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Coronary Artery Atherosclerosis (CABG)

Coronary artery atherosclerosis is the single largest killer of men and women in the United States. It is the principal cause of coronary artery disease (CAD), in which atherosclerotic changes are present within the walls of the coronary arteries. CAD is a progressive disease process that generally begins in childhood and manifests clinically in middle to late adulthood. The word atherosclerosis is of Greek origin and literally means focal accumulation of lipid (ie, athere [gruel]) and thickening of arterial intima (ie, sclerosis [hardening]). Atherosclerosis is a disease of large and medium-sized muscular arteries and is characterized by the following: y y y y y y y y Endothelial dysfunction Vascular inflammation Buildup of lipids, cholesterol, calcium, and cellular debris within the intima of the vessel wall Atherosclerotic buildup results in the following: Plaque formation Vascular remodeling Acute and chronic luminal obstruction Abnormalities of blood flow Diminished oxygen supply to target organs By impairing or obstructing normal blood flow, atherosclerotic buildup causes myocardial ischemia. (See Pathophysiology.) Approximately 14 million Americans have CAD. Each year, 1.5 million individuals develop acute myocardial infarction (AMI), the most deadly presentation of CAD, and more than 500,000 of these individuals die. (See Epidemiology.) Nonetheless, there has been a 30% reduction in mortality from CAD since the late 20th century. Many factors have contributed to this, including the introduction of coronary care units, coronary artery bypass grafting (CABG), thrombolytic therapy, percutaneous coronary intervention (PCI), and a renewed emphasis on lifestyle modification. (See Treatment Strategies and Management.) A major advance in the treatment of coronary artery atherosclerosis has been the development of a refined understanding of the nature of atherosclerotic plaque and the phenomenon of plaque rupture, which is the predominant cause of acute coronary syndrome (ACS) and AMI. Cardiologists now know that in many cases (perhaps more than half), the plaque that ruptures and results in the clinical syndromes of ACS and AMI is less than 50% occlusive. These so-called vulnerable plaques, as compared with stable plaques, consist of a large lipid core, inflammatory cells, and thin, fibrous caps that are subjected to greater biomechanical stress, thus leading to rupture that perpetuates thrombosis and ACS. The process of plaque rupture is illustrated in the diagram below.

A vulnerable plaque and the mechanism of plaque rupture.

The treatment of such ruptured plaques has taken a leap forward with the widespread use of newer antiplatelet and antithrombotic agents. Nonetheless, the greatest impact on the CAD epidemic can only be achieved through therapies tailored to prevent the rupture of these vulnerable plaques. Such plaques are likely more prevalent than occlusive plaques are. Currently, it is not possible to clinically identify most vulnerable plaques, and no data support the local treatment of them. On the other hand,

strong evidence from many randomized trials supports the efficacy of statin-class drugs in lipid lowering and of angiotensin-converting enzyme (ACE) inhibitors in improving endothelial function, with the use of both types of agents likely leading to plaque stabilization. (See Medication.)

The healthy epicardial coronary artery consists of the following 3 layers: y y y Intima Media Adventitia The intima is an inner monolayer of endothelial cells lining the lumen; it is bound on the outside by internal elastic lamina, a fenestrated sheet of elastin fibers. The thin subendothelial space in between contains thin elastin and collagen fibers along with a few smooth muscle cells (SMCs). The media are bound on the outside by an external elastic lamina that separates them from the adventitia, which consists mainly of fibroblasts, SMCs, and a matrix containing collagen and proteoglycans. The endothelium is the monolayered inner lining of the vascular system. It covers almost 700 m2 and weighs 1.5 kg. The endothelium has various functions. It provides a nonthrombogenic surface via a surface covering of heparan sulfate and through the production of prostaglandin derivatives such as prostacyclin, which is a potent vasodilator and an inhibitor of platelet aggregation. The endothelium secretes the most potent vasodilator, endothelium-derived relaxing factor (EDRF), a thiolated form of nitric oxide. EDRF formation by endothelium is critical in maintaining a balance between vasoconstriction and vasodilation in the process of arterial homeostasis. The endothelium also secretes agents that are effective in lysing fibrin clots. These agents include plasminogen and procoagulant materials, such as von Willebrand factor and type 1 plasminogen activator inhibitor. In addition, the endothelium secretes various cytokines and adhesion molecules, such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, and numerous vasoactive agents, such as endothelin, A-II, serotonin, and platelet-derived growth factor, which may be important in vasoconstriction. Endothelium, through the above mechanisms, regulates the following: y y y y y y Vascular tone Platelet activation Monocyte adhesion and inflammation Thrombus generation Lipid metabolism Cellular growth and vascular remodeling

Initially thought to be a chronic, slowly progressive, degenerative disease, atherosclerosis is a disorder with periods of activity and quiescence. Although a systemic disease, atherosclerosis manifests in a focal manner and affects different organ systems in different patients for reasons that remain unclear

Plaque growth and vascular remodeling

The lesions of atherosclerosis do not occur in a random fashion. Hemodynamic factors interact with the activated vascular endothelium. Fluid shear stresses generated by blood flow influence the phenotype of the endothelial cells by modulation of gene expression and regulation of the activity o f flow-sensitive proteins. Atherosclerotic plaques (or atheromas), which may require 10-15 years for full development, characteristically occur in regions of branching and marked curvature at areas of geometric irregularity and where blood undergoes sudden changes in velocity and direction of flow. Decreased shear stress and turbulence may promote atherogenesis at these important sites within the coronary arteries, the

major branches of the thoracic and abdominal aorta, and the large conduit vessels of the lower extremities. The earliest pathologic lesion of atherosclerosis is the fatty streak, which is observed in the aorta and coronary arteries of most individuals by age 20 years. The fatty streak is the result of focal accumulation of serum lipoproteins within the intima of the vessel wall. Microscopy reveals lipid-laden macrophages, T lymphocytes, and smooth muscle cells in varying proportions. The fatty streak may progress to form a fibrous plaque, the result of progressive lipid accumulation and the migration and proliferation of SMCs. Platelet-derived growth factor, insulinlike growth factor, transforming growth factors alpha and beta, thrombin, and angiotensin II (A-II) are potent mitogens that are produced by activated platelets, macrophages, and dysfunctional endothelial cells that characterize early atherogenesis, vascular inflammation, and platelet-rich thrombosis at sites of endothelial disruption. The relative deficiency of endothelium-derived nitric oxide further potentiates this proliferative stage of plaque maturation. The SMCs are responsible for the deposition of extracellular connective tissue matrix and form a fibrous cap that overlies a core of lipid-laden foam cells, extracellular lipid, and necrotic cellular debris. Growth of the fibrous plaque results in vascular remodeling, progressive luminal narrowing, blood-flow abnormalities, and compromised oxygen supply to the target organ. Human coronary arteries enlarge in response to plaque formation, and luminal stenosis may occur only when the plaque occupies more than 40% of the area bounded by the internal elastic lamina. Developing atherosclerotic plaques acquire their own microvascular network, the vasa vasorum, which are prone to hemorrhage and contribute to progression of atherosclerosis.[1] As endothelial injury and inflammation progress, fibroatheromas grow and form the plaque. As the plaque grows, 2 types of remodeling?positive remodeling and negative remodeling?occur, as illustrated in the image below.

Positive and negative arterial remodeling.

