Printer Friendly

Atherosclerosis: the underlying disease.

ATHEROSCLEROSIS WAS IDENTIFIED in Egyptian mummies from as early as 1500 BC(1) and has been studied clinically for more than 100 years. (2) Despite our longstanding awareness of atherosclerosis and its association with myocardial infarction and sudden cardiac death, only recently have we been able to study the pathology and progression of atherosclerotic plaque formation. Novel methods of imaging the arterial wall have enabled the identification of preclinical disease and plaque progression, as well as better evaluation of therapeutic interventions. Thanks in large part to advances in imaging technology, this deeper understanding of the stages of atherosclerosis progression underscores the importance of primary and secondary preventive efforts.

Patients are becoming increasingly sophisticated in their knowledge of health issues and often want to know more about their own illnesses. Unfortunately, a plethora of inaccurate, biased, or incomplete information is readily available through the Internet, television, and print media. So-called advocacy groups claiming to protect the populace against dangerous drugs also amplify the risks of many drug therapies and downplaytheir benefits, to the detriment of public health. Family physicians play an important role in educating patients about risk factor identification and management and treatment of coronary artery disease. In particular, family physicians can help patients understand the implications and clinical utility of new research findings related to atherosderosis. The text and figures that follow will review new developments in our understanding of the pathogenesis of atherosclerosis and newways that changes in atherosclerotic plaque size and volume can be measured.

The pathogenesis of atherosclerosis

The development of atherosderosis is a gradual, insidious, complex process that is caused by the interaction among risk factors, endothelial cell dysfunction, lipid oxidation, and lipid scavenging/accumulation. (3-6) Endothelial cells become dysfunctional when exposed to an athemgenic milieu. Individual risk factors, such as tobacco smoking, aging, hypercholesterolemia, hyperglycemia, and obesity, all promote endothelial damage and dysfunction. (7) Dysfunctional endothelial cells express a variety of adhesion molecules and selectins. These molecules function as cell surface receptors, which promote the binding, rolling, and stable arrest of inflammatory white blood cells (eg, monocytes, T lymphocytes) along their surface. (5) As monocytes encounter defects or leaky gap junctions along the endothelial surface, they rearrange their cytoskeleton and traverse the endothelial barrier into the subendothellal space in response to a monocyte chemoattractant protein-1 gradient. (8) As more inflammatorywhite cells infiltrate the vessel wall, they create an inflammatory nidus, and monocytes differentiate into macrophages. (5)

Lipid accumulation and oxidation play an important role in the pathogenesis of atherosclerosis. As atherogenic lipoproteins such as very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) infiltrate the subendothelial space, they can be oxidized by such enzymes as myeloperoxidase, 5'-lipoxygenase, and

NADH oxidase. (9) Oxidatively modified lipoprotein induces an autoimmune response, ultimately leading to the activation of resident macrophages. Macrophages upregulate the expression of families of scavenging receptors that bind and take up lipoproteins. (10) As the amount of intracellular lipid increases, macrophages assume a foamy appearance and are described as foam cells. As foam cells coalesce, they form fatty streaks and, ultimately, atheromatous plaque. Macrophages, Tlymphocytes, and mast cells potentiate inflammation by secreting a host of interleukins, cytokines, reactive oxygen species, and growth factors. (5)

Fatty streak formation is an early manifestation of atherosclerosis (FIGURE 1). (11) Fatty streaks begin during childhood or adolescence and in at- risk individuals can progress to clinically significant fibrous plaques by young adulthood. (12) It is important to note that fatty streaks and some atherosderotic plaques (especially if they are not yet extensively fibrotic, necrotic, or calcified) are reversible as long as the lipid in the lesion can be mobilized and removed from the vessel wall. (5) Reverse cholesterol transport is a sequence of enzymemediated reactions by which high-density lipoproteins (HDL) promote the mobilization and removal of cholesterol from foam cells and deliver it back to the liver for disposal. (13,14) Factors that decrease LDL cholesterol (LDLC) reduce atherosclerotic plaque development. Likewise, increased levels of HDL cholesterol (HDL-C) promote the removal of plaque from the arterial wall. (5) Two recent metaanalyses suggest that the best way to describe the benefits of statin therapy on cardiovascular morbidity and mortality and progression/regression of atherosclerotic plaque is by the magnitude of HDL-C elevation and LDL-C reduction. (15,16) This is consistent with the need to limit LDL-C availability and infiltration and to promote HDL-mediated cholesterol clearance.

