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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Circulation. Author manuscript; available in PMC Apr 26, 2011.
Published in final edited form as:
PMCID: PMC3003265
NIHMSID: NIHMS250604

High-Resolution Magnetic Resonance Imaging Enhanced With Superparamagnetic Nanoparticles Measures Macrophage Burden in Atherosclerosis

Abstract

Background

Macrophages contribute to the progression and acute complications of atherosclerosis. Macrophage imaging may serve as a biomarker to identify subclinical inflamed lesions, to predict future risk, and to aid in the assessment of novel therapies.

Methods and Results

To test the hypothesis that nanoparticle-enhanced, high-resolution magnetic resonance imaging (MRI) can measure plaque macrophage accumulation, we used 3-T MRI with a macrophage-targeted superparamagnetic nanoparticle preparation (monocrystalline iron oxide nanoparticles-47 [MION-47]) in cholesterol-fed New Zealand White rabbits 6 months after balloon injury. In vivo MRI visualized thickened abdominal aortas on both T1- and T2-weighted spin-echo images (T1 spin echo, 20 axial slices per animal; T2 spin echo, 28 slices per animal). Seventy-two hours after MION-47 injection, aortas exhibited lower T2 signal intensity compared with before contrast imaging (signal intensity ratio, aortic wall/muscle: before, 1.44±0.26 versus after, 0.95±0.22; 164 slices; P<0.01), whereas T1 spin echo images showed no significant change. MRI on ex vivo specimens provided similar results. Histological studies colocalized iron accumulation with immunoreactive macrophages in atheromata. The magnitude of signal intensity reduction on T2 spin echo in vivo images further correlated with macrophage areas in situ (150 slices; r=0.73). Treatment with rosuvastatin for 3 months yielded diminished macrophage content (P<0.05) and reversed T2 signal intensity changes (P<0.005). Signal changes in rosuvastatin-treated rabbits correlated with reduced macrophage burden (r=0.73). In vitro validation studies showed concentration-dependent MION-47 uptake by human primary macrophages.

Conclusion

The magnitude of T2 signal intensity reduction in high-resolution MRI after administration of superparamagnetic phagocytosable nanoparticles can assess macrophage burden in atheromata, providing a clinically translatable tool to identify inflamed plaques and to monitor therapy-mediated changes in plaque inflammation.

Keywords: atherosclerosis, inflammation, macrophages, magnetic resonance imaging, nanoparticles

Accumulation of activated macrophages influences clinical outcomes of cardiovascular diseases such as atherosclerosis and its acute complications, cardiac remodeling after acute infarction, and arterial and valvular calcification. In atherosclerosis, macrophage accumulation initiates lesion development and triggers clinical events by elaborating various molecules that promote inflammation, plaque disruption, and subsequent thrombus formation.14 However, conventional anatomic measures of advanced lesions (eg, plaque size or luminal stenoses) do not necessarily correlate with macrophage content. Imaging of macrophages should therefore offer a much-needed strategy for identifying inflamed plaques, often precursors of acute thrombotic events, enabling pathophysiological investigations, and assessing the effects of interventions.

Molecular imaging visualizes specific cell types or biological processes.59 Magnetic resonance imaging (MRI) noninvasively produces tomographic images with high soft-tissue contrast and excellent spatial resolution. Previous studies, including ours, reported that MRI with a 1.5-T scanner detects the progression and regression of aortic atherosclerosis in rabbits,10,11 characterizes human plaque components,12 and monitors changes in plaques in patients during drug interventions.13 The introduction of macrophage-targeted superparamagnetic nanoparticles improves the capabilities of MRI to image vascular targets specifically.14,15 Macrophages internalize such nanoparticles, altering the local magnetic field and thus producing the T2 shortening effect as visualized by signal reduction.1619 The present study used a 3-T clinical MRI scanner in combination with recently developed biocompatible monocrystalline iron oxide nanoparticles-47 (MION-47) to test the specific hypothesis that high-resolution MRI enhanced with superparamagnetic nanoparticles can measure macrophage accumulation in atherosclerotic plaques and monitor changes in inflammatory burden during statin treatment.

Methods

See the online-only Data Supplement for detailed methods.

