High Levels of Remnant Lipoprotein Cholesterol Is a Risk Factor for Large Artery Atherosclerotic Stroke

김정연,박종호,정상욱,Dawid Schellingerhout,박진억,이동근,최원진,채석래,김동억 대한신경과학회 2011 Journal of Clinical Neurology Vol.7 No.4

Background and Purpose Remnant lipoproteins (RLPs) are products of partially catabolized chylomicrons and very-low-density lipoprotein, from which some triglycerides have been removed. These particles are smaller and denser than the parent particles and are believed to be strongly atherogenic. We explored the association between RLP cholesterol (RLP-C) and ischemic stroke, including stroke subtypes. Methods A cohort of 142 ischemic stroke patients (90 men and 52 women; age, 65.2±12.8 years,mean±SD) was enrolled; all had acute infarcts confirmed by diffusion-weighted MRI, and had fasting lipograms. A full stroke-related evaluation was conducted on each patient. An outpatient population of 88 subjects without a history of cerebrovascular or cardiovascular disease served as a control group. Serum RLP fractions were isolated using an immunoaffinity gel containing specific antiapolipoprotein (anti-apo)B-100 and anti-apoA-I antibodies. RLP-C values were considered to be high when they were in the highest quartile of all values in the study. Results High RLP-C values were more common in stroke patients than in control patients (31.0% vs. 14.8%, p=0.01), when 5.6 mg/dL (>75th percentile) was used as the cutoff value. Multivariable analyses indicated that RLP-C was a risk factor for stroke, with an odds ratio of 2.54 (p=0.045). The RLP-C level was higher in the large artery atherosclerosis subgroup (5.7±3.9 mg/dL) than in any other stroke subgroup (small vessel occlusion, 4.9±5.9 mg/dL; cardioembolism, 1.8±2.3 mg/dL; stroke of undetermined etiology, 3.1±2.9 mg/dL). Conclusions We have found an association between high RLP-C levels and ischemic stroke, and in particular large artery atherosclerotic stroke.

Will Molecular Optical Imaging Have Clinically Important Roles in Stroke Management, and How?

이동근,Matthias Nahrendorf,Dawid Schellingerhout,김동억 대한신경과학회 2010 Journal of Clinical Neurology Vol.6 No.1

Molecular imaging is a novel technology to visualize biological processes at the cellular and molecular levels, which is reshaping both biomedical research and clinical practice. By providing molecular information to supplement and augment conventional anatomy-based imaging, molecular imaging is expected to allow 1) the earlier detection of diseases, 2) precise evaluation of disease stages, and 3) both diagnostic and therapeutic monitoring of disease progression in a quantitative manner. In this brief review, we present our view on the prospects of molecular optical imaging in the field of stroke practice, focusing on the imaging vulnerability of atherosclerotic plaques, thrombolytic resistance, real-time cerebral perfusion, and penumbra.

Complementarity between 18F-FDG PET/CT and Ultrasonography or Angiography in Carotid Plaque Characterization

노상미,최원준,강병택,정상욱,이동근,Dawid Schellingerhout,여정석,김동억 대한신경과학회 2013 Journal of Clinical Neurology Vol.9 No.3

Background and Purpose To estimate clinical roles of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) versus angiography and ultrasonography in carotid plaque characterization. Methods We characterized two groups of patients with recently (<1 month) symptomatic (n=14;age=71.8±8.6 years, mean±SD) or chronic (n=13, age=68.9±9.0 years) carotid stenosis using a battery of imaging tests: diffusion magnetic resonance (MR) imaging, MR or transfemoral angiography, duplex ultrasonography (DUS), and carotid FDG-PET/computed tomography. Results The degree of angiographic stenosis was greater in patients with recently symptomatic carotid plaques (67.5±21.5%) than in patients with chronic carotid plaques (32.4±26.8%,p=0.001). Despite the significant difference in the degree of stenosis, lesional maximum standardized uptake values (maxSUVs) on the carotid FDG-PET did not differ between the recently symptomatic (1.56±0.53) and chronic (1.56±0.34, p=0.65) stenosis groups. However, lesional-tocontralesional maxSUV ratios were higher in the recently symptomatic stenosis group (113±17%) than in the chronic stenosis group (98±10%, p=0.017). The grayscale median value of the lesional DUS echodensities was lower in the recently symptomatic stenosis group (28.2±10.0, n=9) than in the chronic stenosis group (53.9±14.0, n=8; p=0.001). Overall, there were no significant correlations between angiographic stenosis, DUS echodensity, and FDG-PET maxSUV. Case/subgroup analyses suggested complementarity between imaging modalities. Conclusions There were both correspondences and discrepancies between the carotid FDG-PET images and DUS or angiography data. Further studies are required to determine whether FDGPET could improve the clinical management of carotid stenosis.

