Coronary Artery Atherosclerosis

8/6/2019 Coronary Artery Atherosclerosis

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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 isthe principal cause of coronary artery disease (CAD), in which atherosclerotic changes are presentwithin the walls of the coronary arteries. CAD is a progressive disease process that generally begins inchildhood 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 adisease of large and medium-sized muscular arteries and is characterized by the following:

y Endothelial dysfunction

y Vascular inflammation

y Buildup of lipids, cholesterol, calcium, and cellular debris within the intima of the vessel wall

Atherosclerotic buildup results in the following:

y Plaque formation

y Vascular remodeling

y Acute and chronic luminal obstruction

y Abnormalities of blood flow

y 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 acutemyocardial infarction (AMI), the most deadly presentation of CAD, and more than 500,000 of theseindividuals die. (See Epidemiology.)

Nonetheless, there has been a 30% reduction in mortality from CAD since the late 20th century. Manyfactors have contributed to this, including the introduction of coronary care units, coronary arterybypass grafting (CABG), thrombolytic therapy, percutaneous coronary intervention (PCI), and arenewed emphasis on lifestyle modification. (See Treatment Strategies and Management.)

A major advance in the treatment of coronary artery atherosclerosis has been the development of arefined understanding of the nature of atherosclerotic plaque and the phenomenon of plaque rupture,which is the predominant cause ofacute coronary syndrome (ACS) and AMI. Cardiologists now knowthat in many cases (perhaps more than half), the plaque that ruptures and results in the clinicalsyndromes of ACS and AMI is less than 50% occlusive. These so-called vulnerable plaques, ascompared with stable plaques, consist of a large lipid core, inflammatory cells, and thin, fibrous capsthat are subjected to greater biomechanical stress, thus leading to rupture that perpetuates thrombosisand 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 newerantiplatelet and antithrombotic agents. Nonetheless, the greatest impact on the CAD epidemic canonly be achieved through therapies tailored to prevent the rupture of these vulnerable plaques. Suchplaques are likely more prevalent than occlusive plaques are. Currently, it is not possible to clinicallyidentify most vulnerable plaques, and no data support the local treatment of them. On the other hand,


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

The healthy epicardial coronary artery consists of the following 3 layers:

y

Intimay Media

y AdventitiaThe intima is an inner monolayer of endothelial cells lining the lumen; it is bound on the outside byinternal elastic lamina, a fenestrated sheet of elastin fibers. The thin subendothelial space in betweencontains 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 theadventitia, which consists mainly of fibroblasts, SMCs, and a matrix containing collagen andproteoglycans.

The endothelium is the monolayered inner lining of the vascular system. It covers almost 700 m2 andweighs 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, whichis a potent vasodilator and an inhibitor of platelet aggregation.

The endothelium secretes the most potent vasodilator, endothelium-derived relaxing factor (EDRF), athiolated form of nitric oxide. EDRF formation by endothelium is critical in maintaining a balancebetween vasoconstriction and vasodilation in the process of arterial homeostasis. The endotheliumalso secretes agents that are effective in lysing fibrin clots. These agents include plasminogen andprocoagulant materials, such as von Willebrand factor and type 1 plasminogen activator inhibitor. Inaddition, the endothelium secretes various cytokines and adhesion molecules, such as vascular celladhesion molecule-1 and intercellular adhesion molecule-1, and numerous vasoactive agents, such asendothelin, A-II, serotonin, and platelet-derived growth factor, which may be important invasoconstriction.

Endothelium, through the above mechanisms, regulates the following:

y Vascular tone

y Platelet activation

y Monocyte adhesion and inflammation

y Thrombus generation

y Lipid metabolism

y Cellular growth and vascular remodeling

Pathophysiology

Initially thought to be a chronic, slowly progressive, degenerative disease, atherosclerosis is a disorderwith periods of activity and quiescence. Although a systemic disease, atherosclerosis manifests in afocal 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 withthe activated vascular endothelium. Fluid shear stresses generated by blood flow influence thephenotype of the endothelial cells by modulation of gene expression and regulation of the activity of

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 irregularityand where blood undergoes sudden changes in velocity and direction of flow. Decreased shear stressand turbulence may promote atherogenesis at these important sites within the coronary arteries, the


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major branches of the thoracic and abdominal aorta, and the large conduit vessels of the lowerextremities.

The earliest pathologic lesion of atherosclerosis is the fatty streak, which is observed in the aorta andcoronary arteries of most individuals by age 20 years. The fatty streak is the result of focalaccumulation of serum lipoproteins within the intima of the vessel wall. Microscopy reveals lipid-ladenmacrophages, T lymphocytes, and smooth muscle cells in varying proportions. The fatty streak mayprogress to form a fibrous plaque, the result of progressive lipid accumulation and the migration andproliferation 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, vascularinflammation, 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 afibrous 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-flowabnormalities, and compromised oxygen supply to the target organ. Human coronary arteries enlargein response to plaque formation, and luminal stenosis may occur only when the plaque occupies morethan 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 andcontribute to progression of atherosclerosis.[1]

As endothelial injury and inflammation progress, fibroatheromas grow and form the plaque. As theplaque grows, 2 types of remodeling?positive remodeling and negative remodeling?occur, asillustrated 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 significantfor a long time. In fact, the plaque does not begin to encroach on the lumen until it occupies 40% ofthe cross-sectional area. The encroachment must be at least 50-70% to cause flow limitation. Suchpositively remodeled lesions thus form the bulk of the vulnerable plaques, grow for years, and aremore prone to result in plaque rupture and ACS than stable angina, as documented by intravascularultrasonography (IVUS) studies.Many fewer lesions exhibit almost no compensatory vascular dilation, and the atheroma steadily growsinward, causing gradual luminal narrowing. Many of the plaques with initial positive remodelingeventually progress to the negative remodeling stage, causing narrowing of the vascular lumen. Suchplaques usually lead to the development of stable angina. They are also vulnerable to plaque ruptureand thrombosis.

