eMedicine Specialties > Cardiology > Atherosclerosis and Risk Factors

Atherosclerosis

F Brian Boudi, MD, Clinical Assistant Professor, Department of Medicine, Fellow, Sarver Heart Center, University of Arizona College of Medicine; Adjunct Assistant Professor of Medicine, Mid-Western University; Consulting Staff, Director of Ambulatory Medicine Clinical Rotation, Carl T Hayden Veterans Affairs Medical Center
Chowdhury H Ahsan, MD, MRCP, PhD, FRSCAI, Clinical Professor of Medicine, Director of Cardiac Catheterization and Intervention, Director of Cardiovascular Research, Division of Cardiology, University of California Irvine, University Medical Center

Updated: Nov 17, 2009

Introduction

Background

Atherosclerosis is a disease of large and medium-sized muscular arteries and is characterized by endothelial dysfunction, vascular inflammation, and the buildup of lipids, cholesterol, calcium, and cellular debris within the intima of the vessel wall. This buildup results in plaque formation, vascular remodeling, acute and chronic luminal obstruction, abnormalities of blood flow, and diminished oxygen supply to target organs.

Pathophysiology

A complex and incompletely understood interaction exists between the critical cellular elements of the atherosclerotic lesion. These cellular elements are endothelial cells, smooth muscle cells, platelets, and leucocytes. Vasomotor function, the thrombogenicity of the blood vessel wall, the state of activation of the coagulation cascade, the fibrinolytic system, smooth muscle cell migration and proliferation, and cellular inflammation are complex and interrelated biological processes that contribute to atherogenesis and the clinical manifestations of atherosclerosis.

The mechanisms of atherogenesis remain uncertain. The "response-to-injury" theory is most widely accepted. Endothelial injury causes vascular inflammation and a fibroproliferative response ensues. Probable causes of endothelial injury include oxidized low-density lipoprotein (LDL) cholesterol; infectious agents; toxins, including the byproducts of cigarette smoking; hyperglycemia; and hyperhomocystinemia. Circulating monocytes infiltrate the intima of the vessel wall, and these tissue macrophages act as scavenger cells, taking up LDL cholesterol and forming the characteristic foam cell of early atherosclerosis. These activated macrophages produce numerous factors that are injurious to the endothelium.

Elevated serum levels of LDL cholesterol overwhelm the antioxidant properties of the healthy endothelium and result in abnormal endothelial metabolism of this lipid moiety. Oxidized LDL is capable of a wide range of toxic effects and cell/vessel wall dysfunctions that are characteristically and consistently associated with the development of atherosclerosis. These dysfunctions include impaired endothelium-dependent dilation and paradoxical vasoconstriction. These dysfunctions are the result of direct inactivation of nitric oxide by the excess production of free radicals, reduced transcription of nitric oxide synthase messenger RNA (mRNA), and posttranscriptional destabilization of mRNA.

The decrease in the availability of nitric oxide also is associated with increased platelet adhesion, increased plasminogen activator inhibitor, decreased plasminogen activator, increased tissue factor, decreased thrombomodulin, and alterations in heparin sulfate proteoglycans. The consequences include a procoagulant milieu and enhanced platelet thrombus formation. Furthermore, oxidized LDL activates inflammatory processes at the level of gene transcription by up-regulation of nuclear factor kappa-B, expression of adhesion molecules, and recruitment of monocytes/macrophages.

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 of flow-sensitive proteins. Atherosclerotic plaques 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. The fatty streak 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 smooth muscle cells. Platelet-derived growth factor, insulinlike growth factor, transforming growth factors alpha and beta, thrombin, and angiotensin 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.

These smooth muscle cells 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 only occur once the plaque occupies greater than 40% of the area bounded by the internal elastic lamina. Developing atherosclerotic plaques acquire their own microvascular network called vasa vasorum, which are prone to hemorrhage and contribute to progression of atherosclerosis.¹

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.

Frequency

United States

In the United States, about 80 million people, or 36.3% of the population, have existing cardiovascular diseases. In addition 795,000 people suffer new or recurrent strokes each year.²

International

The frequency of clinical manifestations of atherosclerosis in Great Britain, west of Scotland in particular, is especially high. The same is true of Finland, in particular, and Scandinavia in general. 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.

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.³ The rate of coronary artery disease in ethnic immigrant populations in the United States approaches that of the disease in whites, supporting the role of these putative environmental factors.

Mortality/Morbidity

Atherosclerosis is the leading cause of death in the developed world, and atherosclerosis is predicted to be the leading cause of death in the developing world within the first quarter of the next century.

• In 2005, cardiovascular disease was responsible for 864,5000 deaths, or 35.3% of all deaths that year. They included 151,000 deaths from myocardial infarction and 143,600 deaths from stroke.²
• An encouraging decrease in mortality due to coronary heart disease in the developed world has occurred. Unfortunately, this decrease has not occurred in the developing world, and an exponential increase in tobacco habituation and the adoption of a Western diet high in saturated fats likely predicts the continued increase in death and disability due to coronary heart disease.

Sex

Atherosclerosis is more common among men than women. The higher prevalence of atherosclerosis in men is thought to be due to the protective effects of the female sex hormones. This sex effect is absent after menopause in women. The incidence of coronary heart disease among women parallels that of men, but women demonstrate an approximately 10-year chronological delay in the onset of clinical manifestations.

Age

Most cases of atherosclerotic vascular disease become clinically apparent in patients aged 40 and older.

Clinical

History

The symptoms of atherosclerosis are highly variable. Patients with mild atherosclerosis may present with clinically important symptoms and signs of disease and myocardial infarction, 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. Initially thought to be a chronic, slowly progressive, degenerative disease, it is now apparent that atherosclerosis is a disease 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.