Protease Imaging of Human Atheromata Captures Molecular Information of Atherosclerosis, Complementing Anatomic Imaging

Kim, D.-E.,Kim, J.-Y.,Schellingerhout, D.,Kim, E.-J.,Kim, H.K.,Lee, S.,Kim, K.,Kwon, I.C.,Shon, S.-M.,Jeong, S.-W. AMERICAN HEART ASSOCIATION 2010 Arteriosclerosis, thrombosis, and vascular biology Vol.30 No.3

Cytokine Response to Diet and Exercise Affects Atheromatous Matrix Metalloproteinase-2/9 Activity in Mice

Shon, Soo-Min,Jang, Hee Jeong,Schellingerhout, Dawid,Kim, Jeong-Yeon,Ryu, Wi-Sun,Lee, Su-Kyoung,Kim, Jiwon,Park, Jin-Yong,Oh, Ji Hye,Kang, Jeong Wook UNKNOWN 2017 CIRCULATION JOURNAL Vol.81 No.10

Estimation of Acute Infarct Volume with Reference Maps: A Simple Visual Tool for Decision Making in Thrombectomy Cases

Kim, Dong-Eog,Ryu, Wi-Sun,Schellingerhout, Dawid,Jeong, Han‐,Gil,Kim, Paul,Jeong, Sang-Wuk,Park, Man-Seok,Choi, Kang-Ho,Kim, Joon-Tae,Kim, Beom Joon,Han, Moon-Ku,Lee, Jun,Cha, Jae-Kwan,Kim, Dae- Korean Stroke Society 2019 Journal of stroke Vol.21 No.1

<P><B>Background and Purpose</B></P><P>Thrombectomy within 24 hours can improve outcomes in selected patients with a clinical-infarct mismatch. We devised an easy-to-use visual estimation tool that allows infarct volume estimation in centers with limited resources. </P><P><B>Methods</B></P><P>We identified 1,031 patients with cardioembolic or large-artery atherosclerosis infarction on diffusion-weighted images (DWIs) obtained before recanalization therapy and within 24 hours of onset, and occlusion of the internal carotid or middle cerebral artery. Acute DWIs were mapped onto a standard template and used to create visual reference maps with known lesion volumes, which were then used in a validation study (with 130 cases) against software estimates of infarct volume. </P><P><B>Results</B></P><P>The DWI reference map chart comprises 144 maps corresponding to 12 different infarct volumes (0.5, 1, 2, 3, 5, 7, 9, 11, 13, 15, 17, and 19 mL) in each of 12 template slices (Montreal Neurological Institute z-axis –15 to 51 mm). Infarct volume in a patient is estimated by selecting a slice with a similar infarct size at the corresponding z-axis level on the reference maps and then adding up over all slices. The method yielded good correlations to software volumetrics and was easily learned by both experienced and junior physicians, with approximately 1 to 2 minutes spent per case. The sensitivity, specificity, and accuracy for detecting threshold infarct volumes (<21, <31, and <51 mL) were very high (all about >90%). </P><P><B>Conclusions</B></P><P>We developed easy-to-use reference maps that allow prompt and reliable visual estimation of infarct volumes for triaging patients to thrombectomy in acute stroke.</P>

Quantitative Imaging of Cerebral Thromboemboli In Vivo : The Effects of Tissue-Type Plasminogen Activator

Kim, Dong-Eog,Kim, Jeong-Yeon,Schellingerhout, Dawid,Ryu, Ju Hee,Lee, Su-Kyoung,Jeon, Sangmin,Lee, Ji Sung,Kim, Jiwon,Jang, Hee Jeong,Park, Jung E.,Kim, Eo Jin,Kwon, Ick Chan,Ahn, Cheol-Hee,Nahrendorf American Heart Association 2017 Stroke Vol. No.