Plaque rupture

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


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exposure constitutes an advanced or complicated lesion. The plaque rupture occurs due to weakeningof the fibrous cap. Inflammatory cells localize to the shoulder region of the vulnerable plaque. Tlymphocytes elaborate interferon gamma, an important cytokine that impairs vascular smooth musclecell proliferation and collagen synthesis. Furthermore, activated macrophages produce matrixmetalloproteinases that degrade collagen.

These mechanisms explain the predisposition to plaque rupture and highlight the role of inflammationin the genesis of the complications of the fibrous atheromatous plaque. A plaque rupture may result inthrombus formation, partial or complete occlusion of the blood vessel, and progression of theatherosclerotic lesion due to organization of the thrombus and incorporation within the plaque.

Plaque rupture is the main event that causes acute presentations. However, severely obstructivecoronary atheromas do not usually cause ACS and MI. In fact, most of the atheromas that cause ACSare 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 thehighly thrombogenic lipid core and the blood. These modestly obstructive plaques, which have agreater burden of soft lipid core and thinner fibrous caps with chemoactive cellular infiltration near theshoulder region, are called vulnerable plaques. The amount of collagen in the fibrous cap depends onthe 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 interferongamma, which inhibits collagen synthesis. Already-formed collagen is degraded by macrophages thatproduce 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 IL-1, tumor necrosis factor (TNF), and CD154 or TNF-alpha. Authorities postulate that lipid loweringstabilizes 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 histologiccomposition 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 subendothelialspace.

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 lipidcore.

In a type V lesion, SMCs and fibroblasts move in, forming fibroatheromas with soft inner lipid coresand 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 extensivecollagen content (type VIII lesion).

Etiology

A complex and incompletely understood interaction is observed between the critical cellular elementsof the atherosclerotic lesion. These cellular elements include endothelial cells, smooth muscle cells,platelets, and leukocytes. Interrelated biologic processes that contribute to atherogenesis and theclinical manifestations of atherosclerosis are as follows:

y Vasomotor function

y Thrombogenicity of the blood vessel wall

y State of activation of the coagulation cascade

y The fibrinolytic system

y SMC migration and proliferation


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y Cellular inflammation

The encrustation theory, proposed by Rokitansky in 1851, suggested that atherosclerosis begins inthe intima with deposition of thrombus and its subsequent organization by the infiltration of fibroblastsand secondary lipid deposition.

In 1856, Virchow proposed that atherosclerosis starts with lipid transudation into the arterial wall andits 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 endothelialinjury, making the endothelium susceptible to the accumulation of lipids and the deposition ofthrombus. The mechanisms of atherogenesis remain uncertain, but the response-to-injury hypothesisis the most widely accepted proposal.

In the 1990s, Ross and Fuster proposed that vascular injury starts the atherosclerotic process.[3] Suchinjuries can be classified as follows:

y Type I - Vascular injury involving functional changes in the endothelium, with minimal structuralchanges, (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 syndromesAccording to the response-tovascular injury theory, injury to the endothelium by local disturbances ofblood flow at angulated or branch points, along with systemic risk factors, perpetuates a series ofevents that culminate in the development of atherosclerotic plaque.

As discussed in greater detail below, endothelial damage occurs in many clinical settings and can bedemonstrated in individuals with dyslipidemia, hypertension, diabetes, advanced age, nicotineexposure, and products of infective organisms (ie, Chlamydia pneumoniae). Damage to theendothelium may cause changes that are localized or generalized and that are transient or persistent,as follows:

y Increased permeability to lipoproteins

y Decreased nitric oxide production

y Increased leukocyte migration and adhesion

y Prothrombotic dominance

y Vascular growth stimulation

y Vasoactive substance releaseEndothelial 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 andgrowth factors promotes intimal migration, SMC proliferation, and accumulation of collagen matrix andof monocytes and other white blood cells, forming an atheroma. More advanced atheromas, eventhough 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 serumcholesterol. The endothelium's ability to modify lipoproteins may be particularly important inatherogenesis. LDLs appear to be modified by a process of low-level oxidation when bound to the LDLreceptor, 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 exceedinglyatherogenic, is picked up by the scavenger receptors on macrophages, which absorb the LDL.

Cholesterol accumulation in macrophages is promoted by oxLDL; the macrophages then becomefoam 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,


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oxLDL alters the SMC response to A-II stimulation and increasing vascular A-II concentrations. TheSMCs 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 ofadvanced atherosclerosis is now widely accepted.

Substantial evidence suggests that oxLDL is the prominent component of atheromas. Antibodiesagainst oxLDL react with atherosclerotic plaques, and plasma levels of immunoreactive altered LDLare greater in persons with AMI than in controls. Oxidative stress has therefore been recognized asthe most significant contributor to atherosclerosis by causing LDL oxidation and increasing nitric oxidebreakdown.

Risk factors for coronary artery atherosclerosis

A number of large epidemiologic studies in North America and Europe have identified numerous riskfactors for the development and progression of atherosclerosis. These factors, which can be classifiedas either modifiable or nonmodifiable, include the following:

y Hyperlipidemia and dyslipidemia

y Hypertension

y Cigarette habituation

y Air pollution

y Diabetes mellitus

y Agey Sex

The American College of Cardiology Foundation/American Heart Association 2010 report oncardiovascular 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 adultwomen and men.[5]

Numerous novel risk factors have been identified that add to the predictive value of the establishedrisk 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 gestationaldiabetes, preeclampsia, third trimester bleeding, preterm birth, and birth of an infant small forgestational 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 includea detailed history of pregnancy complications. It also states that postpartum, obstetricians should referwomen 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 causesendothelial dysfunction, decreases endothelial thromboresistance, and increases platelet activity, thusaccelerating atherosclerosis.

Established risk factors successfully predict future cardiac events in about 50-60% of patients. Aconcerted effort to identify is also being made to validate new markers of future risk of the clinicalconsequences of atherosclerosis has been made.

