Yoonkyung Chang

Low levels of plasma omega 3-polyunsaturated fatty acids are associated with cerebral small vessel diseases in acute ischemic stroke patients

Cerebral small vessel diseases (SVDs) are related to stroke or cognitive dysfunction. n-3-polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) represent possible disease-modifying factors for cardiovascular disease or dementia. Our hypothesis was that a low proportion of plasma FAs would be associated with cerebral SVDs. We prospectively enrolled 220 patients with a first-episode cerebral infarction within 7 days after symptom onset. The composition of plasma FAs was analyzed by gas chromatography methods. The presence and burden of cerebral microbleeds (CMBs), high-grade white matter changes (HWCs), high-grade perivascular spaces (HPVSs), and asymptomatic lacunar infarctions (ALIs) were investigated. The mean proportion (± SD) was 2.0 ± 0.7 for EPA, 8.9 ± 1.5 for DHA, and 12.0 ± 2.1 for ∑ n-3-PUFAs. In total, 46 (20.9%) patients had CMBs, 64 (29.1 %) had HWCs, 57 (25.9%) had HPVSs, and 65 (29.5%) had ALIs. In univariate analyses, CMBs, HWCs, and HPVSs were each negatively correlated with the proportion of EPA, DHA, and ∑ n-3-PUFAs. In the multivariate analysis, a lower proportion of EPA, DHA and ∑ n-3-PUFAs was associated with the presence of CMBs, HWCs and HPVS, but not ALIs. Total SVDs score was inversely correlated with the proportion of EPA, DHA and ∑ n-3-PUFAs. Overall, we found an association between low proportions of plasma n-3-PUFAs and cerebral SVDs pathologies. Further studies are needed to explore the association and potential therapeutic role of FAs in cerebral SVDs.

Low Plasma Proportion of Omega 3-Polyunsaturated Fatty Acids Predicts Poor Outcome in Acute Non-Cardiogenic Ischemic Stroke Patients

Background and Purpose Alterations in blood fatty acid (FA) composition are associated with cardiovascular diseases. We investigated whether plasma FA composition was related to stroke severity and functional outcome in acute ischemic stroke patients. Methods We prospectively enrolled 156 patients with first-episode cerebral infarction, within 7 days of symptom onset. The proportion of FAs was analyzed using gas chromatography, and the summation of the omega-3 polyunsaturated fatty acids (ω3-PUFA), 18:3 ω3 α-linolenic acid, 20:3 ω3 eicosatrienoic acid, 20:5 ω3 eicosapentaenoic acid (EPA), and 22:6 ω3 docosahexaenoic acid (DHA) was reported as Σω3-PUFAs. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) score on admission. Poor functional outcome was defined by modified Rankin scale (mRS) ≥3 at three months after the index stroke. Results Lower proportions of EPA (β=-0.751), DHA (β=-0.610), and Σω3-PUFAs (β=-0.462) were independently associated with higher NIHSS score, after adjusting for stroke subtype, hemoglobin, high density lipoprotein, high sensitivity C-reactive protein, fasting glucose, 16:0 palmitic acid, and Σsaturated fatty acids. Moreover, a lower proportion of DHA (odds ratio [OR]: 0.20, 95% confidence interval [CI]: 0.04-0.88), and Σω3-PUFAs (OR: 0.22, 95% CI: 0.05-0.84) showed an independent relationship with poor functional outcome after adjusting for age, sex, smoking status, NIHSS score, stroke subtype, and 16:0 palmitic acid. Conclusions Our results demonstrate that ω3-PUFAs correlated with stroke severity on admission and functional outcomes at 3 months. ω3-PUFAs are potential blood biomarkers for prognosis of acute non-cardiogenic ischemic stroke patients.

