Noncoronary Atherosclerosis Overview of Atherosclerosis
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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.
Noncoronary atherosclerosis refers to atherosclerotic disease affecting large and medium-sized noncoronary arteries (eg, extracranial cerebrovascular disease, lower extremity occlusive disease, aneurysmal disease).
The signs and symptoms of noncoronary atherosclerosis are highly variable. Patients with mild atherosclerosis may present with clinically important symptoms and signs of disease. However, many patients with anatomically advanced disease may have no symptoms and experience no functional impairment.
Signs and symptoms of noncoronary atherosclerosis that affect different organ systems include the following:
Central nervous system: Stroke, reversible ischemic neurologic deficit, transient ischemic attack
Peripheral vascular system: Intermittent claudication, impotence, nonhealing ulceration and infection of the extremities
Gastrointestinal (GI) vascular system: Mesenteric angina characterized by epigastric or periumbilical postprandial pain—may be associated with hematemesis, hematochezia, melena, diarrhea, nutritional deficiencies, and weight loss; abdominal aortic aneurysm that is typically asymptomatic (sometimes pulsatile) until the dramatic, and often fatal, signs and symptoms of rupture
Target organ failure: Occult or symptomatic visceral ischemia
Examination findings of noncoronary atherosclerosis are highly variable but may provide objective evidence of extracellular lipid deposition, stenosis or dilatation of large muscular arteries, or target organ ischemia or infarction, such as the following:
Hyperlipidemia: Xanthelasma and tendon xanthomata
Cerebrovascular disease: Diminished carotid pulses, carotid artery bruits, and focal neurologic deficits
Peripheral vascular disease: Decreased peripheral pulses, peripheral arterial bruits, pallor, peripheral cyanosis, gangrene, and ulceration
Abdominal aortic aneurysm: Pulsatile abdominal mass, peripheral embolism, and circulatory collapse
Atheroembolism: Livedo reticularis, gangrene, cyanosis, ulceration, digital necrosis, GI bleeding, retinal ischemia, cerebral infarction, and renal failure
Laboratory testing
Lipid profile
Blood glucose and hemoglobin A1c
Imaging studies
Ultrasonography: For evaluating brachial artery reactivity and carotid artery intima-media thickness (measures of vessel wall function and anatomy, respectively)
Intravascular ultrasonography: Generally considered the criterion standard for the anatomic study of the vessel wall (provides images of the thickness and the acoustic density of the vessel wall)
Magnetic resonance imaging: For noninvasive assessment of blood vessel wall structure and characterization of plaque composition
Nuclear perfusion imaging with single-photon emission computed tomography (SPECT) scanning or positron emission tomography (PET) scanning
The prevention and treatment of atherosclerosis require risk factor control, including the medical management of hypertension, hyperlipidemia and dyslipidemia, diabetes mellitus, and cigarette habituation.
Pharmacotherapy
The following medications may be used in the management of noncoronary atherosclerosis:
HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme) reductase inhibitors (eg, pravastatin, simvastatin, lovastatin, fluvastatin, atorvastatin, rosuvastatin, pitavastatin)
Fibric acid derivatives (eg, fenofibrate, gemfibrozil)
Bile acid sequestrants (eg, cholestyramine, colestipol)
Vitamin E
Omega-3 polyunsaturated fatty acid
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.
Go to Coronary Artery Atherosclerosis for complete information on this topic.
The mechanisms of atherogenesis remain uncertain. An incompletely understood interaction exists between the critical cellular elements—endothelial cells, smooth muscle cells, platelets, and leucocytes—of the atherosclerotic lesion. 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 biologic processes that contribute to atherogenesis and the clinical manifestations of atherosclerosis.
The “response-to-injury” theory is most widely accepted explanation for atherogenesis. 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 ribonucleic acid (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. (This article will focus on noncoronary sites of atherogenesis.)
