Chia-Ti Tsai

Taipei Medical University, T’ai-pei, Taipei, Taiwan

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Publications (81)305.48 Total impact

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    ABSTRACT: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Genome-wide association studies (GWAS) have identified common variants in nine genomic regions associated with AF (KCNN3, PRRX1, PITX2, WNT8A, CAV1, C9orf3, SYNE2, HCN4 and ZFHX3 genes); however, the genetic variability of these risk variants does not explain the entire genetic susceptibility to AF. Rare variants missed by GWAS may also contribute to genetic risk of AF.
    Journal of medical genetics. 11/2014;
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    ABSTRACT: Anti-anxiety medication in patients with anxiety may lessen the stress and thereby lower their risk for myocardial infarction (MI). The aim of current study is to examine an association between the use of anti-anxiety medication and long-term mortality risk in patients following MI.
    Atherosclerosis 06/2014; 235(2):496-502. · 3.71 Impact Factor
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    ABSTRACT: Little evidence is available for the impact of genetic polymorphisms on the risk of stroke in patients with AF. Angiotensin II plays a pathophysiological role in prothrombotic atrial endocardial remodeling. We investigated the effect of polymorphisms of renin-angiotensin system genes on the incidence of stroke in a prospective cohort of patients with atrial fibrillation (AF). We longitudinally followed up 712 AF patients for 10.3±2.7 years. Eight polymorphisms of renin-angiotensin system genes were genotyped. We found that patients carrying G-6 allele in the promoter of angiotensinogen gene, which was associated with a higher promoter activity, were more likely to develop stroke than non-carriers (hazard ratio 2.54 [95% CI 1.26-5.12; P=0.009] after adjustment for CHADS2 score). G-6A polymorphism provides additional information to CHADS2 on stroke risk prediction (C-statistic 0.672 vs 0.724; P=0.039). In haplotype analysis, angiotensinogen gene promoter haplotypes containing -217G/-6G, which was associated with the highest promoter activity, were associated with an increased risk of stroke (P=0.004). G-217/G-6 haplotype carriers were even more likely to develop stroke than non-carriers (HR 2.78 [95% CI 1.37-5.64]; P=0.003 after multivariable adjustment). In pharmacogenetic analysis, the increased risk of stroke in subjects carrying G-6 was eliminated by concomitant treatment with ACEI or ARB (P=0.012 for interaction). In addition to CHADS2 score, angiotensinogen gene polymorphisms may be considered an additional genetic predictor of stroke for patients with AF. Genotyping of angiotensinogen gene are helpful to determine which AF patients may benefit from ACEI or ARB treatment.
    Heart rhythm: the official journal of the Heart Rhythm Society 04/2014; · 4.56 Impact Factor
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    ABSTRACT: Congenital long QT syndrome (LQTS) is an ion channelopathy associated with genetic mutations. It is well known that most LQTS patients (91%) have a single mutation. The purpose of this study was to investigate the clinical characteristics of congenital LQTS patients with bigenic mutations in Taiwan, China. Congenital LQTS patients were recruited consecutively at Taiwan University Hospital in Taiwan from 2003 to 2009. The diagnosis of LQTS was defined by an LQTS Schwartz score greater than 4. Mutation screening in KCNQ1, KCNH2, KCNE1, and SCN5A was performed using direct sequencing. Three of 16 LQTS patients (18.7%) were identified with bigenic mutations. One patient had missense mutations in KCNQ1 and KCNH2, the second in KCNQ1 and KCNE1, and the third in KCNH2 and SCN5A. The mean age at onset of LQTS for patients with bigenic mutations was (17±3) years, and all of these patients were female. Two of them experienced seizure and one presented with syncope, although one of them had a family history of syncope. The mean QTc interval was (515±17) ms, similar to those with single mutation or SNPs ((536±74) ms, P = 0.63). Compared to those LQTS patients with single mutation or SNPs, a significantly higher percentage of LQTS patients with bigenic mutations presented with seizure and were younger at onset of the first index event (P = 0.03 and 0.001, respectively), but lower percentage of them presented with sudden cardiac death (P = 0.03). Although the percentage of bigenic mutations in LQTS is less than 10% in Caucasian populations, we identified 3 of 16 LQTS patients (18.7%, 95% confidence interval: 0.04-0.46) with bigenic mutations in Taiwan. However, the severity of their clinical presentations was not higher than those patients with single mutation or SNPs.
