MI [25].

Disturbances in lipoprotein metabolism are often familial. As an example, 54

percent of all patients and 70 percent of those with a lipid abnormality in one
reported series had a familial lipid disorder [107]. The most common familial
disturbances were Lp(a) excess (alone or with other dyslipidemia),
hypertriglyceridemia with hypoalphalipoproteinemia, and combined
hyperlipidemia. Conversely, patients with favorable genetic profiles that result in
lifelong exposure to lower low-density lipoprotein (LDL) cholesterol levels have
been shown to be at decreased risk of MI, coronary revascularization, or death
from CHD [108]. (See "Inherited disorders of LDL-cholesterol metabolism other
than familial hypercholesterolemia".)

Evidence for the pathogenic importance of serum cholesterol has largely come
:
 from randomized trials which showed that reductions in total and LDL cholesterol
levels (almost entirely with statins) reduce coronary events and mortality when
given for primary and secondary prevention [109-111]. Factors other than LDL
cholesterol lowering also may contribute to the observed benefit from statin
therapy. (See "Mechanisms of benefit of lipid-lowering drugs in patients with
coronary heart disease" and "Low-density lipoprotein cholesterol-lowering therapy
in the primary prevention of cardiovascular disease".)

Recommendations for the treatment of hypercholesterolemia are discussed

separately. (See "Low-density lipoprotein cholesterol-lowering therapy in the
primary prevention of cardiovascular disease" and "Management of low density
lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular
disease".)

The following lipid and lipoprotein abnormalities are associated with increased
CHD risk. The supportive data are presented elsewhere as noted:

● Elevated total cholesterol ( figure 2) and elevated LDL cholesterol (see

"Screening for lipid disorders in adults", section on 'Rationale for screening')
● Low HDL cholesterol (see "HDL cholesterol: Clinical aspects of abnormal
values", section on 'Low HDL cholesterol as an ASCVD risk factor')
● Hypertriglyceridemia (see "Hypertriglyceridemia in adults: Management")
● Increased non-HDL cholesterol (see "Screening for lipid disorders in adults",
section on 'Choice of tests')
● Increased Lp(a) (see "Lipoprotein(a)")
● Increased apolipoprotein C-III (see "Lipoprotein classification, metabolism,
and role in atherosclerosis")
● Small, dense LDL particles (see "Inherited disorders of LDL-cholesterol
metabolism other than familial hypercholesterolemia", section on 'Small
dense LDL (LDL phenotype B)')
● Different genotypes of apolipoprotein E (apoE) influence cholesterol and
triglyceride levels as well as the risk of CHD (see "Inherited disorders of LDL-
cholesterol metabolism other than familial hypercholesterolemia", section on
'Genetics')

LDL levels in the normal range correlate with subclinical atherosclerosis in patients
:
 without traditional CHD risk factors, suggesting a continuous relationship with no
clear threshold [112].

The abnormalities discussed above require measurement of lipids or lipoproteins.

Proton nuclear magnetic resonance (NMR) spectroscopy of lipoprotein particles
has been proposed as an alternative method for predicting CVD risk [113]. In a
study of over 27,000 women, this technique was comparable in predictive accuracy
to, but not better than, standard measurement of lipids or apolipoproteins [113].

Diabetes mellitus — Insulin resistance, hyperinsulinemia, and elevated blood

glucose are associated with atherosclerotic CVD [114-121]. In the INTERHEART
study, diabetes accounted for 10 percent of the population-attributable risk of a
first MI [25]. The all-cause mortality risk associated with diabetes has been
compared with the all-cause mortality risk associated with a prior MI [122].

In addition to the importance of diabetes as a risk factor, diabetics have a greater

burden of other atherogenic risk factors than nondiabetics, including
hypertension, obesity, increased total to HDL cholesterol ratio,
hypertriglyceridemia, and elevated plasma fibrinogen. The CHD risk in diabetics
varies widely with the intensity of these risk factors.

Guidelines published by the National Cholesterol Education Program and the sixth
Joint National Committee have provided a framework to treat coronary risk factors
aggressively in diabetics [38,102]. There is compelling evidence of the value of
aggressive therapy of serum cholesterol and hypertension in patients with
diabetes [123-125]. (See "Treatment of hypertension in patients with diabetes
mellitus" and "Management of low density lipoprotein cholesterol (LDL-C) in the
secondary prevention of cardiovascular disease".)

