Joshua T. Chai

Black-Blood Multicontrast Imaging of Carotid Arteries with DANTE-prepared 2D and 3D MR Imaging

PURPOSE To prospectively compare the black-blood ( BB black blood ) imaging efficiency of a delay alternating with nutation for tailored excitation ( DANTE delay alternating with nutation for tailored excitation ) preparation module with conventional double inversion-recovery ( DIR double inversion recovery ) and motion-sensitive driven equilibrium ( MSDE motion-sensitive driven equilibrium ) preparation modules and to introduce a new three-dimensional ( 3D three-dimensional ) T1-weighted magnetic resonance (MR) imaging sequence. MATERIALS AND METHODS Carotid artery wall imaging was performed in 10 healthy volunteers and 15 patients in accordance with an institutional review board-approved protocol. Two-dimensional ( 2D two-dimensional ) turbo spin-echo ( TSE turbo spin echo ) and 3D three-dimensional fast low-angle shot ( FLASH fast low-angle shot ) sequences served as readout modules. DANTE delay alternating with nutation for tailored excitation -prepared T1-, T2-, and proton density-weighted 2D two-dimensional TSE turbo spin echo images, as well as T1-weighted 3D three-dimensional DANTE delay alternating with nutation for tailored excitation -prepared FLASH fast low-angle shot (hereafter, 3D three-dimensional DASH DANTE-prepared FLASH ) images, were acquired in the region of the carotid artery bifurcation. For comparison, 2D two-dimensional DIR double inversion recovery -prepared, 2D two-dimensional MSDE motion-sensitive driven equilibrium -prepared multicontrast TSE turbo spin echo , and 3D three-dimensional MSDE motion-sensitive driven equilibrium -prepared FLASH fast low-angle shot (hereafter, 3D three-dimensional MERGE MSDE-prepared FLASH ) MR images were also acquired. The effective contrast-to-noise ratio ( CNReff effective contrast-to-noise ratio ) per unit time was calculated for all sequences. Paired t tests were performed to test within-group differences in vessel wall CNReff effective contrast-to-noise ratio . RESULTS The CNReff effective contrast-to-noise ratio of DANTE delay alternating with nutation for tailored excitation -prepared T1-, T2-, and proton density-weighted sequences was 27.3, 14.7, and 25.7 mm(-1)min(-1/2), respectively; this represented an improvement of approximately 25%-100% (P < .05) when compared with the CNReff effective contrast-to-noise ratio attained with existing methods. The 3D three-dimensional DASH DANTE-prepared FLASH technique proved to be a fast (<2 seconds per section) and high-spatial-resolution (0.6 mm isotropic) BB black blood technique with higher (75%-100% improvement, P < .001) signal-to-noise ratio efficiency than the 3D three-dimensional MERGE MSDE-prepared FLASH technique. CONCLUSION The DANTE delay alternating with nutation for tailored excitation -prepared multicontrast 2D two-dimensional BB black blood technique is a promising new tool for MR imaging of carotid artery walls. Additionally, the 3D three-dimensional DASH DANTE-prepared FLASH sequence enables 3D three-dimensional high-spatial-resolution fast T1-weighted imaging of carotid artery walls. ©RSNA, 2014 Online supplemental material is available for this article .

In-vivo quantitative T2 mapping of carotid arteries in atherosclerotic patients: segmentation and T2 measurement of plaque components

