Risk Factors for Coronary Artery Disease 

Updated: Mar 30, 2020
  • Author: F Brian Boudi, MD, FACP; Chief Editor: Yasmine S Ali, MD, FACC, FACP, MSCI  more...
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Practice Essentials

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 to the prevention of cardiovascular morbidities and mortality.

Many risk factors are modifiable and account for the majority of the population's attributable risk for myocardial infarction (MI). Cardiovascular disease (CVD) risk stratification determines if traditional risk factors (hypertension, tobacco use, diabetes mellitus, premature family history of CVD, chronic kidney disease, obesity) for CVD is present; looks at the baseline lipid profile; and estimates CVD risk using a validated CVD risk calculator such as the American Heart Association/American College of Cardiology (AHA/ACC) atherosclerotic CVD (ASCVD) risk calculator [1] : http://www.cvriskcalculator.com/. The AHA/ACC and US Preventive Services Task Force (USPSTF) use the above as their recommendations for current risk stratification. The expanding risk factors are included in this review following but are by no means exhaustive of all the current attributing factors.

See the image below.

Risk factors for coronary artery disease. Traditio Risk factors for coronary artery disease. 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.

Risk factors for coronary artery disease

Conventional risk factors

  • Older age: Over age 45 years in men and over age 55 years in women

  • Family history of early heart disease

  • Race: Among persons with CAD, the cardiovascular death rate for African Americans is reported to be particularly high; in Asians, low levels of high-density lipoprotein cholesterol (HDL-C), which are considered to be a risk factor for coronary heart disease, appear to be especially prevalent; South Asians appear to have a higher independent risk for cardiovascular disease as well.

Modifiable risk factors

  • High blood cholesterol levels (specifically, low-density lipoprotein cholesterol [LDL-C])

  • High blood pressure

  • Cigarette smoking: Cessation of cigarette smoking constitutes the single most important preventive measure for CAD

  • Diabetes mellitus [2]

  • Obesity

  • Lack of physical activity

  • Metabolic syndrome

  • Mental stress and depression

  • Sleep disorders

Nontraditional or novel risk factors

High levels of the following are considered to be risk factors for CAD:

  • High-sensitivity C-reactive protein (hsCRP): High levels are related to the presence of inflammation and, according to some research results, may be associated with an increased risk of CAD development and heart attack [3]

  • Lipoprotein(a)

  • Small, dense LDL-C particles

Various medical conditions that can contribute to CAD include the following:

  • End-stage renal disease (ESRD)

  • Chronic inflammatory diseases affecting connective tissues (eg, lupus, rheumatoid arthritis) [4, 5]

  • Human immunodeficiency virus (HIV) infection (acquired immunodeficiency syndrome [AIDS], highly active antiretroviral therapy [HAART]) [6]

  • Familial hypercholesterolemia

Identifying coronary artery disease

Direct plaque imaging

  • Electron-beam computed tomography (EBCT) scanning: To identify coronary calcification; can reveal at-risk individuals and perhaps allow for medical monitoring [7]

  • 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

  • Carotid intima-media thickness (IMT), pulse wave velocity (PWV), and the ankle-brachial index (ABI): Widely used, noninvasive modalities for evaluating atherosclerosis, but still considered surrogates for coronary artery disease; use is primarily limited to clinical trials.

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 as follows:

  • B-type natriuretic peptide (BNP)

  • hsCRP

  • Homocysteine

  • Renin

  • Urinary albumin-to-creatinine ratio

The most informative biomarkers for predicting major cardiovascular events were BNP and the urinary albumin-to-creatinine ratio.

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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 and risk stratification is critical for a clinician to prevent cardiovascular morbidities and mortality. [8, 9, 10] See the image below for traditional and nontraditional risk factor biomarkers.

Risk factors for coronary artery disease. Traditio Risk factors for coronary artery disease. 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.

