Insights into atherosclerosis from invasive and non-invasive imaging studies: Should we treat subclinical atherosclerosis?

Atherosclerosis 205 (2009) 349–356

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Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis

Review

Insights into atherosclerosis from invasive and non-invasive imaging studies: Should we treat subclinical atherosclerosis? Raul D. Santos a , Khurram Nasir b,∗ a b

Lipid Clinic Heart Institute (InCor) University, Sao Paulo Medical School Hospital, Sao Paulo, Brazil Department of Radiology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02115, USA

a r t i c l e

i n f o

Article history: Received 16 May 2008 Received in revised form 24 November 2008 Accepted 8 December 2008 Available online 14 December 2008 Keywords: Carotid intima–media thickness Coronary artery calcification Intravascular ultrasound Magnetic resonance imaging Low-density lipoprotein cholesterol Statins Subclinical atherosclerosis

a b s t r a c t Although atherosclerosis is associated with the elderly, young adults with hypercholesterolemia and other cardiovascular risk factors may have subclinical atherosclerotic disease. In many cases, when two or more risk factors are present, conventional risk assessment using the Framingham score, that was not designed to detect atherosclerotic plaques, may significantly underestimate the extent of atherosclerosis. Several non-invasive imaging technologies now make it possible to identify subclinical atherosclerosis before symptoms appear or major vascular events occur. These include B-mode ultrasound to measure carotid intima–media thickness, computed tomography to measure coronary artery calcification, and high-resolution magnetic resonance imaging to evaluate plaque size and composition. On the basis of available evidence, assessment of subclinical atherosclerosis should be considered in persons judged to be at intermediate risk by Framingham score, because test results may influence risk stratification and, consequently, the intensity of therapeutic intervention. Patients with significant subclinical atherosclerosis are at high risk and, like other high-risk individuals, should receive treatment designed to achieve aggressive low-density lipoprotein cholesterol targets. Clinical studies show that statin therapy may delay atherosclerosis progression and that intensive therapy with rosuvastatin may actually reverse the atherosclerotic process. © 2009 Published by Elsevier Ireland Ltd.

Contents 1. 2. 3. 4. 5.

6. 7.

Overview of the atherosclerotic process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Detecting subclinical atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Impact of lipid-lowering therapy on atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical trials using imaging technologies in CHD patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical trials using imaging technologies in asymptomatic patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Carotid IMT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. High-resolution magnetic resonance imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Coronary artery calcification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Implications for treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Abbreviations: CAC, coronary artery calcification; CACS, coronary artery calcium scores; CAD, coronary artery disease; CHD, coronary heart disease; CRP, C-reactive protein; CT, computer tomography; HDL, high-density lipoprotein; IMT, intima–media thickness; IVUS, intravascular ultrasound; LDL, low-density lipoprotein. ∗ Corresponding author. Tel.: +1 617 667 3532; fax: +1 617 667 3537. E-mail address: [email protected] (K. Nasir). 0021-9150/$ – see front matter © 2009 Published by Elsevier Ireland Ltd. doi:10.1016/j.atherosclerosis.2008.12.017

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Coronary heart disease (CHD) is the single largest killer of American men and women and is responsible for one of every five deaths among Americans [1]. Approximately 700,000 Americans have a first coronary attack each year, while 500,000 have a recurrent event [1]. Individuals who have had a coronary event have a sudden death rate that is four to six times that of the general population. Unfortunately, sudden death is a common manifestation of CHD: according to the National Center for Health Statistics, 325,000 CHD