Hyperglycemia without overt diabetes mellitus — There is good evidence

from observational studies that higher levels of blood glucose and glycated
hemoglobin correlate with cardiovascular risk in patients with and without
diabetes at baseline. Data on this are discussed separately. (See "Prevalence of and
risk factors for coronary heart disease in patients with diabetes mellitus", section
on 'CHD before diabetes' and "Prevalence of and risk factors for coronary heart
disease in patients with diabetes mellitus", section on 'Hyperglycemia'.)
:
 Chronic kidney disease — The increased CHD risk in patients with end-stage
kidney disease has been well described, but there is now clear evidence that mild
to moderate kidney dysfunction is also associated with a substantial increase in
CHD risk [126]. Practice guidelines from the National Kidney Foundation in 2002
and the American College of Cardiology (ACC)/American Heart Association (AHA)
task force in 2004 recommended that chronic kidney disease (CKD) be considered
a CHD risk equivalent [127,128].

Patients with CKD who undergo stress testing have worse outcomes, regardless of
the outcome, when compared with patients without CKD. In a study of 1652
patients who underwent stress radionuclide myocardial perfusion imaging (rMPI),
among whom CKD (defined as estimated globular filtration rate <60
mL/minute/1.73 m2) was present in 36 percent of subjects, patients with CKD had
significantly worse prognosis for similar rMPI result compared with patients
without CKD [129]. With CKD and a normal test, the annual cardiac death rate was
2.7 percent; with no CKD and a normal test, the annual cardiac death rate was
significantly lower (0.8 percent). With CKD and ischemia, the annual cardiac death
rate was 11 percent; with no CKD and ischemia, the annual cardiac death rate was
significantly lower (4.5 percent).

The data supporting this conclusion are presented elsewhere. (See "Chronic kidney
disease and coronary heart disease".)

Lifestyle factors — A variety of lifestyle factors impact the risk of CVD:

Cigarette smoking — Cigarette smoking is an important and reversible risk

factor for CHD. In 2016, approximately 15.5 percent of United States adults age
≥18 years were smoking [4]. The incidence of a MI is increased sixfold in women
and threefold in men who smoke at least 20 cigarettes per day compared with
subjects who never smoked [68,69]. The risk of MI is proportional to tobacco
consumption in both males and females and is higher in inhalers compared with
non-inhalers [69]. In the INTERHEART study, smoking accounted for 36 percent of
the population-attributable risk of a first MI [25].

Conversely, the risk of recurrent infarction in a study of smokers who had an MI

fell by 50 percent within one year of smoking cessation and normalized to that of
:
 nonsmokers within two years [130]. The benefits of smoking cessation are seen
regardless of how long or how much the patient has previously smoked. (See
"Cardiovascular risk of smoking and benefits of smoking cessation".)

Diet — Aspects of diet that have been evaluated for CHD risk include the
glycemic index (GI), fruits and vegetables, meat, trans fatty acids, fiber, coffee, and
low-cholesterol diets.

● Dietary factors that may increase risk

• High glycemic index – Diets containing foods with a high GI or glycemic

load (GL) may contribute to the risk of CHD ( table 6).

• Low consumption of fruits and vegetables – There is growing evidence

that greater fruit and vegetable consumption is inversely related to the
risk of CVD.

High serum concentrations of enterolactone, a putative biomarker of a

diet high in fiber and vegetables, have been inversely correlated with the
risk of acute coronary events and with CHD mortality. (See "Healthy diet in
adults" and "Overview of primary prevention of cardiovascular disease",
section on 'Healthy diet'.)

• High consumption of red meat – Greater intake of red meat has been
associated with higher risks of CVD.

• High consumption of trans fatty acids – Several observational studies

have linked the consumption of trans fatty acids, or foods that contain
them, with adverse cardiovascular outcomes ( table 7). (See "Dietary
fat", section on 'Trans fatty acids'.)

• Low consumption of Fiber – Low fiber intake is inversely related to risk of

CHD. It is also associated with development of cardiovascular risk factors
including hypertension, diabetes mellitus, and elevated lipid levels.
( table 8)

● Dietary factors of uncertain effect

:
 • Coffee – Coffee consumption, both caffeinated and non-caffeinated,
appears to have a neutral effect on the development of CVD. (See
"Benefits and risks of caffeine and caffeinated beverages" and
"Cardiovascular effects of caffeine and caffeinated beverages".)