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Conventional Risk Factors

Many traditional risk factors for coronary artery disease (CAD) are related to lifestyle, and preventative treatment can be tailored to modifying specific factors. [11]

The risk of developing 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. [12]

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. [13]

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. [14]

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. [15]  

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. [16]

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

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, such as the following:

  • 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 studies

  • Specific measures of arterial stiffness

  • Coronary computed tomography angiography

  • MRI for detection of vascular plaque

Note the following:

  • 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, [10] but it 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. [17] 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. [18]

  • 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. [19]

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Modifiable 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. [20]

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. [21]

High blood pressure

Of the 50 million Americans with hypertension, almost one third evade diagnosis and only one fourth receive effective treatment. [22] 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. [23]

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. [24]

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. [22]

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. [25]

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. [26]

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. [27]

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. [28]

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. [29]

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, [9] 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. [30] Another study suggested that meat consumption is associated with a higher incidence of coronary heart disease and diabetes mellitus. [31]

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. [32]

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. [33, 34]

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). [35]

Normal-weight central obesity in older adults with CAD, as defined by either waist circumference or waist-hip ratio, is associated with high mortality risk. [36]

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. [37] 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. [38] Studies have also shown that even 15 minutes a day or 90 minutes a week of moderate-intensity exercise may be beneficial. [39] Adherence to a healthy lifestyle is associated with a low risk of sudden cardiac death among women. [40]

In a prospective study that evaluated cardiorespiratory fitness (via treadmill exercise test) and cardiovascular risk in 4872 young adults (aged 18-30 years) over 1 year, with 2472 of them followed up after 7 years (median follow-up: 26.9 years), Shah et al found that higher levels of fitness at the baseline study visit and improvement in fitness early in adulthood were associated with lower risks for CVD and mortality. [41] In addition, fitness and changes in fitness correlated with myocardial hypertrophy and dysfunction but did not affect coronary artery calcification.

Evidence suggests that screen-based entertainment (television or other “screen time”) increases the risk of cardiovascular disease, regardless of physical activity. [42] 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. [43]

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) [44] :

  • Elevated waist circumference - Waist measurement of 40 inches or more in men, 35 inches or more in women

  • Elevated levels of triglycerides - 150 mg/dL or higher or taking medication for elevated triglyceride levels

  • Low 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 [44] (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. [45] 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. [46] 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. [47] Adrenergic stimulation during stress can increase myocardial oxygen requirements, can cause vasoconstriction, and has been linked to platelet and endothelial dysfunction [48] and metabolic syndrome. [49]

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. [50]

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Nontraditional or Novel Risk Factors

C-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. [3, 10] 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. [51]

The 2013 ACCF/AHA guideline for assessment of cardiovascular risk is based on expert opinion; they state that when risk-based decisions regarding initiation of pharmacological therapy are uncertain following quantitative risk assessment, measurement of C-reactive protein can be useful. Levels of at least 2 mg/L support revising the risk assessment upward.

Lipoprotein(a)

An elevated lipoprotein(a) [Lp(a)] level is an independent risk factor of premature CAD [49] 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. [16]

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. [3]

In patients with genetically confirmed heterozygous familial hypercholesterolemia, the presence of elevated levels of lipoprotein(a), hypertension, and renal insufficiency appear to be independent predictors of CAD beyond elevated pretreatment  low-density lipoprotein (LDL)-cholesterol. [52]

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. [53]

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. [54]

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. [55]

Other factors

Medical conditions such as end-stage renal disease (ESRD), [56] chronic inflammatory diseases affecting connective tissues (eg, lupus, rheumatoid arthritis), [4, 5] human immunodeficiency virus (HIV) infection (acquired immunodeficiency syndrome [AIDS], highly active antiretroviral therapy [HAART]), [6] 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. [56]

Low serum testosterone levels have a significant negative impact on patients with CAD. More studies are needed to assess better treatment. [57] 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. [58]

One study suggests women aged 50 years or younger who undergo a hysterectomy are at an increased risk for cardiovascular disease later in life. [59] Oophorectomy 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. [60]

A population-based study by Laugsand et al found that insomnia is associated with a moderately increased risk of acute myocardial infarction. [61]

Oberg et al suggest an association between birth weight and risk of cardiovascular disease within disease-discordant dizygotic twins but not monozygotic twins. [62] 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. [63]

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. [64]

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Identifying Coronary Artery Disease

Direct 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. [7] 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. [65]

Carotid intima-media thickness (IMT), pulse wave velocity (PWV), and the ankle-brachial index (ABI) are widely used noninvasive modalities for evaluating atherosclerosis. [66]

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. [67]

One study suggested regression or slow progression of carotid IMT due to cardiovascular drug therapies does not reduce cardiovascular events. [68]

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. [69]

Genotype testing is not recommended for coronary heart disease risk assessment in asymptomatic adults. [16]

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. [66] The most informative biomarkers for predicting major cardiovascular events were BNP and the urinary albumin-to-creatinine ratio.