BackgroundAtherosclerotic plaques in carotid arteries can be characterized in-vivo by multicontrast cardiovascular magnetic resonance (CMR), which has been thoroughly validated with histology. However, the non-quantitative nature of multicontrast CMR and the need for extensive post-acquisition interpretation limit the widespread clinical application of in-vivo CMR plaque characterization. Quantitative T2 mapping is a promising alternative since it can provide absolute physical measurements of plaque components that can be standardized among different CMR systems and widely adopted in multi-centre studies. The purpose of this study was to investigate the use of in-vivo T2 mapping for atherosclerotic plaque characterization by performing American Heart Association (AHA) plaque type classification, segmenting carotid T2 maps and measuring in-vivo T2 values of plaque components.MethodsThe carotid arteries of 15 atherosclerotic patients (11 males, 71 ± 10 years) were imaged at 3 T using the conventional multicontrast protocol and Multiple-Spin-Echo (Multi-SE). T2 maps of carotid arteries were generated by mono-exponential fitting to the series of images acquired by Multi-SE using nonlinear least-squares regression. Two reviewers independently classified carotid plaque types following the CMR-modified AHA scheme, one using multicontrast CMR and the other using T2 maps and time-of-flight (TOF) angiography. A semi-automated method based on Bayes classifiers segmented the T2 maps of carotid arteries into 4 classes: calcification, lipid-rich necrotic core (LRNC), fibrous tissue and recent IPH. Mean ± SD of the T2 values of voxels classified as LRNC, fibrous tissue and recent IPH were calculated.ResultsIn 37 images of carotid arteries from 15 patients, AHA plaque type classified by multicontrast CMR and by T2 maps (+ TOF) showed good agreement (76% of matching classifications and Cohen’s κ = 0.68). The T2 maps of 14 normal arteries were used to measure T2 of tunica intima and media (T2 = 54 ± 13 ms). From 11865 voxels in the T2 maps of 15 arteries with advanced atherosclerosis, 2394 voxels were classified by the segmentation algorithm as LRNC (T2 = 37 ± 5 ms) and 7511 voxels as fibrous tissue (T2 = 56 ± 9 ms); 192 voxels were identified as calcification and one recent IPH (236 voxels, T2 = 107 ± 25 ms) was detected on T2 maps and confirmed by multicontrast CMR.ConclusionsThis carotid CMR study shows the potential of in-vivo T2 mapping for atherosclerotic plaque characterization. Agreement between AHA plaque types classified by T2 maps (+TOF) and by conventional multicontrast CMR was good, and T2 measured in-vivo in LRNC, fibrous tissue and recent IPH demonstrated the ability to discriminate plaque components on T2 maps.

Acute myocardial infarction activates distinct inflammation and proliferation pathways in circulating monocytes, prior to recruitment, and identified through conserved transcriptional responses in mice and humans

The immune system plays critical roles in myocardial injury and repair following acute myocardial infarction (AMI). Evidence from experimental models strongly implicates monocytes as critical to these processes and their specific targeting results in a significant reduction in infarct size and improved healing. It is currently unclear if monocytes play a similarly important role in humans. Examining changes in the patterns of gene expression can address this question. Here, we show that the peripheral blood monocyte response following AMI is conserved between species and that monocytes appear to be ‘programmed’ prior to their arrival at sites of myocardial injury. This investigation may translate to the future development of therapeutics to treat patients presenting with AMI that importantly would be effective in the hours after the onset of ischaemia.

Nicotinic acid receptor GPR109A is down-regulated in human macrophage-derived foam cells.

Nicotinic acid (NA) regresses atherosclerosis in human imaging studies and reduces atherosclerosis in mice, mediated by myeloid cells, independent of lipoproteins. Since GPR109A is expressed by human monocytes, we hypothesized that NA may drive cholesterol efflux from foam cells. In THP-1 cells NA suppressed LPS-induced mRNA transcription of MCP-1 by 76.6±12.2% (P<0.01) and TNFα by 56.1±11.5% (P<0.01), yet restored LPS-induced suppression of PPARγ transcription by 536.5±46.4% (P<0.001) and its downstream effector CD36 by 116.8±19.8% (P<0.01). Whilst direct PPARγ-agonism promoted cholesterol efflux from THP-1 derived foam cells by 37.7±3.1% (P<0.01) and stimulated transcription of LXRα by 87.9±9.5% (P<0.001) and ABCG1 by 101.2±15.5% (P<0.01), NA showed no effect in foam cells on either cholesterol efflux or key RCT genes transcription. Upon foam cell induction, NA lost its effect on PPARγ and cAMP pathways, since its receptor, GPR109A, was down-regulated by foam cell transformation. This observation was confirmed in explanted human carotid plaques. In conclusion, despite NA’s anti-inflammatory effect on human macrophages, it has no effect on foam cells in reverse cholesterol transport; due to GPR109A down-regulation.

Quantification of Lipid-Rich Core in Carotid Atherosclerosis Using Magnetic Resonance T2 Mapping: Relation to Clinical Presentation.