• Low-cholesterol diet – The relationship between dietary cholesterol and

development of CVD is unclear due to observational studies with mixed
results. However, the 2020 Dietary Guidelines for Americans suggest
maintaining an overall healthy eating pattern and consuming as little
dietary cholesterol as possible [131].

Exercise — Exercise of even moderate degree has a protective effect against CHD

and all-cause mortality [25,75,132-135]. Exercise may have a variety of beneficial
effects including an elevation in serum HDL cholesterol, a reduction in blood
pressure, less insulin resistance, and weight loss. In addition to the amount of
exercise performed, the degree of cardiovascular fitness (a measure of physical
activity), as determined by duration of exercise and maximal oxygen uptake on a
treadmill, is also associated with a reduction in CHD risk and overall cardiovascular
mortality [136-146].

● Men who engaged in moderately vigorous sports activity have been reported
to have a 23 percent lower risk of death than those who were less active
[132]. Persons with mild to moderate levels of physical activity as part of their
occupation appear to have lower risk of MI compared with sedentary workers
[143].

● In the INTERHEART study, lack of regular physical activity accounted for 12

percent of the population-attributable risk of a first MI [25].

● Cardiovascular fitness has been assessed in several studies [140,141,144-

146]. In a prospective study of 6213 men referred for exercise testing who
were followed for a mean of 6.2 years [140], peak exercise capacity,
measured in metabolic equivalents (METs), was a stronger predictor of
mortality than other established cardiovascular risk factors among men with
and without CVD. In a separate study of 11,190 persons deemed "low-risk" by
FRS and without diabetes mellitus who underwent treadmill exercise testing
:
 and were followed for an average of 27 years, all-cause mortality was
significantly higher among individuals in the lowest quintile of exercise
capacity at baseline (15 versus 6 percent mortality in the highest quintile)
[141]. In a study of cardiorespiratory fitness in 5107 man (mean age 48.8
years) without known CVD who were followed for 46 years, high
cardiorespiratory fitness in the fifth decade of life was associated with
mortality benefits extending for over four decades [145].

Resistance training appears to have a beneficial impact on several risk factors for
cardiovascular disease. These include lowering blood pressure, reducing fasting
serum glucose concentrations, improving insulin sensitivity and dyslipidemia,
decreasing waist circumference, and improving body composition [147-154]. (See
"Strength training for health in adults: Terminology, principles, benefits, and
risks".)

The AHA prepared a listing of the most effective strategies to promote exercise, as
well as a healthy diet, based on a systematic review of studies published in English
between 1999 and 2009 ( table 9). (See "Exercise and fitness in the prevention of
atherosclerotic cardiovascular disease" and "The benefits and risks of aerobic
exercise".)

In 2018, the US Department of Health and Human Services published guidelines

for physical activity in children and adults [155]. (See "Exercise prescription and
guidance for adults", section on 'Prescribing an exercise program'.)

Alcohol — Epidemiologic data indicate that moderate alcohol intake has a

protective effect on CHD. (See "Cardiovascular benefits and risks of moderate
alcohol consumption".)

Obesity — Obesity, defined as a BMI greater than 30, is a highly prevalent

condition, particularly in developed countries, with estimates that 35 percent of
the population of the United States in 2011 to 2012 was obese [156]. Obesity is
associated with a number of risk factors for atherosclerosis, CVD, and
cardiovascular mortality, including hypertension, insulin resistance and glucose
intolerance, hypertriglyceridemia, reduced HDL cholesterol, and low levels of
adiponectin [157-160]. However, in an analysis of data from 4780 adults in the
:
 Framingham Offspring Study, obesity as measured by BMI significantly and
independently predicted the occurrence of CHD and cerebrovascular disease after
adjusting for traditional risk factors [161]. Additionally, there is a continuous linear
relationship between higher BMI and greater risk of CVD [162,163]. These
relationships are discussed in detail elsewhere. (See "Obesity: Association with
cardiovascular disease" and "Overweight and obesity in adults: Health
consequences" and "Obesity in adults: Dietary therapy".)