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deaths occur out of hospital or in hospital emergency departments annually [1]. About two-thirds of unexpected cardiac deaths occur without prior recognition of cardiac disease, and 50% of men and 64% of women who die suddenly of CHD had no previous manifestation of disease [1]. Although the prevalence of CHD increases with age, many younger adults also will experience acute coronary events. For these reasons, attention in the past decade has shifted from a secondary-prevention strategy to one focusing on primary prevention, i.e., preventing vascular events from occurring in the first place [2]. 1. Overview of the atherosclerotic process CHD is a clinical manifestation of atherosclerosis—a chronic and progressive vascular disease that predisposes patients to cerebrovascular disease and peripheral arterial disease, in addition to CHD. Atherosclerosis is a diffuse, systemic disease involving the vasculature of the heart, brain, and peripheral circulation. In general, atherogenesis begins at sites of endothelial injury, which most often results from local shear forces and then is exacerbated by elevated low-density lipoprotein (LDL) cholesterol, hypertension, smoking, diabetes mellitus, or infection [3,4]. Impairment in local endothelial function increases the adhesiveness and permeability of the endothelium, thereby providing a nidus for monocyte and lipid accumulation into the underlying arterial intima [5]. The monocytes subsequently differentiate into macrophages, ingest LDL and other particles, and take on the appearance of lipid-laden foam cells. T-cells infiltrating into the developing lesion may recognize antigenic determinants presented by the activated macrophages and mount a cell-mediated immune response [4,5]. Inflammatory cytokines and growth factors, pro-

duced by either activated T-cells and macrophages within the lesion or platelets adhering to the endothelial surface, stimulate smooth muscle cell migration and proliferation. The smooth muscle cells, in turn, secrete extracellular matrix components that form a fibrous cap over the underlying atherosclerotic lesion. As foam cells accumulate high intracellular cholesterol levels in conjunction with LDL ingestion, they undergo apoptosis, releasing their lipid contents to form an extracellular lipid core that is contained under the fibrous cap (Fig. 1) [6,7]. The probability of an acute coronary event is related to the total atherosclerotic plaque burden and to the vulnerability of individual plaques to rupture [2,8]. In general, atherosclerotic plaques with thin fibrous caps, large lipid cores, and numerous macrophages are most likely to rupture, whereas those with thick fibrous caps, small lipid cores, and high smooth muscle cell content are more stable [6,7]. Once plaque ruptures, the thrombogenic contents of the plaque’s extracellular matrix and lipid core are exposed to platelets and coagulation factors in circulating blood, initiating a potentially fatal cascade of events. A densely packed thrombus containing both platelets and a cross-linked fibrin network may also precipitate a fatal cardiovascular event [5–7]. Many factors contribute to whether plaque rupture will be clinically silent or will precipitate a major event, including the extent of the rupture, size of the thrombus, and diameter and location of the affected artery, as well as the activity of the endogenous fibrinolytic system that attempts to dissolve the thrombus. Although atherosclerosis tends to develop early in life and progresses with age, the progression rate is not entirely predictable and differs among individuals. An understanding of the characteristics of patients at risk has further broadened the paradigm of preventive cardiology beyond an evaluation of risk factors and occurrence of silent myocardial ischemia due to coronary obstruction to include

Fig. 1. Schematic of plaque rupture and thrombosis. Reprinted with permission from Libby P. Nature 2002;420:868–74.