<P>Conclusions-Thromboembolic burden and the efficacy of tPA therapy can be assessed serially, noninvasively, and quantitatively using high-resolution microcomputed tomography and a fibrin-binding nanoparticle imaging agent.</P>

Stroke outcomes are worse with larger leukoaraiosis volumes

Ryu, Wi-Sun,Woo, Sung-Ho,Schellingerhout, Dawid,Jang, Min Uk,Park, Kyoung-Jong,Hong, Keun-Sik,Jeong, Sang-Wuk,Na, Jeong-Yong,Cho, Ki-Hyun,Kim, Joon-Tae,Kim, Beom Joon,Han, Moon-Ku,Lee, Jun,Cha, Jae-Kw Oxford University Press 2017 Brain Vol.140 No.1

<P>Leukoaraiosis or white matter hyperintensities are frequently observed on magnetic resonance imaging of stroke patients. We investigated how white matter hyperintensity volumes affect stroke outcomes, generally and by subtype. In total, 5035 acute ischaemic stroke patients were enrolled. Strokes were classified as large artery atherosclerosis, small vessel occlusion, or cardioembolism. White matter hyperintensity volumes were stratified into quintiles. Mean age (+/- standard deviation) was 66.3 +/- 12.8, 59.6% male. Median (interquartile range) modified Rankin Scale score was 2 (1-3) at discharge and 1 (0-3) at 3 months; 16.5% experienced early neurological deterioration, and 3.3% recurrent stroke. The Cochran-Mantel-Haenszel test with adjustment for age, stroke severity, sex, and thrombolysis status showed that the distributions of 3-month modified Rankin Scale scores differed across white matter hyperintensity quintiles (P < 0.001). Multiple ordinal logistic regression analysis showed that higher white matter hyperintensity quintiles were independently associated with worse 3-month modified Rankin Scale scores; adjusted odds ratios (95% confidence interval) for the second to fifth quintiles versus the first quintile were 1.29 (1.10-1.52), 1.40 (1.18-1.66), 1.69 (1.42-2.02) and 2.03 (1.69-2.43), respectively. For large artery atherosclerosis (39.0%), outcomes varied by white matter hyperintensity volume (P = 0.01, Cochran-Mantel-Haenszel test), and the upper three white matter hyperintensity quintiles (versus the first quintile) had worse 3-month modified Rankin Scale scores; adjusted odds ratios were 1.45 (1.10-1.90), 1.86 (1.41-2.47), and 1.89 (1.41-2.54), respectively. Patients with large artery atherosclerosis were vulnerable to early neurological deterioration (19.4%), and the top two white matter hyperintensity quintiles were more vulnerable still: 23.5% and 22.3%. Moreover, higher white matter hyperintensities were associated with poor modified Rankin Scale improvement: adjusted odds ratios for the upper two quintiles versus the first quintile were 0.66 (0.47-0.94) and 0.62 (0.43-0.89), respectively. For small vessel occlusion (17.8%), outcomes tended to vary by white matter hyperintensitiy volume (P = 0.10, Cochran-Mantel-Haenszel test), and the highest quintile was associated with worse 3-month modified Rankin Scale scores: adjusted odds ratio for the fifth quintile versus first quintile, 1.98 (1.23-3.18). In this subtype, worse white matter hyperintensities were associated with worse National Institute of Health Stroke Scale scores at presentation. For cardioembolism (20.6%), outcomes did not vary significantly by white matter hyperintensity volume (P = 0.19, Cochran-Mantel-Haenszel test); however, the adjusted odds ratio for the highest versus lowest quintiles was 1.62 (1.09-2.40). Regardless of stroke subtype, white matter hyperintensities were not associated with stroke recurrence within 3 months of follow-up. In conclusion, white matter hyperintensity volume independently correlates with stroke outcomes in acute ischaemic stroke. There are some suggestions that stroke outcomes may be affected by leukoaraiosis differentially depending on stroke subtypes, to be confirmed in future investigations.</P>

Grading and Interpretation of White Matter Hyperintensities Using Statistical Maps

