ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Overview of established risk factors for cardiovascular disease

Overview of established risk factors for cardiovascular disease
Literature review current through: Jan 2024.
This topic last updated: Oct 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.

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 risk modification'.)

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".)

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.)

  1. Laslett LJ, Alagona P Jr, Clark BA 3rd, et al. The worldwide environment of cardiovascular disease: prevalence, diagnosis, therapy, and policy issues: a report from the American College of Cardiology. J Am Coll Cardiol 2012; 60:S1.
  2. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015; 385:117.
  3. Roth GA, Huffman MD, Moran AE, et al. Global and regional patterns in cardiovascular mortality from 1990 to 2013. Circulation 2015; 132:1667.
  4. Benjamin EJ, Muntner P, Alonso A, et al. Heart Disease and Stroke Statistics-2019 Update: A Report From the American Heart Association. Circulation 2019; 139:e56.
  5. Rapsomaniki E, Timmis A, George J, et al. Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1·25 million people. Lancet 2014; 383:1899.
  6. Lopez AD, Mathers CD, Ezzati M, et al. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006; 367:1747.
  7. Lloyd-Jones DM, Larson MG, Beiser A, Levy D. Lifetime risk of developing coronary heart disease. Lancet 1999; 353:89.
  8. Berry JD, Dyer A, Cai X, et al. Lifetime risks of cardiovascular disease. N Engl J Med 2012; 366:321.
  9. Webber BJ, Seguin PG, Burnett DG, et al. Prevalence of and risk factors for autopsy-determined atherosclerosis among US service members, 2001-2011. JAMA 2012; 308:2577.
  10. Cooper R, Cutler J, Desvigne-Nickens P, et al. Trends and disparities in coronary heart disease, stroke, and other cardiovascular diseases in the United States: findings of the national conference on cardiovascular disease prevention. Circulation 2000; 102:3137.
  11. Smolina K, Wright FL, Rayner M, Goldacre MJ. Determinants of the decline in mortality from acute myocardial infarction in England between 2002 and 2010: linked national database study. BMJ 2012; 344:d8059.
  12. Schmidt M, Jacobsen JB, Lash TL, et al. 25 year trends in first time hospitalisation for acute myocardial infarction, subsequent short and long term mortality, and the prognostic impact of sex and comorbidity: a Danish nationwide cohort study. BMJ 2012; 344:e356.
  13. Bandosz P, O'Flaherty M, Drygas W, et al. Decline in mortality from coronary heart disease in Poland after socioeconomic transformation: modelling study. BMJ 2012; 344:d8136.
  14. Koton S, Schneider AL, Rosamond WD, et al. Stroke incidence and mortality trends in US communities, 1987 to 2011. JAMA 2014; 312:259.
  15. George J, Rapsomaniki E, Pujades-Rodriguez M, et al. How Does Cardiovascular Disease First Present in Women and Men? Incidence of 12 Cardiovascular Diseases in a Contemporary Cohort of 1,937,360 People. Circulation 2015; 132:1320.
  16. Nichols M, Townsend N, Scarborough P, Rayner M. Cardiovascular disease in Europe 2014: epidemiological update. Eur Heart J 2014; 35:2950.
  17. Ritchey MD, Wall HK, Gillespie C, et al. Million hearts: prevalence of leading cardiovascular disease risk factors--United States, 2005-2012. MMWR Morb Mortal Wkly Rep 2014; 63:462.
  18. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics--2014 update: a report from the American Heart Association. Circulation 2014; 129:e28.
  19. Hajat C, Harrison O. The Abu Dhabi Cardiovascular Program: the continuation of Framingham. Prog Cardiovasc Dis 2010; 53:28.
  20. Reddy KS, Satija A. The Framingham Heart Study: impact on the prevention and control of cardiovascular diseases in India. Prog Cardiovasc Dis 2010; 53:21.
  21. Vartiainen E, Laatikainen T, Peltonen M, et al. Thirty-five-year trends in cardiovascular risk factors in Finland. Int J Epidemiol 2010; 39:504.
  22. Moran AE, Forouzanfar MH, Roth GA, et al. The global burden of ischemic heart disease in 1990 and 2010: the Global Burden of Disease 2010 study. Circulation 2014; 129:1493.
  23. Moran AE, Forouzanfar MH, Roth GA, et al. Temporal trends in ischemic heart disease mortality in 21 world regions, 1980 to 2010: the Global Burden of Disease 2010 study. Circulation 2014; 129:1483.
  24. Yusuf S, Rangarajan S, Teo K, et al. Cardiovascular risk and events in 17 low-, middle-, and high-income countries. N Engl J Med 2014; 371:818.
