Lp(a) (Lipoprotein(a)) Levels Predict Progression of Carotid Atherosclerosis in Subjects With Atherosclerotic Cardiovascular Disease on Intensive Lipid Therapy: An Analysis of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) Carotid Magnetic Resonance Imaging Substudy-Brief Report.

OBJECTIVE: To assess whether Lp(a) (lipoprotein(a)) levels and other lipid levels were predictive of progression of atherosclerosis burden as assessed by carotid magnetic resonance imaging in subjects who have been treated with LDL-C (low-density lipoprotein cholesterol)-lowering therapy and participated in the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes). APPROACH AND RESULTS: AIM-HIGH was a randomized, double-blind study of subjects with established vascular disease, elevated triglycerides, and low HDL-C (high-density lipoprotein cholesterol). One hundred fifty-two AIM-HIGH subjects underwent both baseline and 2-year follow-up carotid artery magnetic resonance imaging. Plaque burden was measured by the percent wall volume (%WV) of the carotid artery. Associations between annualized change in %WV with baseline and on-study (1 year) lipid variables were evaluated using multivariate linear regression and the Bonferroni correction to account for multiple comparisons. Average %WV at baseline was 41.6±6.8% and annualized change in %WV over 2 years ranged from -3.2% to 3.7% per year (mean: 0.2±1.1% per year; P=0.032). Increases in %WV were significantly associated with higher baseline Lp(a) (ß=0.34 per 1-SD increase of Lp(a); 95% confidence interval, 0.15-0.52; P<0.001) after adjusting for clinical risk factors and other lipid levels. On-study Lp(a) had a similar positive association with %WV progression (ß=0.33; 95% confidence interval, 0.15-0.52; P<0.001). CONCLUSIONS: Despite intensive lipid therapy, aimed at aggressively lowering LDL-C to <70 mg/dL, carotid atherosclerosis continued to progress as assessed by carotid magnetic resonance imaging and that elevated Lp(a) levels were independent predictors of increases in atherosclerosis burden.

Effects of combination lipid therapy in type 2 diabetes mellitus.

BACKGROUND: We investigated whether combination therapy with a statin plus a fibrate, as compared with statin monotherapy, would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease. METHODS: We randomly assigned 5518 patients with type 2 diabetes who were being treated with open-label simvastatin to receive either masked fenofibrate or placebo. The primary outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years. RESULTS: The annual rate of the primary outcome was 2.2% in the fenofibrate group and 2.4% in the placebo group (hazard ratio in the fenofibrate group, 0.92; 95% confidence interval [CI], 0.79 to 1.08; P=0.32). There were also no significant differences between the two study groups with respect to any secondary outcome. Annual rates of death were 1.5% in the fenofibrate group and 1.6% in the placebo group (hazard ratio, 0.91; 95% CI, 0.75 to 1.10; P=0.33). Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex, with a benefit for men and possible harm for women (P=0.01 for interaction), and a possible interaction according to lipid subgroup, with a possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high-density lipoprotein cholesterol (P=0.057 for interaction). CONCLUSIONS: The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.)

The association between chronic stress type and C-reactive protein in the multi-ethnic study of atherosclerosis: does gender make a difference?

The objective of this study is to examine how chronic stress in major life domains [relationship, work, sympathetic-caregiving, financial] relates to CVD risk, operationalized using the inflammatory marker C-Reactive Protein (CRP), and whether gender differences exist. Participants were 6,583 individuals aged 45-84 years, recruited as part of the Multi-Ethnic Study of Atherosclerosis. Demographic and behavioral factors, health history, and chronic stress were self-reported. CRP was obtained through venous blood draw. In aggregate, gender by chronic stress interaction effects accounted for a significant, albeit small, amount of variance in CRP (P < .01). The sympathetic-caregiving stress by gender interaction was significant (P < .01); the work stress by gender effect approached significance (P = .05). Women with sympathetic-caregiving stress had higher CRP than those without, whereas no difference in CRP by stress group was observed for men. Findings underscore the importance of considering gender as an effect modifier in analyses of stress-CVD risk relationships.

Magnetic Resonance Imaging of Intraplaque Hemorrhage and Plaque Lipid Content With Continued Lipid-Lowering Therapy: Results of a Magnetic Resonance Imaging Substudy in AIM-HIGH.

