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Background and Aims: Increase soluble E-selectin (sE-selectin) levels are associated with various inflammation and cardiometabolic disorders., Methods: This study aimed to investigate the genetic determinants of circulating sE-selectin levels by genome-wide association study (GWAS) in 4,525 Taiwan Biobank (TWB) participants and genotype-phenotype association analysis for sE-selectin level-determining alleles in over 80,000 TWB participants., Results: By GWAS, ABO, SELE, and FUT6 gene variants were identified as the determinants of sE-selectin levels, which reach genome-wide significance (maximum p = 3.25 × 10 -271 , 4.81 × 10 -14 , and 9.64 × 10 -12 , respectively). After further adjustment for the lead ABO rs2519093 genotypes, three novel gene loci, EVI5, FER and DMAC1, were associated with sE-selectin levels at p < 5 × 10 -7 . Three other previously reported gene loci, CELSR2, ST3GAL6-AS1, and HNF1A-AS1, also showed supportive evidence for the association with sE-selectin levels (maximum p < 0.0073). A multivariate analysis revealed age, body mass index, current smoking, hemoglobin A1C, hematocrit, leukocyte and platelet counts, serum alanine aminotransferase, triglycerides, and uric acid levels were independently associated with sE-selectin levels, in which the above ten gene loci contribute to 27.68% of the variance. For genotype-phenotype association analysis, a pleiotropic effect was demonstrated with genome-wide significant association between ABO gene variants and total and low-density-lipoprotein cholesterol levels, leukocyte counts and hematocrit., Conclusions: Our data provide novel insight into the regulation of sE-selectin levels. These results may open new avenues in understanding the critical role of E-selectin on the pathogenesis of inflammatory and cardiometabolic disorders., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Platelet count (PLT) is a predictor of metabolic and inflammation-related disorders. Platelets can release prochemerin, which acts as a link between coagulation and inflammation and between innate and adaptive immunity. The causal effect between PLT and circulating chemerin level has not been elucidated., Methods: Nondiabetic participants with samples in the Taiwan Biobank were recruited for a genome-wide association study (GWAS) based on PLT (17,037 participants) and chemerin levels (3887 participants). A bidirectional Mendelian randomization (MR) study was conducted to determine the association between circulating PLT and chemerin levels., Results: For a GWAS of PLT, 11 gene loci were found to have genome-wide significance. For a GWAS of chemerin levels, two gene loci, RARRES2 and HLADQA2-HLADQB1, were found to have genome-wide significance. Age, sex, body mass index, leukocyte count, hemoglobin, mean blood pressure, hemoglobin A1C, serum total bilirubin, aspartate aminotransferase, triglyceride, and low-density-lipoprotein cholesterol levels, estimated glomerular filtration rate, and circulating chemerin level were found to be independently associated with PLT through a stepwise regression analysis. A bidirectional MR study revealed weighted genetic risk scores (WGRSs) for PLT were significantly associated with chemerin levels by using a two-stage least-square method in a multivariate analysis (p = 0.0031), and no significant association between chemerin level WGRSs and PLT was noted. Sensitivity analysis further revealed no violation of the exclusion-restriction assumption with PLT-determining genotypes on chemerin levels., Conclusions: Through a bidirectional MR analysis, our data revealed that chemerin levels were determined based on circulating PLT. Circulating chemerin levels can be intermediates between PLT and future metabolic and inflammation-related disorders., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is an enzyme that detoxifies aldehydes by converting them to carboxylic acids. ALDH2 deficiency is known to increase oxidative stress. Increased oxidative stress plays a pivotal role in abdominal aortic aneurysm (AAA) pathogenesis. Reactive oxygen species (ROS) promote degradation of the extracellular matrix (ECM) and vascular smooth muscle cell (VSMC) apoptosis. Reducing oxidative stress by an ALDH2 activator could have therapeutic potential for limiting AAA development. We hypothesized that ALDH2 deficiency could increase the risk for AAA by decreasing ROS elimination and that an ALDH2 activator could provide an alternative option for AAA treatment. The National Center for Biotechnology (NCBI) Gene Expression Omnibus (GEO) database was used. Human aortic smooth muscle cells (HASMCs) were used for the in vitro experiments. Gene-targeted ALDH2*2 KI knock-in mice on a C57BL/6J background and apolipoprotein E knockout (ApoE KO) mice were obtained. An animal model of AAA was constructed using osmotic minipumps to deliver 1000 ng/kg/min angiotensin II (AngII) for 28 days. Patients with AAA had significantly lower ALDH2 expression levels than normal subjects. ALDH2*2 KI mice were susceptible to AngII administration, exhibiting significantly increased AAA incidence rates and increased aortic diameters. Alda-1, an ALDH2 activator, reduced AngII-induced ROS production, NF-kB activation, and apoptosis in HASMCs. Alda-1 attenuated AngII-induced aneurysm formation and decreased aortic expansion in ApoE KO mice. We concluded that ALDH2 deficiency is associated with the development of AAAs in humans and a murine disease model. ALDH2 deficiency increases susceptibility to AngII-induced AAA formation by attenuating anti-ROS effects and increasing VSMC apoptosis and vascular inflammation. Alda-1 was shown to attenuate the progression of experimental AAA in a murine model., (© 2020 Federation of American Societies for Experimental Biology.)

