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Imaging the Permeable Endothelium

2016; Lippincott Williams & Wilkins; Volume: 9; Issue: 12 Linguagem: Inglês

10.1161/circimaging.116.005955

1942-0080

Claudia Calcagno, Zahi A. Fayad,

Advanced MRI Techniques and Applications

HomeCirculation: Cardiovascular ImagingVol. 9, No. 12Imaging the Permeable Endothelium Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBImaging the Permeable EndotheliumPredicting Plaque Rupture in Atherosclerotic Rabbits Claudia Calcagno, MD, PhD and Zahi A. Fayad, PhD Claudia CalcagnoClaudia Calcagno From the Translational and Molecular Imaging Institute (C.C., Z.A.F.) and Department of Radiology (C.C., Z.A.F.), Icahn School of Medicine at Mount Sinai, New York, NY. and Zahi A. FayadZahi A. Fayad From the Translational and Molecular Imaging Institute (C.C., Z.A.F.) and Department of Radiology (C.C., Z.A.F.), Icahn School of Medicine at Mount Sinai, New York, NY. Originally published9 Dec 2016https://doi.org/10.1161/CIRCIMAGING.116.005955Circulation: Cardiovascular Imaging. 2016;9:e005955Endothelial Dysfunction and Permeability in AtherosclerosisThe vascular endothelium is the natural barrier that regulates the translocation of cells and molecules between the systemic circulation and peripheral tissues. Endothelial dysfunction, such as decreased vascular tone, increased arterial stiffness, and leakage of cells and molecules through the endothelial barrier, is key both for initial atheroma formation and for atherosclerosis progression. Vulnerable atherosclerotic plaques that are prone to rupture, and at high risk for causing severe acute clinical events, are characterized by an increased amount of fragile, dysmorphic, intraplaque microvessels with enhanced endothelial permeability. These leaky microvessels are the entry door for inflammatory cells, also key players in the formation of high-risk atheromas and in precipitating plaque rupture.1 Building on this knowledge, in the past 15 years, endothelial permeability has emerged as a promising diagnostic target to better stratify subjects at risk for cardiovascular disease and to quantify the effects of known or novel drugs on atherosclerosis progression. Concomitantly, the magnetic resonance imaging (MRI) community has made significant strides in developing and validating quantitative, noninvasive imaging methods to measure endothelial dysfunction and permeability in vivo.See Article by Phinikaridou et alNoninvasive, Quantitative MRI of Endothelial Permeability in Atherosclerosis: Delayed Enhancement and Dynamic Contrast–Enhanced MRIMRI using either low-molecular weight (gadolinium [Gd] chelates) or Gd-based albumin binding agents (such as gadofosveset trisodium) has been extensively used to estimate endothelial permeability in atherosclerosis. Delayed enhancement imaging with MRI consists of the acquisition of one pre-image and one post-image acquired after contrast agent injection. The percent signal enhancement observed in the postcontrast acquisition, with respect to precontrast, is a semiquantitative measure of contrast agent extravasation in the vessel wall and, therefore, a surrogate measure of endothelial permeability. Increased magnetic resonance signal enhancement has indeed been demonstrated in human symptomatic carotid plaques using delayed enhancement imaging with both Gd diethylenetriaminepentaacetic acid2 and gadofosveset.3 Delayed enhancement imaging after Gd diethylenetriaminepentaacetic acid injection has also been used in mice to estimate a reduction in endothelial permeability in the aortic root after administration of statin-loaded nanoparticles.4 In a rabbit model of atherosclerosis, increased gadofosveset uptake was observed during plaque progression and after pharmacological triggering for plaque disruption.5 Better than semiquantitative measures, dynamic contrast–enhanced (DCE) MRI can be used to more accurately quantify vascular permeability and plaque microvessels density in both humans and animal models. DCE-MRI entails the rapid acquisition of images before, during, and after contrast agent injection, thus, allowing one to follow the contrast agent uptake kinetics in the vessel wall. Kinetic modeling of uptake curves allows the calculation of quantitative parameters related to endothelial permeability (Ktrans) and microvascular volume (vp). Alternatively, nonmodel-based parameters, such as uptake slope and area under the uptake curve can also be calculated. Ktrans and vp derived from 2-dimensional fast low-angle shot DCE-MRI were found to correlate with plaque