• Progressive luminal narrowing of an artery due to expansion of a fibrous plaque results in impairment of flow once more than 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 thrombus formation, which may partially or completely occlude flow in the involved artery. Unstable angina pectoris, myocardial infarction, 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 pectoris that may be associated with diaphoresis is suggestive of myocardial infarction.
• Stroke, reversible ischemic neurological deficit, and transient ischemic attack are a range of manifestations of impairment of vascular supply to the central nervous system and are characterized by the sudden onset of a focal neurological deficit of variable duration, respectively.
• Peripheral vascular disease typically manifests as intermittent claudication, impotence, and nonhealing ulceration and infection of the extremities. Intermittent claudication describes calf, thigh, or buttock pain that is exacerbated by exercise and relieved by rest. Intermittent claudication may be accompanied by pallor of the extremity and paresthesias.
• Visceral ischemia may be occult or symptomatic prior to symptoms and signs of target organ failure.
• Mesenteric angina is characterized by epigastric or periumbilical postprandial pain and may be associated with hematemesis, hematochezia, melena, diarrhea, nutritional deficiencies, and weight loss.
• Abdominal aortic aneurysm typically is asymptomatic prior to the dramatic and often fatal symptoms and signs of rupture, although patients may describe a pulsatile abdominal mass.
• Atheroembolism may present with symptoms of digital necrosis, gastrointestinal bleeding, myocardial infarction, retinal ischemia, cerebral infarction, and renal failure.

Physical

The physical signs of atherosclerosis provide objective evidence of extracellular lipid deposition, stenosis or dilatation of large muscular arteries, or target organ ischemia or infarction.

• Hyperlipidemia - Xanthelasma, tendon xanthomata
• Coronary artery disease - Fourth heart sound, tachycardia, hypotension, hypertension
• Cerebrovascular disease - Diminished carotid pulses, carotid artery bruits, focal neurological deficits
• Peripheral vascular disease - Decreased peripheral pulses, peripheral arterial bruits, pallor, peripheral cyanosis, gangrene, ulceration
• Abdominal aortic aneurysm - Pulsatile abdominal mass, peripheral embolism, circulatory collapse
• Atheroembolism - Livedo reticularis, gangrene, cyanosis, ulceration (The presence of pedal pulses in the setting of peripheral ischemia suggests microvascular disease and includes cholesterol embolization.)
• Valvular heart disease (particularly calcific aortic stenosis, now recognized to be linked to atherosclerosis) – Cardiac murmur

Causes

A number of large epidemiological studies in North America and Europe have identified numerous risk factors for the development and progression of atherosclerosis. 
 
The risk factors can be divided into modifiable and nonmodifiable risk factors and include hyperlipidemia, hypertension, cigarette habituation, diabetes mellitus, age, and sex. More recently, a number of 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.

• Hyperlipidemia: Hyperlipidemia and dyslipidemia are established risk factors for atherosclerosis. Convincing evidence exists that lowering serum cholesterol reduces the risk of subsequent coronary heart disease events and overall mortality. For additional resources, visit Hyperlipidemia.
• Hypertension
  • Hypertension is a risk factor for the development of atherosclerosis, atherosclerotic cardiovascular disease, and stroke. The mechanism by which hypertension causes these effects is not known, and some uncertainty exists as to what the primary and secondary factors are in a typically multifactorial syndrome. These factors may include hyperlipidemia, hypertension, diabetes mellitus, obesity, and physical inactivity. For additional resources, visit Hypertensive Heart Disease.
  • Hypertension is associated with morphologic alterations of the arterial intima and functional alterations of the endothelium that are similar to the changes observed in hypercholesterolemia and established atherosclerosis. Endothelial dysfunction is a feature of hypertension, hyperlipidemia, and atherosclerosis and is known to represent and contribute to the procoagulant, proinflammatory, and proliferative components of atherogenesis. Hypertension has been shown, in both epidemiologic and experimental studies, to accelerate atherosclerotic vascular disease and increase the incidence of clinical complications.
• Diabetes mellitus: An important risk factor for hyperlipidemia and atherosclerosis and commonly associated with hypertension, abnormalities of coagulation, platelet adhesion and aggregation, increased oxidative stress, and functional and anatomic abnormalities of the endothelium and endothelial vasomotion.
• Cigarette smoking: Cigarette smokers are two to four times more likely to develop coronary heart disease than non-smokers and they have double the risk for stroke.² The mechanisms are complex and likely multifactorial and result in endothelial dysfunction and a relatively hypercoagulable state. It is known that after smokers give up smoking, their risk of mortality and future cardiac events declines, although whether cardiovascular risk for former smokers ever reaches that of never smokers. Using data from the Third National Health and Nutrition Examination Survey (NHANES III), researchers found that the smoking-associated inflammatory response subsides within 5 years after smoking cessation, suggesting that the cardiovascular risk subsides gradually with reduced exposure.⁴
• Obesity
• Metabolic syndrome
• In recent years, air pollution has gained increasing recognition as a contributing modifiable risk factor in the urban communities.⁵ The mechanism is thought to be through the participation of combustion-derived nanoparticles acting through proinflammatory or alternatively direct cardiac toxic pathways.

Of note, algorithms for predicting the risk of cardiovascular disease have generally been developed for a follow-up period of 10 years or less. Clustering of risk factors at younger ages and increasing life expectancy suggest the need for longer-term risk prediction.

