Risk Factors for Coronary Artery Disease

Risk Factor Biomarkers

Risk factors for coronary artery disease (CAD) were not formally established until the initial findings of the Framingham Heart Study in the early 1960s. The understanding of such factors is critical for a clinician to prevent cardiovascular morbidities and mortality.[1, 2] See the image below for traditional and nontraditional risk factor biomarkers.

Traditional versus nontraditional risk factors for coronary artery disease (CAD). The expanding list of nontraditional biomarkers is outweighed by the standard risk factors for predicting future cardiovascular events and adds only moderately to standard risk factors. BNP = B-type natriuretic peptide; BP = blood pressure; CRP = C-reactive protein; HDL = high-density lipoprotein cholesterol; HIV = human immunodeficiency virus infection.

For more information see Coronary Artery Disease.

NextConventional Risk Factors

The risk of developing coronary artery disease (CAD) increases with age, and includes age greater than 45 years in men and greater than 55 years in women.

A family history of early heart disease is also a risk factor, including heart disease in the father or a brother diagnosed before age 55 years and in the mother or a sister diagnosed before age 65 years.

The prospective, observational Reduction of Atherothrombosis for Continued Health (REACH) registry, a large international study of individuals with atherothrombotic disease, documented ethnic-specific differences in cardiovascular risk factors and variations in cardiovascular mortality worldwide. The study found that although prevalence of traditional atherothrombotic risk factors widely varied among the ethnic and racial groups, the use of medical therapies to reduce risk was comparable among all groups. At 2-year follow-up, the rate of cardiovascular death was significantly higher in blacks, and cardiovascular death rates were significantly lower in the Asian groups.[3]

Results from the Atherosclerosis Risk in Communities (ARIC) study suggest that lipoprotein(a) levels are positively associated with cardiovascular disease events, and that these associations were at least as strong, with a larger range of lipoprotein(a) concentrations, in blacks compared with whites.[4]

One meta-analysis by Huxley et al suggests that isolated low high-density lipoprotein cholesterol (HDL-C) is a novel lipid phenotype that appears to be more prevalent among Asian populations; this phenotype also increases the risk of coronary heart disease in the Asian population.[5]

The American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) have produced guidelines for the procedures of detection, management, or prevention of cardiovascular disease. One set of recommendations focuses on cardiovascular risk in asymptomatic results, and these recommendations are discussed below.[6]

For all asymptomatic adults, global risk scoring should be performed and a family history of cardiovascular disease should be obtained for cardiovascular risk assessment.

The ACCF/AHA 2010 guideline does not recommend the following measures for coronary heart disease risk assessment in asymptomatic adults:

Measurement of lipid parameters beyond a standard fasting lipid profile (A standard fasting lipid profile is recommended as part of global risk scoring.) Brachial/peripheral arterial flow-mediated dilation studiesSpecific measures of arterial stiffnessCoronary computed tomography angiographyMRI for detection of vascular plaque

Other tests and measures for cardiovascular risk assessment in asymptomatic adults are recommended as reasonable, might be reasonable, or may be considered for specific patient populations and risk levels:

A resting electrocardiogram (ECG) is reasonable for asymptomatic adults with hypertension or diabetes and may be considered in asymptomatic adults without hypertension or diabetes. An exercise ECG may be considered in intermediate-risk asymptomatic adults (including sedentary adults considering starting a vigorous exercise program), particularly when attention is paid to non-ECG markers such as exercise capacity. Transthoracic echocardiography to detect left ventricular hypertrophy may be considered for asymptomatic adults with hypertension but is not recommended in asymptomatic adults without hypertension. Stress echocardiography is not indicated for low- or intermediate-risk asymptomatic adults.Coronary artery calcium (CAC) measurement is reasonable for asymptomatic intermediate-risk adults but should not be performed for persons at low risk; it may be reasonable when the patient’s risk falls between low and intermediate. For cardiovascular risk assessment in asymptomatic adults with diabetes mellitus, measurement of CAC is reasonable in patients older than 40 years. Measurement of hemoglobin A1C and stress myocardial perfusion imaging (MPI) may be considered. MRI among asymptomatic individuals with regional myocardial dysfunction (RMD) is an independent predictor beyond traditional risk factors and global left ventricle (LV) assessment for incident heart failure and atherosclerotic cardiovascular events.[7] The Heart and Estrogen/progestin Replacement Study evaluated the effects of hormone replacement therapy on cardiovascular events among 2763 postmenopausal women with CAD. Sudden cardiac death comprised most cardiac deaths among these postmenopausal women. Independent predictors of sudden cardiac death included myocardial infarction, congestive heart failure, an estimated glomerular filtration rate of less than 40 mL/min/1.73 m2, atrial fibrillation, physical inactivity, and diabetes. These risk factors should be considered when left ventricular ejection fraction (LVEF) is present.[8] PreviousNextModifiable Risk Factors

