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.

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.

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.

Serial magnetic resonance imaging correlates with neurological outcome in an experimental model of spinal cord ischemia.

BACKGROUND: Paraplegia complicating surgical thoracoabdominal aneurysm (TAA) repair remains an unpredictable and poorly understood phenomenon. The ability to identify patients at increased risk of delayed paraplegia before the process becomes irreversible could allow early interventions to attenuate this risk. METHODS: In a rabbit model of infra-renal spinal cord ischemia, serial T2 weighted (T2W) magnetic resonance (MR) imaging was performed 2- and 8 h after the ischemic insult with changes correlated with clinical outcome. Using the axial T2W images, signal intensity measurements of the lateral horns of the spinal cord were acquired, both above (that is, thoracolumbar cord) and below (that is, lumbar cord) the renal arteries. This ratio (lumbar/thoracolumbar cord signal intensity) was evaluated and compared between groups. RESULTS: No changes were seen in the signal intensity of rabbits that remained neurologically intact. Rabbits with delayed paralysis showed a significant (P<0.01) decrease in signal intensity ratio at 2 h (1.13+/-0.03), while a significant (P<0.01) increase was noted in those rabbits with immediate persistent paralysis (1.43+/-0.04). There was a significant (P<0.01) increase in the signal intensity ratios at 2 h in the delayed paralysis group (1.55+/-0.14), with a further significant (P<0.01) increase at 8 h in the immediate persistent paralysis group (1.76+/-0.07). CONCLUSIONS: Findings on MR imaging can differentiate clinical outcomes in this experimental model of spinal cord ischemia. While further studies are required, MR could be useful in predicting which patients are at risk for delayed paraplegia after TAA repair.

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.

Characterization of aortic root atherosclerosis in ApoE knockout mice: high-resolution in vivo and ex vivo MRM with histological correlation.

In vivo, cardiac-gated, black-blood, and ex vivo magnetic resonance microscopy (MRM) images of the aortic root, and histopathology data were obtained from 12 transgenic and wild-type (WT) mice. MRM was performed using a black-blood imaging spin-echo sequence with upstream and downstream in-flow saturation pulses to obtain aortic root images in three contrast techniques: proton density-weighted (PDW), T(1)- (T(1)W), and T(2)-weighted (T(2)W). Aortic wall thickness and area were measured and correlated with histopathology data (R > 0.90). Ex vivo lesion components (lipid core, fibrous tissue, and cell tissue) were identified and characterized by differing image contrast in PDW, T(1)W, and T(2)W MRM, and by histopathology. The differences between WT and transgenic mice for maximal wall thickness and area were statistically significant (P < 0.05). This study demonstrates the feasibility of in vivo murine aortic root lesion assessment and ex vivo plaque characterization by MRM.

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.

The assessment of the vulnerable atherosclerotic plaque using MR imaging: a brief review.

The study of atherosclerotic disease during its natural history and after therapeutic intervention may 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 non-invasive imaging techniques are available to assess atherosclerotic disease 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 atherosclerotic disease. 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 and 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 of atherosclerosis.

Cardiac gated breath-hold black blood MRI of the coronary artery wall: an in vivo and ex vivo comparison.

BACKGROUND: High resolution magnetic resonance (MR) imaging of the coronary artery wall in vivo has been limited by the cardiac and respiratory motion, flow artifacts as well as the relatively small size of the coronary arteries. We sought to validate in vivo black blood MR imaging of the coronary artery wall using a double inversion recovery fast spin echo MR imaging sequence with limited breath-holding and cardiac gating for suppression of motion artifacts by comparison with ex vivo MR imaging. METHODS: Yorkshire albino swine (n = 6) were used in this study and coronary lesions were induced with balloon angioplasty. Four weeks after balloon injury of the coronary arteries MR imaging of the coronary artery lesions was performed. High resolution in vivo and ex vivo images of the coronary artery wall and lesions were obtained using a double inversion recovery fast spin echo sequence in a 1.5 T MR system. There was a statistically significant agreement (p < 0.0001) between measurements of vessel wall area (r = 0.87, slope = 0.87) and maximal wall thickness (r = 0.84, slope = 0.88) from in vivo and ex vivo MR images of the coronary arteries. The mean differences between in vivo and ex vivo measurements were 0.56 +/- 1.98 mm2 for vessel wall area and 0.02 +/- 0.36 mm for maximal wall thickness. CONCLUSIONS: Using breathholding and cardiac gating, it is possible to perform high resolution MR imaging of the coronary artery wall in vivo with good suppression of motion artifacts with a double inversion recovery fast spin echo black blood imaging sequence.

Dramatic remodeling of advanced atherosclerotic plaques of the apolipoprotein E-deficient mouse in a novel transplantation model.

OBJECTIVE: Regression of atherosclerotic lesions is an important goal. No extensive experimental evidence shows that it can be achieved for advanced lesions. To study this, we developed a model to maintain a long-term change in the plasma lipoprotein environment of advanced arterial lesions of hyperlipidemic (apolipoprotein E [apoE]-deficient) mice. METHODS: The apoE-deficient mice (plasma total cholesterol of 1334 +/- 219 [+/- SEM] mg/dL) on a typical Western diet for 38 weeks had advanced atherosclerotic lesions (ie, beyond the macrophage foam cell stage) throughout the arterial tree. Lesion-containing thoracic aortas were transplanted (replacing a segment of abdominal aorta) into either apoE-deficient or wild-type (WT) (total cholesterol of 86 +/- 10 mg/dL) recipients. Grafts were harvested after 9 weeks. RESULTS: Compared with pretransplant lesions (area = 0.0892 +/- 0.0179 mm(2)), lesion size tended to increase in apoE-deficient to apoE-deficient grafts (0.2411 +/- 0.0636 mm(2); P =.06), whereas a significant reduction was seen in apoE-deficient to WT grafts (0.0214 +/- 0.0049 mm(2); P <.001). Also, foam cells were absent in apoE-deficient to WT grafts, but abundant in pretransplant lesions and apoE-deficient to apoE-deficient grafts. Grafts were evaluated noninvasively in vivo with magnetic resonance imaging, and wall thickening was detected in the apoE-deficient to apoE-deficient group. CONCLUSIONS: Nearly complete regression of advanced atherosclerotic lesions can be achieved with sustained normalization of the plasma lipoprotein profile. Syngeneic arterial transplantation in mice is a novel and valuable model system for atherosclerosis research; and magnetic resonance imaging can detect differences in characteristics in lesions undergoing regression.

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).

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.

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.

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.

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.

Predicting plaque rupture: enhancing diagnosis and clinical decision-making in coronary artery disease.

Atherosclerosis is the process underlying coronary artery disease, myocardial infarction and cerebrovascular disease and is a leading cause of morbidity and mortality in industrialized countries. The atherosclerotic plaque is often indolent and progressive and may destabilize without warning. Components of the atherosclerotic plaque, including structural, cellular and molecular characteristics, determine its vulnerability to rupture. The imaging techniques currently available utilize invasive and non-invasive methods to characterize coronary artery stenoses. Detection, however, usually occurs late in the course of disease after symptoms have presented. Much effort has recently been directed at early detection and in defining markers of atherosclerotic disease. Our challenge for the future is to find non-invasive imaging modalities that can predict plaque vulnerability before irreversible damage has occurred. Through early detection and a targeted treatment strategy we hope to reduce the burden of ischemic heart disease.

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.