Seong-Eun Kim

In vivo evaluation of the delivery and efficacy of a sirolimus-laden polymer gel for inhibition of hyperplasia in a porcine model of arteriovenous hemodialysis graft stenosis

Synthetic arteriovenous (AV) hemodialysis grafts are plagued by hyperplasia resulting in occlusion and graft failure yet there are no clinically available preventative treatments. Here the delivery and degradation of a sirolimus-laden polymer gel were monitored in vivo by magnetic resonance imaging (MRI) and its efficacy for inhibiting hyperplasia was evaluated in a porcine model of AV graft stenosis. Synthetic grafts were placed between the carotid artery and ipsilateral jugular vein of swine. A biodegradable polymer gel loaded with sirolimus (2.5mg/mL) was immediately applied perivascularly to the venous anastomosis, and reapplied by ultrasound-guided injections at one, two and three weeks. Control grafts received neither sirolimus nor polymer. The lumen cross-sectional area at the graft-vein anastomosis was assessed in vivo by non-invasive MRI. The explanted tissues also underwent histological analysis. A specifically developed MRI pulse sequence provided a high contrast-to-noise ratio (CNR) between the polymer and surrounding tissue that allowed confirmation of gel location after injection. Polymer signal decreased up to 80% at three to four weeks after injection, slightly faster than its degradation kinetics in vitro. The MR image of the polymer was confirmed by visual assessment at necropsy. On histological assessment, the mean hyperplasia surface area of the treated graft was 52% lower than that of the control grafts (0.43mm(2) vs. 0.89mm(2); p<0.003), while the minimum cross-sectional lumen area, as measured on MRI, was doubled (5.3mm(2) vs 2.5mm(2); p<0.05). In conclusion, customized MRI allowed non-invasive monitoring of the location and degradation of drug delivery polymer gels in vivo. Perivascular application of sirolimus-laden polymer yielded a significant decrease in hyperplasia development and an increase in lumen area at the venous anastomosis of AV grafts.

Carotid MPRAGE Signal Is Associated with Acute Territorial Cerebral Ischemic Events Detected by Diffusion Weighted MRI

Background— Carotid intraplaque hemorrhage has been associated with symptomatic stroke and can be accurately detected with magnetization-prepared rapid acquisition with gradient-echo (MPRAGE). Currently, there are no studies analyzing carotid MPRAGE signal and territorial ischemic events defined by diffusion restriction in the acute setting. Our aim was to determine the association of carotid MPRAGE signal with acute territorial ischemic events using carotid MPRAGE and brain diffusion tensor imaging. Methods and Results— After the addition of the MPRAGE sequence to the neck MR angiographic protocol, 159 patients with suspected acute stroke were evaluated with both brain diffusion tensor imaging and carotid MPRAGE sequences over 2 years, providing 318 carotid artery and paired brain images for analysis. Forty-eight arteries were excluded due to extracarotid sources of brain ischemia and 4 were excluded due to carotid occlusion. Two hundred sixty-six arteries were eligible for data analysis. Carotid MPRAGE-positive signal was associated with an acute cerebral territorial ischemic event with a relative risk of 6.4 (P<0.001). The relative risk of a diffusion tensor imaging-positive territorial ischemic event with carotid MPRAGE-positive signal was increased in mild, moderate, and severe stenosis categories (10.3, P<0.001; 2.9, P=0.01; and 2.2, P=0.01, respectively). Conclusions— In the workup of acute stroke, carotid MPRAGE-positive signal was associated with an increased risk of territorial cerebral ischemic events as detected objectively by brain diffusion tensor imaging. The relative risk of stroke was increased in all carotid stenosis categories but was most elevated in the mild stenosis category.Background —Carotid intraplaque hemorrhage has been associated with symptomatic stroke and can be accurately detected with Magnetization-Prepared Rapid Acquisition with Gradient-Echo (MPRAGE). Currently, there are no studies analyzing carotid MPRAGE signal and territorial ischemic events defined by diffusion restriction in the acute setting. Our aim was to determine the association of carotid MPRAGE signal with acute territorial ischemic events using carotid MPRAGE and brain diffusion tensor imaging (DTI). Methods and Results —After the addition of the MPRAGE sequence to the neck MRA protocol, 159 patients with suspected acute stroke were evaluated with both brain DTI and carotid MPRAGE sequences over 2 years, providing 318 carotid artery and paired brain images for analysis. 48 arteries were excluded due to extracarotid sources of brain ischemia and 4 were excluded due to carotid occlusion. 266 arteries were eligible for data analysis. Carotid MPRAGE positive signal was associated with an acute cerebral territorial ischemic event with a relative risk of 6.4 (p<0.001). The relative risk of a DTI positive territorial ischemic event with carotid MPRAGE positive signal was increased in mild, moderate and severe stenosis categories (10.3 p<0.001, 2.9 p=0.01, and 2.2 p=0.01 respectively). Conclusions —In the workup of acute stroke, carotid MPRAGE positive signal was associated with an increased risk of territorial cerebral ischemic events as detected objectively by brain DTI. The relative risk of stroke was increased in all carotid stenosis categories, but was most elevated in the mild stenosis category.