Atherosclerotic plaques grow larger over time and can become unstable. Unstable plaques are characterized by a large lipid core, a high density of macrophages, and increased inflammatory tone. Rupture, fissuring, or erosion of unstable plaque can lead to the formation of an overlying thrombus and development of acute coronary syndromes. (5) A necrotic core can form in a plaque. As macrophages maximize lipid uptake, they can undergo apoptosis or programmed cell death. (5) If the phagocytic function of macrophages is overwhelmed, apoptotic bodies, cellular debris, and lipid will accumulate, thereby expanding the volume of the plaque. In addition to surface changes, a plaque can rupture secondary to intraplaque hemorrhage as the vasa vasora in the adventitia are injured or become leaky over time. (6)


Fibrous cap atheromas

Fibrous cap atheromas are considered the first pathognomonic lesions of atherosclemsis (FIGURE 1). (11) Lipid-rich foam cells, other inflammatory cells, cellular debris, calcium deposits, and connective tissue accumulate in the fatty streak and increase inflammation, leading to cell death. As the lipid core and necrotic debris increase, the lesion further invades the arterial wall, occupying more of the infimal layer. Connective tissue made up of smooth muscle cells and collagen covers the lipid-rich necrotic core (LRNC), forming a fibrous cap located under the endothelium. (5,6)

Inflammation of atherosclerotic plaque correlates with increased levels of some serum biomarkers of inflammation, of which C-reactive protein (CRP) has been best studied. Circulating levels of CRP in healthy persons are very low, but levels increase markedly in persons with atherosclerosis, even in asymptomatic individuals with early-stage disease. Other conditions highly correlated with increased systemic inflammation and elevated CRP include active infection, malignancy, and rheumatologic disease. The robust relationship between CRP and coronary artery disease has spurred an intense research effort to assess the utility of CRP as a biomarker in predicting cardiovascular risk in asymptomatic individuals and recurrent cardiac events in patients with existing coronary artery disease. (11,17)

Thin fibrous cap atheromas

As the LRNC of the lesion enlarges, macrophages and lymphocytes infiltrate the fibrous cap, causing it to thin. Macrophage infiltration weakens the fibrous cap by phagocytosing the extracellular matrix and releasing proteolytic enzymes (eg, plasminogen activators, matrix metalloproteinases). The thinned fibrous cap is vulnerable to rupture, which exposes the inflammatory, highly thrombogenic contents (tissue factor, collagen) of the LRNC and increases the risk for thrombosis (FIGURE 1). (6,11,18)


Early growth of the atherosclerotic lesion does not initially reduce arterial lumen size and cause stenosis. Rather, compensatory enlargement of the arterial wall (vascular remodeling) occurs and lumen size is maintained, secondary to ectatic or outward progression of plaque during the initial phases of atherosclerosis. (5,19) Indeed, acute coronary events often are associated with lesions that are only mildly stenotic (FIGURE 2). (20) Most acute coronary syndromes (eg, myocardial infarction, unstable angina) and sudden cardiac death are caused by the rupture of mild to moderately severe atherosderotic lesions that suddenly become unstable. (18,21) Although stenotic narrowing of the arterial lumen undoubtedly remains an important cause of ischemia, plaque destabilization and rupture are increasingly recognized as the pivotal pathophysiologic processes in cardiac events. (2)

Persistence of thin fibrous cap atheromas can be a cyclic process characterized by rupture of the fibrous cap, thrombosis, thrombus dissolution by fibrinolysis, repair/scarring, and subsequent rupture. The rupture is spontaneously re paired when additional collagen and cellular material are deposited on the plaque surface. These events can be asymptomatic. With repetition, this cycle results in multiple layers of healed scar tissue. Calcium, which may be deposited in the arterial wall during plaque evolution or hemorrhage, may be exposed after rupture of a plaque and, although rare, can be a site for thrombosis. (6) Until the plaque occupies roughly 40% of the volume encompassed by the outer wall of the artery, it does not begin to narrow the lumen and therefore is not visible by traditional coronary angiography, thus underscoring the importance of emerging technologies used to detect early-stage atherosclerosis. (5,22)