One study suggested that hypercholesterolemia-induced neutrophilia develops in arteries primarily during early stages of atherosclerotic lesion formation. [1]
The earliest pathologic lesion of atherosclerosis is the fatty streak, which 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 the activated platelets, macrophages, and dysfunctional endothelial cells that characterize early atherogenesis, vascular inflammation, and platelet-rich thrombosis at sites of endothelial disruption. The relative deficiency of endothelium-derived nitric oxide further potentiates this proliferative stage of plaque maturation.
The proliferating 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.
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. Flow impairment causes symptoms of inadequate blood supply to the target organ in the event of increased metabolic activity and oxygen demand.
Developing atherosclerotic plaques acquire their own microvascular network, which consists of a collection of vessels known as the vasa vasorum. These vessels are prone to hemorrhage and contribute to the progression of atherosclerosis. [2]
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. In addition, 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.
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 persons 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.
A number of large epidemiologic 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 types and include hyperlipidemia, hypertension, cigarette habituation, diabetes mellitus, age, sex, physical inactivity, and obesity. In addition, 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.
Hypertension has been shown, in epidemiologic and experimental studies, to accelerate atherosclerotic vascular disease and increase the incidence of clinical complications.
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 the above-mentioned hyperlipidemia, hypertension, diabetes mellitus, obesity, and physical inactivity.
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.
This is an important risk factor for hyperlipidemia and atherosclerosis and is 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 smokers have double the risk for stroke compared with nonsmokers. [3]
In a cohort of healthy men, baseline C-reactive protein (CRP) levels were found to be predictive of symptomatic peripheral vascular disease. 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 CRP levels are a truly modifiable risk factor remains unclear.
Fibrinogen may be elevated in association with risk factors for atherosclerosis, including smoking, age, and diet.
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. Homozygous familial hypercholesterolemia occurs in approximately 1 in 1 million individuals in the United States, and total cholesterol may exceed 1000 mg/dL.
Also see Risk Factors for Coronary Artery Disease.
The true frequency of atherosclerosis is difficult, if not impossible, to accurately determine, because it is a predominantly asymptomatic condition.
A study by Semba et al suggests that high concentrations of plasma klotho, a hormone that has been implicated in atherosclerosis, are independently associated with a lower likelihood of having CVD. [4]
Atherosclerosis is more common in men than in women. The higher prevalence of atherosclerosis in men is thought to be due to the protective effects of female sex hormones. This effect is absent after menopause in women.
Most cases of atherosclerotic vascular disease become clinically apparent in patients aged 40 years or older.
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 the atherosclerotic disease process and determine the prognosis of atherosclerosis.
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.
For patient education information, see eMedicineHealth’s Cholesterol Center and Brain and Nervous System Center, as well as High Cholesterol, Cholesterol Charts, Lifestyle Cholesterol Management, and Stroke.
The symptoms of noncoronary atherosclerosis are highly variable. Patients with mild atherosclerosis may present with clinically important symptoms and signs of disease. However, many patients with anatomically advanced disease may have no symptoms and experience no functional impairment.
Although atherosclerosis was initially thought to be a chronic, slowly progressive, degenerative disease, it is now apparent that the disorder has 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.
Stroke, reversible ischemic neurologic deficit, and transient ischemic attack are manifestations of the impairment of the patient’s vascular supply to his or her central nervous system and are characterized by the sudden onset of a focal neurologic deficit of variable duration.
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. (A patient with limb claudication can be assumed to have a 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.)
Visceral ischemia may be occult or symptomatic prior to the signs and symptoms 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.
As previously mentioned, the symptoms of noncoronary atherosclerosis are highly variable. Patients with mild atherosclerosis may present with clinically important disease signs and symptoms, while many patients with anatomically advanced disease display no symptoms and have no associated functional impairment.
