Dipeptidyl Peptidase 4/Midline-1 Axis Promotes T Lymphocyte Motility in Atherosclerosis.

T cells play a crucial role in atherosclerosis, with its infiltration preceding the formation of atheroma. However, how T-cell infiltration is regulated in atherosclerosis remains largely unknown. Here, this work demonstrates that dipeptidyl peptidase-4 (DPP4) is a novel regulator of T-cell motility in atherosclerosis. Single-cell ribonucleic acid (RNA) sequencing and flow cytometry show that CD4+ T cells in atherosclerotic patients display a marked increase of DPP4. Lack of DPP4 in hematopoietic cells or T cells reduces T-cell infiltration and atherosclerotic plaque volume in atherosclerosis mouse models. Mechanistically, DPP4 deficiency reduces T-cell motility by suppressing the expression of microtubule associated protein midline-1 (Mid1) in T cells. Deletion of either DPP4 or Mid1 inhibits chemokine-induced shape change and motility, while restitution of Mid1 in Dpp4-/- T cell largely restores its migratory ability. Thus, DPP4/Mid1, as a novel regulator of T-cell motility, may be a potential inflammatory target in atherosclerosis.

A relaxometry method that emphasizes practicality and availability.

PURPOSE: Although many methods have been proposed to quantitatively map the main MRI parameters (e.g., T1 , T2 , C × M0 ), these methods often involve special sequences not readily available on clinical scanners and/or may require long scan times. In contrast, the proposed method can readily run on most scanners, offer flexible tradeoffs between scan time and image quality, and map MRI parameters jointly to ensure spatial alignment. METHODS: The approach is based on the multi-shot spin-echo (SE) EPI sequence. The corresponding signal equation was derived and strategies for solving it were developed. As usual with multi-shot EPI, scan time can readily be traded-off against image quality by adjusting the echo train length. Validation was performed against reference relaxometry methods, in gel phantoms with varying concentrations of gadobutrol and gadoterate meglumine contrast agents. In vivo examples are further presented, from 3 neuroradiology patients. RESULTS: Bland-Altman analysis was performed: for T2 , as compared to 2D SE, bias was 0.29 ms and the 95% limits of agreement ranged from -1.15 to +1.73 ms. For T1 , compared to inversion-recovery SE (and MOLLI), bias was -20.2 ms (and -14.5 ms) and the limits of agreement ranged from -62.4 to +22.0 ms (and -53.8 to +24.9 ms). The mean relative T1 error between the proposed method and each of the 2 reference methods was similar to that of the reference methods among themselves. CONCLUSION: In the constellation of existing relaxometry methods, the proposed method is meant to stand out in terms of its practicality and availability.

Noncontrast Magnetic Resonance Angiography for the Diagnosis of Peripheral Vascular Disease.

Contrast-enhanced magnetic resonance angiography (MRA) provides excellent assessment of the peripheral arterial vasculature and is considered an important adjunctive diagnostic modality for the assessment of peripheral arterial disease. However, given the high prevalence of chronic kidney disease in patients with peripheral arterial disease, the association of gadolinium contrast media with nephrogenic systemic fibrosis, and recent concern with consequences of long-term deposition of gadolinium in the brain, there has been a renewed interest in noncontrast MRA approaches. Recent improvements in pulse sequences combined with instrumentation have facilitated the development of newer noncontrast MRA sequences that provide high spatial resolution, allowing the evaluation of distal (infrageniculate and pedal) vessels of importance in patients with critical limb ischemia. Further, many of these sequences are time efficient and versatile, allowing rapid evaluation of the entire lower extremity vasculature. In this comprehensive review, we outline historic techniques and compare these with newer approaches such as quiescent interval slice-selective MRA, 3-dimensional fast spin echo , and velocity-sensitive MRA that are emerging as an alternative to computed tomographic angiography or digital subtraction angiography for the evaluation of lower limb arteries in patients with peripheral arterial disease. Technical details and applications in clinical practice will be discussed.

Comparative Dose of Contrast-Enhanced Spectral Mammography (CESM), Digital Mammography, and Digital Breast Tomosynthesis.