Moderate-to-severe obstructive sleep apnea is associated with cerebral small vessel disease

BACKGROUND Cerebral small vessel disease (SVD) is associated with increased risk of cerebral infarction and hemorrhage. Obstructive sleep apnea (OSA) is known to increase the risk of cerebrovascular disease. This study aimed to investigate the association between cerebral SVD and severity of OSA. METHODS A total of 170 patients were included from the patient registry at the present Sleep Center; these patients underwent both magnetic resonance imaging (MRI) of the brain and polysomnography (PSG) for suspected OSA. The presence and burden of white matter hyperintensities (WMHs), asymptomatic lacunar infarctions (ALIs), cerebral microbleeds (CMBs), and perivascular spaces (PVSs) were determined by MRI, and their relationships with the apnea-hypopnea index (AHI), as determined by PSG, were investigated. RESULTS Among the 170 patients, 25 (14.7%) had high-grade WMHs, 21 (12.4%) had ALIs, 21 (12.4%) had CMBs, and 34 (20.0%) had high-grade PVSs. In the multivariable analysis, after adjusting for factors including age, sex, and other variables for which p <0.1 in univariable analysis (hypertension, diabetes mellitus, previous stroke, minimal SaO2 and arousal index), moderate-to-severe OSA was associated with high-grade WMHs (odds ratio [OR] 4.72; 95% confidence interval [CI] 1.14-19.47), CMBs (OR 3.47; 95% CI 0.89-15.18), or high-grade PVSs (OR 3.64; 95% CI 1.02-13.01), but not with ALIs. The total SVD score was independently associated with increased AHI (p = 0.017), particularly in patients with moderate-to-severe OSA (β [standard error] = 0.448 (0.204), p = 0.030]. CONCLUSION Moderate-to-severe OSA is positively associated with multiple indicators of cerebral SVD, including WMHs, CMBs, and PVSs.

Rescue Stenting for Failed Mechanical Thrombectomy in Acute Ischemic Stroke: A Multicenter Experience

Background and Purpose— Effective rescue treatment has not yet been suggested in patients with mechanical thrombectomy (MT) failure. This study aimed to test whether rescue stenting (RS) improved clinical outcomes in MT-failed patients. Methods— This is a retrospective analysis of the cohorts of the 16 comprehensive stroke centers between September 2010 and December 2015. We identified the patients who underwent MT but failed to recanalize intracranial internal carotid artery or middle cerebral artery M1 occlusion. Patients were dichotomized into 2 groups: patients with RS and without RS after MT failure. Clinical and laboratory findings and outcomes were compared between the 2 groups. It was tested whether RS is associated with functional outcome. Results— MT failed in 148 (25.0%) of the 591 patients with internal carotid artery or middle cerebral artery M1 occlusion. Of these 148 patients, 48 received RS (RS group) and 100 were left without further treatment (no stenting group). Recanalization was successful in 64.6% (31 of 48 patients) of RS group. Compared with no stenting group, RS group showed a significantly higher rate of good outcome (modified Rankin Scale score, 0–2; 39.6% versus 22.0%; P=0.031) without increasing symptomatic intracranial hemorrhage (16.7% versus 20.0%; P=0.823) or mortality (12.5% versus 19.0%; P=0.360). Of the RS group, patients who had recanalization success had 54.8% of good outcome, which is comparable to that (55.4%) of recanalization success group with MT. RS remained independently associated with good outcome after adjustment of other factors (odds ratio, 3.393; 95% confidence interval, 1.192–9.655; P=0.022). Follow-up vascular imaging was available in the 23 (74.2%) of 31 patients with recanalization success with RS. The stent was patent in 20 (87.0%) of the 23 patients. Glycoprotein IIb/IIIa inhibitor was significantly associated with stent patency but not with symptomatic intracranial hemorrhage. Conclusions— RS was independently associated with good outcomes without increasing symptomatic intracranial hemorrhage or mortality. RS seemed considered in MT-failed internal carotid artery or middle cerebral artery M1 occlusion.

Low-Density-Lipoprotein Particle Size Predicts a Poor Outcome in Patients with Atherothrombotic Stroke