In addition to the risk associated with obesity, patients with more significant
fluctuations in body weight (ie, cycles of weight gain and weight loss) appear to
have an increased risk of future CVD events. Among 9509 patients with established
CVD and LDL cholesterol below 130 mg/dL (3.4 mmol/L) who participated in the
randomized Treating to New Targets trial (randomized to 10 mg or 80 mg of daily
atorvastatin), post hoc analysis was performed to assess the impact of fluctuations
in body weight on the composite outcome of any CHD event (combination of death
from CHD, nonfatal MI, resuscitated sudden cardiac arrest, revascularization, and
angina) [50]. For each standard deviation increase in body weight fluctuation
(approximately 1.5 to 1.9 kg deviation from baseline), there was a significant
increase in the hazard of any CHD event (HR 1.04; 95% CI 1.01-1.07). Patients in the
highest quintile of weight fluctuation (mean variability of 3.9 kg) had significantly
higher risks of any CHD event (64 percent higher), any CVD event (85 percent
higher), and total mortality (124 percent higher). These data suggest that frequent
cycles of weight gain and weight loss are associated with an increased risk of CHD
and CVD events, with the greatest magnitude of risk among those who were
overweight or obese at baseline.

Psychosocial factors — Psychosocial factors may contribute to the early

development of atherosclerosis as well as to the acute precipitation of MI and
sudden cardiac death. The link between psychologic stress and atherosclerosis
may be both direct, via damage of the endothelium, and indirect, via aggravation
of traditional risk factors such as smoking, hypertension, and lipid metabolism.
Depression, anger, stress, and other factors have been correlated with
cardiovascular outcomes. (See "Psychosocial factors in coronary and cerebral
vascular disease" and "Psychosocial factors in acute coronary syndrome".)

Sex differences — The importance of some metabolic, behavioral, and

:
 psychosocial risk factors may differ by sex. Data from the Prospective Urban Rural
Epidemiological (PURE) study, which followed adults from 21 high-, middle-, and
low-income countries for 10 years, showed that LDL cholesterol and non-HDL
cholesterol levels generally rose with age in women and after age 55 years were
typically greater in women than in men, which has been attributable to
menopause. The authors also reported that high non-HDL cholesterol was
associated with a higher risk of CVD in men compared with women (HR 1.28, 95%
CI 1.19-1.39 versus HR 1.11, 95% CI 1.01-1.21) [164]. Symptoms of depression were
associated with a higher risk of CVD in men compared with women (HR 1.42, 95%
CI, 1.25-1.60 versus HR 1.09, 95% CI 0.98-1.21). Among behavioral factors of
smoking, alcohol consumption, diet, and physical activity, a lower-quality diet was
more strongly associated with major CVD in women than men (HR 1.17, 95% CI
1.08-1.26 versus HR 1.07, 95% CI 0.99-1.15). The total population attributable
fraction of CVD associated with lifestyle factors were greater in men than in
women (15.7 versus 8.4 percent); this was largely due to the greater prevalence of
smoking to CVD risk in men compared with women (10.7 versus 1.3 percent).

Inflammation — Numerous markers of inflammation markers have been

reported to be associated with increased risk of CVD [165,166]. C-reactive protein
(CRP) is both the most extensively studied marker of inflammation and the marker
most widely used in clinical practice. Its precise role in the assessment of
cardiovascular risk continues to evolve. While the precise role of CRP remains
uncertain, epidemiologic studies have suggested that interleukin (IL)-6 has a direct
causal role in the development of CHD.

C-reactive protein — A person's baseline level of inflammation, as assessed by

the plasma concentration of CRP, predicts the long-term risk of a first MI, ischemic
stroke, or peripheral artery disease ( figure 3) [167-169]. The relationship
between CRP and CVD is discussed in detail separately. (See "C-reactive protein in
cardiovascular disease".)

Measurement of CRP levels improves risk stratification [170,171]. Several

professional societies have issued statements or guidelines suggesting a role for
the measurement of high-sensitivity CRP in patients at intermediate risk for CHD,
in whom measurement may help direct further evaluation and therapy for primary
prevention [172-174]. (See "C-reactive protein in cardiovascular disease", section
:
 on 'Recommendations of others'.)

