Jiunn Rong Chen

Associations Between Carotid Atherosclerosis and High Factor VIII Activity, Dyslipidemia, and Hypertension

BACKGROUND AND PURPOSE A subsample of 147 Chinese subjects from a population-based study of cardiovascular diseases (Cardiovascular Disease Risk Factor Two-Township Study) participated in an ancillary study on extracranial carotid color duplex ultrasonography that aimed to assess the relations of coagulation factors to stroke and carotid atherosclerosis. METHODS Logistic models were used to study the associations between cardiovascular disease risk factors and stroke/carotid atherosclerosis, controlling for the effects of age and sex. RESULTS Stroke was significantly associated with hypertension and high values of plasma glucose but not with fibrinogen, factor VIIc, or factor VIIIc. Carotid plaques identified in this study were mostly mild and moderate. The presence of these mild and moderate carotid plaques was significantly associated with high values of factor VIII activity, hypercholesterolemia, hypertriglyceridemia, and hypertension. The highest tertile of factor VIIIc (> 1.53) was associated with an odds ratio of 3.35 for carotid atherosclerosis when compared with the lowest tertile (< 1.20). A multiple logistic regression including all significant risk factors showed that the degree of association between factor VIIIc and atherosclerosis was attenuated to an odds ratio of 2.65 (P = .061). CONCLUSIONS In the present study, the roles of hypertension, hypercholesterolemia, and hypertriglyceridemia have been implicated in the pathogenesis of carotid atherosclerosis, and roles for hypertension and hyperglycemia in stroke were indicated. A positive association between factor VIIIc and carotid atherosclerosis in this Chinese population was found. Whether this association is independent of the effect of other cardiovascular risk factors awaits further study.

Genetic variants of connexin37 are associated with carotid intima-medial thickness and future onset of ischemic stroke

BACKGROUND Carotid intima-medial thickness (IMT) is a surrogate marker of subclinical atherosclerosis. This study aimed to investigate the impacts of genetic variants on IMT and future development of ischemic stroke in a cohort, followed by an independent replication study. METHODS B-mode carotid ultrasound was performed among 3330 healthy adults in the CVDFACT cohort study, and the genetic effects of atherosclerosis-related genes including connexin37 (GJA4), C-reactive protein (CRP), paraoxonase (PON1), adiponectin (ACDC), angiotensin-converting enzyme (ACE), beta-adrenergic receptor (ADRB1, ADRB2), antithrombin III (SERPINC1), and kinesin family member 6 (KIF6) were evaluated by a multivariate regression model, adjusting for traditional vascular risk factors. Study subjects were prospectively followed for the development of ischemic stroke to assess the prognostic impacts of these genetic variants. An independent case-control study was performed to replicate the genetic association from the cohort study. RESULTS The T allele of connexin37 C1019T polymorphism significantly affected IMT (β=0.014, p=0.013) after adjusting for traditional risk factors. During an average follow-up period of 10.7 years, 80 patients with ischemic stroke (2.4%) were identified. The connexin37 1019T allele was significantly associated with an increased rate of ischemic stroke under an additive model, with hazard ratios (HR) of 2.83 (95% confidence interval, 1.2-6.66) and 1.69 (95% confidence interval, 1.06-2.71), comparing TT and CT genotype with CC, respectively. After Cox analysis, age (HR, 1.78 every 10 years), diabetes mellitus (HR, 2.63), hypertension (HR, 2.08), and the T allele of C1019T polymorphism of GJA4 (HR, 1.69) were identified as independent predictors of ischemic stroke. The relationship between T allele of C1019T polymorphism of GJA4 gene and ischemic stroke was also confirmed by an independent association study. CONCLUSION Connexin 37 genetic variants significantly affect carotid IMT and contribute to future development of ischemic stroke.

Common Carotid End-Diastolic Velocity and Intima-Media Thickness Jointly Predict Ischemic Stroke in Taiwan