Background and Purpose Low-density lipoprotein (LDL) particle size is considered to be one of the more important cardiovascular risk factors, and small LDL particles are known to have atherogenic potential. The aim of this study was to determine whether LDL particle size is associated with stroke severity and functional outcome in patients with atherothrombotic stroke. Methods Between January 2009 and May 2011, 248 patients with first-episode cerebral infarction who were admitted to our hospital within 7 days after symptom onset were prospectively enrolled. LDL particle size was measured using the nondenaturing polyacrylamide gradient gel electrophoresis assay. Stroke severity was assessed by applying the National Institutes of Health Stroke Scale (NIHSS) at admission. Functional outcome was investigated at 3 months after the index stroke using the modified Rankin Scale (mRS), and poor functional outcome was defined as an mRS score of ≥3. Results The LDL particle size in the 248 patients was 25.9±0.9 nm (mean±SD). LDL particle size was inversely correlated with the degree of cerebral artery stenosis (p=0.010). Multinomial multivariate logistic analysis revealed that after adjustment for age, sex, and variables with p<0.1 in univariate analysis, LDL particle size was independently and inversely associated with stroke severity (NIHSS score ≥5; reference, NIHSS score 0-2; odds ratio=0.38, p=0.028) and poor functional outcome (odds ratio=0.44, p=0.038). Conclusions The results of this study demonstrate that small LDL particles are independently correlated with stroke outcomes. LDL particle size is thus a potential biomarker for the prognosis of atherothrombotic stroke.

Interarm Systolic and Diastolic Blood Pressure Difference Is Diversely Associated With Cerebral Atherosclerosis in Noncardioembolic Stroke Patients

BACKGROUND Interarm systolic and diastolic blood pressure differences (IASBD, IADBD) are not infrequent in various populations. Cerebral atherosclerosis, including extracranial cerebral atherosclerosis (ECAS) and intracranial cerebral atherosclerosis (ICAS), is an important risk factor for stroke. In this study, we aimed to investigate the relationship of IASBD, IADBD with presence and burden of ICAS and ECAS. METHODS This was a retrospective hospital-based cross-sectional study. In total, 1,063 consecutive noncardioembolic ischemic stroke patients, who were checked for bi-brachial blood pressures from ankle-brachial index and brain magnetic resonance angiographic images of cerebral arteries, were included. The IASBD and IADBD were defined as absolute value of the blood pressure difference in both arms. RESULTS In all included patients, patients with IASBD ≥10 and IADBD ≥10 were noted in 9.4% (100/1,063) and 5.3% (56/1,063). The patients with IASBD ≥10 mm Hg were more frequently burdened with ICAS (P = 0.001) and ECAS (P = 0.027) and patients with IADBD ≥10 mm Hg were more frequently burdened with ICAS (P = 0.042) but not ECAS (P = 0.187). Multivariate analysis after adjusting gender, age, and a P value <0.1 in univariate analysis showed IASBD ≥10 mm Hg was associated with the presence of both ECAS and ICAS [odds ratio (OR): 2.96, 95% confidence interval (CI): 1.65-5.31]. The IADBD ≥10 mm Hg was related with presence of ICAS only (OR: 1.87, 95% CI: 1.05-3.37) but not with ECAS only (OR: 1.50, 95% CI: 0.73-3.06). CONCLUSIONS Our study showed IASBD and IADBD were diversely associated with cerebral atherosclerosis. In noncardioembolic stroke patients with IASBD ≥10 or IADBD ≥10, the possibility of accompanying cerebral atherosclerosis should be considered.

Recurrent Episodes of Rhabdomyolysis after Seizures in a Patient with Glycogen Storage Disease Type V