Other risk factors for coronary artery atherosclerosis include the following:

y Family history of premature CAD

y Hypoalphalipoproteinemia

y

Obesityy Physical inactivity

y Syndromes of accelerated atherosclerosis - Graft atherosclerosis, CAD after cardiac transplantation

y Chronic kidney disease[7]

y Systemic lupus erythematosus[8]

y Rheumatoid arthritis[9]

y Metabolic syndrome[10]

y Chronic inflammation

y Infectious agents

y Increased fibrinogen levels


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y Increased lipoprotein(a) levels

y Familial hypercholesterolemia

y DepressionAccording to the 2011 update to the American Heart Association guideline for CVD prevention inwomen, risk factors that are more common or may be more significant in women include psychosocialfactors such as depression and autoimmune diseases such as systemic lupus erythematosus andrheumatoid 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 canaffect 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 ofthe 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 andnontraditional 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 greaterthan 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 abrother 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 ofcardiovascular disease. One set of recommendations focuses on cardiovascular risk in asymptomaticresults, and these recommendations are discussed below.[3]

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

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

y Measurement of lipid parameters beyond a standard fasting lipid profile (A standard fasting lipidprofile is recommended as part of global risk scoring.)

y Brachial/peripheral arterial flow-mediated dilation studies

y Specific measures of arterial stiffness

y Coronary computed tomography angiography

y MRI for detection of vascular plaque


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Other tests and measures for cardiovascular risk assessment in asymptomatic adults arerecommended as reasonable, might be reasonable, or may be considered for specific patientpopulations and risk levels:

y A resting electrocardiogram (ECG) is reasonable for asymptomatic adults with hypertension ordiabetes and may be considered in asymptomatic adults without hypertension or diabetes.

y An exercise ECG may be considered in intermediate-risk asymptomatic adults (including sedentaryadults considering starting a vigorous exercise program), particularly when attention is paid to non-ECG markers such as exercise capacity.

y Transthoracic echocardiography to detect left ventricular hypertrophy may be considered forasymptomatic adults with hypertension but is not recommended in asymptomatic adults withouthypertension.

y Stress echocardiography is not indicated for low- or intermediate-risk asymptomatic adults.

y Coronary artery calcium (CAC) measurement is reasonable for asymptomatic intermediate-riskadults but should not be performed for persons at low risk; it may be reasonable when the patientsrisk falls between low and intermediate.

y For cardiovascular risk assessment in asymptomatic adults with diabetes mellitus, measurement ofCAC is reasonable in patients older than 40 years. Measurement of hemoglobin A1C and stressmyocardial perfusion imaging (MPI) may be considered.

y MRI among asymptomatic individuals with regional myocardial dysfunction (RMD) is an independentpredictor beyond traditional risk factors and global left ventricle (LV) assessment for incident heart

failure and atherosclerotic cardiovascular events.

Modifiable Risk Factors

High blood cholesterol levels

The Framingham Heart Study results demonstrated that the higher the cholesterol level, the greaterthe risk of coronary artery disease (CAD); alternatively, CAD was uncommon in people withcholesterol levels below 150 mg/dL. In 1984, the Lipid Research Clinics-Coronary Primary PreventionTrial revealed that lowering total and LDL or bad cholesterol levels significantly reduced CAD. Morerecent series of clinical trials using statin drugs have provided conclusive evidence that lowering LDLcholesterol reduces the rate of myocardial infarction (MI), the need forpercutaneous coronaryinterventionand 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 fourthreceive 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, orboth) 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 BloodPressure (JNC VII) emphasizes weight control; adoption of the Dietary Approaches to StopHypertension (DASH) diet, with sodium restriction and increased intake of potassium and calcium-richfoods; 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 thedevelopment of left ventricular hypertrophy (LVH). LVH has been found to be an independent riskfactor to cardiovascular disease morbidity and mortality. It roughly doubles the risk of cardiovasculardeath in both men and women.[8]

Cigarette smoking

Cessation of cigarette smoking constitutes the single most important preventive measure for CAD. Asearly as the 1950s, studies reported a strong association between cigarette smoke exposure andheart disease. Persons who consume more than 20 cigarettes daily have a 2- to 3-fold increase intotal heart disease. Continued smoking is a major risk factor for recurrent heart attacks. [9]


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Diabetes mellitus

A disorder of metabolism, diabetes mellitus causes the pancreas to produce either insulin deficiency orinsulin 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 largeamounts 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 prevalencefigures (including diagnosed and undiagnosed diabetes) are available at theCenters for DiseaseControl and Prevention (CDC).

Patients with diabetes are 2-8 times more likely to experience future cardiovascular events than age-matched and ethnically matched individuals without diabetes,[2] and a recent study suggested apotential reduction of all-cause and cardiovascular diseasespecific mortality in women with diabetesmellitus who consumed whole-grain and bran.[10]Another study suggested that meat consumption isassociated with a higher incidence of coronary heart disease and diabetes mellitus.[11]

Obesity

Obesity is associated with elevated vascular risk in population studies. In addition, this condition hasbeen associated with glucose intolerance, insulin resistance, hypertension, physical inactivity, anddyslipidemia.[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 exercisereduces myocardial oxygen demand and increases exercise capacity, translating into reducedcoronary 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 therisk of cardiovascular disease, regardless of physical activity.[15] The relationship between inflammatoryand 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 forboth heart disease and type 2 diabetes mellitus. In the Kuopio Ischemic Heart Disease Risk FactorStudy, patients with metabolic syndrome had significantly higher rates of coronary, cardiovascular, andall-cause mortality.[16]

People with metabolic syndrome have 3 of the following 5 traits and medical conditions, as defined bythe American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) CholesterolEducation Program (CEP)[17] :

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

y Elevated levels of triglycerides - 150 mg/dL or higher or taking medication for elevated triglyceridelevels

y

Low levels of HDL (high-density lipoprotein) or good cholesterol - Below 40 mg/dL in men, below 50mg/dL in women, or taking medication for low HDL cholesterol level

y Elevated blood pressure levels - For systolic blood pressure, 130 mm Hg or higher; 85 mm Hg orhigher for diastolic blood pressure; or taking medication for elevated blood pressure levels

y Elevated fasting blood glucose levels - 100 mg/dL or higher or taking medication for elevated bloodglucose levels[17] (Note: The American Association of Clinical Endocrinologists, the InternationalDiabetes Federation, and the World Health Organization have other, similar, definitions for metabolicsyndrome.)