The safety of newer xanthine oxidase inhibitor febuxostat compared to allopurinol remains unclear. To compare the risks of allopurinol hypersensitivity and febuxostat hypersensitivity and cardiovascular diseases (CVDs) in Asians, we conducted a population-based cohort study enrolling patients receiving allopurinol or febuxostat from Chang Gung Memorial Hospital Health System across Taiwan during 2012-2016 and further performed a meta-analysis incorporating two recent studies. Among the 61,539 users, a corresponding 12,007 and 5,680 patients were identified as new users. The overall incidence of febuxostat hypersensitivity was significantly lower than allopurinol hypersensitivity (0.2 vs. 2.7 per 1,000 new users; P < 0.001). There were 33 allopurinol-hypersensitivity reactions (including 18 severe cutaneous adverse drug reactions), and only one patient developed febuxostat-maculopapular exanthema. Moreover, febuxostat did not statistically increase the risk of CVD (hazard ratio (HR), 1.16; P = 0.152) and related death (HR, 1.49; P = 0.496) compared to allopurinol. The result of the meta-analysis also showed a consistent result. In conclusion, the incidence and severity of febuxostat-hypersensitivity are lower than with allopurinol. Febuxostat did not show an increased risk of CVD and related death., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)

Aim: This study aims to investigate whether osteoprotegerin (OPG) or osteopontin (OPN) single nucleotide polymorphisms (SNPs) will predict survival. Materials & methods: This study enrolled 617 participants undergoing health examination, 536 coronary artery disease (CAD) patients and 86 peripheral artery disease (PAD) patients. Genotypes of OPG SNP rs2073618 and OPN SNP rs11730582 were determined. OPG and OPN levels were measured. Results: In both CAD and PAD populations, high OPG and OPN levels were strong predictors of all-cause death. The OPG rs2073618 CC genotype and the OPN rs11730582 TT genotype did not predict mortality. Conclusion: High OPG and high OPN levels, but not OPG rs2073618 CC genotype or OPN rs11730582 TT genotype, were strong predictors of mortality in both CAD and PAD patients.

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is classified as group IV pulmonary hypertension. This study aimed to report our institutional experience in managing CTEPH., Methods: We prospectively collected the data of 23 patients diagnosed with CTEPH between August 2001 and August 2017 in Linkou Chang Gung Memorial Hospital. Baseline characteristics including functional class (FC), 6-minute walk distance (6MWD), comorbidities, hematological and biochemical data, echocardiography, cardiac catheterization, and selective pulmonary angiography were recorded at diagnosis. All patients were referred to a cardiac surgeon for pulmonary endarterectomy (PEA) assessment., Results: The mean age at diagnosis was 48.4 ± 16.1 years. Nineteen patients (83%) underwent PEA with mean postoperative follow-up of 37.7 ± 42.8 months. The in-hospital mortality rate of PEA was 11%. The 1-, 2-, 3- and 5-year overall survival rates were 89%, 89%, 81%, and 50%, respectively. After 3 months of PEA, all patients had improvements in FC, 6MWD (from 326 ± 62 to 420 ± 63 m), B-type natriuretic peptide level (from 602 ± 599 to 268 ± 565 pg/mL), and systolic pulmonary artery pressure (from 79 ± 19 to 48 ± 19 mmHg). The patients with proximal disease (Jamieson type 1 or 2) had better survival than those with distal disease (Jamieson type 3 or 4), but there was no significant difference in mortality between FC III and IV. All of the four patients who did not undergo PEA survived for more than 3 years., Conclusions: Significant improvements in symptoms, functional capacity, and hemodynamics were achieved in the CTEPH patients after PEA. However, the overall survival was still unsatisfactory.