Quantification of diffusivities of the human cervical spinal cord using a 2D single-shot interleaved multisection inner volume diffusion-weighted echo-planar imaging technique.

BACKGROUND AND PURPOSE: DTI is a highly sensitive technique, which can detect pathology not otherwise noted with conventional imaging methods. This paper provides the atlas of reliable normative in vivo DTI parameters in the cervical spinal cord and its potential applications toward quantifying pathology. MATERIALS AND METHODS: In our study, we created a reference of normal diffusivities of the cervical spinal cord by using a 2D ss-IMIV-DWEPI technique from 14 healthy volunteers and compared parameters with those in 8 patients with CSM. The 2D ss-IMIV-DWEPI technique was applied in each subject to acquire diffusion-weighted images. FA, λ∥, and λ⊥ were calculated. A reference of normal DTI indices from 12 regions of interest was created and compared with DTI indices of 8 patients. RESULTS: A map of reference diffusivity values was obtained from healthy controls. We found statistically significant differences in diffusivities between healthy volunteers and patients with CSM with different severities of disease, by using FA, λ∥, and λ⊥ values. CONCLUSIONS: DTI using 2D ss-IMIV-DWPEI is sensitive to spinal cord pathology. This technique can be used to detect and quantify the degree of pathology within the cervical spinal cord from multiple disease states.

Optimal Prediction of Carotid Intraplaque Hemorrhage Using Clinical and Lumen Imaging Markers

BACKGROUND AND PURPOSE: MR imaging detects intraplaque hemorrhage with high accuracy by using the magnetization-prepared rapid acquisition of gradient echo sequence. Still, MR imaging is not readily available for all patients, and many undergo CTA instead. Our goal was to determine essential clinical and lumen imaging predictors of intraplaque hemorrhage, as indicators of its presence and clues to its pathogenesis. MATERIALS AND METHODS: In this retrospective cross-sectional study, patients undergoing stroke work-up with MR imaging/MRA underwent carotid intraplaque hemorrhage imaging. We analyzed 726 carotid plaques, excluding vessels with non-carotid stroke sources (n = 420), occlusions (n = 7), or near-occlusions (n = 3). Potential carotid imaging predictors of intraplaque hemorrhage included percentage diameter and millimeter stenosis, plaque thickness, ulceration, and intraluminal thrombus. Clinical predictors were recorded, and a multivariable logistic regression model was fitted. Backward elimination was used to determine essential intraplaque hemorrhage predictors with a thresholded 2-sided P < .10. Receiver operating characteristic analysis was also performed. RESULTS: Predictors of carotid intraplaque hemorrhage included plaque thickness (OR = 2.20, P < .001), millimeter stenosis (OR = 0.46, P < .001), ulceration (OR = 4.25, P = .020), age (OR = 1.11, P = .001), and male sex (OR = 3.23, P = .077). The final model discriminatory value was excellent (area under the curve = 0.932). This was significantly higher than models using only plaque thickness (area under the curve = 0.881), millimeter stenosis (area under the curve = 0.830), or ulceration (area under the curve= 0.715, P < .001). CONCLUSIONS: Optimal discrimination of carotid intraplaque hemorrhage requires information on plaque thickness, millimeter stenosis, ulceration, age, and male sex. These factors predict intraplaque hemorrhage with high discriminatory power and may provide clues to the pathogenesis of intraplaque hemorrhage. This model could be used to predict the presence of intraplaque hemorrhage when MR imaging is contraindicated.

Correlation of Carotid Intraplaque Hemorrhage and Stroke Using 1.5 T and 3 T MRI

Carotid therosclerotic disease causes approximately 25% of the nearly 690,000 ischemic strokes each year in the United States. Current risk stratification based on percent stenosis does not provide specific information on the actual risk of stroke for most individuals. Prospective randomized studies have found only 10 to 12% of asymptomatic patients will have a symptomatic stroke within 5 years. Measurements of percent stenosis do not determine plaque stability or composition. Reports have concluded that cerebral ischemic events associated with carotid plaque are intimately associated with plaque instability. Analysis of retrospective studies has found that plaque composition is important in risk stratification. Only MRI has the ability to identify and measure the detailed components and morphology of carotid plaque and provides more detailed information than other currently available techniques. MRI can accurately detect carotid hemorrhage, and MRI identified carotid hemorrhage correlates with acute stroke.