BACKGROUND: Intraplaque hemorrhage (IPH) is associated with plaque progression and ischemic events, and plaque lipid content (% lipid core) predicts the residual atherosclerotic cardiovascular disease risk. This study examined the impact of IPH on lipid content change in the setting of intensive lipid-lowering therapy. METHODS: In total, 214 AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low High-Density Lipoprotein/High Triglycerides: Impact on Global Health Outcomes) participants with clinically established ASCVD and low high-density lipoprotein cholesterol received cartoid MRI at baseline and 2 years to assess changes in carotid morphology and composition. Patients were randomized to extended-release niacin or placebo, and all received simvastatin with optional ezetimibe as necessary to lower low-density lipoprotein cholesterol to 40 to 80 mg/dL. Changes in lipid content and carotid morphology were tested using the Wilcoxon signed-rank test. Differences between subjects with and without IPH and between subjects assigned extended-release niacin or placebo were tested using the Wilcoxon rank-sum test. Linear regression was used to test the association of IPH and lipid content changes after adjusting for clinical risk factors. RESULTS: Among 156 patients (61±9 years; 81% men) with complete MRI, prior statin use: <1 year, 26%; 1 to 5 years, 37%; >5 years, 37%. Triglycerides and ApoB decreased significantly, whereas high-density lipoprotein cholesterol and ApoA1 increased significantly over time. Plaque lipid content was significantly reduced (-0.5±2.4 %/year, P = 0.017) without a significant difference between the 2 treatment groups. However, the lipid content increased in plaques with IPH but regressed in plaques without IPH (1.2±2.5 %/year versus -1.0±2.2, P = 0.006). Additionally, IPH was associated with a decrease in lumen area (-0.4±0.9 mm2/year versus 0.3±1.4, P = 0.033). IPH remained significantly associated with increase in lipid content in multivariable analysis (54.4%, 95% CI: 26.8, 88.0, P < 0.001). CONCLUSIONS: Carotid plaques under continued intensive lipid-lowering therapy moved toward stabilization. However, plaques with IPH showed greater increases in lipid content and greater decreases in lumen area than plaques without IPH. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01178320.

Predictive value of brachial flow-mediated dilation for incident cardiovascular events in a population-based study: the multi-ethnic study of atherosclerosis.

BACKGROUND: Although brachial artery flow-mediated dilation (FMD) predicts recurrent cardiovascular events, its predictive value for incident cardiovascular disease (CVD) events in adults free of CVD is not well established. We assessed the predictive value of FMD for incident CVD events in the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS AND RESULTS: Brachial artery FMD was measured in a nested case-cohort sample of 3026 of 6814 subjects (mean+/-SD age, 61.2+/-9.9 years) in MESA, a population-based cohort study of adults free of clinical CVD at baseline recruited at 6 clinic sites in the United States. The sample included 50.2% female, 34.3% white, 19.7% Chinese, 20.8% black, and 25.1% Hispanic subjects. Probability-weighted Cox proportional hazards analysis was used to examine the association between FMD and 5 years of adjudicated incident CVD events, including incident myocardial infarction, definite angina, coronary revascularization (coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, or other revascularization), stroke, resuscitated cardiac arrest, and CVD death. Mean (SD) FMD of the cohort was 4.4% (2.8). In probability-weighted Cox models, FMD/unit SD was significantly associated with incident cardiovascular events in the univariate model (adjusted for age and sex) (hazard ratio, 0.79; 95% confidence interval, 0.65 to 0.97; P=0.01), after adjustment for the Framingham Risk Score (FRS) (hazard ratio, 0.80; 95% confidence interval, 0.62 to 0.97; P=0.025), and in the multivariable model (hazard ratio, 0.84; 95% confidence interval, 0.71 to 0.99; P=0.04) after adjustment for age, sex, diabetes mellitus, cigarette smoking status, systolic blood pressure, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, heart rate, statin use, and blood pressure medication use. The c statistic (area under the curve) values of FMD, FRS, and FRS+FMD were 0.65, 0.74, and 0.74, respectively. Compared with the FRS alone, the addition of FMD to the FRS net correctly reclassifies 52% of subjects with no incident CVD event but net incorrectly reclassifies 23% of subjects with an incident CVD event, an overall net correct reclassification of 29% (P<0.001). CONCLUSIONS: Brachial FMD is a predictor of incident cardiovascular events in population-based adults. Even though the addition of FMD to the FRS did not improve discrimination of subjects at risk of CVD events in receiver operating characteristic analysis, it improved the classification of subjects as low, intermediate, and high CVD risk compared with the FRS.