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. [70]

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. [16] 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. [16]

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. [71]

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Risk Assessment Guidelines

In November 2013, The American College of Cardiology (ACC) and the American Heart Association (AHA) released updated risk-assessment guidelines for atherosclerotic cardiovascular disease. Changes and recommendations include the following [72, 1] :

  • Stroke is added to the list of coronary events traditionally covered by risk prediction equations

  • The guidelines focus primarily on the 10-year risk of atherosclerosis-related events; they focus secondarily on the assessment of lifetime risk for adults aged 59 or younger without high shorter-term risk

  • The strongest predictors of 10-year risk are identified as age, sex, race, total cholesterol, high-density lipoprotein cholesterol (HDL-C), blood pressure, blood-pressure treatment status, diabetes, and current smoking status

  • Adjunct formulas for refining risk estimates by gender and race are provided

  • If risk prediction needs to be further sharpened after risk prediction equations have been performed, the guidelines indicate that coronary-artery calcium scores, family history, high-sensitivity C-reactive protein, and the ankle-brachial index can be used

  • The guidelines recommend that statin therapy be considered in individuals whose 10-year atherosclerotic cardiovascular disease event risk is 7.5% or greater

Guidelines from the American Heart Association and the American College of Cardiology (AHA/ACC) recommend use of a revised calculator for estimating the 10-year risk of developing a first atherosclerotic cardiovascular disease (ASCVD) event, which is defined as a nonfatal myocardial infarction, death from coronary heart disease, or stroke (fatal or nonfatal) in a person who was initially free from ASCVD. [72, 1] The calculator incorporates the following risk factors:

  • Sex

  • Age

  • Race

  • Total cholesterol

  • HDL cholesterol

  • Systolic blood pressure

  • Treatment for elevated blood pressure

  • Diabetes

  • Smoking

For patients 20-79 years of age who do not have existing clinical ASCVD, the guidelines recommend assessing clinical risk factors every 4-6 years. For patients with low 10-year risk (< 7.5%), the guidelines recommend assessing 30-year or lifetime risk in patients 20-59 years old.

Regardless of the patient’s age, clinicians should communicate risk data to the patient and refer to the AHA/ACC lifestyle guidelines, which cover diet and physical activity. For patients with elevated 10-year risk, clinicians should communicate risk data and refer to the AHA/ACC guidelines on blood cholesterol and obesity.

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Primary Prevention of CVD Guidelines

In September 2019, the American College of Cardiology (ACC) and the American Heart Association (AHA) published joint guidelines on the primary prevention of cardiovascular disease. [73]

It is recommended that atherosclerotic cardiovascular disease (ASCVD)–related risk factors be controlled via a team-based approach.

For adults, health-care visits should routinely include counseling on optimization of a physically active lifestyle.

At least 150 minutes per week of accumulated moderate-intensity or 75 minutes per week of vigorous-intensity aerobic physical activity (or an equivalent combination of moderate and vigorous activity) is recommended for ASCVD risk reduction in adults.

Improvement of the ASCVD risk factor profile through weight loss is recommended for patients with overweight or obesity.

It is recommended that adults with overweight or obesity achieve and maintain weight loss with the aid of counseling and comprehensive lifestyle interventions (including calorie restriction).

Improvement of glycemic control, achievement of weight loss (if necessary), and improvement of other ASCVD risk factors, via a tailored nutrition plan aimed at providing a heart-healthy dietary pattern, is recommended for all adults with type 2 diabetes mellitus (T2DM).

Improvement of glycemic control, achievement of weight loss (if necessary), and improvement of other ASCVD risk factors, via at least 150 minutes per week of moderate-intensity physical activity or 75 minutes of vigorous-intensity physical activity, is recommended for adults with T2DM.

If, as a result of a risk discussion, a decision is made to employ statin therapy, adults with high blood cholesterol with an intermediate ASCVD risk (≥7.5% to < 20% 10-year ASCVD risk) should be treated with a moderate-intensity statin.

In patients with high blood cholesterol who have an intermediate ASCVD risk (≥7.5% to < 20% 10-year ASCVD risk), reduction of low-density lipoprotein cholesterol (LDL-C) levels by at least 30% is recommended, while optimal ASCVD risk reduction can be targeted, particularly in high-risk patients (≥20% 10-year ASCVD risk), by reducing LDL-C levels by at least 50%.