Although high consumption of carbohydrates and sugar is associated with higher rates ofcardiovascular disease risk in adults, not much is known about the effect of added sugars in USadolescents.[18]A study of the National Health and Nutrition Examination Survey (NHANES) 1999-


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2004, suggests that added sugar consumption is positively associated with an increase risk ofcardiovascular disease in adolescents. The results of this study suggest that future risk ofcardiovascular 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 stresscan increase myocardial oxygen requirements, can cause vasoconstriction, and has been linked to

platelet and endothelial dysfunction[20] and metabolic syndrome.

Nontraditional orNovel 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. Theinflammation process appears to contribute to the growth of arterial plaque, and in fact, inflammationcharacterizes 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 increasedrisk 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 drugrosuvastatin significantly reduced the incidence of major cardiovascular events.[23]

The 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults statesthat 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 inasymptomatic high-risk adults, low-risk men 50 years or younger, or low-risk women 60 years oryounger.[3]

Lipoprotein(a)

An elevated lipoprotein(a) [Lp(a)] level is an independent risk factor of premature CAD[21] and isparticularly 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 forassessment of cardiovascular risk in asymptomatic adults states that, in asymptomatic intermediate-risk 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 thisvalue. Therefore, low-density lipoprotein (LDL) lowering is probably the best strategy in people withelevated Lp(a) levels.[22]

Homocysteine

Homocysteine is a natural by-product of the dietary breakdown of protein methionine. In the generalpopulation, 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 lackof agents that effectively alter the homocysteine levels, studies have not shown any benefit fromlowering the homocysteine level.

Tissue plasminogen activator

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


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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 ofcardiovascular risk prediction.[24]

Fibrinogen

levels of fibrinogen, an acute-phase reactant, increase during an inflammatory response. This solubleprotein is involved in platelet aggregation and blood viscosity, and it mediates the final step in clotformation. Significant associations were found between fibrinogen level and risk of cardiovascularevents in the Gothenburg, Northwick Park, and Framingham heart studies.[25]

Other factors

Medical conditions such as end-stage renal disease (ESRD),[26] chronic inflammatory diseasesaffecting 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 thedevelopment 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 increasedCAD risk.[26]

The 2010 ACCF/AHA recommendations note that urinalysis to detect microalbuminuria is reasonablefor cardiovascular risk assessment in asymptomatic adults with hypertension or diabetes, and mightbe reasonable for cardiovascular risk assessment in asymptomatic intermediate-risk adults withouthypertension or diabetes.[3]

Low serum testosterone levels have a significant negative impact on patients with CAD. More studiesare needed to assess better treatment.[30]

One study suggests women aged 50 years or younger who undergo a hysterectomy are atanincreased risk for cardiovascular disease later in life.[31] Oopherectomy also increases the risk for bothcoronary heart disease and stroke.

Identifying Coronary Artery Disease

Direct plaque imaging

Studies indicate that using electron-beam computed tomography (EBCT) scanning to identify coronarycalcification can reveal at-risk individuals and perhaps allow for medical monitoring. [32] With the adventof 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 ofatherosclerotic plaques is still a subject of much debate. The negative predictive value of CTangiography, however, is very high. CAD identified by CT angiography has significant prognosticimplications.[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 drugtherapies does not reduce cardiovascular events.[35]

The 2010 ACCF/AHA guideline states that measurement of carotid intima-media thickness isreasonable for cardiovascular risk assessment in asymptomatic intermediate-risk adults, provided thatpublished recommendations on equipment, method, and training are carefully followed. The guidelinealso states that in asymptomatic intermediate-risk adults, measurement of ankle-brachial index isreasonable for cardiovascular risk assessment.[3]


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Genetic markers

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

For patients without diabetes and known CAD, a noninvasive, whole-blood test based on geneexpression and demographic characteristics may be beneficial in assessment of obstructive CAD.[36]

The 2010 ACCF/AHA guideline does not recommend genotype testing for coronary heart disease riskassessment in asymptomatic adults.[3]

Biomarkers

In a 10-year comparison of 10 biomarkers for predicting death and major cardiovascular events inapproximately 3000 individuals, the most informative biomarkers for predicting death were blood levelsof B-type natriuretic peptide (BNP), CRP, homocysteine, renin, and the urinary albumin-to-creatinineratio.[34] The most informative biomarkers for predicting major cardiovascular events were BNP and theurinary albumin-to-creatinine ratio.

The 2010 ACCF/AHA guideline does not recommend measurement of natriuretic peptides for coronaryheart disease risk assessment in asymptomatic adults.[3]

Cystatin C (Cys-C) has been proposed as an indicator of renal dysfunction that is associated withcardiovascular events and it has shown to be a good predictor of long-term mortality in patients withnormal renal function.[37]

Individuals with elevated multimarker scores had a 4-fold higher risk of death and an almost 2-foldhigher risk of major cardiovascular events relative to those with low multimarker scores. [3] However, theinvestigators reported that the use of multiple biomarkers added only moderately to the overallprediction of risk based on conventional cardiovascular risk factors, as evidenced by small changes inthe C-statistic.[3]

Measurement of HDL cholesterol should be used as part of the initial cardiovascular risk assessmentbut should not be used as a predictive tool of residual vascular risk in patients who are treated withpotent high-dose statin therapy to lower LDL cholesterol.

