Imaging of atherosclerosis.

It is now well recognized that the atherosclerotic plaques responsible for thrombus formation are not necessarily those that impinge most on the lumen of the vessel. Nevertheless, clinical investigations for atherosclerosis still focus on quantifying the degree of stenosis caused by plaques. Many of the features associated with a high-risk plaque, including a thin fibrous cap, large necrotic core, macrophage infiltration, neovascularization, and intraplaque hemorrhage, can now be probed by novel imaging techniques. Each technique has its own strengths and drawbacks. In this article, we review the various imaging modalities used for the evaluation and quantification of atherosclerosis.

Clinical imaging of the high-risk or vulnerable atherosclerotic plaque.

The study of atherosclerotic disease during its natural history and after therapeutic intervention will enhance our understanding of disease progression and regression and aid in selecting appropriate treatments. Several invasive and noninvasive imaging techniques are available to assess atherosclerotic vessels. Most of the standard techniques identify luminal diameter, stenosis, wall thickness, and plaque volume; however, none can characterize plaque composition and therefore identify the high-risk plaques. We will present the different imaging modalities that have been used for the direct assessment of the carotid, aortic, and coronary atherosclerotic plaques. We will review in detail the use of high-resolution, multicontrast magnetic resonance for the noninvasive imaging of vulnerable plaques and the characterization of plaques in terms of their various components (ie, lipid, fibrous, calcium, or thrombus).

Non-invasive imaging of atherosclerosis regression with magnetic resonance to guide drug development.

Slowing of progression and inducing the regression of atherosclerosis with medical therapy have been shown to be associated with an extensive reduction in risk of cardiovascular events. This proof of concept was obtained with invasive angiographic studies but these are, for obvious reasons, impractical for sequential investigations. Non-invasive imaging has henceforth replaced the more cumbersome invasive studies and has proven extremely valuable in numerous occasions. Because of excellent reproducibility and no radiation exposure, magnetic resonance imaging (MRI) has become the non-invasive method of choice to assess the efficacy of anti-atherosclerotic drugs. The high accuracy of this technology is particularly helpful in rare diseases where the small number of affected patients makes the conduct of outcome-trials in large cohorts impractical. With MRI it is possible to assess the extent, as well as the composition, of atherosclerotic plaques and this further enhances the utility of this technology.

Noninvasive in vivo human coronary artery lumen and wall imaging using black-blood magnetic resonance imaging.

BACKGROUND: High-resolution MRI has the potential to noninvasively image the human coronary artery wall and define the degree and nature of coronary artery disease. Coronary artery imaging by MR has been limited by artifacts related to blood flow and motion and by low spatial resolution. METHODS AND RESULTS: We used a noninvasive black-blood (BB) MRI (BB-MR) method, free of motion and blood-flow artifacts, for high-resolution (down to 0.46 mm in-plane resolution and 3-mm slice thickness) imaging of the coronary artery lumen and wall. In vivo BB-MR of both normal and atherosclerotic human coronary arteries was performed in 13 subjects: 8 normal subjects and 5 patients with coronary artery disease. The average coronary wall thickness for each cross-sectional image was 0.75+/-0.17 mm (range, 0.55 to 1.0 mm) in the normal subjects. MR images of coronary arteries in patients with >/=40% stenosis as assessed by x-ray angiography showed localized wall thickness of 4.38+/-0.71 mm (range, 3.30 to 5.73 mm). The difference in maximum wall thickness between the normal subjects and patients was statistically significant (P<0.0001). CONCLUSIONS: In vivo high-spatial-resolution BB-MR provides a unique new method to noninvasively image and assess the morphological features of human coronary arteries. This may allow the identification of atherosclerotic disease before it is symptomatic. Further studies are necessary to identify the different plaque components and to assess lesions in asymptomatic patients and their outcomes.

Effects of lipid-lowering by simvastatin on human atherosclerotic lesions: a longitudinal study by high-resolution, noninvasive magnetic resonance imaging.