Positive remodeling is an outward compensatory remodeling (the Glagov phenomenon) in which the arterial wall bulges outward and the lumen remains uncompromised. Such plaques grow further; however, they usually do not cause angina, because they do not become hemodynamically significant for a long time. In fact, the plaque does not begin to encroach on the lumen until it occupies 40% of the cross-sectional area. The encroachment must be at least 50-70% to cause flow limitation. Such positively remodeled lesions thus form the bulk of the vulnerable plaques, grow for years, and are more prone to result in plaque rupture and ACS than stable angina, as documented by intravascular ultrasonography (IVUS) studies. Many fewer lesions exhibit almost no compensatory vascular dilation, and the atheroma steadily grows inward, causing gradual luminal narrowing. Many of the plaques with initial positive remodeling eventually progress to the negative remodeling stage, causing narrowing of the vascular lumen. Such plaques usually lead to the development of stable angina. They are also vulnerable to plaque rupture and thrombosis.

Plaque rupture
Denudation of the overlying endothelium or rupture of the protective fibrous cap may result in exposure of the thrombogenic contents of the core of the plaque to the circulating blood. This

exposure constitutes an advanced or complicated lesion. The plaque rupture occurs due to weakening of the fibrous cap. Inflammatory cells localize to the shoulder region of the vulnerable plaque. T lymphocytes elaborate interferon gamma, an important cytokine that impairs vascular smooth muscle cell proliferation and collagen synthesis. Furthermore, activated macrophages produce matrix metalloproteinases that degrade collagen. These mechanisms explain the predisposition to plaque rupture and highlight the role of inflammation in the genesis of the complications of the fibrous atheromatous plaque. A plaque rupture may result in thrombus formation, partial or complete occlusion of the blood vessel, and progression of the atherosclerotic lesion due to organization of the thrombus and incorporation within the plaque. Plaque rupture is the main event that causes acute presentations. However, severely obstructive coronary atheromas do not usually cause ACS and MI. In fact, most of the atheromas that cause ACS are less than 50% occlusive, as demonstrated by coronary arteriography. Atheromas with smaller obstruction experience greater wall tension, which changes in direct proportion to their radii. Most plaque ruptures occur because of disruption of the fibrous cap, which allows contact between the highly thrombogenic lipid core and the blood. These modestly obstructive plaques, which have a greater burden of soft lipid core and thinner fibrous caps with chemoactive cellular infiltration near the shoulder region, are called vulnerable plaques. The amount of collagen in the fibrous cap depends on the balance between synthesis and destruction of intercellular matrix and inflammatory cell activation. T cells that accumulate at sites of plaque rupture and thrombosis produce the cytokine interferon gamma, which inhibits collagen synthesis. Already-formed collagen is degraded by macrophages that produce proteolytic enzymes and by matrix metalloproteinases (MMPs), particularly MMP-1, MMP-13, MMP-3, and MMP-9. The MMPs are induced by macrophage- and SMC-derived cytokines such as IL1, tumor necrosis factor (TNF), and CD154 or TNF-alpha. Authorities postulate that lipid lowering stabilizes the vulnerable plaques by modulating the activity of the macrophage-derived MMPs.

Histologic composition and structure

A system devised by Stary et al classifies atherosclerotic lesions according to their histologic composition and structure.[2] In a type I lesion, the endothelium expresses surface adhesion molecules E selectin and P selectin, attracting more polymorphonuclear cells and monocytes in the subendothelial space. In a type II lesion, macrophages begin to take up large amounts of LDL (fatty streak). In a type III lesion, as the process continues, macrophages become foam cells. In a type IV lesion, lipid exudes into the extracellular space and begins to coalesce to form the lipid core. In a type V lesion, SMCs and fibroblasts move in, forming fibroatheromas with soft inner lipid cores and outer fibrous caps. In a type VI lesion, rupture of the fibrous cap with resultant thrombosis causes ACS. As lesions stabilize, they become fibrocalcific (type VII lesion) and, ultimately, fibrotic with extensive collagen content (type VIII lesion).

A complex and incompletely understood interaction is observed between the critical cellular elements of the atherosclerotic lesion. These cellular elements include endothelial cells, smooth muscle cells, platelets, and leukocytes. Interrelated biologic processes that contribute to atherogenesis and the clinical manifestations of atherosclerosis are as follows: y y y y y Vasomotor function Thrombogenicity of the blood vessel wall State of activation of the coagulation cascade The fibrinolytic system SMC migration and proliferation

Cellular inflammation The encrustation theory, proposed by Rokitansky in 1851, suggested that atherosclerosis begins in the intima with deposition of thrombus and its subsequent organization by the infiltration of fibroblasts and secondary lipid deposition. In 1856, Virchow proposed that atherosclerosis starts with lipid transudation into the arterial wall and its interaction with cellular and extracellular elements, causing "intimal proliferation."

Endothelial injury as the mechanism of atherosclerosis

In his response-to-injury hypothesis, Ross postulated that atherosclerosis begins with endothelial injury, making the endothelium susceptible to the accumulation of lipids and the deposition of thrombus. The mechanisms of atherogenesis remain uncertain, but the response -to-injury hypothesis is the most widely accepted proposal. In the 1990s, Ross and Fuster proposed that vascular injury starts the atherosclerotic process.[3] Such injuries can be classified as follows: Type I - Vascular injury involving functional changes in the endothelium, with minimal structural changes, (ie, increased lipoprotein permeability and white blood cell adhesion) y Type II - Vascular injury involving endothelial disruption, with minimal thrombosis y Type III - Vascular injury involving damage to media, which may stimulate severe thrombosis, resulting in unstable coronary syndromes According to the response-tovascular injury theory, injury to the endothelium by local disturbances of blood flow at angulated or branch points, along with systemic risk factors, perpetuates a series of events that culminate in the development of atherosclerotic plaque. y As discussed in greater detail below, endothelial damage occurs in many clinical settings and can be demonstrated in individuals with dyslipidemia, hypertension, diabetes, advanced age, nicotine exposure, and products of infective organisms (ie, Chlamydia pneumoniae). Damage to the endothelium may cause changes that are localized or generalized and that are transient or persistent, as follows: y y y y y y Increased permeability to lipoproteins Decreased nitric oxide production Increased leukocyte migration and adhesion Prothrombotic dominance Vascular growth stimulation Vasoactive substance release Endothelial dysfunction is the initial step that allows diffusion of lipids and inflammatory cells (ie, monocytes, T lymphocytes) into the endothelial and subendothelial spaces. Secretion of cytokines and growth factors promotes intimal migration, SMC proliferation, and accumulation of collagen matrix and of monocytes and other white blood cells, forming an atheroma. More advanced atheromas, even though nonocclusive, may rupture, thus leading to thrombosis and the development of ACS and MI.