    Chinese medical journal 04/2014; 127(8):1482-6. · 0.90 Impact Factor
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    ABSTRACT: Background To contain cost, Taiwan's previous National Health Insurance Reimbursement Policy requested that physicians discontinue their patients' statin therapy once the serum cholesterol had reached appropriate levels. This allowed us to evaluate the association between statin continuation and the occurrence of atrial fibrillation/flutter and whether it was modified by chronic kidney disease (CKD) status. Methods Patients who initiated statin therapy between January 1, 2001 and December 31, 2009 were identified from a random sample of one million subjects in the Taiwan National Health Insurance Research Database. The outcome was atrial fibrillation/flutter. A proportional hazard regression model with time-varying statin use was applied to estimate the hazard ratios (HR) and 95% confidence intervals (CIs) for atrial fibrillation/flutter according to current statin use versus treatment discontinuation, adjusted for baseline disease risk scores and time-varying covariates. Results A total of 6767 CKD and 63,678 non-CKD patients initiating statin therapy were included and followed for an average of 4.0 years. A total of 1118 participants experienced new-onset atrial fibrillation/flutter. The incidence of atrial fibrillation/flutter was approximately 2 fold higher in the CKD patients. Continuation of statin therapy was associated with a 22% (adjusted hazard ratio 0.78; 95% CI: 0.65–0.93) and 57% (adjusted HR 0.43; 95% CI: 0.27–0.68) decrease in atrial fibrillation/flutter hazard as compared with discontinuation in non-CKD and CKD patients, respectively. Conclusions Continuation of statin therapy was associated with a decreased risk of atrial fibrillation/flutter among CKD and non-CKD patients. However, further randomized studies are still needed to assess the association.
    Atherosclerosis 01/2014; 232(1):224–230. · 3.71 Impact Factor
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    ABSTRACT: Brugada syndrome (BrS) is an inheritable sudden cardiac death disease mainly caused by SCN5A mutations. Traditional approaches can be costly and time-consuming if all candidate variants need to be validated through in vitro studies. Therefore, we developed a new approach by combining multiple in silico analyses to predict functional and structural changes of candidate SCN5A variants in BrS before conducting in vitro studies. Five SCN5A non-synonymous variants (1651G>A, 1776C>G, 1673A>G, 3269C>T and 3578G>A) were identified in 14 BrS patients using direct DNA sequencing. Several bioinformatics algorithms were applied and predicted that 1651G>A (A551T) and 1776C>G (N592K) were high-risk SCN5A variants (odds ratio 59.59 and 23.93). The results were validated by Mass spectrometry and in vitro electrophysiological assays. We concluded that integrating sequence-based information and secondary protein structures elements may help select highly potential variants in BrS before conducting time-consuming electrophysiological studies and two novel SCN5A mutations were validated.
    Scientific Reports 01/2014; 4:3850. · 5.08 Impact Factor
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    ABSTRACT: Brugada syndrome (BrS) is one of the ion channelopathies associated with sudden cardiac death (SCD). The most common BrS-associated gene (SCN5A) only accounts for approximately 20-25% of BrS patients. This study aims to identify novel mutations across human ion channels in non-familial BrS patients without SCN5A variants through disease-targeted sequencing. We performed disease-targeted multi-gene sequencing across 133 human ion channel genes and 12 reported BrS-associated genes in 15 unrelated, non-familial BrS patients without SCN5A variants. Candidate variants were validated by mass spectrometry and Sanger sequencing. Five de novo mutations were identified in four genes (SCNN1A, KCNJ16, KCNB2, and KCNT1) in three BrS patients (20%). Two of the three patients presented SCD and one had syncope. Interestingly, the two patients presented with SCD had compound mutations (SCNN1A:Arg350Gln and KCNB2:Glu522Lys; SCNN1A:Arg597* and KCNJ16:Ser261Gly). Importantly, two SCNN1A mutations were identified from different families. The KCNT1:Arg1106Gln mutation was identified in a patient with syncope. Bioinformatics algorithms predicted severe functional interruptions in these four mutation loci, suggesting their pivotal roles in BrS. This study identified four novel BrS-associated genes and indicated the effectiveness of this disease-targeted sequencing across ion channel genes for non-familial BrS patients without SCN5A variants.
