Overview of established risk factors for cardiovascular disease

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".)

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.

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 [25]. 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 cardiovascular events'.)

PREVALENCE AND IMPACT OF CARDIOVASCULAR RISK FACTORS

●Prevalence of modifiable risk factors – Modifiable risk factors are common in the general population [26-28]. In two population-based cohort studies of White non-Hispanic United States adults (Framingham Heart Study and Third National Health and Nutrition Examination Survey [NHANES III]), approximately 60 percent of men and 50 percent of women without coronary artery disease (CAD) had one to two of five major coronary heart disease (CHD) risk factors (blood pressure, low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, glucose intolerance, and smoking) (table 2) [27]. In addition, 26 percent of men and 41 percent of women had at least one "borderline" risk factor (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) (table 3).

●Impact of modifiable risk factors – Modifiable risk factors account for over 50 percent of cardiovascular events and up to 90 percent of CHD events.

Modifiable risk factors account for more than half of cardiovascular disease events and cardiovascular mortality [29-31]. As an example, in an analysis of a global cohort of over 1,500,000 individuals, five modifiable risk factors (hypercholesterolemia, diabetes, hypertension, obesity, and smoking) accounted for 57 and 53 percent of 10-year incident cardiovascular disease [29]. Similarly, in a second global cohort of individuals from 21 countries, approximately 70 percent of cardiovascular disease cases were attributable to modifiable risk factors [30].

Modifiable risk factors may account for up to 90 percent of CHD events. An analysis of the Framingham Heart Study and the NHANES III cohort estimated that over 90 percent of CHD events occurred in individuals with at least one modifiable risk factor [27]. Conversely, few events occurred in those with no risk factors, although the complete absence of any elevated or borderline risk factor was rare (0 to 0.4 percent). Similarly, in the INTERHEART study of individuals 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 the greatest risk [26].

●Increased risk with multiple risk factors – Multiple risk factors confer increased cardiovascular risk and, conversely, the absence of major risk factors predicts a much lower risk of CHD [27,28,32-34]. As an example, in a cohort study of 20,000 adults, the presence of two or three risk factors (cholesterol ≥200 mg/dL [≥5.2 mmol/L], elevated blood pressure [≥120/80 mmHg], and cigarette smoking) was associated with a marked increase in the relative risk of CHD (5.5 and 5.7), cardiovascular disease (CVD; 4.1 and 4.5), and all-cause mortality (3.2 and 2.3) in men and women, respectively [33]. A cohort study of 380,000 individuals from Asia, Australia, and New Zealand reported similar results [34].

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) [35]. 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 [36,37]. (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 [38]. 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 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 [39-41].

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 [42,43]. 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 [44-46]:

●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) [46]. 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 [44]. 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 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 [45]. 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 [47-51]. 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) [52]. 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 [52]:

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

●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 [53]:

●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 [54-61]. 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) [62].

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, respectively) [63]. 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) [63]. 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 [64-66]. 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 [67,68]. (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 [69,70]. (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 [41]. 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 [71]. 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 [72,73]. 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 [74-76]. (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 [77]:

●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 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 [78-80]. 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) [80]. 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 [81]. (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) [82]. 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 [83-89]. 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 [90-92]. 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 revascularization in the absence of MI, peripheral artery disease, and abdominal aortic aneurysm (table 4) [92]. 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 [92]. (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 [93]. 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 [83,84,86,87,94-97]. 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 [92].

The importance of a family history of premature CVD death appears to be magnified in families with multiple premature deaths [98-100]. 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) [98]. 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 [99].

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 [88,101]. 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 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) [88]. 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) [90]. 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 [102]. 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.

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 [103,104]. 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 [26]. Greater variations in blood pressure from one visit to the next may also be associated with greater risk of CVD and mortality [105]. (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 [41,106]. 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 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 [107].

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 [85,108]. 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 [26].

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 [108]. 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 [109]. (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 [110-112]. 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 [113].

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 [114]. 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 [114].

Diabetes mellitus — Insulin resistance, hyperinsulinemia, and elevated blood glucose are associated with atherosclerotic CVD [115-122]. In the INTERHEART study, diabetes accounted for 10 percent of the population-attributable risk of a first MI [26]. The all-cause mortality risk associated with diabetes has been compared with the all-cause mortality risk associated with a prior MI [123].

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 [39,103]. There is compelling evidence of the value of aggressive therapy of serum cholesterol and hypertension in patients with diabetes [124-126]. (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 [127]. 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 [128,129].

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 [130]. 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 [69,70]. The risk of MI is proportional to tobacco consumption in both males and females and is higher in inhalers compared with non-inhalers [70]. In the INTERHEART study, smoking accounted for 36 percent of the population-attributable risk of a first MI [26].

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 [131]. 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), sugar sweetened beverages, 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).

•Consumption of sugar sweetened beverages – Consumption of sugar sweetened beverages has been associated with a higher risk of CHD [132].

•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 [133].

Exercise — Exercise of even moderate degree has a protective effect against CHD and all-cause mortality [26,76,134-137]. 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 [138-148].

●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 [134]. 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 [145].

●In the INTERHEART study, lack of regular physical activity accounted for 12 percent of the population-attributable risk of a first MI [26].

●Cardiovascular fitness has been assessed in several studies [142,143,146-148]. In a prospective study of 6213 men referred for exercise testing who were followed for a mean of 6.2 years [142], 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) [143]. 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 [147].

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 [149-156]. (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 [157]. (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 [158]. 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 [159-162]. 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 [163]. Additionally, there is a continuous linear relationship between higher BMI and greater risk of CVD [164,165]. 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) [51]. 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) [166]. 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 [167,168]. 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) [169-171]. 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 [172,173]. 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 [174-176]. (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 [177]. 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 [178,179]:

●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) [178].

●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) [179].

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 [180-183]. 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) [183].

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 [184]. (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 [180-182,184-206]. 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) [207]. 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.)