Does baseline carotid intima-media thickness modify the effect of rosuvastatin when compared with placebo on carotid intima-media thickness progression? The METEOR study.

BACKGROUND: Many studies have used carotid intima-media thickness (CIMT) measurement to study atherosclerosis and the efficacy of interventions. The placebo-controlled Measuring Effects on intima-media Thickness: an Evaluation Of Rosuvastatin (METEOR) study showed significant reduction in the progression rate of maximum CIMT with 2 years of lipid treatment in asymptomatic individuals with subclinical atherosclerosis. DESIGN: The present post-hoc subgroup analysis of METEOR was carried out to determine whether the effect of rosuvastatin treatment varied according to baseline CIMT level. METHODS: To assess the relationship between efficacy of treatment with rosuvastatin versus placebo and baseline CIMT, we analyzed the effects on the primary CIMT endpoint in participants stratified by baseline quartiles of CIMT (Q1-Q4) using all individuals with a baseline reading and at least one post-baseline CIMT reading. Statistical analysis was carried out using a multilevel repeated-measures linear mixed effects model. RESULTS: In total, 876 participants were included in the analysis. In all quartiles, progression of mean maximum CIMT was significantly slower in rosuvastatin-treated individuals as compared with placebo controls. Although the magnitude of the treatment effect appeared larger in those with the highest baseline CIMT, statistical testing indicated that the magnitude of the treatment effect did not vary significantly with levels of baseline CIMT. CONCLUSION: This subgroup analysis of the METEOR study showed that in middle-aged adults with sub-clinical atherosclerosis, rosuvastatin treatment resulted in significant reduction in mean maximum CIMT progression in four quartiles of baseline CIMT, with no evidence for difference in benefit across levels of baseline CIMT.

Brachial flow-mediated dilation predicts incident cardiovascular events in older adults: the Cardiovascular Health Study.

BACKGROUND: The relationship between impaired brachial flow-mediated dilation (FMD) and subsequent clinical cardiovascular events is not well established, especially in older adults whose FMD is often diminished. We assessed the hypothesis that FMD predicts incident cardiovascular events in a population-based cohort of older adults. METHODS AND RESULTS: FMD was measured at the 1997 to 1998 Cardiovascular Health Study clinic visit in 2792 adults aged 72 to 98 years (82.7% white, 58.6% women) recruited at 4 clinic sites in the United States. Log-rank test and Cox proportional hazard models were used to examine the association between FMD and adjudicated cardiovascular events. A total of 674 subjects (24.1%) had an adjudicated event over the 5-year follow-up period. Event-free survival rates for cardiovascular events were significantly higher in subjects with FMD greater than the sex-specific medians than in subjects with FMD less than or equal to the sex-specific medians (78.3% versus 73.6%, log-rank P=0.006). FMD remained a significant predictor of cardiovascular events after adjustment for age, gender, diabetes mellitus, cigarette smoking, systolic and diastolic blood pressure, baseline cardiovascular disease status, and total cholesterol (hazard ratio, 0.91 [95% CI, 0.83 to 0.99], P=0.02 per unit SD of FMD) but added only approximately 1% to the prognostic accuracy of the best Cox model. Brachial artery diameter was also predictive of CV events in the adjusted Cox proportional hazard model (hazard ratio, 1.12 [95% CI, 1.02 to 1.28], P=0.025) and also added approximately 1% to the accuracy of our best Cox model. CONCLUSIONS: FMD is a predictor of future cardiovascular events but adds very little to the prognostic accuracy of traditional cardiovascular risk scores/factors in older adults. FMD and brachial artery diameter may have similar predictive values for cardiovascular events in older adults.

Azithromycin for the secondary prevention of coronary events.