OBJECTIVE: The purpose of this study is to provide a more accurate estimation of the radiation dose of contrast-enhanced spectral mammography (CESM) relative to that of 2D digital mammography and tomosynthesis using phantom and patient data and an accepted dosimetry protocol that eliminates vendor-specific average glandular dose (AGD) estimates while including breast density. MATERIALS AND METHODS: Patient and phantom AGD estimation was performed using two vendors (system 1 and system 2) in five imaging modes, including 2D, 3D, and CESM imaging. Patient AGD was retrospectively estimated from 45 patients who underwent mammography with all imaging modes during 2012-2016. Patient and phantom AGD were estimated using accepted European and International Atomic Energy Agency protocols for dosimetry and were compared across imaging modes using a paired t test with Bonferroni correction. RESULTS: Phantom data showed that the imaging modes with the lowest to highest AGDs were system 1 2D, followed by system 2 2D and system 2 3D, which had comparable values (p = 0.6), followed by system 1 CESM, and then by system 2 2D plus 3D. One hundred eighty views in 45 patients showed that the system 1 CESM AGD was 1.8 times greater than the system 1 2D AGD (p < 0.001), 1.2 times greater than the system 2 2D AGD (p < 0.001), 1.2 times greater than the system 2 3D AGD (p < 0.001), and 0.6 times less than the system 2 2D plus 3D AGD (p < 0.001). CONCLUSION: The CESM dose for system 1 is within an acceptable range as compared with other commonly performed mammographic examinations and should not preclude its use as a diagnostic breast imaging tool.

A new method for CT dose estimation by determining patient water equivalent diameter from localizer radiographs: Geometric transformation and calibration methods using readily available phantoms.

PURPOSE: Water equivalent diameter (Dw) reflects patient's attenuation and is a sound descriptor of patient size, and is used to determine size-specific dose estimator from a CT examination. Calculating Dw from CT localizer radiographs makes it possible to utilize Dw before actual scans and minimizes truncation errors due to limited reconstructed fields of view. One obstacle preventing the user community from implementing this useful tool is the necessity to calibrate localizer pixel values so as to represent water equivalent attenuation. We report a practical method to ease this calibration process. METHODS: Dw is calculated from water equivalent area (Aw) which is deduced from the average localizer pixel value (LPV) of the line(s) in the localizer radiograph that correspond(s) to the axial image. The calibration process is conducted to establish the relationship between Aw and LPV. Localizer and axial images were acquired from phantoms of different total attenuation. We developed a program that automates the geometrical association between axial images and localizer lines and manages the measurements of Dw and average pixel values. We tested the calibration method on three CT scanners: a GE CT750HD, a Siemens Definition AS, and a Toshiba Acquilion Prime80, for both posterior-anterior (PA) and lateral (LAT) localizer directions (for all CTs) and with different localizer filters (for the Toshiba CT). RESULTS: The computer program was able to correctly perform the geometrical association between corresponding axial images and localizer lines. Linear relationships between Aw and LPV were observed (with R2 all greater than 0.998) on all tested conditions, regardless of the direction and image filters used on the localizer radiographs. When comparing LAT and PA directions with the same image filter and for the same scanner, the slope values were close (maximum difference of 0.02 mm), and the intercept values showed larger deviations (maximum difference of 2.8 mm). Water equivalent diameter estimation on phantoms and patients demonstrated high accuracy of the calibration: percentage difference between Dw from axial images and localizers was below 2%. With five clinical chest examinations and five abdominal-pelvic examinations of varying patient sizes, the maximum percentage difference was approximately 5%. CONCLUSIONS: Our study showed that Aw and LPV are highly correlated, providing enough evidence to allow for the Dw determination once the experimental calibration process is established.

Cardiopulmonary exercise testing in the MRI environment.