Dear Editor, Glycogen storage disease type V (GSD-V) is the most common disorder of muscle glycogenosis and is caused by alterations in the PYGM gene.1 Patients with GSD-V typically present with exercise intolerance, episodic rhabdomyolysis, and the second-wind phenomenon. Seizure has been well described as a provocative event for rhabdomyolysis, but it is not classical feature of GSD-V. Here we report recurrent episodes of rhabdomyolysis after seizures in a Korean patient with PYGM mutations. The male proband (II-2 in Fig. 1A) was the first child of nonconsanguineous healthy parents. He achieved normal motor milestones. At the age of 17 years he was hospitalized for rhabdomyolysis with a serum creatine kinase (CK) level of 718,000 IU/L after intense exercise and generalized tonic-clonic seizure (Supplementary Table 1 in the online-only Data Supplement). He did not have fixed muscle weakness. An electromyography study showed no spontaneous activities. Electroencephalography demonstrated a few spikes at the left frontocentral region. He was hydrated, and treated with anticonvulsants, but the serum CK level remained elevated (630 IU/L) at rest. The ischemic forearm exercise test demonstrated no increase in serum lactate level and a normal increase in serum ammonia level. At the age of 18 years he was readmitted to our clinic due to rhabdomyolysis and seizure. His serum CK level was 486,800 IU/L. Subtle muscle weakness was initially found in the shoulder girdle muscles, but recovered after 3 days. At the age of 28 years he was hospitalized for the third event of rhabdomyolysis (serum CK level: 124,500 IU/L) after a seizure. We performed targeted sequencing of 69 myopathy-related genes, including PYGM (Supplementary Table 2 and 3 in the online-only Data Supplement). DNA fragments in the target regions were enriched by solution-based hybridization capture, followed by sequencing with the Illumina Hiseq2000 platform. The sequencing data were analyzed using a standard pipeline (see in Supplementary Information in the online-only Data Suplement). Variants were then filtered further based on the patients phenotype. We identified compound heterozygous PYGM mutations of c.1531delG and c.1999A>T (Fig. 1B). The c.1531delG mutation has been reported previously,2 but the c.1999A>T mutation is novel, since it was not detected in dbSNP138 or the 1000 Genomes Database (September 2014 release). In silico predictions support a deleterious effect of the c.1999A>T mutation on PYGM (Supplementary Table 4 in the online-only Data Supplement). Additionally, genomic evolutionary rate profiling indicated that the affected nucleotide is highly conserved (score=4.91) (Fig. 1C). Thus, we determined that the c.1531delG and c.1999A>T compound heterozygous PYGM mutations were the underlying cause of the observed myopathy. A deltoid muscle biopsy was performed at the age of 18 years. Light microscopy of the sample with hematoxylin and eosin staining revealed moderate variations of fiber size and shape as well as numerous scattered markedly necrotic myofibers with macrophage infiltration (Fig. 1D). The periodic acid-Schiff stain showed a slightly increased positive reaction in the remaining myofibers. Electron microscopy revealed the focal subsarcolemmal accumulation of glycogen (Fig. 1E) and necrotic myofibers exhibiting variable stages of degenerative changes (Fig. 1F). Fig. 1 Pedigree, sequencing chromatograms, conservation profile, and pathology. A: Pedigree of a Korean patient with compound heterozygous PYGM mutations. Arrows indicates the proband (square: male; circle: female; filled: affected; and nonfilled: unaffected). ... We have identified compound heterozygous PYGM mutations (c.1531delG and c.1999A>T) using targeted sequencing of 69 myopathy-related genes. GSD-V is caused by a deficiency of the muscle isoform of phosphorylase, which is encoded by PYGM. Human phosphorylase consists of three isoforms that are differentially expressed in the muscle, brain, and liver, with the muscle isoform being mainly expressed in muscle tissue. Therefore, GSD-V is usually considered to be a pure myopathy. However, both the brain and muscle isoforms were expressed in astrocytes, which predominantly contain glycogen in the adult brain.3 The occurrence of seizures has rarely been reported in patients with GSD-V,1,4 which suggests that the muscle isoform has an additional role in the brain; however, the precise nature of this role remains to be determined. In conclusion, this is the first report of novel compound heterozygous PYGM mutations in a Korean patient with recurrent seizure as rare provocative events of rhabdomyolysis.

Increased Thrombogenicity in Chronic Renal Failure in a Rat Model Induced by 5/6 Ablation/Infarction

Purpose Abnormalities in hemostasis and coagulation have been suggested in chronic renal failure (CRF). In this study, we compared processes of thrombus formation between rats with CRF and those with normal kidney function. Materials and Methods CRF was induced by 5/6 ablation/infarction of the kidneys in Sprague-Dawley rats, and surviving rats after 4 weeks were used. Ferric chloride (FeCl3)-induced thrombosis in the carotid artery was induced to assess thrombus formation. Whole blood clot formation was evaluated using rotational thromboelastometry (ROTEM). Platelet aggregation was assessed with impedance platelet aggregometry. Results FeCl3-induced thrombus formation was initiated faster in the CRF group than in the control group (13.2±1.1 sec vs. 17.8±1.0 sec, p=0.027). On histological examination, the maximal diameters of thrombi were larger in the CRF group than in the control group (394.2±201.1 µm vs. 114.0±145.1 µm, p=0.039). In extrinsic pathway ROTEM, the CRF group showed faster clot initiation (clotting time, 59.0±7.3 sec vs. 72.8±5.0 sec, p=0.032) and increased clot growth kinetics (α angle, 84.8±0.2° vs. 82.0±0.6°, p=0.008), compared to the control group. Maximal platelet aggregation rate was higher in the CRF group than in the control group (58.2±0.2% vs. 44.6±1.2%, p=0.006). Conclusion Our study demonstrated that thrombogenicity is increased in rats with CRF. An activated extrinsic coagulation pathway may play an important role in increasing thrombogenicity in CRF.