Novel imaging techniques

Over the past decade, tremendous strides have been made in our ability to visualize and quantify changes in the progression of athemsclerosis. Contrast angiography has been the standard means of measuring stenotic changes, but angiography does not enable visualization of the entire arterial wall and identification of changes in the underlying disease process--namely, arterial wall thickness, plaque volume, and plaque composition. Novel imaging technologies have allowed the visualization of early changes in arterial plaque and arterial wan thickness in asymptomatic patients with early-stage atherosclerosis, thus advancing our understanding of the natural course and underlying pathophysiology of atherosclerosis. Imaging also is useful in measuring the effects of primary and secondary preventive interventions. (2,5)

Intravascular ultrasound (IVUS) is an invasive method of visualizing arterial lumen diameter, wall thickness, and plaque size that has been used to measure disease progression and the effects of drug therapy. IVUS is used increasingly to detect clinically silent atherosclerotic lesions and to monitor the effects that therapeutic interventions have on them. The use of IVUS has demonstrated that contrast angiography does not accurately assess the full extent of atherosclerosis, and that significant disease can be present in the setting of nonstenotic vessels.(2,20) increasing carotid intima-media thickness (CIMT) over time is a measure of atherosclerosis progression that is imaged with the use of B-mode (ie, brightness-mode) ultrasound--a noninvasive method of monitoring the effects of pharmacologic and nonpharmacologic treatments on changes in the rate of athemsclerosis progression. (2,5)

Computed tomography with contrast media or computed tomographic angiography is a minimally invasive technique that is emerging as a method to assess luminal narrowing and wall thickening of arteries, including the proximal coronary arteries. (2) High-resolution magnetic resonance imaging (MRI) is a promising noninvasive modality that provides a broad overview of the pathologic changes associated with atherosclerosis in aortic and carotid arterial beds, including changes in vessel wall thickness, lumen diameter, vascular remodeling, and plaque composition (eg, fibrous tissue, calcium, LRNC, hemorrhage), (2, 5)

Lessons learned from imaging studies

For many years, the development of atherosclerotic plaques has been viewed as a persistent, progressive process. Relatively recent data from trials, gathered by using novel imaging techniques as therapeutic end points, challenge that view. Although atherosclerosis clearly progresses over time, its course is unpredictable and nonlinear. A large body of evidence supports the notion that the course of plaque development can be slowed or reversed. (5) This homeostatic process has become a target of therapeutic interventions aimed at promoting plaque regression and improving clinical outcomes. (5)

Secondary prevention. Emerging data from several multicenter, randomized clinical trials make a compelling argument that reducing LDL-C levels with statins in individuals with atherosclerosis correlates with stabilization of plaque and regression of existing atherosclerotic lesions. In the Randomized Evaluation of Atorvastatin in Patients with Coronary Heart Disease (REACH) study, a small number of Japanese patients with coronary artery disease and mildly elevated cholesterol (LDL-C between 100 and 140 mg/dL) were randomized to atorvastatin (10 to 20 mg) or usual care. (23) Both groups received identical frequency of aspirin, beta-blockers, angiotensin-converting enzyme inhibitors, and statin therapy. After 12 months of treatment, however, attained LDL-C levels were 83 mg/dL and 115 mg/dL in the atorvastatin and usual-care groups, respectively. A 34% reduction in mean baseline LDL-C levels in the atorvastatin group was accompanied by a modest reduction in mean plaque volume (-1.4 [mm.sup.3] [P = .55]), as determined by IVUS. No change in mean LDL-C was noted in the usual-care group, and plaque volume increased by 7.6 [mm.sup.3] (P<.01). (23) Comparison of intensive statin therapy (atorvastatin 80 mg) vs standard-dose therapy (pravastatin 40 mg) in patients with coronary artery disease in the Reversing Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial demonstrated that after 18 months of treatment, intensive statin therapy reduced LDL-C by 46% to 79 mg/dL and slowed plaque progression (-0.4% change in atheroma volume [P = .98]), as determined by IVOS, whereas standard-dose therapy reduced LDL-C by 25% to 110 mg/dL and resulted in plaque progression (2.7% increase in atheroma volume [P = .001]). Both therapies reduced inflammation, as measured by CRP, with a greater reduction noted with intensive therapy (36% vs 5% [P<.001]). (24)


