Li-Ming Lien

Significantly increased risk of carotid atherosclerosis with arsenic exposure and polymorphisms in arsenic metabolism genes

Individual susceptibility to arsenic-induced carotid atherosclerosis might be associated with genetic variations in arsenic metabolism. The purpose of this study is to explore the interaction effect on risk of carotid atherosclerosis between arsenic exposure and risk genotypes of purine nucleoside phosphorylase (PNP), arsenic (+3) methyltransferase (As3MT), and glutathione S-transferase omega 1 (GSTO1) and omega 2 (GSTO2). A community-based case-control study was conducted in northeastern Taiwan to investigate the arsenic metabolic-related genetic susceptibility to carotid atherosclerosis. In total, 863 subjects, who had been genotyped and for whom the severity of carotid atherosclerosis had been determined, were included in the present study. Individual well water was collected and arsenic concentration determined using hydride generation combined with flame atomic absorption spectrometry. The result showed that a significant dose-response trend (P=0.04) of carotid atherosclerosis risk associated with increasing arsenic concentration. Non-significant association between genetic polymorphisms of PNP Gly51Ser, Pro57Pro, As3MT Met287Thr, GSTO1 Ala140Asp, and GSTO2 A-183G and the risk for development of carotid atherosclerosis were observed. However, the significant interaction effect on carotid atherosclerosis risk was found for arsenic exposure (>50μg/l) and the haplotypes of PNP (p=0.0115). A marked elevated risk of carotid atherosclerosis was observed in subjects with arsenic exposure of >50μg/l in drinking water and those who carried the PNP A-T haplotype and at least either of the As3MT risk polymorphism or GSTO risk haplotypes (OR, 6.43; 95% CI, 1.79-23.19). In conclusion, arsenic metabolic genes, PNP, As3MT, and GSTO, may exacerbate the formation of atherosclerosis in individuals with high levels of arsenic concentration in well water (>50μg/l).

Perfusion status of the stroke-like lesion at the hyperacute stage in MELAS

Hypoperfusion on single-photon emission computed tomography (SPECT) of the stroke-like lesion (SLL) at the hyperacute stage of mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) is considered to be a supportive evidence of the mitochondrial angiopathy theory. Our objectives were to examine whether other neuroimages, especially transcranial color-coded sonography (TCCS), done at the hyperacute stage of stroke-like episode (SLE) is consistent with hypoperfusion of the SLL. We reviewed the magnetic resonance imaging (MRI), SPECT, cerebral angiography, and TCCS of a patient with MELAS syndrome, all of which were performed at the hyperacute stage of one SLE. MRI on the 1st day post SLE showed right temporoparietal lesion with vasogenic edema. SPECT on the 2nd day showed focal decreased uptake of technetium-99m hexamethylpropyleneamine oxime ((99m)Tc-HMPAO) in the same region, but cerebral angiography and TCCS on the 3rd day showed increased regional cerebral blood flow (rCBF) and distal arteriole dilation in the same region. TCCS can delineate increased rCBF of the SLL at the hyperacute stage of SLE. We propose that the discrepancy between the decreased (99m)Tc-HMPAO uptake and increased rCBF might be caused by mitochondrial dysfunction. The phenomenon of hypoperfusion on SPECT might be caused by cell dysfunction but not decreased rCBF. We suggest that SPECT can be complemented by angiography and TCCS in future studies to delineate the perfusion status of SLLs.

High Titer of Anticardiolipin Antibody Is Associated with First-Ever Ischemic Stroke in Taiwan

Background and Purpose: The association between anticardiolipin antibody (aCL) and ischemic stroke is controversial, and there are few case-control studies of Asian populations. The aim of this study, therefore, was to determine whether aCL is an independent risk factor for ischemic stroke in Taiwanese patients over the age of 40 years. Methods: Both the IgG and IgM isotypes of aCL were measured in 273 patients (>40 years of age) hospitalized for first-ever ischemic stroke and in 181 non-stroke controls. Results were defined as: negative (<10 IgG phospholipid units [GPL] or <7.5 IgM phospholipid units [MPL]); low positive (10–20 GPL or 7.5–15 MPL); or, high positive (>20 GPL or >15 MPL). Odds ratios (OR) were estimated by logistic regression with adjustment for potential confounders. Results: A high positive IgG aCL was present in 4.4% of the stroke patients and 1.2% of the controls. Age- and sex-adjusted analysis showed a borderline association between a high positive level for aCL IgG titer and stroke, with an OR of 4.01 (95% CI 0.87–18.37; p = 0.0739). Final analysis, with adjustments for age, sex, hypertension, diabetes, tobacco smoking, atrial fibrillation, left ventricular hypertrophy and hyperlipidemia, revealed an OR of 5.25 (95% CI 1.06–25.89; p = 0.0419). Conclusions: The results of this study suggest that elevated titer of aCL IgG (>20 GPL) is associated with first-ever ischemic stroke in Taiwanese patients aged over 40 years. High positive aCL titer is related to ischemic stroke after adjustment for conventional cerebrovascular risk factors, indicating that it is probably an independent risk factor for ischemic stroke.