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the detection of subclinical atherosclerosis using parameters such as plaque burden and level of inflammation [9]. 2. Detecting subclinical atherosclerosis Despite the importance of risk-factor identification for CHD risk prediction, most individuals who suffer an acute coronary event were not considered to be at high risk for clinical events [10,11]. Previous symptoms are found in <50% of individuals who suffer a first coronary event [1]. One way to supplement current methods of global risk assessment is to identify more clearly high-risk individuals with preclinical atherosclerosis. Identification of such patients may result in more accurate stratification of persons requiring aggressive interventions and appropriate distribution of pharmacotherapy in societies with finite resources. Fortunately, atherosclerosis can be diagnosed precociously when sensitive non-invasive imaging modalities are used to supplement clinical risk-factor evaluation. The emergence of several new technologies now allows earlier visualization of plaque burden. B-mode ultrasound measurement of carotid intima–media thickness (IMT) and computed tomography (CT)-based measurement of coronary artery calcification (CAC) are non-invasive methods for estimating plaque burden. CAC is an excellent surrogate for underlying coronary atherosclerotic burden, while carotid IMT reflects the thickening of the arterial intima and media during the atherosclerotic process. Multiple studies have demonstrated that both carotid IMT and CAC are strong and independent predictors of cardiovascular events, including myocardial infarction and sudden death [12–15]. In a meta-analysis of eight population-based studies, Lorenz et al. [16] showed that every 0.1-mm increase in IMT in the common carotid artery increases age, gender and atherosclerosis risk factors adjusted risk of myocardial infarction by 10% and stroke by 13%. Baldassare et al. [17] conducted a longitudinal study of 1969 consecutive dyslipidemic patients who underwent carotid ultrasound at a lipid clinic. They found that assessing maximum IMT improved the prediction of the Framingham risk score categories. Patients considered to be at intermediate risk based on the Framingham assessment were upgraded to high-risk status when maximum IMT was above the 60th percentile of the maximum IMT distribution in men and above the 80th percentile in women [17]. In certain populations with subclinical atherosclerosis, cardiovascular risk is underestimated using current risk-stratification strategies. Nasir et al. [18] investigated the classification of cardiovascular risk across a continuum of CAC scores. The study population consisted of 1611 asymptomatic individuals with a mean age of 53 years, 67% of whom were men. Overall, 59% of participants with CAC ≥400 and 73% of participants with CAC scores ≥75th percentile did not qualify for pharmacotherapy based on the guidelines of the Third Adult Treatment Panel of the National Cholesterol Education Program (NCEP ATP III) [19], despite the fact that the presence of such atherosclerotic burden is associated with at least time-relative risk of hard CHD compared with persons with no CAC [20]. In fact, 27% of subjects with CAC ≥400 were classified as low risk according to the ATP guidelines. Similar results were found in a study by Grewal et al. [21], in which 23% of asymptomatic individuals with high evidence of subclinical atherosclerosis were considered low risk by Framingham estimates and thus not eligible for lipid-lowering pharmacotherapy. A clinical expert consensus document by the American College of Cardiology Foundation and the American Heart Association provided pooled data for outcome with CAC scores [20]. The report confirmed a very low risk of events (<0.5%) in the absence of CAC. On the other hand, the summary relative risk was, respectively, 4.3

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(95% confidence interval, 3.1–6.1) and 7.2 (95% confidence interval, 5.2–9.9, p < 0.0001) with intermediate and high levels of CAC, compared with low levels (CAC score = 0). The report also noted that CAC scores added significantly to risk prediction beyond traditional Framingham risk scores, particularly among persons considered to be at intermediate risk [20]. More importantly, the consensus document highlighted the fact that in the absence of CAC, patients had a very low risk of future hard CHD events (49 events/11,815 persons, 0.4%), reinforcing the notion that the absence of significant atherosclerosis results in a very low overall cardiovascular risk. Even in higher-risk groups such as persons with diabetes, the absence of CAC is associated with a low future CHD risk, similar to that of nondiabetic persons [22]. 3. Impact of lipid-lowering therapy on atherosclerosis Patients with established CHD and other high-risk equivalent conditions, including diabetes mellitus, chronic kidney disease, peripheral arterial disease, and cerebrovascular disease, require aggressive intervention in order to reduce the risk of coronary events [19,23]. Statins are the most effective pharmacologic agents for reducing LDL-cholesterol, but they have additional beneficial actions on the overall lipid profile, including raising high-density lipoprotein (HDL) cholesterol. Studies with imaging technologies have shown that statins can delay the progression of atherosclerosis or even modestly reverse it. Nicholls et al. [24] pooled data from four prospective randomized trials, in which 1455 patients with angiographic evidence of coronary artery disease (CAD) underwent serial measurements using intravascular ultrasound (IVUS) while receiving statins for 18 or 24 months. The rate of change in plaque volume was independently associated with the LDLcholesterol level achieved during treatment and the change from baseline in HDL-cholesterol. Substantial plaque regression, defined as a ≥5% reduction in plaque volume, was observed in patients who achieved LDL-cholesterol levels below the mean of 87.5 mg/dl and HDL-cholesterol increases above the mean of 7.5%. These findings suggest that the benefits of statin therapy on atherosclerosis may be derived from both decreases in LDL-cholesterol and increases in HDL-cholesterol. Statins also have a variety of effects unrelated to cholesterol modification, which may contribute to their protective effects against atherosclerosis progression. For example, they inhibit endothelial dysfunction and modulate inflammation in the arterial wall, resulting in reduced production of proinflammatory chemokines and cytokines, fewer intraplaque macrophages and T-cells, and less secretion of matrix metalloproteinases by macrophages [25]. Whereas improvements in atherosclerosis progression and clinical outcome are clearly related to the effects of statins on atherogenic lipoproteins, these benefits may also reflect the impact of statins on arterial inflammation. In the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial [26], the rate of atherosclerosis progression measured by IVUS during an 18-month follow-up of 502 CAD patients treated with either moderate statin therapy (pravastatin 40 mg/day) or intensive statin therapy (atorvastatin 80 mg/day) was correlated with changes in both LDL-cholesterol and Creactive protein (CRP), a biomarker of systemic inflammation. Patients who achieved greater-than-median reductions in both LDL-cholesterol and CRP had significantly less atherosclerosis progression than those with less-than-median reductions of these markers (p = 0.001). Comparable results were obtained in the Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial [27], which tested the effects of the same statin treatment strategy used in REVERSAL (an imaging sub-study of PROVE-IT TIMI 22) upon clinical events in