In A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived CoronaryAtheroma Burden (ASTEROID), intensive therapy with rosuvastatin 40 mg for 2 years promoted regression of atherosclerosis on IVUS in patients with coronary artery disease. Intensive rosuvastatin therapy improved the lipid profile at 2 years, with a 53% reduction in LDL-C to 61 mg/dL and a 15% increase in HDL-C to 49 mg/dL. Plaque regression was demonstrated by a reduction in the mean percent atheroma volume from 39.6% at baseline to 38.6% at end point (P<.001); 64% of patients exhibited plaque regression on IVUS. Atheroma volume in the arterial segment with the greatest disease severity decreased from 65.1 to 59.0 [mm.sup.3] (P<.001); 78% of patients demonstrated regression on this parameter. (25) An example of plaque regression in ASTEROID is shown in FIGURE 3. (26)

Newer lipid-modifying agents also have been evaluated for their ability to change the natural course of atherosclerosis. The Pioglitazone Effect on Regression of Intravasculax Sonographic Coronary Obstruction Prospective Evaluation (PERISCOPE) trial compared the effects of the oral antidiabetic agents pioglitazone (a thiazolidinedione) and glimepiride (a sulfonylurea) on the progression of atherosclerosis in diabetic patients with coronary artery disease. Compared with glimepiride, treatment with pioglitazone resulted in significantly greater improvements in the lipid profile, slowing of progression of plaque volume on IVUS, and reduction in high-sensitivity CRP (hsCRP) levels. (27) The Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone (CHICAGO) trial in patients with diabetes mellitus even found that pioglitazone therapy was associated with stabilization of CIMT, whereas glimepiride therapy was associated with an increase in CIMT. (28)


Primary prevention. In individuals at risk for coronary heart disease, fibrous plaques progress to complicated lesions in their 20s and 30s and may predate clinical atherosclerosis by 20 years. (12) Prevention of coronary artery disease before clinical disease becomes apparent is an attractive concept that has been tested in randomized, controlled trials. A small, open-label trial evaluated changes in cholesterol levels and CIMT in asymptomatic individuals with moderately elevated LDL-C over 2 years of simvastatin treatment. Reductions in LDL-C, modest increases in HDL-C, and reductions in vessel wall thickness at 12 months were sustained through 24 months, suggesting a reduction in the rate of plaque progression. (29) The Measuring Effects on Intima-Media Thickness: An Evaluation of Rosuvastatin (METEOR) trial was a much larger (n = 984) and more rigorously controlled evaluation. (30) In METEOR, middle-aged adults at low risk for coronary artery disease (ie, asymptomatic, moderately elevated cholesterol [mean 154 mg/dL] and Framingham Risk Score <10%) but with subclinical atherosclerosis (maximum CIMT 1.2 to <3.5 mm on B-mode ultrasound) were randomly assigned to rosuvastatin 40 mg or placebo for 2 years. Rosuvastatin reduced baseline LDL-C by 49%, increased HDL-C by 8%, and slowed the progression of CIMT, compared with placebo, in this cohort of low-risk, asymptomatic patients. (30)

Positive effects of rosuvastatin on plaque volume and composition in asymptomatic patients with moderate hypercholesterolemia (LDL-C levels between 100 mg/dL and 250 mg/dL) were demonstrated by the Outcome of Rosuvastatin Treatment on Carotid Artery Atheroma: A Magnetic Resonance Imaging Observation (ORLON) trial. (31) Patients were randomized to receive a 2-year course of low-dose rosuvastatin (5 mg) or high-dose rosuvastatin (40 to 80 mg [NB: 80 mg is not a licensed dose of rosuvastatin]), and carotid arterial plaque volume and composition were measured with high-resolution MRI. After 2 years, mean baseline LDL-C levels were reduced by 60% and 38% for the high-dose and low-dose groups, respectively. Mean baseline HDL-C levels increased by 10% in the high-dose group and did not change substantively in the low-dose group. Patients identified on MRL as having plaques with an LRNC at baseline exhibited a 41% reduction in the proportion of the arterial wall consisting of LRNC. No evidence of LRNC development was found in patients without LRNC at baseline. Further, a significant increase in fibrous tissue content of the plaque was found. Overall, no significant changes in lumen volume or arterial wall thickness were observed; this indicates no progression of atherosclerosis. Some patients did exhibit plaque regression during rosuvastatin therapy, as shown in RGURE 4. (31) In addition, increases in HDL-C correlated with greater reductions in wall thickness. (31)