BACKGROUND: This study was designed to investigate the effects of lipid-lowering by simvastatin on human atherosclerotic lesions. METHODS AND RESULTS: Eighteen asymptomatic hypercholesterolemic patients with documented aortic and/or carotid atherosclerotic plaques were selected for the study. A total of 35 aortic and 25 carotid artery plaques were detected. Serial black-blood MRI of the aorta and carotid artery of the patients was performed at baseline and 6 and 12 months after lipid-lowering therapy with simvastatin. The effects of the treatment on atherosclerotic lesions were measured as changes in lumen area, vessel wall thickness, and vessel wall area, a surrogate of atherosclerotic burden. Simvastatin induced a significant (P<0.01) reduction in total and LDL cholesterol levels at 6 weeks that was maintained thereafter. At 6 months, no changes in lumen area, vessel wall thickness, or vessel wall area were observed. However, at 12 months, significant reductions in vessel wall thickness and vessel wall area, without changes in lumen area, were observed in both aortic and carotid arteries (P<0.001). CONCLUSIONS: This in vivo human study demonstrates that effective and maintained lipid-lowering therapy by simvastatin is associated with a significant regression of atherosclerotic lesions. Our observation suggests that statins induce vascular remodeling, as manifested by reduced atherosclerotic burden without changes in the lumen.

Serial in vivo MRI documents arterial remodeling in experimental atherosclerosis.

BACKGROUND: Arterial remodeling in response to atherosclerosis may be outward (positive) or inward (negative) and is an important mechanism in the clinical manifestations of atherosclerosis and restenosis after percutaneous coronary interventions. Postmortem and intravascular ultrasound studies of arterial remodeling do not allow serial and noninvasive data to be obtained. In a rabbit model of atherosclerosis, we sought to validate MRI as a new tool for documentation of arterial remodeling. METHODS AND RESULTS: Watanabe heritable hyperlipidemic rabbits underwent serial MRI at baseline and 6 months after aortic balloon denudation. The lumen area had a small but significant (P=0.006) increase, from 4.36+/-0.16 to 4. 89+/-0.12 mm(2). There was a large, significant (P<0.0001) increase in the outer wall area, from 7.96+/-0.19 to 10.46+/-0.19 mm(2). The vessel wall area (a marker of atherosclerotic burden) increased significantly (P<0.0001), from 3.61+/-0.07 to 5.57+/-0.09 mm(2). Thus, the increase in atherosclerotic burden over time was completely accounted for by positive arterial remodeling. The subgroup used for histopathological validation confirmed a significant (P<0.0001) agreement between histopathology and MRI for assessment of all 3 parameters. CONCLUSIONS: MRI can provide serial and noninvasive data about the arterial wall, allowing assessment of arterial remodeling in this rabbit model. Thus, MRI appears to be a useful tool for the investigation of arterial remodeling both in native atherosclerosis and after percutaneous coronary intervention.

Noninvasive in vivo magnetic resonance imaging of experimental coronary artery lesions in a porcine model.

BACKGROUND: The ability to characterize and quantify coronary artery atherosclerotic lesions accurately, reproducibly, and noninvasively may allow the stratification of risk for future acute coronary syndromes and help direct therapeutic management. MRI has been shown to accurately characterize and quantify atherosclerosis; however, because of the combination of cardiac and respiratory motion artifacts, nonlinear course, and relatively small size of the coronary arteries, these techniques have not been able to be translated to the coronary system in vivo. METHODS AND RESULTS: Coronary lesions were induced in Yorkshire albino swine (n=6) with balloon angioplasty, and 4 weeks later MRI of the coronary artery lesions was performed. High-resolution in vivo images of the coronary artery wall and lesions were obtained with a double-inversion-recovery fast-spin-echo sequence in a 1.5-T MR system. There was good agreement between measurements of vessel wall thickness and area from MR images of the coronary arteries and the matched histopathology sections (n=43). The mean difference (MRI minus histopathology +/- SD) for mean wall thickness was 0.26+/-0.18 mm, and for vessel wall area, 5.65+/-3.51 mm(2). MRI was also able to visualize intralesion hematoma (sensitivity 82%, specificity 84%). CONCLUSIONS: Using a clinical MR system, we were able to image coronary artery lesions in vivo in an experimental porcine model. Further studies are needed to assess the ability of MRI to characterize coronary atherosclerotic lesions in vivo.

In vivo magnetic resonance evaluation of atherosclerotic plaques in the human thoracic aorta: a comparison with transesophageal echocardiography.

