Raphaël Duivenvoorden

Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia

BACKGROUND Ezetimibe, a cholesterol-absorption inhibitor, reduces levels of low-density lipoprotein (LDL) cholesterol when added to statin treatment. However, the effect of ezetimibe on the progression of atherosclerosis remains unknown. METHODS We conducted a double-blind, randomized, 24-month trial comparing the effects of daily therapy with 80 mg of simvastatin either with placebo or with 10 mg of ezetimibe in 720 patients with familial hypercholesterolemia. Patients underwent B-mode ultrasonography to assess the intima-media thickness of the walls of the carotid and femoral arteries. The primary outcome measure was the change in the mean carotid-artery intima-media thickness, which was defined as the average of the means of the far-wall intima-media thickness of the right and left common carotid arteries, carotid bulbs, and internal carotid arteries. RESULTS The primary outcome, the mean (+/-SE) change in the carotid-artery intima-media thickness, was 0.0058+/-0.0037 mm in the simvastatin-only group and 0.0111+/-0.0038 mm in the simvastatin-plus-ezetimibe (combined-therapy) group (P=0.29). Secondary outcomes (consisting of other variables regarding the intima-media thickness of the carotid and femoral arteries) did not differ significantly between the two groups. At the end of the study, the mean (+/-SD) LDL cholesterol level was 192.7+/-60.3 mg per deciliter (4.98+/-1.56 mmol per liter) in the simvastatin group and 141.3+/-52.6 mg per deciliter (3.65+/-1.36 mmol per liter) in the combined-therapy group (a between-group difference of 16.5%, P<0.01). The differences between the two groups in reductions in levels of triglycerides and C-reactive protein were 6.6% and 25.7%, respectively, with greater reductions in the combined-therapy group (P<0.01 for both comparisons). Side-effect and safety profiles were similar in the two groups. CONCLUSIONS In patients with familial hypercholesterolemia, combined therapy with ezetimibe and simvastatin did not result in a significant difference in changes in intima-media thickness, as compared with simvastatin alone, despite decreases in levels of LDL cholesterol and C-reactive protein. (ClinicalTrials.gov number, NCT00552097 [ClinicalTrials.gov].).

Measurement of carotid intima-media thickness to assess progression and regression of atherosclerosis.

Imaging modalities have been developed to assess atherosclerosis in vivo in the arterial wall because large clinical end-point studies are time-consuming and costly. Historically, in-hospital angiography and Doppler ultrasonography have been used to assess atherosclerosis development. Investigations of the arterial lumen are, however, increasingly being replaced by modalities that can measure changes in the arterial wall itself—intravascular ultrasonography, MRI and multislice CT. The fact that intravascular ultrasonography is invasive, CT involves substantial radiation exposure and requires contrast agents, and that MRI is time-consuming and technically challenging all limit the widespread use of these techniques. Moreover, all modalities have high associated costs. B-mode ultrasonographic imaging of the carotid arterial walls occupies a unique position in atherosclerosis research. This method enables sensitive, reproducible and noninvasive assessment of intima–media thickness (IMT) as a continuous variable. Epidemiological and clinical trial evidence as well as digitization and standardization have made carotid IMT a validated and accepted marker for generalized atherosclerosis burden and vascular disease risk. Here we describe the application of carotid IMT measurements as a tool in risk evaluation of individuals and in studies of atherosclerosis progression and regression.

A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation

Inflammation is a key feature of atherosclerosis and a target for therapy. Statins have potent anti-inflammatory properties but these cannot be fully exploited with oral statin therapy due to low systemic bioavailability. Here we present an injectable reconstituted high-density lipoprotein (rHDL) nanoparticle carrier vehicle that delivers statins to atherosclerotic plaques. We demonstrate the anti-inflammatory effect of statin-rHDL in vitro and show this effect is mediated through inhibition of the mevalonate pathway. We also apply statin-rHDL nanoparticles in vivo in an apolipoprotein E-knockout mouse model of atherosclerosis and show they accumulate in atherosclerotic lesions where they directly affect plaque macrophages. Finally we demonstrate that a three-month low-dose statin-rHDL treatment regimen inhibits plaque inflammation progression, while a one-week high-dose regimen markedly decreases inflammation in advanced atherosclerotic plaques. Statin-rHDL represents a novel potent atherosclerosis nanotherapy that directly affects plaque inflammation.