Role of low-density lipoprotein-oxidative stress

The most atherogenic type of lipid is the low-density lipoprotein (LDL) component of total serum cholesterol. The endothelium's ability to modify lipoproteins may be particularly important in atherogenesis. LDLs appear to be modified by a process of low-level oxidation when bound to the LDL receptor, internalized, and transported through the endothelium. LDLs initially accrue in the subendothelial space and stimulate vascular cells to produce cytokines for recruiting monocytes, which causes further LDL oxidation. Extensively oxidized LDL (oxLDL), which is exceedingly atherogenic, is picked up by the scavenger receptors on macrophages, which absorb the LDL. Cholesterol accumulation in macrophages is promoted by oxLDL; the macrophages then become foam cells. In addition, oxLDL enhances endothelial production of leukocyte adhesion molecules (ie, cytokines and growth factors that regulate SMC proliferation, collagen degradation, and thrombosis [eg, vascular cell adhesion molecule-1, intercellular cell adhesion molecule-1]). Oxidized LDL inhibits nitric oxide synthase activity and increasing reactive oxygen species generation (eg, superoxide, hydrogen peroxide), thus reducing endothelium-dependent vasodilation. Moreover,

oxLDL alters the SMC response to A-II stimulation and increasing vascular A-II concentrations. The SMCs that proliferate in the intima to form advanced atheromas are originally derived from the media. The theory that accumulation of SMCs in the intima represents the sine qua non of the lesions of advanced atherosclerosis is now widely accepted. Substantial evidence suggests that oxLDL is the prominent component of atheromas. Antibodies against oxLDL react with atherosclerotic plaques, and plasma levels of immunoreactive altered LDL are greater in persons with AMI than in controls. Oxidative stress has therefore been recognized as the most significant contributor to atherosclerosis by causing LDL oxidation and increasing nitric oxide breakdown.

Risk factors for coronary artery atherosclerosis

A number of large epidemiologic studies in North America and Europe have identified numerous risk factors for the development and progression of atherosclerosis. These factors, which can be classified as either modifiable or nonmodifiable, include the following: y y y y y y y Hyperlipidemia and dyslipidemia Hypertension Cigarette habituation Air pollution Diabetes mellitus Age Sex The American College of Cardiology Foundation/American Heart Association 2010 report on cardiovascular risk assessment in asymptomatic adults recommends global risk scoring (eg, Framingham Risk Score[4] ) and a family history of cardiovascular disease be obtained in all adult women and men.[5] Numerous novel risk factors have been identified that add to the predictive value of the established risk factors and may prove to be a target for future medical interventions. Risk factors specific to women include pregnancy and complications of pregnancy such as gestational diabetes, preeclampsia, third trimester bleeding, preterm birth, and birth of an infant small for gestational age. The 2011 update to the American Heart Association guideline for the prevention of cardiovascular disease (CVD) in women recommends that risk assessment at any stage of life include a detailed history of pregnancy complications. It also states that postpartum, obstetricians should refer women who experience these complications to a primary care physician or cardiologist.[6] The presence of risk factors accelerates the rate of development of atherosclerosis. Diabetes causes endothelial dysfunction, decreases endothelial thromboresistance, and increases platelet activity, thus accelerating atherosclerosis. Established risk factors successfully predict future cardiac events in about 50-60% of patients. A concerted effort to identify is also being made to validate new markers of future risk of the clinical consequences of atherosclerosis has been made. Other risk factors for coronary artery atherosclerosis include the following: y y y y y y y y y y y y Family history of premature CAD Hypoalphalipoproteinemia Obesity Physical inactivity Syndromes of accelerated atherosclerosis - Graft atherosclerosis, CAD after cardiac transplantation Chronic kidney disease[7] Systemic lupus erythematosus[8] Rheumatoid arthritis[9] Metabolic syndrome[10] Chronic inflammation Infectious agents Increased fibrinogen levels

y y y

Increased lipoprotein(a) levels Familial hypercholesterolemia Depression According to the 2011 update to the American Heart Association guideline for CVD prevention in women, risk factors that are more common or may be more significant in women include psychosocial factors such as depression and autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Women with these conditions should be evaluated for CVD and for other risk factors. Women with clinically evident CVD should also be screened for these conditions, which can affect adherence or otherwise complicate secondary CVD prevention efforts.[6]

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.

Conventional 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 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.[3] 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: y y y y y 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

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: y y 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 nonECG 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 patients 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.

y y

Modifiable Risk Factors

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 interventionand the mortality associated with CAD-related causes.[5]

High blood pressure

Of the 50 million Americans with hypertension, almost one third evade diagnosis and only one fourth receive effective treatment.[6] 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.[7] 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.[6] 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.[8]

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.[9]

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 agematched and ethnically matched individuals without diabetes,[2] and a recent study suggested a potential reduction of all-cause and cardiovascular diseasespecific mortality in women with diabetes mellitus who consumed whole-grain and bran.[10] Another study suggested that meat consumption is associated with a higher incidence of coronary heart disease and diabetes mellitus.[11]

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.[12]

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.[13] 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.[14] Evidence suggests that screen-based entertainment (television or other screen time) increases the risk of cardiovascular disease, regardless of physical activity.[15] 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.[16] 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)[17] : y y y y y 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[17] (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.[18] 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.

Mental stress, depression, cardiovascular risk

Depression has been strongly implicated in predicting CAD[19] . Adrenergic stimulation during stress can increase myocardial oxygen requirements, can cause vasoconstri tion, and has been linked to c platelet and endothelial dysfunction[20] and metabolic syndrome.

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.[22] 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.[23] 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 patients 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.[3]

An elevated lipoprotein(a) [Lp(a)] level is an independent risk factor of premature CAD[21] 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 intermediaterisk adults, lipoprotein-associated phospholipase A2 might be reasonable for cardiovascular risk assessment.[3] 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.[22]

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.[24]

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.[25]

Other factors
Medical conditions such as end-stage renal disease (ESRD),[26] chronic inflammatory diseases affecting connective tissues (eg, lupus, rheumatoid arthritis),[27, 28] human immunodeficiency virus (HIV) infection (acquired immunodeficiency syndrome [AIDS], highly active antiretroviral therapy [HAART]),[29] 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. [26] 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.[3] Low serum testosterone levels have a significant negative impact on patients with CAD. More studies are needed to assess better treatment.[30] One study suggests women aged 50 years or younger who undergo a hysterectomy are atan increased risk for cardiovascular disease later in life.[31] Oopherectomy also increases the risk for both coronary heart disease and stroke.

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.[32] 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.[33] Carotid intima-media thickness (IMT), pulse wave velocity (PWV), and the ankle-brachial index (ABI) are widely used noninvasive modalities for evaluating atherosclerosis.[34] One study suggested regression or slow progression of carotid IMT due to cardiovascular drug therapies does not reduce cardiovascular events.[35] 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.[3]

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 ob structive CAD. [36] The 2010 ACCF/AHA guideline does not recommend genotype testing for coronary heart disease risk assessment in asymptomatic adults.[3]

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.[34] 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.[3] 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.[37] 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.[3] 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.[3] 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.

The true frequency of atherosclerosis is difficult, if not impossible, to accurately determine because it is a predominantly asymptomatic condition. The process of atherosclerosis begins in childhood w ith the development of fatty streaks. These lesions can be found in the aorta shortly after birth and appear in increasing numbers in those aged 8-18 years. More advanced lesions begin to develop when individuals are aged approximately 25 years. Subsequently, an increasing prevalence of the advanced complicated lesions of atherosclerosis is noted, and the organ-specific clinical manifestations of the disease increase with age through the fifth and sixth decades of life.

United States statistics

In the United States, approximately 14 million persons experience CAD and its various complications. Congestive heart failure (CHF) that develops because of ischemic cardiomyopathy in hypertensive MI survivors has become the most common discharge diagnosis for patient in American hospitals. s Approximately 80 million people, or 36.3% of the population, have cardiovascular disease. Annually, approximately 1.5 million Americans have an AMI, a third of whom die. In 2009, 785,000 Americans were estimated to have suffered a first MI, and about 470,000 Americans were estimated to have had a recurrent event. An additional 195,000 "silent" heart attacks are estimated to occur each year. About every 34 seconds, an American will have an MI. CAD remains the number 1 cause of death for men and women in the United States and is responsible for approximately 20% of all US deaths. From 19952005, the death rate from CAD declined 34.3%, but the actual number of deaths declined only 19.4%.