High-Resolution Diffusion-Weighted Imaging of Neck Lymph Nodes Using 2D-Single-Shot Interleaved Multiple Inner Volume Imaging Diffusion-Weighted Echo-Planar Imaging at 3T

BACKGROUND AND PURPOSE: 2D-ss-IMIV-DWEPI is an ss-DWEPI with greatly reduced geometric distortion. The purposes of this paper are to 1) evaluate of the utility of 2D-ss-IMIV-DWEPI for high-resolution neck LN imaging; 2) determine whether 2D-ss-IMIV-DWEPI can depict normal LN hilum; and 3) evaluate whether the inclusion of LN hilum within ROIs affects the measured LN ADC. MATERIALS AND METHODS: HR-DWI was acquired with 1-mm2 in-plane resolution and 2-mm section thickness by using 2D-ss-IMIV-DWEPI. In total, 58 LNs from 18 subjects were evaluated. The ADC map was calculated by using DWI with b = 10 and 300 s/mm2. In those LNs where the LN hilum could be recognized, the LN ADC was measured with and without inclusion of the hilum, and the mean difference of the resulting ADC values was determined. RESULTS: The hilar structure was identified by DWI in 15 LNs. The ADC of the hilum was 1.981 ± 0.331 × 10−3 mm2/s. In these 15 LNs, the ADC value excluding hilar structure was significantly lower than the ADC value including hilar structure (0.983 ± 0.169 versus 1.206 ± 0.244 × 10−3 mm2/s; P < .0001). The mean ADC in a total of 58 LNs excluding the hilar structure was significantly lower than the value obtained including the hilar structure (1.034 ± 0.183 versus 1.095 ± 0.213 × 10−3 mm2/s; P = .0002). CONCLUSIONS: HR-DWI of neck LNs obtained by using 2D-ss-IMIV-DWEPI could identify the hilar structure. The ADC of normal neck LNs seemed significantly different when the hilum was included. The results suggest that HR-DWI may be helpful to aid selection of proper ROIs within LNs for accurate and reliable ADC measurements.

Impact of age on exercise-induced ATP supply during supramaximal plantar flexion in humans

Currently, the physiological factors responsible for exercise intolerance and bioenergetic alterations with age are poorly understood due, at least in art, to the confounding effect of reduced physical activity in the elderly. Thus, in 40 healthy young (22 ± 2 yr) and old (74 ± 8 yr) activity-matched subjects, we assessed the impact of age on: 1) the relative contribution of the three major pathways of ATP synthesis (oxidative ATP synthesis, glycolysis, and the creatine kinase reaction) and 2) the ATP cost of contraction during high-intensity exercise. Specifically, during supramaximal plantar flexion (120% of maximal aerobic power), to stress the functional limits of the skeletal muscle energy systems, we used (31)P-labeled magnetic resonance spectroscopy to assess metabolism. Although glycolytic activation was delayed in the old, ATP synthesis from the main energy pathways was not significantly different between groups. Similarly, the inferred peak rate of mitochondrial ATP synthesis was not significantly different between the young (25 ± 8 mM/min) and old (24 ± 6 mM/min). In contrast, the ATP cost of contraction was significantly elevated in the old compared with the young (5.1 ± 2.0 and 3.7 ± 1.7 mM·min(-1)·W(-1), respectively; P < 0.05). Overall, these findings suggest that, when young and old subjects are activity matched, there is no evidence of age-related mitochondrial and glycolytic dysfunction. However, this study does confirm an abnormal elevation in exercise-induced skeletal muscle metabolic demand in the old that may contribute to the decline in exercise capacity with advancing age.

Prediction of Carotid Intraplaque Hemorrhage Using Adventitial Calcification and Plaque Thickness on CTA