Background and Purpose— In Asian populations, few studies investigated the association between stroke and common carotid artery intima-media thickness (IMT). Our previous case-control studies showed that low end-diastolic velocity (EDV) in common carotid artery, a potential hemodynamic marker of intracranial resistance, was associated with ischemic stroke. Therefore, we investigated the relationship between both EDV and IMT and incident ischemic stroke in an Asian population. Methods— Baseline data from 3175 adults (30 years or older) in the Cardiovascular Diseases Risk Factor Two-Township Study were linked to incidental ischemic stroke status derived from insurance claims and death certificate records. Hazard ratios for risk of ischemic stroke for high IMT and low EDV values measured in common carotid artery were calculated using Cox proportional hazard models. Results— With 9.85 years (median) of follow-up, 184 persons had ischemic stroke develop. Compared with the first tertile of IMT, hazard ratios were 2.03 (95% confidence intervals, 1.27–3.25) for the second tertile and 3.87 (95% confidence intervals, 2.36–5.69) for the third tertile. Hazard ratios of EDV were 5.31 (95% confidence intervals, 3.52–7.99; first tertile) and 1.94 (95% confidence intervals, 1.21–3.09; second tertile) compared with the third tertile. The individuals with high IMT and low EDV had >2-fold ischemic stroke risk compared to those with low IMT and high EDV (2.10; 95% confidence intervals, 1.35–3.26) after adjusting for age, sex, and traditional cardiovascular risk. Conclusions— Common carotid IMT and EDV jointly and independently predicted future ischemic stroke in this Taiwanese population. More prospective studies are required in various ethnic groups to understand the significance and implication of the current findings, particularly with respect to EDV.

Shorter GT repeat polymorphism in the heme oxygenase-1 gene promoter has protective effect on ischemic stroke in dyslipidemia patients

BackgroundThe microsatellite polymorphism of heme oxygenase (HO)-1 gene promoter has been shown to be associated with the susceptibility to ischemic event, including coronary artery disease (CAD), myocardial infarction, and peripheral vascular disease. We aimed to examine whether the length of (GT)n repeats in HO-1 gene promoter is associated with ischemic stroke in people with CAD risk factors, especially low level of HDL.MethodsA total of 183 consecutive firstever ischemic stroke inpatients and 164 non-stroke patients were screened for the length of (GT)n repeats in HO-1 promoter. The long (L) and short (S) genotype are defined as the averaged repeat number >26 and ≦26, respectively.ResultsStroke patients tended to have more proportions of hypertension, diabetics and genotype L, than those of genotype S. Patients with genotype L of HO-1 gene promoter have higher stroke risk in comparison with genotype S especially in dyslipidemia individuals. The significant differences on stroke risk in multivariate odds ratios were found especially in people with low HDL-C levels.ConclusionsSubjects carrying longer (GT)n repeats in HO-1 gene promoter may have greater susceptibility to develop cerebral ischemic only in the presence of low HDL-C, suggesting the protective effects in HO-1 genotype S in the process of ischemic stroke, particularly in subjects with poor HDL-C status.

Comparison of Transcranial Color‐Coded Sonography and Magnetic Resonance Angiography in Acute Ischemic Stroke

Background and Purpose. This study was designed to assess the accuracy of transcranial color‐coded sonography (TCCS) as compared to magnetic resonance angiography (MRA) for detecting intracranial arterial stenosis in patients with acute cerebral ischemia. Methods. The authors prospectively identified 120 consecutive patients admitted with acute ischemic stroke and performed both TCCS and MRA with a mean interval of 1 day. TCCS data (sampling depth, peak systolic and end diastolic angle‐corrected velocity, mean angle‐corrected velocity, and pulsatility index) for middle cerebral arteries (MCAs) were compared to MRA data and classified into 4 grades: normal (grade 1): normal caliber and signal; mild stenosis (grade 2): irregular lumen with reduced signal; severe stenosis (grade 3): absent signal in the stenotic segment (flow gap) and reconstituted distal signal; and possible occlusion (grade 4): absent signal. The cutoffs were chosen to maximize diagnostic accuracy. Results. Interobserver agreement for MRA grading resulted in a weighted‐kappa value of 0.776. The rate of poor temporal window was 37% (89/240). Doppler signals were obtained in 135 vessels, and the angle‐corrected velocities (peak systolic, end diastolic, mean) were significantly different (P= .001, P= .006, P < .001) among the MRA grades: grade 1 (100, 47, 68 cm/s), grade 2 (171, 72, 110 cm/s), grade 3 (226, 79, 134 cm/s), grade 4 (61, 26, 39 cm/s). Additionally, an angle‐corrected MCA peak systolic velocity ≥120 cm/s correlates with intracranial stenosis on MRA (grade 2 or worse) with high specificity (90.5%; 95% confidence interval = 78.5%∼96.8%) and positive predictive value (93.9%) but relatively low sensitivity (66.7%; 95% confidence interval = 61.2%∼69.5%) and negative predictive value (55.1%). Conclusion. Elevated MCA velocities on TCCS correlate with intracranial stenosis detected on MRA. An angle‐corrected peak systolic velocity ≥120 cm/s is highly specific for detecting intracranial stenosis as defined by significant MRA abnormality.