Maximal oxygen consumption ([Formula: see text]max) measured by cardiopulmonary exercise testing (CPX) is the gold standard for assessment of cardiorespiratory fitness. Likewise, cardiovascular magnetic resonance (CMR) is the gold standard for quantification of cardiac function. The combination of CPX and CMR may offer unique insights into cardiopulmonary pathophysiology; however, the MRI-compatible equipment needed to combine these tests has not been available to date. We sought to determine whether CPX testing in the MRI environment, using equipment modified for MRI yields results equivalent to those obtained in standard exercise physiology (EP) lab. Ten recreationally trained subjects completed [Formula: see text]max tests in different locations; an EP laboratory and an MRI laboratory, using site specific equipment. CMR cine images of the heart were acquired before and immediately after maximal exercise to measure cardiac function. Subjects in all tests met criteria indicating that peak exercise was achieved. Despite equipment modifications for the MRI environment, [Formula: see text]max was nearly identical between tests run in the different labs (95% lower confidence limit (LCL) = 0.8182). The mean difference in [Formula: see text]max was less than 3.40 ml (kg/min)(-1), within the variability expected for tests performed on different days, in different locations, using different metabolic carts. MRI performed at rest and following peak exercise stress indicated cardiac output increased from 5.1 ± 1.0 l min(-1) to 16.4 ± 5.6 l min(-1), LVEF increased from 65.2 ± 3.3% to 78.4 ± 4.8%, while RVEF increased from 52.8 ± 5.3% to 63.4 ± 5.3%. Regression analysis revealed a significant positive correlation between [Formula: see text]max and stroke volume (R = 0.788, P = 0.006), while the correlation with cardiac output did not reach statistical significance (R = 0.505, P = 0.137). [Formula: see text]max CPX testing can be effectively performed in the MRI environment, enabling direct combination of physiological data with advanced post-exercise imaging in the same test session.

Lipoicmethylenedioxyphenol Reduces Experimental Atherosclerosis through Activation of Nrf2 Signaling.

OBJECTIVE: Oxidative stress is implicated in the pathogenesis of atherosclerosis, and Nrf2 is the transcriptional factor central in cellular antioxidant responses. In the present study, we investigate the effect of a dihydrolipoic acid derivative lipoicmethylenedioxyphenol (LMDP) on the progression of atherosclerosis and test whether its effect on atherosclerosis is mediated by Nrf2. METHODS AND RESULTS: Both magnetic resonance imaging (MRI) scanning and en face analysis reveal that 14 weeks of treatment with LMDP markedly reduced atherosclerotic burden in a rabbit balloon vascular injury model. Myograph analyses show decreased aortic contractile response to phenylephrine and increased aortic response to acetylcholine and insulin in LMDP-treated animals, suggesting that LMDP inhibits atherosclerosis through improving vascular function. A role of Nrf2 signaling in mediating the amelioration of vascular function by LMDP was supported by increased Nrf2 translocation into nuclear and increased expression of Nrf2 target genes. Furthermore, chemotaxis analysis with Boydem chamber shows that leukocytes isolated from LMDP-treated rabbits had reduced chemotaxis, and knock-down of Nrf2 significantly reduced the effect of LMDP on the chemotaxis of mouse macrophages. CONCLUSION: Our results support that LMDP has an anti-atherosclerotic effect likely through activation of Nrf2 signaling and subsequent inhibition of macrophage chemotaxis.

Rapid assessment of quantitative T1, T2 and T2* in lower extremity muscles in response to maximal treadmill exercise.

MRI provides a non-invasive diagnostic platform to quantify the physical and physiological attributes of skeletal muscle at rest and in response to exercise. MR relaxation parameters (T1, T2 and T2*) are characteristic of tissue composition and metabolic properties. With the recent advent of quantitative techniques that allow rapid acquisition of T1, T2 and T2* maps, we posited that an integrated treadmill exercise-quantitative relaxometry paradigm can rapidly characterize exercise-induced changes in skeletal muscle relaxation parameters. Accordingly, we investigated the rest/recovery kinetics of T1, T2 and T2* in response to treadmill exercise in the anterior tibialis, soleus and gastrocnemius muscles of healthy volunteers, and the relationship of these parameters to age and gender. Thirty healthy volunteers (50.3 ± 16.6 years) performed the Bruce treadmill exercise protocol to maximal exhaustion. Relaxometric maps were sequentially acquired at baseline and for approximately 44 minutes post-exercise. Our results show that T1, T2 and T2* are significantly and differentially increased immediately post-exercise among the leg muscle groups, and these values recover to near baseline within 30-44 minutes. Our results demonstrate the potential to characterize the kinetics of relaxation parameters with quantitative mapping and upright exercise, providing normative values and some clarity on the impact of age and gender.

