[Show abstract][Hide abstract] ABSTRACT: 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 that this effect is mediated through the inhibition of the mevalonate pathway. We also apply statin-rHDL nanoparticles in vivo in an apolipoprotein E-knockout mouse model of atherosclerosis and show that they accumulate in atherosclerotic lesions in which they directly affect plaque macrophages. Finally, we demonstrate that a 3-month low-dose statin-rHDL treatment regimen inhibits plaque inflammation progression, while a 1-week high-dose regimen markedly decreases inflammation in advanced atherosclerotic plaques. Statin-rHDL represents a novel potent atherosclerosis nanotherapy that directly affects plaque inflammation.
[Show abstract][Hide abstract] ABSTRACT: This study hypothesized that (1)H magnetic resonance spectroscopy ((1)H-MRS) can identify carotid plaque cholesteryl ester in vivo in humans.
Liquid phase cholesteryl ester comprises a major fraction of atherosclerotic plaque, and its abundance is associated with plaque rupture and atherothrombosis. A noninvasive imaging technique to detect liquid cholesteryl ester that has been applied ex vivo is now demonstrated in vivo.
(1)H-MRS scans were obtained of carotid plaques of 35 subjects at 3.0 T. Turbo spin echo, black blood, T1-weighted images were acquired for localization. Spectra were acquired using a 2-dimensional point resolved spectroscopy sequence: repetition time/echo time = 1,100/30 ms, 5-mm slice thickness, 8 × 8-cm field of view, 16 × 16 matrix size, and 13-min acquisition time. Saturation bands were placed around the artery. Resonance of methylene protons and allylic methylene protons were assigned to 1.2 ppm and 2.0 ppm. The 2.0:1.2 ppm ratio was calculated to reflect the ratio of the fatty acid composition of plaque cholesteryl ester to that of triglycerides of perivascular tissue. We obtained spectra of lipid standards as a reference.
Our (1)H-MRS data showed typical spectra of cholesteryl ester mixed with triglycerides, with intense resonance from methylene (1.2 ppm) and allylic methylene (2.0 ppm) protons. The average 2.0:1.2 ppm ratio was 0.10 (SD 0.03). The 2.0:1.2 ppm ratio correlated with the plaque tissue volume to perivascular tissue volume ratio (Spearman rho = 0.55, p = 0.02), suggesting that more (1)H-MRS signal was obtained from cholesteryl ester when the (1)H-MRS voxel comprised more plaque tissue. Repeat (1)H-MRS scans in 4 subjects showed an intraclass correlation coefficient of 0.92 (95% prediction intervals: 0.40 to 0.99), indicating good reproducibility. Seventeen of the 35 (1)H-MRS spectra were of adequate quality for analysis.
In vivo image-guided (1)H-MRS for detection of liquid phase cholesteryl ester in carotid atherosclerotic plaques in humans is feasible.
[Show abstract][Hide abstract] ABSTRACT: This study sought to longitudinally investigate the relationship between a broad spectrum of serum inflammatory biomarkers and plaque inflammation assessed by (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT).
Both plaque inflammation and serum biomarkers of inflammation are associated with atherothrombotic events; however, the relationship between them is unclear.
We conducted a post hoc analysis of the dal-PLAQUE (A Randomized Placebo-Controlled Study of the Effect of RO4607381 on Progression or Regression of Atherosclerotic Plaque in Patients With Coronary Heart Disease [CHD] Including Patients With Other CHD Risk Factors), a randomized, placebo-controlled study of dalcetrapib, a cholesteryl ester transfer protein inhibitor, in 130 patients with coronary heart disease, or coronary heart disease risk equivalents on stable lipid-lowering therapy. Baseline and change after 3-month follow-up in inflammatory biomarker levels and baseline and change after 3-month follow-up in aorta and carotid (18)F-FDG PET/CT (mean maximum target-to-background ratio of the most diseased segment [TBRmds]) were analyzed.