Odegaard et al suggest that an increasing number of protective lifestyle factors are associated with a marked decrease in risk of coronary heart disease, cerebrovascular disease, and overall CVD mortality in Chinese men and women. Protective lifestyle factors included dietary pattern, physical activity, alcohol intake, usual sleep, smoking status, and body mass index.[9]

High blood cholesterol levels

The Framingham Heart Study results demonstrated that the higher the cholesterol level, the greater the risk of coronary artery disease (CAD); alternatively, CAD was uncommon in people with cholesterol levels below 150 mg/dL. In 1984, the Lipid Research Clinics-Coronary Primary Prevention Trial revealed that lowering total and LDL or bad cholesterol levels significantly reduced CAD. More recent series of clinical trials using statin drugs have provided conclusive evidence that lowering LDL cholesterol reduces the rate of myocardial infarction (MI), the need for percutaneous coronary intervention and the mortality associated with CAD-related causes.[10]

High blood pressure

Of the 50 million Americans with hypertension, almost one third evade diagnosis and only one fourth receive effective treatment.[11] In the Framingham Heart Study, even high-normal blood pressure (defined as a systolic blood pressure of 130-139 mm Hg, diastolic blood pressure of 85-89 mm Hg, or both) increased the risk of cardiovascular disease 2-fold, as compared with healthy individuals.[12]

A study by Allen et al found that people who have increases or decreases in blood pressure during middle age have associated higher and lower remaining lifetime risk for cardiovascular disease. This suggests that prevention efforts should continue to emphasize the importance of lowering blood pressure in order to avoid hypertension.[13]

The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) emphasizes weight control; adoption of the Dietary Approaches to Stop Hypertension (DASH) diet, with sodium restriction and increased intake of potassium and calcium-rich foods; moderation of alcohol consumption to less than 2 drinks daily; and increased physical activity.[11]

A meta-analysis performed by Nordmann et al found that the Mediterranean diet had more favorable changes in weighted mean differences of body weight, body mass index, systolic blood pressure, diastolic blood pressure, fasting plasma glucose, total cholesterol, and high-sensitivity C-reactive protein than low-fat diets.[14]

A randomized controlled trial indicated that soy and milk protein intake reduce systolic blood pressure compared with a high-glycemic-index refined carbohydrate among patients with prehypertension and stage 1 hypertension. This suggests that partially replacing carbohydrate with soy or milk protein is a good intervention and treatment for hypertension.[15]

Hypertension, along with other factors such as obesity, have been said to contribute to the development of left ventricular hypertrophy (LVH). LVH has been found to be an independent risk factor to cardiovascular disease morbidity and mortality. It roughly doubles the risk of cardiovascular death in both men and women.[16]

Cigarette smoking

Cessation of cigarette smoking constitutes the single most important preventive measure for CAD. As early as the 1950s, studies reported a strong association between cigarette smoke exposure and heart disease. Persons who consume more than 20 cigarettes daily have a 2- to 3-fold increase in total heart disease. Continued smoking is a major risk factor for recurrent heart attacks.[17]

Smoking is a risk factor for CVD in women and men; however, a systematic review and meta-analysis by Huxley and Woodward suggests that in some countries, smoking by women is on the rise; the study suggests that proper counseling and nicotine addiction programs should focus on young women.[18]

Diabetes mellitus

A disorder of metabolism, diabetes mellitus causes the pancreas to produce either insulin deficiency or insulin resistance. Glucose builds up in the blood stream, overflows through the kidneys into the urine, and results in the body losing its main source of energy, even though the blood contains large amounts of glucose.

An estimated 20.8 million people in the United States (7% of the population) have diabetes; 14.6 million have been diagnosed, and 6.2 million have not yet been diagnosed. Diabetes prevalence figures (including diagnosed and undiagnosed diabetes) are available at the Centers for Disease Control and Prevention (CDC).