Maximally tolerated statin therapy is recommended in patients aged 20-75 years with an LDL-C level of at least 190 mg/dL (≥4.9 mmol/L).

Among the nonpharmacologic interventions recommended for adults with elevated blood pressure (BP) or hypertension, including patients who need antihypertensive agents, are the following:

  • Weight loss

  • A heart-healthy dietary pattern

  • Sodium reduction

  • Dietary potassium supplementation

  • Increased physical activity with a structured exercise program

  • Limited alcohol

Primary prevention of cardiovascular disease (CVD) with BP-lowering medications is recommended for adults with an estimated 10-year ASCVD risk of at least 10% and an average systolic BP (SBP) of 130 mm Hg or higher or an average diastolic BP (DBP) of at least 80 mm Hg.

A BP target of below 130/80 mm Hg is recommended for adults with confirmed hypertension and a 10-year ASCVD event risk of at least 10%.

Treatment to a BP goal of below 130/80 mm Hg is recommended for adults with hypertension and chronic kidney disease.

Antihypertensive drug treatment should be administered to adults with T2DM and hypertension who have a BP of 130/80 mm Hg or higher, the aim being to reduce BP to below 130/80 mm Hg.

For adults, cessation of tobacco use should be facilitated by evaluation of such use at every health-care visit, with the status of a patient’s tobacco use recorded as a vital sign.

All adult tobacco users should be advised to quit.

In adult tobacco users, quit rates should be maximized by combining behavioral interventions with pharmacotherapy.

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Physical Activity Guidelines

The guidelines on physical activity were released in November 2018 by the Physical Activity Guidelines Advisory Committee of the US Department of Health and Human Services (USDHHS). [74, 75]

Age- and Condition-Related Recommendations

Children aged 3-5 years: Should be physically active throughout the day to enhance growth and development.

Children aged 6-17 years: Sixty minutes or more of moderate-to-vigorous physical activity per day.

Adults: At least 150-300 minutes per week of moderate-intensity aerobic physical activity, OR  75-150 minutes per week of vigorous-intensity aerobic physical activity, OR an equivalent combination of moderate- and vigorous-intensity aerobic activity; muscle-strengthening activities should be performed on two or more days per week.

Older adults: Multicomponent physical activity to include balance training, aerobic activity, and muscle-strengthening activity.

Pregnant and postpartum women: At least 150 minutes of moderate-intensity aerobic activity weekly.

Adults with chronic conditions or disabilities who are able: Follow key guidelines and perform both aerobic and muscle-strengthening activities.

Sleep, Daily Functioning, and Mental Health

Strong evidence demonstrates that moderate-to-vigorous physical activity improves sleep quality by decreasing the time it takes to fall asleep; it can also increase deep-sleep time and decrease daytime sleepiness.

Single episodes of physical activity promote improvements in executive function, to include organization of daily activities and future planning. Cognition (ie, memory, processing speed, attention, academic performance) also can be improved with physical exercise.

Regular physical activity reduces the risk of clinical depression, as well as reducing depressive symptoms and symptoms of anxiety.

Strong evidence demonstrates regular physical activity improves perceived quality of life.

Risk of Diseases and Conditions

Regular physical activity minimizes excessive weight gain, helps maintain weight within a healthy range, improves bone health, and prevents obesity, even in children as young as 3-5 years.

In pregnant women, physical activity helps reduce excessive weight gain in pregnancy and helps reduce the risk of developing gestational diabetes and postpartum depression.

Regular physical activity has been shown to improve cognitive function and to reduce the risk of dementia; falls and fall-related injuries; and cancers of the breast, esophagus, colon, bladder, lung, endometrium, kidney, and stomach. It also helps retard the progression of osteoarthritis, type 2 diabetes, and hypertension.

Promotion of Physical Activity

School- and community-based programs can be effective.

Environmental and policy changes should improve access to physical activity and support of physical activity behavior.

Information and technology should be used to promote physical activity, to include activity monitors (eg, wearable devices), smartphone apps, computer-tailored printed material, and Internet-based programs for self-monitoring, message delivery, and support.

