Atherosclerosis

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

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.

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.
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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. Hypertension o 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. o 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. The mechanisms are complex and likely multifactorial and result in
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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 smokingassociated inflammatory response subsides within 5 years after smoking cessation, suggesting that the cardiovascular risk subsides gradually with reduced exposure. Obesity Metabolic syndrome In recent years, air pollution has gained increasing recognition as a contributing modifiable risk factor in the urban communities. 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. o 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
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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. 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.

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Laboratory Studies

Lipid profile: Elevated LDL cholesterol is a risk factor for atherosclerotic vascular disease. High triglycerides associated with low high-density lipoprotein (HDL) cholesterola pattern categorized as atherogenic dyslipidemia and often found in insulin resistanceare also a risk factor for vascular disease. The National Cholesterol Education Program (NCEP) has issued guidelines for the diagnosis and optimal treatment of dyslipidemia. Blood glucose and hemoglobin A1c: Routine measurement of blood glucose and hemoglobin A1c 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 decisionmaking is unclear, and including them in routine clinical practice is premature.

Research An indication of the role of HDL on atherosclerosis has been with the rare Apo-A1 Milano human genetic variant of this HDL protein. A small short-term trial using bacterial synthetized human Apo-A1 Milano HDL in people with unstable angina produced fairly dramatic reduction in measured coronary plaque volume in only 6 weeks vs. the usual increase in plaque volume in those randomized to placebo. The trial was published in JAMA in early 2006. Ongoing work starting in the 1990s may lead to human clinical trialsprobably by about 2008. These may use synthesized Apo-A1 Milano HDL directly. Or they may use gene-transfer methods to pass the ability to synthesize the Apo-A1 Milano HDLipoprotein. Methods to increase high-density lipoprotein (HDL) particle concentrations, which in some animal studies largely reverses and remove atheromas, are being developed and researched. Niacin has HDL raising effects (by 10 - 30%) and showed clinical trial benefit in the Coronary Drug Project and is commonly used in combination with other lipoprotein agents to improve efficacy of changing lipoprotein for the better. However most individuals have nuisance symptoms with short term flushing reactions, especially initially, and so working with a physician with a history of successful experience with niacin implementation, careful selection of brand, dosing strategy, etc. are usually critical to success. However, increasing HDL by any means is not necessarily helpful. For example, the drug torcetrapib is the most effective agent currently known for raising HDL (by up to
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60%). However, in clinical trials it also raised deaths by 60%. All studies regarding this drug were halted in December 2006. The ERASE trial is a newer trial of an HDL booster, which has shown promise. The ASTEROID trial used a high-dose of rosuvastatinthe statin with typically the most potent dose/response correlation track record (both for LDLipoproteins and HDLipoproteins.) It found plaque (intima + media volume) reduction.[3] Several additional rosuvastatin treatment/placebo trials for evaluating other clinical outcomes are in progress. The actions of macrophages drive atherosclerotic plaque progression. Immunomodulation of atherosclerosis is the term for techniques that modulate immune system function to suppress this macrophage action. Immunomodulation has been pursued with considerable success in both mice and rabbits since about 2002. Plans for human trials, hoped for by about 2008, are in progress. Research on genetic expression and control mechanisms is progressing. Topics include PPAR, known to be important in blood sugar and variants of lipoprotein production and function; The multiple variants of the proteins that form the lipoprotein transport particles. Some controversial research has suggested a link between atherosclerosis and the presence of several different nanobacteria in the arteries, e.g., Chlamydophila pneumoniae, though trials of current antibiotic treatments known to be usually effective in suppressing growth or killing these bacteria have not been successful in improving outcomes. The immunomodulation approaches mentioned above, because they deal with innate responses of the host to promote atherosclerosis, have far greater prospects for success.

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Imaging Studies

Ultrasonography Ultrasonography aids in evaluating brachial artery reactivity and carotid artery intimamedia 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 highresolution 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.

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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.