Objectives: Both acid-sensing ion channel acid-sensing ion channel 3 (ASIC3) and transient receptor potential vanilloid 1 (TRPV1) have been proposed to be involved in the pathophysiology of hypertension. Common colocalization of ASIC3 and TRPV1 channels in the same sensory neuron has been reported. We aimed to study the combined ASIC3 and TRPV1 gene polymorphisms in the risk of hypertension., Materials and Methods: To test the statistical association between genetic polymorphisms of the ASIC3 and TRPV1 genes and blood pressure (BP) variations in Taiwanese, 551 unrelated individuals (286 men and 265 women) having routine health examinations were recruited. The participants had no history of cardiovascular disease or use of medication for hypertension., Results: Six ASIC3 and four TRPV1 gene polymorphisms were genotyped, and only the ASIC3 rs2288646 polymorphism was associated with variations in BP in the participants. In subgroup analysis, we found participants carrying the combined ASIC3 rs2288646 AA or AG and TRPV1 rs8065080 CC genotypes (combined genotypes) had significantly higher systolic, mean and diastolic BP compared with the other subgroups ( P = 0.009, 0.003, and 0.006, respectively, after Bonferroni correction). Interaction analysis also revealed significant gene-gene interaction in the systolic, mean, and diastolic BP in the ASIC3 and TRPV1 genotypes (interaction P = 0.006, 0.002, and 0.002, respectively). A trend of increasing frequencies of the combined genotype was observed in normotensive, prehypertensive, and hypertensive subgroups ( P for trend = 0.001), as well as in those with higher systolic and diastolic BPs ( P for trend = 9.13 × 10 -4 and P for trend = 5.5 × 10 -5 , respectively)., Conclusion: Our data show a combined effect of ASIC3 and TRPV1 gene polymorphisms in BP variations in Taiwanese. These results suggest that the interaction between ASIC3 and TRPV1 is involved in BP regulation., Competing Interests: There are no conflicts of interest.

Background: Clinical studies have suggested predictive parameters in mortality risk assessment for pulmonary arterial hypertension (PAH) patients. However, these studies predominantly include Caucasian population; information in Asian population is relatively deficient. In this study, we investigated the long-term survival of PAH patients and the predictors of mortality in our population., Methods: We prospectively collected 70 patients with PAH at the Chang Gung Memorial Hospital between March 2002 and February 2015. Baseline data including functional class (FC), 6-minute walk distance (6MWD), hematological and biochemical data, echocardiography and cardiac catheterization were obtained before commencing PAH- targeted treatment. The follow-up period for analyses of survivors ended in October 2015., Results: The mean age at diagnosis was 40.7 ± 15.2 years. Mean follow-up period was 4.6 ± 3.4 years, with 1-, 2-, 3-, and 5-year survival rates of 93%, 88%, 84%, and 77%, respectively. The baseline FC was worse in non-survivors than in survivors. More frequent presence of pericardial effusion, higher serum glucose levels, higher estimated systolic pulmonary artery pressure (SPAP) by echocardiography, and higher right atrial pressure (RAP) were found in non-survivors. Higher FC, lower 6MWD, and presence of pericardial effusion were associated with risk of mortality. Patients with worsening FC and increased serum uric acid had an increased risk of mortality during follow-up., Conclusions: The overall survival remained unsatisfactory in PAH patients. Baseline FC, 6MWD, pericardial effusion, RAP, and a worsening FC and an increased serum uric acid levels during follow-up were significant prognostic parameters.

A left bundle-branch block (LBBB) contraction pattern identified from longitudinal-strain analysis predicts outcomes following cardiac resynchronization therapy (CRT). We investigated the use of an LBBB-contraction pattern identified from radial- or circumferential-strain analysis in the prediction of CRT benefits. Eighty CRT candidates were prospectively enrolled. Before CRT implantation, speckle-tracking analyses in three deformation directions were performed to determine whether an LBBB-contraction pattern was present. The study endpoints were reverse remodeling at 6 months, and adverse outcomes including death or heart failure hospitalization. At 6 months, 49 (61%) patients had reverse remodeling. An LBBB-contraction pattern identified from the radial strain in the mid-ventricular short-axis view or longitudinal strain in the four-chamber view provided excellent true-positive (86%) and false-negative (8%) rates for predicting reverse remodeling. During a median follow-up of 30 months, 31 patients (39%) had adverse outcomes. Absence of an LBBB-contraction pattern in radial (hazard ratio 3.74; 95% confidence interval 1.83-7.62) or longitudinal strain (hazard ratio 3.49; 95% confidence interval 1.71-7.13) was significantly associated with an increased risk of adverse outcomes. Adding the LBBB-pattern assessment by radial-(model χ 2 from 8.2 to 18.5, p = 0.005), or longitudinal-strain analysis (model χ 2 from 8.2 to 16.9, p = 0.011) to a risk model significantly improved the model, including QRS duration and ischemic etiology. In conclusion, an LBBB-contraction pattern identified from radial-strain analysis in the mid-ventricular short-axis view predicted reverse remodeling and outcome following CRT, similarly to the longitudinal-strain analysis.