    Scientific reports. 01/2014; 4:6733.
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    ABSTRACT: Background Little evidence is available for the impact of genetic polymorphisms on the risk of stroke in patients with AF. Angiotensin II plays a pathophysiological role in prothrombotic atrial endocardial remodeling. Objective We investigated the effect of polymorphisms of renin-angiotensin system genes on the incidence of stroke in a prospective cohort of patients with atrial fibrillation (AF). Methods and Results We longitudinally followed up 712 AF patients for 10.3±2.7 years. Eight polymorphisms of renin-angiotensin system genes were genotyped. We found that patients carrying G-6 allele in the promoter of angiotensinogen gene, which was associated with a higher promoter activity, were more likely to develop stroke than non-carriers (hazard ratio 2.54 [95% CI 1.26-5.12; P=0.009] after adjustment for CHADS2 score). G-6A polymorphism provides additional information to CHADS2 on stroke risk prediction (C-statistic 0.672 vs 0.724; P=0.039). In haplotype analysis, angiotensinogen gene promoter haplotypes containing -217G/-6G, which was associated with the highest promoter activity, were associated with an increased risk of stroke (P=0.004). G-217/G-6 haplotype carriers were even more likely to develop stroke than non-carriers (HR 2.78 [95% CI 1.37-5.64]; P=0.003 after multivariable adjustment). In pharmacogenetic analysis, the increased risk of stroke in subjects carrying G-6 was eliminated by concomitant treatment with ACEI or ARB (P=0.012 for interaction). Conclusions In addition to CHADS2 score, angiotensinogen gene polymorphisms may be considered an additional genetic predictor of stroke for patients with AF. Genotyping of angiotensinogen gene are helpful to determine which AF patients may benefit from ACEI or ARB treatment.
    Heart Rhythm. 01/2014;
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    ABSTRACT: Connective tissue growth factor (CTGF) is an emerging marker for tissue fibrosis. We investigated the association between CTGF and cardiac diastolic function using cellular and animal models and clinical human data. A total of 125 patients with a diagnosis of diastolic heart failure (DHF) were recruited from 1283 patients of the Taiwan Diastolic Heart Failure Registry. The severity of DHF was determined by tissue Doppler imaging (E/e'). Cardiac magnetic resonance imaging (CMRI) was used to evaluate myocardial fibrosis in some of the patients (n = 25). Stretch of cardiomyocytes on a flexible membrane base serves as a cellular phenotype of cardiac diastolic dysfunction (DD). A canine model of DD was induced by aortic banding. A significant correlation was found between plasma CTGF and E/e' in DHF patients. The severity of cardiac fibrosis evaluated by CMRI also correlated with CTGF. In the cell model, stretch increased secretion of CTGF from cardiomyocytes. In the canine model, myocardial tissue CTGF expression and fibrosis significantly increased after 2 weeks of aortic banding. Notably, the expression of CTGF paralleled the severity of LV DD (r = 0.40, P < 0.001 for E/e') and haemodynamic changes (r = 0.80, P < 0.001). After adjusting for confounding factors, CTGF levels still correlated with diastolic parameters in both human and canine models (human plasma CTGF, P < 0.001; canine tissue CTGF, P = 0.04). Plasma CTGF level correlated with the severity of DD and tissue fibrosis in DHF patients. The mechanism may be through myocardial stretch. Our study indicated that CTGF may serve as an early marker for DHF.