BACKGROUND: The structure and composition of aortic atherosclerotic plaques are associated with the risk of future cardiovascular events. Magnetic resonance (MR) imaging may allow accurate visualization and characterization of aortic plaques. METHODS AND RESULTS: We developed a noninvasive MR method, free of motion and blood flow artifacts, for submillimeter imaging of the thoracic aortic wall. MR imaging was performed on a clinical MR system in 10 patients with aortic plaques identified by transesophageal echocardiography (TEE). Plaque composition, extent, and size were assessed from T1-, proton density-, and T2- weighted images. Comparison of 25 matched MR and TEE cross-sectional aortic plaque images showed a strong correlation for plaque composition (chi(2) = 43.5, P<0.0001; 80% overall agreement; n = 25) and mean maximum plaque thickness (r = 0.88, n = 25; 4.56+/-0.21 mm by MR and 4.62+/-0.31 mm by TEE). Overall aortic plaque extent as assessed by TEE and MR was also statistically significant (chi(2) = 61.77, P<0.0001; 80% overall agreement; n = 30 regions). CONCLUSIONS: This study demonstrates that noninvasive MR evaluation of the aorta compares well with TEE imaging for the assessment of atherosclerotic plaque thickness, extent, and composition. This MR method may prove useful for the in vivo study of aortic atherosclerosis.

Atherosclerotic aortic component quantification by noninvasive magnetic resonance imaging: an in vivo study in rabbits.

OBJECTIVES: We sought to demonstrate the ability that noninvasive in vivo magnetic resonance imaging (MRI) has to quantify the different components within atherosclerotic plaque. BACKGROUND: Atherosclerotic plaque composition plays a critical role in both lesion stability and subsequent thrombogenicity. Noninvasive MRI is a promising tool for the characterization of plaque composition. METHOD: Thoracic and abdominal aortic atherosclerotic lesions were induced in rabbits (n = 5). Nine months later, MRI was performed in a 1.5T system. Fast spin-echo sequences (proton density-weighted and T2-weighted [T2W] images) were obtained (in-plane resolution: 350 x 350 microns, slice thickness: 3 mm). Magnetic resonance images were correlated with matched histopathological sections (n = 108). RESULTS: A significant correlation (p < 0.001) was observed for mean wall thickness and vessel wall area between MRI and histopathology (r = 0.87 and r = 0.85, respectively). The correlation was also present on subanalysis of the thoracic and upper part of the abdominal aorta, susceptible to respiratory motion artifacts. There was a significant correlation for plaque composition (p < 0.05) between MRI and histopathology for the analysis of lipidic (low signal on T2W, r = 0.81) and fibrous (high signal on T2W, r = 0.86) areas with Oil Red O staining. T2-weighted images showed greater contrast than proton density-weighted between these different components of the plaques as assessed by signal intensity ratio analysis with the mean difference in signal ratios of 0.47 (S.E. 0.012, adjusted for clustering of observations within lesions) being significantly different from 0 (t1 = 39.1, p = 0.016). CONCLUSIONS: In vivo noninvasive high resolution MRI accurately quantifies fibrotic and lipidic components of atherosclerosis in this model. This may permit the serial analysis of therapeutic strategies on atherosclerotic plaque stabilization.

Integration of vascular biology and magnetic resonance imaging in the understanding of atherothrombosis and acute coronary syndromes.

The interaction between the vulnerable atherosclerotic plaque prone to disruption and thrombus formation is the cornerstone of acute coronary syndrome (ACS). Although distinct from one another, the atherosclerotic and thrombotic processes appear to be interdependent, hence the term atherothrombosis. Inflammation is a crucial common pathophysiological mechanism. Overall, the association of plaque vulnerability and ACS has been well documented. Given the multifactorial origin of atherothrombosis the best preventive approach should be aggressive management of all the risk factors. New interventions should be directed toward decreasing vulnerability of the lesions thereby decreasing the risk of ACS.

High resolution ex vivo magnetic resonance imaging of in situ coronary and aortic atherosclerotic plaque in a porcine model.

Atherosclerotic plaque composition is central to the pathogenesis of plaque disruption and acute thrombosis. Thus, there is a need for accurate imaging and characterization of atherosclerotic lesions. Even though there is no ideal animal model of atherosclerosis, the porcine model is considered to most closely resemble human atherosclerosis. We report the feasibility of MR imaging and characterizing of atherosclerotic lesions from in situ coronary arteries and aortas in an ex vivo setting and validate this with histopathology. Coronary and aortic atherosclerosis was induced in Yucatan mini-swine (n=4) by a combination of atherogenic diet (6 months) and balloon injury. All coronary arteries were imaged ex vivo on the intact heart, preserving the curvature of their course. The aorta also underwent MR imaging. The MR images were correlated with the matched histopathology sections for both the coronary arteries (n=54) and the aortas (n=43). MR imaging accurately characterized complex atherosclerotic lesions, including calcified, lipid rich, fibrocellular and hemorrhagic regions. Mean wall thickness for the coronary arteries (r=0.94, slope: 0.81) and aortas (r=0.94, slope: 0.81) as well as aortic plaque area (r=0.97, slope: 0.90) was accurately determined by MR imaging (P<0.0001). Coronary artery MR imaging is not limited by the curvature of the coronary arteries in the heart. MR imaging accurately quantifies and characterizes coronary and aortic atherosclerotic lesions, including the vessel wall, in this experimental porcine model of complex atherosclerosis. This model may be useful for future study of MR imaging of atherosclerosis in vivo.