Patients with diabetes are 2-8 times more likely to experience future cardiovascular events than age-matched and ethnically matched individuals without diabetes,[2] and a recent study suggested a potential reduction of all-cause and cardiovascular disease–specific mortality in women with diabetes mellitus who consumed whole-grain and bran.[19] Another study suggested that meat consumption is associated with a higher incidence of coronary heart disease and diabetes mellitus.[20]

Paynter et al found significant improvements in predictive ability of CVD risk using models incorporating HbA1c levels compared with classification of diabetes in both men and women.[21]

Obesity

Obesity is associated with elevated vascular risk in population studies. In addition, this condition has been associated with glucose intolerance, insulin resistance, hypertension, physical inactivity, and dyslipidemia.[22]

A study by Das et al examined more than 50,000 patients from the National Cardiovascular Data Registry with STEMI. The results suggest that although patients who are extremely obese (body mass index [BMI] >40) present at a younger age with STEMI, they have less extensive coronary artery disease and better LV function. However, as expected, their in-hospital mortality following STEMI is increased (adjusted odds ratio, 1.64).[23]

Lack of physical activity

The cardioprotective benefits of exercise include reducing adipose tissue, which decreases obesity; lowering blood pressure, lipids, and vascular inflammation; improving endothelial dysfunction, improving insulin sensitivity, and improving endogenous fibrinolysis.[24] In addition, regular exercise reduces myocardial oxygen demand and increases exercise capacity, translating into reduced coronary risk. In the Women's Health Initiative study, walking briskly for 30 minutes, 5 times per week, was associated with a 30% reduction in vascular events during a 3.5-year follow-up period.[25] Studies have also shown that even 15 minutes a day or 90 minutes a week of moderate-intensity exercise may be beneficial.[26] Adherence to a healthy lifestyle is associated with a low risk of sudden cardiac death among women.[27]

Evidence suggests that screen-based entertainment (television or other “screen time”) increases the risk of cardiovascular disease, regardless of physical activity.[28] The relationship between inflammatory and metabolic risk factors may partly explain this relationship.

Metabolic syndrome

Metabolic syndrome is characterized by a group of medical conditions that places people at risk for both heart disease and type 2 diabetes mellitus. In the Kuopio Ischemic Heart Disease Risk Factor Study, patients with metabolic syndrome had significantly higher rates of coronary, cardiovascular, and all-cause mortality.[29]

People with metabolic syndrome have 3 of the following 5 traits and medical conditions, as defined by the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) Cholesterol Education Program (CEP)[30] :

Elevated waist circumference - Waist measurement of 40 inches or more in men, 35 inches or more in womenElevated levels of triglycerides - 150 mg/dL or higher or taking medication for elevated triglyceride levelsLow levels of HDL (high-density lipoprotein) or good cholesterol - Below 40 mg/dL in men, below 50 mg/dL in women, or taking medication for low HDL cholesterol level Elevated blood pressure levels - For systolic blood pressure, 130 mm Hg or higher; 85 mm Hg or higher for diastolic blood pressure; or taking medication for elevated blood pressure levels Elevated fasting blood glucose levels - 100 mg/dL or higher or taking medication for elevated blood glucose levels[30] (Note: The American Association of Clinical Endocrinologists, the International Diabetes Federation, and the World Health Organization have other, similar, definitions for metabolic syndrome.)

Although high consumption of carbohydrates and sugar is associated with higher rates of cardiovascular disease risk in adults, not much is known about the effect of added sugars in US adolescents.[31] A study of the National Health and Nutrition Examination Survey (NHANES) 1999-2004, suggests that added sugar consumption is positively associated with an increase risk of cardiovascular disease in adolescents. The results of this study suggest that future risk of cardiovascular disease may be reduced by minimizing sugar intake.

A meta-analysis of multiple population studies associated chocolate consumption with a substantial risk reduction (approximately 30%) in cardiometabolic disorders, including coronary disease, cardiac deaths, diabetes, and stroke.[32] The apparent benefits of chocolate may accrue from a beneficial impact of polyphenols present in cocoa products that increase the bioavailability of nitric oxide. These findings are based on observational studies, and further experimental studies are warranted to confirm the finding of a potential beneficial effect of chocolate consumption.

Mental stress, depression, cardiovascular risk

Depression has been strongly implicated in predicting CAD[33] . Adrenergic stimulation during stress can increase myocardial oxygen requirements, can cause vasoconstriction, and has been linked to platelet and endothelial dysfunction[34] and metabolic syndrome.[35]

Shah et al found that in adults younger than 40 years, depression and history of attempted suicide are significant independent predictors of premature cardiovascular disease and ischemic heart disease mortality in both males and females.[36]

PreviousNextNontraditional or Novel Risk FactorsC-reactive protein

C-reactive protein (CRP) is a protein in the blood that demonstrates the presence of inflammation, which is the body's response to injury or infection; CRP levels rise if inflammation is present. The inflammation process appears to contribute to the growth of arterial plaque, and in fact, inflammation characterizes all phases of atherothrombosis and is actively involved in plaque formation and rupture.