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a cohort of 3745 patients with acute coronary syndromes. Patients who achieved LDL-cholesterol levels of <70 mg/dl and CRP <2 mg/l had a significantly lower risk of recurrent events than those who achieved either or neither of these levels (p < 0.001 for trend). These two studies show that intensive statin therapy was more likely than moderate therapy to allow achievement of low LDL-cholesterol, low CRP levels, less atherosclerosis progression and most important less cardiovascular events. The benefit of statin therapy on atherosclerosis progression may be evident as early as 6 months after initiation of therapy. Mercuri et al. [28] performed serial carotid IMT measurements every 6 months for up to 3 years in a cohort of 305 asymptomatic hypercholesterolemic patients who had been randomly assigned to pravastatin or placebo. Atherosclerosis progression, measured from the mean of 12 maximum carotid IMT values at each assessment, was significantly slower in the statin group than in the placebo group (−0.0043 mm/year vs. +0.009 mm/year, p < 0.0007). 4. Clinical trials using imaging technologies in CHD patients Angiographic evidence that statin therapy reduces the rate of atherosclerosis progression defined as a ≥10% increment in percent diameter stenosis was obtained in a series of studies conducted in the 1990s [29–33]. The Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) study [34] used carotid IMT to compare intensive statin therapy with atorvastatin 80 mg/day and moderate statin therapy with pravastatin 40 mg/day in 161 patients who met NCEP criteria for lipid-lowering drug therapy. Intensive therapy reduced carotid IMT from baseline, whereas carotid IMT increased in the moderate-therapy group over the 12-month follow-up (−0.034 mm vs. +0.025 mm, p = 0.03). In the REVERSAL study, IVUS showed that intensive statin therapy with 80 mg atorvastatin, on average (no non-inferiority limits), prevented atherosclerosis progression defined as a non-significant change in percent atheroma volume from baseline, median (95% CI): 0.2 (−0.3 to 0.5) [35]. This was not the case in less intensive lipid lowering treatment with 40 mg pravastatin where percent atheroma volume significantly increased after the 18-month follow-up, median (95% CI): 1.6 (1.2–2.2). A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID) [36] evaluated intensive therapy with rosuvastatin 40 mg/day in a study population comparable to that of REVERSAL. Rosuvastatin reduced LDL-cholesterol to a mean of 60.8 mg/dl – a reduction of 53% from baseline – and raised HDL-cholesterol to a mean of 49.0 mg/dl—an increase of 15% from baseline. Unlike REVERSAL, these lipid changes were associated with statistically significant regression of atherosclerosis [36,37]. Over 2 years of follow-up, rosuvastatin significantly reduced the median of percent atheroma volume by 0.79% from baseline (p < 0.001). Approximately 64% of rosuvastatin-treated patients showed regression as measured by reductions in percent atheroma volume versus baseline, and 78% showed reduction when measured by change in atheroma volume in the subsegment with greatest disease severity (Fig. 2) [37]. The regression in atherosclerosis achieved in ASTEROID is consistent with the linear relationship between mean achieved LDL-cholesterol and median change in atheroma volume seen across IVUS studies (r2 = 0.97; p < 0.001) [36]. These studies in patients with evidence of CAD show that moderate statin therapy reduces atherosclerosis progression relative to placebo, and that intensive therapy further reduces progression. Moreover, based on findings from ASTEROID, intensive therapy, which results in both very low LDL-cholesterol levels and elevated HDL levels, appears to promote regression of coronary atherosclerosis.