BACKGROUND AND PURPOSE: Carotid intraplaque hemorrhage is associated with stroke, plaque thickness, stenosis, ulceration, and adventitial inflammation. Conflicting data exist on whether calcification is a marker of plaque instability, and no data exist on adventitial calcification. Our goal was to determine whether adventitial calcification and soft plaque (a rim sign) help predict carotid intraplaque hemorrhage. MATERIALS AND METHODS: This was a retrospective cohort study of 96 patients who underwent carotid MRA and CTA within 1 month, from 2009 to 2016. We excluded occlusions (n = 4) and near occlusions (n = 0), leaving 188 carotid arteries. Intraplaque hemorrhage was detected by using MPRAGE. Calcification, adventitial pattern, stenosis, maximum plaque thickness (total, soft, and hard), ulceration, and intraluminal thrombus on CTA were recorded. Atherosclerosis risk factors and medications were recorded. We used mixed-effects multivariable Poisson regression, accounting for 2 vessels per patient. For the final model, backward elimination was used with a threshold of P < .10. Receiver operating characteristic analysis determined intraplaque hemorrhage by using the area under the curve. RESULTS: Our final model included the rim sign (prevalence ratio = 11.9, P < .001) and maximum soft-plaque thickness (prevalence ratio = 1.2, P = .06). This model had excellent intraplaque hemorrhage prediction (area under the curve = 0.94), outperforming the rim sign, maximum soft-plaque thickness, NASCET stenosis, and ulceration (area under the curve = 0.88, 0.86, 0.77, and 0.63, respectively; P < .001). Addition of the rim sign performed better than each marker alone, including maximum soft-plaque thickness (area under the curve = 0.94 versus 0.86, P < .001), NASCET stenosis (area under the curve = 0.90 versus 0.77, P < .001), and ulceration (area under the curve = 0.90 versus 0.63, P < .001). CONCLUSIONS: The CTA rim sign of adventitial calcification with internal soft plaque is highly predictive of carotid intraplaque hemorrhage.

Assessment of novel anti-thrombotic fusion proteins for inhibition of stenosis in a porcine model of arteriovenous graft

Background Hemodialysis arteriovenous synthetic grafts (AVG) provide high volumetric blood flow rates shortly after surgical placement. However, stenosis often develops at the vein-graft anastomosis contributing to thrombosis and early graft failure. Two novel fusion proteins, ANV-6L15 and TAP-ANV, inhibit the tissue factor/factor VIIa coagulation complex and the factor Xa/factor Va complex, respectively. Each inhibitor domain is fused to an annexin V domain that targets the inhibitor activity to sites of vascular injury to locally inhibit thrombosis. This study’s objective was to determine if these antithrombotic proteins are safe and effective in inhibiting AVG stenosis. Methods A bolus of either TAP-ANV or ANV-6L15 fusion protein was administered intravenously immediately prior to surgical placement of a synthetic graft between the external jugular vein and common carotid artery in a porcine model. At surgery, the vein and artery were irrigated with the anti-thrombotic fusion protein. Control animals received intravenous heparin. At 4 weeks, MRI was performed to evaluate graft patency, the pigs were then euthanized and grafts and attached vessels were explanted for histomorphometric assessment of neointimal hyperplasia at the vein-graft anastomosis. Blood was collected at surgery, immediately after surgery and at euthanasia for serum metabolic panels and coagulation chemistries. Results No acute thrombosis occurred in the control group or in either experimental group. No abnormal serum chemistries, activated clotting times or PT, PTT values were observed after treatment in experimental or control animals. However, at the vein-graft anastomosis, there was no difference between the control and experimental groups in cross-sectional lumen areas, as measured on MRI, and no difference in hyperplasia areas as determined by histomorphometry. These results suggest that local irrigation of TAP-ANV or ANV-6L15 intra-operatively was as effective in inhibiting acute graft thrombosis as intravenous administration of heparin, but failed to inhibit hyperplasia development and stenosis in AVG.

Reproducibility of Lumen and Vessel Wall Measurements in Carotid Magnetic Resonance Imaging

Atherosclerotic carotid artery disease is estimated to represent the etiology for one quarter of all strokes. Carotid magnetic resonance imaging and magnetic resonance angiography are promising tools in the evaluation of carotid atherosclerotic vascular disease. In this study, we evaluate the reliability of high resolution carotid wall magnetic resonance (MR) imaging by investigating the inter-observer, intra-observer, and inter-scan variability in measurements of carotid vessel total lumen area and mean wall thickness. This HIPAA compliant study received IRB approval and all subjects gave written informed consent. Nineteen subjects were imaged on a 3T MRI scanner with custom-built 4-element receive-only phased-array coils optimized for carotid anatomy. Three observers manually drew regions of interest around the lumen and outer wall for both left and right carotid arteries. Intraclass correlation coefficients (ICC) showed excellent agreement between Observer 1 and the others (>0.92). A two- way analysis of variance (ANOVA) found no significant difference between observers (p>0.05). Intra-observer variability for Observer 1 was measured by coefficient of variation (CV) with 0.03 for total lumen area and 0.03 for mean wall thickness. Similarly, the inter-scan variability of Observer 1 was found by CV to be 0.05±0.02 for total lumen area and 0.04±0.03 for mean wall thickness. Our results demonstrate that the MR measurements of total lumen area and mean wall thickness are highly reproducible and provide a reliable foundation for the evaluation of carotid atherosclerotic vascular disease.