The physical signs of noncoronary atherosclerosis provide objective evidence of extracellular lipid deposition, stenosis or dilatation of large muscular arteries, or target organ ischemia or infarction. These symptoms include the following:
Hyperlipidemia – Xanthelasma and tendon xanthomata
Cerebrovascular disease – Diminished carotid pulses, carotid artery bruits, and focal neurologic deficits
Peripheral vascular disease – Decreased peripheral pulses, peripheral arterial bruits, pallor, peripheral cyanosis, gangrene, and ulceration
Abdominal aortic aneurysm – Pulsatile abdominal mass, peripheral embolism, and circulatory collapse
Atheroembolism – Livedo reticularis, gangrene, cyanosis, ulceration, digital necrosis, gastrointestinal bleeding, retinal ischemia, cerebral infarction, and renal failure
The Copenhagen City Heart Study found that xanthelasmata (raised yellow patches around the eyelids) but not arcus corneae (white or grey rings around the cornea) constitutes an independent risk factor for cardiovascular disease. Presence of xanthelasmata indicated increased risk for myocardial infarction, ischemic heart disease, and severe atherosclerosis. [5]
With regard to atheroembolism, the presence of pedal pulses in the setting of peripheral ischemia suggests microvascular disease and includes cholesterol embolization.
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. [6, 7, 8]
The dal-PLAQUE trial tested the safety and efficacy of dalcetrapib, using novel noninvasive multimodality imaging to assess structural and inflammatory indices of atherosclerosis as primary endpoints. The results suggest that dalcetrapib showed no evidence of a pathological effect related to the arterial wall over 24 months; however, dalcetrapib may have potential beneficial vascular effects, including the reduction in total vessel enlargement over 24 months. The long-term safety and efficacy needs to be further investigated. [9]
Nicholls et al studied the efficacy and safety of cholesteryl ester transfer protein (CETP) inhibitors in combination with commonly used statins. They found that, compared with placebo or statin monotherapy, evacetrapib raised HDL-C and lowered LDL-C levels, with or without a statin drug. [10]
In an industry-supported study, patients with atherosclerotic cardiovascular disease and LDL-C levels of < 70 mg/dl (1.81 mol/L) experienced no incremental clinical benefit from the addition of niacin to statin therapy during a 36-month follow-up period, despite significant improvements in HDL-C and triglyceride levels. [11]
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 decision-making is unclear, and including them in routine clinical practice is premature.
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.
The loss of endothelium-dependent vasodilation is a feature of even the early stages of atherosclerosis.
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.
The availability of high-resolution ultrasonographic systems makes the visualization and measurement of small, peripheral conduit vessels, such as the human brachial artery, possible.
B-mode ultrasonography of the common and internal carotid arteries is a noninvasive measure of arterial wall anatomy that may be performed repeatedly and reliably in asymptomatic individuals. The combined thickness of the intima and media of the carotid artery is associated with the prevalence of cardiovascular risk factors and disease and an increased risk of myocardial infarction and stroke. This association is at least as strong as the associations observed with traditional risk factors.
Intravascular 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.
Magnetic resonance imaging (MRI) may be used to gain information noninvasively about blood vessel wall structure and to characterize plaque composition.
Nuclear perfusion imaging is performed with the use of single-photon emission computed tomography (SPECT) scanning or positron emission tomography (PET) scanning, which relies on the administration of radionuclide isotope that is accumulated by the targeted tissue.
The prevention and treatment of atherosclerosis require risk factor control, including the medical treatment of hypertension, hyperlipidemia, diabetes mellitus, and cigarette habituation.
Some studies have claimed reversal of atherosclerosis with pharmacologic agents such as statins and cilostazol, but these need to be further tested before it can be determined whether they offer any significant benefit in reducing clinical events. [12]
Advances in the understanding of the vascular biology of atherosclerosis have raised the possibility of using novel therapies to 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 (ACE) inhibitors, and angiotensin receptor blockers may prove to prevent or slow the progression of the disease.