Fig. 2. Disease regression in the ASTEROID trial. Most patients had regression with rosuvastatin 40 mg/dl. Reprinted with permission from Sipahi I, et al. Cleve Clin J Med 2006;73:937–44.

5. Clinical trials using imaging technologies in asymptomatic patients 5.1. Carotid IMT A number of imaging studies also evaluated the benefits of statin therapy in patients with subclinical atherosclerosis (Table 1) [38–43]. The Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) trial [38] compared intensive therapy with atorvastatin 80 mg/day versus moderate therapy with simvastatin 40 mg/day in 325 patients with familial hypercholesterolemia. Mean age was 48 ± 10 years, baseline LDL-cholesterol 311 ± 71 mg/dl and mean overall IMT was 0.93 ± 0.20 mm. Atorvastatin reduced mean carotid IMT by 0.031 mm from baseline during the 2-year study, whereas carotid IMT increased by a mean of 0.036 mm in the simvastatin group (p = 0.0005). Carotid IMT was also used in the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial [44], which randomly assigned 720 patients with familial hypercholesterolemia to intensive treatment with simvastatin 80 mg/day with or without ezetimibe 10 mg/day for 2 years. Mean age was 46 ± 10 years, baseline LDL-cholesterol 318 ± 65 mg/dl and mean overall IMT was 0.70 ± 0.13 mm. Recently published results showed that combination therapy with simvastatin plus ezetimibe did not slow the progression of atherosclerosis compared with simvastatin monotherapy, despite greater decreases in LDL-cholesterol. Moreover, although the highest approved dose of simvastatin was used in both arms of the trial, both treatment groups showed significant progression of atherosclerosis compared with baseline over the course of the trial [44]. Whether the negative results were due to population selection or lack of effectiveness of ezetimibe on atherosclerosis remains to be determined.

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Table 1 Impact of Statin therapy on measures of subclinical atherosclerosis in asymptomatic patients [38–43]. Method

Study

Patients

Treatment

Follow-up

Results

Carotid ultrasound

ASAP

325 with familial hypercholesterolemia

Atorvastatin 80 mg Simvastatin 40 mg

2 years

METEOR

984 with low CHD risk and moderate carotid IMT thickening 21 asymptomatic subjects with atherosclerotic plaques in the carotid arteries and the aorta

Rosuvastatin 40 mg Placebo

2 years

Simvastatin dose to reduce LDL-cholesterol 30–35%

2 years

Difference in mean carotid IMT favoring atorvastatin (−0.031 mm vs. +0.036 mm; p 0.0005) Difference in maximum carotid IMT at 12 sites favoring rosuvastatin; (−0.0014 vs. +0.0131; p < 0.001) Significant (p < 0.01) reductions in maximal vessel wall thickness and vessel wall area at 12 months (10% and 11% for aortic and 8% and 11% for carotid plaques, respectively), without changes in lumen area Change in carotid wall volume and decrease in lipid-rich necrotic core favoring high-dose rosuvastatin Change in coronary artery calcium score did not differ between treatments

MRI

Corti et al.

MRI

ORION

43 with radiographic evidence of carotid stenosis

Rosuvastatin 40/80 mg rosuvastatin 5 mg

2 years

EBCT

BELLES

615 postmenopausal women with LDL-cholesterol above NCEP targets

Atorvastatin 80 mg pravastatin 40 mg

1 year

ASAP = Atorvastatin versus Simvastatin on Atherosclerosis Progression; BELLES = Beyond Endorsed Lipid Lowering With EBT Scanning; CHD = coronary heart disease; EBCT = electron-beam computed tomography; IMT = intima–media thickness; LDL = low-density lipoprotein; METEOR = Measuring Effects on Intima–Media Thickness: an Evaluation of Rosuvastatin; MRI = magnetic resonance imaging; NCEP = National Cholesterol Education Program; ORION = Outcome of Rosuvastatin treatment on carotid artery atheroma: a magnetic resonance Imaging Observation.

