Ji Hoe Heo

Matrix Metalloproteinases Increase Very Early during Experimental Focal Cerebral Ischemia

Microvascular integrity is lost during focal cerebral ischemia. The degradation of the basal lamina and extracellular matrix are, in part, responsible for the loss of vascular integrity. Matrix metalloproteinases (MMPs) may play a primary role in basal lamina degradation. By using a sensitive modification of gelatin zymography, the authors investigated the activity of MMP-2 and MMP-9 in frozen 10-µm sections of ischemic and nonischemic basal ganglia and plasma samples of 27 non-human primates after middle cerebral artery occlusion/reperfusion (MCAO/R) for various periods. The gelatinolytic activities were compared with parallel cell dUTP incorporation in the ischemic zones of adjacent sections. In the brain, the integrated density of MMP-2 increased significantly by 1 hour after MCAO and was persistently elevated thereafter. Matrix metalloproteinase-2 expression was highly correlated with the extent of neuron injury and the number of injured neurons (r = 0.9763, SE = 0.004, 2P < 0.0008). Matrix metalloproteinase-9 expression only was significantly increased in subjects with hemorrhagic transformation. In plasma, only MMP-9 increased transiently at 2 hours of MCAO. These findings highlight the early potential role of MMP-2 in the degradation of basal lamina leading to neuronal injury, and an association of MMP-9 with hemorrhagic transformation after focal cerebral ischemia.

Yonsei Stroke Registry

Background and Purpose: The hospital-based stroke registry is a well-established method useful for understanding diverse clinical characteristics of stroke related to geographical, racial or environmental differences. We analyzed the data from 1,000 patients with acute cerebral infarctions registered with the Yonsei Stroke Registry (YSR) which is the first prospective hospital-based observational study in Korea. Methods: All patients had cerebral infarctions and presented within 7 days of onset. CT or MRI was performed in all patients and a vascular imaging study (digital subtraction or magnetic resonance angiography) was conducted in 53.9% of the patients. Subtype classification was made through a consensus approach based on the strict application of TOAST criteria. Results: The mean age of patients was 62 ± 12 years, and 60.8% were males. Undetermined cause (UD) was the most frequent subtype (40.6%), which was followed by lacunar stroke (LS 21.5%), cardiac embolism (CE 18.3%), large-artery atherosclerosis (LAA 16.5%) and other determined causes (3.1%). Hypertension was found in 64.3%, smoking in 35.2%, diabetes mellitus in 26.9%, hypercholesterolemia in 24.1%, high hematocrit (≧50%) in 21.8%, clinically identified potential cardiac sources of embolism in 18.3%, a history of previous stroke in 22.0% and a history of previous transient ischemic attack in 4.7%. Recurrent stroke was associated with a higher number of risk factors (p < 0.001) and a higher incidence of LAA (p = 0.003) than the first stroke. Vertebrobasilar artery territorial infarction was found in 39.8%, which was associated with higher incidences of LAA and LS and a lower incidence of CE than carotid artery territorial lesions (p = 0.001). The 30-day mortality rate was 5.3% and cerebral herniation caused early death in 52%. Conclusion: The distribution of stroke subtypes in the YSR was largely comparable with that of western registries. The highest incidence of UD might be related to the strict application of TOAST criteria.

Stroke Statistics in Korea: Part I. Epidemiology and Risk Factors: A Report from the Korean Stroke Society and Clinical Research Center for Stroke

The aim of the Part I of Stroke Statistics in Korea is to summarize nationally representative data of the epidemiology and risk factors of stroke in a single document. Every year, approximately 105,000 people experience a new or recurrent stroke and more than 26,000 die of stroke, which indicates that every 5 minutes stroke attacks someone and every 20 minutes stroke kills someone in Korea. Stroke accounts for roughly 1 of every 10 deaths. The estimated stroke prevalence is about 795,000 in people aged ≥30 years. The nationwide total cost for stroke care was 3,737 billion Korean won (US

Early recanalization after intravenous administration of recombinant tissue plasminogen activator as assessed by pre-and post-thrombolytic angiography in acute ischemic stroke patients

3.3 billion) in 2005. Fortunately, the annual stroke mortality rate decreased substantially by 28.3% during the first decade of the 21th century (53.2/100,000 in 2010). Among OECD countries, Korea had the lowest in-hospital 30-day case-fatality rate for ischemic stroke and ranked third lowest for hemorrhagic stroke in 2009. The proportion of ischemic stroke has steadily increased and accounted for 76% of all strokes in 2009. According to hospital registry studies, the 90-day mortality rate was 3-7% for ischemic stroke and 17% for intracerebral hemorrhage. For risk factors, among Korean adults ≥30 years of age, one in 3-4 has hypertension, one in 10 diabetes, and one in 7 hypercholesterolemia. One in 3 Korean adults ≥19 years of age is obese. Over the last 10 years, the prevalence of hypertension slightly decreased, but the prevalence of diabetes, hypercholesterolemia, and obesity increased. Smoking prevalence in men has decreased, but is still as high as 48%. This report could be a valuable resource for establishing health care policy and guiding future research directions.