Epidemiology

The true frequency of atherosclerosis is difficult, if not impossible, to accurately determine because itis a predominantly asymptomatic condition. The process of atherosclerosis begins in childhood withthe development of fatty streaks. These lesions can be found in the aorta shortly after birth and appearin increasing numbers in those aged 8-18 years. More advanced lesions begin to develop whenindividuals are aged approximately 25 years. Subsequently, an increasing prevalence of the advancedcomplicated lesions of atherosclerosis is noted, and the organ-specific clinical manifestations of thedisease 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 patients in American hospitals.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, 785,000Americans were estimated to have suffered a first MI, and about 470,000 Americans were estimatedto have had a recurrent event. An additional 195,000 "silent" heart attacks are estimated to occur eachyear. About every 34 seconds, an American will have an MI. CAD remains the number 1 cause ofdeath for men and women in the United States and is responsible for approximately 20% of all USdeaths. From 19952005, the death rate from CAD declined 34.3%, but the actual number of deathsdeclined only 19.4%.


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International statistics

The international incidence of ACS and AMI, especially in developed countries, is similar to thatobserved in the United States. Despite consumption of rich foods, inhabitants of France and theMediterranean region appear to have a lower incidence of CAD. This phenomenon (sometimes calledthe 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 monounsaturatedfatty 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 oilscontaining 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 thecase 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 largestimpact 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 inparticular, 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 exponentialincrease in the frequency of coronary heart disease that likely is the result of widespread economichardship 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 inthe West. Ill-defined genetic reasons for this phenomenon may exist, but significant interest surroundsthe role of diet and other environmental factors in the absence of clinical atherosclerotic vasculardisease in these populations. Atherosclerotic cardiovascular disease is also rare on the Africancontinent, although growing evidence indicates that this too is changing, as a result of rapidwesternization and urbanization of the traditionally rural and agrarian African populations. Theprevalence of coronary heart disease is also increasing in the Middle East, India, and Central andSouth America.[1] The rate of CAD in ethnic immigrant populations in the United States approaches thatof 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 theresponse to therapy.

Blacks appear to have higher morbidity and mortality rates of CAD, even when the statistics arecorrected for educational and socioeconomic status. The risk-factor burden experienced by blacksdiffers from that of whites. The prevalence of hypertension, obesity, dysmetabolic syndrome, and lackof physical activity are much higher in blacks, whereas the prevalence of hypercholesterolemia islower. Blacks with AMI present for treatment later than patients do on average, are less oftensubjected 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. Theyalso 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, whichaccounts 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


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experience greater overall mortality. (Similar statistics can also be cited for the presentation andtreatment of patients with stable CAD.)

The 2011 update to the American Heart Association guideline for the prevention of cardiovasculardisease in women recommends changes in prevention and treatment practices:[6]

y Women should be considered as high risk, and as candidates for aggressive treatment, if their risk ofdying from any cardiovascular event in the next 10 years is 10% or greater.

y Research studies should publish efficacy and adverse drug reactions (ADRs) by gender, as both candiffer in women.

y Evidence from clinical trials tends to overestimate the real-world efficacy of therapies in femalepatients, who are generally older and have more comorbidities than test subjects. The guideline isnow effectiveness-based rather than evidence-based.

y Effectiveness-based considerations have reduced the strength of previous recommendations for useof aspirin, statins (in women with elevated C-reactive protein but normal cholesterol), and aggressiveglycemic 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 clinicallyapparent in patients aged 40 years or older, but elderly persons experience higher mortality andmorbidity 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 patientsform a high-risk subgroup.

Calculating risk of coronary artery atherosclerosis

Of note, algorithms for predicting the risk of cardiovascular disease have generally been developed fora follow-up period of no more than 10 years. However, clustering of risk factors at younger ages andincreasing 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, myocardialinfarction, and stroke and remained significant when updated regularly. This 2009 study by Pencinaand colleagues, which utilized 4506 participants of the Framingham Offspring cohort, employed analgorithm 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 updaterisk factors.

Prognosis

As previously mentioned, approximately 1.5 million Americans per year have an AMI, with a third ofthese events proving fatal. The survivors of MI have a poor prognosis, carrying a 1.5- to 15-fold higherrisk of mortality and morbidity than the rest of the population. Historically, for example, 25% of menand 38% of women die within 1 year after having an MI, although these rates may overstate the 1-yearmortality 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% ofwomen die suddenly, 22% of men and 46% of women are disabled with CHF, and 8% of men and11% of women have a stroke.

The prognosis in patients with atherosclerosis depends on the following factors:

y Presence of inducible ischemia

y Left ventricular function

y Presence of arrhythmias

y Revascularization potential (complete vs incomplete)

y Aggressiveness of risk alteration

y Compliance with medical therapyThe 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


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burden of disease. Conversely, MI or sudden cardiac death may be the first clinical manifestation ofatherosclerotic cardiovascular disease in a patient who is otherwise asymptomatic with minimalluminal stenosis and a light burden of disease.

Much of this phenotypic variability is likely to be determined by the relative stability of the vascularplaque burden. Plaque rupture and exposure of the thrombogenic lipid core are critical events in theexpression of this disease process and determine the prognosis. The ability to determine and quantifyrisk and prognosis in patients with atherosclerosis is limited by the inability to objectively measureplaque stability and other predictors of clinical events.

Patient Education

Education regarding CAD is extremely important. Publications and articles available fromtheAmerican Heart Association provide a wealth of information.

The most effective and probably the most cost-efficient means of reducing the burden of diseasesecondary to atherosclerosis in the general population is primary prevention. The role of diet andexercise in the prevention of atherosclerotic cardiovascular disease has been well established.Education of the general population regarding healthy dietary habits and regular exercise will reducethe prevalence of multiple coronary heart disease risk factors. (See Treatment Strategies andManagement) For patients with risk factors refractory to lifestyle interventions, education can enhancecompliance 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 CholesterolManagement, Chest Pain, Coronary Heart Disease,Heart Attack,Angina Pectoris, and Statins andCholesterol.