The Measuring Effects on Intima–Media Thickness: an Evaluation of Rosuvastatin (METEOR) trial [39] used carotid IMT to evaluate intensive statin therapy with rosuvastatin 40 mg/day in 984 subjects, mean age 57 ± 6 years with subclinical atherosclerosis. Enrollees were characterized by a 10-year CHD risk of< 10% on Framingham risk assessment, modest carotid IMT thickening with a maximum thickness of 1.2 to <3.5 mm (the mean of maximum IMT on 12 carotid sites was roughly 1.16 mm in both groups), and LDL-cholesterol of 120 to <190 mg/dl (155 mg/dl on average). Subjects were randomly assigned to rosuvastatin or placebo for 2 years, resulting in achieved LDL-cholesterol levels of 78 and 152 mg/dl, respectively (p < 0.001). After 2 years, the mean of the maximum IMT measured at 12 carotid sites – the primary efficacy variable – was essentially unchanged in the rosuvastatin group (p = 0.32 vs. baseline) but increased in the placebo group (−0.0014 mm/year vs. +0.0131 mm/year, p < 0.001 vs. rosuvastatin group) [39]. Similarly, the maximum IMT at the carotid bulb (−0.0040 mm/year vs. +0.0172 mm/year, p < 0.001) and internal carotid artery (+0.0039 mm/year vs. +0.0145 mm/year, p = 0.02) favored rosuvastatin (which did not progress vs. baseline) over placebo. After 2 years, maximum IMT measured at the common carotid artery decreased significantly in the rosuvastatin group – i.e., regressed – and was again different from placebo (−0.0038 mm/year vs. +0.0084 mm/year, respectively; p < 0.001) [39]. These results suggest that intensive therapy with rosuvastatin can significantly reduce the progression of carotid IMT in subjects with subclinical atherosclerosis. 5.2. High-resolution magnetic resonance imaging Changes in atherosclerotic plaque by statin treatment can be detected in the carotids and in the thoracic aorta by high-resolution magnetic resonance imaging (MRI). Corti et al. [40] evaluated the effect of simvastatin treatment on atherosclerotic plaque size by MRI after 2 years in 21 subjects with LDL-C >130 mg/dl. The effects of simvastatin on these atherosclerotic lesions were evaluated as changes versus baseline in lumen area, vessel wall thickness, and vessel wall area by MRI. Maximal reduction of plasma LDL-C by simvastatin, 38% was achieved after approximately 6 weeks of therapy and maintained thereafter throughout the study. Significant (P < 0.01) reductions in maximal vessel wall thickness and vessel wall area at 12 months (10% and 11% for aortic and 8% and 11% for

carotid plaques, respectively), without changes in lumen area, have been reported. Further decreases in vessel wall thickness and vessel wall area ranging from 12% to 20% were observed at 18 and 24 months. A slight but significant increase (ranging from 4% to 6%) in lumen area was seen in both carotid and aortic lesions at these later time points. The Outcome of Rosuvastatin treatment on carotid artery atheroma: a magnetic resonance Imaging ObservatioN (ORION) study [41,42] used high-resolution MRI to compare the effects of low-dose (5 mg) and high-dose (40/80 mg) rosuvastatin therapy on carotid atherosclerosis in 43 patients with LDL-cholesterol levels of 100–250 mg/dl and evidence of carotid stenosis detected by ultrasound or plaque with a lipid-rich necrotic core detected by MRI. The mean percent change in carotid artery wall volume after 2 years of treatment was 3.0% and 2.3% with low-dose and high-dose rosuvastatin, respectively, but the difference was not statistically significant. However, subjects with reductions from baseline in carotid wall volume had significantly lower LDLcholesterol concentrations on treatment than those whose wall volume increased (69 mg/dl vs. 84 mg/dl) [42]. The size of the lipid-rich necrotic core in the 18 patients with such lesions at baseline declined by 46.7% with low-dose rosuvastatin (p = NS) and by 37.0% with high-dose rosuvastatin (p = 0.014). Moreover, no other patients developed new plaque with a lipid-rich necrotic core during rosuvastatin therapy [41]. These findings suggest that intensive therapy with a highly efficacious statin not only arrests atherosclerosis progression but also may produce changes in plaque composition consistent with a reduction in vulnerability to rupture. 5.3. Coronary artery calcification Callister et al. [45] conducted a retrospective evaluation of the impact of statin therapy on CAC in a cohort of 149 subjects without CAD, which included 105 patients treated with statins and 44 patients who were untreated. Over a 12- to 15-month period, coronary artery calcium-volume scores increased from baseline by 52% in the untreated group and by 25% in those treated with statins who achieved LDL-cholesterol levels ≥120 mg/dl (mean, 139 mg/dl), but fell by 7% when statin therapy reduced LDLcholesterol to <120 mg/dl (mean, 100 mg/dl). Despite these early findings, prospective studies have not shown that intensive statin