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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. Some studies have claimed reversal of atherosclerois with pharmacologic agents such as statins and cilostazol, but these need to be further tested to show any significant benefit in reducing clinical events.11 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. 12 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).
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The Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6HDL and LDL Treatment Strategies (ARBITER 6HALTS) trial compared the effects of 2 lipid-lowering combination therapies on carotid intima-media thickness.13 In a prospective, randomized, parallel-group, open-label study, 363 patients received either extended-release niacin (2 g/d target dose) or ezetimibe (10 mg/d) in addition to their long-term statin therapy. All participants had been treated with statin monotherapy at a consistent dose. Inclusion required that lipid panels were obtained within 3 months before enrollment showing both an LDL cholesterol level less than 100 mg/dL (2.6 mmol/L) and HDL cholesterol level less than 50 mg/dL (men) or 55 mg/dL (women) (1.3 or 1.4 mmol/L, respectively). The mean common carotid intima-media thickness change from baseline after 14 months was the studys primary end point. 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 intimamedia thickness over 14 months compared with ezetimibe (P =0.003), leading to significant reduction of both mean (P =0.001) and maximal carotid intimamedia thickness (P 0.001 for all comparisons). This trial concluded that niacin is superior to ezetimibe for combination therapy in highrisk 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.14,15 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.

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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.16,17 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. 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. 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. 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
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(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.22 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. 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.24
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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. The mechanism(s) of this benefit is not well understood. It should be noted that although alcohol may have cardiovascular benefits for women, even moderate intake of alcohol in women has been associated with a significantly increased risk for breast cancer. 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. A meta-analysis by Ferdowsian and Barnard suggests that plant-based diets are effective in lowering plasma cholesterol concentrations. In a review of 4 types of plant-based diets studied in 27 trials, a vegetarian or vegan diet combined with nuts, soy, and/or fiber demonstrated the greatest effects (up to 35% reduction in plasma low-density lipoprotein cholesterol, followed by vegan and ovolactovegetarian diets. Diets that included small amounts of lean meat demonstrated less dramatic reductions in levels of total cholesterol and lowdensity lipoprotein.

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.
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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 upregulation 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.

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Pravastatin (Pravachol) Effective in reducing circulating lipid levels and improving the clinical and anatomic course of atherosclerosis. Adult 10-40 mg/d PO hs Pediatric Not established

Simvastatin (Zocor) Inhibits cholesterol synthesis and increases cholesterol metabolism. Adult 5-80 mg/d PO hs Pediatric Not established

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

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Fluvastatin (Lescol) Used as an adjunct to dietary therapy in decreasing cholesterol levels. Adult 20-80 mg/d PO qd or divided bid Pediatric Not established

Atorvastatin (Lipitor) Adjunct to dietary therapy in reducing serum cholesterol. Adult 10 mg PO qd; titrate to maximum 80 mg/d Pediatric Not established

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. 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

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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.

Adult 2 mg PO qd; not to exceed 4 mg/d Pediatric Not established 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 1015%. 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.

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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. Adult 67 mg/d PO Pediatric Not established

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. Adult 1200 mg/d PO divided bid 30 min before breakfast and dinner Pediatric Not established 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.

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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. 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

Colestipol (Colestid) Forms a soluble complex after binding to bile acid, increasing fecal loss of bile acidbound LDL cholesterol. Adult Granules: 5-30 g/d PO qd or divided bid mixed with liquid Pediatric Not established Antioxidants

Vitamin E (Vita-Plus E, Softgels, Aquasol E) Protects polyunsaturated fatty acids in membranes from attack by free radicals. 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

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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 immediateand extended-release formulations. Extended-release formulation may reduce flushing, an unpleasant adverse effect that causes 30-40% of patients to discontinue therapy. Adult 2-6 g/d PO with food divided tid Pediatric Not established 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. Adult 4-12 g/d PO in divided doses as directed Pediatric Not established
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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.

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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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Complications list for Atherosclerosis:

The list of complications that have been mentioned in various sources for Atherosclerosis includes:

Heart disease Blood clots Angina Heart attack Coronary thrombosis Heart failure Stroke Peripheral vascular disease Leg blood clot Claudication Intermittent claudication Erectile dysfunction Plaque ruptures and clots inside the artery lumen over the ruptures Stenosis (narrowing) of the artery (both locally and in smaller downstream branches), or worse, complete closure, and, therefore, an insufficient blood supply to the tissues and organ it Aneurysm Thrombus formation Infarction Stroke, Myocardial infarction