Aims: The ratio of transmitral early filling velocity (E) to early diastolic tissue velocity (E') is a key diastolic function parameter. The early diastolic strain rate (E'sr) has been proposed as a substitute for E' in the E/E' ratio for better estimation of left ventricular (LV) filling pressure. This study aims to assess the predictive value of combined E/E'sr ratio and global longitudinal strain (GLS) for prognosis in systolic heart failure (SHF)., Methods and Results: We retrospectively analysed 330 SHF patients with an LV ejection fraction (LVEF) ≤ 40%. Study end points were defined as all-cause mortality or heart transplantation. The incremental value of GLS and the E/E'sr ratio over LVEF and E/E' for outcome prediction was assessed using nested Cox models. Ninety-nine (30%) patients reached the end point over a median follow-up of 46 months. Baseline variables associated with outcomes were age, glomerular filtration rate, pulmonary artery systolic pressure, and LV end-systolic volume index. After multivariate adjustment, GLS (hazard ratio: 1.48, P = 0.025) and the E/E'sr ratio (hazard ratio: 1.41, P = 0.002) were both independent predictors. LVEF or E/E' was not an independent predictor when GLS and E/E'sr were included in the model. Patients with impaired GLS (absolute value <7.5%) and elevated E/E'sr ratios (E/E'sr ≥ 195 cm) showed poor outcomes., Conclusion: The E/E'sr ratio is stronger than E/E' ratio in predicting prognosis of patients with systolic HF. Combined assessments of GLS and E/E'sr by speckle-tracking longitudinal strain facilitate risk stratification of these patients., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Structural and electrical remodeling in the atrium constitutes the main feature of atrial fibrillation (AF), which is characterized by increased oxidative stress. Heme oxygenase-1 (HO-1) is a potent anti-oxidant system that may provide protection against various oxidative stress-related diseases. The aim of this study is to investigate whether HO-1 has a protective effect on AF-related remodeling. Cultured atrium-derived myocytes (HL-1 cell line) were used to evaluate tachypacing-induced oxidative stress, structural, and electrical remodeling. Transforming growth factor-β (TGF-β) was utilized to assess collagen (a main fibrosis-related protein) expression in atrial fibroblasts. Tachypacing in HL-1 myocytes and treatment of atrial fibroblasts with TGF-β enhanced the expression of HO-1, both of which were mediated by the activation of nuclear factor erythroid-2-related factor 2. Over-expression of HO-1 in HL-1 cells attenuated tachypacing-induced oxidative stress, myofibril degradation, down-regulation of L-type calcium channel, and shortening of action potential duration. Furthermore, HO-1 over-expression in atrial fibroblasts blocked the up-regulation of collagen by TGF-β, implicating a protective role of HO-1 in structural and electrical remodeling in the atrium. In vivo, HO-1(-/-) mice exhibited a higher degree of oxidative stress, myofibril degradation, and collagen deposit in their atria than wild-type mice. Moreover, burst atrial pacing induced a greater susceptibility to AF in HO-1(-/-) mice than in wild-type mice. In conclusion, a negative-feedback regulation of HO-1 in activated atrial myocytes and fibroblasts may provide protection against AF-related remodeling and AF development.

Objectives: The TBX5 gene, a member of the T-box family, is associated with congenital heart disease, electrocardiographic parameters, and development of atrial fibrillation in the general population. This study aimed to elucidate the role of TBX5 gene polymorphisms in metabolic and inflammatory profiles possibly linked to TBX5 -related pathologies., Materials and Methods: A sample population of 597 individuals having routine health examinations was enrolled. Five tagging TBX5 single nucleotide polymorphisms (SNPs) were analyzed using polymerase chain reaction and restriction enzyme digestion or TaqMan SNP genotyping assays. Associations between genotypes/haplotypes and matrix metalloproteinase 9 (MMP9) levels were investigated using generalized linear model analysis. Interactions between each genotype/haplotype, MMP9 level, and obesity status were tested using two-way analysis of variance with Golden Helix SVS Win32 7.3.1 software., Results: After adjusting for clinical covariates, TBX5 genotypes were found to be associated with MMP9 levels ( p = 0.002 and p = 0.001 for rs4113925 and rs3825214, respectively) in a dominant inheritance model. Haplotype analysis using three tag SNPs (rs11067101, rs1247973, and rs3825214) revealed a significant association between TBX5 haplotype GCG and MMP9 levels (uncorrected p = 0.0093 and the corrected false discovery rate p = 0.0435). Multivariate analysis identified that SNP rs3825214, in addition to the MMP9 and E-selectin genotypes, was independently associated with MMP9 levels ( p < 0.001). Using a dominant inheritance model, subgroup and interaction analysis showed associations between the rs4113925, rs3825214, and MMP9 levels only in nonobese individuals ( p = 1.04 × 10 -4 and p = 7.11 × 10 -5 , respectively; interaction p = 0.009 and 0.018, respectively). Subgroup analysis showed a borderline significant association between haplotype GCG and MMP9 levels (uncorrected p = 0.020 and corrected false discovery rate p = 0.073), but with no evidence of interaction., Conclusion: TBX5 genotypes/haplotypes are independently associated with MMP9 in Taiwanese individuals and occur predominantly in nonobese people. These associations may broaden our understanding of the mechanism underlying T-box family gene activity and related cardiovascular pathologies., Competing Interests: Conflicts of interest: none.