According to some research results, high blood levels of CRP may be associated with an increased risk of developing coronary artery disease (CAD) and having a heart attack.[37] In the Jupiter trial, in healthy persons without hyperlipidemia but with elevated high-sensitivity CRP levels, the statin drug rosuvastatin significantly reduced the incidence of major cardiovascular events.[38]

The 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults states that measurement of C-reactive protein can be useful in selecting patients for statin therapy and may be reasonable for cardiovascular risk assessment, depending on the patient’s age and risk level. C-reactive protein measurement is not recommended for cardiovascular risk assessment in asymptomatic high-risk adults, low-risk men 50 years or younger, or low-risk women 60 years or younger.[6]

Lipoprotein(a)

An elevated lipoprotein(a) [Lp(a)] level is an independent risk factor of premature CAD[35] and is particularly a significant risk factor for premature atherothrombosis and cardiovascular events. Measurement of Lp(a) is more useful for young individuals with a personal or family history of premature vascular disease and repeat coronary interventions. The 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults states that, in asymptomatic intermediate-risk adults, lipoprotein-associated phospholipase A2 might be reasonable for cardiovascular risk assessment.[6]

Lp(a) may be used to identify people at increased cardiovascular risk, but as of yet, there have been no studies on Lp(a) lowering because of the lack of available agents that are effective in reducing this value. Therefore, low-density lipoprotein (LDL) lowering is probably the best strategy in people with elevated Lp(a) levels.[37]

Homocysteine

Homocysteine is a natural by-product of the dietary breakdown of protein methionine. In the general population, mild to moderate elevations are due to insufficient dietary intake of folic acid. Homocysteine levels may identify people at increased risk of heart disease, but again, due to the lack of agents that effectively alter the homocysteine levels, studies have not shown any benefit from lowering the homocysteine level.

Tissue plasminogen activator

An imbalance of the clot dissolving enzymes (eg, tissue plasminogen activator [tPA]) and their respective inhibitors (plasminogen activator inhibitor-1 [PAI-1]) may predispose individuals to myocardial infarctions.

Small, Dense LDL

Individuals with a predominance of small, dense LDL particles are at increased risk for CAD. Thus, core lipid composition and lipoprotein particle size and concentration may provide a better measure of cardiovascular risk prediction.[39]

One study suggests that the risk of coronary heart disease contributed by LDL appeared to result to a large extent from LDL that contains apolipoprotein C-III.[40]

Fibrinogen

levels of fibrinogen, an acute-phase reactant, increase during an inflammatory response. This soluble protein is involved in platelet aggregation and blood viscosity, and it mediates the final step in clot formation. Significant associations were found between fibrinogen level and risk of cardiovascular events in the Gothenburg, Northwick Park, and Framingham heart studies.[41]

Other factors

Medical conditions such as end-stage renal disease (ESRD),[42] chronic inflammatory diseases affecting connective tissues (eg, lupus, rheumatoid arthritis),[43, 44] human immunodeficiency virus (HIV) infection (acquired immunodeficiency syndrome [AIDS], highly active antiretroviral therapy [HAART]),[45] and other markers of inflammation have all been widely reported to contribute to the development of CAD.

ESRD is associated with anemia, hyperhomocysteinemia, increased calcium phosphate product, calcium deposits, hypoalbuminemia, increased troponin, increased markers of inflammation, increased oxidant stress, and decreased nitric oxide activity factors, all of which may contribute to increased CAD risk.[42]

The 2010 ACCF/AHA recommendations note that urinalysis to detect microalbuminuria is reasonable for cardiovascular risk assessment in asymptomatic adults with hypertension or diabetes, and might be reasonable for cardiovascular risk assessment in asymptomatic intermediate-risk adults without hypertension or diabetes.[6]

Low serum testosterone levels have a significant negative impact on patients with CAD. More studies are needed to assess better treatment.[46] One meta-analysis suggests that the presence of erectile dysfunction increases the risk of cardiovascular disease, coronary heart disease, stroke, and all-cause mortality. This additional risk may be independent of conventional cardiovascular risk factors.[47]

One study suggests women aged 50 years or younger who undergo a hysterectomy are at an increased risk for cardiovascular disease later in life.[48] Oopherectomy also increases the risk for both coronary heart disease and stroke.