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Home testing

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Frequently asked questions

1. Is atherosclerosis genetic in origin? Infrequently. Although many physicians and the lay public believe that atherosclerosis is genetic, the evidence for that is slim. One way to define the genetic variety of atherosclerosis is by the presence or absence of low-density lipoprotein (LDL) receptors in the liver. Patients with homozygous familial hypercholesterolemia have no LDL receptors in the liver, and their total cholesterol levels from birth are usually >800 mg/dL. The frequency of this genetic defect is 1 in 1,000,000. Patients with heterozygous familial hypercholesterolemia have only 50% of the normal number of LDL receptors in the liver. These patients generally have total cholesterol levels about 300 mg/dL, and they generally die (without lipid-lowering therapy) in their 40s or early 50s. The incidence of this familial defect is 1 in 500. The rest of us apparently have normal numbers of LDL receptors in the liver. Of course, a few patients have genetic defects involving high-density lipoprotein (HDL) cholesterol and triglyceride production and uptake, but these individuals are relatively few in number. Thus, the genetic defect producing atherosclerosis occurs in no more than 1 in 200 and possibly as low as 1 in 400 or 500 persons. This means, of course, that most persons with atherosclerosis acquire it by the types of calories they consume. 2. Is atherosclerosis a consequence of aging and therefore a degenerative disease? No. When I was in medical school, I was taught that atherosclerosis was a disease of aging and that it was to be expected as we got older. It is true that symptomatic and fatal atherosclerosis is usually a problem of older people. But, not too old. Patients with homozygous familial hypercholesterolemia, however, may have lipid plaques in their arteries at the time of birth. It appears that atherosclerosis requires certain serum cholesterol levels over certain periods of time. Therefore, if one has a serum total cholesterol of 1000 mg/dL, death usually occurs by age 15 (without lipid-lowering therapy). Those with total cholesterol levels of approximately 300 mg/dL live into their 30s and 40s. The average age of death from coronary artery disease in the USA is 60 years in men and 68 years in women. Sudden death is primarily a problem of
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young men. Therefore, those who make it to the hospital are usually older than these ages. Nevertheless, atherosclerosis is a disease of relatively young people as well as a disease of older persons. The point here is that atherosclerosis does not have to occur just because of aging. The more years we live, the longer the time period we have to keep our cholesterol levels elevated and thus to develop plaques. Multiplying our serum cholesterol level by our age in years may provide a rough indication of when we have developed enough atherosclerotic plaque to have symptomatic or fatal atherosclerosis. 3. Of the various atherosclerotic risk factors, which one is an absolute prerequisite for development of atherosclerosis? The answer is hypercholesterolemia. What level of total cholesterol and specifically LDL cholesterol is required for atherosclerotic plaques to develop? Symptomatic and fatal atherosclerosis is extremely uncommon in societies where serum total cholesterol levels are <150 mg/dL and serum LDL cholesterol levels are <100 mg/dL .If the LDL cholesterol level is <100 and possibly it needs to be <80 mg/dLthe other previously mentioned risk factors in and of themselves are not associated with atherosclerosis. In other words, if the serum total cholesterol is 90 to 140 mg/dL, there is no evidence that cigarette smoking, systemic hypertension, diabetes mellitus, inactivity, or obesity produces atherosclerotic plaques. Hypercholesterolemia is the onlydirect atherosclerotic risk factor; the others are indirect. If, however, the total cholesterol level is >150 mg/dL and the LDL cholesterol is >100 mg/dL, the other risk factors clearly accelerate atherosclerosis. 4. What evidence connects atherosclerosis to cholesterol? The connection between cholesterol and atherosclerosis is strong . a. Atherosclerotic plaques similar to those in humans can be produced in nonhuman herbivores by feeding them large quantities of cholesterol and/or saturated fat. It is not possible to produce atherosclerotic plaques experimentally in carnivores. b. Cholesterol is found within atherosclerotic plaques. c. In societies where the serum total cholesterol is <150 mg/dL, the frequency of symptomatic and fatal atherosclerosis is exceedingly uncommon; in contrast, in societies where the total cholesterol level is >150 mg/dL, the frequency of symptomatic and fatal atherosclerosis increases as the level above 150 increases.
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d. The higher the serum total cholesterol level, and specifically the higher the serum LDL cholesterol, the greater the frequency of symptomatic atherosclerosis, the greater the frequency of fatal atherosclerosis, and the greater the quantity of plaque at necropsy. e. In placebo-controlled, double-blind, lipid-lowering studies of adults without symptomatic atherosclerosis, the group with lowered serum LDL cholesterol developed fewer symptomatic and fatal atherosclerotic events compared with controls. f. In placebo-controlled, double-blind, lipid-lowering studies of adults with previous symptomatic atherosclerosis, the group with lowered LDL cholesterol levels after the event had fewer subsequent atherosclerotic events than did the group that did not lower their cholesterol levels (controls). g. LDL receptors were discovered in the liver by Brown and Goldstein, and the absence or decreased numbers of LDL receptors in patients with quite elevated serum cholesterol levels indicates a genetic defect in an occasional patient . 5. What are the major sources of cholesterol in calories? Cholesterol comes from animals and their products. Therefore, if we do not eat animals and their products, we do not take in cholesterol. Most Americans now take in only about 300 to 400 mg of cholesterol daily. This amount is hardly enough to obtain a calorie from it. A toothpick weighs 100 mg, so most in the USA take in the equivalency of 3 or 4 toothpicks of cholesterol every day. There are 2 major sources of cholesterol in our diet: 1) cows, including their muscle (beef), milk, butter, and cheese, and 2) eggs. About 45% of the cholesterol we obtain in our diet comes from the visible and nonvisible eggs we eat, and about 40% comes from bovine muscle and bovine milk and its products. 6. What are the major sources of fat in calories? Fat comes from many sources. A major source in the USA is bovine muscle (beef). Cows naturally do not have so much fat, but in the USA most are fattened before slaughter. They are placed in feed lots their last 4 to 6 months of life and fed 20 to 25 pounds of various grains and soybeans every day, and the result is a huge increase in body fat. Cows slaughtered directly from pasture have far less fat between their muscle fibers and that overlying them. In the USA most adults now consume approximately 140 grams of fat daily. Our upper limit should be 75