The efficacy and safety of cilostazol in ischemic stroke patients with peripheral arterial disease (SPAD): protocol of a randomized, double-blind, placebo-controlled multicenter trial

Rationale It is not uncommon for patients with ischemic stroke to have peripheral arterial disease (PAD). Patients with polyvascular diseases carry greater burden of atherosclerosis and higher risks of developing vascular events and death. More effective regimens, such as dual antiplatelet agents, may be more effective for controlling progression of atherosclerosis in secondary prevention. Aim This study aims to evaluate whether cilostazol plus aspirin is more efficacious than aspirin alone for preventing progression of atherosclerosis in patients with ischemic stroke or transient ischemic attack (TIA) who also have peripheral arterial disease. Design The Safety and Efficacy of Cilostazol in Ischemic Stroke Patients with Peripheral Arterial Disease (SPAD) study is a randomized double-blinded placebo-controlled trial. Patients with previous ischemic stroke or TIA who had been taking aspirin (100 mg per day), aged 50 years or older, with PAD in the lower limbs based on ankle-brachial index (ABI) <1·0 will be randomized into the treatment group with cilostazol (200 mg/day) or the placebo group on 1:1 basis. Study outcomes Patients will be evaluated at 1, 3, 6, 9 and 12 months after randomization. The primary endpoint is difference in change in ABI between groups. The secondary and tertiary endpoints are the difference between groups in change in carotid intima-media thickness (IMT) and incidence rate of major cardiovascular events, including recurrent stroke, myocardial infarction, unstable angina, other vascular events, and death; and the safety measures, including major bleeding events, hemorrhagic stroke and death of any cause. Conclusion The SPAD trial is the first study to evaluate the safety and efficacy of dual antiplatelet agents, aspirin plus cilostazol, in comparison with aspirin alone in patients with both ischemic stroke or TIA and PAD. Results from this trial will provide important information on the merit of adding cilostazol to aspirin for slowing down progression of atherosclerosis in patients with ischemic stroke and PAD.

Association between plasma levels of hyaluronic acid and functional outcome in acute stroke patients

BackgroundActivation of hyaluronic acid (HA) and associated enzyme synthesis has been demonstrated in experimental stroke animal models. Our study aimed to investigate the plasma levels of HA in acute stroke patients and the associations between HA levels and functional outcome.MethodsThis was a multicenter case–control study. Acute stroke patients and age- and sex-matched non-stroke controls were recruited. Plasma levels of HA in acute stroke patients were determined at <48 hours and at 48 to 72xa0hours after stroke onset by standard ELISA. Favorable functional outcome was defined as modified Rankin scale ≤2 at 3xa0months after stroke.ResultsThe study included 206 acute stroke patients, including 43 who had intracerebral hemorrhage and 163 who had ischemic stroke, and 159 controls. The plasma levels of HA in the acute stroke patients were significantly higher than those in the controls (219.7u2009±u2009203.4xa0ng/ml for <48xa0hours and 343.1u2009±u2009710.3xa0ng/ml for 48 to 72xa0hours versus 170.4u2009±u2009127.9xa0ng/ml in the controls; both Pu2009<u20090.05). For intracerebral hemorrhage patients, HA ≤500xa0ng/ml (<48xa0hours) was an independent favorable outcome predictor (Pu2009=u20090.016). For ischemic stroke patients, an inverted U-shaped association between plasma HA (48 to 72xa0hours) and outcome was noted, indicating that ischemic stroke patients with too high or too low plasma HA levels tended to have an unfavorable outcome.ConclusionHA plasma level was elevated in patients with acute stroke, and can predict 3-month functional outcome, particularly for patients with intracerebral hemorrhage.

Epistasis analysis for estrogen metabolic and signaling pathway genes on young ischemic stroke patients.

Background Endogenous estrogens play an important role in the overall cardiocirculatory system. However, there are no studies exploring the hormone metabolism and signaling pathway genes together on ischemic stroke, including sulfotransferase family 1E (SULT1E1), catechol-O-methyl-transferase (COMT), and estrogen receptor α (ESR1). Methods A case-control study was conducted on 305 young ischemic stroke subjects aged ≦ 50 years and 309 age-matched healthy controls. SULT1E1 -64G/A, COMT Val158Met, ESR1 c.454−397 T/C and c.454−351 A/G genes were genotyped and compared between cases and controls to identify single nucleotide polymorphisms associated with ischemic stroke susceptibility. Gene-gene interaction effects were analyzed using entropy-based multifactor dimensionality reduction (MDR), classification and regression tree (CART), and traditional multiple regression models. Results COMT Val158Met polymorphism showed a significant association with susceptibility of young ischemic stroke among females. There was a two-way interaction between SULT1E1 -64G/A and COMT Val158Met in both MDR and CART analysis. The logistic regression model also showed there was a significant interaction effect between SULT1E1 -64G/A and COMT Val158Met on ischemic stroke of the young (P for interactionu200a=u200a0.0171). We further found that lower estradiol level could increase the risk of young ischemic stroke for those who carry either SULT1E1 or COMT risk genotypes, showing a significant interaction effect (P for interactionu200a=u200a0.0174). Conclusions Our findings support that a significant epistasis effect exists among estrogen metabolic and signaling pathway genes and gene-environment interactions on young ischemic stroke subjects.