International statistics
The international incidence of ACS and AMI, especially in developed countries, is similar to that observed in the United States. Despite consumption of rich foods, inhabitants of France and the Mediterranean region appear to have a lower incidence of CAD. This phenomenon (sometim called es the French paradox) is partly explained by greater use of alcohol, with its possible HDL-raising benefit, and by consumption of the Mediterranean diet, which includes predominant use of monounsaturated fatty acids, such as olive oil or canola oil, as well as omega-3 fatty acids, which are less atherogenic. Eskimos have been found to have a lower prevalence of CAD as a result of consuming fish oils containing omega-3 fatty acids. Findings from the World Health Organization's Monitor Trends in Cardiovascular Diseases (MONICA) project involving 21 countries showed a 4% fall in CAD death rates. Improvement in the case fatality rate accounted for only one third of the decline. However, two thirds of the decline resulted from a reduction in the number of events. These findings strongly suggest that the largest impact on decreasing the global burden of atherosclerosis will come from prevention of events. The frequency of clinical manifestations of atherosclerosis in Great Britain, west of Scotland in particular, is especially high. The same is true of Scandinavia in general and of Finland in particular. Russia and many of the former states of the Soviet Union have recently experienced an exponential increase in the frequency of coronary heart disease that likely is the result of widespread economic hardship and social upheaval, a high prevalence of cigarette habituation, and a diet high in saturated fats.

Westernization and the rise of coronary heart disease

The frequency of coronary heart disease in the Far East is significantly lower than that documented in the West. Ill-defined genetic reasons for this phenomenon may exist, but significant interest surrounds the role of diet and other environmental factors in the absence of clinical atherosclerotic vascular disease in these populations. Atherosclerotic cardiovascular disease is also rare on the African continent, although growing evidence indicates that this too is changing, as a result of rapid westernization and urbanization of the traditionally rural and agrarian African populations. The prevalence of coronary heart disease is also increasing in the Middle East, India, and Central and South America.[1] The rate of CAD in ethnic immigrant populations in the United States approaches that of the disease in whites, supporting the role of these putative environmental factors.

Race-associated prevalences of coronary artery disease

The incidence, prevalence, and manifestations of CAD vary significantly with race, as does the response to therapy. Blacks appear to have higher morbidity and mortality rates of CAD, even when the statistics are corrected for educational and socioeconomic status. The risk-factor burden experienced by blacks differs from that of whites. The prevalence of hypertension, obesity, dysmetabolic syndrome, and lack of physical activity are much higher in blacks, whereas the prevalence of hypercholesterolemia is lower. Blacks with AMI present for treatment later than patients do on average, are less often subjected to invasive strategies, and experience greater overall mortality. (Similar statistics can also be cited for presentation and treatment of patients with stable CAD.) Asian Indians exhibit a 2- to 3-fold higher prevalence of CAD than do whites in the United States. They also have greater prevalences of hypoalphalipoproteinemia, high lipoprotein(a) levels, and diabetes.

Sex-associated prevalences of coronary artery disease

Men traditionally have a higher prevalence of CAD. Women, however, follow men by 10 years, especially after menopause. (The value of estrogen supplementation for prevention of CAD has been discredited by the Heart and Estrogen/Progestin Replacement Study [HERS]). [11, 12] The presence of diabetes, as well as tobacco use, eliminates the protection from heart disease associated with female sex. In women, as in men, the most common cause of death is CAD, which accounts for more deaths in women than those related to breast and uterine diseases combined. Women with AMI present later than average, are less often subjected to invasive strategies, and

experience greater overall mortality. (Similar statistics can also be cited for the presentation and treatment of patients with stable CAD.) The 2011 update to the American Heart Association guideline for the prevention of cardiovascular [6] disease in women recommends changes in prevention and treatment practices: y y y Women should be considered as high risk, and as candidates for aggressive treatment, if their risk of dying from any cardiovascular event in the next 10 years is 10% or greater. Research studies should publish efficacy and adverse drug reactions (ADRs) by gender, as both can differ in women. Evidence from clinical trials tends to overestimate the real-world efficacy of therapies in female patients, who are generally older and have more comorbidities than test subjects. The guideline is now effectiveness-based rather than evidence-based. Effectiveness-based considerations have reduced the strength of previous recommendations for use of aspirin, statins (in women with elevated C-reactive protein but normal cholesterol), and aggressive glycemic control in diabetes.

The elderly and coronary artery disease

Age is the strongest risk factor for the development of CAD. Most cases of CAD become clinically apparent in patients aged 40 years or older, but elderly persons experience higher mortality and morbidity rates from it. Approximately 82% of people who die of CAD are 65 years or older. Complication rates of multiple therapeutic interventions tend to be higher in the elderly; however, the magnitude of benefit from the same interventions is greater in this population, because these patients form a high-risk subgroup.

Calculating risk of coronary artery atherosclerosis

Of note, algorithms for predicting the risk of cardiovascular disease have generally been developed for a follow-up period of no more than 10 years. However, clustering of risk factors at younger ages and increasing life expectancy suggest the need for longer-term risk prediction. In a prospective, 30-year follow-up study, standard risk factors (male sex, systolic blood pressure, antihypertensive treatment, total and high-density lipoprotein cholesterol, smoking, diabetes mellitus), measured at baseline, were significantly related to the incidence of coronary death, myocardial infarction, and stroke and remained significant when updated regularly. This 2009 study by Pencina and colleagues, which utilized 4506 participants of the Framingham Offspring cohort, employed an algorithm for predicting 30-year risk for the above events. The investigators also found that body mass index was associated positively with 30-year risk of such events, but only in models that did not update risk factors.

As previously mentioned, approximately 1.5 million Americans per year have an AMI, with a third of these events proving fatal. The survivors of MI have a poor prognosis, carrying a 1.5- to 15-fold higher risk of mortality and morbidity than the rest of the population. Historically, for example, 25% of men and 38% of women die within 1 year after having an MI, although these rates may overstate the 1-year mortality rate today, given advances in the treatment of CHF and sudden cardiac death. Among survivors, 18% of men and 34% of women have a second MI within 6 years, 7% of men and 6% of women die suddenly, 22% of men and 46% of women are disabled with CHF, and 8% of men and 11% of women have a stroke. The prognosis in patients with atherosclerosis depends on the following factors: y y y y y y Presence of inducible ischemia Left ventricular function Presence of arrhythmias Revascularization potential (complete vs incomplete) Aggressiveness of risk alteration Compliance with medical therapy The prognosis of atherosclerosis also depends on systemic burden of disease, the vascular bed(s) involved, and the degree of flow limitation. Wide variability is noted, and clinicians appreciate that many patients with critical limitation of flow to vital organs may survive many years, despite a heavy

burden of disease. Conversely, MI or sudden cardiac death may be the first clinical manifestation of atherosclerotic cardiovascular disease in a patient who is otherwise asymptomatic with minimal luminal stenosis and a light burden of disease. Much of this phenotypic variability is likely to be determined by the relative stability of the vascular plaque burden. Plaque rupture and exposure of the thrombogenic lipid core are critical events in the expression of this disease process and determine the prognosis. The ability to determine and quantify risk and prognosis in patients with atherosclerosis is limited by the inability to objectively measure plaque stability and other predictors of clinical events.