High Dietary Glycemic Load is Associated with Poor Functional Outcome in Patients with Acute Cerebral Infarction

Background and Purpose Elevated postprandial blood glucose is a critical risk factor for stroke. The dietary glycemic load (GL) and glycemic index (GI) are frequently used as markers of the postprandial blood glucose response to estimate the overall glycemic effect of diets. We hypothesized that high dietary GL, GI, or total carbohydrate intake is associated with a poor functional outcome in patients with acute ischemic stroke. Methods We prospectively included 263 first-ever ischemic stroke patients who completed a semiquantitative food-frequency questionnaire. The dietary GL, GI, and total carbohydrate intake were investigated by examining the average frequency of intake during the previous year based on reference amounts for various food items. Poor functional outcome was defined as a score on the modified Rankin Scale (mRS) of ≥3 at 3 months after stroke. Results The patients were aged 65.4±11.7 years (mean±standard deviation), and 58.2% of them were male. A multivariate analysis adjusted for age, sex, marital status, prestroke mRS score, diabetes mellitus, hyperlipidemia, body mass index, triglycerides, low-density lipoprotein, hemoglobin A1c, stroke classification, and National Institutes of Health Stroke Scale score, early neurological deterioration, and high-grade white-matter hyperintensities revealed that the dietary GL and total carbohydrate intake were associated with a poor functional outcome, with odds ratios for the top quartile relative to the bottom quartile of 28.93 (95% confidence interval=2.82–296.04) and 36.84 (95% confidence interval=2.99–453.42), respectively (p for trend=0.002 and 0.002, respectively). In contrast, high dietary GI was not associated with a poor functional outcome (p for trend=0.481). Conclusions Increased dietary GL and carbohydrate intake were associated with a poor short-term functional outcome after an acute ischemic stroke.

Interarm Blood Pressure Difference is Associated with Early Neurological Deterioration, Poor Short-Term Functional Outcome, and Mortality in Noncardioembolic Stroke Patients

BACKGROUND AND PURPOSE Interarm differences in the systolic and diastolic blood pressures (IASBD and IADBD, respectively) are found in various populations, including stroke patients, but their significance for stroke outcomes has rarely been reported. We aimed to determine the associations of IASBD and IADBD with early neurological deterioration (END), functional outcome, and mortality. METHODS This study included 1,008 consecutive noncardioembolic cerebral infarction patients who were admitted within 24 hours of onset and had automatic measurements of blood pressures in the bilateral arms. END was assessed within 72 hours of stroke onset according to predefined criteria. A poor functional outcome was defined as a score on the modified Rankin Scale ≥3 at 3 months after the index stroke. All-cause mortality was also investigated during a median follow-up of 24 months. The absolute difference of blood pressure measurements in both arms were used to define IASBD and IADBD. RESULTS END occurred in 15.3% (155/1,008) of the patients. A multivariate analysis including sex, age, and variables for which the p value was <0.1 in a univariate analysis revealed that IASBD ≥10 mm Hg was significantly associated with END [odds ratio (OR)=1.75, 95% CI=1.02-3.01]. IADBD ≥10 mm Hg was also related to END (OR=3.11, 95% CI=1.61-5.99). Moreover, having both IASBD ≥10 mm Hg and IADBD ≥10 mm Hg was related to a poor functional outcome (OR=2.67, 95% CI=1.36-5.35) and mortality (hazard ratio=7.67, 95% CI=3.76-12.83) even after adjusting for END. CONCLUSIONS This study suggests that an interarm blood pressure difference of ≥10 mm Hg could be a useful indicator for the risks of END, poor functional outcome, and mortality.