Baseline myeloperoxidase positively correlated with baseline carotid TBRmds (rho = 0.25, p = 0.02). This correlation remained at the 3-month follow-up and was independent of traditional cardiovascular disease risk factors. Baseline lipoprotein-associated phospholipase A2 mass correlated with aorta TBRmds (rho = 0.21, p = 0.03). However, this correlation disappeared at the 3-month follow-up and was not independent of cardiovascular disease risk factors. There was no association between change from baseline in myeloperoxidase or lipoprotein-associated phospholipase A2 mass and change from baseline in aorta and carotid TBRmds. Baseline and change from baseline in high sensitivity C-reactive protein, interleukin 6, soluble P-selectin, soluble E-selectin, soluble intracellular adhesion molecule 1, soluble vascular cell adhesion molecule 1, and matrix-metalloproteinase 3 and 9 did not correlate with baseline or change from baseline in carotid or aorta TBRmds.
Our data show that, in patients with coronary heart disease or at high risk of coronary heart disease on stable lipid-lowering therapy, circulating myeloperoxidase levels are associated with carotid plaque inflammation. (A Randomized, Placebo-controlled Study of the Effect of RO4607381 on Progression or Regression of Atherosclerotic Plaque in Patients With Coronary Heart Disease [CHD] Including Patients With Other CHD Risk Factors [dal-PLAQUE]; NCT00655473).
[Show abstract][Hide abstract] ABSTRACT: To improve carotid 3T magnetic resonance imaging (MRI) dimension measurements in patients with overt atherosclerotic carotid artery disease.
In 31 patients with advanced atherosclerotic carotid artery disease, two high resolution (0.25 × 0.25 mm(2); HR) and two routinely used low resolution (0.50 × 0.50 mm(2); LR) carotid 3T MRI scans were performed within 1 month. After manual delineation of carotid wall contours in a dedicated image analyses program in eight slices covering the atherosclerotic plaque, image reproducibility, as well as the within-reader and between-reader variability were determined.
We found significantly higher intraclass correlation coefficients for total wall volume, mean wall area and mean wall thickness for the HR measurements (all p < 0.05). We found a significant lower signal-to-noise and contrast-to-noise ratio for the HR compared to the LR measurements. The carotid arterial wall dimension measurements of all parameters were significantly lower for the HR compared to the LR measurements. No significant differences were observed between the within-reader and between-reader reproducibility for HR versus LR measurements.
Increasing the in-plane resolution improves the reproducibility of 3T MRI carotid arterial wall dimension measurements. The use of HR imaging will contribute to a reduced sample size needed in intervention trials using MRI scanning of the carotid artery as surrogate marker for atherosclerosis progression.
MAGMA Magnetic Resonance Materials in Physics Biology and Medicine 09/2013; · 1.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: AimsLow 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 resultsWe 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.
European Heart Journal 11/2012; · 14.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: Carriers of a functional mutation in LCAT, encoding lecithin:cholesterol acyl transferase, are exposed to lifelong low high-density lipoprotein cholesterol (HDL-c) levels. We investigated whether LCAT mutation carriers have increased arterial stiffness as a marker of cardiovascular disease and whether arterial stiffness was associated with carotid wall thickening. METHODS: We assessed 45 carriers of LCAT mutations (mean age ± SD 46 ± 13 yrs) and 45 age-matched controls. Probands referred with established cardiovascular disease were excluded. We measured carotid-fermoral pulse wave velocity (PWV) and carotid artery wall thickening by ultrasound and 3.0 T magnetic resonance imaging. RESULTS: In carriers, HDL-c was lower (32 ± 12 vs. 59 ± 16 mg/dl; p < 0.0001) and triglycerides were higher (median 116 [IQR 80-170] vs. 71 [IQR 53-89] mg/dl; p < 0.001) vs. controls. PWV was higher in carriers vs. controls (7.9 ± 2.0 m/s vs. 7.1 ± 1.6 m/s; p < 0.01). This difference retained significance in multivariate analysis including age, sex, mean arterial pressure and body mass index, and after exclusion of carriers and controls with cardiovascular disease. Both in carriers and controls, PWV was correlated with wall thickening of the carotid arteries as assessed by ultrasound (R 0.50, p < 0.001 for carriers and R 0.36, p < 0.04 for controls) and 3.0 T magnetic resonance imaging (R 0.54, p < 0.001 for carriers and R 0.58, p < 0.001 for controls). CONCLUSION: Pulse wave velocity is increased in LCAT mutation carriers with low HDL-c and is associated with carotid wall thickening.