The effects of other lipid-modifying agents on atherosclerosis progression also have been studied. Micronized fenofibrate plus antihypertensive agents were compared with antihypertensive agents alone for effect on atherosclerosis progression in hypertensive patients with modestly increased LDL-C. Fenofibrate treatment significantly improved the lipid profile and lowered levels of biomarkers of inflammation, including hsCRP, compared with antihypertensive agents alone. In addition, fenofibrate stabilized measures of CIMT on B-mode ultrasound. (32) In another study, the effect of angiotensin-converting enzyme inhibitors, zofenopril and enalapril, on CIMT was examined in newly diagnosed hypertensive patients without atherosclerotic risk factors. After 5 years, zofenopril resulted in significantly slower progression of CIMT than occurred with enalapril. (33)

The combination of a cholesterol absorption inhibitor, ezetimibe, and statin therapy was compared with statin alone in a secondary analysis from the Stop Atherosclerosis in Native Diabetics Study (SANDS) in hypertensive adults with type 2 diabetes, LDL-C >100 mg/dL, and no prior cardiac events. (34) After 36 months, a high-dose statin alone or high-dose statin plus ezetimibe reduced LDL-C to similar aggressive targets (LDL-C [less than or equal to] 70 mg/dL) and slowed progression of CIMT in diabetic Native Americans to a similar degree, (34) whereas in the Ezetimibe and Simvastarin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial, combination therapy with ezetimibe and high-dose simvastatin did not result in slowing of progression of CIMT versus high-dose simvastatin monotherapy after 24 months of therapy, despite a significantly greater reduction in LDL-C with the combination (P < .01). (35) It is unclear why the combination of ezetimibe and statin therapy did not augment slowing of CIMT progression more than did statin monotherapy. It is possible that the CIMT was simply too thin (0.69 mm), or it may be unreasonable to expect significant slowing of disease with a mean attained LDL-C of 141 mg/dL in patients who, for the most part, had already been receiving chronic lipid-lowering therapy and lifestyle modification. Consistent with the former hypothesis, in the Carotid Atorvastatin Study in Hyperlipidemic Post-Menopausal Women: A Randomised Evaluation of Atorvastatin Versus Placebo (CASHMERE) trial, in which atorvastatin 80 mg dally was compared with placebo in postmenopausal women with similar mean baseline CIMT, there was no measurable difference in progression between groups. (36) Additionally, antidiabetic thiazolidinediones have been studied for their ability to promote plaque regression in patients with diabetes and preclinical atherosclerosis. (37) Rosiglitazone (37, 38) and pioglitazone (28) slowed progression of CIMT over 6 to 18 months of treatment in patients with type 2 diabetes and subclinical atherosclerosis.

The notion that statin therapy may reduce the risk for cardiac events in persons whose LDL-C levels are below current treatment thresholds, but who have elevated levels of CRP, was tested in Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER), in which adults with LDL-C levels <130 mg/dL and elevated hsCRP ([greater than or equal to] 2 mg/L) were randomized to rosuvastatin 20 mg or placebo. (39) The primary end point was a first major cardiac event. The JUPITER trial was halted prematurely after a median follow-up of 1.9 years, when it became apparent that rosuvastatin reduced the occurrence of a first major cardiac event by 44%, compared with placebo. Over the course of the trial, rosuvastatin reduced LDL-C by a median of 50% to a median 55 mg/dL and hsCRP by 37% to 1.8 mg/L. Benefits were consistent in various predefined subgroups across the risk spectrum, including women and non-Caucasians, and did not depend on the presence of metabolic syndrome or obesity. (39)