BACKGROUND: Epidemiologic, laboratory, animal, and clinical studies suggest that there is an association between Chlamydia pneumoniae infection and atherogenesis. We evaluated the efficacy of one year of azithromycin treatment for the secondary prevention of coronary events. METHODS: In this randomized, prospective trial, we assigned 4012 patients with documented stable coronary artery disease to receive either 600 mg of azithromycin or placebo weekly for one year. The participants were followed for a mean of 3.9 years at 28 clinical centers throughout the United States. RESULTS: The primary end point, a composite of death due to coronary heart disease, nonfatal myocardial infarction, coronary revascularization, or hospitalization for unstable angina, occurred in 446 of the participants who had been randomly assigned to receive azithromycin and 449 of those who had been randomly assigned to receive placebo. There was no significant risk reduction in the azithromycin group as compared with the placebo group with regard to the primary end point (risk reduction, 1 percent [95 percent confidence interval, -13 to 13 percent]). There were also no significant risk reductions with regard to any of the components of the primary end point, death from any cause, or stroke. The results did not differ when the participants were stratified according to sex, age, smoking status, presence or absence of diabetes mellitus, or C. pneumoniae serologic status at baseline. CONCLUSIONS: A one-year course of weekly azithromycin did not alter the risk of cardiac events among patients with stable coronary artery disease.

Differences in carotid arterial morphology and composition between individuals with and without obstructive coronary artery disease: a cardiovascular magnetic resonance study.

OBJECTIVE: We sought to determine differences with cardiovascular magnetic resonance (CMR) in the morphology and composition of the carotid arteries between individuals with angiographically-defined obstructive coronary artery disease (CAD, > or = 50% stenosis, cases) and those with angiographically normal coronaries (no lumen irregularities, controls). METHODS AND RESULTS: 191 participants (50.3% female; 50.8% CAD cases) were imaged with a multi-sequence, carotid CMR protocol at 1.5T. For each segment of the carotid, lumen area, wall area, total vessel area (lumen area + wall area), mean wall thickness and the presence or absence of calcification and lipid-rich necrotic core were recorded bilaterally. In male CAD cases compared to male controls, the distal bulb had a significantly smaller lumen area (60.0 +/- 3.1 vs. 79.7 +/- 3.2 mm2, p < 0.001) and total vessel area (99.6 +/- 4.0 vs. 119.8 +/- 4.1 mm2; p < 0.001), and larger mean wall thickness (1.25 +/- 0.03 vs. 1.11 +/- 0.03 mm; p = 0.002). Similarly, the internal carotid had a smaller lumen area (37.5 +/- 1.8 vs. 44.6 +/- 1.8 mm2; p = 0.006) and smaller total vessel area (64.0 +/- 2.3 vs. 70.9 +/- 2.4 mm2; p = 0.04). These metrics were not significantly different between female groups in the distal bulb and internal carotid or for either gender in the common carotid. Male CAD cases had an increased prevalence of lipid-rich necrotic core (49.0% vs. 19.6%; p = 0.003), while calcification was more prevalent in both male (46.9% vs. 17.4%; p = 0.002) and female (33.3% vs. 14.6%; p = 0.031) CAD cases compared to controls. CONCLUSION: Males with obstructive CAD compared to male controls had carotid bulbs and internal carotid arteries with smaller total vessel and lumen areas, and an increased prevalence of lipid-rich necrotic core. Carotid calcification was related to CAD status in both males and females. Carotid CMR identifies distinct morphological and compositional differences in the carotid arteries between individuals with and without angiographically-defined obstructive CAD.

An evaluation of rosuvastatin: pharmacokinetics, clinical efficacy and tolerability.

BACKGROUND: The HMG Co-A reductase inhibitors (statins) are the most efficacious agents for lowering cholesterol. Statins reduce clinical cardiovascular events and are generally well tolerated. OBJECTIVE: To review the efficacy and safety of rosuvastatin, the newest and most potent of the approved statins. METHODS: A comprehensive (PubMed) search was performed to identify relevant publications up to May 2007. RESULTS/CONCLUSIONS: Rosuvastatin reduces LDL cholesterol (LDL-C) by up to 50%, and by 70% when combined with ezetimibe. Rosuvastatin also reduces plasma triglycerides and increases HDL-C, and slows atherosclerosis progression in coronary and carotid arteries in both low-risk and high-risk individuals. Tolerability is comparable with other statins. Clinical trials to evaluate cardiovascular outcomes have recently been published (CORONA) or are underway.