In a 2009 study, Pencina and colleagues constructed an algorithm for predicting 30-year risk of coronary death, myocardial infarction, or stroke—"hard" CVD events. Prospective 30-year follow-up of 4,506 participants of the Framingham Offspring cohort showed that standard risk factors (male sex, systolic blood pressure, antihypertensive treatment, total and high-density lipoprotein cholesterol, smoking, and diabetes mellitus), measured at baseline, were significantly related to the incidence of hard cardiovascular disease and remained significant when updated regularly on follow-up. Body mass index was associated positively with 30-year risk of hard CVD only in models that did not update risk factors.⁶

• Novel risk factors: The established risk factors noted above successfully predict future cardiac events in about 50-60% of patients. In recent years, a concerted effort to identify and validate new markers of future risk of the clinical consequences of atherosclerosis has been made.
  • C-reactive protein: Baseline C-reactive protein (CRP) levels add to the predictive value of lipid parameters in determining the risk of first myocardial infarction in apparently healthy men and women without a history of coronary heart disease. Baseline CRP levels also were found to be predictive of symptomatic peripheral vascular disease in a cohort of healthy men. CRP reflects systemic inflammation, and these results support the hypothesis that chronic inflammation may play a role in the pathogenesis and progression of atherosclerosis. Standardization of the CRP assay is required before this test may be clinically useful, and whether this is a truly modifiable risk factor remains unclear. Some early evidence exists that risk factor modification, particularly the use of aspirin and the hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, may reduce plaque inflammation.⁷
  • Fibrinogen: Fibrinogen may be elevated in association with risk factors for atherosclerosis, including smoking, age, and diet; however, recent evidence suggests that elevated levels of fibrinogen are a strong independent predictor of future cardiovascular events in apparently healthy patients and patients with a prior history of cardiovascular disease. This association may be as strong as the established association between hypercholesterolemia and coronary heart disease.
  • Lipoprotein (a): Numerous studies have linked elevated plasma levels of lipoprotein (a), an LDL-like moiety that circulates in the blood attached to apolipoprotein (a), with the development of coronary artery disease. This complex shares structural domains with the fibrinolytic enzyme plasminogen and may render the molecule prothrombotic. The LDL-like moiety is susceptible to oxidation and may be particularly atherogenic. However, the results of prospective studies have been discordant and have not proven the relationship between elevated plasma levels of lipoprotein (a) and coronary artery disease inconclusively. Niacin is known to reduce plasma levels of lipoprotein (a), although whether this truly is a modifiable risk factor remains unclear.

Workup

Laboratory Studies

• Lipid profile: Elevated LDL cholesterol is a risk factor for atherosclerotic vascular disease. High triglycerides associated with low high-density lipoprotein (HDL) cholesterol—a pattern categorized as atherogenic dyslipidemia and often found in insulin resistance — are also a risk factor for vascular disease. The National Cholesterol Education Program (NCEP) has issued guidelines for the diagnosis and optimal treatment of dyslipidemia.^8,9,10
• Blood glucose and hemoglobin A_1c: Routine measurement of blood glucose and hemoglobin A_1c is appropriate in patients with diabetes mellitus. Measuring any number of parameters that may reflect inflammation, coagulation, fibrinolytic status, and platelet aggregability is possible. These measurements may prove to be valuable, but, at this time, how these measurements affect clinical decision-making is unclear, and including them in routine clinical practice is premature.

Imaging Studies

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 remain research techniques at this time but hold promise as reliable noninvasive, and therefore repeatable, measures of disease and surrogate end-points 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.

Coronary angiography 

Coronary angiography was the first available in vivo assessment of the coronary arteries consisting of injection of an iodinated contrast agent through a catheter placed at the ostium of the coronaries. The contrast agent is then visualized through x-ray fluoroscopic examination of the heart. One of the 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, although it can be assessed with intravascular ultrasound, as described below.

Intravascular ultrasound (IVUS)

Intravascular ultrasound (IVUS) is a catheter-based examination that provides images of the thickness and the acoustic density of the vessel wall. It has long been considered the criterion standard for the study of the anatomy of the vessel wall. IVUS can depict the presence of atherosclerotic plaques not visible with contrast coronary angiography and may reveal signs of recent disruption.

Computed tomography 

Multidetector computed tomography (MDCT) technology 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.

Magnetic resonance imaging

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

Scintigraphic techniques

Nuclear perfusion imaging is performed with the use of single-photon emission computed tomography (SPECT) or positron emission tomography (PET) which relies on administration of radionuclide isotope that is accumulated by the targeted tissue, and may help diagnose myocardial ischemia or infarction.

Treatment

Medical Care

The prevention and treatment of atherosclerosis requires control of the known modifiable risk factors for this disease. This includes the medical treatment of hypertension, hyperlipidemia, diabetes mellitus, and cigarette smoking.

Hypertension

Hypertension is a risk factor for the development of atherosclerosis, atherosclerotic cardiovascular disease, and stroke. See eMedicine article Hypertensive Heart Disease. The mechanism by which hypertension causes these effects is not known, and some uncertainty exists as to what the primary and secondary factors are in a typically multifactorial syndrome. These factors may include hyperlipidemia, hypertension, diabetes mellitus, obesity, and physical inactivity. 

Dietary and pharmacological treatment of hypertension is associated with a decreased incidence of stroke and, to a lesser degree, atherosclerotic cardiovascular disease.

Hyperlipidemia and dyslipidemia

Convincing evidence exists that lowering serum cholesterol and treating dyslipidemia reduces the risk of subsequent coronary heart disease events and overall mortality.¹¹

The HMG-CoA reductase inhibitors inhibit the rate-limiting step of cholesterol synthesis in the liver. HMG-CoA reductase inhibitors are effective in lowering the serum total cholesterol, LDL cholesterol, and triglyceride levels and in raising the serum HDL cholesterol level, and they have a low incidence of adverse effects, the most common being hepatotoxicity and myopathy.

The success of the HMG-CoA reductase inhibitors in reducing circulating lipid levels and improving the clinical and anatomic course of atherosclerosis has focused attention on the management of hyperlipidemia. In addition, an important role remains for other hypolipidemic agents that may be of particular benefit for patients with refractory LDL hypercholesterolemia, hypertriglyceridemia, low HDL cholesterol, and elevated lipoprotein(a).