Right and left ventricular volume and ejection fraction by tomographic gated blood-pool scintigraphy.

UNLABELLED: Tomographic techniques separate overlying structures, permitting measurements of absolute ventricular volumes. The purpose of this study was to determine absolute right and left ventricular volume and ejection fraction measurements with tomographic gated equilibrium blood-pool scintigraphy (TMUGA) compared to MRI and conventional planar scintigraphy. METHODS: Eighteen patients were studied. Ventricular volumes for TMUGA and MRI were calculated by modified Simpson's rule. TMUGA regions were defined by constraints including phase analysis, intensity threshold and visual inspection. MRI studies were acquired with a fast gradient-echo, ECG-gated, breath-hold technique and boundaries were defined by a semiautomated contour method. Conventional gated first-pass radionuclide angiography (FP) and planar gated equilibrium blood-pool scintigraphy (PMUGA) were performed for RV EF and LV EF, respectively. RESULTS: TMUGA absolute right ventricular volumes showed excellent-correlation with MRI for both right ventricular volumes (r = 0.91, slope = 0.90, s.e.e. = 15.7) and left ventricular volumes (r = 0.96, slope = 0.88, s.e.e. = 18.2). For left ventricular ejection fraction, TMUGA also showed excellent correlation with MRI (r = 0.94, slope = 1.10, s.e.e. = 9.0) and planar MUGA (r = 0.97, slope = 1.23, s.e.e. = 6.2). For right ventricular ejection fraction, TMUGA showed good correlation with both MRI (r = 0.88, slope = 0.79, s.e.e. = 6.0) and first-pass planar scintigraphy (r = 0.86, slope = 1.2, s.e.e. = 7.9). CONCLUSION: Tomographic gated blood-pool scintigraphy absolute right and left ventricular volumes and ejection fractions show good correlation with accepted techniques. Further studies are necessary to define the reproducibility of this method.

The human high-risk plaque and its detection by magnetic resonance imaging.

The study of atherosclerotic disease during its natural history and after therapeutic intervention will enhance our understanding of the progression and regression of this disease and will aid in selecting the appropriate treatments. Several invasive and noninvasive imaging techniques are available to assess vessels in atherosclerotic disease. Most of the standard techniques, however, identify luminal diameter or stenosis, wall thickness, or plaque volume. None of the standard techniques can characterize the composition of an atherosclerotic plaque and therefore are incapable of identifying the high-risk plaques. High-resolution, multicontrast, magnetic resonance imaging (MRI) can noninvasively image vulnerable plaques and characterize plaques in terms of their different components (ie, lipid, fibrous, calcium, or thrombus). Application of MRI opens up whole new areas for diagnosis, prevention, and treatment of atherosclerosis.

Characterization of atherosclerotic plaques by magnetic resonance imaging.

The study of atherosclerotic disease during its natural history and after therapeutic intervention will enhance our understanding of the progression and regression of this disease and will aid in selecting the appropriate medical treatments or surgical interventions. Several invasive and noninvasive imaging techniques are available to assess atherosclerotic vessels. Most of these techniques are strong in identifying the morphological features of the disease, such as lumenal diameter and stenosis or wall thickness, and in some cases provide an assessment of the relative risk associated with the atherosclerosis. However, none of these techniques can fully characterize the composition of the atherosclerotic plaque in the vessel wall and, therefore, are incapable of identifying the vulnerable plaques. High-resolution, multi-contrast, magnetic resonance (MR) can non-invasively image vulnerable plaques, characterize plaques in terms of lipid and fibrous content, and identify the presence of thrombus or calcium. Application of MR imaging opens up whole new areas for diagnosis, prevention, and treatment (e.g., lipid-lowering drug regimens) of atherosclerosis.

New understanding of atherosclerosis (clinically and experimentally) with evolving MRI technology in vivo.

Atherosclerosis and its thrombotic complications are the major cause of morbidity and mortality in industrialized countries. Despite advances in our understanding of the pathogenetic mechanisms and new treatment modalities, the absence of an adequate noninvasive method for early detection limits the prevention or treatment of patients with various degrees and localizations of atherothrombotic disease. High-resolution magnetic resonance (MR) has recently emerged as one of the most promising techniques for the noninvasive study of atherothrombotic disease. Most importantly, MR can be used to characterize plaque composition and monitor progression. Thus, MR opens new strategies, ranging from the screening of high-risk patients for early detection and treatment as well as the monitoring of target areas for pharmacological intervention.