Quality Improvement in Acute Ischemic Stroke Care in Taiwan: The Breakthrough Collaborative in Stroke

In the management of acute ischemic stroke, guideline adherence is often suboptimal, particularly for intravenous thrombolysis or anticoagulation for atrial fibrillation. We sought to improve stroke care quality via a collaborative model, the Breakthrough Series (BTS)-Stroke activity, in a nationwide, multi-center activity in Taiwan. A BTS Collaborative, a short-term learning system for a large number of multidisciplinary teams from hospitals, was applied to enhance acute ischemic stroke care quality. Twenty-four hospitals participated in and submitted data for this stroke quality improvement campaign in 2010–2011. Totally, 14 stroke quality measures, adopted from the Get With The Guideline (GWTG)-Stroke program, were used to evaluate the performance and outcome of the ischemic stroke patients. Data for a one-year period from 24 hospitals with 13,181 acute ischemic stroke patients were analyzed. In 14 hospitals, most stroke quality measures improved significantly during the BTS-activity compared with a pre-BTS-Stroke activity period (2006–08). The rate of intravenous thrombolysis increased from 1.2% to 4.6%, door-to-needle time ≤60 minutes improved from 7.1% to 50.8%, symptomatic hemorrhage after intravenous thrombolysis decreased from 11.0% to 5.6%, and anticoagulation therapy for atrial fibrillation increased from 32.1% to 64.1%. The yearly composite measures of five stroke quality measures revealed significant improvements from 2006 to 2011 (75% to 86.3%, p<0.001). The quarterly composite measures also improved significantly during the BTS-Stroke activity. In conclusion, a BTS collaborative model is associated with improved guideline adherence for patients with acute ischemic stroke. GWTG-Stroke recommendations can be successfully applied in countries besides the United States.

Low Pulse Pressure After Acute Ischemic Stroke is Associated With Unfavorable Outcomes: The Taiwan Stroke Registry

Background Pulse pressure (PP) is related to cardiac function, arterial stiffness, fluid status, and vascular events. This study aimed to explore the prognostic role of PP upon admission in patients with acute ischemic stroke (AIS) based on a nation‐wide stroke registry. Methods and Results We evaluated the association between PP upon admission and outcomes 3 months after a stroke in patients who had an AIS registered in the Taiwan Stroke Registry, including 56 academic and community hospitals between 2006 and 2013. Three months after the stroke, unfavorable outcomes were defined using a modified Rankin scale of 3 to 6. Of 33 530 patients (female, 40.6%; mean age, 68.8±13.3 years) who had an AIS, PP upon admission had a reverse J‐curve association with an unfavorable outcome. After adjusting for clinical variables, including AIS subtypes, initial National Institutes of Health Stroke Scale, and systolic and diastolic blood pressure upon admission, a PP of <50 mm Hg was associated with unfavorable outcomes (P<0.0001). Compared with patients with a PP of 50 to 69 mm Hg, the odds ratios for unfavorable outcomes were 1.24 (95% CI, 1.14–1.36) with a PP of 30 to 49 mm Hg and 1.85 (95% CI, 1.50–2.28) with a PP of <30 mm Hg. Moreover, the prognostic impact of PP upon admission was similar across all AIS subtypes. Conclusions Low PP upon admission was associated with unfavorable patient outcomes in AIS.

Pre-stroke physical activity is associated with fewer post-stroke complications, lower mortality and a better long-term outcome

Physical activity is associated with a reduced incidence of first‐time stroke. However, few studies have examined the effect of pre‐stroke physical activity on post‐stroke complications and clinical outcomes.

Significant Synergistic Effect of Peroxisome Proliferator–Activated Receptor γ C-2821T and Diabetes on the Risk of Ischemic Stroke

OBJECTIVE To explore the relationship between the genetic polymorphisms of PPARγ (Pro12Ala, C1431T, and C-2821T) and the risk of ischemic stroke and to investigate whether these genetic polymorphisms of PPARγ would modify the risk of ischemic stroke among patients with hypertension or diabetes. RESEARCH DESIGN AND METHODS The case-control study was conducted with 537 ischemic stroke patients and 537 control subjects. A structured questionnaire was used to collect information on conventional cardiovascular risk factors and laboratory results. The genetic polymorphisms of PPARγ were determined by PCR–restriction fragment–length polymorphism. RESULTS A significant interaction was seen between the −2821C allele and diabetes but not between this allele and hypertension. A markedly elevated risk of ischemic stroke (odds ratio 9.7) was found in the subjects with diabetes and the −2821C allele compared with that in those without these two risk factors. CONCLUSIONS The −2821C allele of PPARγ was a strong predictor of ischemic stroke for diabetic patients.