Ryu, Wi-Sun,Woo, Sung-Ho,Schellingerhout, Dawid,Chung, Moo K.,Kim, Chi Kyung,Jang, Min Uk,Park, Kyoung-Jong,Hong, Keun-Sik,Jeong, Sang-Wuk,Na, Jeong-Yong,Cho, Ki-Hyun,Kim, Joon-Tae,Kim, Beom Joon,Han, American Heart Association, Inc. 2014 Stroke Vol.45 No.12

<P><B>Background and Purpose—</B></P><P>We aimed to generate rigorous graphical and statistical reference data based on volumetric measurements for assessing the relative severity of white matter hyperintensities (WMHs) in patients with stroke.</P><P><B>Methods—</B></P><P>We prospectively mapped WMHs from 2699 patients with first-ever ischemic stroke (mean age=66.8±13.0 years) enrolled consecutively from 11 nationwide stroke centers, from patient (fluid-attenuated-inversion-recovery) MRIs onto a standard brain template set. Using multivariable analyses, we assessed the impact of major (age/hypertension) and minor risk factors on WMH variability.</P><P><B>Results—</B></P><P>We have produced a large reference data library showing the location and quantity of WMHs as topographical frequency-volume maps. This easy-to-use graphical reference data set allows the quantitative estimation of the severity of WMH as a percentile rank score. For all patients (median age=69 years), multivariable analysis showed that age, hypertension, atrial fibrillation, and left ventricular hypertrophy were independently associated with increasing WMH (0–9.4%, median=0.6%, of the measured brain volume). For younger (≤69) hypertensives (n=819), age and left ventricular hypertrophy were positively associated with WMH. For older (≥70) hypertensives (n=944), age and cholesterol had positive relationships with WMH, whereas diabetes mellitus, hyperlipidemia, and atrial fibrillation had negative relationships with WMH. For younger nonhypertensives (n=578), age and diabetes mellitus were positively related to WMH. For older nonhypertensives (n=328), only age was positively associated with WMH.</P><P><B>Conclusions—</B></P><P>We have generated a novel graphical WMH grading (Kim statistical WMH scoring) system, correlated to risk factors and adjusted for age/hypertension. Further studies are required to confirm whether the combined data set allows grading of WMH burden in individual patients and a tailored patient-specific interpretation in ischemic stroke-related clinical practice.</P>

Exercise attenuates matrix metalloproteinase activity in preexisting atherosclerotic plaque

Shon, S.M.,Park, J.H.,Nahrendorf, M.,Schellingerhout, D.,Kim, J.Y.,Kang, B.T.,Jeong, S.W.,Kim, E.J.,Ryu, J.H.,Kim, K.,Kwon, I.C.,Lee, D.K.,Lee, M.M.,Kim, D.E. Elsevier Scientific Publ. Co 2011 Atherosclerosis Vol.216 No.1

Objective: Few studies have investigated if exercise by itself has anti-atherosclerotic effects, without combining interventions with a low-fat diet. We studied the effects of exercise as a stand-alone intervention on preexisting atheromata by measuring not only plaque size but also the levels of plaque-destabilizing matrix-metalloproteinase (MMP) activity in vivo. Methods and results: We used near-infrared fluorescent (NIRF) molecular imaging with an MMP-2/9 activatable NIRF probe to visualize the inflammatory protease activity within preexisting atheromata of 17-week-old ApoE<SUP>-/-</SUP> mice on: (a) normal chow diet (NCD), (b) Western diet (WD), and (c) WD with treadmill exercise for 10 weeks. We also measured tissue levels of aortic lipid peroxidation (LPO) and plasma levels of glucose/lipid/cytokine profiles. Exercise did not attenuate growth of preexisting atheromatous plaques. However, exercise strongly decreased proteolytic activity in plaques for animals on WD, with levels decreasing almost to NCD levels. Exercise was associated with decreased aortic LPO levels and increased blood adiponectin/leptin levels; however, exercise did not affect WD-consumption/weight-gain or improve blood glucose/lipid profiles. Conclusions: Exercise training reduced aortic MMP activity in mice with preexisting atheromata, even though they remained on a high fat diet and plaque-growth was not attenuated.