    European Journal of Heart Failure 12/2013; · 5.25 Impact Factor
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    ABSTRACT: CHA2DS2-VASC may not be better than CHADS2 in predicting thromboembolic risk for patients with atrial fibrillation (AF) in Asians. Metabolic syndrome is associated with an increased risk of thrombosis. We sought to evaluate if metabolic syndrome offers incremental information over CHADS2 scheme in predicting thromboembolic risk for AF patients in the Taiwanese population. The study population consisted of 721 consecutive AF patients who had been followed-up for a median of 10.8 years. Thromboembolic endpoints were defined as ischemic stroke/transient ischemic accident and peripheral embolisms. Clinical factors associated with thromboembolic endpoints were identified by Cox regression analysis. Different score schemes were compared by receiver operating characteristics (ROC) analysis. We found components in CHADS₂ scheme were associated with increased risk of thromboembolism. CHA₂DS₂-VASC did not provide additional information to CHADS₂ on thromboembolism risk (ROC area 0.670 vs 0.665; P>0.05). Metabolic syndrome components were also associated with increased risk of thromboembolism. The incident thromboembolic rate incrementally increased when metabolic syndrome score increased. Additional metabolic syndrome components provide additional information to CHADS₂ on thromboembolism risk (ROC area 0.670 vs 0.729; P=0.034). We therefore proposed a new scoring scheme called CHADS₂-MS score. In subjects with low-intermediate CHADS2 scores (0 to 1), use of CHADS₂-MS score may additionally identify high risk AF patients for future thromboembolism. We for the first time demonstrated that metabolic syndrome components were associated with thromboembolic risk in Taiwanese AF patients. In addition to conventional CHADS₂ scheme, calculation of CHADS₂-MS score provides additional information on stroke risk assessment.
    Heart rhythm: the official journal of the Heart Rhythm Society 11/2013; · 4.56 Impact Factor
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    ABSTRACT: BACKGROUND: The association between diastolic abnormality and postexercise contractile decompensation is uncertain in heart failure (HF) patients with reduced left ventricular ejection fraction (LVEF). HYPOTHESIS: The higher mitral E/annular early diastolic velocity (E/e') is relevant to postexercise regional myocardial contractile maladaptation. METHODS: Seventy HF patients with LVEF <50 % (56 males, 58 ± 15 years) were studied pre- and postexercise using tissue Doppler echocardiography. We evaluated the mean and standard deviation of systolic myocardial velocity (Sm) and electromechanical delay (Ts) of 12 left ventricular segments, and further analyzed the corresponding changes of septal and posterolateral segments. RESULTS: The higher mitral E/e' was associated with more blunted heterogeneity of Sm and greater ventricular dyssynchrony after exercise. This is due to the posterolateral wall not being able to increase Sm with exercise to the same degree as the septum (decreased posterolateral/septal Sm ratio). Furthermore, the postexercise aggravated difference of Ts between septum and posterolateral segments leads to more dyssynchronous contraction in the higher E/e' groups. An E/e' ≥10 predicted a postexercise posterolateral/septal Sm ≤ 1 (odds ratio [OR]: 5.8, 95% confidence interval [CI]: 1.5-22.6, P = 0.011), and a difference of Ts between septum and posterolateral segments >65 ms (OR: 64, 95% CI: = 6-651, P < 0.001) in HF patients with reduced LVEF in multivariate analysis. CONCLUSIONS: The higher mitral E/e'-related postexercise maladaptation of myocardial contractile motion and synchronicity suggests the involvement of systolic abnormality in exercise pathophysiology in HF patients with reduced LVEF.