Background: Pulmonary arterial hypertension (PAH) is a serious and progressive disorder that can result in right ventricular (RV) dysfunction and mortality. Consequently, it is important to monitor RV function during management of PAH. The aim of this study was to investigate the change in RV function by echocardiography before and after disease-specific therapy., Methods: We recruited 31 PAH patients with functional class (FC) III or IV. All the patients received a comprehensive assessment before disease-specific therapy was administered, including observation of clinical symptoms, 6-min walk distance (6MWD), serum brain natriuretic peptide (BNP) level, and transthoracic echocardiography. The assessment was repeated 12 weeks after therapy., Results: Twenty-eight patients with a mean age of 40 years completed the study, of whom 82% were women. We found that the etiologies were mainly connective tissue disease-associated and idiopathic PAH. Of the patients in our study, 36% received endothelin receptor antagonist and 64% received phosphodiesterase-5 inhibitor. There was a significant improvement in FC after disease-specific therapy (p < 0.001). The 6MWD increased from 326 to 403 m (p < 0.001), and the serum BNP level decreased from 242 to 130 pg/mL (p = 0.008) after treatment. Echocardiography showed significant reduction in the right atrial and RV areas, pulmonary artery pressure, RV free wall thickness, and inferior vena cava diameter. The myocardial performance index and left ventricular eccentricity index were significantly reduced after therapy., Conclusions: For PAH patients in our study, disease-specific therapy for 12 weeks resulted in an improvement in FC, 6MWD, serum BNP levels, and RV function., Key Words: Disease-specific therapy; Pulmonary arterial hypertension; Right ventricular function.

Background: The expanded usage of drug-eluting stents (DES) in treating patients with multivessel coronary artery disease (CAD) may sometimes be limited in real-world practice due to cost concerns. We compared the clinical outcomes of exclusive and selective DES use in treating patients with multivessel CAD., Methods: From November 2004 to December 2011, 110 patients with multivessel CAD who received four or more stents were enrolled into this study, and divided into two groups according to the DES strategy employed: exclusive DES (n = 52), or selective DES (n = 58). In the selective DES group, DES was reserved for complex lesions only, such that the incidence and predictors of clinical events were assessed., Results: At a mean follow-up of 41.4 ± 26.5 months, there were no significant differences between the two strategies in terms of baseline characteristics, all-cause mortality (exclusive vs. selective: 1.9% vs. 6.9%, p = 0.21), cardiac death (1.9% vs. 1.7%, p = 0.94) and nonfatal myocardial infarction (3.8% vs. 5.2%, p = 0.74). Despite the presence of more ostial lesions in the exclusive DES group, there was a trend such that major adverse cardiac events (MACE) and target lesion revascularization (TLR) rates were higher in the selective DES group (MACE: 17.3% vs. 31%, p = 0.16; TLR: 11.5% vs. 24.1%, p = 0.08). The higher MACE rate in the selective DES group was mainly driven by a higher target vessel revascularization (TVR) rate (15.4% vs. 29.3%, p = 0.08). In the exclusive DES group, SYNTAX score was an independent predictor of MACE [Haxard ratio (HR): 1.09, 95% confidence internal (CI): 1.02-1.16, p = 0.01] and TVR (HR 1.08, 95% CI 1.01-1.15, p = 0.04)., Conclusions: Compared to the exclusive DES strategy, the selective DES strategy with reservation of DES for complex lesions is associated with numerically higher, but not statistically significant, rates of MACE and all-cause mortality in this small group of patients with multivessel CAD receiving four or more stents., Key Words: Bare metal stent; Drug-eluting stent; Multivessel coronary artery disease.

Background: Leptin and adiponectin are secreted from adipose tissue and exert opposing effects on C-reactive protein (CRP) levels and insulin resistance. As hypertrophic adipocytes secrete more leptin and less adiponectin, the leptin-to adiponectin ratio (LAR) has been proposed as a useful measure of insulin resistance and vascular risk. We investigated whether LAR may serve as a better predictor than either leptin or adiponectin alone for low-grade inflammation and insulin resistance independent of obesity in a non-diabetic Taiwanese population., Methods: This study included 568 non-diabetic Taiwanese individuals (297 men, 271 women). CRP, leptin and adiponectin were measured using enzyme-linked immunosorbent assay. The degree of insulin resistance was determined using the homeostasis model assessment of insulin resistance (HOMA-IR)., Results: In the receiver operator characteristic analysis, the area under the curve of LAR in predicting individuals with elevated CRP and insulin resistance was significantly greater than that for either leptin (p = 0.0035 vs. elevated CRP, p < 0.0001 vs. insulin resistance) or adiponectin alone (p = 0.0131 vs. elevated CRP, p = 0.0006 vs. insulin resistance), suggesting that LAR might be a better predictor of individuals with low grade inflammation and insulin resistance. In the multivariable analysis adjusted for age, gender, smoking status, and components of metabolic syndrome, LAR was still strongly associated with levels of CRP (p < 0.001, all participants; p = 0.002, nonobese individuals; p < 0.001, obese individuals) and HOMA-IR index (p < 0.001, all participants, obese and nonobese individuals)., Conclusions: The LAR is related to low grade inflammation and insulin resistance independent of obesity in non-diabetic Taiwanese, and the strength of associations between LAR with CRP and HOMA-IR are greater than the association with leptin or adiponectin alone., Key Words: Adiponectin; C-reactive protein; Insulin resistance; Leptin; Obesity.