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CV Risk Reduction Therapies in Type 2 Diabetes and CVD

The expert consensus decision pathways on the use of two major new classes of diabetes drugs—sodium-glucose cotransporter type 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1RAs)—for cardiovascular (CV) risk reduction in patients with type 2 diabetes (TD2) and atherosclerotic CV disease (ASCVD) were released in November 2018 by the American College of Cardiology. [76, 77] The main focus of management is in the outpatient ambulatory setting.

The SGLT2 inhibitors appear to reduce major adverse CV events (MACE) and the risk of heart failure (HF) but increase the risk for genital mycotic infections, whereas GLP-1RAs offer reductions in MACE but are associated with transient nausea and vomiting. Both classes of agents have benefits in reducing blood pressure and weight, and they have a low risk for hypoglycemia.

For CV risk reduction, initiate agents with demonstrated CV benefit from either drug class at the lowest doses; no uptitration is necessary for SGLT2 inhibitors, whereas the GLP-1RAs should be slowly uptitrated (to avoid nausea) to the maximal tolerated dose.

At the initiation of an SGLT2 inhibitor or a GLP-1RA agent, clinicians should avoid hypoglycemia in patients by monitoring those with A1C levels near or below target, particularly when patients' existing diabetes therapies include sulfonylureas, glinides, or insulin.

In addition to reducing MACE and CV death, SGLT2 inhibitors are also suitable for preventing hospitalization for HF.

Empagliflozin is the preferred SGLT2 inhibitor based on the available evidence and overall benefit-risk balance.

Liraglutide should be the preferred agent among the GLP-1RAs for CV event risk reduction.

Two SGLT2 inhibitors (ie, canagliflozin, ertugliflozin) appear to be associated with an increased risk of amputation. It is unclear whether or not this is a class effect; therefore, clinicians should closely monitor patients on these agents who have a history of amputation, peripheral arterial disease, neuropathy, or diabetic foot ulcers.

Patients with T2D and clinical ASCVD on metformin therapy (or in whom metformin is contraindicated or not tolerated) should have an SGLT2 inhibitor or GLP-1RA with proven CV benefit added to their treatment regimen. For patients not on background metformin therapy, practitioners may use their clinical judgment to prescribe an SGLT2 inhibitor or GLP-1RA for CV risk reduction.

It appears reasonable to concomitantly use an SGLT2 inhibitor and a GLP-1RA with demonstrated CV benefit if clinically indicated, although such combination therapy has not been studied for CVD risk reduction.

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Heart Failure Clinical Practice Guidelines

In February 2020, the Canadian Cardiovascular Society (CCS) and Canadian Heart Failure Society (CHFS) released their recommendations on selected topics of high clinical relevance in the management of heart failure (HF). [78] These guidelines incorporate new evidence from randomized clinical trials published after 2017.

Percutaneous Mitral Valve Repair for HF and Reduced Ejection Fraction and Severe Functional Mitral Regurgitation

The CCS/CHFS recommends maximally tolerated guideline-directed medical therapy (GDMT), including cardiac resynchronization therapy and revascularization where appropriate, be implemented before consideration of percutaneous mitral valve repair (PMVR) for patients with HF and reduced ejection fraction (HFrEF) and severe functional mitral regurgitation (FMR) (strong recommendation).

It is suggested that patients with symptomatic HF (HFrEF) despite maximal GDMT and severe mitral regurgitation be evaluated for PMVR (weak recommendation).

The CCS/CHFS recommends that a multidisciplinary dedicated heart team (including interventionalists, cardiac surgeons, imaging specialists, and HF specialists) evaluate and manage the care of potential candidates for PMVR (strong recommendation).

Practical tips

Use caution when treating FMR in patients with HFrEF.

Patients with HFrEF and FMR who have severe left ventricular (LV) dilatation (typically LV end diastolic dimension >70 mm) and less than severe mitral regurgitation may be poor candidates for PMVR with MitraClip.

Patients with FMR should first receive maximally tolerated GDMT, including pharmacologic and nonpharmacologic HF therapies (eg, cardiac resynchronization therapy where applicable) for a reasonable minimum period (eg, 3 months), before PMVR is considered.

Refer patients considered for PMVR to centers experienced in evaluating patients with advanced HF, have high volumes of patients with valve disease managed medically and surgically, and have a high likelihood of achieving the volume of PMVR (eg, 2-4 per month) required for developing and maintaining competence in well-selected patients.