Patient Education
Education regarding CAD is extremely important. Publications and articles available from the American Heart Association provide a wealth of information. The most effective and probably the most cost-efficient means of reducing the burden of disease secondary to atherosclerosis in the general population is primary prevention. The role of diet and exercise in the prevention of atherosclerotic cardiovascular disease has been well established. Education of the general population regarding healthy dietary habits and regular exercise will reduce the prevalence of multiple coronary heart disease risk factors. (See Treatment Strategies and Management) For patients with risk factors refractory to lifestyle interventions, education can enhance compliance with prescribed therapy. For excellent patient education resources, visit eMedicine's Cholesterol Center, Statins Center, and Circulatory Problems Center. In addition, see eMedicine's patient education articles High Cholesterol,Lifestyle Cholesterol Management, Chest Pain, Coronary Heart Disease,Heart Attack, Angina Pectoris, and Statins and Cholesterol.

The symptoms of atherosclerosis vary widely. Patients with mild atherosclerosis may present with clinically important symptoms and signs of disease and MI, or sudden cardiac death may be the first symptom of coronary heart disease. However, many patients with anatomically advanced disease may have no symptoms and experience no functional impairment. The spectrum of presentation includes symptoms and signs consistent with the following conditions: y y y y y y y Asymptomatic state (subclinical phase) Stable angina pectoris Unstable angina (ie, ACS) AMI Chronic ischemic cardiomyopathy Congestive heart failure Sudden cardiac arrest History may include the following: Chest pain Shortness of breath Weakness, tiredness, reduced exertional capacity Dizziness, palpitations Leg swelling Weight gain Symptoms related to risk factors Progressive luminal narrowing of an artery due to expansion of a fibrous plaque results in impairment of flow once at least 50-70% of the lumen diameter is obstructed. This impairment in flow results in symptoms of inadequate blood supply to the target organ in the event of increased metabolic activity and oxygen demand. Stable angina pectoris, intermittent claudication, and mesenteric angina are examples of the clinical consequences of this mismatch. Rupture of a plaque or denudation of the endothelium overlying a fibrous plaque may result in exposure of the highly thrombogenic subendothelium and lipid core. This exposure may result in

y y y y y y y

thrombus formation, which may partially or completely occlude flow in the involved artery. Unstable angina pectoris, MI, transient ischemic attack, and stroke are examples of the clinical sequelae of partial or complete acute occlusion of an artery. Atheroembolism is a distinct clinical entity that may occur spontaneously or as a complication of aortic surgery, angiography, or thrombolytic therapy in patients with advanced and diffuse atherosclerosis. Angina pectoris is characterized by retrosternal chest discomfort that typically radiates to the left arm and may be associated with dyspnea. Angina pectoris is exacerbated by exertion and relieved by rest or nitrate therapy. Unstable angina pectoris describes a pattern of increasing frequency or intensity of episodes of angina pectoris and includes pain at rest. A prolonged episode of angina pectors that may i be associated with diaphoresis is suggestive of MI.

Physical Examination
Tachycardia is common in persons with ACS and AMI. Heart rate irregularity may signal the presence of atrial fibrillation or frequent supraventricular or ventricular ectopic beats. Ventricular tachycardia is the most common cause of death in persons with AMI. High or low blood pressure may be noted. Hypotension often reflects hemodynamic compromise and is a predictor of poor outcome in the setting of AMI. Diaphoresis is a common finding. Patients often have rapid breathing (ie, tachypnea). Signs and symptoms of congestive heart failure (CHF) may indicate cardiogenic shock or a mechanical complication of AMI, such as ischemic mitral valve regurgitation. An S4 gallop is a common early finding. The presence of an S3 is an indication of reduced left ventricular function. Heart murmurs, particularly those of mitral regurgitation and ventricular septal defect, may be found after the initial presentation; their presence indicates a grave prognosis. The murmur of aortic insufficiency may signal the presence of aortic dissection as a primary etiology, with or without the complication of AMI. Central obesity is often seen. Patients may develop xanthelasmas, livedo reticularis, or both. Patients may have scarring from CABG or similar surgeries. The following may also be noted: y y y y y y y y y Shock Syncope Leg edema Pulmonary congestion Rales Diagonal ear crease Short stature Baldness Thoracic hairiness

Diagnostic Considerations
Typical angina symptoms, such as a substernal pressurelike chest pain with radiation to the jaw or left arm may not be present. Less typical symptoms, such as sharp chest pain, dyspnea, diaphoresis, back pain, neck pain, nausea, fatigue, and palpitations may be manifestations of myocardial ischemia. Less typical symptoms are more prevalent in women. In addition, symptoms suggestive of angina may in fact be due to other causes, listed in Differentials

y y y y y y y y Angina Pectoris Atherosclerosis Buerger Disease (Thromboangiitis Obliterans) Cardiomyopathy, Dilated Coronary Artery Vasospasm Diabetes Mellitus, Type 1 Diabetes Mellitus, Type 2 Giant Cell Arteritis

y y y y y y y y y y y y y y

Hypercholesterolemia, Familial Hypercholesterolemia, Polygenic Hypertension Hypertensive Heart Disease Isolated Coronary Artery Anomalies Kawasaki Disease Myocardial Ischemia - Nuclear Medicine and Risk Stratification Myocarditis Nicotine Addiction Pericarditis, Acute Pulmonary Embolism Right Ventricular Infarction Treadmill Stress Testing Unstable Angina

Approach Considerations
Routine blood tests include complete blood count (CBC), chemistry panel, lipid profile, and thyroid function tests (to exclude thyroid disorders). Routine measurement of blood glucose and hemoglobin A1C is appropriate in patients with diabetes mellitus. Measuring any number of parameters that may reflect coagulation, fibrinolytic status, and platelet aggregability is possible. These measurements may prove to be valuable, but how these measurements affect clinical decision-making is unclear at this time, and including them in routine clinical practice is premature. Standardization of the CRP assay is required before this test may be clinically useful, and whether CRP is a truly modifiable risk factor remains unclear. The majority of atherosclerotic lesions responsible for the most serious CAD events (that is, the lesions that are most likely to rupture) are mild stenoses of inconsequential hemodynamic significance and are characterized by an abundance of lipid, numerous inflammatory cells, and a thin, fragile fibrous cap. This suggests that although measurements of coronary flow reserve (CFR) and fractional flow reserve (FFR), both of which are discussed below, may be useful in the assessment of the severity of stenoses and in the identification of lesions responsible for effort angina, they are not likely to identify the more dangerous plaques responsible for unstable angina, AMI, and sudden ischemic death.

Fractional Flow Reserve

Myocardial FFR has been used as an index of functional severity of coronary artery stenosis. FFR represents the fraction of the normal maximal coronary flow that can be achieved in an artery in which flow is restricted by a coronary stenosis. The concept of FFR is based on the observation that myocardial perfusion is entirely pressure dependent during maximal hyperemia. Maximal blood flow in the presence of a stenosis is therefore determined by the driving pressure distal (Pd) to the stenosis, whereas the theoretical normal maximal blood flow is determined by the pressure proximal (Pp) to the stenosis. FFR is calculated during maximal hyperemia (obtained with adenosine or papaverine) as FFR = Pd/Pp. FFR less than 0.75 is typically associated with other objective evidence of myocardial ischemia. FFR is calculated from the ratio of the mean pressure distal to a coronary stenosis to the mean aortic pressure during maximal hyperemia. If the FFR is less than 0.75, sensitivity is at least 80% and specificity is at least 85% for the presence of ischemia on noninvasive stress testing.

