Atherosclerotic plaques that cause stroke and myocardial infarction are characterized by increased microvascular permeability and inflammation. Dynamic contrast-enhanced MRI (DCE-MRI) has been proposed as a method to quantify vessel wall microvascular permeability in vivo. Until now, most DCE-MRI studies of atherosclerosis have been limited to two-dimensional (2D) multi-slice imaging. Although providing the high spatial resolution required to image the arterial vessel wall, these approaches do not allow the quantification of plaque permeability with extensive anatomical coverage, an essential feature when imaging heterogeneous diseases, such as atherosclerosis. To our knowledge, we present the first systematic evaluation of three-dimensional (3D), high-resolution, DCE-MRI for the extensive quantification of plaque permeability along an entire vascular bed, with validation in atherosclerotic rabbits. We compare two acquisitions: 3D turbo field echo (TFE) with motion-sensitized-driven equilibrium (MSDE) preparation and 3D turbo spin echo (TSE). We find 3D TFE DCE-MRI to be superior to 3D TSE DCE-MRI in terms of temporal stability metrics. Both sequences show good intra- and inter-observer reliability, and significant correlation with ex vivo permeability measurements by Evans Blue near-infrared fluorescence (NIRF). In addition, we explore the feasibility of using compressed sensing to accelerate 3D DCE-MRI of atherosclerosis, to improve its temporal resolution and therefore the accuracy of permeability quantification. Using retrospective under-sampling and reconstructions, we show that compressed sensing alone may allow the acceleration of 3D DCE-MRI by up to four-fold. We anticipate that the development of high-spatial-resolution 3D DCE-MRI with prospective compressed sensing acceleration may allow for the more accurate and extensive quantification of atherosclerotic plaque permeability along an entire vascular bed. We foresee that this approach may allow for the comprehensive and accurate evaluation of plaque permeability in patients, and may be a useful tool to assess the therapeutic response to approved and novel drugs for cardiovascular disease.

/pdf/three-dimensional-dynamic-contrast-enhanced-mri-for-the-l36d11gbyc.pdf

Three-dimensional dynamic contrast-enhanced MRI for the accurate, extensive quantification of microvascular permeability in atherosclerotic plaques.

Rupture of a vulnerable atherosclerotic plaque of the carotid artery is an important underlying cause of clinical ischemic events, such as stroke. Abundant microvasculature has been identified as an important aspect contributing to plaque vulnerability. Plaque microvasculature can be studied non-invasively with dynamic contrast-enhanced (DCE-)MRI in animals and patients. In recent years, several DCE-MRI studies have been published evaluating the association between microvasculature and other key features of plaque vulnerability (e.g., inflammation and intraplaque hemorrhage), as well as the effects of novel therapeutic interventions. The present paper reviews this literature, focusing on DCE-MRI methods of acquisition and analysis of atherosclerotic plaques, the current state and future potential of DCE-MRI in the evaluation of plaque microvasculature in clinical and preclinical settings.

/pdf/dynamic-contrast-enhanced-mri-to-study-atherosclerotic-32373vl5ug.pdf

Dynamic Contrast-Enhanced MRI to Study Atherosclerotic Plaque Microvasculature

Purpose
To evaluate the usefulness of quantitative characteristics of morphology and signal intensity of arterial wall measured by 3D multicontrast magnetic resonance vessel wall imaging (MRVWI) in identification of carotid early atherosclerosis (CEAS).

Materials and Methods
In all, 61 older subjects (mean age 71.8 ± 5.6 years old; 25 males) without cardiovascular symptoms in the last 6 months were recruited. The carotid arteries without advanced plaque features on 3.0T MRI were included for analysis. Ultrasound imaging was used as a reference to identify CEAS. The morphological parameters including lumen area (LA), wall area (WA), wall thickness (WT), and normalized wall index (NWI = WA/[WA+LA] × 100%) and the signal intensity on 3.0T MR T2-weighted images (T2SI) of the carotid arterial wall were measured. Three regression models were built to identify CEAS with the following parameters: Model 1 with both morphological and T2SI parameters; Model 2 with T2SI parameters; and Model 3 with morphological parameters. All models were adjusted for age and sex. Area under the curve (AUC) was calculated to validate models.

Results
Of the 86 carotid arteries without advanced plaques, 47 (54.7%) were found to have early plaques determined by ultrasound. Among three regression models, Model 1 showed the highest AUC values in identifying CEAS (left: AUC = 0.856, P < 0.001; right: AUC = 0.867, P < 0.001), followed by Model 2 (left: AUC = 0.843, P < 0.001; right: AUC = 0.798, P = 0.001), and Model 3 (left: AUC = 0.790, P = 0.002; right: AUC = 0.806, P < 0.001).

Conclusion
The combination of morphology and normalized T2SI of arterial wall measured by MRVWI is more effective than each characteristic alone in identification of CEAS. J. Magn. Reson. Imaging 2016;44:1270–1276.

Identification of early atherosclerotic lesions in carotid arteries with quantitative characteristics measured by 3D MRI.