History

The symptoms of atherosclerosis vary widely. Patients with mild atherosclerosis may present withclinically important symptoms and signs of disease and MI, or sudden cardiac death may be the firstsymptom of coronary heart disease. However, many patients with anatomically advanced disease mayhave no symptoms and experience no functional impairment.

The spectrum of presentation includes symptoms and signs consistent with the following conditions:

y Asymptomatic state (subclinical phase)

y Stable angina pectoris

y Unstable angina (ie, ACS)

y AMI

y Chronic ischemic cardiomyopathy

y Congestive heart failure

y Sudden cardiac arrestHistory may include the following:

y Chest pain

y Shortness of breath

y Weakness, tiredness, reduced exertional capacity

y Dizziness, palpitations

y Leg swellingy Weight gain

y Symptoms related to risk factorsProgressive luminal narrowing of an artery due to expansion of a fibrous plaque results in impairmentof flow once at least 50-70% of the lumen diameter is obstructed. This impairment in flow results insymptoms of inadequate blood supply to the target organ in the event of increased metabolic activityand oxygen demand. Stable angina pectoris, intermittent claudication, and mesenteric angina areexamples of the clinical consequences of this mismatch.

Rupture of a plaque or denudation of the endothelium overlying a fibrous plaque may result inexposure of the highly thrombogenic subendothelium and lipid core. This exposure may result in


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thrombus formation, which may partially or completely occlude flow in the involved artery. Unstableangina pectoris, MI, transient ischemic attack, and stroke are examples of the clinical sequelae ofpartial or complete acute occlusion of an artery. Atheroembolism is a distinct clinical entity that mayoccur spontaneously or as a complication of aortic surgery, angiography, or thrombolytic therapy inpatients with advanced and diffuse atherosclerosis.

Angina pectoris is characterized by retrosternal chest discomfort that typically radiates to the left armand may be associated with dyspnea. Angina pectoris is exacerbated by exertion and relieved by restor nitrate therapy. Unstable angina pectoris describes a pattern of increasing frequency or intensity ofepisodes of angina pectoris and includes pain at rest. A prolonged episode of angina pectoris that maybe associated with diaphoresis is suggestive of MI.

Physical Examination

Tachycardia is common in persons with ACS and AMI. Heart rate irregularity may signal the presenceof atrial fibrillation or frequent supraventricular or ventricular ectopic beats. Ventricular tachycardia isthe most common cause of death in persons with AMI.

High or low blood pressure may be noted. Hypotension often reflects hemodynamic compromise andis a predictor of poor outcome in the setting of AMI. Diaphoresis is a common finding. Patients oftenhave rapid breathing (ie, tachypnea). Signs and symptoms of congestive heart failure (CHF) mayindicate cardiogenic shock or a mechanical complication of AMI, such as ischemic mitral valveregurgitation.

An S4 gallop is a common early finding. The presence of an S3 is an indication of reduced leftventricular function. Heart murmurs, particularly those of mitral regurgitation and ventricular septaldefect, may be found after the initial presentation; their presence indicates a grave prognosis. Themurmur of aortic insufficiency may signal the presence of aortic dissection as a primary etiology, withor 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 Shock

y Syncope

y Leg edema

y Pulmonary congestion

y Ralesy Diagonal ear crease

y Short stature

y Baldness

y Thoracic hairiness

Diagnostic Considerations

Typical angina symptoms, such as a substernal pressurelike chest pain with radiation to the jaw orleft 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 mayin fact be due to other causes, listed in Differentials

Differentials

y Angina Pectoris

y Atherosclerosis

y Buerger Disease (Thromboangiitis Obliterans)

y Cardiomyopathy, Dilated

y Coronary Artery Vasospasm

y Diabetes Mellitus, Type 1

y Diabetes Mellitus, Type 2

y Giant Cell Arteritis


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y Hypercholesterolemia, Familial

y Hypercholesterolemia, Polygenic

y Hypertension

y Hypertensive Heart Disease

y Isolated Coronary Artery Anomalies

y Kawasaki Disease

y Myocardial Ischemia - Nuclear Medicine and Risk Stratification

y Myocarditisy Nicotine Addiction

y Pericarditis, Acute

y Pulmonary Embolism

y Right Ventricular Infarction

y Treadmill Stress Testing

y Unstable Angina

Approach Considerations

Routine blood tests include complete blood count (CBC), chemistry panel, lipid profile, and thyroidfunction tests (to exclude thyroid disorders). Routine measurement of blood glucose and hemoglobinA1C is appropriate in patients with diabetes mellitus.

Measuring any number of parameters that may reflect coagulation, fibrinolytic status, and plateletaggregability is possible. These measurements may prove to be valuable, but how thesemeasurements affect clinical decision-making is unclear at this time, and including them in routineclinical practice is premature.

Standardization of the CRP assay is required before this test may be clinically useful, and whetherCRP is a truly modifiable risk factor remains unclear.

The majority of atherosclerotic lesions responsible for the most serious CAD events (that is, thelesions that are most likely to rupture) are mild stenoses of inconsequential hemodynamic significanceand are characterized by an abundance of lipid, numerous inflammatory cells, and a thin, fragilefibrous cap. This suggests that although measurements of coronary flow reserve (CFR) and fractionalflow reserve (FFR), both of which are discussed below, may be useful in the assessment of theseverity 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 ischemicdeath.

Fractional Flow Reserve

Myocardial FFR has been used as an index of functional severity of coronary artery stenosis. FFRrepresents the fraction of the normal maximal coronary flow that can be achieved in an artery in whichflow is restricted by a coronary stenosis. The concept of FFR is based on the observation thatmyocardial 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 pressureproximal (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 objectiveevidence 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 noninvasivestress testing.