Lipid Studies
Fasting lipid profile includes the following[13, 14, 15] : y y y Total cholesterol level LDL cholesterol (LDL-C) level HDL cholesterol (HDL-C) level

y y y y y

Triglyceride level Specific lipid studies (if necessary) include the following: Small, dense LDL-C level Lipoprotein (a) level Apoprotein profile Direct measurement of HDL-C

C-Reactive Protein
CRP appears to provide prognostic information for CAD, although as stated above, the CRP assay must be standardized before CRP testing has a clinical benefit. Men with CRP levels in the highest quartile had a 3-fold greater risk of MI, according to the Physicians Health Study. Use of aspirin resulted in a significant (55.7%) reduction in the risk of MI in men in the highest CRP quartile, suggesting that the aspirin-related reduction in the risk of first MI was clearly related to the level of CRP. [16] One study found that patients with baseline CRP levels of more than 10 mg/L had significantly worse outcomes than did patients with lower CRP levels. This investigation, the Fragmin and/or Early Revascularization During Instability in Coronary Artery (FRISC-II) study, included 900 subjects followed for 4 years.[17] CRP can also help to predict treatment efficacy, as demonstrated in the Cholesterol and Recurrent Events (CARE) trial of pravastatin treatment in post-MI patients. CRP levels tended to increase over time in the studys placebo group, whereas levels remained lower in the statin-treatment group at 5 years. Additionally, the efficacy of statin therapy was greater in subjects with higher levels of CRP.

Serum Markers
Serum markers in patients with suspected acute cardiac events (ACS, MI) include the following: y y y y Troponins (I or T) Creatine kinase with MB isozymes Lactate dehydrogenase and lactate dehydrogenase isozymes Serum aspartate aminotransferase

In a 10-year comparison of 10 biomarkers for predicting death and first major cardiovascular events in approximately 3000 individuals, the most informative biomarkers for predicting death were the following[19] : y y y y y B-type natriuretic peptide CRP Homocysteine Renin Urinary albumin-to-creatinine ratio The most informative biomarkers for predicting major cardiovascular events were B-type natriuretic peptide and the urinary albumin-to-creatinine ratio. Individuals with elevated multimarker scores had a risk of death 4 times higher and a risk of major cardiovascular events almost 2 times higher than those with low multimarker scores. However, the use of multiple biomarkers added only moderately to the overall prediction of risk based on conventional cardiovascular risk factors.

Transthoracic echocardiography helps to assess left ventricular function, wall-motion abnormalities in the setting of ACS or AMI, and mechanical complications of AMI. Transesophageal echocardiography is most often used for assessing possible aortic dissection in the setting of AMI. Stress echocardiography can be used to evaluate hemodynamically significant stenoses in stable patients who are thought to have CAD. Treadmill echocardiography stress testing and dobutamine echocardiography stress testing provide equivalent predictive values. ECG findings are depicted below.

Stress test, part 1. Resting ECG showing normal baseline ST segments. (See the image below for part 2.)

Stress test, part 2. Stress ECG showing significant ST-segment depression. (See the image above for part 1.)

Nuclear Imaging Studies

These studies are useful in assessing patients for hemodynamically significant coronary artery stenoses. Stress and rest nuclear scintigraphic studies using thallium, sestamibi, or teboroxime are sometimes helpful. Types of nuclear imaging stress tests include a treadmill nuclear stress test, a dipyridamole (Persantine) or adenosine nuclear stress test, and a dobutamine nuclear stress test. Stress nuclear imaging findings are depicted below.

Stress nuclear imaging showing anterior, apical, and septal wall perfusion defect during stress, which is reversible as observed on the rest images. This defect strongly suggests the presence of significant stenosis in the left anterior descending coronary artery.

Radionuclide stress myocardial perfusion imaging can be used to quantify CFR. Thallium-201 (201 Tl) or sestamibi are widely used for this. Flow reserve is typically assessed during exercise or with pharmacologic coronary vasodilators. MI-avid scintigraphy may be indicated for detection and localization of infarcted myocardium if evidence from other tests is inconclusive.

Computed Tomography Scanning

Multidetector computed tomography (MDCT) scanning can allow excellent visualization of the coronary arteries, but its relatively high radiation dose is one of the limitations of this approach. Newer generations of CT scanners may be able to reduce the required radiation exposure to make this technology more promising for screening asymptomatic patients. Low-dose CT attenuation correction (CTAC), which is performed for hybrid positron emission tomography (PET)/CT and single-photon emission computed tomography (SPECT)/CT myocardial perfusion imaging (MPI) can visually assess coronary artery calcium with high agreement with the Agatston score (AS).[20] These scans should routinely be assessed for visually estimated coronary artery calcium. However, guidelines that address the use of CAD imaging tests may disagree. A study by Ferket, et al found several guidelines for risk assessment of asymptomatic CAD to have conflicting recommendations.[21]More research, especially randomized controlled trials, are needed in order to establish the actual impact imaging has on clinical outcomes.

Electron Beam Computed Tomography Scanning

Electron beam CT (EBCT) scanning is a relatively new, noninvasive method of evaluating calcium content in the coronary arteries. Healthy coronary arteries lack calcium. As atherosclerotic plaques grow, calcium accumulates because of a perpetuating inflammatory process or the healing and scarring induced by this process. EBCT is currently used as a screening test in asymptomatic patients and as a diagnostic test for obstructive CAD in symptomatic patients, although experts in the field have reached no consensus regarding indications for its use. EBCT scanning has been demonstrated to have high sensitivity, with an overall predictive accuracy of 70%, according to the American College of Cardiology (ACC)/American Heart Association (AHA) Expert Consensus Document.[22] However, EBCT has low specificity, ie, a substantial false-positive rate, which raises the index of suspicion for CAD and leads to expensive and unwarranted additional testing to exclude CAD. Consequently, the ACC/AHA report did not recommend EBCT scanning to help diagnose obstructive CAD. Whether EBCT scanning is a worthwhile tool for screening of CAD is still unclear. Well-established clinical indicators, such as the Framingham risk score and the National Cholesterol Education Program (NCEP) risk calculator, already accurately predict the likelihood of CAD. Whether EBCT scanning adds to these indicators has yet to be shown. The Multi-Ethnic Study of Atherosclerosis (MESA), sponsored by the US National Institutes of Health, has been assessing prospective evaluation of EBCT scanning in asymptomatic subjects to answer this question.[23] EBCT scanning may have niche uses, including (1) determination of whether individuals who appear to be at intermediate risk are really at a higher risk (eg, asymptomatic elderly patients who have high calcium scores) and (2) determination of a low likelihood of significant CAD if EBCT scanning demonstrates a low or absent calcium score.

Optical Coherence Tomography Imaging

Optical coherence tomography (OCT) imaging is a method of catheter-based, high-resolution intravascular imaging. Unlike IVUS, it measures the backreflection of infrared light rather than sound. The main advantage of OCT is its remarkable resolution, which is in the range of 10-20 m. In addition, acquisition rates are near video speed, an advantage relative to many other technologies for assessing plaque. In contrast to IVUS scanning, the typical OCT catheters contain no transducers within their frame, which makes them small and inexpensive. Because OCT imaging uses light, a variety of spectroscopic techniques are available, including polarization spectroscopy, absorption spectroscopy, elastography, OCT Doppler, and dispersion analysis.