    Clinical Cardiology 05/2013; · 1.83 Impact Factor
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    ABSTRACT: The objective of this study was to examine the relationship between renin-angiotensin system genotypes and the pharmacogenetics of angiotensin-converting enzyme (ACE) inhibitors in Chinese patients with coronary artery disease (CAD). Patients with angiographic CAD were recruited from 1995 to 2003. The baseline characteristics and genetic polymorphisms [ACE gene insertion/deletion (I/D) polymorphisms, six polymorphisms of the angiotensinogen (AGT) gene, and A-1166C polymorphisms of the angiotensin-II type I receptor gene (AGT1R)] were established. Patients were divided into two groups (ACE inhibitor or no ACE inhibitor) and followed for up to 12 years. Kaplan-Meier curves and Cox regression models were used to determine the survival and major cardiovascular events (MACE) event-free survival trends. Pharmacogenetic effects were determined by several Cox regression models. Of the 784 patients, 432 were treated with ACE inhibitors and 352 were not. ACE inhibitors were associated with a lower MACE rate at 4000 days. In addition, the ACE I/D gene D and AGT1R gene C alleles were associated with a higher MACE rate on the basis of a multivariate regression analysis. This effect was attenuated by the pharmacogenetic interaction of ACE inhibitors and the ACE gene (ACE inhibitors* ACE gene, hazard ratio: 0.8, 95% confidence interval: 0.62-0.94, P=0.03). ACE inhibitors were associated with a significant decrease in MACE in Chinese patients diagnosed with CAD. Genetic variants were also associated with event-free survival, but their effects were modified by the use of ACE inhibitors.
    Pharmacogenetics and Genomics 04/2013; 23(4):181-9. · 3.61 Impact Factor
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    ABSTRACT: BACKGROUND: We investigated the measurement of soluble ST2 (sST2) in stable heart failure (HF) with a normal ejection fraction (HFNEF) in hypertensive patients. METHODS AND RESULTS: Echocardiography and serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) and sST2 concentrations were evaluated in 107 hypertensive patients (65 ± 12 years, 57 male) with ejection fraction (EF) >50%. Among them, 68 patients with stable HF in functional class II and III were the HFNEF group. We found that the area under the receiver operating characteristic curve (AUC) for sST2 was 0.80 (95% CI 0.70-0.89; P < .001), relatively better than that for NT-proBNP (AUC 0.70, 95% CI 0.58-0.79; P = .003) to detect HFNEF. However, the NT-proBNP concentration, rather than sST2, was higher in HFNEF patients with functional class III (562 ± 891 vs 185 ± 242 pg/mL in functional class II; P = .009), and correlated better with mitral E/e' (annular early diastolic velocity) (r = 0.327; P = .008) than sST2 concentrations in HFNEF patients. Multivariate analysis showed that sST2 >13.5 ng/mL was independently associated with HFNEF in hypertensive patients (odds ratio 11.7, 95% CI = 2.9-47.4; P = .001). CONCLUSIONS: sST2 measurement provides diagnostic aid of stable HFNEF for hypertensive patients. Addition of NT-proBNP to sST2 could give further information regarding HF functional class and diastolic abnormality.
    Journal of cardiac failure 03/2013; 19(3):163-168. · 3.25 Impact Factor
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    ABSTRACT: Background Although heart failure with preserved ejection fraction (HFpEF) is a clinically important issue, the factors that affect its prognosis are still unclear. The aim of this study was to establish prognostic factors and develop a severity scale for the disease based on a long-term follow-up cohort of HFpEF patients. Methods The study included 438 HFpEF patients, as confirmed via echocardiography. Baseline characteristics, including echocardiographic findings and genetic polymorphisms, were determined. Patients were followed-up for up to 12 years. Kaplan–Meier curves and Cox regression models were used to determine the risk factors for mortality and major cardiovascular events (MACE). A severity scale was established using the significant risk factors. The receiver operating characteristics (ROC) curves for the scale were plotted. Results The prescription of angiotensin-converting enzyme (ACE) inhibitors [hazard ratio (HR) 0.28; 95% confidence interval (CI): 0.13–0.58 for mortality] and calcium channel blockers (CCB) was associated with a significant decrease in overall mortality and MACE. Echocardiographic E/Em ratio and ACE gene D polymorphisms were powerful factors associated with both mortality and MACE [(E/Em; HR 1.66; 95% CI: 1.32–2.29 for mortality) and (ACE gene D allele, HR 1.99; 95% CI: 1.26–3.16 for mortality)]. The ROC curves indicated a good diagnostic efficiency for severity scores (area under the curve 0.72). Conclusions In a long-term follow-up cohort of HFpEF patients, simple clinical, echocardiographic, medication, and even genetic variables were associated with MACE or mortality, and the developed composite severity scale identified patients with a higher probability of experiencing the events.