microvessel density, macrophages, and loose matrix in human carotid endarterectomy specimens. Ktrans was also found to correlate with decreased high-density lipoprotein levels and C-reactive protein in the blood plasma, was higher in smokers compared with nonsmokers,6 and was associated with the presence of intraplaque hemorrhage.7 Using this same acquisition, Ktrans was found to decrease in the carotid arteries of patients treated with statins.8 In a rabbit model of atherosclerosis, the nonmodeling parameter area under the curve calculated from 2D turbo spin echo DCE-MRI was found to significantly correlate with plaque microvessel density.9–11 Furthermore, DCE-MRI was used in this same model to quantify therapeutic efficacy of several Food and Drug Administration-approved (atorvastatin,10 pioglitazone11) and novel therapeutics (liposome-encapsulated glucocorticoids, liver-X-receptor agonists10). In the same model,12Ktrans was demonstrated to increase during plaque progression and to significantly correlate with plaque macrophages. Recently, 3-dimensional DCE-MRI based on a segmented turbo field echo sequence, with motion sensitized driven equilibrium preparation for black blood imaging, was developed and applied to obtain whole-vessel coverage in the rabbit abdominal aorta. Area under the curve calculated from this acquisition method was found to significantly correlate with the extravasation of Evans Blue (a dye that binds to albumin)13 and of Cy7 fluorescently labeled nanoparticles.14Postcontrast Vessel Wall T1/R1 Mapping by MRI as a Measure of Endothelial Permeability in the Arterial WallBuilding on their previous work in atherosclerotic mice,15 in this issue of Circulation: Cardiovascular Imaging, Phinikaridou et al16 describe the application of MRI after the injection of gadofosveset to quantify plaque endothelial permeability in a rabbit animal model of atherosclerosis and thrombosis. Endothelial permeability was estimated by calculating the vessel wall's relaxation rate (R1, s−1) 30 minutes after contrast agent injection, an imaging parameter related to tissue contrast agent deposition. Atherosclerosis was induced in 10 New Zealand White male rabbits by a well-validated combination of high-fat diet and balloon injury of the abdominal aorta. Atheromas were allowed to develop in the rabbits' aortas for 12 weeks, after which thrombosis was induced through triggering with Russel's viper venom and histamine. Four noninjured animals were used as controls. MRI was used to quantify (1) plaque area using a T1-weighted black blood sequence; (2) endothelial permeability, using a Look-Locker T1 mapping sequence; (3) vasodilation using an ECG-triggered steady state free precession sequence; and (4) vessel wall stiffness using QFlow images. These measurements were performed at 2 time points before triggering (3 and 12 weeks after diet initiation) to evaluate plaque progression. During the post-triggering imaging session arterial, thrombus was quantified using T1-weighted black blood imaging. Plaques identified on the 12-week pretrigger scan were retrospectively classified as stable or rupture-prone based on the absence/presence of thrombus on the post-trigger scan. The authors found that in diseased rabbits, while vessel wall area was significantly increased between 3 and 12 weeks as a result of disease progression, it was not significantly different among stable and prone-rupture plaques at both time points. On the other hand, at 12 weeks, in diseased animals, the postcontrast R1 was significantly higher in prone-rupture compared with stable plaques and in diseased versus control animals. A relationship between higher R1 and increased endothelial permeability to the contrast agent was confirmed by the higher concentration of Gd and albumin, as well as microvessel density, in diseased versus control animals and in rupture-prone versus stable plaques. Vasodilation was lower in atherosclerotic compared with control animals, at both 3 and 12 weeks after diet initiation, and lower in rupture-prone versus stable lesions at all time points. Arterial stiffness was higher in atherosclerotic animals after 12 weeks of diet, compared with 3 weeks and to controls, while no difference was observed at both time points between rupture-prone and stable plaques. As opposed to that seen with vasodilation, arterial stiffness correlated with plaque area at 12 weeks.Magnetic Resonance Measurements of Vessel Wall Relaxation Rate After Contrast Agent Injection Are Highly Predictive of Atheromas at Risk for Rupture and Thrombosis in Atherosclerotic