Activated Microvessels Express Vascular Endothelial Growth Factor and Integrin αvβ3 During Focal Cerebral Ischemia

Background and Purpose— Recanalization rates after the intravenous (IV) recombinant tissue plasminogen activator (rt-PA) treatment have been poorly studied in acute stroke. Methods— CT angiography was performed before IV rt-PA in all patients and digital subtraction angiography was undertaken for intra-arterial thrombolysis in cases of no improvement after rt-PA infusion. Results— Forty-five patients were treated with IV rt-PA. Initial CT angiography showed relevant arterial occlusions in 35 patients. Recanalization after rt-PA therapy was demonstrated by digital subtraction angiography in 7 of the 31 patients with the occlusion on initial CT angiography: 2/16 in the internal carotid or proximal middle cerebral artery, 3/11 in the distal middle cerebral artery and 2/4 in the basilar artery occlusion. Conclusions— The early recanalization rate after IV rt-PA use was very low in cases with large proximal arterial occlusions. CT angiography before IV rt-PA may be useful for the prediction of its efficacy.

Activation systems for latent matrix metalloproteinase-2 are upregulated immediately after focal cerebral ischemia

Both vascular endothelial growth factor (VEGF) and integrin αvβ3 play roles in angiogenesis. In noncerebral vascular systems, VEGF can induce endothelial integrin αvβ3 expression. However, it is unknown whether VEGF, like integrin αvβ3, appears in the initial response of microvessels to focal brain ischemia. Their coordinate expression in microvessels of the basal ganglia after middle cerebral artery occlusion (MCAO) in the nonhuman primate model was examined quantitatively. Cells incorporating deoxyuridine triphosphate (dUTP+) by the polymerase I reaction at 1 hour (n = 3), 2 hours (n = 3), and 7 days (n = 4) after MCAO defined the ischemic core (Ic) and peripheral regions. Both VEGF and integrin αvβ3 were expressed by activated noncapillary (7.5- to 30.0-μm diameter) microvessels in the Ic region at 1 and 2 hours after MCAO. At 7 days after MCAO, the number of VEGF+, integrin αvβ3+, or proliferating cell nuclear antigen-positive microvessels had decreased within the Ic region. The expressions of VEGF, integrin αvβ3, and proliferating cell nuclear antigen were highly correlated on the same microvessels using hierarchical log-linear statistical models. Also, VEGF and subunit αv messenger ribonucleic acids were coexpressed on selected microvessels. Here, noncapillary microvessels are activated specifically early during a focal cerebral ischemic insult and rapidly express VEGF and integrin αvβ3 together.

Left Atrial Appendage Thrombi in Stroke Patients: Detection with Two-Phase Cardiac CT Angiography versus Transesophageal Echocardiography

During focal cerebral ischemia, matrix metalloproteinase-2 (MMP-2) can contribute to the loss of microvessel integrity within ischemic regions by degrading the basal lamina. MMP-2 is secreted in latent form (pro-MMP-2), but the activation of pro-MMP-2 in the ischemic territory has not been shown. Immunohistochemical and in situ hybridization studies of the expression of the direct activators of MMP-2, MT1-MMP and MT3-MMP, and the indirect activation system tissue plasminogen activator, urokinase (u-PA), its receptor (u-PAR), and its inhibitor PAI-1 after middle cerebral artery occlusion/reperfusion were undertaken in basal ganglia samples from 26 adolescent male baboons. The expressions of all three MMPs, u-PA, u-PAR, and PA1-1, but not tissue plasminogen activator, were increased from 1 hour after middle cerebral artery occlusion in the ischemic core. mRNA transcripts confirmed the increases in latent MMP-2, u-PA, u-PAR, and PAI-1 antigen very early after middle cerebral artery occlusion. The expression patterns are consistent with secretion of pro-MMP-2 and its activators in the ischemic core, perhaps from separate cell compartments. The rapid and coordinate appearance of pro-MMP-2 and its activation apparatus suggest that in the primate striatum this protease may participate in matrix injury during focal cerebral ischemia.