Estrogen plus progestin and the risk of coronary heart disease.

BACKGROUND: Recent randomized clinical trials have suggested that estrogen plus progestin does not confer cardiac protection and may increase the risk of coronary heart disease (CHD). In this report, we provide the final results with regard to estrogen plus progestin and CHD from the Women's Health Initiative (WHI). METHODS: The WHI included a randomized primary-prevention trial of estrogen plus progestin in 16,608 postmenopausal women who were 50 to 79 years of age at base line. Participants were randomly assigned to receive conjugated equine estrogens (0.625 mg per day) plus medroxyprogesterone acetate (2.5 mg per day) or placebo. The primary efficacy outcome of the trial was CHD (nonfatal myocardial infarction or death due to CHD). RESULTS: After a mean follow-up of 5.2 years (planned duration, 8.5 years), the data and safety monitoring board recommended terminating the estrogen-plus-progestin trial because the overall risks exceeded the benefits. Combined hormone therapy was associated with a hazard ratio for CHD of 1.24 (nominal 95 percent confidence interval, 1.00 to 1.54; 95 percent confidence interval after adjustment for sequential monitoring, 0.97 to 1.60). The elevation in risk was most apparent at one year (hazard ratio, 1.81 [95 percent confidence interval, 1.09 to 3.01]). Although higher base-line levels of low-density lipoprotein cholesterol were associated with an excess risk of CHD among women who received hormone therapy, higher base-line levels of C-reactive protein, other biomarkers, and other clinical characteristics did not significantly modify the treatment-related risk of CHD. CONCLUSIONS: Estrogen plus progestin does not confer cardiac protection and may increase the risk of CHD among generally healthy postmenopausal women, especially during the first year after the initiation of hormone use. This treatment should not be prescribed for the prevention of cardiovascular disease.

Effect of simvastatin (80 mg) on coronary and abdominal aortic arterial calcium (from the coronary artery calcification treatment with zocor [CATZ] study).

We tested the hypothesis that, compared with placebo, simvastatin would reduce the progression of coronary artery calcium (CAC) and abdominal aortic calcium (AAC) levels in participants asymptomatic for vascular disease. Total CAC and AAC were measured with multidetector cardiac computed tomography. Inclusion criteria were a CAC score of >or=50 Agatston units, high-density lipoprotein (HDL) cholesterol levelor=2 other risk factors. Diabetes and history of vascular disease were exclusion criteria. Participants were randomized to receive 80 mg simvastatin (n=40) or matching placebo (n=40) for 12 months. Lipids were measured at 3-month intervals, and CAC and AAC measurements were repeated at 6 and 12 months. Total cholesterol, triglycerides, and LDL decreased significantly with simvastatin treatment (p<0.0001 for all comparisons, adjusted for baseline levels), whereas lipids remained unchanged for subjects randomized to receive placebo. Total CAC volume increased from baseline in both treatment groups. For subjects in the active treatment group, CAC volume increased by 9%, whereas in the placebo group, plaque volume increased by 5% (p=0.12 for treatment effect). AAC volume also increased in both treatment groups (p=0.15 for treatment effect). In conclusion, simvastatin treatment does not reduce progression of CAC or AAC compared with placebo.

Evolution of the lipid trial protocol of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial aims to test whether a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) plus a fibrate is more efficacious in reducing cardiovascular events than a statin plus placebo in patients with type 2 diabetes mellitus with defined glycemic control. This is a blinded component in a 5,518-patient subset of the ACCORD cohort. These participants were randomized to either be (1) treated with simvastatin (titrated to 40 mg/day if necessary to achieve a goal low-density lipoprotein [LDL] cholesterol level of <2.59 mmol/L [100 mg/dL]) plus placebo or (2) treated to the same goal LDL cholesterol level with the statin plus active fenofibrate 160 mg/day or its bioequivalent (or 54 mg/day if the estimated glomerular filtration rate ranges from 30 to <50 mL/min per 1.73 m2). Setting an upper limit of LDL cholesterol qualifying for randomization excluded patients who would not likely achieve the LDL cholesterol goal. Recruitment for ACCORD began in January 2001, and follow-up is scheduled to end in June 2009. Since recruitment began, several clinical trials and consensus statements have been published that led to changes in the details of the lipid treatment algorithm and protocol. This report describes the design of the lipid protocol and modifications to the protocol during the course of the study in response to and in anticipation of these developments. The current protocol is designed to provide an ethically justifiable test of combined statin plus fibrate treatment consistent with the highest level of safety and lipid treatment standards of care.