    International journal of cardiology 01/2013; · 6.18 Impact Factor
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    ABSTRACT: Sudden cardiac death due to malignant ventricular arrhythmia is a devastating manifestation of cardiac hypertrophy. Sarcomere protein myosin binding protein C is functionally related to cardiac diastolic function and hypertrophy. Zebrafish is a better model to study human electrophysiology and arrhythmia than rodents because of the electrophysiological characteristics similar to those of humans. We established a zebrafish model of cardiac hypertrophy and diastolic dysfunction by genetic knockdown of myosin binding protein C gene (mybpc3) and investigated the electrophysiological phenotypes in this model. We found expression of zebrafish mybpc3 restrictively in the heart and slow muscle, and mybpc3 gene was evolutionally conservative with sequence homology between zebrafish and human mybpc3 genes. Zebrafish with genetic knockdown of mybpc3 by morpholino showed ventricular hypertrophy with increased myocardial wall thickness and diastolic heart failure, manifesting as decreased ventricular diastolic relaxation velocity, pericardial effusion, and dilatation of the atrium. In terms of electrophysiological phenotypes, mybpc3 knockdown fish had a longer ventricular action potential duration and slower ventricular diastolic calcium reuptake, both of which are typical electrophysiological features in human cardiac hypertrophy and heart failure. Impaired calcium reuptake resulted in increased susceptibility to calcium transient alternans and action potential duration alternans, which have been proved to be central to the genesis of malignant ventricular fibrillation and a sensitive marker of sudden cardiac death. mybpc3 knockdown in zebrafish recapitulated the morphological, mechanical, and electrophysiological phenotypes of human cardiac hypertrophy and diastolic heart failure. Our study also first demonstrated arrhythmogenic cardiac alternans in cardiac hypertrophy.
    Journal of the American Heart Association. 01/2013; 2(5):e000231.
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    ABSTRACT: Aim:To identify a key protein that binds monomeric G protein RhoA and activates the RhoA/Rho kinase/MYPT1 axis in vascular smooth muscle cells (VSMCs) upon angiotensin II (Ang II) stimulation.Methods:Primary cultured VSMCs from Sprague-Dawley rats were transfected with siRNAs against leukemia-associated RhoGEF (LARG), and then treated with Ang II, losartan, PD123319, or Val(5)-Ang II. The target mRNA and protein levels were determined using qPCR and Western blot analysis, respectively. Rat aortic rings were isolated, and the isometric contraction was measured with a force transducer and recorder.Results:Stimulation with Ang II (0.1 μmol/L) for 0.5 h significantly increased the level of LARG mRNA in VSMCs. At 3, 6, and 9 h after the treatment with Ang II (0.1 μmol/L) plus AT(2) antagonist PD123319 (1 μmol/L) or with AT(1) agonist Val(5)-Ang II (1 μmol/L), the LARG protein, RhoA activity, and phosphorylation level of myosin phosphatase target subunit 1 (MYPT1) in VSMCs were significantly increased. Knockdown of LARG with siRNA reduced these effects caused by AT(1) receptor activation. In rat aortic rings pretreated with LARG siRNA, Ang II-induced contraction was diminished.Conclusion:Ang II upregulates LARG gene expression and activates the LARG/RhoA/MYPT1 axis via AT(1), thereby maintaining vascular tone.