Treatment of Cardiac Amyloidosis

When cardiac amyloidosis (CA) is suspected, rule out light-chain amyloidosis (AL amyloidosis) using serum free light chains (kappa and lambda), and serum and urine protein electrophoresis with immunofixation. Accurate identification of the amyloid subtype is essential to initiate specific treatment and avoid inappropriate application of therapy.

Practical tips

In the setting of undifferentiated CA, the presence of light chains does not confirm the diagnosis of light chain cardiac amyloidosis (AL-CA) because monoclonal gammopathy of unknown significance and transthyretin cardiac amyloidosis (ATTR-CA) can coexist. In such settings, tissue biopsy is often necessary to exclude AL-CA.

Perform technetium-labeled scintigraphy, where available, to diagnose ATTR-CA when plasma cell dyscrasias have been ruled out.

Patient selection for tafamidis, a transthyretin tetramer stabilizer, should reflect the inclusion criteria for the Transthyretin Amyloidosis Cardiomyopathy Trial (ATTR-ACT) that showed clinical benefits of tafamidis over placebo with respect to mortality and cardiovascular hospitalization, including established ATTR-CA and objective evidence of HF (with elevated natriuretic peptides, where available).

Do not routinely consider treatment with tafamidis for patients with New York Heart Association (NYHA) class IV symptoms or severe functional disability, measured using a 6-minute walk test < 100 m. (These patient were excluded from ATTR-ACT.) Subgroup analysis from the ATTR-ACT trial suggested that the reduction in cardiovascular hospitalizations seen with tafamidis might be limited to patients with less severe symptoms (NYHA class I or II).

Because of the complexity in diagnosing CA and the potential for offering advanced or experimental treatment options, consider referring patients with CA to experienced centers. Other agents are currently under investigation, which might modify current treatment recommendations.

New Evidence for Angiotensin Receptor Neprilysin Inhibitors in HFpEF

The Prospective Comparison of ARNI (angiotensin receptor-neprilysin inhibitors) with ARB (angiotensin-receptor blockers) Global Outcomes in Heart Failure With Preserved Ejection Fraction (PARAGON-HF) trial, which compared sacubitril/valsartan with valsartan in HFpEF patients, showed a modest but nonsignificant 13% reduction in the primary outcome of first and recurrent HF hospitalizations and cardiovascular death. A secondary end point analysis revealed improvement in quality of life and renal function, which suggested potential benefits with sacubitril/valsartan compared with valsartan. The data further suggest heterogeneity in the treatment response with greater benefit in women and in individuals with a lower LVEF.

The CCS/CHFS indicate that the statistically negative results of the primary end point analysis preclude any recommendation for the general use of sacubitril/valsartan in patients with HFpEF.

New Evidence for SGLT2 Inhibitors and HF

The CCS/CHFS recommend use of SGLT2 inhibitors (eg, empagliflozin, canagliflozin, dapagliflozin) for treatment of patients with type 2 diabetes and atherosclerotic cardiovascular disease to reduce the risk of HF hospitalization and death (strong recommendation).

SGLT2 inhibitors, such as dapagliflozin, are recommended for use in patients with the following features:

  • Type 2 diabetes, aged >50 years, with additional risk factors for atherosclerotic cardiovascular disease, to reduce the risk of HF hospitalization (strong recommendation)
  • Mild to moderate HF due to reduced LVEF (≤ 40%) and concomitant type 2 diabetes, to improve symptoms and quality of life and to reduce the risk of hospitalization and cardiovascular mortality (strong recommendation)
  • Mild to moderate HF due to reduced LVEF (≤ 40%) and without concomitant diabetes, to improve symptoms and quality of life and to reduce the risk of hospitalization and cardiovascular mortality (conditional recommendation)

The CCS/CHFS recommend SGLT2 inhibitors, such as canagliflozin, be used in patients aged >30 years with type 2 diabetes, and macroalbumineric renal disease, to reduce the risk of HF hospitalization and progression of renal disease (strong recommendation).

Practical tips

Note that SGLT2 inhibitors are currently contraindicated for patients with type 1 diabetes.

The most common adverse effects of SGLT2 inhibitors are genital mycotic infections (GMIs), with the highest risk in women (10%-15% risk), those with previous GMIs, and uncircumcised men. GMIs can generally be managed with antifungal drugs and do not require discontinuation of therapy.

SGLT2 inhibitors might result in an up to 15% temporary reduction of estimated glomerular filtration rate (eGFR) (usually resolves within 1-3 months). These drugs have also been associated with acute kidney injury, and increased monitoring is warranted in those at risk.