Reproducibility of thoracic and abdominal aortic wall measurements with three-dimensional, variable flip angle (SPACE) MRI.

PURPOSE: To evaluate the reproducibility and repeatability of high-resolution, isotropic thoracic and abdominal aortic wall measurements, and determine the implications they have on the number of subjects necessary for future clinical trials. MATERIALS AND METHODS: Using a T1-weighted three-dimensional MRI SPACE sequence, we evaluated the interobserver, intraobserver, and scan-rescan variability of isotropic thoracic and abdominal aortic wall measurements in 15 cardiovascular diseased patients and 6 normal volunteers. Main outcome analyses were intracorrelation coefficient (ICC), mean relative error (mRE), and sample size calculation at 80% power to be used to compare placebo group and treatment group means in future two-arm randomized clinical trials. RESULTS: Excellent reliability, ICC > 0.8 (P < 0.001) and small mRE < 10% were demonstrated for the interobserver, intraobserver, and scan-rescan variability for all investigated measures: lumen area (LA), outer wall area (OWA), wall area (VWA), total wall volume (TWV), and percentage wall volume (%WV). Sample size calculation revealed slightly different sample size per treatment arm for thoracic and abdominal aorta segments (maximum number of subjects: 352 subjects for thoracic segment versus 421 subjects for abdominal segment for LA at 5% difference, and minimum of 3 thoracic versus 4 abdominal subjects needed for %WV evaluation at 25% difference). CONCLUSION: Our study demonstrates the reproducibility and repeatability of SPACE aortic plaque measurements, and gives insight into the number of subjects needed for the design of therapeutic studies in aortic atherosclerosis.

Aliskiren effect on plaque progression in established atherosclerosis using high resolution 3D MRI (ALPINE): a double-blind placebo-controlled trial.

BACKGROUND: The renin-angiotensin system is well recognized as a mediator of pathophysiological events in atherosclerosis. The benefits of renin inhibition in atherosclerosis, especially when used in combination with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) are currently not known. We hypothesized that treatment with the renin inhibitor aliskiren in patients with established cardiovascular disease will prevent the progression of atherosclerosis as determined by high-resolution magnetic resonance imaging (MRI) measurements of arterial wall volume in the thoracic and abdominal aortas of high-risk patients with preexisting cardiovascular disease. METHODS AND RESULTS: This was a single-center, randomized, double-blind, placebo-controlled trial in patients with established cardiovascular disease. After a 2-week single-blind placebo phase, patients were randomized to receive either placebo (n=37, mean ± SD age 64.5 ± 8.9 years, 3 women) or 150 mg of aliskiren (n=34, mean ± SD age 63.9 ± 11.5 years, 9 women). Treatment dose was escalated to 300 mg at 2 weeks and maintained during the remainder of the study. Patients underwent dark-blood, 3-dimensional MRI assessment of atherosclerotic plaque in the thoracic and abdominal segments at baseline and on study completion or termination (up to 36 weeks of drug or matching placebo). Aliskiren use resulted in significant progression of aortic wall volume (normalized total wall volume 5.31 ± 6.57 vs 0.15 ± 4.39 mm(3), P=0.03, and percentage wall volume 3.37 ± 2.96% vs 0.97 ± 2.02%, P=0.04) compared with placebo. In a subgroup analysis of subjects receiving ACEI/ARB therapy, atherosclerosis progression was observed only in the aliskiren group, not in the placebo group. CONCLUSIONS: MRI quantification of atheroma plaque burden demonstrated that aliskiren use in patients with preexisting cardiovascular disease resulted in an unexpected increase in aortic atherosclerosis compared with placebo. Although preliminary, these results may have implications for the use of renin inhibition as a therapeutic strategy in patients with cardiovascular disease, especially in those receiving ACEI/ARB therapy. CLINICAL TRIAL REGISTRATION: URL: http://ClinicalTrials.gov Unique identifier: NCT01417104.

Improved in vivo human carotid artery wall T2 estimation.