In this thesis the potential of nanomedicine to treat atherosclerotic disease is examined. The research presented addresses the development and characterization of various nanodrugs, nanoparticle targeting concepts in atherosclerotic disease, as well as the use of noninvasive imaging to characterize therapeutic efficacy of new atherosclerosis therapeutics. The thesis consist of three parts, with the first part focusing on a natural nanoparticle, high-density lipoprotein (HDL). Development, characterization and application of an HDL nanoparticle to specifically inhibit atherosclerotic plaque inflammation are shown. The second part of this thesis is centered on long-circulating nanoparticles. Methods to non-invasively image atherosclerosis are developed, as well as methods to produce liposomal nanoparticles according to good manufacturing practice (GMP). The third part is focused on the use of liposomal nanoparticles to reduce inflammation in atherosclerosis. The anti-inflammatory drugs, glucocorticoids, are encapsulated in liposomal nanoparticles and their therapeutic efficacy is assessed by noninvasive multimodal imaging in a model of atherosclerosis. Consequently GMP production is commenced, and therapeutic efficacy of the nanoparticles is assessed. Afterwards a clinical trial is reported, in which delivery and therapeutic efficacy of liposomal nanoparticles is evaluated in patients with atherosclerosis. Nanomedicine holds promise as a type of personalized medicine for the management of cardiovascular disease in general, particularly the target-specific treatment and imaging of atherosclerotic disease. The continuous discovery of new molecular targets, improved understanding of the pathophysiology of atherosclerosis, as well as developments in nanoparticle synthesis methods and imaging technologies will aid in the prevention and treatment of this disease.

/pdf/exploration-and-application-of-nanomedicine-in-53uo4obuuy.pdf

Exploration and application of nanomedicine in atherosclerotic disease

Purpose
To propose a large coverage black-bright blood interleaved imaging sequence (LaBBI) for 3D dynamic contrast-enhanced MRI (DCE-MRI) of the vessel wall.

Methods
LaBBI consists of a 3D black-blood stack-of-stars golden angle radial acquisition with high spatial resolution for vessel wall imaging and a 2D bright-blood Cartesian acquisition with high temporal resolution for arterial input function estimation. The two acquisitions were performed in an interleaved fashion within a single scan. Simulations, phantom experiments, and in vivo tests in three patients were performed to investigate the feasibility and performance of the proposed LaBBI.

Results
In simulation tests, the estimated Ktrans and vp by LaBBI were more accurate than conventional bright-blood DCE-MRI with lower root mean square error in all the tested conditions. In phantom test, no signal interference was found on the 2D scan in LaBBI. Pharmacokinetic analysis of the patients’ data acquired by LaBBI showed that Ktrans was higher in fibrous tissue (0.0717 ± 0.0279 min−1), while lower in necrotic core (0.0206 ± 0.0040 min−1) and intraplaque hemorrhage (0.0078 ± 0.0007 min−1), compared with normal vessel wall (0.0273 ± 0.0052 min−1).

Conclusion
The proposed LaBBI sequence, with high spatial and temporal resolution, and large coverage blood suppression, was promising to probe the perfusion properties of vessel wall lesions. Magn Reson Med 79:1334–1344, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

/pdf/large-coverage-black-bright-blood-interleaved-imaging-45besx1012.pdf

Large coverage black-bright blood interleaved imaging sequence (LaBBI) for 3D dynamic contrast-enhanced MRI of vessel wall.

Purpose
To present a HOmologous Black-Bright-blood and flexible Interleaved imaging (HOBBI) sequence for dynamic contrast-enhanced magnetic resonance imaging (MRI) of the vessel wall.

Theory and Methods
A HOBBI sequence is proposed to acquire high-spatial-resolution black-blood and high-temporal-resolution bright-blood dynamic contrast-enhanced images in an interleaved fashion. Black-blood imaging allows for thin vessel wall evaluation, whereas bright-blood imaging obtains the arterial input function accurately. A simulation was performed to assess the accuracy of the pharmacokinetic parameters [transfer constant (Ktrans) and fractional plasma volume (vp)] generated from HOBBI. In vivo evaluation was also used to validate HOBBI in an animal model of aortic atherosclerosis.

Results
In the simulation test, the estimated Ktrans and vp measured by HOBBI were more accurate than those from black-blood dynamic contrast-enhanced-MRI. In the animal model testing, Ktrans and vp also demonstrated good interscan reproducibility (Ktrans: ICC = 0.77, vp: ICC = 0.72, respectively). Additionally, Ktrans showed a significant increase from 1 month (0.026 ± 0.013 min−1) to 2 months (0.069 ± 0.018 min−1) in animal model plaque progression after balloon injury.

Conclusion
The proposed HOBBI sequence was demonstrated to be feasible and accurate in estimating the pharmacokinetic parameters of the atherosclerotic vessel wall, and has potential to become an early screening tool for atherosclerosis disease. Magn Reson Med 73:1754–1763, 2015. © 2014 Wiley Periodicals, Inc.

Homologous black‐bright‐blood and flexible interleaved imaging sequence (HOBBI) for dynamic contrast‐enhanced MRI of the vessel wall

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Homologous black‐bright‐blood and flexible interleaved imaging sequence (HOBBI) for dynamic contrast‐enhanced MRI of the vessel wall