Common carotid artery end-diastolic velocity is independently associated with future cardiovascular events:

Background Carotid ultrasound is widely used to measure haemodynamic parameters, such as intima-media thickness and blood flow velocities (i.e. peak-systolic velocity [PSV], end-diastolic velocity [EDV], and resistive index [RI]). However, the association between blood flow velocities and cardiovascular events remains unclear. Design and methods Baseline data, including quantitative ultrasonography, were obtained from 3146 adults as part of the Cardiovascular Diseases Risk Factor Two-Township Study. Occurrence of ischaemic heart disease (IHD) and stroke was determined from insurance claims and death certificates. The hazard ratio (HR) of CVD (IHD and stroke combined) was calculated for EDV and PSV of the common carotid artery using Cox models. Net reclassification index and integrated discrimination index were used to evaluate the capacity of EDV to predict IHD, stroke, and CVD. Results Median follow-up was 12.8 years. There were 220 cases of IHD and 247 cases of stroke. The HR (95% CI) for CVD from univariate analysis was 4.54 (3.51–5.85) for EDV <15 cm/s relative to EDV ≥ 20 cm/s (p < 0.0001), and 3.23 (2.51–4.15) for PSV < 65 cm/s relative to PSV ≥ 80 cm/s (p < 0.0001). The HR (95% CI) for CVD from multivariate analysis was 1.66 (1.22–2.26) for EDV < 15 cm/s relative to EDV ≥ 20 cm/s, and 1.39 (1.03–1.89) for PSV < 65 cm/s relative to PSV ≥ 80 cm/s. EDV slightly but significantly improved prediction of CVD (integrated discrimination index 0.56%, p = 0.016). Conclusions Low common carotid EDV and PSV were independently associated with future CVD, and EDV improved the prediction of future CVD. More prospective studies are required in different ethnic groups to understand the significance and implication of these findings.

Rapid adiposity growth increases risks of new-onset asthma and airway inflammation in children

Background/Objectives:We aim to (1) examine the influence of long-term adiposity status/short-term adiposity changes on asthma with high or low fractional exhaled nitric oxide (FeNO), and (2) to determine the differences in long-term adiposity status/short-term adiposity changes on atopy, airway inflammation and pulmonary function.Subjects/Methods:We recruited 2450 fourth- to sixth-grade children from the nationwide Taiwan Children Health Study. Data regarding various adiposity indicators, atopic status, pulmonary function tests and asthma outcomes were collected annually. New-onset asthma was stratified by airway inflammation status using FeNO. The generalized estimating equation was used for analyzing longitudinal relationships between long-term adiposity status/short-term adiposity changes and new-onset asthma. Individual adiposity growth slopes were obtained using a hierarchical linear model to establish the relationships between short-term adiposity changes and asthma among children with high airway inflammation.Results:We found long-term adiposity status predicted childhood asthma with low FeNO, whereas short-term adiposity changes may increase risks of childhood asthma with high FeNO. Long-term adiposity status reduced pulmonary function, whereas short-term adiposity increase were associated with atopic diseases and airway inflammation.Conclusions:Obesity-induced asthma could be mediated by high or low airway inflammation, depending on the velocity of increase in adiposity. Rapid adiposity growth may increase risks of childhood asthma and airway inflammation.

Intake of potassium- and magnesium-enriched salt improves functional outcome after stroke: a randomized, multicenter, double-blind controlled trial

Background: Stroke is one of the leading causes of mortality and neurologic deficits. Management measures to improve neurologic outcomes are in great need. Our previous intervention trial in elderly subjects successfully used salt as a carrier for potassium, demonstrating a 41% reduction in cardiovascular mortality by switching to potassium-enriched salt. Dietary magnesium has been associated with lowered diabetes and/or stroke risk in humans and with neuroprotection in animals.Objective: Because a large proportion of Taiwanese individuals are in marginal deficiency states for potassium and for magnesium and salt is a good carrier for minerals, it is justifiable to study whether further enriching salt with magnesium at an amount near the Dietary Reference Intake (DRI) amount may provide additional benefit for stroke recovery.Design: This was a double-blind, randomized controlled trial comprising 291 discharged stroke patients with modified Rankin scale (mRS) ≤4. There were 3 arms: 1) regular salt (Na salt) (n = 99), 2) potassium-enriched salt (K salt) (n = 97), and 3) potassium- and magnesium-enriched salt (K/Mg salt) (n = 95). The NIH Stroke Scale (NIHSS), Barthel Index (BI), and mRS were evaluated at discharge, at 3 mo, and at 6 mo. A good neurologic performance was defined by NIHSS = 0, BI = 100, and mRS ≤1.Results: After the 6-mo intervention, the proportion of patients with good neurologic performance increased in a greater magnitude in the K/Mg salt group than in the K salt group and the Na salt group, in that order. The K/Mg salt group had a significantly increased OR (2.25; 95% CI: 1.09, 4.67) of achieving good neurologic performance compared with the Na salt group. But the effect of K salt alone (OR: 1.58; 95% CI: 0.77, 3.22) was not significant.Conclusions: This study suggests that providing the DRI amount of magnesium and potassium together long term is beneficial for stroke patient recovery from neurologic deficits. This trial was registered at clinicaltrials.gov as NCT02910427.