T(2) quantification has been shown to noninvasively and accurately estimate tissue iron content in the liver and heart; applying this to thin-walled carotid arteries introduces a new challenge to the estimation process. With most imaging voxels in a vessel being along its boundaries, errors in parameter estimation may result from partial volume mixing and misregistration due to motion in addition to noise and other common error sources. To minimize these errors, we propose a novel technique to reliably estimate T(2) in thin regions of vessel wall. The technique weights data points to reduce the influence of expected error sources. It uses neighborhoods of data to increase the number of points for fitting and to assess lack of fit for automated outlier detection and deletion. The performance of this method was observed in simulations, phantom and in vivo patient studies and compared to results obtained using a pixelwise linear least squares estimation of T(2). The new proposed method showed a closer match to the expected results, and a 4.2-fold decrease in interobserver variability for in vivo studies. This increased confidence in estimation should improve the ability to reliably quantify iron noninvasively in the arterial wall.

Z-Group ketone chain transfer agents for RAFT polymer nanoparticle modification via hydrazone conjugation.

A ketal-containing trithiocarbonyl compound has been synthesized and characterized as a chain transfer agent (CTA) in Reversible Addition Fragmentation Transfer (RAFT) polymerization. The ketal functionality does not interfere with RAFT polymerization of acrylate monomers, which proceeds as previously reported to yield macro-CTA polymers and block co-polymers. Post-polymerization ketal cleavage revealed ketone functionality at the polar terminus of an amphiphilic block co-polymer. Hydrazone-formation was facile in both organic solution as well as in aqueous buffer where polymer nanoparticle assemblies were formed, indicating a conjugation/end-functionalization yield of 40-50%. Conjugation was verified with fluorescein, biotin and Gd-DOTA derivatives, and though the trithiocarbonate linkage is hydrolytically labile, we observed stable conjugation for several days at pH 7.4. and 37°C. As expected, streptavidin binding to biotinylated polymer micelles was observed, and size-change based relaxivity increases were observed when Gd-DOTA hydrazide was conjugated to polymer micelles. Cell-uptake of fluorescently labeled polymer micelles was also readily tracked by FACS and fluorescence microscopy. These polymer derivatives demonstrate a range of potential theranostic/biotechnological applications for this conveniently accessible keto-CTA, which include ligand-based nanoparticle targeting and fluorescent/MR nanoparticle contrast agents.

The prolonged survival of fibroblasts with forced lipid catabolism in visceral fat following encapsulation in alginate-poly-L-lysine.

Although alginate-poly-L-lysine (AP(L)) encapsulation of cells producing bioactive peptides has been widely tested, it is unknown whether AP(L) supports lasting catabolic functions of encapsulated cells in adipose tissue, which are required for obesity reduction. We tested functions of AP(L)-encapsulated fibroblasts isolated from wild-type (WT) and aldehyde dehydrogenase 1a1 knockout mice (KO), which resist obesity on a high-fat (HF) diet, have a higher metabolic rate, and express increased levels of thermogenic uncoupling protein-1 (Ucp1) in their deleterious visceral fat depots compared to WT mice. To enable in vivo detection and quantification, fibroblasts were stably transfected with green-fluorescent protein. WT- or KO-containing microcapsules were injected into two visceral depots of WT mice fed an HF diet. Eighty days after transplantation, microcapsules were located in vivo using magnetic resonance imaging. KO microcapsules prevented weight gain in obese WT mice compared to a mock- and WT capsule-injected groups on an HF diet. The weight loss in KO-treated mice corresponded to lipid reduction and induction of thermogenesis in the injected visceral fat. The non-treated subcutaneous fat was not altered. Our data suggest that the AP(L) polymer supports long-term catabolic functions of genetically-modified fibroblasts, which can be potentially used for depot-specific obesity treatment.

In vivo targeting of inflammation-associated myeloid-related protein 8/14 via gadolinium immunonanoparticles.