Low plasma levels of FGF-2 and PDGF-BB are associated with cardiovascular events in type II diabetes mellitus (diabetes heart study).

OBJECTIVE: We tested associations of the growth factors VEGF, FGF-2, HGF and PDGF-BB with coronary artery calcium scores and cardiovascular events (CVD) in type 2 diabetes mellitus (T2DM). METHODS: A cross-sectional study selected 40 frequency matched (by age, gender and race) subjects with T2DM from the first (0-111) and the third (> 1400) coronary artery calcium (CAC) score tertiles in the Diabetes Heart Study (DHS), in which 36 were with and 41 were without history of CVD events. Plasma levels of VEGF, FGF-2, HGF and PDGF-BB were measured in all subjects. RESULTS: None of the growth factors was significantly different between the first and third CAC score tertiles. Mean plasma FGF-2 and PDGF-BB levels were significantly higher in the group without prior CVD events compared with the group with prior CVD events [mean(95%CI): 219.20 (194.42-247.15) vs. 152.93 (135.64-172.43) pg/ml, p=0.03] and [mean(95%CI): 106.70 (89.12-127.74) vs. 61.56 (50.91-74.44) pg/ml, p=0.03], respectively. Subgroup analysis in the first CAC tertile showed a significantly higher PDGF-BB levels in those without compared with those with CVD events [mean (95%CI): 208.36 (190.57-228.15) vs. 102.93 (80.64-125.21) pg/ml, p=0.004]. CONCLUSION: Plasma growth factor levels were not significantly different between the extremes of CAC scores in T2DM. However, low plasma levels of PDGF-BB and FGF-2 are associated with prior cardiovascular events in T2DM. Studies are needed to confirm our results and also to establish temporality of this association.

Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial.

CONTEXT: Atherosclerosis is often advanced before symptoms appear and it is not clear whether treatment is beneficial in middle-aged individuals with a low Framingham risk score (FRS) and mild to moderate subclinical atherosclerosis. OBJECTIVE: To assess whether statin therapy could slow progression and/or cause regression of carotid intima-media thickness (CIMT) over 2 years. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled study (Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin [METEOR]) of 984 individuals, with either age (mean, 57 years) as the only coronary heart disease risk factor or a 10-year FRS of less than 10%, modest CIMT thickening (1.2-<3.5 mm), and elevated LDL cholesterol (mean, 154 mg/dL); conducted at 61 primary care centers in the United States and Europe between August 2002 and May 2006. INTERVENTION: Participants received either a 40-mg dose of rosuvastatin or placebo. MAIN OUTCOME MEASURES: Rate of change in maximum CIMT (assessed with B-mode ultrasound) for 12 carotid sites; changes in maximum CIMT of the common carotid artery, carotid bulb, and internal carotid artery sites and in mean CIMT of the common carotid artery sites. CIMT regression was assessed in the rosuvastatin group only. RESULTS: Among participants in the rosuvastatin group, the mean (SD) baseline LDL cholesterol level of 155 (24.1) mg/dL declined to 78 (27.5) mg/dL, a mean reduction of 49% (P<.001 vs placebo group). The change in maximum CIMT for the 12 carotid sites was -0.0014 (95% CI, -0.0041 to 0.0014) mm/y for the rosuvastatin group vs 0.0131 (95% CI, 0.0087-0.0174) mm/y for the placebo group (P<.001). The change in maximum CIMT for the rosuvastatin group was -0.0038 (95% CI, -0.0064 to -0.0013) mm/y for the common carotid artery sites (P<.001), -0.0040 (95% CI, -0.0090 to 0.0010) mm/y for the carotid bulb sites (P<.001), and 0.0039 (95% CI, -0.0009 to 0.0088) mm/y for the internal carotid artery sites (P = .02). The change in mean CIMT for the rosuvastatin group for the common carotid artery sites was 0.0004 (95% CI, -0.0011 to 0.0019) mm/y (P<.001). All P values are vs placebo group. Overall, rosuvastatin was well tolerated with infrequent serious adverse cardiovascular events (6 participants [0.86%] had 8 events [1.1%] over 2 years). CONCLUSIONS: In middle-aged adults with an FRS of less than 10% and evidence of subclinical atherosclerosis, rosuvastatin resulted in statistically significant reductions in the rate of progression of maximum CIMT over 2 years vs placebo. Rosuvastatin did not induce disease regression. Larger, longer-term trials are needed to determine the clinical implications of these findings. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00225589