A new subtype classification of ischemic stroke based on treatment and etiologic mechanism.

PURPOSE To assess the diagnostic accuracy of two-phase 64-section cardiac computed tomographic (CT) angiography for detection of left atrial appendage (LAA) thrombi and differentiation between thrombus and circulatory stasis in patients with stroke, with transesophageal echocardiography (TEE) as the reference standard. MATERIALS AND METHODS This study was institutional review board approved, and all patients gave written informed consent. Fifty-five consecutive patients (36 men, 19 women; mean age, 61 years) who had recently experienced a stroke, had high-risk factors for thrombus formation, and underwent both two-phase 64-section cardiac CT angiography and TEE up to 5 days apart were examined. Agreement between CT and TEE for detection of thrombus was assessed with kappa statistics. For quantitative analysis, the LAA-ascending aorta attenuation ratio (LAA/AA, in Hounsfield units) was measured on early- and late-phase CT images. The significance of differences in CT attenuation measurements were assessed by using the Student t test. RESULTS A total of 14 thrombi were detected in the 55 patients at TEE. With TEE as the reference standard, the overall sensitivity, specificity, and positive and negative predictive values of cardiac CT angiography for the detection of thrombus in the LAA were 100% (14 of 14 patients), 98% (40 of 41 patients), 93% (14 of 15 patients), and 100% (40 of 40 patients), respectively. Concordance between cardiac CT angiography and TEE for the detection of thrombus in the LAA was high (overall kappa = 0.953). Mean LAA/AA values were significantly different between thrombus (0.29 HU +/- 0.12 [standard deviation]) and circulatory stasis (0.85 HU +/- 0.12) on late-phase CT images (P < .001). CONCLUSION Two-phase 64-section cardiac CT angiography is a noninvasive sensitive modality for detecting LAA thrombi and differentiating thrombus from circulatory stasis in stroke patients.

Stroke awareness decreases prehospital delay after acute ischemic stroke in korea

A new subtype classification of ischemic stroke was developed to reflect recent therapeutic strategies as well as evolving concepts of stroke definitions and mechanisms. In 200 consecutive patients with acute ischemic stroke, the inter-rater reliability and proportion of subtypes of the new classification system were assessed and compared with those of the Trial of ORG 10172 in the Acute Stroke Treatment (TOAST) classification. The most frequent subtype of the new classification was atherothrombosis (n = 80, 40%), followed by stroke of undetermined etiology (n = 54, 27%), small artery disease (n = 33, 16.5%), cardioembolism (n = 26, 13%), and stroke of other determined etiology (n = 7, 3.5%). Three raters agreed to the stroke subtype diagnosis in 165 out of 200 cases and the overall ĸ value was excellent (ĸ = 0.82). The new classification system for brain infarction was easy to use and had high inter-rater reliability.

Immediate reocclusion following a successful thrombolysis in acute stroke: A pilot study

BackgroundDelayed arrival at hospital is one of the major obstacles in enhancing the rate of thrombolysis therapy in patients with acute ischemic stroke. Our study aimed to investigate factors associated with prehospital delay after acute ischemic stroke in Korea.MethodsA prospective, multicenter study was conducted at 14 tertiary hospitals in Korea from March 2009 to July 2009. We interviewed 500 consecutive patients with acute ischemic stroke who arrived within 48 hours. Univariate and multivariate analyses were performed to evaluate factors influencing prehospital delay.ResultsAmong the 500 patients (median 67 years, 62% men), the median time interval from symptom onset to arrival was 474 minutes (interquartile range, 170-1313). Early arrival within 3 hours of symptom onset was significantly associated with the following factors: high National Institutes of Health Stroke Scale (NIHSS) score, previous stroke, atrial fibrillation, use of ambulance, knowledge about thrombolysis and awareness of the patient/bystander that the initial symptom was a stroke. Multivariable logistic regression analysis indicated that awareness of the patient/bystander that the initial symptom was a stroke (OR 4.438, 95% CI 2.669-7.381), knowledge about thrombolysis (OR 2.002, 95% CI 1.104-3.633) and use of ambulance (OR 1.961, 95% CI 1.176-3.270) were significantly associated with early arrival.ConclusionsIn Korea, stroke awareness not only on the part of patients, but also of bystanders, had a great impact on early arrival at hospital. To increase the rate of thrombolysis therapy and the incidence of favorable outcomes, extensive general public education including how to recognize stroke symptoms would be important.