  25. Steg PG, Bhatt DL, Wilson PW, et al. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA 2007; 297:1197.
  26. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364:937.
  27. Vasan RS, Sullivan LM, Wilson PW, et al. Relative importance of borderline and elevated levels of coronary heart disease risk factors. Ann Intern Med 2005; 142:393.
  28. Stamler J, Stamler R, Neaton JD, et al. Low risk-factor profile and long-term cardiovascular and noncardiovascular mortality and life expectancy: findings for 5 large cohorts of young adult and middle-aged men and women. JAMA 1999; 282:2012.
  29. Global Cardiovascular Risk Consortium, Magnussen C, Ojeda FM, et al. Global Effect of Modifiable Risk Factors on Cardiovascular Disease and Mortality. N Engl J Med 2023; 389:1273.
  30. Yusuf S, Joseph P, Rangarajan S, et al. Modifiable risk factors, cardiovascular disease, and mortality in 155 722 individuals from 21 high-income, middle-income, and low-income countries (PURE): a prospective cohort study. Lancet 2020; 395:795.
  31. Patel SA, Winkel M, Ali MK, et al. Cardiovascular mortality associated with 5 leading risk factors: national and state preventable fractions estimated from survey data. Ann Intern Med 2015; 163:245.
  32. Jackson R, Lawes CM, Bennett DA, et al. Treatment with drugs to lower blood pressure and blood cholesterol based on an individual's absolute cardiovascular risk. Lancet 2005; 365:434.
  33. Lowe LP, Greenland P, Ruth KJ, et al. Impact of major cardiovascular disease risk factors, particularly in combination, on 22-year mortality in women and men. Arch Intern Med 1998; 158:2007.
  34. Asia Pacific Cohort Studies Collaboration. Joint effects of systolic blood pressure and serum cholesterol on cardiovascular disease in the Asia Pacific region. Circulation 2005; 112:3384.
  35. Wilson PW. Established risk factors and coronary artery disease: the Framingham Study. Am J Hypertens 1994; 7:7S.
  36. Wilson PW, D'Agostino RB, Levy D, et al. Prediction of coronary heart disease using risk factor categories. Circulation 1998; 97:1837.
  37. Ridker PM. Evaluating novel cardiovascular risk factors: can we better predict heart attacks? Ann Intern Med 1999; 130:933.
  38. Jousilahti P, Vartiainen E, Tuomilehto J, Puska P. Sex, age, cardiovascular risk factors, and coronary heart disease: a prospective follow-up study of 14 786 middle-aged men and women in Finland. Circulation 1999; 99:1165.
  39. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002; 106:3143.
  40. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:837.
  41. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311:507.
  42. Hennekens CH. Increasing burden of cardiovascular disease: current knowledge and future directions for research on risk factors. Circulation 1998; 97:1095.
  43. Canto JG, Iskandrian AE. Major risk factors for cardiovascular disease: debunking the "only 50%" myth. JAMA 2003; 290:947.
  44. Greenland P, Knoll MD, Stamler J, et al. Major risk factors as antecedents of fatal and nonfatal coronary heart disease events. JAMA 2003; 290:891.
  45. Khot UN, Khot MB, Bajzer CT, et al. Prevalence of conventional risk factors in patients with coronary heart disease. JAMA 2003; 290:898.
  46. Canto JG, Kiefe CI, Rogers WJ, et al. Number of coronary heart disease risk factors and mortality in patients with first myocardial infarction. JAMA 2011; 306:2120.
  47. Stevens SL, Wood S, Koshiaris C, et al. Blood pressure variability and cardiovascular disease: systematic review and meta-analysis. BMJ 2016; 354:i4098.
  48. Gosmanova EO, Mikkelsen MK, Molnar MZ, et al. Association of Systolic Blood Pressure Variability With Mortality, Coronary Heart Disease, Stroke, and Renal Disease. J Am Coll Cardiol 2016; 68:1375.
  49. Bangalore S, Breazna A, DeMicco DA, et al. Visit-to-visit low-density lipoprotein cholesterol variability and risk of cardiovascular outcomes: insights from the TNT trial. J Am Coll Cardiol 2015; 65:1539.
  50. Kim MK, Han K, Kim HS, et al. Cholesterol variability and the risk of mortality, myocardial infarction, and stroke: a nationwide population-based study. Eur Heart J 2017; 38:3560.
  51. Bangalore S, Fayyad R, Laskey R, et al. Body-Weight Fluctuations and Outcomes in Coronary Disease. N Engl J Med 2017; 376:1332.