Animal Protocol

Aortic atherosclerosis was induced in 9 male New Zealand White rabbits through consumption of an atherogenic diet and mechanical injury, as previously described.11,20 In 3 rabbits, the atherogenic diet was halted at 3 months, and rosuvastatin (1 mg · kg−1 · d−1, Astra-Zeneca, London, UK) was administered mixed in a regular diet; the 6 other rabbits continued the atherogenic diet.

Superparamagnetic Nanoparticles

MION-47 has a ≈5-nm diameter core of superparamagnetic iron oxide coated with a ≈10-nm-thick dextran layer and has a long blood half-life, which facilitates its accumulation in macrophages of atherosclerotic plaques. The characteristics of MION have been described previously.17,21

A previous study rigorously evaluated toxicity of a similar class of nanoparticles.22 Researchers in this study infused rats and dogs with up to 168 mg Fe/kg AMI-25. Peak concentrations of Fe were found in the liver after 2 hours and in the spleen after 4 hours. Fe slowly cleared from the liver (half-life, 3 days) and spleen (half-life, 4 days) and was incorporated into the hemoglobin of erythrocytes in a time-dependent fashion. Histological and serological studies detected no acute or subacute toxic effects. In addition, MION-47 has similar size and biological properties as ferumoxtran-10, a Food and Drug Administration–approved agent.23

MION-47 was infused via an ear vein (10 mg Fe/kg, ≈40 mg Fe per rabbit). This dose was chosen on the basis of a preliminary in vivo MRI study comparing the effects of 2.6, 10, and 30 mg Fe/kg on changes in T2 signal intensity (SI) on spin-echo (SE) images. The recommended dose of ferumoxtran is 2.6 mg Fe/kg and of ferumoxytol is 7 mg Fe/kg, with higher doses possible in severely anemic patients. Although 2.6 mg Fe/kg produced no significant T2 effect on the aorta, 30 mg Fe/kg resulted in overwhelming signal reduction in various tissues surrounding the aorta, eg, back muscles. Seventy-two hours after injections of 10 mg Fe/kg MION-47, the signal loss in back muscles had already returned to baseline while reliably producing T2 signal reduction of the atherosclerotic aorta in these preliminary experiments.

MRI Procedure

Rabbits were sedated and imaged supine in a GE 3-T MRI system using a 4-channel knee coil. Twenty-eight axial slices on T2-weighted SE sequence (echo time, 34 ms; repetition time, 1800 ms) and 20 axial slices on T1-weighted fast SE (echo time, 13 ms; repetition time, 800 ms) of the abdominal aorta were acquired. Other general conditions included the following: number of excitations, 6; field of view, 6×6 cm; slice/gap, 2.0/1.0 mm; data matrix, 256×192; and in-plane resolution, 234×312 μm, plus spatial/spectral saturation pulses to null blood and peri-adventitial fat signal.

Results

Human Primary Macrophages Internalize MION-47 In Vitro

Initial validation studies examined in vitro whether macrophages internalize MION-47. After incubation with MION-47, human primary macrophages differentiated in culture media containing 5% human serum for 14 days tended to accumulate iron particles in a concentration-dependent manner at greater levels than did day 1 monocytes (Figure 1A and 1B). Iron nanoparticle uptake, if any, in cultured human smooth muscle and endothelial cells fell below the threshold of detection of the assay.

Figure 1
Kinetics of superparamagnetic nanoparticles (MION-47). A, In vitro macrophage uptake of MION-47 increased during differentiation from day 1 to 14. The cultured human primary macrophages contained MION-47 in a concentration-dependent manner (0, 30, 100, ...

3-T MRI Detects Progression of Atherosclerosis

Normocholesterolemic rabbits usually have an abdominal aortic wall thinner than 200 to 300 μm. The 3-T MRI system used in the present study, which afforded resolutions of 234×312 μm per pixel, barely visualized the normal aortic wall (Figure 2A). After mechanical injury and cholesterol supplementation for 3 or 6 months, however, this instrumentation readily detected the thickened wall (Figure 2B). The aortic wall area on T2SE correlated well with the histomorphometric measurements (Figure 2C). The vessel wall appeared isointense to muscle on T1SE, whereas it generally appeared brighter than muscle on T2SE (Figure 2D).