Following a prespecified interim analysis conducted after 208 patients (mean age 65 y, 80% men) had completed the trial, the trial was terminated early on the basis of efficacy. The results are described for these 208 patients. In the niacin group, HDL cholesterol levels were increased by 18.4% to 50 mg/dL (P <0.001). Niacin also significantly reduced LDL cholesterol and triglyceride levels. The ezetimibe group showed a decrease of LDL cholesterol levels by 19.2% to 66 mg/dL (1.7 mmol/L) (P <0.001). Ezetimibe did not increase HDL cholesterol (HDL levels were actually reduced), but it did reduce triglycerides. Niacin had greater efficacy regarding the change in mean carotid intima–media thickness over 14 months compared with ezetimibe (P =0.003), leading to significant reduction of both mean (P =0.001) and maximal carotid intima–media thickness (P £0.001 for all comparisons).

This trial concluded that niacin is superior to ezetimibe for combination therapy in high-risk patients taking statin monotherapy. Two editorials stated the early termination, the small number of patients, and limited duration of follow-up do not yet merit changes in cholesterol therapy guidelines, but they did support niacin as the preferred agent for statin combination therapy until the completion of clinical trials with clinical end points can be completed.^13,14 Two well-powered studies of clinical end points, AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes; NCT00120289) and HPS2-THRIVE (Heart Protection Study 2: Treatment of HDL to Reduce the Incidence of Vascular Events; NCT00461630), will hopefully determine if adding niacin to statin therapy leads to a further risk reduction in patients with hypercholesterolemia.¹⁴

Secondary prevention of coronary artery disease

The Scandinavian Simvastatin Survival Study (4S) examined the effects of simvastatin on mortality in 4444 patients with established coronary heart disease and elevated total serum cholesterol. A statistically significant 29% reduction in the overall mortality rate (8.2% vs 11.5%) and a 42% reduction in the cardiac mortality rate (5% vs 8.5%) occurred after an average of 5.4 years of follow-up.^15,16

The Cholesterol and Recurrent Events (CARE) study examined the effects of pravastatin on mortality rates and cardiac events in 1159 patients with established coronary heart disease and serum cholesterol concentrations that are within the reference range or are mildly elevated. A statistically significant 24% reduction in the incidence of fatal coronary heart disease or nonfatal myocardial infarction (9.9% vs 12.9%) occurred after an average of 5 years of follow-up. A lower total mortality rate (8.6% vs 9.4%) and coronary heart disease mortality rate (4.6% vs 5.7%) occurred in patients receiving pravastatin, although the results were not statistically significant.¹⁷

The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial examined the effects of 40 mg of pravastatin on the incidence of coronary events over a period of 6.1 years in 9014 patients with known coronary heart disease and a broad range of initial cholesterol levels. The following relative risk reductions occurred: 24% for death from coronary heart disease (P <0.001), 22% for the overall mortality rate (P <0.001), 29% for all cardiovascular outcomes (P <0.001), and 19% for stroke (P = 0.048). The effects were similar for all predefined subgroups.¹⁸

Primary prevention of coronary artery disease

The Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER Trial) was stopped early in 2008 when results showed a reduction in cardiovascular morbidity and mortality in patients treated with rosuvastatin compared with placebo. Notably, the patients studied had no evidence of cardiovascular disease and low to normal LDL-C. However, their C-reactive protein (CRP) levels were elevated, which the statin effectively lowered, suggesting that its effect on inflammation may be as important as lowering cholesterol.^19,20

The West of Scotland Coronary Prevention Study (WOSCOPS) examined the effects of pravastatin on the incidence of nonfatal myocardial infarction and coronary mortality rates in 6595 men with moderate hypercholesterolemia and no prior history of coronary heart disease. A statistically significant 29% reduction in nonfatal myocardial infarction (4.6% vs 6.5%) and a 30% reduction in death from all cardiovascular causes (1.6% vs 2.3%) occurred after an average of 4.9 years of follow-up.²¹

The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) examined the effects of lovastatin on the incidence of a first major coronary event in 5608 men and 997 women with average total cholesterol and LDL cholesterol and below-average HDL cholesterol levels. A statistically significant 37% reduction in the incidence of the first major coronary event (4% vs 6.8%) occurred after an average of 5.2 years.²²

Therapy with lipid-lowering 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. The NCEP guidelines recommend aggressive lipid-lowering therapy for patients at high risk for coronary heart disease and for anyone with LDL-C over 160 mg/dL.{Ref6} More than 50 million individuals in the United States are candidates for some form of dietary and/or pharmacological intervention to modify their lipid profile. Pharmacoeconomic studies of implementation of the NCEP guidelines confirm the cost-effectiveness of primary and secondary prevention.

Diabetes mellitus

For patients with diabetes mellitus, strict control of comorbid risk factors is especially important, and ample evidence exists that this reduces the incidence of the clinical complications of microvascular and macrovascular disease.

• Cholesterol lowering with the HMG-CoA reductase inhibitors has yielded important reductions in coronary heart disease events in patients with diabetes mellitus.
• The benefit of strict glycemic control in the prevention of macrovascular disease has been difficult to confirm, although this intuitively is beneficial and is known to retard the progression of microvascular disease.

Cigarette smoking

Some evidence suggest that cardiovascular risk subsides within about 5 years after smoking cessation.²³

Diet

• The National Cholesterol Education Program (NCEP) and the American Heart Association (AHA) made specific recommendations for dietary therapy for coronary heart disease prevention.
• Moderate alcohol intake (20 g/day or less) in men is associated with a reduced incidence of coronary heart disease events.²⁴ The mechanism(s) of this benefit is not well understood. It should be noted that although alcohol may have cardiovascular benefits for women,²⁵ even moderate intake of alcohol in women has been associated with a significantly increased risk for breast cancer.²⁶ Heavy alcohol intake is associated with an increased incidence of coronary heart disease events, as well as cardiomyopathy, arrhythmia, and other adverse health effects and obviously should be discouraged.
• Sinha and colleagues concluded that high intakes of red or processed meat were associated with modest increases in total mortality, cancer mortality, and cardiovascular disease mortality. The baseline population was a cohort of half a million people aged 50-71 years from the National Institutes of Health-AARP (formerly known as the American Association of Retired Persons) Diet and Health Study.²⁷

Activity

Physical inactivity is another modifiable risk factor for coronary heart disease, and regular exercise has been shown to reduce the risk of coronary heart disease in a number of observational epidemiological studies. The mechanisms for this apparent benefit may include an increase in HDL cholesterol and nitric oxide release and a decrease in body weight, insulin resistance, and blood pressure. Most health benefits occur with at least 150 minutes a week of moderate-intensity physical activity, such as brisk walking. Additional benefits occur with more physical activity.²⁸

Medication

Prevention and treatment of atherosclerosis requires risk factor control, including the medical treatment of hypertension, diabetes mellitus, and cigarette habituation.