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) may be used to gain information noninvasively about blood vessel wall structure and to characterize plaque composition.

Coronary Angiography
Coronary angiography was the first available in vivo assessment of the coronary arteries. In this technique, an iodinated contrast agent is injected through a catheter placed at the ostium of the coronaries. The contrast agent is then visualized through radiographic fluoroscopic examination of the heart. Coronary angiography remains the criterion standard for detecting significant flow-limiting stenoses that may be revascularized through percutaneous or surgical intervention (as seen in the image below).

Cardiac catheterization and coronary angiography in the left panel shows severe left anterior descending coronary artery stenosis. This lesion was treated with stent placement in the left anterior descending coronary artery, as observed in the right panel.

Quantitative coronary angiography (QCA) is used to perform computerized quantitative analysis of the entire coronary tree and has been widely employed in many trials of atherosclerotic progression and regression. Coronary angiography has several limitations. Severity of stenosis is generally estimated visually, but estimation is limited by the fact that interobserver variability may range from 30-60%. The presence of diffuse disease may also lead to underestimation of stenoses, because the stenosed areas are expressed as a percent of luminal diameter compared with adjacent normal coronary segments, and, in diffuse disease, no such segments are noted. This usually occurs in diabetic patients, in whom coronary arteries are traditionally described as small-caliber vessels, when that appearance is actually due to the presence of diffuse symmetrical involvement of the entire vessel, as elucidated by IVUS studies. One of the other limitations of coronary angiography is that only the vessel space occupied by blood is visualized. The actual extent of atherosclerotic plaque volume in the wall cannot be assessed with this technique. Angiography does not provide information about plaque burden, which may be significant due to positive remodeling of the plaque, even when the degree of luminal obstruction is mild. Because of the inherent limitations of coronary angiography, attention has been directed toward using physiologic approaches to determine the severity of coronary stenoses. The commonly used methods of measuring human coronary blood flow in the cardiac catheterization laboratory are Doppler velocity probes (for measuring CFR) and pressure wires (for measuring FFR). Although most current methods measure relative changes in coronary blood flow, useful information about the physiologic significance of stenosis, cardiac hypertrophy, and pharmacologic interventions can be obtained from these measurements.

Doppler Velocity Probes

Doppler velocity probes use a Doppler flow meter, which is based on the principle of the Doppler effect. This is the most widely applied technique for measuring coronary flow in humans. Highfrequency sound waves are reflected from moving red blood cells and undergo a shift in sound frequency proportional to the velocity of the blood flow. In pulsed-wave Doppler methods, a single piezoelectric crystal can transmit and receive highfrequency sound waves. These methods have been successfully applied in humansby using miniaturized crystals fixed to the tip of catheters. Technological developments have further miniaturized steerable 12-MHz Doppler guide wires to a diameter of 0.014 inches. Flow to a stenosis can therefore be assessed distally and proximally. The Doppler guidewire measures phasic flow velocity patterns and tracks linearly with flow rates in small, straight coronary arteries.

Indications for Doppler velocity probe use include determining the severity of intermediate stenosis (40-60%) and evaluating whether normal blood flow has been restored after percutaneous transluminal coronary angioplasty (PTCA). The use of smaller Doppler catheters allows measurement of selective coronary artery flow velocity. By noting the increase in flow velocity following administration of a strong coronary vasodilator, such as papaverine or adenosine, the CFR can be defined. CFR provides an index of the functional significance of coronary lesions that obviates some of the ambiguity of anatomical description. The current Doppler probe method has limitations. Limitations include the following: Only changes in flow velocity, rather than absolute velocity or volumetric flow, are measurable The change in flow velocity is directly proportional to changes in volumetric flow only when vessel dimensions are constant at the site of the sample volume y Other factors, including left ventricular hypertrophy and myocardial scarring, can also affect CFR y Changes in luminal diameter and arterial cross-sectional area during interventions are not reflected in measurements of flow velocity, thus potentially causing underestimation of the true volume flow Because this technique does not measure absolute coronary blood flow, several indices of flow velocity have been used for assessing the physiologic significance of coronary stenoses. Coronary flow velocity reserve is the ratio of maximum flow velocity to baseline flow velocity. y y Patients with a coronary flow velocity ratio of less than 2 typically have other corroborating evidence of myocardial ischemia and improve symptomatically with revascularization. Conversely, patients with a ratio of more than 2 usually lack other objective evidence of myocardial ischemia and have a favorable outcome with conservative management; therefore, flow velocity measurements can be helpful in the treatment of patients with coronary lesions of intermediate severity.

Relative coronary flow reserve

Relative CFR is calculated as follows: ([rCFR] = CFR target/CFR reference). Relative CFR involves Doppler coronary flow measurements of target and reference vessel CFR with a Doppler-tipped guidewire. In one report, El-Shafei et al found that, compared with patients who had negative stressimaging study findings, patients who had positive stress-study findings showed more angiographically severe stenoses (74% +/- 13% vs 44% +/- 24%) with lower target CFRs (1.68 +/- 0.55 vs 2.46 +/0.74) and lower rCFRs (0.72 +/- 0.22 vs 1 +/- 0.26).[24] Based on cut points (CFR >1.9; rCFR >0.75), compared with CFR, rCFR had similar agreement (kappa 0.54 vs 0.5), sensitivity (63% vs 71%), specificity (88% vs 83%), and positive predictive value (83% vs 81%) with myocardial perfusion tomography. Although rCFR, as with CFR, correlates with stress myocardial perfusion imaging results, rCFR did not have significant incremental prognostic value over CFR alone for myocardial perfusion imaging. However, rCFR does provide additional information regarding the status of the microcirculation in patients with CAD and complements the CFR for lesion assessment.

Ultrasonography aids in evaluating brachial artery reactivity and carotid artery intima media thickness, which are measures of vessel wall function and anatomy, respectively. These evaluations remain research techniques at this time but hold promise as reliable noninvasive, and therefore repeatable, measures of disease and surrogate endpoints for the evaluation of therapeutic interventions.

Brachial Artery Reactivity

The loss of endothelium-dependent vasodilation is a feature of even the early stages of atherosclerosis. The availability of high-resolution ultrasonographic systems makes the visualization and measurement of small peripheral conduit vessels, such as the human brachial artery, possible. Flow-mediated dilation of the brachial artery has been pioneered as a means of evaluating the health and integrity of the endothelium. The healthy endothelium dilates in response to an increase in blood flow, whereas vessels affected by atherosclerosis do not dilate and may paradoxically constrict.

Carotid artery intima-media thickness

B-mode ultrasonography of the common and internal carotid arteries is a noninvasive measure of arterial wall anatomy that may be performed repeatedly and reliably in asymptomatic individuals. The combined thickness of the intima and media of the carotid artery is associated with the prevalence of cardiovascular risk factors and disease and an increased risk of myocardial infarction and stroke. This association is at least as strong as the associations observed with traditional risk factors.