Carotid Plaque Lipid Content and Fibrous Cap Status Predict Systemic CV Outcomes: The MRI Substudy in AIM-HIGH.

OBJECTIVES: The aim of this study was to investigate whether and what carotid plaque characteristics predict systemic cardiovascular outcomes in patients with clinically established atherosclerotic disease. BACKGROUND: Advancements in atherosclerosis imaging have allowed assessment of various plaque characteristics, some of which are more directly linked to the pathogenesis of acute cardiovascular events compared to plaque burden. METHODS: As part of the event-driven clinical trial AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes), subjects with clinically established atherosclerotic disease underwent multicontrast carotid magnetic resonance imaging (MRI) to detect plaque tissue composition and high-risk features. Prospective associations between MRI measurements and the AIM-HIGH primary endpoint (fatal and nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, and symptom-driven revascularization) were analyzed using Cox proportional hazards survival models. RESULTS: Of the 232 subjects recruited, 214 (92.2%) with diagnostic image quality constituted the study population (82% male, mean age 61 ± 9 years, 94% statin use). During median follow-up of 35.1 months, 18 subjects (8.4%) reached the AIM-HIGH endpoint. High lipid content (hazard ratio [HR] per 1 SD increase in percent lipid core volume: 1.57; p = 0.002) and thin/ruptured fibrous cap (HR: 4.31; p = 0.003) in carotid plaques were strongly associated with the AIM-HIGH endpoint. Intraplaque hemorrhage had a low prevalence (8%) and was marginally associated with the AIM-HIGH endpoint (HR: 3.00; p = 0.053). High calcification content (HR per 1 SD increase in percent calcification volume: 0.66; p = 0.20), plaque burden metrics, and clinical risk factors were not significantly associated with the AIM-HIGH endpoint. The associations between carotid plaque characteristics and the AIM-HIGH endpoint changed little after adjusting for clinical risk factors, plaque burden, or AIM-HIGH randomized treatment assignment. CONCLUSIONS: Among patients with clinically established atherosclerotic disease, carotid plaque lipid content and fibrous cap status were strongly associated with systemic cardiovascular outcomes. Markers of carotid plaque vulnerability may serve as novel surrogate markers for systemic atherothrombotic risk.

Left ventricular concentric remodeling is associated with decreased global and regional systolic function: the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: The transition from compensatory concentric remodeling to myocardial failure is not completely understood in humans. To investigate determinants of incipient myocardial dysfunction, we examined the association between concentric remodeling and regional LV function in asymptomatic participants of the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS AND RESULTS: Myocardial tagged MRI was performed. Regional myocardial function expressed as peak systolic midwall circumferential strain (Ecc) was analyzed in 441 consecutive studies by HARP (Harmonic Phase) tool. Peak Ecc was correlated with the extent of concentric remodeling determined by the ratio of left ventricular mass to end-diastolic volume (M/V ratio). In men, a gradual decline in peak global Ecc was seen with increasing M/V ratio (test for trend, P<0.001). Among women, however, Ecc tended to be lower only in the fifth compared with the first quintile of M/V ratio (P=0.1). The association of lower Ecc with increasing M/V ratio was regionally heterogeneous but was particularly prominent in the LAD region in men (test for trend, P<0.001) and in women (test for trend, P=0.02). In the right coronary and left circumflex artery territories, these associations were less marked in both genders. CONCLUSIONS: In this cross-sectional study of asymptomatic individuals, concentric left ventricular remodeling was related to decreased regional systolic function. The reduction in regional function, which was more pronounced in the left anterior descending coronary artery territory, may reflect the local transition from compensatory remodeling to myocardial dysfunction.