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therapy is more effective than moderate statin therapy in reducing progression of CAC. In the Beyond Endorsed Lipid Lowering with EBT Scanning (BELLES) trial [43], 615 postmenopausal women with LDL-cholesterol above NCEP-defined target levels were randomly assigned to receive high-dose (atorvastatin 80 mg/day) or moderate-dose (pravastatin 40 mg/day) therapy for 12 months. As expected, the achieved LDL-cholesterol was significantly lower with high-dose atorvastatin than with moderate dose pravastatin (92 mg/dl vs. 129 mg/dl, p < 0.0001). Nevertheless, changes in CAC measured by electron-beam CT did not differ significantly between treatments [43]. Raggi et al. [46] showed in 495 asymptomatic subjects receiving statin treatment, followed up for a mean 3.2 years, that CAC progression was associated with an increased risk of myocardial infarction despite similar on treatment LDL-cholesterol levels. Relative risk of having an infarction in the presence of CAC progression was 17.2-fold (95% CI: 4.1–71.2) higher than without CAC progression (P < 0.0001). In a Cox proportional hazard model, a score change >15% per year (p < 0.001) was an independent predictor of time to myocardial infarction. This study suggests that although statin therapy might not change CAC evolution, CAC progression may be a good prognostic marker even under statin treatment. In the St. Francis Heart Study [47], moderate statin therapy with atorvastatin 20 mg/day for 4 years did not affect CAC scores in subjects with severe subclinical atherosclerosis defined by age- and gender-adjusted coronary calcification at or above the 80th percentile. Overall there was no reduction in clinical events in subjects with CAC, but in subjects with baseline calcium scores (CACS) >400 (47% of the study population), treatment reduced the incidence of all cardiovascular events by 42% (20 of 229 [8.7%] vs. 36 of 240 [15.0%], p = 0.046). These results suggest that statin therapy may not change CAC progression but may benefit subjects with increased subclinical plaque burden and at high risk of clinical events. Indeed Nicholls et al. reported that patients with a greater amount of CAC evaluated by IVUS have more extensive plaque and are less likely to

undergo changes in response to intensive risk-factor modification [48]. These findings suggests that CAC identifies patients at high cardiovascular risk but cannot be used as a marker to track the effectiveness of statin therapy, at least in patients who already have substantial calcification. However, other effects of statins, such as reduction of plaque inflammation and activity, need to be considered in these patients [49]. It is important to keep in mind that persons with a high burden of CAC are at a much higher risk than those without CAC [50]. These patients are candidates for aggressive treatment with statins, which have been shown to effectively reduce the risk of future events in primary-prevention as well as in secondary-prevention cohorts. Future studies with intensive statin therapy may need to enroll subjects at earlier stages of subclinical atherosclerosis and follow them for longer periods, in order to determine whether statins can influence CAC. 6. Implications for treatment Cardiovascular imaging has achieved a great development in recent years and is emerging as a prognostic as well as a diagnostic modality. Because non-invasive imaging techniques are expensive and must be used judiciously, consensus statements have been published in an effort to provide guidance on the appropriate use of these techniques [19,51]. To date, however, recommendations for the use of these modalities in primary prevention are limited in number. The consensus document on the appropriate use of CAC [19] states that it may be reasonable to consider use of this measurement in asymptomatic individuals who are at intermediate risk based on their Framingham risk score. This statement was based on the possibility that such individuals might be reclassified to a higher risk status based on a high CAC score, and that subsequent patient management might be modified accordingly. Data from Framingham indicate that 52% of men 50–59 years of age, 81% of men 60–69 years of age, and 36% of women 70–79 years of age are at intermediate risk and could potentially undergo CAC testing to determine

Fig. 3. SHAPE guideline for CHD prevention based on the severity of subclinical atherosclerosis. Reprinted with permission from Naghavi M, et al. Am J Cardiol 2006;98(2A):2H–15H.