Figure 2
MRI (3 T) detects atherosclerotic plaque burden in hypercholesterolemic rabbits. A, MRI (3 T) barely visualized normal rabbit abdominal aorta in vivo. B, MRI (3 T) detected thickened aortic wall on a T2-weighted sequence (T2SE) in vivo 3 or 6 months after ...

MION-47 Produces T2 Signal Reduction in Atherosclerotic Aortic Wall MRIs

Plasma iron concentrations in rabbits increased dramatically immediately after MION-47 injection as expected (10 mg Fe/kg), and returned to the levels of control rabbits within 72 hours (Figure 3A). MRI showed vessel wall signal reduction on T2SE in vivo at 24 hours (not shown) and 48 hours after MION-47 injection (Figure 3B). T2-weighted signal also declined in other tissues, including back muscle (Figure 3B). This SI decline in atherosclerotic aortas persisted at 72 hours; however, other organs, including back muscles, rebounded to their initial SIs (Figure 3C). Iron nanoparticles did not appear to alter the aortic wall SI on T1SE (Figure 3C). Superimposing subtraction pseudocolor images (Figure 4A, top) illustrates the localization and magnitude of T2 signal reduction. Reconstructing the axial MRIs 3-dimensionally into the coronal views demonstrated that T2 signal reduction occurred in the entire abdominal aorta, although its magnitude varied (Figure 4A, bottom).

Figure 3
Superparamagnetic iron nanoparticles (MION-47) produced T2-signal reduction in atherosclerotic plaques. A, In vivo kinetics of MION-47 in rabbits. Plasma concentrations of iron after MION-47 injection were determined by the quantitative colorimetric iron ...
Figure 4
Superparamagnetic nanoparticles (MION-47) reduced signal on T2SE consistently in atherosclerotic aortas. A, top, Axial MRIs (left and middle) showed the T2 signal reduction in the abdominal aorta of a cholesterol-fed rabbit 72 hours after MION-47 injection ...

Quantitative analysis of 164 MRI slices from 6 hypercholesterolemic rabbits on atherogenic diet without rosuvastatin treatment demonstrated that MION-47 administration (10 mg Fe/kg) reduced the T2-SI in the aortic wall 72 hours after injection, whereas T2-SI in back muscles did not differ substantially between preadministration and postadministration images (Figure 4B). These quantitative data agree with representative images shown in Figures 3C and and4A.4A. Despite the lack of apparent change in muscle T2-SI, further normalizing the aortic wall SI by the muscle SI on each MRI (SI ratio=aortic wall SI/back muscle SI) enabled the measurement of net T2-SI reduction in the aorta and compensated for the superior-inferior inhomogeneity of the MRI receiver coil. The data demonstrated that MION-47 produced significant T2-SI changes in all 28 slices of an individual rabbit (Figure 4C). Notably, all 6 rabbits studied showed similar results (164 slices; Figure 4D), which correlates with the data on the aortic wall T2-SI (Figure 4B). In contrast, MION-47 injection did not substantially alter the SI ratio on T1SE (Figure 4E). Ex vivo MRI on excised aortas further validated the MION-47–mediated T2-SI changes in vivo (Figure 5). Fixatives such as paraformaldehyde may affect MR signal characteristics24; in our past work, however, it did not cause appreciable alterations in SI.12 Moreover, in the present study, fixation does not appear to affect the colocalization of iron and macrophages on histological examination, which correlates with regions of T2-SI loss on MRI. Arteries from rabbits injected with MION-47 show T2-SI suppression even after paraformaldehyde fixation.

Figure 5
MRI validated ex vivo the T2 signal reduction effect of MION-47 administration. Before MION-47 injection, the ex vivo atherosclerotic wall showed high T2-SI (top left; ex vivo, pre). The image localizer indicates levels of slices 1 and 2 (bottom). Both ...

T2-SI Changes In Vivo Correlate With Macrophage Accumulation In Situ

Macrophage immunostaining and iron staining corroborated the mechanisms of T2-SI loss in the atherosclerotic aorta of hypercholesterolemic rabbits in vivo and ex vivo (Figure 6A through 6C). Conversely, segments of the aorta that exhibited little (if any) T2-SI reduction contained sparse macrophages or iron (Figure 6D).