Background: Elevated plasma C-reactive protein (CRP) levels can be used to predict an increased risk of future atrial fibrillation (AF). However, several single polynucleotide polymorphisms (SNPs) in the CRP gene affect CRP levels. This study aims to elucidate the correlation between CRP gene polymorphisms and the risk of AF among a Chinese population in Taiwan., Methods: A total of 200 patients with AF and 240 age- and gender-comparable control subjects were enrolled in this study. From these patients, five SNPs in the CRP gene were selected and genotyped., Results: Patients with AF had significantly higher plasma CRP levels than the controls. In the total study population, the minor alleles of rs3091244 and rs1205 were significantly associated with higher CRP level (p = 0.001 and 0.045, respectively). The frequency of rs1800947 minor allele (C) was significantly higher in patients with AF than that in control subjects (12.8% and 4.6%, respectively; p < 0.001). On multivariate analysis, the presence of the C allele of rs1800947 was significantly and independently associated with AF after adjustment for age, gender, body mass index, hypertension, diabetes, smoking, hypercholesterolemia, coronary artery disease, concomitant medication, and CRP levels (odds ratio = 3.21; 95% confidence interval = 1.54-6.68; p = 0.01). Haplotype analysis further verified that the rs3091244C and rs1800947C bi-loci haplotype was significantly overpresented in patients with AF than in the controls., Conclusions: Our results suggest that the presence of the C allele of rs1800947 may indicate susceptibility to AF in a Chinese population in Taiwan., Key Words: Atrial fibrillation; C-reactive protein; Polymorphism.

Aims: Previous studies have identified four baseline characteristics associated with a favourable response to cardiac resynchronization therapy (CRT): female, non-ischaemic aetiology of heart failure, left bundle-branch block (LBBB), and QRS duration ≥150 ms. This study evaluated the incremental value of discoordination and dyssynchrony indices over these characteristics for the prediction of the response to CRT., Methods and Results: The speckle-tracking strain analysis was performed in 120 CRT candidates. Patients were divided into subgroups according to the gender (male vs. female), aetiology of heart failure (ischaemic vs. non-ischaemic), QRS morphology (LBBB vs. non-LBBB), and QRS duration (≥150 vs. <150 ms), respectively. Discoordination was measured using the mid-ventricular radial discoordination index (RDI-M), the ratio of the average mid-ventricular thinning to thickening during ejection. Patients with one of the four favourable characteristics were more likely to exhibit other favourable characteristics and had greater amounts of average myocardial thinning during ejection and RDI-M than those without (all P< 0.05). In contrast, dyssynchrony indices failed to demonstrate significant differences between male and female and between ischaemic and non-ischaemic subjects. Of 39 patients who had 6-month follow-up data after CRT, left ventricular reverse remodelling was found in 22 patients (56%). Combining the favourable characteristics and RDI-M provides the best ability to predict reverse remodelling after CRT (area under the curve = 0.85, 95% confidence interval 0.73-0.98, P < 0.001)., Conclusion: Mechanical discoordination rather than mechanical dyssynchrony provides a significant incremental value over the baseline characteristics for the prediction of the response to CRT.

Background: E-selectin is implicated in various inflammatory processes and related disorders. We aimed to investigate the role of SELE-gene genotypes/haplotypes on plasma levels of MMP9 and sE-selectin in Taiwanese individuals., Methods: Five hundred twenty individuals were enrolled. Seven tagging SELE single nucleotide polymorphisms were analyzed., Results: SELE genotypes were found associated with MMP9 and sE-selectin levels. Multivariate analysis identified that the most significant genetic polymorphism (rs5368 genotype) was independently associated with MMP9 levels (P < 0.001). One haplotype (GGAGAGT) was marginally associated with MMP9 levels (P = 0.0490). One SELE SNP, (rs3917406, P = 0.031) was associated with sE-selectin levels after adjusting for MMP9 and sICAM1 levels. Subgroup and interaction analysis revealed association of SELE SNP rs10800469 with sE-selectin levels only in the highest quartile of MMP9 level (P = 0.002, interaction P = 0.023). Haplotype analysis showed one haplotype (AAAAAGC) borderline associated with sE-selectin level (P = 0.0511)., Conclusion: SELE genotypes/haplotypes are independently associated with MMP9 and E-selectin levels in Taiwanese individuals. The associations of SELE genotypes/haplotypes with sE-selectin levels are affected by MMP9 levels.