Molecular imaging for the diagnosis of high-risk plaque.

Despite advances in our understanding of the pathogenesis of atherosclerosis and new therapeutic modalities, the absence of an adequate method for early detection limits the prevention and treatment of the disease. High-resolution magnetic resonance has recently emerged as one of the most promising techniques for the non-invasive study of atherothrombotic disease, as it can characterize plaque composition and monitor progression. This review of plaque imaging focuses on the most recent technique: "molecular imaging", which uses specific contrast agents targeted to plaque components, and may allow for better stratification of "high-risk" plaque and "high-risk" patients.

Monitoring plaque inflammation in atherosclerotic rabbits with an iron oxide (P904) and (18)F-FDG using a combined PET/MR scanner.

PURPOSE: The aim of this study was to compare the ability of (18)F-FDG PET and iron contrast-enhanced MRI with a novel USPIO (P904) to assess change in plaque inflammation induced by atorvastatin and dietary change in a rabbit model of atherosclerosis using a combined PET/MR scanner. MATERIALS AND METHODS: Atherosclerotic rabbits underwent USPIO-enhanced MRI and (18)F-FDG PET in PET/MR hybrid system at baseline and were then randomly divided into a progression group (high cholesterol diet) and a regression group (chow diet and atorvastatin). Each group was scanned again 6 months after baseline imaging. R2* (i.e. 1/T2*) values were calculated pre/post P904 injection. (18)F-FDG PET data were analyzed by averaging the mean Standard Uptake Value (SUVmean) over the abdominal aorta. The in vivo imaging was then correlated with matched histological sections stained for macrophages. RESULTS: (18)F-FDG PET showed strong FDG uptake in the abdominal aorta and P904 injection revealed an increase in R2* values in the aortic wall at baseline. At 6 months, SUVmean values measured in the regression group showed a significant decrease from baseline (p = 0.015). In comparison, progression group values remained constant (p = 0.681). R2* values showed a similar decreasing trend in the regression group suggesting less USPIO uptake in the aortic wall. Correlations between SUVmean or Change in R2* value and macrophages density (RAM-11 staining) were good (R(2) = 0.778 and 0.707 respectively). CONCLUSION: This experimental study confirms the possibility to combine two functional imaging modalities to assess changes in the inflammation of atherosclerotic plaques. (18)F-FDG-PET seems to be more sensitive than USPIO P904 to detect early changes in plaque inflammation.

Design and performance evaluation of a whole-body Ingenuity TF PET-MRI system.

The Ingenuity TF PET-MRI is a newly released whole-body hybrid PET-MR imaging system with a Philips time-of-flight GEMINI TF PET and Achieva 3T X-series MRI system. Compared to PET-CT, modifications to the positron emission tomography (PET) gantry were made to avoid mutual system interference and deliver uncompromising performance which is equivalent to the standalone systems. The PET gantry was redesigned to introduce magnetic shielding for the photomultiplier tubes (PMTs). Stringent electromagnetic noise requirements of the MR system necessitated the removal of PET gantry electronics to be housed in the PET-MR equipment room. We report the standard NEMA measurements for the PET scanner. PET imaging and performance measurements were done at Geneva University Hospital as described in the NEMA Standards NU 2-2007 manual. The scatter fraction (SF) and noise equivalent count rate (NECR) measurements with the NEMA cylinder (20 cm diameter) were repeated for two larger cylinders (27 cm and 35 cm diameter), which better represent average and heavy patients. A NEMA/IEC torso phantom was used for overall assessment of image quality. The transverse and axial resolution near the center was 4.7 mm. Timing and energy resolution of the PET-MR system were measured to be 525 ps and 12%, respectively. The results were comparable to PET-CT systems demonstrating that the effect of design modifications required on the PET system to remove the harmful effect of the magnetic field on the PMTs was negligible. The absolute sensitivity of this scanner was 7.0 cps kBq(-1), whereas SF was 26%. NECR measurements performed with cylinders having three different diameters, and image quality measurements performed with IEC phantom yielded excellent results. The Ingenuity TF PET-MRI represents the first commercial whole-body hybrid PET-MRI system. The performance of the PET subsystem was comparable to the GEMINI TF PET-CT system using phantom and patient studies. It is conceived that advantages of hybrid PET-MRI will become more evident in the near future.