Advances in the understanding of the vascular biology of atherosclerosis raises the possibility of novel therapies that may address more directly the various aspects of endothelial dysfunction and the role of endothelial dysfunction in atherogenesis. Potential cellular targets include vascular smooth muscle cells, monocyte/macrophage cell lines, platelets, and endothelial cells. Evidence exists that antiplatelet agents, antioxidant therapies, amino acid supplementation, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers may prove to prevent or slow the progression of the disease.

Combination therapy in the future may allow for even greater achievement of greater LDL-C lowering with associated cardiovascular benefit. As one example, however, Vytorin, which combines ezetimibe (decreases small intestinal absorption of cholesterol) with simvastatin, has shown no incremental benefit on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin alone.

HMG-CoA reductase inhibitors

These agents are competitive inhibitors of 3-hydroxy-3-methyl Co-A reductase, an enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis, resulting in up-regulation of LDL receptors in response to the decrease in intracellular cholesterol. The HMG-CoA reductase inhibitors are indicated for the secondary prevention of cardiovascular events and for the treatment of hypercholesterolemia and mixed dyslipidemia.

A number of HMG-CoA reductase inhibitors are indicated for patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments. However, these agents may be less effective in patients with rare homozygous familial hypercholesterolemia, possibly because these patients are lacking functional LDL receptors, making it more likely to raise serum transaminases.

Pravastatin (Pravachol)

Effective in reducing circulating lipid levels and improving the clinical and anatomic course of atherosclerosis.

Dosing

Adult

10-40 mg/d PO hs

Pediatric

Not established

Interactions

Immunosuppressive agents, gemfibrozil, clofibrate, cholestyramine, niacin, and erythromycin increase toxicity; may increase the PT when coadministered with warfarin; coadministration with either niacin or erythromycin has been associated with rhabdomyolysis

Contraindications

Documented hypersensitivity; active liver disease; unexplained elevations in liver function tests; pregnancy; breast-feeding

Precautions

Pregnancy

X - Contraindicated in pregnancy

Precautions

May elevate creatine kinase and transaminase levels; caution in liver disease and ethanol abuse

Simvastatin (Zocor)

Inhibits cholesterol synthesis and increases cholesterol metabolism.

Dosing

Adult

5-80 mg/d PO hs

Pediatric

Not established

Interactions

Mibefradil, cyclosporine, itraconazole, ketoconazole, gemfibrozil, niacin, erythromycin, clarithromycin, and nefazodone increase toxicity; coadministration with warfarin may increase PT; rifampin and nicotinic acid may decrease effects; coadministration with either niacin or erythromycin has been associated with rhabdomyolysis

Contraindications

Documented hypersensitivity; active liver disease; unexplained elevation of liver enzymes; pregnancy; breastfeeding

Precautions

Pregnancy

X - Contraindicated in pregnancy

Precautions

May elevate creatine kinase and transaminase levels; discontinue therapy if symptoms of myopathy or renal failure develop; caution in patients with a history of liver disease and in those who consume excessive amounts of alcohol

Lovastatin (Mevacor, Altocor)

Adjunct to dietary therapy in reducing serum cholesterol. Immediate-release (Mevacor) and extended-release (Altocor) are available.

Dosing

Adult

Immediate-release: 10-80 mg/d PO qd or divided bid
Sustained-release: 10-20 mg PO hs initially; may increase dose q4wk, not to exceed 60 mg/d

Pediatric

Not established

Interactions

Mibefradil, cyclosporine, itraconazole, ketoconazole, gemfibrozil, niacin, erythromycin, clarithromycin, and nefazodone increase toxicity; coadministration with warfarin may increase PT; increases effects of levothyroxine; rifampin, nicotinic acid, bile acid sequestrants, and propranolol may decrease effects

Contraindications

Documented hypersensitivity; active liver disease; unexplained elevations in liver function tests; pregnancy; breastfeeding

Precautions

Pregnancy

X - Contraindicated in pregnancy

Precautions

May elevate creatine kinase and transaminase levels; discontinue therapy if symptoms of myopathy or renal failure develop; caution in patients with a history of liver disease and in those who consume excessive amounts of alcohol

Fluvastatin (Lescol)

Used as an adjunct to dietary therapy in decreasing cholesterol levels.

Dosing

Adult

20-80 mg/d PO qd or divided bid

Pediatric

Not established

Interactions

Toxicity increases when coadministered with triazole antifungals, CNS depressants, macrolide antibiotics, mibefradil, immunosuppressive agents, gemfibrozil, and niacin; coadministration with warfarin may increase PT; rifampin, nicotinic acid, bile acid sequestrants, and propranolol may decrease effects

Contraindications

Documented hypersensitivity; active liver disease; unexplained elevations in liver function tests; pregnancy; breastfeeding

Precautions

Pregnancy

X - Contraindicated in pregnancy

Precautions

May elevate creatine kinase and transaminase levels; photosensitivity may occur with prolonged exposure to sunlight or tanning equipment

Atorvastatin (Lipitor)

Adjunct to dietary therapy in reducing serum cholesterol.