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their atherosclerotic risk [52]. This would entail an unprecedented use of healthcare resources. A different view has been proposed by the Screening for Heart Attack Prevention Taskforce (SHAPE) [53]. In contrast to the existing traditional risk factor-based guidelines, this new strategy is primarily based on non-invasive screening for subclinical atherosclerosis using two well-established non-invasive imaging modalities: CT for measurement of CACS and B-mode ultrasound for measurement of carotid IMT and carotid plaque (Fig. 3). The premise behind this guideline is that the higher the atherosclerotic plaque burden, the higher the risk of future clinical events. Consequently, similar to the NCEP guidelines [23], subjects at higher level of risk should be treated more aggressively in terms of their LDL-cholesterol levels. Individuals with negative tests for atherosclerosis (defined as CACS = 0, or carotid IMT <50th percentile without carotid plaque) are classified as lower risk (those without conventional risk factors) or moderate risk (those with established risk factors), and treated as recommended in the NCEP guidelines, with LDL-cholesterol targets of <160 mg/dl and <130 mg/dl, respectively. Reassessment is recommended within 5–10 years unless otherwise indicated. Those who test positive for atherosclerosis (CACS ≥ >1, or CIMT ≥50th percentile or presence of carotid plaque) are further stratified according to the magnitude of atherosclerotic burden into the following risk categories: A, moderately high risk: CACS <100 (but >0) and <75th percentile, or a carotid IMT <1 mm and <75th percentile (but ≥50th percentile) without discernible carotid plaque. Treatment includes lifestyle modifications and a LDL-cholesterol goal of <130 mg/dl; targeting to 100 mg/dl is optional. B, high risk: CACS 100–399 or >75th percentile, or a CIMT ≥1 mm or >75th percentile or a carotid plaque causing <50% stenosis. Aggressive lifestyle modifications should be implemented as well as a LDLcholesterol target of <100 mg/dl; targeting to <70 mg/dl is optional. C, very high risk: CACS ≥100 and >90th percentile or a CACS ≥400, or carotid plaque causing ≥50% stenosis. Treatment includes aggressive lifestyle modification and a LDL-C goal of <70 mg/dl. The SHAPE authors estimate that their algorithm would lead to 50–65% increase in the size of the “satin eligible” population [53]. The costeffectiveness of this proposal remains to be determined. Independently of the used guideline dyslipidemia remains a major risk factor for CHD. As recommended in the NCEP ATP III guidelines [19], the focus of intervention initially is on lowering LDL-cholesterol to target levels, based on the patient’s level of risk. The utilization of available and emerging imaging modalities could help determine which patients would benefit from aggressive versus conservative lipid management. Consistent with the high event rates associated with a higher CAC/IMT burden, it may be appropriate to initiate drug therapy to achieve a target LDL of ≤70 mg/dl, or even lower, if severe subclinical atherosclerosis is present. At the same time, identifying persons with no or very mild plaque burden, which can be managed with a more conservative strategy, could be a cost-effective use of technology in clinical practice. 7. Conclusion Established techniques such as measurement of carotid IMT and CT-based assessment of CAC offer the potential to identify subclinical atherosclerosis plaque burden. These technologies can detect atherosclerosis before it becomes symptomatic or a major vascular event occurs. On the basis of current evidence, these imaging technologies are best used in asymptomatic individuals considered to be at risk, for whom test results can improve risk stratification and affect the intensity of the therapeutic intervention. Clinical studies show that statin therapy in the primary-prevention setting can delay progression of atherosclerosis and, with aggressive treatment such as rosuvastatin, may even reverse this process. Patients with significant subclinical atherosclerosis are at risk, and like other at-

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