Objectives The aim of this study was to: 1) provide tissue validation of quantitative T2 mapping to measure plaque lipid content; and 2) investigate whether this technique could discern differences in plaque characteristics between symptom-related and non–symptom-related carotid plaques. Background Noninvasive plaque lipid quantification is appealing both for stratification in treatment selection and as a possible predictor of future plaque rupture. However, current cardiovascular magnetic resonance (CMR) methods are insensitive, require a coalesced mass of lipid core, and rely on multicontrast acquisition with contrast media and extensive post-processing. Methods Patients scheduled for carotid endarterectomy were recruited for 3-T carotid CMR before surgery. Lipid area was derived from segmented T2 maps and compared directly to plaque lipid defined by histology. Results Lipid area (%) on T2 mapping and histology showed excellent correlation, both by individual slices (R = 0.85, p < 0.001) and plaque average (R = 0.83, p < 0.001). Lipid area (%) on T2 maps was significantly higher in symptomatic compared with asymptomatic plaques (31.5 ± 3.7% vs. 15.8 ± 3.1%; p = 0.005) despite similar degrees of carotid stenosis and only modest difference in plaque volume (128.0 ± 6.0 mm3 symptomatic vs. 105.6 ± 9.4 mm3 asymptomatic; p = 0.04). Receiver-operating characteristic analysis showed that T2 mapping has a good ability to discriminate between symptomatic and asymptomatic plaques with 67% sensitivity and 91% specificity (area under the curve: 0.79; p = 0.012). Conclusions CMR T2 mapping distinguishes different plaque components and accurately quantifies plaque lipid content noninvasively. Compared with asymptomatic plaques, greater lipid content was found in symptomatic plaques despite similar degree of luminal stenosis and only modest difference in plaque volumes. This new technique may find a role in determining optimum treatment (e.g., providing an indication for intensive lipid lowering or by informing decisions of stents vs. surgery).

Plaque imaging to refine indications for emerging lipid-lowering drugs.

Statins have been effective in reducing adverse cardiovascular events. Their benefits have been proportional to the level of plasma LDL-cholesterol reduction and seem to extend to patients with ‘normal’ levels of cholesterol at outset. Statins are also inexpensive and have a favourable side-effect profile. As a result, they are used widely (almost indiscriminately) in patients with atherosclerotic vascular disease, and in those at risk of disease. Next generation lipid-modifying drugs seem unlikely to offer the same simplicity of application. The recent trials of new classes of lipid modifying drugs underline the need for a risk stratification tool which is not based on patients’ category of diagnosis (for example, post-myocardial infarction) but based on the characterization of disease in that individual patient. Mechanistic staging, a process that matches the target of the drug action with an identifiable disease characteristic, may offer an opportunity to achieve more precise intervention. The upshots of this targeted approach will be greater efficacy, requiring smaller clinical trials to demonstrate effectiveness; a reduced number needed to treat to yield benefits and more cost-effective prescribing. This will be important, as purchasers require ever more rigorous demonstration of both efficacy and cost-effectiveness. In this context, we will discuss available pharmacological strategies of lipid reduction in anti-atherosclerotic treatment and how plaque imaging techniques may provide an ideal method in stratifying patients for new lipid-modifying drugs.

Quantification of carotid plaque lipid content with magnetic resonance T2 mapping in patients undergoing carotid endarterectomy

Background and purpose Techniques to stratify subgroups of patients with asymptomatic carotid artery disease are urgently needed to guide decisions on optimal treatment. Reliance on estimates of % luminal stenosis has not been effective, perhaps because that approach entirely disregards potentially important information on the pathological process in the wall of the artery. Methods Since plaque lipid is a key determinant of plaque behaviour we used a newly validated, high-sensitivity T2-mapping MR technique for a systematic survey of the quantity and distribution of plaque lipid in patients undergoing endarterectomy. Lipid percentage was quantified in 50 carotid endarterectomy patients. Lipid distribution was tested, using two imaging indices (contribution of the largest lipid deposit towards total lipid (LLD %) and a newly-developed LAI ‘lipid aggregation index’). Results The bifurcation contained maximal lipid volume. Lipid percentage was higher in symptomatic vs. asymptomatic patients with degree of stenosis (DS ≥ 50%) and in the total cohort (P = 0.013 and P = 0.005, respectively). Both LLD % and LAI was higher in symptomatic patients (P = 0.028 and P = 0.018, respectively), suggesting that for a given plaque lipid volume, coalesced deposits were more likely to be associated with symptomatic events. There was no correlation between plaque volume or lipid content and degree of luminal stenosis measured on ultrasound duplex (r = -0.09, P = 0.53 and r = -0.05, P = 0.75), respectively. However, there was a strong correlation in lipid between left and right carotid arteries (r = 0.5, P <0.0001, respectively). Conclusions Plaque lipid content and distribution is associated with symptomatic status of the carotid plaque. Importantly, plaque lipid content was not related to the degree of luminal stenosis assessed by ultrasound. Determination of plaque lipid content may prove useful for stratification of asymptomatic patients, including selection of optimal invasive treatments.