    Acta Pharmacologica Sinica 11/2012; · 2.35 Impact Factor
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    ABSTRACT: Severe inflammation leads to cardiac diastolic dysfunction, an independent prognostic marker for the mortality of critically ill patients. We investigated the possible molecular mechanism from inflammatory cytokines (tumor necrosis factor α [TNF-α] and interleukin 6 [IL-6]) causing left ventricular (LV) diastolic dysfunction in critically burned patients. We consecutively enrolled 56 critically burned patients who were admitted to the intensive care unit and performed transthoracic echocardiography to evaluate LV diastolic function. Sarcoplasmic reticulum Ca²⁺-ATPase 2 (SERCA2) gene expression in HL-1 cardiomyocytes was used as a molecular phenotype of diastolic heart failure. Soluble plasma levels of TNF-α and IL-6 were measured in all subjects. The effect of serum from the burned patients on SERCA2 gene expression of HL-1 cardiomyocytes was investigated. The total body surface area of burned patients was proportional to serum level of IL-6 and TNF-α (P < 0.001 for each). Significant correlations were found for TNF-α and decelerating time, E/A, and E/Em (r² = 0.59, 0.45, and 0.52; P <0.001 for each) and for IL-6 and decelerating time, E/A, and E/Em (r² = 0.63, 0.60, and 0.62; P < 0.001 for each). Diastolic function improved significantly in association with decrease in cytokines after burned patients were transferred to general ward (P < 0.001). Tumor necrosis factor α, IL-6, and sera from critically burned patients downregulated the expression of the SERCA2 gene in HL-1 cardiomyocytes. There was a significant correlation between LV diastolic dysfunction and in-hospital mortality in critically burned patients (hazard ratio, 3.92; P = 0.034) after risk factors were adjusted. Inflammatory cytokines may be associated with cardiac diastolic, which could be an independent prognostic factor in burn patients. Novel therapeutic strategies may be applied in critically burned patients with LV diastolic dysfunction by modulating inflammatory reactions.
    Shock (Augusta, Ga.) 05/2012; 37(5):457-62. · 2.87 Impact Factor
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    ABSTRACT: We hypothesized left ventricular (LV) dyssynchrony would affect postexercise accommodation of regional myocardial motion in patients with heart failure and a normal ejection fraction (HFNEF). Tissue-Doppler echocardiography was studied in 100 hypertensive patients with LV ejection fraction >50%. Among them, 70 HFNEF patients were classified into the systolic dyssynchrony (Dys: >65 ms difference of electromechanical delay between septal and lateral segments) (43 patients) and nondyssynchrony (Ndys: 27 patients) groups, and the other 30 patients were as the control (Ctrl). The systolic myocardial velocities (Sm) of 6-basal LV segments at baseline and after exercise were analyzed. When compared with the Ctrl group, the baseline lower mean Sm of 6 LV segments in the Ndys group could increase to a similar postexercise level as that in the Ctrl group, whereas that in the Dys group remained lower after exercise (7.8 ± 1.3 versus Ndys: 8.6 ± 1.5 and Ctrl: 8.9 ± 1.2 cm/s, P < .05, respectively). This is mainly due to a much higher percentage increase of lateral Sm after exercise in the Ndys group (Ndys: 49 versus Dys: 29%, P < .05). Dyssynchrony-related regional myocardial contractile abnormality after exercise in HFNEF patients suggested the detrimental impact of electromechanical uncoupling on HF symptoms.