  52. Gregg EW, Cheng YJ, Cadwell BL, et al. Secular trends in cardiovascular disease risk factors according to body mass index in US adults. JAMA 2005; 293:1868.
  53. Lloyd-Jones DM, Hong Y, Labarthe D, et al. Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association's strategic Impact Goal through 2020 and beyond. Circulation 2010; 121:586.
  54. Yang Q, Cogswell ME, Flanders WD, et al. Trends in cardiovascular health metrics and associations with all-cause and CVD mortality among US adults. JAMA 2012; 307:1273.
  55. Ford ES, Greenlund KJ, Hong Y. Ideal cardiovascular health and mortality from all causes and diseases of the circulatory system among adults in the United States. Circulation 2012; 125:987.
  56. Hwang SJ, Onuma O, Massaro JM, et al. Maintenance of Ideal Cardiovascular Health and Coronary Artery Calcium Progression in Low-Risk Men and Women in the Framingham Heart Study. Circ Cardiovasc Imaging 2018; 11:e006209.
  57. Dong C, Rundek T, Wright CB, et al. Ideal cardiovascular health predicts lower risks of myocardial infarction, stroke, and vascular death across whites, blacks, and hispanics: the northern Manhattan study. Circulation 2012; 125:2975.
  58. Akesson A, Larsson SC, Discacciati A, Wolk A. Low-risk diet and lifestyle habits in the primary prevention of myocardial infarction in men: a population-based prospective cohort study. J Am Coll Cardiol 2014; 64:1299.
  59. Record NB, Onion DK, Prior RE, et al. Community-wide cardiovascular disease prevention programs and health outcomes in a rural county, 1970-2010. JAMA 2015; 313:147.
  60. Chomistek AK, Chiuve SE, Eliassen AH, et al. Healthy lifestyle in the primordial prevention of cardiovascular disease among young women. J Am Coll Cardiol 2015; 65:43.
  61. Li Y, Pan A, Wang DD, et al. Impact of Healthy Lifestyle Factors on Life Expectancies in the US Population. Circulation 2018; 138:345.
  62. Ramírez-Vélez R, Saavedra JM, Lobelo F, et al. Ideal Cardiovascular Health and Incident Cardiovascular Disease Among Adults: A Systematic Review and Meta-analysis. Mayo Clin Proc 2018; 93:1589.
  63. Yang ZJ, Liu J, Ge JP, et al. Prevalence of cardiovascular disease risk factor in the Chinese population: the 2007-2008 China National Diabetes and Metabolic Disorders Study. Eur Heart J 2012; 33:213.
  64. Li S, Chen W, Srinivasan SR, et al. Childhood cardiovascular risk factors and carotid vascular changes in adulthood: the Bogalusa Heart Study. JAMA 2003; 290:2271.
  65. Raitakari OT, Juonala M, Kähönen M, et al. Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study. JAMA 2003; 290:2277.
  66. Davis PH, Dawson JD, Riley WA, Lauer RM. Carotid intimal-medial thickness is related to cardiovascular risk factors measured from childhood through middle age: The Muscatine Study. Circulation 2001; 104:2815.
  67. Fox CS, Coady S, Sorlie PD, et al. Trends in cardiovascular complications of diabetes. JAMA 2004; 292:2495.
  68. Fox CS, Pencina MJ, Wilson PW, et al. Lifetime risk of cardiovascular disease among individuals with and without diabetes stratified by obesity status in the Framingham heart study. Diabetes Care 2008; 31:1582.
  69. Njølstad I, Arnesen E, Lund-Larsen PG. Smoking, serum lipids, blood pressure, and sex differences in myocardial infarction. A 12-year follow-up of the Finnmark Study. Circulation 1996; 93:450.
  70. Prescott E, Hippe M, Schnohr P, et al. Smoking and risk of myocardial infarction in women and men: longitudinal population study. BMJ 1998; 316:1043.
  71. Franklin SS, Larson MG, Khan SA, et al. Does the relation of blood pressure to coronary heart disease risk change with aging? The Framingham Heart Study. Circulation 2001; 103:1245.
  72. Harris T, Cook EF, Kannel WB, Goldman L. Proportional hazards analysis of risk factors for coronary heart disease in individuals aged 65 or older. The Framingham Heart Study. J Am Geriatr Soc 1988; 36:1023.
  73. Wilson PW, Kannel WB. Hypercholesterolemia and Coronary Risk in the Elderly: The Framingham Study. Am J Geriatr Cardiol 1993; 2:56.
  74. Hung J, Whitford EG, Parsons RW, Hillman DR. Association of sleep apnoea with myocardial infarction in men. Lancet 1990; 336:261.