Coronary artery calcium outperforms carotid artery intima-media thickness as a noninvasive index of prevalent coronary artery stenosis.

OBJECTIVE: Increased carotid artery intima-media thickness (IMT) and increased coronary artery calcium (CAC) are noninvasive surrogate indices of prevalent coronary artery disease (CAD). We compared CAC to IMT for noninvasive detection of prevalent CAD in participants whose coronary status was identified by coronary angiography. METHODS AND RESULTS: Male and female CAD patients (> or =50% stenosis in one or more coronary artery, n=79) and controls (no lumen irregularities, n=93) were identified using coronary angiography. Mean maximum carotid IMT was quantified using B-mode ultrasound and total CAC was measured using ECG-gated helical computed tomography (HCT). Carotid IMT was approximately 20% higher in CAD cases compared with controls (P<0.001), whereas mean CAC was 1000% higher in CAD cases than controls (P<0.0001). In multivariable models adjusted for age and sex, IMT greater than the median (1.13 mm) was associated with 2-fold increase in likelihood of prevalent CAD compared with scores below that cut point (P=0.015). CAC scores that exceeded the median score of 92 were associated with 28-fold increase in likelihood of prevalent CAD (P<0.0001). Although associations of increased IMT with prevalent CAD were similar in males and females, CAC scores above the median in females were associated with 39-fold increase in odds of prevalent CAD, whereas males with elevated CAC had 19-fold risk of CAD. CONCLUSIONS: HCT-measured CAC compares favorably with carotid IMT measured by B-mode ultrasound as a noninvasive index of prevalent CAD.

Associations of extracranial carotid atherosclerosis progression with coronary status and risk factors in patients with and without coronary artery disease.

BACKGROUND: Intimal medial thickness of the extracranial carotid arteries (IMT) is related to coronary artery disease (CAD) and CAD risk factors. Few studies have explored the association of risk factors with progression of IMT, and none have evaluated their associations with IMT progression specifically in patients with and without CAD. METHODS AND RESULTS: We used coronary angiography to identify 280 patients equally divided between men and women and those with either > or =50% coronary artery stenosis or no CAD. Risk factors were measured at baseline and IMT was measured at baseline and yearly for 3 years in 241 of these individuals. Baseline risk factors and CAD status were related to IMT progression. IMT of patients with CAD progressed 3 times faster than that of patients with no CAD (mean+/-SEM, 33.7+/-7.4 versus 8.9+/-7.1 microm/year; P=0.02), and CAD status and high-density lipoprotein (HDL) cholesterol were independently associated with IMT progression. Male sex, increased waist to hip ratio, cigarette smoking, increased triglycerides, and decreased HDL cholesterol were associated with increased progression in CAD patients. CONCLUSIONS: Patients with CAD have more rapid progression of IMT than CAD-free controls, and risk factors are related to progression in them.

Carotid arterial structure in patients with documented coronary artery disease and disease-free control subjects.

BACKGROUND: Although atherosclerosis often leads to lumen narrowing and symptomatic cardiovascular disease, it is now recognized that arteries have the potential to compensate by enlarging in response to atherosclerosis. We tested the hypotheses that carotid arterial interadventitial (IA) and lumen diameters were related to wall thickness and that carotid arterial diameters of individuals with coronary artery disease (CAD) differed from those of CAD-free controls. METHODS AND RESULTS: We measured lumen diameter, IA diameter, and intima-media thickness (IMT) using B-mode ultrasound in the common and internal carotid arteries of 141 CAD case patients and 139 disease-free control subjects. Common carotid IA diameter was greater in CAD cases than controls after adjustment for age, height, and sex (P<0.01). Common carotid lumen diameter was marginally larger in individuals with greater IMT (P=0.06) but was not associated with case status. Conversely, mean internal carotid IA and lumen diameters were smaller in CAD cases than controls in both univariable and multivariable models (both P<0.001), and lumina were smaller in individuals with greater IMT. Despite these cross-sectional differences in carotid artery dimensions, we were unable to detect any statistically significant interactive effects of CAD case status on the association of IMT with arterial dimensions. CONCLUSIONS: Internal carotid artery lumen and IA diameters are both smaller in CAD cases than controls. The association of increased IMT with arterial dimensions varies in a manner that is segment-specific for the common and internal carotid arteries.