New guidelines released in late 2013 by the American Heart Association/American College of Cardiology (AHA/ACC), recommend use of a revised calculator for estimating the 10-year and lifetime risk of developing a first atherosclerotic cardiovascular disease (ASCVD) event, including stroke (fatal or nonfatal), in a person who was initially free from ASCVD. [13]
For patients 20-79 years of age who do not have existing clinical ASCVD, the guidelines recommend assessing clinical risk factors every 4-6 years. For patients with low 10-year risk (< 7.5%), the guidelines recommend assessing 30-year or lifetime risk in patients 20-59 years old.
Regardless of the patient’s age, clinicians should communicate risk data to the patient and refer to the AHA/ACC lifestyle guidelines, which cover diet and physical activity. For patients with elevated 10-year risk, clinicians should communicate risk data and refer to the AHA/ACC guidelines on blood cholesterol and obesity.
The dietary and pharmacologic treatment of hypertension is associated with a decreased incidence of stroke.
The 3-hydroxy-3-methyl Co-A (HMG-CoA) reductase inhibitors inhibit the rate-limiting step of cholesterol synthesis in the liver. They are effective in lowering the serum total cholesterol, LDL cholesterol, and triglyceride levels and in raising the serum HDL cholesterol level. HMG-CoA reductase inhibitors also 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).
The 2013 AHA/ACC guidelines on the management of elevated blood cholesterol no longer specify LDL- and non-HDL-cholesterol targets for the primary and secondary prevention of atherosclerotic cardiovascular disease, including stroke and peripheral arterial disease. [14]
The guidelines identify four groups of primary- and secondary-prevention patients in whom efforts should be focused to reduce cardiovascular disease events and recommend appropriate levels of statin therapy for these groups.
Treatment recommendations include the following :
In patients with atherosclerotic cardiovascular disease, or those with LDL cholesterol levels 190 mg/dL or higher (eg, due to familial hypercholesterolemia), and no contraindications, high-intensity statin therapy should be prescribed to achieve at least a 50% reduction in LDL cholesterol
In patients aged 40 to 75 years of age with diabetes, a moderate-intensity statin that lowers LDL cholesterol by 30% to 49% should be used; in those patients who also have a 10-year risk of atherosclerotic cardiovascular disease exceeding 7.5%, a high-intensity statin is a reasonable choice
In individuals aged 40 to 75 years without cardiovascular disease or diabetes but with a 10-year risk of clinical events >7.5% and an LDL-cholesterol level of 70-189 mg/dL, a moderate- or high-intensity statin should be used
For patients with diabetes mellitus, strict control of comorbid risk factors is especially important. Ample evidence exists that such control reduces the incidence of the clinical complications of microvascular and macrovascular disease.
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.
Treatment options for familial hypercholesterolemia 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. Liver transplantation has been performed on young patients with severe disease.
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. One study suggests that the maximal doses of rosuvastatin and atorvastatin resulted in significant regression of coronary atherosclerosis. Although rosuvastatin resulted in lower LDL cholesterol levels and higher HDL cholesterol levels, a similar degree of regression of percent atheroma value (PAV) was observed in the two groups. [15] 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.
HMG-CoA reductase inhibitors include the following:
Pravastatin (Pravachol)
Simvastatin (Zocor)
Lovastatin (Mevacor, Altocor)
Fluvastatin (Lescol)
Atorvastatin (Lipitor)
Rosuvastatin (Crestor)
Pitavastatin (Livalo)
The precise mechanism of action of this class of drugs is complex and incompletely understood. These agents 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 decrease in VLDL and triglyceride levels results from the ability of fibric acid derivatives to enhance the synthesis of lipoprotein lipase.
The effect of fibric acid derivatives 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.
Fibric acid derivatives include fenofibrate (Tricor) and gemfibrozil (Lopid).
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.
Bile acid sequestrants include cholestyramine (Questran, LoCholest, Prevalite) and colestipol (Colestid).
This antioxidant protects polyunsaturated fatty acids in membranes from attack by free radicals.