[Show abstract][Hide abstract] ABSTRACT: PURPOSE OF REVIEW: Cholesteryl ester transfer protein (CETP)-inhibiting drugs effectively raise HDL cholesterol. In 2007, the CETP inhibitor torcetrapib unexpectedly showed increased fatality and cardiovascular events, possibly related to increased blood pressure and aldosterone levels caused by torcetrapib. Since then, novel CETP inhibiting drugs have been investigated. This review will discuss the safety of the CETP-inhibiting drugs. RECENT FINDINGS: The novel CETP inhibitors dalcetrapib, evacetrapib and anacetrapib did not show harmful effects on blood pressure or aldosterone levels. Ultrasound brachial artery flow-mediated vasodilation, carotid MRI and F-fluordeoxyglucose PET imaging studies, showed that dalcetrapib therapy had neither harmful nor beneficial effects on endothelial function, atherosclerosis progression, or vessel wall inflammation. Recently, the clinical endpoint study investigating dalcetrapib was announced to be terminated early, after the second interim analysis showed that dalcetrapib lacked clinically meaningful efficacy. SUMMARY: Dalcetrapib, evacetrapib and anacetrapib did not show the harmful effects on aldosterone and blood pressure that were exhibited by torcetrapib, indicating that CETP inhibition is well tolerated. So far CETP inhibition did not show beneficial effects on clinical outcome. The phase III study with anacetrapib will give final answers on whether CETP inhibition can reduce cardiovascular events.
Current opinion in lipidology 09/2012; · 6.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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).
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.
Journal of the American College of Cardiology 12/2011; 58(24):2481-7. · 14.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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).
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.
[Show abstract][Hide abstract] ABSTRACT: Small autopsy studies and clinical practice indicated that carotid atherosclerosis develops in an asymmetrical helical pattern coinciding with regions of low shear stress. We investigated the distribution of carotid atherosclerosis as determined by maximum carotid intima-media thickness (CIMT), to assess if we could confirm this atherosclerotic configuration across various populations with different cardiovascular risk.
We used the individual baseline CIMT data from 3364 subjects from four recent international multicentre randomized controlled trials in which the carotid artery was systematically examined using the same ultrasound protocol and method to quantify CIMT. For each subject, circumferential information on the maximum CIMT of the left and right carotid arteries was obtained for the common carotid, bifurcation, and internal carotid artery segments. In each segment (common, bifurcation, internal), mixed modelling was used to study the differences in CIMT between angles, sides, gender, age, race, and studies. Each segment showed a different circumferential CIMT pattern. In all segments there were statistically significant differences between maximum CIMT across circumferential angles (p < 0.001); on average CIMT was highest in the posteromedial wall of the bifurcation and internal carotid segments and in the anterolateral wall of the common carotid segment. This asymmetric circumferential pattern was found to be identical in men and women, in young and old age, in different race groups, and across the studies.
We confirmed the asymmetrical helix-like distribution of atherosclerosis in the carotid arteries and expand the evidence by showing that the atherosclerotic configuration is similar across populations with different vascular risks and across gender, age, and race. This has implications for future design of carotid ultrasound studies, as the angle of insonation is an important predictor of maximum CIMT.
European journal of preventive cardiology. 05/2011; 19(4):687-97.
[Show abstract][Hide abstract] ABSTRACT: Decreased level of high density-lipoprotein cholesterol (HDL-C) is a rigorous predictor for future cardiovascular events. Much effort is being made to develop HDL-C-raising pharmacotherapies in the attempt to avert the pandemic of atherosclerotic disease. Important properties by which HDL-C-raising compounds are effective involve improvement of cholesterol uptake from macrophages in plaque for transport back to the liver, improvement of endothelial function, and anti-inflammatory effects. Vascular imaging can aid in the determination which HDL-C-raising compounds are effective. Ultrasound and MRI have proved suitable for assessment of structural changes of the vessel wall. Ultrasound can also be used or assessment of endothelial function. 18F-fluordeoxyglucose positron emission tomography has opened up the possibility to assess vessel wall inflammation. In this article we discuss these various imaging techniques and how they can assess efficacy as well as provide pathophysiologic information on the mechanism of action of novel HDL-C-raising drugs.