Objective: Repeated puncture is a mechanical injury to the hemodialysis accesses. We systemically observed the vascular changes at the puncture segments of arteriovenous fistulas., Methods: The native arteriovenous fistulas in 104 patients on maintenance hemodialysis using the buttonhole technique for puncture were studied. We used the duplex scan to observe the intimal lesions, the maximal diameters at the arterial and venous puncture segments, and the references., Results: Intimal lesions were found in 42% and 40% of the arterial and venous puncture segments, none of which resulted in significant luminal stenosis. The differences between diameters at the arterial or venous puncture segments and the corresponding references were significant (arterial, 11.07 +/- 4.45 vs 6.85 +/- 2.35 mm, P < .001; venous, 8.82 +/- 4.13 vs 5.54 +/- 2.22 mm, P < .001). All segments, except only three arterial and four venous puncture segments, were larger than the corresponding references. The degree of vascular dilatation, defined as the diameter difference between the puncture segments and the references calibrated by the reference diameter, were 64.1 +/- 49.6% at arterial puncture segments and 59.9 +/- 42.2% at venous segments. Multivariate analysis revealed that the patient age and the puncture duration were strongly correlated with the degree of vascular dilatation at both the arterial (P = .018 and .007, respectively) and venous puncture segments (P = .020 and .011, respectively)., Conclusion: Puncture of arteriovenous fistula using a buttonhole technique resulted in a consistent vascular dilatation and moderately high incidence of intimal thickness, but no significant luminal stenosis was found.

A 21-bp deletion mutation of the exon 11 of the myocyte enhancer factor-2A (MEF2A) gene was shown to cause familial coronary artery disease. This finding raises the possibility that MEF2A variants may contribute to the risk of coronary artery disease. In total, 258 patients with coronary artery disease and 258 controls were analyzed for the MEF2A variants. The analysis revealed that all patients were negative for Pro279Leu and 21-bp deletion mutations in exons 7 and 11, respectively. The distribution of the allele frequencies of MEF2A exon 11 CAG repeat (CAG)n polymorphism was similar in both patients and controls; Further, no significant association was noted between MEF2A exon 11 (CAG)n polymorphism and the risk of myocardial infarction. Our data suggest that there is no evidence of an association between the MEF2A exon 11 (CAG)n polymorphism and the risk of coronary artery disease/myocardial infarction in the Chinese population in Taiwan.

Propylthiouracil (PTU), independent of its antithyroid effect, is recently found to have an antiatherosclerotic effect. The aim of this study is to determine the impact of PTU on phenotypic modulation of vascular smooth muscle cells (VSMCs), as phenotypic modulation may contribute to the growth of atherosclerotic lesions and neointimal formation after arterial injury. Propylthiouracil reduced neointimal formation in balloon-injured rat carotid arteries. In vitro, PTU may convert VSMCs from a serum-induced dedifferentiation state to a differentiated state, as indicated by a spindle-shaped morphology and an increase in the expression of SMC differentiation marker contractile proteins, including calponin and smooth muscle (SM)-myosin heavy chain (SM-MHC). Transient transfection studies in VSMCs demonstrated that PTU induced the activity of SMC marker genes (calponin and SM-MHC) promoters, indicating that PTU up-regulates these genes expression predominantly at the transcriptional level. Furthermore, PTU enhanced the expression of PTEN and inhibition of PTEN by siRNA knockdown blocked PTU-induced activation of contractile proteins expression and promoter activity. In the rat carotid injury model, PTU reversed the down-regulation of contractile proteins and up-regulated PTEN in the neointima induced by balloon injury. Propylthiouracil promotes VSMC differentiation, at lest in part, via induction of the PTEN-mediated pathway. These findings suggest a possible mechanism by which PTU may contribute to its beneficial effects on atherogenesis and neointimal formation after arterial injury.

Abnormal keratinocyte terminal differentiation is one of the important characteristics of psoriatic lesions. Filaggrin (FLG) is a key protein that facilitates the terminal differentiation of the epidermis. Thus, FLG genetic variants may modify the risk of psoriasis. In total, 314 patients with psoriasis and 611 control subjects were analyzed for the presence of FLG R501X, 2282del4 mutations, and P478S (rs11584340, C/T base change) polymorphism by polymerase chain reaction (PCR). The analysis revealed that both the R501X and 2282del4 mutations were not present in a subset of 200 patients (64%) with psoriasis. In contrast, a marginally significant difference (P = 0.020) was found in the distribution of rs11584340 genotype frequencies between psoriatic patients and controls. The frequency of the TT genotype in psoriasis patients was significantly higher than in controls (37.9% vs. 29.1%, respectively, P = 0.007). The T allele frequency of patients (60.5%) was also significantly higher than that of controls (53.9%) (P = 0.007). After adjusting for age and gender, carriers of the TT genotype were 1.46 (95% CI, 1.08-1.96) times more likely than non-carriers to have psoriasis (P = 0.013). In conclusion, our results suggest that FLG P478S polymorphism may confer susceptibility to the development of psoriasis among Taiwanese Chinese.