The possible benefits of omega-3 polyunsaturated fatty acid in the treatment of atherosclerosis include effects on lipoprotein metabolism, hemostatic function, platelet/vessel wall interactions, antiarrhythmic actions, and the 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.
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Semba RD, Cappola AR, Sun K, et al. Plasma Klotho and Cardiovascular Disease in Adults. J Am Geriatr Soc. 2011 Aug 24. [Medline].
Christoffersen M, Frikke-Schmidt R, Schnohr P, et al. Xanthelasmata, arcus corneae, and ischaemic vascular disease and death in general population: prospective cohort study. BMJ. 2011 Sep 15. 343:d5497. [Medline]. [Full Text].
Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol. 2004 Aug 4. 44(3):720-32. [Medline].
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Fayad ZA, Mani V, Woodward M, et al. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial. Lancet. 2011 Oct 29. 378(9802):1547-59. [Medline].
Nicholls SJ, Brewer HB, Kastelein JJ, et al. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA. 2011 Nov 16. 306(19):2099-109. [Medline].
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Katakami N, Kim YS, Kawamori R, Yamasaki Y. The phosphodiesterase inhibitor cilostazol induces regression of carotid atherosclerosis in subjects with type 2 diabetes mellitus: principal results of the Diabetic Atherosclerosis Prevention by Cilostazol (DAPC) study: a randomized trial. Circulation. 2010 Jun 15. 121(23):2584-91. [Medline].
[Guideline] Goff DC Jr, Lloyd-Jones DM, Bennett G, Coady S, D’Agostino RB Sr, Gibbons R, et al. 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2013 Nov 12. [Medline]. [Full Text].
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F Brian Boudi, MD, FACP Clinical Associate Professor, University of Arizona College of Medicine (Phoenix Campus); Fellow, Sarver Heart Center, University of Arizona College of Medicine; Regional Faculty, American Heart Association; Adjunct Assistant Professor of Medicine, Mid-Western University; Staff Physician, Site Director for Clinical Rotations Emergency Medicine, Phoenix Veterans Administration Health Care System
F Brian Boudi, MD, FACP is a member of the following medical societies: American Association for the Advancement of Science, American College of Cardiology, American College of Physicians, American Society of Echocardiography, Arizona Medical Association, Association of Program Directors in Internal Medicine, American College of Healthcare Executives, American Society of Nuclear Cardiology
Disclosure: Nothing to disclose.
Chowdhury H Ahsan, MD, PhD, MRCP, FSCAI Clinical Professor of Medicine, Director of Cardiac Catheterization and Intervention, Marlon Cardiac Catheterization Laboratory, Director of Cardiovascular Research, University Medical Center, University of Nevada School of Medicine
Chowdhury H Ahsan, MD, PhD, MRCP, FSCAI is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Heart Association, Society for Cardiovascular Angiography and Interventions, American Stroke Association
Disclosure: Received consulting fee from sanofi for consulting; Received honoraria from astra zeneca for speaking and teaching; Received honoraria from BI for speaking and teaching.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Steven J Compton, MD, FACC, FACP, FHRS Director of Cardiac Electrophysiology, Alaska Heart Institute, Providence and Alaska Regional Hospitals
Steven J Compton, MD, FACC, FACP, FHRS is a member of the following medical societies: American College of Physicians, American Heart Association, American Medical Association, Heart Rhythm Society, Alaska State Medical Association, American College of Cardiology
Disclosure: Nothing to disclose.
Yasmine S Ali, MD, FACC, FACP, MSCI President, Nashville Preventive Cardiology, PLLC; Assistant Clinical Professor of Medicine, Vanderbilt University School of Medicine
Yasmine S Ali, MD, FACC, FACP, MSCI is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Heart Association, American Medical Association, National Lipid Association, Tennessee Medical Association
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: MCG Health, LLC.
The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors James L Orford, MBChB and Andrew P Selwyn, MD, MA, FACC, FRCP, to the development and writing of the source article.
Noncoronary Atherosclerosis Overview of Atherosclerosis
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