RabbitsThe study by Phinikaridou et al16 represents a significant advancement in the development and validation of noninvasive MRI to quantify endothelial dysfunction and permeability in atherosclerosis. First, previous results obtained in the brachiocephalic artery of genetically modified ApoE−/− mice with the same15 or similar17 techniques are here successfully translated into a rabbit model of disease. This result indicates that this approach can robustly detect changes in endothelial permeability in different animal models of atherosclerosis, an important feature for the future translation of these measurements into the clinics. Furthermore, the ability to trigger plaque thrombosis and rupture at a precise time point in the rabbit model has allowed the authors to retrospectively quantify endothelial permeability in plaques classified as either stable or rupture-prone. Importantly, receiver operating characteristic curve analysis indicated that R1, R1/plaque area at 12 weeks, and %ΔR1 area between 3 and 12 weeks were highly predictive of rupture-prone plaques.Future DirectionsThese results represent another fundamental step toward the future clinical application of noninvasive permeability imaging as a predictive marker of plaque rupture, thrombosis, and cardiovascular risk in humans. In the near future, we foresee that these, or similar, noninvasive measurements of endothelial permeability may be used in combination with other imaging modalities to better stratify, diagnose, and treat subjects at risk for cardiovascular disease. A first necessary step in this direction will be establishing the positive predictive values of permeability imaging for cardiovascular events in multicenter clinical trials in humans. Practical challenges to accomplishing this necessary goal will be the inevitable costs associated with running extensive, lengthy clinical trials and the considerable efforts required to conform MRI protocols among different sites, scanner vendors, and field strengths. Furthermore, a more systematic evaluation of the role of permeability imaging in relationship with other established imaging modalities in atherosclerosis (such as positron emission tomography with 18F-fluorodeoxyglucose or other tracers to quantify plaque inflammation18–20) is warranted in both mechanistic studies using animal models and in translational applications in patients. The recent advent of dual-modality imaging systems, such as combined positron emission tomography/MRI, will offer the unprecedented opportunity to rigorously explore the relationship between these different surrogate imaging markers of plaque vulnerability and their underlying biological correlates.Sources of FundingWe acknowledge EB009638 from the National Institutes of Health (ZAF) and 16SDG27250090 from the American Heart Association (CC).DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Zahi A. Fayad, PhD, Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1234, New York, NY. E-mail [email protected]References1. Boulanger CM.Endothelium.Arterioscler Thromb Vasc Biol. 2016; 36:e26–e31. doi: 10.1161/ATVBAHA.116.306940.LinkGoogle Scholar2. 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Castro F, Martins C, Silveira M, Moura R, Pereira C and Sarmento B (2021) Advances on erythrocyte-mimicking nanovehicles to overcome barriers in biological microenvironments, Advanced Drug Delivery Reviews, 10.1016/j.addr.2020.09.001, 170, (312-339), Online publication date: 1-Mar-2021. Li C, Dou Y, Chen Y, Qi Y, Li L, Han S, Jin T, Guo J, Chen J and Zhang J (2020) Site‐Specific MicroRNA‐33 Antagonism by pH‐Responsive Nanotherapies for Treatment of Atherosclerosis via Regulating Cholesterol Efflux and Adaptive Immunity, Advanced Functional Materials, 10.1002/adfm.202002131, 30:42, (2002131), Online publication date: 1-Oct-2020. Curaj A, Wu Z, Rix A, Gresch O, Sternkopf M, Alampour-Rajabi S, Lammers T, van Zandvoort M, Weber C, Koenen R, Liehn E and Kiessling F (2017) Molecular Ultrasound Imaging of Junctional Adhesion Molecule A Depicts Acute Alterations in Blood Flow and Early Endothelial Dysregulation, Arteriosclerosis, Thrombosis, and Vascular Biology, 38:1, (40-48), Online publication date: 1-Jan-2018. December 2016Vol 9, Issue 12 Advertisement Article InformationMetrics © 2016 American Heart Association, Inc.https://doi.org/10.1161/CIRCIMAGING.116.005955PMID: 27940960 Originally publishedDecember 9, 2016 KeywordsEditorialsimagingcontrast mediamagnetic resonance imagingatherosclerosisangiogenesisPDF download Advertisement SubjectsAtherosclerosisMagnetic Resonance Imaging (MRI)