OBJECTIVE: Myeloid-related protein (Mrp) 8/14 complex (is a highly expressed extracellularly secreted protein, implicated in atherosclerosis. In this study, we evaluated the feasibility of targeting Mrp in vivo through synthetic immuno-nanoprobes. METHODS AND RESULTS: Anti-Mrp-14 and nonspecific IgG-conjugated gadolinium nanoprobes (aMrp-) were synthesized and characterized. Pharmacokinetics and vascular targeting via MRI of the formulations were assessed in vivo in high fat-fed apolipoprotein E deficient (ApoE(-/-)), ApoE(-/-)/Mrp14(-/-) (double knockout) and chow-fed wild-type (C57BL/6) mice. Bone marrow-derived myeloid progenitor cells were isolated from both ApoE(-/-) and double knockout mice, differentiated to macrophages, and were treated with LPS, with or without Mrp8, Mrp14, or Mrp8/14; conditioned media was used for in vitro studies. Mrp-activated cells secreted significant amounts of proinflammatory cytokines, which was abolished by pretreatment with aMrp-NP. We show in vitro that aMrp-NP binds endothelial cells previously treated with conditioned media containing Mrp8/14. MRI following intravenous delivery of aMrp-NP revealed prolonged and substantial delineation of plaque in ApoE(-/-) but not double knockout or wild-type animals. Nonspecific IgG-conjugated gadolinium nanoprobe-injected animals in all groups did not show vessel wall enhancement. Flow-cytometric analysis of aortic digesta revealed that aMrp-NP present in Ly-6G(+), CD11b(+), CD11c(+), and CD31(+) cells in ApoE(-/-) but not in double knockout animals. CONCLUSIONS: Targeted imaging with aMrp-NP demonstrates enhancement of plaque with binding to inflammatory cells and reduction in inflammation. This strategy has promise as a theranostic approach for atherosclerosis.

Post-interventional three-dimensional dark blood MRI in the adult with congenital heart disease.

BACKGROUND: Investigate a novel three-dimensional (3D) turbo spin echo (TSE) magnetic resonance imaging (MRI) sequence to assess stented segments in adults with congenital heart disease (CHD) after transcatheter intervention. METHODS: Adults with CHD referred for computed tomography (CT) after transcatheter intervention underwent MR exam with a 3D respiratory gated TSE sequence. Data obtained at the time of the study included type of CHD, radiation dose, length of time between exams, and luminal diameters of stented segments from each exam. Continuous variables were analyzed using Student'st and Bland-Altman plots performed to analyze measurements obtained from both examinations. RESULTS: Eleven patients underwent both examinations. Type of defects included coarctation of the aorta (n=6) and tetralogy of Fallot. Average radiation dose was 19.6 mSv and average time between CT and MRI was 99 ± 160 days. Luminal diameters of stented vessels correlated closely between TSE MRI and CT (r(2)=.85) with a bias toward overestimation with MRI (mean 22.4 ± 4.3mm and 20.9 ± 3.7 mm, p<.01). CONCLUSION: This novel 3D respiratory gated TSE MR technique provides a feasible method to reduce metallic artifact and improve visualization of stented segments and surrounding anatomic structures without exposure to radiation.

Non-rigid registration and KLT filter to improve SNR and CNR in GRE-EPI myocardial perfusion imaging.

The purpose of the study was to evaluate the effect of motion compensation by non-rigid registration combined with the Karhunen-Loeve Transform (KLT) filter on the signal to noise (SNR) and contrast-to-noise ratio (CNR) of hybrid gradient-echo echoplanar (GRE-EPI) first-pass myocardial perfusion imaging. Twenty one consecutive first-pass adenosine stress perfusion MR data sets interpreted positive for ischemia or infarction were processed by non-rigid Registration followed by KLT filtering. SNR and CNR were measured in abnormal and normal myocardium in unfiltered and KLT filtered images following non-rigid registration to compensate for respiratory and other motions. Image artifacts introduced by filtering in registered and nonregistered images were evaluated by two observers. There was a statistically significant increase in both SNR and CNR between normal and abnormal myocardium with KLT filtering (mean SNR increased by 62.18% ± 21.05% and mean CNR increased by 58.84% ± 18.06%; p = 0.01). Motion correction prior to KLT filtering reduced significantly the occurrence of filter induced artifacts (KLT only-artifacts in 42 out of 55 image series vs. registered plus KLT-artifacts in 3 out of 55 image series). In conclusion the combination of non- rigid registration and KLT filtering was shown to increase the SNR and CNR of GRE-EPI perfusion images. Subjective evaluation of image artifacts revealed that prior motion compensation significantly reduced the artifacts introduced by the KLT filtering process.

Assessment of carotid stenosis using three-dimensional T2-weighted dark blood imaging: Initial experience.