  75. Dannenberg AL, Keller JB, Wilson PW, Castelli WP. Leisure time physical activity in the Framingham Offspring Study. Description, seasonal variation, and risk factor correlates. Am J Epidemiol 1989; 129:76.
  76. Powell KE, Thompson PD, Caspersen CJ, Kendrick JS. Physical activity and the incidence of coronary heart disease. Annu Rev Public Health 1987; 8:253.
  77. Savji N, Rockman CB, Skolnick AH, et al. Association between advanced age and vascular disease in different arterial territories: a population database of over 3.6 million subjects. J Am Coll Cardiol 2013; 61:1736.
  78. Tunstall-Pedoe H, Kuulasmaa K, Mähönen M, et al. Contribution of trends in survival and coronary-event rates to changes in coronary heart disease mortality: 10-year results from 37 WHO MONICA project populations. Monitoring trends and determinants in cardiovascular disease. Lancet 1999; 353:1547.
  79. D'Agostino RB Sr, Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation 2008; 117:743.
  80. Kappert K, Böhm M, Schmieder R, et al. Impact of sex on cardiovascular outcome in patients at high cardiovascular risk: analysis of the Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects With Cardiovascular Disease (TRANSCEND) and the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET). Circulation 2012; 126:934.
  81. Gordon T, Kannel WB, Hjortland MC, McNamara PM. Menopause and coronary heart disease. The Framingham Study. Ann Intern Med 1978; 89:157.
  82. Charchar FJ, Bloomer LD, Barnes TA, et al. Inheritance of coronary artery disease in men: an analysis of the role of the Y chromosome. Lancet 2012; 379:915.
  83. Sesso HD, Lee IM, Gaziano JM, et al. Maternal and paternal history of myocardial infarction and risk of cardiovascular disease in men and women. Circulation 2001; 104:393.
  84. Andresdottir MB, Sigurdsson G, Sigvaldason H, et al. Fifteen percent of myocardial infarctions and coronary revascularizations explained by family history unrelated to conventional risk factors. The Reykjavik Cohort Study. Eur Heart J 2002; 23:1655.
  85. Roncaglioni MC, Santoro L, D'Avanzo B, et al. Role of family history in patients with myocardial infarction. An Italian case-control study. GISSI-EFRIM Investigators. Circulation 1992; 85:2065.
  86. Lloyd-Jones DM, Nam BH, D'Agostino RB Sr, et al. Parental cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults: a prospective study of parents and offspring. JAMA 2004; 291:2204.
  87. Murabito JM, Pencina MJ, Nam BH, et al. Sibling cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults. JAMA 2005; 294:3117.
  88. Sivapalaratnam S, Boekholdt SM, Trip MD, et al. Family history of premature coronary heart disease and risk prediction in the EPIC-Norfolk prospective population study. Heart 2010; 96:1985.
  89. Otaki Y, Gransar H, Berman DS, et al. Impact of family history of coronary artery disease in young individuals (from the CONFIRM registry). Am J Cardiol 2013; 111:1081.
  90. Berg AO, Baird MA, Botkin JR, et al. National Institutes of Health State-of-the-Science Conference Statement: Family History and Improving Health. Ann Intern Med 2009; 151:872.
  91. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 63:2889.
  92. Patel J, Al Rifai M, Scheuner MT, et al. Basic vs More Complex Definitions of Family History in the Prediction of Coronary Heart Disease: The Multi-Ethnic Study of Atherosclerosis. Mayo Clin Proc 2018; 93:1213.
  93. Benjamin EJ, Blaha MJ, Chiuve SE, et al. Heart Disease and Stroke Statistics-2017 Update: A Report From the American Heart Association. Circulation 2017; 135:e146.
  94. Bachmann JM, Willis BL, Ayers CR, et al. Association between family history and coronary heart disease death across long-term follow-up in men: the Cooper Center Longitudinal Study. Circulation 2012; 125:3092.
  95. Chow CK, Islam S, Bautista L, et al. Parental history and myocardial infarction risk across the world: the INTERHEART Study. J Am Coll Cardiol 2011; 57:619.
  96. Nielsen M, Andersson C, Gerds TA, et al. Familial clustering of myocardial infarction in first-degree relatives: a nationwide study. Eur Heart J 2013; 34:1198.
  97. Paixao AR, Berry JD, Neeland IJ, et al. Coronary artery calcification and family history of myocardial infarction in the Dallas heart study. JACC Cardiovasc Imaging 2014; 7:679.