Lipid Studies

Fasting lipid profile includes the following[13, 14, 15] :

y Total cholesterol level

y LDL cholesterol (LDL-C) level

y HDL cholesterol (HDL-C) level


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y Triglyceride level

Specific lipid studies (if necessary) include the following:

y Small, dense LDL-C level

y Lipoprotein (a) level

y Apoprotein profile

y Direct measurement of HDL-C

C-Reactive Protein

CRP appears to provide prognostic information for CAD, although as stated above, the CRP assaymust 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 thehighest CRP quartile, suggesting that the aspirin-related reduction in the risk of first MI was clearlyrelated to the level of CRP. [16]

One study found that patients with baseline CRP levels of more than 10 mg/L had significantly worseoutcomes than did patients with lower CRP levels. This investigation, the Fragmin and/or EarlyRevascularization During Instability in Coronary Artery (FRISC-II) study, included 900 subjectsfollowed for 4 years.[17]

CRP can also help to predict treatment efficacy, as demonstrated in the Cholesterol and RecurrentEvents (CARE) trial of pravastatin treatment in post-MI patients. CRP levels tended to increase overtime in the studys placebo group, whereas levels remained lower in the statin-treatment group at 5years. 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 Troponins (I or T)

y Creatine kinase with MB isozymes

y Lactate dehydrogenase and lactate dehydrogenase isozymes

y Serum aspartate aminotransferase

Biomarkers

In a 10-year comparison of 10 biomarkers for predicting death and first major cardiovascular events inapproximately 3000 individuals, the most informative biomarkers for predicting death were thefollowing[19] :

y B-type natriuretic peptide

y CRP

y Homocysteine

y Renin

y Urinary albumin-to-creatinine ratioThe most informative biomarkers for predicting major cardiovascular events were B-type natriureticpeptide and the urinary albumin-to-creatinine ratio. Individuals with elevated multimarker scores had arisk of death 4 times higher and a risk of major cardiovascular events almost 2 times higher than thosewith low multimarker scores. However, the use of multiple biomarkers added only moderately to the

overall prediction of risk based on conventional cardiovascular risk factors.

Echocardiography

Transthoracic echocardiography helps to assess left ventricular function, wall-motion abnormalities inthe setting of ACS or AMI, and mechanical complications of AMI.

Transesophageal echocardiography is most often used for assessing possible aortic dissection in thesetting of AMI. Stress echocardiography can be used to evaluate hemodynamically significantstenoses in stable patients who are thought to have CAD. Treadmill echocardiography stress testingand dobutamine echocardiography stress testing provide equivalent predictive values. ECG findingsare depicted below.


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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 arterystenoses. Stress and rest nuclear scintigraphic studies using thallium, sestamibi, or teboroxime aresometimes 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 nuclearimaging findings are depicted below.

Stress nuclear imaging showing anterior, apical, and septal wall perfusion defect during stress, which is reversible asobserved on the rest images. This defect strongly suggests the presence of significant stenosis in the left anteriordescending 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 withpharmacologic coronary vasodilators.MI-avid scintigraphy may be indicated for detection and localization of infarcted myocardium ifevidence from other tests is inconclusive.


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Computed Tomography Scanning

Multidetector computed tomography (MDCT) scanning can allow excellent visualization of thecoronary arteries, but its relatively high radiation dose is one of the limitations of this approach. Newergenerations 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-photonemission 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 shouldroutinely 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 alfound several guidelines for risk assessment of asymptomatic CAD to have conflictingrecommendations.[21]More research, especially randomized controlled trials, are needed in order toestablish 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 calciumcontent in the coronary arteries. Healthy coronary arteries lack calcium. As atherosclerotic plaquesgrow, calcium accumulates because of a perpetuating inflammatory process or the healing andscarring induced by this process. EBCT is currently used as a screening test in asymptomatic patientsand 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 of70%, 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 ofsuspicion 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 obstructiveCAD.

Whether EBCT scanning is a worthwhile tool for screening of CAD is still unclear. Well-establishedclinical indicators, such as the Framingham risk score and the National Cholesterol EducationProgram (NCEP) risk calculator, already accurately predict the likelihood of CAD. Whether EBCTscanning 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 prospectiveevaluation of EBCT scanning in asymptomatic subjects to answer this question.[23]

EBCT scanning may have niche uses, including (1) determination of whether individuals who appearto be at intermediate risk are really at a higher risk (eg, asymptomatic elderly patients who have highcalcium scores) and (2) determination of a low likelihood of significant CAD if EBCT scanningdemonstrates 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 transducerswithin 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.


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Coronary Angiography

Coronary angiography was the first available in vivo assessment of the coronary arteries. In thistechnique, an iodinated contrast agent is injected through a catheter placed at the ostium of thecoronaries. 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 imagebelow).

Cardiac catheterization and coronary angiography in the left panel showssevere left anterior descending coronary artery stenosis. This lesion was treated with stent placement in the left anteriordescending 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 andregression.Coronary angiography has several limitations. Severity of stenosis is generally estimated visually, butestimation is limited by the fact that interobserver variability may range from 30-60%. The presence ofdiffuse disease may also lead to underestimation of stenoses, because the stenosed areas areexpressed 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 whomcoronary arteries are traditionally described as small-caliber vessels, when that appearance is actuallydue to the presence of diffuse symmetrical involvement of the entire vessel, as elucidated by IVUSstudies.

One of the other limitations of coronary angiography is that only the vessel space occupied by blood isvisualized. The actual extent of atherosclerotic plaque volume in the wall cannot be assessed with thistechnique.

Angiography does not provide information about plaque burden, which may be significant due topositive 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 usingphysiologic approaches to determine the severity of coronary stenoses. The commonly used methodsof measuring human coronary blood flow in the cardiac catheterization laboratory are Doppler velocityprobes (for measuring CFR) and pressure wires (for measuring FFR). Although most current methodsmeasure relative changes in coronary blood flow, useful information about the physiologic significanceof 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. High-frequency sound waves are reflected from moving red blood cells and undergo a shift in soundfrequency proportional to the velocity of the blood flow.