Current Atherosclerosis Reports 04/2011; 13(3):277-84. · 2.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dalcetrapib increases high-density lipoprotein cholesterol (HDL-C) levels through effects on cholesteryl ester transfer protein (CETP). As part of the dalcetrapib dal-HEART clinical trial programme, the efficacy and safety of dalcetrapib is assessed in coronary heart disease (CHD) patients in the dal-VESSEL study (ClinicalTrials.gov identifier: NCT00655538), the design and methods of which are presented here. RESEARCH DESIGN AND STUDY METHOD: Men and women with CHD or CHD risk equivalent, with HDL-C levels <50 mg/dL were recruited for a 36-week, double-blinded, placebo-controlled trial. After a pre-randomisation phase of up to 8 weeks, patients received dalcetrapib 600 mg/day or placebo in addition to their existing treatments. Brachial flow-mediated dilatation (FMD) measured by B-mode ultrasound represents endothelial function and is a validated marker for early atherosclerosis and cardiovascular disease risk.
The primary efficacy outcome is change from baseline in brachial FMD after 12 weeks. The primary safety endpoint is 24-hour ambulatory blood pressure monitoring (ABPM) assessed at week 4. Secondary endpoints include brachial FMD at 36 weeks, ABPM at 12 and 36 weeks, lipid profile, CETP mass and activity, and markers of inflammation, oxidation, and cardiovascular risk. Clinical endpoints are assessed as a composite endpoint for the dal-HEART Program.
In 19 European clinical centres, 476 subjects met inclusion criteria and have entered the study. In conclusion, the dal-VESSEL study is the largest multicentre trial with brachial FMD ever performed. The study assesses efficacy and safety of dalcetrapib on endothelial function, blood pressure, lipids, and clinical outcomes in CHD patients with below average HDL-C and will therefore provide vital information regarding its potential role in the preventative treatment of CHD risk.
Current Medical Research and Opinion 01/2011; 27(1):141-50. · 2.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Low endothelial shear stress (ESS) elicits endothelial dysfunction. However, the relationship between ESS and arterial remodeling and arterial stiffness is unknown in humans. We developed a 3.0-T MRI protocol to evaluate the contribution of ESS to arterial remodeling and stiffness.
Fifteen young (aged 26 ± 3 years) and 15 older (aged 57 ± 3 years) healthy volunteers as well as 15 patients with cardiovascular disease (aged 63 ± 10 years) were enrolled. Phase-contrast MRI of the common carotid arteries was used to derive ESS data from the spatial velocity gradients close to the arterial wall. ESS measurements were performed on 3 occasions and showed excellent reproducibility (intraclass correlation coefficient, 0.79). Multiple linear regression analysis accounting for age and blood pressure revealed that ESS was an independent predictor of the following response variables: carotid wall thickness (regression coefficient [b], -0.19 mm(2) per N/m(2); P=0.02), lumen area (b, -15.5 mm(2) per N/m(2); P<0.001), and vessel size (b, -24.0 mm(2) per N/m(2); P<0.001). Segments of the artery wall exposed to lower ESS were significantly thicker than segments exposed to higher ESS within the same artery (P=0.009). Furthermore, ESS was associated with arterial compliance, accounting for age, blood pressure, and wall thickness (b, -0.003 mm(2)/mm Hg per N/m(2); P=0.04).
Our carotid MRI data show that ESS is an important determinant of arterial remodeling and arterial stiffness in humans. The data warrant further studies to evaluate use of carotid ESS as a noninvasive tool to improve the understanding of individual cardiovascular disease risk and to assess novel drug therapies in cardiovascular disease prevention.