  98. Ranthe MF, Carstensen L, Oyen N, et al. Family history of premature death and risk of early onset cardiovascular disease. J Am Coll Cardiol 2012; 60:814.
  99. Zöller B, Li X, Sundquist J, Sundquist K. Multiplex sibling history of coronary heart disease is a strong risk factor for coronary heart disease. Eur Heart J 2012; 33:2849.
  100. Kral BG, Becker LC, Vaidya D, et al. Noncalcified coronary plaque volumes in healthy people with a family history of early onset coronary artery disease. Circ Cardiovasc Imaging 2014; 7:446.
  101. Qureshi N, Armstrong S, Dhiman P, et al. Effect of adding systematic family history enquiry to cardiovascular disease risk assessment in primary care: a matched-pair, cluster randomized trial. Ann Intern Med 2012; 156:253.
  102. Murabito JM, Nam BH, D'Agostino RB Sr, et al. Accuracy of offspring reports of parental cardiovascular disease history: the Framingham Offspring Study. Ann Intern Med 2004; 140:434.
  103. Miura K, Daviglus ML, Dyer AR, et al. Relationship of blood pressure to 25-year mortality due to coronary heart disease, cardiovascular diseases, and all causes in young adult men: the Chicago Heart Association Detection Project in Industry. Arch Intern Med 2001; 161:1501.
  104. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360:1903.
  105. Muntner P, Whittle J, Lynch AI, et al. Visit-to-Visit Variability of Blood Pressure and Coronary Heart Disease, Stroke, Heart Failure, and Mortality: A Cohort Study. Ann Intern Med 2015; 163:329.
  106. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 25:1105.
  107. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002; 106:3143.
  108. Genest JJ Jr, Martin-Munley SS, McNamara JR, et al. Familial lipoprotein disorders in patients with premature coronary artery disease. Circulation 1992; 85:2025.
  109. Ference BA, Bhatt DL, Catapano AL, et al. Association of Genetic Variants Related to Combined Exposure to Lower Low-Density Lipoproteins and Lower Systolic Blood Pressure With Lifetime Risk of Cardiovascular Disease. JAMA 2019; 322:1381.
  110. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995; 333:1301.
  111. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998; 279:1615.
  112. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996; 335:1001.
  113. Fernández-Friera L, Fuster V, López-Melgar B, et al. Normal LDL-Cholesterol Levels Are Associated With Subclinical Atherosclerosis in the Absence of Risk Factors. J Am Coll Cardiol 2017; 70:2979.
  114. Mora S, Otvos JD, Rifai N, et al. Lipoprotein particle profiles by nuclear magnetic resonance compared with standard lipids and apolipoproteins in predicting incident cardiovascular disease in women. Circulation 2009; 119:931.
  115. Kannel WB, McGee DL. Diabetes and cardiovascular risk factors: the Framingham study. Circulation 1979; 59:8.
  116. Kannel WB, McGee DL. Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framingham study. Diabetes Care 1979; 2:120.
  117. Almdal T, Scharling H, Jensen JS, Vestergaard H. The independent effect of type 2 diabetes mellitus on ischemic heart disease, stroke, and death: a population-based study of 13,000 men and women with 20 years of follow-up. Arch Intern Med 2004; 164:1422.
  118. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988; 37:1595.
  119. Zavaroni I, Bonora E, Pagliara M, et al. Risk factors for coronary artery disease in healthy persons with hyperinsulinemia and normal glucose tolerance. N Engl J Med 1989; 320:702.
  120. Singer DE, Nathan DM, Anderson KM, et al. Association of HbA1c with prevalent cardiovascular disease in the original cohort of the Framingham Heart Study. Diabetes 1992; 41:202.
  121. Gerstein HC, Pais P, Pogue J, Yusuf S. Relationship of glucose and insulin levels to the risk of myocardial infarction: a case-control study. J Am Coll Cardiol 1999; 33:612.
  122. Al-Delaimy WK, Merchant AT, Rimm EB, et al. Effect of type 2 diabetes and its duration on the risk of peripheral arterial disease among men. Am J Med 2004; 116:236.
  123. Vaccaro O, Eberly LE, Neaton JD, et al. Impact of diabetes and previous myocardial infarction on long-term survival: 25-year mortality follow-up of primary screenees of the Multiple Risk Factor Intervention Trial. Arch Intern Med 2004; 164:1438.
  124. Heart Outcomes Prevention Evaluation Study Investigators, Yusuf S, Sleight P, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342:145.
  125. Fox KM, EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003; 362:782.
  126. Nissen SE, Tuzcu EM, Libby P, et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA 2004; 292:2217.
  127. Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, et al. Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet 2013; 382:339.