Dosing

Adult

10 mg PO qd; titrate to maximum 80 mg/d

Pediatric

Not established

Interactions

Toxicity increases when coadministered with triazole antifungals, CNS depressants, macrolide antibiotics, mibefradil, cyclosporine, fibric acid derivatives, and niacin; increases toxicity of levothyroxine; coadministration with warfarin may increase the PT

Contraindications

Documented hypersensitivity; significant hepatic impairment; pregnancy; breastfeeding

Precautions

Pregnancy

X - Contraindicated in pregnancy

Precautions

May elevate creatine kinase and transaminase levels; caution in patients receiving drugs that prolong QRS or QT interval; discontinue therapy if symptoms of myopathy or renal failure develop; caution in patients with a history of liver disease and in those who consume excessive amounts of alcohol

Rosuvastatin (Crestor)

HMG-CoA reductase inhibitor that in turn decreases cholesterol synthesis and increases cholesterol metabolism. Reduces total-C, LDL-C, and TG levels and increases HDL-C level. Used adjunctively with diet and exercise to treat hypercholesterolemia.

Dosing

Adult

5-10 mg PO qd initially; may increase dose if needed, not to exceed 40 mg/d; for marked hypercholesterolemia (ie, LDL-C >190 mg/dL), initiate with 20 mg/d PO

Pediatric

Not established

Interactions

Cyclosporine or gemfibrozil significantly increase C_max and AUC, thereby increasing myopathy and rhabdomyolysis risk; limit dose to 5 mg/d when coadministered with cyclosporine and 10 mg/d when coadministered with gemfibrozil; coadministration with aluminum and magnesium hydroxide antacids decreases plasma concentrations (administer antacids 2 h after rosuvastatin); may increase oral contraceptive plasma concentrations; alcohol may increase hepatotoxic risk

Contraindications

Documented hypersensitivity; active liver disease; unexplained serum transaminase elevation

Precautions

Pregnancy

X - Contraindicated in pregnancy

Precautions

Common adverse effects include muscle aches, stomach pain, constipation, nausea, and weakness; may cause myopathy, rhabdomyolysis, and kidney failure; monitor LFTs (ie, baseline, 12 wk after drug initiation and any dose elevation, and semiannually), discontinue if elevation persists; decrease dose with CrCl <30 mL/min; doses 40 mg or greater associated with hematuria and proteinuria

Pitavastatin (Livalo)

HMG-CoA reductase inhibitor (statin) indicated for primary or mixed hyperlipidemia. In clinical trials, 2 mg/d reduced total cholesterol and LDL cholesterol similar to atorvastatin 10 mg/d and simvastatin 20 mg/d.

Dosing

Adult

2 mg PO qd; not to exceed 4 mg/d

Pediatric

Not established

Interactions

Data limited; CYP2C9 substrate; OATP1B1 transporter substrate; 4-fold increase in AUC when coadministered with cyclosporine (an OATP1B1 inhibitor); coadministration with other drugs that cause myopathy (eg, gemfibrozil) may increase risk; CYP2C9 inhibitors (eg, fluconazole, gemfibrozil, nevirapine, sulfisoxazole) may decrease metabolism and thereby increase serum concentration

Contraindications

Documented hypersensitivity; active liver disease; pregnancy

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Common adverse effects include myalgias and myopathy, joint pain, back pain, and constipation; caution with history of liver/renal impairment

Fibric acid derivatives

The precise mechanism of action of this class of drugs is complex and incompletely understood. They increase the activity of lipoprotein lipase and enhance the catabolism of triglyceride-rich lipoproteins, which is responsible for an increase in the HDL cholesterol fraction. A decrease in hepatic very low-density lipoprotein (VLDL) synthesis and an increase in cholesterol excretion into bile also appear to occur. The fibrates typically reduce triglyceride levels by 20-50% and increase HDL cholesterol levels by 10-15%.

The effect on LDL cholesterol is variable. Levels may be expected to decrease by 10-15%. In patients with marked hypertriglyceridemia, LDL cholesterol levels may increase, which likely reflects the ability of the LDL receptor to clear the increased LDL generated by increased VLDL catabolism. Fibrate therapy may also be responsible for a decrease in the clotting ability of platelets and fibrinogen levels, which may account for some of the reported clinical benefits.

These agents can enhance the synthesis of lipoprotein lipase, which can cause triglycerides and very low density lipoprotein levels to decrease.

Fenofibrate (Tricor)

Adjunct to dietary therapy in treating hyperlipidemias associated with hypertriglyceridemia, including type IV and type V. Not proven to be of use in prevention of coronary artery disease.

Dosing

Adult

67 mg/d PO

Pediatric

Not established

Interactions

May increase effects of warfarin; the benefits and risks of administration with immunosuppressants and other nephrotoxic drugs should be considered carefully and the lowest possible dose used; a theoretical risk of severe myositis, rhabdomyolysis, and renal failure exists if combined with the HMG-CoA reductase inhibitors, and close monitoring of serum creatine kinase is appropriate

Contraindications

Documented hypersensitivity; hepatic or renal dysfunction, including primary biliary cirrhosis; unexplained persistent liver function abnormalities; gallbladder disease; caution in hypothyroidism

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause cholelithiasis or cholecystitis; associated with myositis and elevated creatine kinase levels, particularly when used with HMG-CoA reductase inhibitors; increased incidence of malignancy

Gemfibrozil (Lopid)

Adjunct to dietary therapy in adult patients with type IV and V hyperlipidemias presenting at risk for pancreatitis. Adjunctive therapy in coronary heart disease prevention in patients with type IIb hyperlipidemia (low HDL, elevated LDL and triglycerides) not responding to other agents or diet modifications.