In pulsed-wave Doppler methods, a single piezoelectric crystal can transmit and receive high-frequency sound waves. These methods have been successfully applied in humansby usingminiaturized crystals fixed to the tip of catheters. Technological developments have furtherminiaturized steerable 12-MHz Doppler guide wires to a diameter of 0.014 inches. Flow to a stenosiscan therefore be assessed distally and proximally. The Doppler guidewire measures phasic flowvelocity patterns and tracks linearly with flow rates in small, straight coronary arteries.


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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 percutaneoustransluminal 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, suchas papaverine or adenosine, the CFR can be defined. CFR provides an index of the functionalsignificance of coronary lesions that obviates some of the ambiguity of anatomical description.

The current Doppler probe method has limitations. Limitations include the following:

y Only changes in flow velocity, rather than absolute velocity or volumetric flow, are measurable

y The change in flow velocity is directly proportional to changes in volumetric flow only when vesseldimensions 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 reflectedin 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 flowvelocity have been used for assessing the physiologic significance of coronary stenoses. Coronaryflow velocity reserve is the ratio of maximum flow velocity to baseline flow velocity.

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 aratio of more than 2 usually lack other objective evidence of myocardial ischemia and have a favorableoutcome with conservative management; therefore, flow velocity measurements can be helpful in thetreatment 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 involvesDoppler coronary flow measurements of target and reference vessel CFR with a Doppler-tippedguidewire. In one report, El-Shafei et al found that, compared with patients who had negative stress-imaging study findings, patients who had positive stress-study findings showed more angiographicallysevere 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 nothave significant incremental prognostic value over CFR alone for myocardial perfusion imaging.However, rCFR does provide additional information regarding the status of the microcirculation inpatients with CAD and complements the CFR for lesion assessment.

Ultrasonography

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 remainresearch 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 ofatherosclerosis. The availability of high-resolution ultrasonographic systems makes the visualizationand 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 healthand 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.


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Carotid artery intima-media thickness

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

IntravascularUltrasonography

IVUS demonstrates the luminal dimensions and, more importantly, the tissue composition of thevascular wall in tomographic subsegments that can be summated to create a 3-dimensional pictureshowing arterial remodeling and the diffuseness of atherosclerosis with clarity unobtainable byangiography.

IVUS delineates vascular remodelingpositive and negative. Positive remodeling shows adaptiveoutward expansion of the external elastic membrane to accommodate growing plaques (Glagovphenomenon). Negative remodeling exhibits discrete areas of vascular luminal encroachment by theingrowing plaques.

Positive remodeling is more commonly associated with unstable angina, whereas negative remodelingis associated with stable angina, according to an IVUS study of 85 patients by Schoenhagen andcolleagues.[25]

The apparently paradoxical findings of angiographic studies suggesting that AMI most often occurs inless 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 tobe large plaques that have positively remodeled, thus causing minimal luminal encroachment andexhibiting 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 insome ways makes it better than angiography, the less-than-perfect criterion standard. IVUS can muchmore clearly demonstrate the presence or absence of fibrosis, calcium, and ulceration, as well aseccentricity of the plaques.

Ostial lesions can also be better defined by IVUS.

Histology

A system devised by Stary et al classifies atherosclerotic lesions according to their histologiccomposition 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 lipidcore.

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 extensivecollagen content (type VIII lesion).

Approach Considerations

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


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The mainstays of pharmacologic therapy of angina include nitrates, beta-blockers, statins, calcium-channel blockers, and ranolazine.[26] The prevention and treatment of atherosclerosis requires controlof the known modifiable risk factors for this disease. This includes therapeutic lifestyle changes andthe 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 oftheir treatment is the index event. The past 4 decades have witnessed tremendous progress in theareas 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 ofatherosclerosis.

High-risk subgroups, in particular, can be targeted for early intervention. Grover and colleaguesshowed statin therapy in diabetic patients without CAD to be as cost-effective as statin therapy innondiabetic 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 ofagents 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 thecase 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 ondecreasing 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. Thisprovides an excellent opportunity to intervene in order to reduce the number and severity ofcardiovascular 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 greatsuccess in the treatment of patients with coronary artery atherosclerosis. In addition, addressing riskfactors with lifestyle changes is an integral part of atherosclerosis prevention. Therapy with lipid-lowering agents should be a component of multiple risk factor intervention and is indicated in primaryprevention as an adjunct to diet therapy when the response to a diet restricted in saturated fat andcholesterol has been inadequate.

Substantial evidence supports the use of statins in the secondary prevention of CAD, and the efficacyof statins has recently been extended to include primary prevention of CAD in patients with averagecholesterol levels. Niacin is superior to ezetimibe for combination therapy in high-risk patients beingtreated with statin monotherapy.

In a meta-analysis of nearly 5000 patients, findings showed that statins administered before invasiveprocedures significantly reduced the risk for postprocedural myocardial infarction.[27] The risk for MIwas reduced after percutaneous coronary intervention and noncardiac surgical procedures, but not forcoronary artery bypass grafting (CABG). Statins decreased the risk for atrial fibrillation followingCABG.

Statin therapy is also safe and can improve liver tests while reducing cardiovascular morbidity inpatients 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 fromthe NCEP Adult Treatment Panel (ATP). In high-risk persons, the recommended LDL-C goal is lessthan 100 mg/dL, but when risk is very high, an LDL-C goal of less than 70 mg/dL is a therapeuticoption and a reasonable clinical strategy based on available clinical trial evidence. For moderatelyhigh-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.


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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 withdiabetes and is often referred to as atherogenic dyslipidemia. Many of these patients havemetabolicsyndrome.

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 eventsand a 41% reduction in CHD deaths, in 769 male subjects with diabetes mellitus and CHD who hadHDL-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 insulinresistance, 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 majorcardiovascular events and of greater benefit from gemfibrozil treatment.[29, 30]

Somewhat inexplicable was the finding that despite higher plasma triglyceride and lower HDL-C levelsin insulin-resistant subjects, these measurements were associated with greater treatment benefit only

in those s

Coronary Artery Atherosclerosis

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