Development of atherosclerosis is a gradual, insidious process that begins in youth and continues through adulthood. Atherosclerosis is the net result of the interplay among increased intravascular inflammation, endothelial dysfunction, and a host of risk factors (including elevated LDL-C levels) that initiate a cycle of lipid accumulation in the subendothelial space and subsequently lead to fatty streak and plaque formation, plaque rupture and repair, thrombosis, and progressive stenosis. A substantial majority of all ischemic cardiac events are due to atherosclerosis. It is important to note that atherosclerotic plaques leading to these events are often mildly or moderately stenotic. Thus, intense research efforts are focused on understanding the pathophysiology and progression of atherosclerosis.

Application of novel technologies that image the arterial wall and plaque composition allows the visualization of atherosclerotic processes for the first lime. These novel imaging techniques have led to a growing number of rigorously controlled clinical studies designed to measure the effects of statins and other lipid-modifying agents on the progression of atherosclerosis in asymptomatic patients with subclinical disease. Further, we now are able to visualize and quantify the disease-modifying effects of statins and other drugs in patients with atherosclerosis and established coronary artery disease.

Despite the remarkable progress that has been achieved in the past decade, much work remains before we will fully understand atherosclerosis and will be able to prevent its occurrence. Only a few studies have directly compared one statin versus another (eg, REVERSAL, Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 [PROVE IT-TIMI 22], Atorvastatin versus Simvastatin on Atherosclerosis Progression [ASAP], and Incremental Decrease in End Points Through Aggressive Lipid Lowering [DEAL]), and only REVERSAL and ASAP compared the effects of different statins on the progression of atherosclerosis. (40-44) The Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin versus Atorvastatin (SATURN) is an ongoing randomized, controlled study that will compare the effects of rosuvastatin 40 mg and atorvastatin 80 mg on the progression and regression of atherosclerosis in patients with coronary artery disease by measuring changes in plaque volume using IVUS. (45)

The aim of disease-modifying treatment for atherosclerosis is to provide comprehensive cardiovascular risk factor management. A cornerstone in this approach is to reduce the burden of atherogenic lipoproteins to a level that fosters favorable changes in the size, composition, and biological activity of atherosclerotic plaque, with the ultimate goal of preventing first and recurrent episodes of cardiac events. Family physicians are uniquely positioned to apply this new information to treatment strategies that will reduce cardiovascular risk and improve outcomes for their patients.


The author thanks Sally Laden, MS, freelance medical writer, and Jinling Wu, PhD, and Judy Fallon, PharmD, from Scientific Connexions, Newtown, Pennsylvania, for medical writing support, and Maria D'Alassandro and Dolores Matthews from Scientific Connexions for editorial assistance, all funded by AstraZeneca LP, Wilmington, Delaware.


Dr Toth has disclosed that he has served as a consultant to Abbott, AstraZeneca, Merck, Merck-Schering-Plough, and Kowa Pharmaceuticals. He has served on the speakers bureaus of Abbott, AstraZeneca, Merck, Merck-Schering-Plough, GSK, and Takeda.


(1.) Hanke H, Lenz C, Finking G. The discovery of the pathophysiological aspects of atherosclerosis--a review. Acta Chir Belg. 2001;101:162-169.

(2.) Crouse JR III. Imaging atherosclerosis: state of the art. J Lipid Res. 2006;47:1677-1699.

(3.) Burke AP, Kolodgie FD, Farb A, et al. Healed plaque ruptures and sudden coronary death: evidence that subclinical rupture has a role in plaque progression. Circulation. 2001;103:934-940.

(4.) Eggen DA, Solberg LA. Variation of atheroselerosis with age, Lab Invest. 1968;18:571-579.

(5.) Ibanez B, Vilahur G, Badimon JJ. Plaque progression and regression in atherothrombosis. J Thromb Haemost. 2007;5(suppl 1):292-299.

(6.) Virmani R, Kolodgie FD, Burke AP, et al. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2000;20:1262-1275.

(7.) Hadi HAR, Cart CS, Suwaidi JA. Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome. Vase Health Risk Manag. 2005;1:183-198.