Dosing

Adult

1200 mg/d PO divided bid 30 min before breakfast and dinner

Pediatric

Not established

Interactions

May potentiate effects of warfarin; closely monitor if coadministered with lovastatin

Contraindications

Documented hypersensitivity; gallbladder disease; renal or hepatic insufficiencies

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Discontinue if reduction in triglyceride levels is not observed after 3 mo of therapy; monitor for abnormal elevation of ALT, AST, LDH, bilirubin, and alkaline phosphatase serum levels; may increase cholesterol excretion into bile, leading to cholelithiasis; incidence of myositis is higher among patients with renal impairment; caution in diabetes and hypothyroidism

Bile acid sequestrants

The bile acid sequestrants block enterohepatic circulation of bile acids and increase the fecal loss of cholesterol. This results in a decrease in intrahepatic levels of cholesterol. The liver compensates by up-regulating hepatocyte LDL receptor activity. The net effect is a 10-25% reduction in LDL cholesterol, but no consistent effect on triglycerides or HDL cholesterol exists.

Cholestyramine (Questran, LoCholest, Prevalite)

May use as adjunct in primary hypercholesterolemia. Forms a nonabsorbable complex with bile acids in the intestine, which, in turn, inhibits enterohepatic reuptake of intestinal bile salts.

Dosing

Adult

4-24 g PO ac divided bid; not to exceed 24 g/d or 6 doses per d

Pediatric

Not established; suggested dosing is 240 mg/kg/d PO divided bid/tid; not to exceed 8 g/d

Interactions

Inhibits absorption of many drugs, including warfarin, thyroid hormone, amiodarone, NSAIDs, methotrexate, digitalis glycosides, glipizide, phenytoin, imipramine, niacin, methyldopa, tetracyclines, clofibrate, hydrocortisone, and penicillin G

Contraindications

Documented hypersensitivity; biliary obstruction

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Patients may require fat-soluble vitamins and folic acid replacement with long-term therapy; caution in constipation and phenylketonuria; administer 1-2 h before or 4-6 h after bile acid sequestrant

Colestipol (Colestid)

Forms a soluble complex after binding to bile acid, increasing fecal loss of bile acid-bound LDL cholesterol.

Dosing

Adult

Granules: 5-30 g/d PO qd or divided bid mixed with liquid

Pediatric

Not established

Interactions

Decreases absorption of methotrexate, glipizide, imipramine, phenytoin, tolbutamide, niacin, clindamycin, NSAIDs, gemfibrozil, ursodiol, clofibrate, phenobarbital, warfarin, digitalis glycosides, propranolol, phenobarbital, hydrocortisone, and other drugs by inhibiting their absorption in the intestine

Contraindications

Documented hypersensitivity; complete biliary obstruction

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Patients may require fat-soluble vitamins and folic acid replacement with long-term therapy; may be associated with increase in bleeding tendencies due to hypoprothrombinemia resulting from a decrease in vitamin K absorption; administer 1-2 h before or 4-6 h after bile acid sequestrant

Vitamin E (Vita-Plus E, Softgels, Aquasol E)

Protects polyunsaturated fatty acids in membranes from attack by free radicals.

Dosing

Adult

60-75 IU/d PO/IM; study doses for the prevention of coronary artery disease have ranged from 400-800 IU/d PO

Pediatric

Not established

Interactions

Mineral oil decreases absorption of vitamin E; vitamin E delays absorption of iron and increases effects of anticoagulants

Contraindications

Documented hypersensitivity; iron deficiency anemia

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Large doses of vitamin E may result in vitamin K deficiency, enhancing the anticoagulant activity of warfarin and increasing the risk of major and minor bleeding complications, especially in patients who are also taking antiplatelet medication; necrotizing enterocolitis may occur

Nicotinic acid derivatives

Niacin (vitamin B-3) inhibits the hepatic secretion of VLDL cholesterol. Niacin is effective in most categories of hyperlipidemia. Niacin has been demonstrated to lower LDL cholesterol and triglyceride levels by 32% and 20-50%, respectively, and to raise the HDL cholesterol level by 43%. Niacin lowers lipoprotein (a) levels, which may be of some clinical importance because lipoprotein (a) levels have been associated with coronary heart disease in numerous epidemiological studies. The clinical benefit of lowering lipoprotein (a) levels has not been determined.

Niacin (Niaspan, Niacor, Slo-Niacin)

Used in tissue respiration, lipid metabolism, and glycogenolysis. Available in immediate- and extended-release formulations. Extended-release formulation may reduce flushing, an unpleasant adverse effect that causes 30-40% of patients to discontinue therapy.

Dosing

Adult

2-6 g/d PO with food divided tid

Pediatric

Not established

Interactions

HMG-CoA reductase inhibitors increase the risk of rhabdomyolysis; cutaneous vasodilation may be a problem if high dose is used with peripheral dilators such as nitroglycerine; taking aspirin 30-60 min before first dose of the day may help alleviate prostaglandin-mediated adverse effects (eg, flushing, itching); clonidine may inhibit niacin-induced flushing; separate dosing of bile acid sequestrants by at least 4-6 h; may increase PT when coadministered with warfarin

Contraindications

Documented hypersensitivity; active liver disease or unexplained significant increases in AST and ALT; substantial alcohol consumption; active peptic ulcer disease; active gout; hyperuricemia

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in patients with gallbladder disease or diabetes in those predisposed to gout; monitor blood glucose; may elevate uric acid levels and lower blood phosphate levels

Nutritional Agent

Omega-3 polyunsaturated fatty acid

Possible benefits in the treatment of atherosclerosis include effects on lipoprotein metabolism, hemostatic function, platelet/vessel wall interactions, anti-arrhythmic actions and also inhibition of proliferation of smooth muscle cells and therefore growth of the atherosclerotic plaque. Fish oil feeding has also been found to result in moderate reductions in blood pressure and to modify vascular neuroeffector mechanisms.