  128. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002; 39:S1.
  129. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction. www.acc.org/qualityandscience/clinical/statements.htm (Accessed on August 24, 2006).
  130. Hakeem A, Bhatti S, Dillie KS, et al. Predictive value of myocardial perfusion single-photon emission computed tomography and the impact of renal function on cardiac death. Circulation 2008; 118:2540.
  131. Wilhelmsson C, Vedin JA, Elmfeldt D, et al. Smoking and myocardial infarction. Lancet 1975; 1:415.
  132. Huang Y, Chen Z, Chen B, et al. Dietary sugar consumption and health: umbrella review. BMJ 2023; 381:e071609.
  133. https://health.gov/dietaryguidelines/2015/guidelines/chapter-1/a-closer-look-inside-healthy-eating-patterns/ (Accessed on March 19, 2019).
  134. Paffenbarger RS Jr, Hyde RT, Wing AL, et al. The association of changes in physical-activity level and other lifestyle characteristics with mortality among men. N Engl J Med 1993; 328:538.
  135. Leon AS, Connett J, Jacobs DR Jr, Rauramaa R. Leisure-time physical activity levels and risk of coronary heart disease and death. The Multiple Risk Factor Intervention Trial. JAMA 1987; 258:2388.
  136. Lee DC, Sui X, Artero EG, et al. Long-term effects of changes in cardiorespiratory fitness and body mass index on all-cause and cardiovascular disease mortality in men: the Aerobics Center Longitudinal Study. Circulation 2011; 124:2483.
  137. Kubota Y, Evenson KR, Maclehose RF, et al. Physical Activity and Lifetime Risk of Cardiovascular Disease and Cancer. Med Sci Sports Exerc 2017; 49:1599.
  138. Sandvik L, Erikssen J, Thaulow E, et al. Physical fitness as a predictor of mortality among healthy, middle-aged Norwegian men. N Engl J Med 1993; 328:533.
  139. Blair SN, Kohl HW 3rd, Paffenbarger RS Jr, et al. Physical fitness and all-cause mortality. A prospective study of healthy men and women. JAMA 1989; 262:2395.
  140. LaMonte MJ, Eisenman PA, Adams TD, et al. Cardiorespiratory fitness and coronary heart disease risk factors: the LDS Hospital Fitness Institute cohort. Circulation 2000; 102:1623.
  141. Laukkanen JA, Lakka TA, Rauramaa R, et al. Cardiovascular fitness as a predictor of mortality in men. Arch Intern Med 2001; 161:825.
  142. Myers J, Prakash M, Froelicher V, et al. Exercise capacity and mortality among men referred for exercise testing. N Engl J Med 2002; 346:793.
  143. Barlow CE, Defina LF, Radford NB, et al. Cardiorespiratory fitness and long-term survival in "low-risk" adults. J Am Heart Assoc 2012; 1:e001354.
  144. Mandsager K, Harb S, Cremer P, et al. Association of Cardiorespiratory Fitness With Long-term Mortality Among Adults Undergoing Exercise Treadmill Testing. JAMA Netw Open 2018; 1:e183605.
  145. Held C, Iqbal R, Lear SA, et al. Physical activity levels, ownership of goods promoting sedentary behaviour and risk of myocardial infarction: results of the INTERHEART study. Eur Heart J 2012; 33:452.
  146. Berry JD, Willis B, Gupta S, et al. Lifetime risks for cardiovascular disease mortality by cardiorespiratory fitness levels measured at ages 45, 55, and 65 years in men. The Cooper Center Longitudinal Study. J Am Coll Cardiol 2011; 57:1604.
  147. Clausen JSR, Marott JL, Holtermann A, et al. Midlife Cardiorespiratory Fitness and the Long-Term Risk of Mortality: 46 Years of Follow-Up. J Am Coll Cardiol 2018; 72:987.
  148. Imboden MT, Harber MP, Whaley MH, et al. Cardiorespiratory Fitness and Mortality in Healthy Men and Women. J Am Coll Cardiol 2018; 72:2283.
  149. Ho SS, Dhaliwal SS, Hills AP, Pal S. The effect of 12 weeks of aerobic, resistance or combination exercise training on cardiovascular risk factors in the overweight and obese in a randomized trial. BMC Public Health 2012; 12:704.
  150. Kerksick C, Thomas A, Campbell B, et al. Effects of a popular exercise and weight loss program on weight loss, body composition, energy expenditure and health in obese women. Nutr Metab (Lond) 2009; 6:23.
  151. Mekary RA, Grøntved A, Despres JP, et al. Weight training, aerobic physical activities, and long-term waist circumference change in men. Obesity (Silver Spring) 2015; 23:461.
