Chia-Ti Tsai

National Taiwan University Hospital, Hsin-chu-hsien, Taiwan, Taiwan

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Publications (108)491.57 Total impact


  • No preview · Article · Feb 2016 · Nature Communications
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    ABSTRACT: Although Amiodarone, a class III antiarrhythmic drug, inhibits zebrafish cardiac valve formation, the detailed molecular pathway is still unclear. Here, we proved that Amiodarone acts as an upstream regulator, stimulating similar to versican b (s-vcanb) overexpression at zebrafish embryonic heart and promoting cdh-5 overexpression by inhibiting snail1b at atrioventricular canal (AVC), thus blocking invagination of endocardial cells and, as a result, preventing the formation of cardiac valves. A closer investigation showed that an intricate set of signaling events ultimately caused the up-regulation of cdh5. In particular, we investigated the role of EGFR signaling and the activity of Gsk3b. It was found that knockdown of EGFR signaling resulted in phenotypes similar to those of Amiodarone-treated embryos. Since the reduced phosphorylation of EGFR was rescued by knockdown of s-vcanb, it was concluded that the inhibition of EGFR activity by Amiodarone is s-vcanb-dependent. Moreover, the activity of Gsk3b, a downstream effector of EGFR, was greatly increased in both Amiodarone-treated embryos and EGFR-inhibited embryos. Therefore, it was concluded that reduced EGFR signaling induced by Amiodarone treatment results in the inhibition of Snail functions through increased Gsk3b activity, which, in turn, reduces snail1b expression, leading to the up-regulation the cdh5 at the AVC, finally resulting in defective formation of valves. This signaling cascade implicates the EGFR/Gsk3b/Snail axis as the molecular basis for the inhibition of cardiac valve formation by Amiodarone.
    Full-text · Article · Dec 2015 · PLoS ONE
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    ABSTRACT: Current evidence suggests that beta-blocker lower the risk of development of atrial fibrillation (AF) and in-hospital stroke after cardiac surgery. This study was to assess whether beta-blockers could decrease incidence of new-onset AF in patients with end stage renal disease (ESRD). We identified patients from a nation-wide database called Registry for Catastrophic Illness, which encompassed almost 100% of the patients receiving dialysis therapy in Taiwan from 1995 to 2008. Propensity score matching and Cox € s proportional hazards regression model were used to estimate hazard ratios (HRs) for new-onset AF. Among 100066 patients, 41.7% received beta-blockers. After a median follow-up of 1500 days, the incidence of new-onset AF significantly decreased in patients treated with beta-blockers (HR = 0.483, 95% confidence interval = 0.437-0.534). The prevention of new-onset AF was significantly better in patients taking longer duration of beta-blockers therapy (P for time trend <0.001). The AF prevention effect remains robust in subgroup analyses. In conclusion, beta-blockers seem effective in the primary prevention of AF in ESRD patients. Hence, beta-blockers may be the target about upstream treatment of AF.
    Preview · Article · Dec 2015 · Scientific Reports
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    ABSTRACT: Heart failure with preserved ejection fraction (HFPEF) is characterized by myocardial interstitial fibrosis. A total of 146 patients with HFPEF, were recruited. HFPEF severity was determined using Doppler imaging (E/Em) and also cardiac magnetic resonance imaging (CMRI). Canine modeling of HFPEF was induced by aortic banding. Hemodynamic and echocardiographic data were obtained before and after pressure loading and myocardial Galectin-3 was determined. Mechanical stretch of cultured cardiomyocytes served as the cellular model of HFPEF. Patients with severe HFPEF had significantly higher plasma Galectin-3 levels. Significant correlation between plasma Galectin-3 and E/Em in advanced HFPEF patients was noted. After 2 weeks of pressure overload in canine models, the protein expression of Galectin-3 from LV myocardial tissue was significantly increased (p < 0.01) compared with controls. Galectin-3 expression paralleled the severity of LV diastolic dysfunction by evaluation of CMRI (r = -0.58, p = 0.003) and tissue fibrosis (r = 0.59, p = 0.002). After adjusting for confounders for diastolic dysfunction, Galectin-3 levels were still associated with diastolic parameters both in humans (p < 0.001) and canine model (p = 0.041). Mechanical stretch increased Galectin-3 secretion in cultured cardiomyocytes. Both plasma and myocardial Galectin-3 levels correlated with severity of cardiac diastolic dysfunction.