Figure 6
The magnitude of MION-47–mediated T2-SI reduction is associated with the extent of macrophage accumulation in rabbit aortic atherosclerosis. A and B, MRIs show similar patterns of T2-SI reduction in vivo and ex vivo. C, Histological analyses of ...

The Magnitude of T2-SI Reduction Quantitatively Reflects Plaque Macrophage Burden

The present study tested the specific hypothesis that MRI can quantify macrophage burden in atherosclerosis by examining whether T2-SI changes correlate with macrophage burden. Macrophage content in atherosclerotic plaques represented by percent immunoreactive area in situ (absolute positive area/absolute aortic wall area) correlated closely with the magnitude of T2-SI reduction in vivo (Figure 7A). These data agree with the representative images shown in Figure 6. In contrast, the magnitude of T2-SI reduction correlated poorly with the wall area (Figure 7B). Collectively, these results suggest that nanoparticle-enhanced MRI can measure the extent of macrophage accumulation and does not merely reflect anatomic plaque burden, affirming our study hypothesis.

Figure 7
Quantitative analyses correlate T2-SI changes and precontrast T2-SI levels with macrophage burden. A, Quantitative analysis demonstrated that in vivo magnitude of T2-SI reduction correlated with macrophage content in situ (percent macrophage-positive ...

T2-SI Reduction Correlates With Pre–MION-47 T2 SI Levels

Accumulating evidence suggests that hyperintensity on T2-weighted MRI is associated with inflamed lesions that contain increased free water content (water not bound by macromolecules or organelles).25 Aortic wall with higher SI on T2SE before MION-47 administration produced greater T2-SI changes after injection (Figure 7C). Similarly, precontrast T2-SI levels correlated with macrophage accumulation (Figure 7D), indicating that precontrast T2-SI may also reflect, indirectly via water content, macrophage burden in atherosclerosis.

Statin Administration Decreases Macrophage Accumulation and T2-SI Reduction in Atherosclerosis

We further tested whether an intervention could alter this imaging index of macrophage content. Rosuvastatin administration was started in rabbits 3 months after mechanical injury and initiation of a high-cholesterol diet. The 3 rabbits treated with rosuvastatin added to a standard diet for 3 months had lower total cholesterol levels than the 6 untreated rabbits (control group, 1122±89 mg/dL; rosuvastatin group, 63±18 mg/dL; P<0.01). Rosuvastatin-treated rabbits exhibited reversal of T2-SI changes in atherosclerosis in vivo and ex vivo, validated by histological analyses exhibiting less macrophage burden and iron accumulation within the intima (Figure 8A and 8B) compared with rabbits that did not receive rosuvastatin (Figure 6). MION-47 did not significantly reduce T2-SI in rosuvastatin-treated rabbits (Figure 8C). The magnitude of T2-SI reduction in rabbits treated with rosuvastatin was significantly lower than that of controlled rabbits that continued on the atherogenic diet (Figure 8D). Furthermore, these 2 factors, T2-SI changes and macrophage burden, were closely correlated (Figure 8E; see Figure 7A for the untreated rabbits). Although precontrast T2-SI was not substantially decreased in rosuvastatin-treated rabbits (Figure 8F), this metric remained positively correlated with T2-SI reduction (Figure 8G).

Figure 8
Cholesterol lowering with rosuvastatin reduced macrophage accumulation and T2-SI reduction. A, MION-47 administration produced few, if any, T2-SI changes in vivo and ex vivo in the aortic wall of a rabbit treated for 3 months with rosuvastatin. Histological ...

Discussion

Macrophage burden influences clinical outcomes of various inflammatory diseases, including atherosclerosis.1,3,4 Therefore, development of novel circulating or imaging biomarkers targeting macrophages should help identify patients with subclinical inflamed lesions and provide new and important insights into preventive cardiovascular medicine. The present study demonstrated in vivo and validated ex vivo and in situ that the magnitude of T2-SI reduction, resulting from the presence of superparamagnetic iron nanoparticles (MION-47), reflects the extent of macrophage accumulation in the aorta of hypercholesterolemic rabbits, supporting the ability of this technique to measure inflammatory burden in atherosclerosis. Such a noninvasive imaging approach might also monitor changes in inflammation during therapeutic interventions.