ACAT Inhibition and Progression of Carotid Atherosclerosis in Patients With Familial Hypercholesterolemia: The CAPTIVATE Randomized Trial

CONTEXT Inhibition of acyl coenzyme A:cholesterol acyltransferase (ACAT), an intracellular enzyme involved in cholesterol accumulation, with pactimibe was developed to assist in the prevention of cardiovascular disease. OBJECTIVE To evaluate the efficacy and safety of pactimibe in inhibition of atherosclerosis. DESIGN, SETTING, AND PATIENTS A prospective, randomized, stratified, double-blind, placebo-controlled study (Carotid Atherosclerosis Progression Trial Investigating Vascular ACAT Inhibition Treatment Effects [CAPTIVATE]) of 892 patients heterozygous for familial hypercholesterolemia conducted at 40 lipid clinics in the United States, Canada, Europe, South Africa, and Israel between February 1, 2004, and December 31, 2005. Study was terminated on October 26, 2005. INTERVENTION Participants received either 100 mg/d of pactimibe (n = 443) or matching placebo (n = 438), in addition to standard lipid-lowering therapy. MAIN OUTCOME MEASURES Carotid atherosclerosis, assessed by ultrasound carotid intima-media thickness (CIMT), at baseline, 12, 18, and 24 months. Maximum CIMT was the primary end point and mean CIMT the secondary end point. RESULTS Because pactimibe failed to show efficacy in the intravascular coronary ultrasound ACTIVATE study, the CAPTIVATE study was terminated prematurely after a follow-up of 15 months. After 6 months of treatment with pactimibe, low-density lipoprotein cholesterol increased by 7.3% (SD, 23%) compared with 1.4% (SD, 28%) in the placebo group (P = .001). The carotid ultrasonographic scans of the 716 patients with at least 2 scans and obtained at least 40 weeks apart were analyzed. Maximum CIMT measurements did not show a pactimibe treatment effect (difference, 0.004 mm; 95% confidence interval [CI], -0.023 to 0.015 mm; P = .64); however, the less variable mean CIMT measurement revealed an increase of 0.014 mm (95% CI, -0.027 to 0.000 mm; P = .04) in patients administered pactimibe vs placebo. Major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) occurred more often in patients administered pactimibe vs placebo (10/443 [2.3%] vs 1/438 [0.2%]; P = .01). CONCLUSIONS In patients with familial hypercholesterolemia, pactimibe had no effect on atherosclerosis as assessed by changes in maximum CIMT compared with placebo but was associated with an increase in mean CIMT as well as increased incidence of major cardiovascular events. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00151788.

In vivo quantification of carotid artery wall dimensions: 3.0 Tesla MRI versus B-mode ultrasound imaging.

Background— Our aim was to compare common carotid mean wall thickness (MWT) measurements by 3.0-T MRI with B-mode ultrasound common carotid intima-media thickness (CCIMT) measurements, a validated surrogate marker for cardiovascular disease. Methods and Results— B-mode ultrasound and 3.0-T MRI scans of the left and right common carotid arteries were repeated 3 times in 15 healthy younger volunteers (age, 26±2.6 years), 15 healthy older volunteers (age, 57±3.2 years), and 15 subjects with cardiovascular disease and carotid atherosclerosis (age, 63±9.8 years). MWT was 0.711 (SD, 0.229) mm and mean CCIMT was 0.800 (SD, 0.206) mm. MWT and CCIMT were highly correlated ( r =0.89, P <0.001). The intraclass correlation coefficients for interscan and interobserver and intraobserver agreements of MRI MWT measurements were larger than 0.95 with small confidence intervals, indicating excellent reproducibility. Power calculations indicate that 89 subjects are required to detect a 4% difference in MRI MWT compared with 469 subjects to detect similar differences with ultrasound IMT in follow-up studies. Conclusions— The study data for carotid MRI and ultrasound IMT showed strong agreement, indicating that both modalities measure the thickness of the intima and media. The advantage of MRI over ultrasound is that the measurement variability is smaller, enabling smaller sample sizes and potentially shorter study duration in cardiovascular prevention trials. Received April 28, 2008; accepted January 26, 2009.Background—Our aim was to compare common carotid mean wall thickness (MWT) measurements by 3.0-T MRI with B-mode ultrasound common carotid intima-media thickness (CCIMT) measurements, a validated surrogate marker for cardiovascular disease. Methods and Results—B-mode ultrasound and 3.0-T MRI scans of the left and right common carotid arteries were repeated 3 times in 15 healthy younger volunteers (age, 26±2.6 years), 15 healthy older volunteers (age, 57±3.2 years), and 15 subjects with cardiovascular disease and carotid atherosclerosis (age, 63±9.8 years). MWT was 0.711 (SD, 0.229) mm and mean CCIMT was 0.800 (SD, 0.206) mm. MWT and CCIMT were highly correlated (r=0.89, P<0.001). The intraclass correlation coefficients for interscan and interobserver and intraobserver agreements of MRI MWT measurements were larger than 0.95 with small confidence intervals, indicating excellent reproducibility. Power calculations indicate that 89 subjects are required to detect a 4% difference in MRI MWT compared with 469 subjects to detect similar differences with ultrasound IMT in follow-up studies. Conclusions—The study data for carotid MRI and ultrasound IMT showed strong agreement, indicating that both modalities measure the thickness of the intima and media. The advantage of MRI over ultrasound is that the measurement variability is smaller, enabling smaller sample sizes and potentially shorter study duration in cardiovascular prevention trials.

Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation.

Nanoparticle-based delivery of simvastatin inhibits plaque macrophage proliferation in apolipoprotein E–deficient mice. Inflammation drives atherosclerotic plaque progression and rupture, and is a compelling therapeutic target. Consequently, attenuating inflammation by reducing local macrophage accumulation is an appealing approach. This can potentially be accomplished by either blocking blood monocyte recruitment to the plaque or increasing macrophage apoptosis and emigration. Because macrophage proliferation was recently shown to dominate macrophage accumulation in advanced plaques, locally inhibiting macrophage proliferation may reduce plaque inflammation and produce long-term therapeutic benefits. To test this hypothesis, we used nanoparticle-based delivery of simvastatin to inhibit plaque macrophage proliferation in apolipoprotein E–deficient mice (Apoe−/−) with advanced atherosclerotic plaques. This resulted in the rapid reduction of plaque inflammation and favorable phenotype remodeling. We then combined this short-term nanoparticle intervention with an 8-week oral statin treatment, and this regimen rapidly reduced and continuously suppressed plaque inflammation. Our results demonstrate that pharmacologically inhibiting local macrophage proliferation can effectively treat inflammation in atherosclerosis.

Surrogate markers in clinical trials—Challenges and opportunities

Surrogate markers have recently come under scrutiny since a few of the considered most reliable intermediate endpoints (LDL-c, HDL-c and HbA(1c)) have failed to predict clinical benefit following pharmacological intervention in the causal pathway. However, it follows that comprehending the pathophysiological complexity of atherosclerotic vascular disease, no single surrogate is likely to be omniscient in the translation of benefit or harm of a certain therapy. Especially surrogates that are assessed in the circulation merely reflect a part of the complex multipathway disease. Such markers do not have the ability to monitor potential side effects of interventions or assess the activation of unknown pro-atherogenic pathways. Contrary to such soluble endpoints, vascular imaging data can provide information on atherosclerosis as a continuous variable, since the disease process of the vascular wall itself is assessed. Understanding this continuity from the earliest stages through to the vascular complications is essential, as the arterial wall reflects the net effect of either known or yet to be discovered hereditary as well as environmental factors. In this review we will focus on challenges and pitfalls using plasma biomarkers as surrogate endpoints for the assessment of cardiovascular drug efficacy. Subsequently, we will focus on vascular imaging modalities as tools to investigate atherosclerosis.

Prevalence and Risk Factors of Carotid Vessel Wall Inflammation in Coronary Artery Disease Patients FDG-PET and CT Imaging Study

OBJECTIVES We investigated the prevalence and clinical risk factors of carotid vessel wall inflammation by means of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in a population consisting of coronary artery disease (CAD) patients. BACKGROUND The atherosclerotic disease process is characterized by infiltration and retention of oxidized lipids in the artery wall, triggering a disproportionate inflammatory response. Efforts have been made to use noninvasive imaging to quantify this inflammatory response in the vessel wall. Recently, carotid FDG-PET has been shown to reflect the metabolic rate of glucose, a process known to be enhanced in inflamed tissue. METHODS Carotid inflammation was quantified in 82 CAD patients (age 62 ± 10 years) as the maximum target-to-background ratio ((wholevessel)TBR(max)). Furthermore, we assessed the maximal standardized uptake value values ((wholevessel)SUV(max)), the single hottest segment (SHS), and the percent active segments (PAS) of the FDG uptake in the artery wall, measured by FDG-PET. RESULTS Whole-vessel TBR(max) >1.8 was present in 67%, >2.0 in 39%, >2.2 in 23%, and >2.4 in 12% of the population. Multiple linear regression analysis with backward elimination revealed that body mass index (BMI) ≥30 kg/m2 (p < 0.0001), age >65 years (p = 0.01), smoking (p = 0.02), and hypertension (p = 0.01) were associated with (wholevessel)TBR(max). The number of components of the metabolic syndrome was also associated with (wholevessel)TBR(max) (p = 0.02). In similar analyses, (wholevessel)SUV(max) was associated with BMI ≥30 kg/m2 (p < 0.0001), age >65 years (p = 0.004), male gender (p = 0.02), and hypertension (p = 0.04); SHS with BMI ≥30 kg/m2 (p < 0.0001), age >65 years (p = 0.02), smoking (p = 0.04), and hypertension (p = 0.05); PAS with BMI ≥30 kg/m2 (p = 0.001), smoking (p = 0.03), and hypertension (p = 0.01). CONCLUSIONS Carotid inflammation as revealed by FDG-PET is highly prevalent in the CAD population and is associated with obesity, age over 65 years, history of hypertension, smoking, and male gender. Artery wall FDG uptake increased when components of the metabolic syndrome clustered.