SGLT2 inhibitors do not cause hypoglycemia in the absence of concomitant insulin and/or secretagogue therapy. Background therapies might need adjustment to prevent hypoglycemia.

SGLT2 inhibitors should be held in the setting of concomitant dehydrating illness as part of “sick day” management. Patients should be educated on “sick day” management.

These agents have been associated with diabetic ketoacidosis (incidence 0.1%). Patients might present with normal or only modestly elevated blood glucose level (< 14 mmol/L). Rarely, SGLT2 inhibitors might be associated with normal anion gap acidosis (best detected with measurement of serum ketones). Nonspecific symptoms associated with diabetic ketoacidosis include dyspnea, nausea/vomiting, abdominal pain, confusion, anorexia, excessive thirst, and lethargy.

Exercise caution when combining SGLT2 inhibitors, ARNIs, and diuretics because of their concomitant effects to promote diuresis.

For more information, please go to Heart Failure and Cardiac Amyloidosis.

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Questions & Answers

Overview

How are risk factors for coronary artery disease (AD) stratified?

What are conventional risk factors for coronary artery disease (AD)?

What are the modifiable risk factors for coronary artery disease (AD)?

What are the nontraditional risk factors for coronary artery disease (CAD)?

Which medical conditions increase the risk for coronary artery disease (CAD)?

Which imaging modalities are used to identify coronary artery disease (CAD)?

Which biomarkers are used to identify coronary artery disease (CAD)?

When were risk factors for coronary artery disease (CAD) first identified?

How does age affect the risk for coronary artery disease (CAD)?

How does ethnicity affect the risk for coronary artery disease (CAD)?

What are the ACCF-AHA recommendations coronary artery disease (CAD) risk assessment in asymptomatic adults?

What are the modifiable risk factors for coronary artery disease (AD)?

How do cholesterol levels affect the risk for coronary artery disease (CAD)?

How does blood pressure affect the risk for coronary artery disease (CAD)?

How does smoking affect the risk for coronary artery disease (CAD)?

How does diabetes mellitus affect the risk for coronary artery disease (CAD)?

How does body weight affect the risk for coronary artery disease (CAD)?

How does physical activity affect the risk for coronary artery disease (CAD)?

How does metabolic syndrome affect the risk for coronary artery disease (CAD)?

How does depression affect the risk for coronary artery disease (CAD)?

How does C-reactive protein (CRP) affect the risk for coronary artery disease (CAD)?

How does homocysteine affect the risk for coronary artery disease (CAD)?

How does lipoprotein (a) affect the risk for coronary artery disease (CAD)?

How do tissue plasminogen activators affect the risk for coronary artery disease (CAD)?

How does dense LDL particles affect the risk for coronary artery disease (CAD)?

How does fibrinogen affect the risk for coronary artery disease (CAD)?

How does end-stage renal disease (ESRD) affect the risk for coronary artery disease (CAD)?

How do low serum testosterone levels affect the risk for coronary artery disease (CAD)?

Which gynecologic procedures increase the risk for coronary artery disease (CAD)?

How does sleep affect the risk for coronary artery disease (CAD)?

How does birth weight affect the risk for coronary artery disease (CAD)?

How does xanthelasmata affect the risk for coronary artery disease (CAD)?

How do vitamin D and parathyroid hormone levels affect the risk for coronary artery disease (CAD)?

What is the role of imaging in stratifying risk for coronary artery disease?

What is the role of genetic markers in stratifying risk for coronary artery disease?

What is the role of biomarkers markers in stratifying risk for coronary artery disease?

What are the ACCF-AHA guidelines for coronary artery disease (CAD) risk assessment?

What are the ACCF-AHA guidelines for primary prevention of coronary artery disease (CAD)?

Which organization has issued physical activity guidelines for the prevention of coronary artery disease (CAD)?

What are the US Department of Health and Human Services (USDHHS) age related physical activity guidelines for the prevention of coronary artery disease (CAD)?

What are the US Department of Health and Human Services (USDHHS) sleep guidelines for the prevention of coronary artery disease (CAD)?

What are the results of physical activity that help prevent coronary artery disease (CAD)?

What are effective ways to promote physical activity for the prevention of coronary artery disease (CAD)?

What is the role of SGLT2 inhibitors in the reduction of risk for coronary artery disease (CAD)?

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