    Journal of cardiac failure 02/2012; 18(2):134-9. · 3.25 Impact Factor
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    ABSTRACT: Myosin binding protein C (MYBPC3) plays a role in ventricular relaxation. The aim of the study was to investigate the association between cardiac myosin binding protein C (MYBPC3) gene polymorphisms and diastolic heart failure (DHF) in a human case-control study. A total of 352 participants of 1752 consecutive patients from the National Taiwan University Hospital and its affiliated hospital were enrolled. 176 patients diagnosed with DHF confirmed by echocardiography were recruited. Controls were matched 1-to-1 by age, sex, hypertension, diabetes, renal function and medication use. We genotyped 12 single nucleotide polymorphisms (SNPs) according to HapMap Han Chinese Beijing databank across a 40 kb genetic region containing the MYBPC3 gene and the neighboring DNA sequences to capture 100% of haplotype variance in all SNPs with minor allele frequencies ≥ 5%. We also analyzed associations of these tagging SNPs and haplotypes with DHF and linkage disequilibrium (LD) structure of the MYBPC3 gene. In a single locus analysis, SNP rs2290149 was associated with DHF (allele-specific p = 0.004; permuted p = 0.031). The SNP with a minor allele frequency of 9.4%, had an odds ratio 2.14 (95% CI 1.25-3.66; p = 0.004) for the additive model and 2.06 for the autosomal dominant model (GG+GA : AA, 95% CI 1.17-3.63; p = 0.013), corresponding to a population attributable risk fraction of 12.02%. The haplotypes in a LD block of rs2290149 (C-C-G-C) was also significantly associated with DHF (odds ratio 2.10 (1.53-2.89); permuted p = 0.029). We identified a SNP (rs2290149) among the tagging SNP set that was significantly associated with early DHF in a Chinese population.
    PLoS ONE 01/2012; 7(4):e35242. · 3.53 Impact Factor
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    ABSTRACT: Studies to explore angiotensin II (Ang II) and its downstream signaling pathways via Rho guanine nucleotide exchange factors (RhoGEFs) and RhoA signaling are crucial to understanding the mechanisms of smooth muscle contraction leading to hypertension. This study aimed to investigate the Ang II-induced expression of RhoGEFs in vascular smooth muscle cells (VSMCs) of spontaneously hypertensive rats (SHRs) and to identify the possible regulator associated with hypertension. Cultured VSMCs of the aorta from SHRs and Wistar-Kyoto (WKY) rats were treated with or without Ang II or Ang II plus Ang II type 2 receptor antagonists. The expression levels of RhoGEF messenger RNA (mRNA) and protein were determined. To evaluate the changes of aortic ring contractile force in response to Ang II, a nonviral carrier system was adopted to deliver the leukemia-associated RhoGEF (LARG) small interfering RNA via nanoparticles into aortic rings. The baseline mRNA levels of three RhoGEFs in cultured VSMCs of WKY rats did not increase with age, but they were significantly higher in 12-week-old SHRs than in 5-week-old SHRs. Expression levels of LARG mRNA were higher in SHRs than in age-matched WKY rats. The baseline LAGR protein of 12-week-old SHRs was about four times higher than that of WKY rats of the same age. After Ang II-stimulation, LAGR protein expression was significantly increased in 12-week-old WKY rats but remained unchanged in 12-week-old SHRs. LARG small interfering RNA was successfully delivered into aortic rings using nanoparticles. LARG knockdown resulted in 12-week-old SHRs showing the greatest reduction in aortic ring contraction. There were differences in age-related RhoGEF expression at baseline and in response to Ang II-stimulation between SHRs and WKY rats in this study. Nanotechnology can assist in studying the silencing of LARG in tissue culture. The findings of this study indicate that LARG gene expression may be associated with the genesis of hypertension in SHRs.
    International Journal of Nanomedicine 01/2012; 7:5929-39. · 4.20 Impact Factor

Publication Stats

1k Citations
305.48 Total Impact Points

Institutions

  • 2007–2014
    • Taipei Medical University
      • • Department of Internal Medicine
      • • Graduate Institute of Clinical Medicine
      • • Division of Cardiology
      T’ai-pei, Taipei, Taiwan
  • 2002–2014
    • National Taiwan University Hospital
      • Department of Internal Medicine
      T’ai-pei, Taipei, Taiwan
  • 2013
    • Tamkang University
      • Department of Chemistry
      T’ai-pei, Taipei, Taiwan
  • 2012
    • Lotung Poh-Ai Hospital
      I-lan-hsien, Taiwan, Taiwan
    • Far Eastern Memorial Hospital
      T’ai-pei, Taipei, Taiwan
  • 2011
    • National Yang Ming University
      • Department of Internal Medicine
      T’ai-pei, Taipei, Taiwan
  • 2007–2010
    • National Taiwan University
      • School of Medicine
      T’ai-pei, Taipei, Taiwan