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grams. (A deck of cards weighs 75 grams.) If we were to limit our fat intake to 50 grams a day, the health of the US population would skyrocket. 7. Which of the 3 components of fatty acids raise the serum total and LDL cholesterol levels? Each triglyceride particle contains a saturated, a monounsaturated, and a polyunsaturated fatty acid. There is no such thing as a pure saturated fatty acid or a pure monounsaturated or a pure polyunsaturated fatty acid. The question is which one is dominant in the triglyceride particles. The saturated portion, when dominant, clearly raises our total and LDL cholesterol levels; the monoand polyunsaturated, when dominant, either lower them or have a neutral effect. Saturated fatty acids are solid at room temperature, and that fact is easy to remember by the s in saturated. The fatty acids with the highest saturated component are coconut oil, palm kernel oil, beef tallow, and butter. Olive oil has the highest monounsaturated percentage (approximately 75%); peanut oil has approximately 50% monounsaturated fatty acids. Grundy and colleagues (11) have demonstrated that monounsaturated fatty acids have healthier features than do polyunsaturated fatty acids. 8. What percentage of reduction in the serum total and LDL cholesterol levels can be expected by decreasing the percentage of calories from fat by 25%, 50%, and 75%? Hunninghake and colleagues demonstrated that reducing the percentage of calories from fat from 40% to 30%, a 25% reduction, reduces on averagethe serum total cholesterol level by 5% and the LDL cholesterol level by 5%. Getting 30% of calories from fat is the most commonly prescribed diet by physicians in the USA, and its effect on cholesterol levels is relatively small. There is great individual variability, so that it is not possible to predict what drop in cholesterol levels will occur in a single individual. The drop in a single individual may be as high as 20%, but in some individuals the total and LDL cholesterol levels increase by as much as 20% .A reduction in percentage of calories from fat from 40% to 20%, a 50% reduction, generally leads to approximately a 20% reduction in both serum total and LDL cholesterol levels .A drop in percentage of calories from fat from 40% to 10%, a 75% reduction, generally leads to reductions in total and LDL cholesterol levels of about 40% (14). The 10% of calories from fat is a vegetarian-fruit diet. 9. How safe are the statin drugs?
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These are some of the safest drugs that have been produced .They are considerably safer than aspirin or nonsteroidal anti-inflammatory drugs. They are safer than many drugs presently available over the counter. At the lower doses there is no evidence that statin drugs have detrimental effects on the liver. The frequency of liver enzyme elevation at the lower doses is the same as in placebo groups .Evidence is now accumulating that possibly even at the higher doses the statin drugs do not in themselves affect the liver detrimentally. Individuals with elevated liver enzymes associated with the intake of statin drugs have never had permanent damage to the liver produced by the statin drug. The only serious side effect of the statin drugs is myopathy, and that occurs in 1 of 10,000 persons taking the drug. The toxicity is not the statin drug; the toxicity is atherosclerosis! The risk-benefit ratio of using statin drugs in patients with atherosclerosis, either to prevent further plaque formation or to prevent its formation in the first place, favors drug use. 10. How effective are the statin drugs in preventing strokes? Very effective. The statin drugs decrease the frequency of strokes in a 5-year period by approximately 30% Until recently the statin drugs were the only drugs other than an antihypertensive drug demonstrated to decrease the frequency of stroke. Recently, the angiotensin-converting enzyme inhibitor ramapril has been shown to decrease the frequency of strokes also by approximately 30%

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