  152. Hunter GR, Bryan DR, Wetzstein CJ, et al. Resistance training and intra-abdominal adipose tissue in older men and women. Med Sci Sports Exerc 2002; 34:1023.
  153. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346:393.
  154. Ross R. Effects of diet- and exercise-induced weight loss on visceral adipose tissue in men and women. Sports Med 1997; 24:55.
  155. Curioni CC, Lourenço PM. Long-term weight loss after diet and exercise: a systematic review. Int J Obes (Lond) 2005; 29:1168.
  156. Mann S, Beedie C, Jimenez A. Differential effects of aerobic exercise, resistance training and combined exercise modalities on cholesterol and the lipid profile: review, synthesis and recommendations. Sports Med 2014; 44:211.
  157. Piercy KL, Trolano RP, Ballard RM, et al.. The Physical Activity Guidelines for Americans. J Am Med Assoc 2018.
  158. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011-2012. JAMA 2014; 311:806.
  159. Eckel RH, York DA, Rössner S, et al. Prevention Conference VII: Obesity, a worldwide epidemic related to heart disease and stroke: executive summary. Circulation 2004; 110:2968.
  160. Calle EE, Thun MJ, Petrelli JM, et al. Body-mass index and mortality in a prospective cohort of U.S. adults. N Engl J Med 1999; 341:1097.
  161. Wolk R, Berger P, Lennon RJ, et al. Association between plasma adiponectin levels and unstable coronary syndromes. Eur Heart J 2007; 28:292.
  162. Tirosh A, Shai I, Afek A, et al. Adolescent BMI trajectory and risk of diabetes versus coronary disease. N Engl J Med 2011; 364:1315.
  163. Wilson PW, Bozeman SR, Burton TM, et al. Prediction of first events of coronary heart disease and stroke with consideration of adiposity. Circulation 2008; 118:124.
  164. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation 2014; 129:S102.
  165. Twig G, Yaniv G, Levine H, et al. Body-Mass Index in 2.3 Million Adolescents and Cardiovascular Death in Adulthood. N Engl J Med 2016; 374:2430.
  166. Walli-Attaei M, Rosengren A, Rangarajan S, et al. Metabolic, behavioural, and psychosocial risk factors and cardiovascular disease in women compared with men in 21 high-income, middle-income, and low-income countries: an analysis of the PURE study. Lancet 2022; 400:811.
  167. Emerging Risk Factors Collaboration, Kaptoge S, Di Angelantonio E, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 2010; 375:132.
  168. Antonopoulos AS, Angelopoulos A, Papanikolaou P, et al. Biomarkers of Vascular Inflammation for Cardiovascular Risk Prognostication: A Meta-Analysis. JACC Cardiovasc Imaging 2022; 15:460.
  169. Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation 1998; 97:2007.
  170. Koenig W, Sund M, Fröhlich M, et al. C-Reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation 1999; 99:237.
  171. Ridker PM, Buring JE, Shih J, et al. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 1998; 98:731.
  172. Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA 2007; 297:611.
  173. Wilson PW, Pencina M, Jacques P, et al. C-reactive protein and reclassification of cardiovascular risk in the Framingham Heart Study. Circ Cardiovasc Qual Outcomes 2008; 1:92.
  174. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003; 107:499.
  175. Genest J, McPherson R, Frohlich J, et al. 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult - 2009 recommendations. Can J Cardiol 2009; 25:567.
  176. US Preventive Services Task Force, Curry SJ, Krist AH, et al. Risk Assessment for Cardiovascular Disease With Nontraditional Risk Factors: US Preventive Services Task Force Recommendation Statement. JAMA 2018; 320:272.
  177. Reich D, Patterson N, Ramesh V, et al. Admixture mapping of an allele affecting interleukin 6 soluble receptor and interleukin 6 levels. Am J Hum Genet 2007; 80:716.
  178. IL6R Genetics Consortium Emerging Risk Factors Collaboration, Sarwar N, Butterworth AS, et al. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet 2012; 379:1205.
  179. Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium, Swerdlow DI, Holmes MV, et al. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. Lancet 2012; 379:1214.
  180. Brennan ML, Penn MS, Van Lente F, et al. Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med 2003; 349:1595.
  181. Zheng L, Nukuna B, Brennan ML, et al. Apolipoprotein A-I is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease. J Clin Invest 2004; 114:529.
  182. Zhang R, Brennan ML, Fu X, et al. Association between myeloperoxidase levels and risk of coronary artery disease. JAMA 2001; 286:2136.