Dosing

Adult

4-12 g/d PO in divided doses as directed

Pediatric

Not established

Interactions

May increase effects of antiplatelet agents; concomitant use of other oils (eg, olive oil) may reduce effects

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause fishy odor, diarrhea, hyperglycemia, and bleeding due to decreased platelet aggregation; caution in bleeding disorders or diabetes

Follow-up

Prognosis

• The prognosis of atherosclerosis depends on a number of factors, including systemic burden of disease, the vascular bed(s) involved, and the degree of flow limitation. Wide variability exists, 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, myocardial infarction 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

• 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. Medical therapies aimed at improving blood pressure control and various lipid parameters are appropriate for the prevention of first coronary heart disease events, if these risk factors are refractory to lifestyle interventions.
• For excellent patient education resources, visit eMedicine's Cholesterol Center, Statins Center, Circulatory Problems Center, and Stroke Center. Also, see eMedicine's patient education articles High Cholesterol, Understanding Your Cholesterol Level, Lifestyle Cholesterol Management, Chest Pain, Coronary Heart Disease, Heart Attack, Angina Pectoris, and Stroke.

Miscellaneous

Medicolegal Pitfalls

As previously noted, clinical sequelae of atherosclerosis are hard to predict because of the nonlinear rate of progression of this systemic disease. Address the underlying causes of atherosclerosis in an attempt to slow this process and stabilize the existing plaque burden. Failure to do so results in predictable clinical events in the same or other vascular beds, and this is a common cause of medical/legal error. For example, a patient with limb claudication can be assumed to have significant atherosclerotic plaque burden in multiple vascular beds, including the coronary and cerebral vessels. In evaluating preoperative risk in such a patient, pay particular attention to careful risk stratification and medical or interventional efforts to reduce this risk.

Special Concerns

Familial hypercholesterolemia is an autosomal dominant disorder caused by a defect in the gene for the hepatic LDL receptor. In the United States, heterozygous familial hypercholesterolemia occurs in approximately 1 in 500 individuals and typically results in symptomatic coronary heart disease by the fifth decade of life in men and sixth decade of life in women. In the United States, homozygous familial hypercholesterolemia occurs in approximately 1 in 1 million individuals, and total cholesterol may exceed 1000 mg/dL and result in symptomatic coronary heart disease by the second decade of life.

Treatment options include combination drug therapy, although drug therapy alone often is inadequate because of the relative or absolute deficiency of hepatic LDL receptors. Lipid apheresis is an effective means of reducing circulating lipid levels and coronary heart disease events. Liver transplantation has been performed on young patients with severe disease and patients experiencing very early onset of symptomatic coronary artery disease.

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Keywords

myocardial infarction, transient ischemic attack, TIA, stroke, atheroembolism, coronary heart disease, coronary artery atherosclerosis, peripheral vascular disease, ischemia, atherosclerosis, hyperlipidemia, coronary artery disease, cerebrovascular disease, sudden cardiac death, hypertension, hypotension, atherosclerotic cardiovascular disease, diabetes mellitus

Contributor Information and Disclosures

Author

F Brian Boudi, MD, Clinical Assistant Professor, Department of Medicine, Fellow, Sarver Heart Center, University of Arizona College of Medicine; Adjunct Assistant Professor of Medicine, Mid-Western University; Consulting Staff, Director of Ambulatory Medicine Clinical Rotation, Carl T Hayden Veterans Affairs Medical Center
F Brian Boudi, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Cardiology, American College of Healthcare Executives, American College of Physicians, American Society of Echocardiography, American Society of Nuclear Cardiology, Arizona Medical Association, and Association of Program Directors in Internal Medicine
Disclosure: Nothing to disclose.

Coauthor(s)

Chowdhury H Ahsan, MD, MRCP, PhD, FRSCAI, Clinical Professor of Medicine, Director of Cardiac Catheterization and Intervention, Director of Cardiovascular Research, Division of Cardiology, University of California Irvine, University Medical Center
Chowdhury H Ahsan, MD, MRCP, PhD, FRSCAI is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Heart Association, American Stroke Association, and Society for Cardiac Angiography and Interventions
Disclosure: Nothing to disclose.

Medical Editor

Alan D Forker, MD, Professor of Medicine, Program Director of Cardiovascular Fellowship, University of Missouri at Kansas City School of Medicine; Director, Outpatient Lipid Diabetes Research Center, MidAmerica Heart Institute of St Luke's Hospital
Alan D Forker, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Cardiology, American College of Physicians, American Heart Association, American Medical Association, American Society of Hypertension, and Phi Beta Kappa
Disclosure: Research Grant Grant/research funds Hospital contracts to do research; I am a hospital employee with no personal profit; Speakers Bureau Honoraria Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Steven J Compton, MD, FACC, FACP, Director of Cardiac Electrophysiology, Alaska Heart Institute, Providence and Alaska Regional Hospitals
Steven J Compton, MD, FACC, FACP is a member of the following medical societies: Alaska State Medical Association, American College of Cardiology, American College of Physicians, American Heart Association, American Medical Association, and Heart Rhythm Society
Disclosure: Nothing to disclose.

CME Editor

Amer Suleman, MD, Consultant in Electrophysiology and Cardiovascular Medicine, Department of Internal Medicine, Division of Cardiology, Medical City Dallas Hospital
Amer Suleman, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Institute of Stress, American Society of Hypertension, Federation of American Societies for Experimental Biology, Royal Society of Medicine, and Society of Cardiac Angiography and Interventions
Disclosure: Nothing to disclose.

Chief Editor

Yasmine Subhi Ali, MD, MSCI, Assistant Professor of Medicine, Director of Preventive Cardiology, Director of Echocardiography, Meharry Medical College; Assistant Clinical Professor of Medicine, Vanderbilt University School of Medicine
Yasmine Subhi Ali, MD, MSCI is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Heart Association, American Medical Association, American Society of Echocardiography, American Society of Nuclear Cardiology, and National Lipid Association
Disclosure: Pfizer I own a small number of shares of Pfizer stock. These were NOT given to me by Pfizer, but rather purchased by myself as a personal investor for my diversified investment portfolio. None

The authors and editors of eMedicine gratefully acknowledge the contributions of previous James L Orford, MBChB and Andrew P Selwyn, MD, MA, FACC, FRCPto the development and writing of this article.

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