Interleukin-6 — While the association between inflammation and the

development of atherosclerotic disease is well-known, proving causation for any
particular biomarker of inflammation has been difficult. IL-6 signals a downstream
proinflammatory response by activating membrane-bound IL-6 receptors (IL-6R)
on the cell surface. IL-6 and IL-6R appear to have a direct causal role in the
development of CHD and may be a future target for therapeutic interventions to
prevent CHD. (See "Pathogenesis of atherosclerosis", section on 'Inflammation'.)

The presence of Asp358Ala (rs2228145, formerly rs8192284), a variant allele of the

IL6R gene encoding IL-6R, is associated with reduced membrane-bound IL-6R,
resulting in decreased IL-6R signalling and less inflammation [175]. Two large
meta-analyses have confirmed the crucial role played by IL-6 and IL-6R in the
generation of inflammation and the associated risk of CHD [176,177]:

● In a collaborative meta-analysis incorporating genetic and biomarker data

from over 200,000 persons, each inherited copy of the Asp358Ala allele was
independently associated with significantly increased soluble IL-6R levels,
significantly decreased CRP levels, and significantly decreased risk of CHD
(3.4 percent, 95% CI 1.8-5.0) [176].

● In a Mendelian randomization analysis of over 133,000 persons analyzed for

the single nucleotide polymorphism (SNP) rs7529229, which has strong
linkage disequilibrium with Asp358Ala, each allele that contained the SNP
rs7529229 was independently associated with significantly increased soluble
IL-6R levels, significantly decreased CRP levels, and significantly decreased
risk of CHD (5 percent decrease, 95% CI 3-7) [177].

Both studies demonstrate an association between IL-6 and IL-6R levels and CHD
that is dose-dependent (two variant alleles provided more benefit than one variant
allele which provided more benefit than no variant alleles). Increased soluble (ie,
circulating) IL-6R levels led to reduced membrane-bound IL-6R, thereby reducing
signaling and downstream inflammation (reduced CRP levels). Taken together,
these results provide evidence supporting a direct causal role of IL-6 and IL-6R in
the development of CHD and suggest a future target for therapeutic interventions
:
 to prevent CHD.

Myeloperoxidase — Higher levels of the leukocyte enzyme myeloperoxidase,

which is secreted during acute inflammation and promotes oxidation of
lipoproteins, are associated with the presence of coronary disease and may be
predictive of the presence of acute coronary syndrome in patients with chest pain
[178-181]. As an example, in a nested case-cohort study from the MONICA/KORA
Augsburg involving 333 cases with CHD and 1727 controls followed for an average
of nearly 11 years, patients with elevated myeloperoxidase levels had significantly
greater likelihood of developing CHD after adjusting for traditional major
cardiovascular risk factors (HR 1.70 for top tertile versus bottom two tertiles, 95%
CI 1.25-2.30) [181].

Among patients with chronic systolic heart failure, elevated plasma

myeloperoxidase levels have been associated with an increased likelihood of more
advanced heart failure and may be predictive of a higher rate of adverse clinical
outcomes [182]. (See "Pathophysiology of heart failure with reduced ejection
fraction: Hemodynamic alterations and remodeling", section on 'Other factors'.)

Other inflammatory markers — Cardiovascular risk has also been associated

with a variety of other markers of inflammation, though to a lesser extent than
CRP. Elevated levels of white blood cells, erythrocyte sedimentation rates, IL-18,
tumor necrosis factor alpha, transforming growth factor beta, soluble intercellular
adhesion molecule-1, P-selectin, cathepsin S, and lipoprotein-associated
phospholipase A2 have been reported as markers of increased CHD risk [178-
180,182-204]. While this adds further support to the role of inflammation in the
development of atherosclerosis and CVD, most of these are not routinely used in
clinical practice.

HIV infection — Widespread use of effective antiretroviral therapies (ARTs) in the

treatment of human immunodeficiency virus (HIV) infection has led to increased
longevity, exposing HIV-positive patients to many common medical conditions
seen in an aging population, such as CVD. The risk of CVD in HIV-positive patients
is predominantly influenced by the presence of traditional CVD risk factors.
However, studies correcting for traditional CVD risk factors have shown higher
rates of CHD and MI in HIV-positive patients compared with HIV-negative controls.
:
 (See "Epidemiology of cardiovascular disease and risk factors in patients with HIV"
and "Management of cardiovascular risk (including dyslipidemia) in patients with
HIV".)