PURPOSE: To evaluate the use of a T2-weighted SPACE sequence (T2w-SPACE) to assess carotid stenosis via several methods and compare its performance with contrast-enhanced magnetic resonance angiography (ceMRA). MATERIALS AND METHODS: Fifteen patients with carotid atherosclerosis underwent dark blood (DB)-MRI using a 3D turbo spin echo with variable flip angles sequence (T2w-SPACE) and ceMRA. Images were coregistered and evaluated by two observers. Comparisons were made for luminal diameter, luminal area, degree of luminal stenosis (NASCET: North American Symptomatic Endarterectomy Trial; ECST: European Carotid Surgery Trial, and area stenosis), and vessel wall area. Degree of NASCET stenosis was clinically classified as mild (<50%), moderate (50%-69%), or severe (>69%). RESULTS: Excellent agreement was seen between ceMRA and T2w-SPACE and between observers for assessment of lumen diameter, lumen area, vessel wall area, and degree of NASCET stenosis (r > 0.80, P < 0.001). ECST stenosis was consistently higher than NASCET stenosis (48 ± 14% vs. 24 ± 22%, P < 0.001). Area stenosis (72 ± 2%) was significantly higher (P < 0.001) than both ESCT and NASCET stenosis. CONCLUSION: DB-MRI of carotid arteries using T2w-SPACE is clinically feasible. It provides accurate measurements of lumen size and degree of stenosis in comparison with ceMRA and offers a more reproducible measure of ECST stenosis than ceMRA.

Long-term dipeptidyl-peptidase 4 inhibition reduces atherosclerosis and inflammation via effects on monocyte recruitment and chemotaxis.

BACKGROUND: Dipeptidyl-peptidase 4 (DPP-4) inhibitors are increasingly used to accomplish glycemic targets in patients with type II diabetes mellitus. Because DPP-4 is expressed in inflammatory cells, we hypothesized that its inhibition will exert favorable effects in atherosclerosis. METHODS AND RESULTS: Male LDLR(-/-) mice (6 weeks) were fed a high-fat diet or normal chow diet for 4 weeks and then randomized to vehicle or alogliptin, a high-affinity DPP-4 inhibitor (40 mg · kg(-1) · d(-1)), for 12 weeks. Metabolic parameters, blood pressure, vascular function, atherosclerosis burden, and indexes of inflammation were obtained in target tissues, including the vasculature, adipose, and bone marrow, with assessment of global and cell-specific inflammatory pathways. In vitro and in vivo assays of DPP-4 inhibition (DPP-4i) on monocyte activation/migration were conducted in both human and murine cells and in a short-term ApoE(-/-) mouse model. DPP-4i improved markers of insulin resistance and reduced blood pressure. DPP-4i reduced visceral adipose tissue macrophage content (adipose tissue macrophages; CD11b(+), CD11c(+), Ly6C(hi)) concomitant with upregulation of CD163. DPP-4 was highly expressed in bone marrow-derived CD11b(+) cells, with DPP-4i downregulating proinflammatory genes in these cells. DPP-4i decreased aortic plaque with a striking reduction in plaque macrophages. DPP-4i prevented monocyte migration and actin polymerization in in vitro assays via Rac-dependent mechanisms and prevented in vivo migration of labeled monocytes to the aorta in response to exogenous tumor necrosis factor-α and DPP-4. CONCLUSION: DPP-4i exerts antiatherosclerotic effects and reduces inflammation via inhibition of monocyte activation/chemotaxis. These findings have important implications for the use of this class of drugs in atherosclerosis.

Noncontrast MRA for the diagnosis of vascular diseases.

The association between gadolinium-based contrast agents and neprogenic systemic fibrosis has helped propel noncontrast angiography techniques to center stage in the MR evaluation of vascular disease, especially in individuals with intrinsic renal diseases. Although balanced steady-state free precession, phase contrast, and time-of-flight sequences are currently being revisited and improved, new noncontrast angiographic methods have been created and are under development: ECG-gated 3D partial-Fourier fast spin echo (FSE) and 3D variable flip angle FSE (SPACE). All of these are attempts to develop noncontrast methods that offer equal or superior vascular diagnosis as compared with contrast-enhanced MR angiography.