(8.) Randolph GJ, Furie MB. A soluble gradient of endogenous monocyte chemoattractant protein-1 promotes the transendothelial migration of monocytes in vitro. J Immunol. 1995;155:3610-3618.

(9.) Stocker R, Keaney JF Jr. Role of oxidative modifications in atherosclerosis. Physiol Rev. 2004;84:13811478.

(10.) de Winther MP, Hofker MH. Scavenging new insights into atherogenesis. J Clin invest. 2000;105:10391041.

(11.) Koenig W, Khuseyinova N. Biomarkers of atherosclerotic plaque instability and rupture. Arterioscler Thromb Vasc Biol. 2007;27:15-26.

(12.) McGill HC Jr, McMahan CA, Gidding SS. Preventing heart disease in the 21st century: implications of the Pathohiological Determinants of Atherosclerosis in Youth (PDAY) study. Circulation. 2008;117:12161227.

(13.) Toth PP. When high is low: raising low levels of highdensity lipoprotein cholesterol. Curt Cardiol Rep. 2000; 10:488-496.

(14.) Toth PP. Novel therapies for increasing serum levels of HDL. Endocrinol Metab Clin North Am. 2009;38:151-170.

(15.) Nicholls SJ, Tuzcu EM, Sipahi I, et al. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis, JAMA. 2007;297:499-608.

(16.) Brown BG, Stukovsky KH, Zhao XQ. Simultaneous low-density lipoprotein-C lowering and high-density lipoprotein-C elevation for optimum cardiovascular disease prevention with various drug classes, and their combinations: a meta-analysis of 23 randomized lipid trials. Curr Opin Lipidol. 2006; 17:631636.

(17.) Biasucci LM. CDC/AHA workshop on markers of inflammation and cardiovascular disease, Circulation. 2004;110:e560-e567.

(18.) Theroux P, Fuster V. Acute coronary syndromes: tinstable angina and non-Q-wave myocardial infarction. Circulation. 1998;97:1195-1206.

(19.) Cheruvu PK, Finn AV, Gardner C, et al. Frequency and distribution of thin-cap fibroathemma and ruptured plaques in human coronary arteries: a pathologic study, J Am Coll Cardiol. 2007;50:940-949.

(20.) Ibanez B, Navarro F, Cordoba M, et al. Tako-tsubo transient left ventricular apical ballooning: is intravascular ultrasound the key to resolve the enigma? Heart. 2005;91:102-104.

(21.) Brown BG, Zhao X-Q, Sacco DE, et al. Lipid lowering and plaque regression: new insights into prevention of plaque disruption and clinical events in coronary disease. Circulation. 1993;87:1781-1791.

(22.) Insull W Jr. The pathology of atherosclerosis: plaque development and plaque responses to medical treatment. Am J Med. 2009;122:S3-S14.

(23.) Yamada T, Azuma A, Sasaki S, et al, for the REACH Study Group. Randomized evaluation of atorvastalin in patients with coronary heart disease: a serial intravascular ultrasound study. Circ J. 2007;71:18451850.

(24.) Nissen SE, Tuzcu EM, Schoanhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial, JAMA. 2004;291:1071-1080.

(25.) Nissen SE, Nicholls SJ, Sipahi I, et al, for the ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295:1556-1565.

(26.) Sipahi I, Nicholis SJ, Tuzcu EM, et al. interpreting the ASTEROID trial: coronary atherosclerosis can regress with very intensive stalin therapy. Cleve Clin J Med. 2006;73:937-944.

(27.) Nissen SE, Nicholls SJ, Wolski K, et al, for the PERiSCOPE Investigators. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes. JAMA. 2008;299:1561-1573.

(28.) Mazzone T, Meyer PM, Feinstein SB, et al. Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial. JAMA. 2006;296:2572-2581.

(29.) Corti R, Fuster V, Fayad ZA, et al. Lipid lowering by simvastatin induces regression of human atherosclerotic lesions: two years' follow-up by high-resolution noninvasive magnetic resonance imaging. Circulation. 2002;106:2884-2887.

(30.) Crouse JR III, Raichlen JS, Riley WA, et al, for the METEOR Study Group. Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR trial. JAMA. 2007;297:1344-1353.