There are several causes for ST segment abnormalities in leads V1 to V3. Hypercalcaemia and Brugada syndrome are among them. Both are known to produce ventricular arrhythmia, albeit only rare cases have been reported with documented evidence of ventricular arrhythmias in association with a hypercalcaemic crisis but none when hypercalcaemic coexists with Brugada syndrome. We describe a patient with primary hyperparathyroidism who presented with ventricular fibrillation, and the ECG showed changes similar to Brugada syndrome. The provocation test with flecainide was conducted twice. This was positive, both before and after parathyroidectomy when serum calcium and parathormone levels had normalized. The patient was treated for hypercalcaemia and underwent parathyroidectomy. This is the first report of oral flecainide test unmasking the diagnostic coved Brugada ECG pattern in a patient with primary hyperparathyroidism and raising attention to hypercalcaemia as a potential trigger for life-threatening arrhythmia in Brugada syndrome.

To determine the genetic risk factors for venous thromboembolism (VTE), this study examined 14 genetic variants from 10 hemostatic genes in 186 Taiwanese VTE patients and the same number of matched controls, which demonstrated FGA (encoding alpha fibrinogen) Thr312Ala polymorphism was the only variant significantly associated with VTE. Nine genetic polymorphisms on the fibrinogen cluster region of chromosome 4q28 were further studied, in which four FGA polymorphisms were found in strong linkage disequilibrium and were significantly associated with VTE by genotype and allele frequency analyses. Haplotype analysis showed significantly different FGA haplotype frequencies between VTE patients and controls with the haplotype F1, containing -1051G, -3A, 312Ala and TaqI duplication alleles, significantly associated with susceptibility to VTE (P = 0.001). Haplotype-pair analysis results also indicated a strong association of the haplotype-pair F1F1 with VTE in various VTE patient subgroups. In vitro functional analysis indicated that FGA -1051G, -3A and TaqI duplication alleles enhanced significantly the transcription level of FGA; however, control subjects with FGA genotypes containing these alleles had no elevated plasma fibrinogen levels. In conclusion, our experimental data indicated that functional genetic variants in FGA are risk factors for VTE in Taiwanese populations. Determination of FGA genotypes will likely contribute to primary prevention of this condition.

Background: Thrombosis is the dominant cause of failure of arteriovenous fistulas for hemodialysis access. Vascular inflammation, an important pathologic change in various human vascular diseases, may be involved in the thrombotic process of arteriovenous fistulas., Methods: The inflammatory activities of 23 thrombosed and 13 non-thrombosed stenotic arteriovenous fistulas were compared by investigating the contents of macrophages and lymphocytes, and the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) using immunohistochemistry method. The expression of matrix metalloproteinase (MMP)-2 and MMP-9, which play important roles in thrombosis of human coronary artery, was also investigated. The immunoreaction results were characterized using a semiquantitative scoring system., Results: The macrophage and lymphocyte contents of the thrombosed group were abundant, and markedly greater than those of the non-thrombosed group (P < 0.001 and P = 0.001, respectively). The infiltration of macrophages and neovasculature were spatially closely correlated. The expressions of VCAM-1, IL-6, and TNF-alpha, but not ICAM-1, were significantly higher in the thrombosed group (P = 0.031, P = 0.010, P < 0.001, and P= 1.000, respectively). The expression of MMP-2 was not different in either groups (P = 0. 344). Differential expression of MMP-9 by macrophages near the vascular lumen, but not those distant from the lumen, was observed in most thrombosed specimens., Conclusion: This study demonstrated that the thrombosed arteriovenous fistula was characterized by marked inflammation. We hypothesize that the preferential expression of MMP-9 at luminal edge may cause disruption of the anticoagulant endothelial barrier and contribute to luminal thrombosis of arteriovenous fistulas.

Single-beat determination of left ventricular systolic function at a beat with equal subsequent cardiac cycles has been proposed as an accurate method in atrial fibrillation. However, there has still been substantial variability between the values calculated from beats with equal subsequent cycles. Therefore, some refinement on the single-beat method is needed. In 100 patients with atrial fibrillation, Doppler aortic flow time-velocity integral was determined for at least 20 consecutive cardiac cycles. The values at beats with equal subsequent cardiac cycles were chosen and compared with the average values over all cardiac cycles. The values at beats with cycle lengths shorter than 500 milliseconds were usually far below the average values over all cardiac cycles. Bland-Altman agreement analysis revealed improved accuracy by gradually narrowing the range of the limits of agreement when 2 or 3 beats with equal subsequent cycles and cycle lengths longer than 500 milliseconds were used for evaluation.

Iliacus abscess is an extremely rare complication of percutaneous transfemoral artery catheterization. This is a report of a case of iliacus abscess and Acinetobacter baumanii sepsis following percutaneous transfemoral artery catheterization. After a 43-day course of intravenous antibiotics treatment and repeated drainage, clinical recovery was achieved, though without complete radiologic resolution.