Previous studies, including our own, proved MRI useful in detecting plaque size changes during the progression or regression of experimental atherosclerosis.10,11,13 Yet, anatomic assessments of atherosclerosis may not reflect the pathophysiology underlying acute clinical events. We and others established the role of macrophage products in the onset of acute thrombotic complications of atherosclerosis.24,20,26 Recent contributions have linked clinical evidence, macrophage biology, and molecular imaging research to establish the feasibility of visualizing macrophage burden or activation in cardiovascular diseases.8,9,18,19,27,28 The present results affirm that an MR approach combined with ultrasmall superparamagnetic iron oxide particles can quantitatively assess inflammatory burden within the plaque. This imaging approach, when translated to humans, should aid the study of patients with subclinical high-risk lesions.

Clinical evidence established that cholesterol lowering reduces acute coronary events.29,30 Preclinical studies, including our own, further demonstrated that dietary cholesterol lowering and statin treatment can limit inflammation, improve endothelial activation/dysfunction, and limit monocyte/macrophage infiltration in arteries.1,2,20,26,31 Diminished macrophage burden should limit proteolytic and thrombogenic activities in atheromata, reducing cardiovascular risk. Therefore, establishing methods that can noninvasively monitor changes in plaque macrophage content or activity during interventions will likely provide new insights into preventive cardiovascular medicine and offer powerful tools for choosing doses and assessing efficacy in pilot clinical trials on novel antiinflammatory therapies. Indeed, the present results shed mechanistic light on recent clinical studies that indirectly suggested that an antiinflammatory effect of statins may contribute to their clinical benefit.32,33

Accumulating evidence suggests that macrophages internalize superparamagnetic iron nanoparticles to a greater extent than do endothelial and smooth muscle cells.16,34 The present study shows in vitro that MION-47 uptake by macrophages depends on their state of differentiation. The underlying mechanisms of macrophage uptake of such MRI contrast agents remain incompletely understood and may involve multiple mechanisms (eg, fluid-phase versus receptor-mediated endocytosis).16,35 Recent studies suggested the role of several molecules in this process, including macrophage-scavenger receptor A and integrin Mac-1 (CD11b/CD18).36,37 Activation of macrophages may also enhance the uptake of superparamagnetic nanoparticles.37 Although the mechanisms of endocytosis remain uncertain, the T2-SI reduction caused by iron accumulation in macrophages reflects metabolic activity of these proinflammatory phagocytes, providing direct relevance to complications of atherosclerosis.

Increased iron accumulation in inflamed plaques may involve other factors. Enhanced vascular permeability resulting from injured endothelium or leaky microvessels may promote nano-particle penetration into atherosclerotic lesions, augmenting access of the iron oxide to macrophages. The long half-life of the latest class of ultrasmall superparamagnetic iron oxide particles, including MION-47 and ferumoxtran-10, also favors efficient accumulation within plaques. In addition, hyperintense appearance on T2-weighted MRI without any enhancing agents likely results from increased free water.25,38 Thus, the association of inflammation in atherosclerosis with local edema may lead indirectly to its detection. Oxidative stress mediated by reactive oxygen species may also affect T2-SI.39

In support, a previous study correlated T2-SI with serum levels of biomarkers of inflammation in humans.40 Extensive quantitative analyses in the present study positively correlated precontrast T2-SI and plaque macrophage content (Figure 7C). Precontrast T2-SI further associated with the magnitude of T2-SI reduction in atherosclerotic aortas (Figure 7D). Intervention with rosuvastatin, an agent with lipid-lowering and likely antiinflammatory actions, further supported these findings. As discussed above, cholesterol lowering improves aspects of endothelial cell dysfunction and reduces macrophage accumulation.20,26,31 The present study demonstrates that statin treatment reduced total cholesterol levels in hypercholesterolemic rabbits and substantially reduced T2-SI in both precontrast and postcontrast images (Figure 8).

This investigation used a 3-T high-resolution clinical MRI scanner and consistently produced satisfactory in vivo plaque images. The spatial resolution produced in this study (234×312 μm) should suffice for imaging macrophage burden in human carotid or proximal coronary arteries. MRI combined with the superparamagnetic iron nanoparticles documented here presents a favorable method for screening and monitoring arteries in patients because of its noninvasive nature and the absence of iodine-based contrast or radioactive agents. Although recent developments now enable positive contrast with superparamagnetic iron nanoparticles,41 the techniques used here permit clinical translation without modification of the software on the MRI scanner.