(31.) Underhill HR, Yuan C, Zhao X-Q, et al. Effect of rosuvastatin therapy on carotid plaque morphology and composition in moderately hypercholesteroleimic patients: a high-resolution magnetic resonance imaging trial. Am Heart J. 2008;155:564.e1-584.e8.

(32.) Zhu S, Su G, Meng QH. Inhibitory effects of micronized fenofibrate on carotid atherosdemsis in patients with essential hypertension. Clin Chem. 2006;52:2036-2042.

(33.) Napoli C, Bruzzese G, Ignarro LJ, et al. Long-term treatment with sulfhydryl angiotensin-converting enzyme inhibition reduces carotid intima-media thickening and improves the nitric oxide/oxidative stress pathways in newly diagnosed patients with mild to moderate primary hypertension. Am Heart J. 2008;156:1154.e1-1154.e8.

(34.) Fleg JL, Mete M, Howard BV, et al. Effect of statins alone versus statins plus ezetimibe on carotid atherosclerosis in type 2 diabetes: the SANDS (Stop Atherosclerosis in Native Diabetics Study) trial. J Am Coll Cardiol. 2008;52:2198-2205.

(35.) Kastelein JJP, Akdim F, Stroes ESG, et al, for the ENHANCE Investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008;358:1431-1443.

(36.) CASHMERE trial results available at

(37.) Stocker DJ, Taylor AJ, Langley RW, et al. A randomized trial of the effects of rosiglitazone and metformin on inflammation and subclinical atherosclerosis in patients with type 2 diabetes. Am Heart J. 2007; 153:445.e1-445.e6.

(38.) Hedblad B, Zambanini A, Nilsson P, et al. Rosiglitazone and carotid IMT progression rate in a mixed cohort of patients with type 2 diabetes and the insulin resistance syndrome: main results from the Rosiglitazone Atherosclerosis study. J Intern Med. 2007;261:293-305.

(39.) Ridker PM, Danielson E, Fonseca FAH, et al, for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-2207.

(40.) Cannon CE Braunwald E, McCabe CH, et al. intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504.

(41.) Pedersen TR, Faergeman O, Kastelein JJP, et al. Highdose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial, JAMA. 2005;294:2437-2445.

(42.) Smilde TJ, van Wissen S, Wollersheim H, et al. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet. 2001;357:577-581.

(43.) Nicholls SJ, Tuzcu EM, Sipahi I, et al. Effects of obesity on lipid-lowering, anti-inflammatory, and antiatherosclerotic benefits of atorvastatin or pravastatin in patients with coronary artery disease (from the REVERSAL Study). Am J Cardiol. 2006;97:1563-1557.

(44.) Schoenhagan P, Tuzcu EM, Apperson-Hansen C, et al. Determinants of arterial wall remodeling during lipid-lowering therapy: serial intravascular ultrasound observations from the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial. Circulation. 2006;113:2826-2834.

(45.) Nicholis S, Ralchlen J, Ballantyne C, et al. Intravascular ultrasound evaluation of the effect of rosuvastatin versus atorvastatin on progression of coronary atherosclerosis: design of the SATURN study. Atherosclerosis Suppl. 2008;9:202. Abstract PO48-746.


Peter R Toth, MD, PhD, FAAFP, FICA, FNLA, FCCP, FAHA, FACC Director of Preventive Cardiology Sterling Rock Falls Clinic, Ltd. Sterling, IL 61081 Email:

Peter R Toth, MD, PhD,



Clinical Associate Professor

Department of Family and

Community Medicine

University of Illinois School

of Medicine

Peoria, Illinois

Director of Preventive Cardiology

Sterling Rock Falls Clinic

Sterling, Illinois
COPYRIGHT 2009 Quadrant Healthcom, Inc.
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2009 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Toth, Peter P.
Publication:Journal of Family Practice
Article Type:Disease/Disorder overview
Geographic Code:1USA
Date:Nov 1, 2009
Previous Article:Introduction.
Next Article:Assessing cardiovascular risk one patient at a time.

Terms of use | Privacy policy | Copyright © 2020 Farlex, Inc. | Feedback | For webmasters