A systemic review and meta-analysis by Cappuccio et al suggests that too little sleep (≤5-6 h per night) or too much sleep (>8-9 h per night) increases risk of coronary heart disease. Too little sleep is also associated with an increased risk of stroke. The association between sleep and cardiac events is consistent across different populations.[49]

A population-based study by Laugsand et al found that insomnia is associated with a moderately increased risk of acute myocardial infarction.[50]

Oberg et al suggest an association between birth weight and risk of cardiovascular disease within disease-discordant dizygotic twins but not monozygotic twins.[51] This could be a result of common cause factors that vary within dizygotic but not monozygotic twin pairs, which may help identify them.

The Copenhagen City Heart Study found that xanthelasmata (raised yellow patches around the eyelids) but not arcus corneae (white or grey rings around the cornea) constitutes an independent risk factor for cardiovascular disease. Presence of xanthelasmata indicated increased risk for myocardial infarction, ischemic heart disease, and severe atherosclerosis.[52]

A prospective cohort study (n=2312) by Kestenbaum et al evaluated older patients without CAD over 14 years. Vitamin D and parathyroid hormone (PTH) were measured, and the outcomes included myocardial infarction, heart failure, cardiovascular death, and all-cause mortality. Vitamin D deficiency was associated with increased mortality and myocardial infarction (each 10 ng/mL drop in vitamin D was associated with 9% greater increase in death and 25% increase in MI). PTH excess was associated with a 30% increased risk of heart failure. Further randomized controlled trials are required.[53]

PreviousNextIdentifying Coronary Artery DiseaseDirect plaque imaging

Studies indicate that using electron-beam computed tomography (EBCT) scanning to identify coronary calcification can reveal at-risk individuals and perhaps allow for medical monitoring.[54] With the advent of new 64-slice CT angiography, bulky plaques may be identified in asymptomatic patients.

The risk benefit of using CT angiography in an asymptomatic patient for the identification of atherosclerotic plaques is still a subject of much debate. The negative predictive value of CT angiography, however, is very high. CAD identified by CT angiography has significant prognostic implications.[55]

Carotid intima-media thickness (IMT), pulse wave velocity (PWV), and the ankle-brachial index (ABI) are widely used noninvasive modalities for evaluating atherosclerosis.[56]

Polak et al suggest the maximum intima-media thickness of the internal carotid artery along with the presence of plaque significantly but modestly improves the classification of risk of cardiovascular disease in the Framingham Offspring Study cohort.[57]

One study suggested regression or slow progression of carotid IMT due to cardiovascular drug therapies does not reduce cardiovascular events.[58]

The 2010 ACCF/AHA guideline states that measurement of carotid intima-media thickness is reasonable for cardiovascular risk assessment in asymptomatic intermediate-risk adults, provided that published recommendations on equipment, method, and training are carefully followed. The guideline also states that in asymptomatic intermediate-risk adults, measurement of ankle-brachial index is reasonable for cardiovascular risk assessment.[6]

Genetic markers

Other potential risk factors for developing CAD have yet to be defined. However, as data are deciphered from the human genome project, the list of genetic contributors to CAD should greatly increase.

For patients without diabetes and known CAD, a noninvasive, whole-blood test based on gene expression and demographic characteristics may be beneficial in assessment of obstructive CAD.[59]

The 2010 ACCF/AHA guideline does not recommend genotype testing for coronary heart disease risk assessment in asymptomatic adults.[6]

Biomarkers

In a 10-year comparison of 10 biomarkers for predicting death and major cardiovascular events in approximately 3000 individuals, the most informative biomarkers for predicting death were blood levels of B-type natriuretic peptide (BNP), CRP, homocysteine, renin, and the urinary albumin-to-creatinine ratio.[56] The most informative biomarkers for predicting major cardiovascular events were BNP and the urinary albumin-to-creatinine ratio.

The 2010 ACCF/AHA guideline does not recommend measurement of natriuretic peptides for coronary heart disease risk assessment in asymptomatic adults.[6]

Cystatin C (Cys-C) has been proposed as an indicator of renal dysfunction that is associated with cardiovascular events and it has shown to be a good predictor of long-term mortality in patients with normal renal function.[60]

Individuals with elevated multimarker scores had a 4-fold higher risk of death and an almost 2-fold higher risk of major cardiovascular events relative to those with low multimarker scores.[6] However, the investigators reported that the use of multiple biomarkers added only moderately to the overall prediction of risk based on conventional cardiovascular risk factors, as evidenced by small changes in the C-statistic.[6]

Measurement of HDL cholesterol should be used as part of the initial cardiovascular risk assessment but should not be used as a predictive tool of residual vascular risk in patients who are treated with potent high-dose statin therapy to lower LDL cholesterol.[61]

Previous, Risk Factors for Coronary Artery Disease