Histological validation of carotid plaque characterization by in-vivo T2 mapping in patients with recent cerebrovascular events: preliminary results

Background Multicontrast CMR is the conventional method for invivo characterization of carotid plaques. However, its non-quantitative nature and the need for extensive postacquisition interpretation limit its clinical application. We have recently proposed using in-vivo quantitative T2 mapping for atherosclerotic plaque characterization [Biasiolli et al. JCMR 2013, 15:69]. T2 maps have the advantage of providing an absolute physical measure of plaque components that can be standardized among different MR systems and widely adopted in multi-centre studies. This pilot study investigates the agreement between T2 mapping and histology using AHA plaque type classification.

Fast three-dimensional black-blood MR imaging for carotid artery intra-plaque haemorrhage using DANTE-prepared FLASH (3D-DASH)

Background DANTE (Delays Alternating with Nutation for Tailored Excitation) pulse trains are a rapid series of low flip angle RF pulses interspersed with gradients. We have previously demonstrated that when using DANTE pulse trains as a preparation module prior to imaging readout, the longitudinal magnetization of flowing spins is substantially attenuated, whereas the longitudinal magnetization of static tissue/fluid is mostly preserved [1]. In this study we introduce a new DANTE-prepared 3D FLASH T1 weighted (T1w) sequence (denoted ‘3DDASH’) [2] that is able to generate 0.6 mm isotropic resolution images with an average imaging speed better than 2 sec/slice.

NICOTINIC ACID RECEPTOR GPR109A IS DOWN-REGULATED IN HUMAN MACROPHAGE-DERIVED FOAM CELLS

Introduction Nicotinic acid (NA) has been known to exert favourable effects on plasma lipoproteins. It regresses atherosclerosis in human imaging studies and reduces atherosclerosis in mice, mediated by its receptor GPR109a on myeloid cells, independent of its lipoprotein effect. Since GPR109a is expressed by human monocytes, we hypothesized that NA may drive cholesterol efflux from human macrophage-derived foam cells. Methods THP-1 cells were induced into foam cells by acetylated LDL. After treatment with NA, GW1929 (a PPARγ agonist) and vehicle controls, cholesterol efflux was assessed using HDL3 and apo-AI as cholesterol acceptors. qRT-PCR was performed using primers for genes responsible for inflammation and reverse cholesterol transport (RCT). ELISAs for PPARγ activity and cAMP response were performed to investigate NAs putative cellular mechanisms of action. Fluorescence immunohistochemistry on ex-vivo human carotid atherosclerotic plaques was carried out against CD68, adipophilin (a foam cells marker), as well as GPR109a. Immediately adjacent sections were stained with Oil-red-O to visualized lipid content and distribution. Results In basal THP-1 cells, NA suppressed LPS-induced mRNA transcription of MCP-1 by 76.6±12.2% (P<0.01) and TNF-α by 56.1±11.5% (P<0.01), yet restored LPS-induced suppression of PPARγ transcription by 536.5±46.4% (P<0.001) and its downstream effector CD36 by 116.8±19.8% (P<0.01). Whilst direct PPARγ-agonism promoted cholesterol efflux from THP-1 derived foam cells by 37.7±3.1% (P<0.01) and stimulated transcription of LXRα by 87.9±9.5% (P<0.001) and ABCG1 by 101.2±15.5% (P<0.01), NA showed no effect in foam cells on either cholesterol efflux or key RCT genes transcription. NA was found to activate PPARγ pathway and suppress cAMP response in basal macrophages; but these effects were lost in foam cells, since its receptor, GPR109a, was down-regulated by foam cell transformation. This observation was confirmed in explanted human carotid plaques. Plaque CD68 positive macrophages were found clustered at the interface between the acellular lipid pool (LP) and the overlying fibrous cap. GPR109a co-expression was observed in CD68-positive cells outside the LP, whereas CD68-positive cells within the LP, which are highly likely to represent macrophage-derived foam cells, do not co-express GPR109a. This co-expression finding was further confirmed using antibody raised against a specific lipid-droplet associated protein, adipophilin. Conclusions This study shows that despite NAs anti-inflammatory effect on human macrophages, it does not appear to enhance cholesterol efflux in foam cells, which is at least partially ascribed to GPR109a down-regulation upon foam cell transformation. This implies that direct NA-promotion of cholesterol efflux from foam cells may not contribute to atherosclerosis regression, which has been demonstrated with this drug. Figure 1 Figure 2