  183. Karakas M, Koenig W, Zierer A, et al. Myeloperoxidase is associated with incident coronary heart disease independently of traditional risk factors: results from the MONICA/KORA Augsburg study. J Intern Med 2012; 271:43.
  184. Tang WH, Tong W, Troughton RW, et al. Prognostic value and echocardiographic determinants of plasma myeloperoxidase levels in chronic heart failure. J Am Coll Cardiol 2007; 49:2364.
  185. Horne BD, Anderson JL, John JM, et al. Which white blood cell subtypes predict increased cardiovascular risk? J Am Coll Cardiol 2005; 45:1638.
  186. Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004; 350:1387.
  187. Pai JK, Pischon T, Ma J, et al. Inflammatory markers and the risk of coronary heart disease in men and women. N Engl J Med 2004; 351:2599.
  188. Woods A, Brull DJ, Humphries SE, Montgomery HE. Genetics of inflammation and risk of coronary artery disease: the central role of interleukin-6. Eur Heart J 2000; 21:1574.
  189. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000; 101:1767.
  190. Blankenberg S, Tiret L, Bickel C, et al. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation 2002; 106:24.
  191. Tiret L, Godefroy T, Lubos E, et al. Genetic analysis of the interleukin-18 system highlights the role of the interleukin-18 gene in cardiovascular disease. Circulation 2005; 112:643.
  192. Valgimigli M, Ceconi C, Malagutti P, et al. Tumor necrosis factor-alpha receptor 1 is a major predictor of mortality and new-onset heart failure in patients with acute myocardial infarction: the Cytokine-Activation and Long-Term Prognosis in Myocardial Infarction (C-ALPHA) study. Circulation 2005; 111:863.
  193. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000; 342:836.
  194. Ridker PM, Buring JE, Rifai N. Soluble P-selectin and the risk of future cardiovascular events. Circulation 2001; 103:491.
  195. Haim M, Tanne D, Boyko V, et al. Soluble intercellular adhesion molecule-1 and long-term risk of acute coronary events in patients with chronic coronary heart disease. Data from the Bezafibrate Infarction Prevention (BIP) Study. J Am Coll Cardiol 2002; 39:1133.
  196. Blankenberg S, Rupprecht HJ, Bickel C, et al. Circulating cell adhesion molecules and death in patients with coronary artery disease. Circulation 2001; 104:1336.
  197. Malik I, Danesh J, Whincup P, et al. Soluble adhesion molecules and prediction of coronary heart disease: a prospective study and meta-analysis. Lancet 2001; 358:971.
  198. Roldán V, Marín F, Lip GY, Blann AD. Soluble E-selectin in cardiovascular disease and its risk factors. A review of the literature. Thromb Haemost 2003; 90:1007.
  199. Oei HH, van der Meer IM, Hofman A, et al. Lipoprotein-associated phospholipase A2 activity is associated with risk of coronary heart disease and ischemic stroke: the Rotterdam Study. Circulation 2005; 111:570.
  200. Ballantyne CM, Hoogeveen RC, Bang H, et al. Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Circulation 2004; 109:837.
  201. Packard CJ, O'Reilly DS, Caslake MJ, et al. Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. West of Scotland Coronary Prevention Study Group. N Engl J Med 2000; 343:1148.
  202. Koenig W, Khuseyinova N, Löwel H, et al. Lipoprotein-associated phospholipase A2 adds to risk prediction of incident coronary events by C-reactive protein in apparently healthy middle-aged men from the general population: results from the 14-year follow-up of a large cohort from southern Germany. Circulation 2004; 110:1903.
  203. Blake GJ, Dada N, Fox JC, et al. A prospective evaluation of lipoprotein-associated phospholipase A(2) levels and the risk of future cardiovascular events in women. J Am Coll Cardiol 2001; 38:1302.
  204. Garza CA, Montori VM, McConnell JP, et al. Association between lipoprotein-associated phospholipase A2 and cardiovascular disease: a systematic review. Mayo Clin Proc 2007; 82:159.
  205. Jobs E, Ingelsson E, Risérus U, et al. Association between serum cathepsin S and mortality in older adults. JAMA 2011; 306:1113.
  206. Agarwal I, Glazer NL, Barasch E, et al. Fibrosis-related biomarkers and risk of total and cause-specific mortality: the cardiovascular health study. Am J Epidemiol 2014; 179:1331.
  207. Khalid Y, Fradley M, Dasu N, et al. Gender disparity in cardiovascular mortality following radiation therapy for Hodgkin's lymphoma: a systematic review. Cardiooncology 2020; 6:12.
Topic 1506 Version 76.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