Mediastinal radiation — Exposure to mediastinal or chest wall radiation during

treatment for malignancy (eg, Hodgkin lymphoma, breast cancer) has been linked
to subsequent development of cardiac disease, including pericardial disease,
valvular disease, cardiomyopathy, and CHD. CHD following radiation tends to
involve the ostia of the left main and right coronary arteries and may manifest as
either angina or acute MI, potentially requiring revascularization. Furthermore, the
risk of cardiac disease may be further increased by treatment with systemic
anticancer agents (eg, anthracyclines, trastuzumab).

Females have a greater likelihood of having cardiovascular disease following

radiation than males. In a network meta-analysis of 10 studies among 13,975
patients who received radiation for Hodgkin lymphoma, incident CVD
events/mortality were more common in females (OR 3.74, 95% CI 2.44-5.72) as was
all-cause mortality (OR 1.94, 95% CI 1.10-3.44) [205]. This study was somewhat
limited by high heterogeneity among studies analyzed.

More information on the cardiac toxicity of mediastinal radiation and systemic

anticancer therapy is discussed elsewhere. (See "Clinical manifestations, diagnosis,
and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of
anthracycline cardiotoxicity" and "Cardiotoxicity of cancer chemotherapy agents
other than anthracyclines, HER2-targeted agents, and fluoropyrimidines" and
"Cardiotoxicity of trastuzumab and other HER2-targeted agents" and
"Cardiotoxicity of radiation therapy for Hodgkin lymphoma and pediatric
malignancies", section on 'Incidence of cardiovascular disease'.)

Metabolic syndrome — Patients with the constellation of abdominal obesity,

hypertension, diabetes, and dyslipidemia are considered to have the metabolic
syndrome (also called the insulin resistance syndrome or syndrome X). Individuals
with the metabolic syndrome have a markedly increased risk of coronary artery
disease. This disorder is discussed in detail elsewhere. (See "Metabolic syndrome
(insulin resistance syndrome or syndrome X)".)
:
 Microalbuminuria — Microalbuminuria (30 to 300 mg albumin/g creatinine in a
urine specimen) is an indicator of greater risk for CVD and deterioration in renal
function. Its presence appears to be a marker of early arterial disease. While
microalbuminuria is accepted as an important risk factor for CVD and early
cardiovascular mortality, the mechanism by which microalbuminuria is associated
with CVD remains unclear. (See "Moderately increased albuminuria
(microalbuminuria) and cardiovascular disease".)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries

and regions around the world are provided separately. (See "Society guideline
links: Assessment of cardiovascular risk".)

SUMMARY AND RECOMMENDATIONS

● Importance – Cardiovascular disease (CVD) is the leading cause of death in

most developed countries, with a prevalence that is rapidly increasing in
resource-limited countries as well. Many risk factors for CVD are modifiable
by specific preventive measures, therein offering an opportunity to reduce
the burden of CVD worldwide. (See 'Introduction' above.)

● High-risk patients – Some patients without known coronary heart disease

(CHD) have a risk of subsequent cardiovascular events that is equivalent to
that of patients with established coronary disease. Examples of such high-
risk patients include patients with noncoronary atherosclerotic arterial
disease, diabetes mellitus, and chronic kidney disease (CKD). All patients with
a CHD risk equivalent should be managed as aggressively as those with prior
CHD. (See 'Noncoronary atherosclerotic disease' above.)

● Family history – Family history is a significant independent risk factor for

CHD, particularly among younger individuals with a family history of
premature disease. (See 'Family history' above.)

● Hypertension and dyslipidemia – Hypertension and dyslipidemia are well

:
 established risk factors for CVD. Effectively treating both hypertension and
dyslipidemia can significantly reduce the risk of future CVD events. (See
'Hypertension' above and 'Lipids and lipoproteins' above.)

● Lifestyle factors – A variety of lifestyle factors, including cigarette smoking,

diet, exercise, alcohol intake, and obesity, significantly impact the risk of
developing CVD. (See 'Lifestyle factors' above.)

● Inflammation – Numerous markers of inflammation markers have been

reported to be associated with increased risk of CVD. (See 'Inflammation'
above.)

Use of UpToDate is subject to the Terms of Use.

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