Intravascular Ultrasonography
IVUS demonstrates the luminal dimensions and, more importantly, the tissue composition of the vascular wall in tomographic subsegments that can be summated to create a 3-dimensional picture showing arterial remodeling and the diffuseness of atherosclerosis with clarity unobtainable by angiography. IVUS delineates vascular remodelingpositive and negative. Positive remodeling shows adaptive outward expansion of the external elastic membrane to accommodate growing plaques (Glagov phenomenon). Negative remodeling exhibits discrete areas of vascular luminal encroachment by the ingrowing plaques. Positive remodeling is more commonly associated with unstable angina, whereas negative remodeling is associated with stable angina, according to an IVUS study of 85 patients by Schoenhagen and colleagues.[25] The apparently paradoxical findings of angiographic studies suggesting that AMI most often occurs in less than 50% of stenosed arterial segments, and those of autopsy studies showing AMI to be associated with large plaques, are reconciled by IVUS findings. IVUS shows the responsible lesions to be large plaques that have positively remodeled, thus causing minimal luminal encroachment and exhibiting echolucency suggesting a lipid-rich pool in the plaque center. The ability of IVUS to identify positively remodeled plaques and the presence of diffuse disease in some ways makes it better than angiography, the less-than-perfect criterion standard. IVUS can much more clearly demonstrate the presence or absence of fibrosis, calcium, and ulceration, as well as eccentricity of the plaques. Ostial lesions can also be better defined by IVUS.

A system devised by Stary et al classifies atherosclerotic lesions according to their histologic composition and structure.[2] In a type I lesion, the endothelium expresses surface adhesion molecules E selectin and P selectin, attracting more polymorphonuclear cells and monocytes in the subendothelial space. In a type II lesion, macrophages begin to take up large amounts of LDL (fatty streak). In a type III lesion, as the process continues, macrophages become foam cells. In a type IV lesion, lipid exudes into the extracellular space and begins to coalesce to form the lipid core. In a type V lesion, SMCs and fibroblasts move in, forming fibroatheromas with soft inner lipid cores and outer fibrous caps. In a type VI lesion, rupture of the fibrous cap with resultant thrombosis causes ACS. As lesions stabilize, they become fibrocalcific (type VII lesion) and, ultimately, fibrotic with extensive collagen content (type VIII lesion).

Approach Considerations
The treatment goals for patients with coronary artery atherosclerosis are to relieve symptoms of CAD and to prevent future cardiac events, such as unstable angina, AMI, and death.

The mainstays of pharmacologic therapy of angina include nitrates, beta-blockers, statins, calciumchannel blockers, and ranolazine.[26] The prevention and treatment of atherosclerosis requires control of the known modifiable risk factors for this disease. This includes therapeutic lifestyle changes and the medical treatment of hypertension, hyperlipidemia, and diabetes mellitus. Typically, patients with CAD are first seen after they present with a cardiac event. The main focus of their treatment is the index event. The past 4 decades have witnessed tremendous progress in the areas of acute cardiac care, coronary care unit expansion, thrombolytic usage, and PCI. Nevertheless, prevention of cardiac events is likely to have the largest impact on decreasing the burden of atherosclerosis. High-risk subgroups, in particular, can be targeted for early intervention. Grover and colleagues showed statin therapy in diabetic patients without CAD to be as cost-effective as statin therapy in nondiabetic patients with CAD. Pharmacotherapeutic strategies that affect the risk factor profile, such as the administration of statins for low-density lipoprotein (LDL) reduction or the administration of agents that alter atherosclerotic plaque, are of paramount importance.

Prevention of future cardiac events

Findings from the World Health Organization's Monitor Trends in Cardiovascular Diseases (MONICA) project involving 21 countries showed a 4% fall in CAD death rates. Improvement in the case fatality rate accounted for only one third of the decline; two thirds of the decline resulted from a reduction in the number of events. These findings strongly suggest that the largest impact on decreasing the global burden of atherosclerosis will come from prevention of events. Fortunately, the natural history of CAD is characterized by early onset and a long dormant phase. This provides an excellent opportunity to intervene in order to reduce the number and severity of cardiovascular events.

Pharmacologic Strategies
The goals of therapy should include arresting atherosclerosis or even reversing its progression. Large, multicenter randomized trials of various pharmacologic modalities have recently achieved great success in the treatment of patients with coronary artery atherosclerosis. In addition, addressing risk factors with lifestyle changes is an integral part of atherosclerosis prevention. Therapy with lipidlowering agents should be a component of multiple risk factor intervention and is indicated in primary prevention as an adjunct to diet therapy when the response to a diet restricted in saturated fat and cholesterol has been inadequate. Substantial evidence supports the use of statins in the secondary prevention of CAD, and the efficacy of statins has recently been extended to include primary prevention of CAD in patients with average cholesterol levels. Niacin is superior to ezetimibe for combination therapy in high-risk patients being treated with statin monotherapy. In a meta-analysis of nearly 5000 patients, findings showed that statins administered before invasive procedures significantly reduced the risk for postprocedural myocardial infarction.[27] The risk for MI was reduced after percutaneous coronary intervention and noncardiac surgical procedures, but not for coronary artery bypass grafting (CABG). Statins decreased the risk for atrial fibrillation following CABG. Statin therapy is also safe and can improve liver tests while reducing cardiovascular morbidity in patients with mild- to moderately-abnormal liver test results that may be attributable to nonalcoholic fatty liver disease.[28] In the United States, the most commonly used guidelines for cholesterol management are those from the NCEP Adult Treatment Panel (ATP). In high-risk persons, the recommended LDL-C goal is less than 100 mg/dL, but when risk is very high, an LDL-C goal of less than 70 mg/dL is a therapeutic option and a reasonable clinical strategy based on available clinical trial evidence. For moderately high-risk persons (2 risk factors and 10-y risk of 10-20%), the recommended LDL-C goal is less than 130 mg/dL, but an LDL-C goal of less than 100 mg/dL is a therapeutic option based on trial evidence. To see complete information on Statins, please go to the main article.

Treatment of Low HDL levels and High Triglyceride levels in Patients with Diabetes
A combination of low HDL levels and high triglyceride levels is frequently encountered in patients with diabetes and is often referred to as atherogenic dyslipidemia. Many of these patients have metabolic syndrome. Additional follow-up and analysis of the Veterans Affairs HDL Intervention Trial (VA-HIT) indicated that treatment with gemfibrozil versus placebo resulted in a 32% reduction in major cardiovascular events and a 41% reduction in CHD deaths, in 769 male subjects with diabetes mellitus and CHD who had HDL-C levels of less than 40 mg/dL and LDL-C levels of less than 140 mg/dL. Interestingly, among 1733 nondiabetic men, increased plasma fasting insulin levels and insulin resistance, as assessed by the homeostasis model assessment for insulin resistance (HOMA-IR; fasting insulin [U/mL] X fasting glucose [mmol/L]/22.5), were predictive of increased major cardiovascular events and of greater benefit from gemfibrozil treatment.[29, 30] Somewhat inexplicable was the finding that despite higher plasma triglyceride and lower HDL-C levels in insulin-resistant subjects, these measurements were associated with greater treatment benefit only in those subjects classified as not having insulin resistance by HOMA-IR. This was the first trial to demonstrate the cardiovascular benefit of treating diabetic and insulinresistant subjects with low HDL-C levels. Interestingly, the insulin resistance was more predictive of CHD event rate and benefit from gemfibrozil than were HDL-C or triglyceride levels. Because no significant reduction in LDL-C was realized with gemfibrozil therapy, one possibility is that additional CHD benefit would be accrued by adding statins, which have been shown in subgroup analyses of several trials to benefit CHD risk in diabetic patients and in nondiabetic patients with low HDL-C levels. One caveat is that because of the relatively higher risk of myopathy with combined gemfibrozil-statin treatment and findings that indicate much less risk with statins and fenofibrate, the latter is currently the preferred choice for combined treatment.