[Show abstract][Hide abstract] ABSTRACT: Current ultrasound protocols to measure carotid intima-media thickness (CIMT) in trials rather differ. The ideal protocol combines high reproducibility with a high precision in the measurement of the rate of change in CIMT over time and with a precise estimate of a treatment effect. To study these aspects, a post-hoc analysis was performed using data from two randomized double-blind, placebo-controlled trials: one among 872 subjects with familial hypercholesterolemia (FH) and the other among 752 subjects with mixed dyslipidemia (MD), respectively. Participants were randomized to torcetrapib or placebo on top of optimal atorvastatin therapy.
CIMT information was collected from the left and right carotid artery from two walls (the near and far wall) of three segments (common carotid, bifurcation, and internal carotid artery) at four different angles (right: 90, 120, 150, and 180 degrees on Meijer's carotid arc; left: 270, 240, 210, and 180 degrees, respectively). Based on combinations of these measurements, 60 different protocols were constructed to estimate a CIMT measure per participant (20 protocols for mean common CIMT, 40 protocols for mean maximum CIMT). For each protocol we assessed reproducibility (intra-class correlation coefficient (ICC), mean difference of duplicate base-line scans); 2-year progression rate in the atorvastatin group with its standard error (SE); and treatment effect (difference in rate of change in CIMT between torcetrapib and placebo) with its SE.
Reproducibility: ICC ranged from 0.77 to 0.91 among FH patients and from 0.68 to 0.86 among MD patients. CIMT progression rates ranged from -0.0030 to 0.0020 mm/year in the FH trial and from 0.00084 to 0.01057 mm/year in the MD trial, with SE ranging from 0.00054 to 0.00162 and from 0.00083 to 0.00229, respectively. The difference in CIMT progression rate between treatment arms ranged from -0.00133 to 0.00400 mm/year in the FH trial and from -0.00231 to 0.00486 mm/year in the MD trial. The protocol with the highest reproducibility, highest CIMT progression/precision ratio, and the highest treatment effect/precision ratio were those measuring mean common CIMT with measurements of the near and far wall at multiple angles. When the interest is in the mean maximum CIMT, protocols using multiple segments and angles performed the best.
Our findings support the position that the number and specific combination of segments, angles, and walls interrogated are associated with differences in reproducibility, magnitude, and precision of progression of CIMT over time, and treatment effect. The best protocols were mean common CIMT protocols in which both the near and far walls are measured at multiple angles.
Annals of Medicine 09/2010; 42(6):447-64. · 4.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Until recently, patients with heterozygous familial hypercholesterolemia (HeFH) were considered the best subjects for the assessment of changes in carotid intima-media thickness (cIMT) in randomized intervention trials. Our aims were to investigate whether contemporary statin-treated HeFH patients still show accelerated cIMT increase and to assess the impact of statin treatment, before and after random assignment, on atherosclerosis progression.
We retrospectively evaluated cIMT change, and prior statin treatment and postbaseline LDL-C change as predictors of cIMT change, in 1513 HeFH patients who were randomly assigned to the statin arms of the early ASAP and more recent RADIANCE 1, CAPTIVATE, and ENHANCE studies. In the 3 recent studies combined, mean cIMT increased at only 33%of the rate of the simvastatin-treated patients in the ASAP study (0.014 mm/2 years [95% confidence interval, -0.0003-0.028] versus 0.041 mm/2 years [95% confidence interval, 0.020-0.061]; P<0.05). Patients whose statin therapy could be intensified, as evidenced by an LDL-C decrease after the initiation of on-trial statin therapy, showed cIMT decrease in the first 6 to 12 months and a much lower cIMT increase measured over the full 2 years. In line with this, previously statin-naive HeFH patients showed a lower overall cIMT increase.
Over the years, intensification of statin therapy in HeFH patients has resulted in an impressive decrease in carotid atherosclerosis progression. In studies that assess other antiatherosclerotic modalities, statin therapy may still induce rapid changes in cIMT. For future cIMT studies, our analyses suggest that patient populations other than intensively pretreated HeFH patients should be selected and that the statin regimen should not be changed on study initiation.