ABCA1 mutation carriers with low high-density lipoprotein cholesterol are characterized by a larger atherosclerotic burden.

AIMS Low HDL-C is a potent risk factor for cardiovascular disease (CVD). Yet, mutations in ABCA1, a major determinant of circulating HDL-C levels, were previously not associated with CVD risk in cohort studies. To study the consequences of low plasma levels of high-density lipoprotein cholesterol (HDL-C) due to ATP-binding cassette transporter A1 (ABCA1) dysfunction for atherosclerotic vascular disease in the carotid arteries. METHODS AND RESULTS We performed 3.0 Tesla magnetic resonance imaging (MRI) measurements of the carotid arteries in 36 carriers of high impact functional ABCA1 mutations and 36 normolipidemic controls. Carriers presented with 42% lower HDL-C levels (P < 0.001), a larger mean wall area (18.6 ± 6.0 vs. 15.8 ± 4.3 mm(2); P = 0.02), a larger mean wall thickness (0.82 ± 0.21 vs. 0.70 ± 0.14 mm; P = 0.005), and a higher normalized wall index (0.37 ± 0.06 vs. 0.33 ± 0.04; P = 0.005) compared with controls, retaining significance after adjustment for smoking, alcohol consumption, systolic blood pressure, diabetes, body mass index, history of CVD, LDL-C, and statin use (P = 0.002). CONCLUSION Carriers of loss of function ABCA1 mutations display a larger atherosclerotic burden compared with age and sex-matched controls, implying a higher risk for CVD. Further studies are needed to elucidate the full function of ABCA1 in the protection against atherosclerosis. These data support the development of strategies to up-regulate ABCA1 in patients with established CVD.

Cholesterol Acyltransferase Gene Mutations Have Accelerated Atherogenesis as Assessed by Carotid 3.0-T Magnetic Resonance Imaging: Carriers of Lecithin

OBJECTIVES The aim of this study was to investigate the role of reduced lecithin: cholesterol acyltransferase (LCAT) function on atherogenesis using 3.0-T carotid magnetic resonance imaging (MRI) and B-mode ultrasound. BACKGROUND The role of low high-density lipoprotein cholesterol as a causal factor in atherogenesis has recently been questioned. LCAT plays a key role in high-density lipoprotein cholesterol metabolism. METHODS Carotid 3.0-T MRI and B-mode ultrasound measurements were performed in 40 carriers of LCAT gene mutations and 40 controls, matched for age. Patients with cardiovascular disease were excluded. RESULTS Carriers had 31% lower LCAT activity levels and 38% decreased high-density lipoprotein cholesterol levels (both p < 0.001 vs. controls). Carriers presented with a 10% higher normalized wall index (0.34 ± 0.07 vs. 0.31 ± 0.04, p = 0.002), a 22% higher mean wall area (17.3 ± 8.5 mm(2) vs. 14.2 ± 4.1 mm(2), p = 0.01), and a 22% higher total wall volume (1,039 ± 508 mm(3) vs. 851 ± 247 mm(3), p = 0.01 vs. controls) as measured by MRI. The prevalence (20 vs. 5, p = 0.002) and the total volume (102 mm(3) vs. 3 mm(3)) of atherosclerotic plaque components on MRI relating to lipid-rich tissue or calcification were also higher in carriers than in controls. All differences retained significance after adjustment for age, sex, blood pressure, low-density lipoprotein cholesterol, body mass index, smoking, and family history of cardiovascular disease. Common carotid intima-media thickness measured with ultrasound was increased in carriers by 12.5% (0.72 ± 0.33 mm vs. 0.64 ± 0.15 mm, p = 0.14). CONCLUSIONS Carriers of LCAT gene mutations exhibit increased carotid atherosclerosis, indicating an increased risk of cardiovascular disease. The present findings imply that increasing LCAT activity may be an attractive target in cardiovascular prevention strategies.