Low cholesterol level associated with severity and outcome of spontaneous intracerebral hemorrhage: Results from Taiwan Stroke Registry

The relationship between cholesterol level and hemorrhagic stroke is inconclusive. We hypothesized that low cholesterol levels may have association with intracerebral hemorrhage (ICH) severity at admission and 3-month outcomes. This study used data obtained from a multi-center stroke registry program in Taiwan. We categorized acute spontaneous ICH patients, based on their baseline levels of total cholesterol (TC) measured at admission, into 3 groups with <160, 160–200 and >200 mg/dL of TC. We evaluated risk of having initial stroke severity, with National Institutes of Health Stroke Scale (NIHSS) >15 and unfavorable outcomes (modified Rankin Scale [mRS] score >2, 3-month mortality) after ICH by the TC group. A total of 2444 ICH patients (mean age 62.5±14.2 years; 64.2% men) were included in this study and 854 (34.9%) of them had baseline TC <160 mg/dL. Patients with TC <160 mg/dL presented more often severe neurological deficit (NIHSS >15), with an adjusted odds ratio [aOR] of 1.80; 95% confidence interval [CI], 1.41–2.30), and 3-month mRS >2 (aOR, 1.41; 95% CI, 1.11–1.78) using patients with TC >200 mg/dL as reference. Those with TC >160 mg/dL and body mass index (BMI) <22 kg/m2 had higher risk of 3-month mortality (aOR 3.94, 95% CI 1.76–8.80). Prior use of lipid-lowering drugs (2.8% of the ICH population) was not associated with initial severity and 3-month outcomes. A total cholesterol level lower than 160 mg/dL was common in patients with acute ICH and was associated with greater neurological severity on presentation and poor 3-month outcomes, especially with lower BMI.

Blood Pressure, Carotid Flow Pulsatility, and the Risk of Stroke A Community-Based Study

Background and Purpose— High blood pressure is a major cause of cardiovascular events, and carotid flow pulsatility may be associated with cardiovascular events. However, the combined effect of blood pressure and flow pulsatility on the development of stroke remains unclear. Therefore, we investigated the combined influence of central blood pressure and pulsatility index (PI) on the incidence of stroke. Methods— Baseline data from 2033 adults (≥30 years) without stroke history in the Cardiovascular Disease Risk Factor Two-Township Study were linked to incident stroke. Common carotid flow PI was calculated by peak systolic velocity, end-diastolic velocity, and mean vessel velocity, which were measured in the common carotid artery. Hazard ratios for the risk of total stroke resulting from high central systolic blood pressure (CSBP) and high PI were calculated with Cox proportional hazard models. Results— Over a median follow-up of 9.81 years, 132 people incurred stroke events. The incidence rates of stroke were 1.3, 6.4, and 13.2 per 1000 person-years for tertile groups of CSBP (P for trend<0.05) and 4.3, 7.0, and 9.4 per 1000 person-years for tertile groups of PI (P for trend<0.05). Compared with the first tertile of CSBP, hazard ratios were 4.88 (95% confidence interval, 2.29–10.43) for the second tertile and 10.42 (5.05–21.53) for the third tertile. Hazard ratios of PI were 2.18 (1.39–3.42; third tertile) and 1.64 (1.02–2.63; second tertile) compared with the first tertile. The individuals with a high CSBP and high PI had a 13-fold higher stroke risk compared with those with low CSBP and low PI (13.2; 1.75–99.71) after adjusting for age, sex, and traditional cardiovascular risk. Conclusions— CSBP and common carotid PI jointly and independently predicted future stroke. Carotid flow pulsatility may play an important role in the development of stroke.