Recent efforts have also attempted to establish noninvasive MRI as a tool for detecting other aspects of plaque inflammation, including cell growth or apoptosis,42 thin fibrous caps,43 intraplaque microvessels or hemorrhage,44,45 thrombus formation,46 and lipids.47,48 Ongoing studies are further exploring the feasibility of visualizing plaque macrophages in a manner more specific to the activated state using small-molecule conjugates49 or detecting specific molecules associated with acute complications of atherosclerosis such as myeloperoxidase, a product of macrophages and other inflammatory leukocytes, and vascular cell adhesion molecule 1.50

The present study expands more than a decade of fundamental research into the inflammatory mechanisms that prevail in atheromata and promote its clinical expression.1,2 Gauging plaque macrophage accumulation as a well-validated indicator of local inflammatory status has several clinical applications, including the assessment of the inflammatory burden, rather than the mere anatomy, of atherosclerotic plaques in individual patients before clinical complication occurs. Visualizing macrophage accumulation or function as a biomarker thus offers a potentially powerful strategy in personalized preventive medicine. This method will also provide a research tool to further dissect the role of vascular inflammation in clinical outcomes. Finally, noninvasive imaging of macrophage burden directly implicated in plaque pathobiology may furnish an important functional biomarker for the evaluation of novel antiinflammatory therapies in humans.

CLINICAL PERSPECTIVE

Accumulation of macrophages influences clinical outcomes of various inflammatory diseases, including atherosclerosis. Particularly, these proinflammatory phagocytes promote not only development of atherosclerosis but also its acute thrombotic complications. Development of novel circulating or imaging biomarkers targeting macrophages should thus help to identify patients with subclinical inflamed lesions and to provide new and important insights into preventive cardiovascular medicine. Molecular or functional imaging, a rapidly emerging technology, visualizes biological or pathological processes in specific organs or disease contexts, in addition to providing anatomic information. The present study represents modern molecular imaging that can assess vascular inflammation. We demonstrate that high-resolution 3-T MRI enhanced with superparamagnetic iron nanoparticles can measure inflammatory burden in atherosclerosis of hypercholesterolemic rabbits. Macrophages internalize such iron particles, most likely via phagocytosis, thus changing the magnetic field in inflamed tissues. The present study demonstrates that the magnitude of T2-weighted signal intensity loss, reflecting phagocytic activity of macrophages, is associated positively with the extent of accumulation of these immune cells in atherosclerotic plaques. Such a noninvasive imaging approach might also offer a powerful tool to monitor the effects of antiinflammatory therapies in clinical practice or during clinical trials for new drugs. Our study indeed reports that the magnitude of T2-weighted signal intensity loss significantly decreased after statin treatment and correlated well with the reduction of lesional macrophage accumulation. Furthermore, such macrophage-targeted molecular imaging should provide novel insight into the mechanisms of atherosclerosis and its acute complications.

Acknowledgments

We thank Dr Robert Glynn for statistical analysis; Drs Hirokazu Fujiwara, Raymond Kwong, and Eric Larose for their help with protocol development; and Joan Edgett and Sara Karwacki for their editorial assistance.

Sources of Funding

This work was supported in part by grants from the Reynolds Foundation (Drs Libby and Weissleder), the National Institutes of Health (HL56895 to Drs Libby, Aikawa, and Ganz; HL66086 to Dr Aikawa; HL80472 to Dr Libby; HL078641 to Dr Weissleder; TPEN grant U01-HL080731 to Drs Weissleder and Libby; U41RR19703 to D.F. Kacher), the AstraZeneca Investigator-Sponsored Study Program (Dr Aikawa), the Japan Heart Foundation/Bayer (Dr Morishige), and the Uehara Memorial Foundation (Dr Morishige).

Footnotes

The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.109.891804/DC1.

Disclosures

Dr Aikawa has received a research grant from AstraZeneca. Dr Ganz has received honoraria from Pfizer for his speakers’ bureau appointments. Dr Libby has served as an unpaid consultant to and member of the steering committees of investigator-initiated clinical trials for Astra-Zeneca, including A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID), Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), and Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN). The other authors report no conflicts.

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