    Preview · Article · Nov 2015 · Scientific Reports
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    ABSTRACT: Background: We propose a novel integrated score index, which could be used to quantify and grade left ventricular (LV) diastolic function. Methods: We enrolled 629 participants [393 healthy subjects, 145 with hypertension (HTN), 24 with hypertrophic cardiomyopathy (HCM), and 67 with coronary artery disease (CAD)]. This score index was with a score of 1 for an E/A ratio < 1, a score of 1 for a septal e'/a' ratio ≤ 0.8, a score of 2 for a lateral e'/a' ratio ≤ 1, a score of 2 for a septal E/e' ratio ≥10-15, a score of 3 for a lateral E/e' ratio ≥8-15, and a score of 1 for a deceleration time >240 ms. The sum of each score was considered as the final value in this scoring method (either a septal or a lateral E/e' ratio > 15 was given a total score of 10, regardless of the other measurements). Results: After analysis, the AUROC of this integrated score index for predicting any diastolic dysfunction (discriminated by the American Society of Echocardiography guidelines) was 0.962, and the AUROC of the method from the logistic regression was 0.970. The mean values of the score index for the groups were 3.81 ± 0.12 in healthy, 6.48 ± 0.19 in HTN, 7.35 ± 0.46 in HCM, and 6.62 ± 0.29 in CAD. Using the score index, the healthy subjects obtained lower scores compared with those of HTN (p = 0.00), HCM (p = 0.00), and CAD (p = 0.00). Therefore, this score index could discriminate patients with diseases with impaired diastolic function from the healthy subjects when the total sum of the score was equal to or greater than 4. Conclusions: If the presently used methods cannot allow the clear diagnosis of LV diastolic dysfunction, this integrated score index might be helpful for discriminating diseases with impaired diastolic function.
    Preview · Article · Nov 2015 · PLoS ONE
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    ABSTRACT: Context: The effect of aldosterone on vascular smooth muscle cell function is still unclear. One method to measure vascular smooth muscle cell function is endothelial-independent vascular dilation, for which the key factor is sarcoplasmic reticulum ATPase (SERCA). Objective: Our objective was to investigate the effect of aldosterone on vascular smooth muscle cell function and SERCA regulation. Design: We prospectively analyzed 35 patients with primary aldosteronism (PA; 32 patients with aldosterone-producing adenoma and 3 patients with idiopathic hyperaldosteronism), and 30 patients with essential hypertension (EH) who were enrolled as the control group. Flow and nitrate-mediated dilation (F/NMD) were performed in both groups and 1 year after adrenalectomy in the patients with aldosterone-producing adenoma. In addition, we investigated the effect of aldosterone on SERCA regulation in human aortic smooth muscle cells (HAOSMCs) Setting: Academic clinical research center Participants: Thirty-five patients with PA and 30 patients with EH Interventions: Adrenalectomy in patients with aldosterone-producing adenoma Results: The PA patients had significantly lower FMD and NMD values than the patients with EH (FMD: 13±6 vs. 16±4; NMD: 16±6 vs.19±5; both p<0.05). FMD/NMD were significantly correlated with log 24 hour-urine aldosterone (FMD: r=-0.287, p=0.048; NMD: r=-0.402, p=0.005) but not blood pressure. The impaired FMD and NMD values were significantly restored 1 year after adrenalectomy (FMD: 11±4 to 19±7; NMD: 15±6 to 21±6; both p<0.01). Under confocal microscopy, aldosterone was shown to suppress the expression of SERCA2a of HAOSMCs. Aldosterone significantly suppressed the expression of SERCA2a from 10(-8) M in mRNA and protein levels. This suppression was through down-regulation of mineralocorticoid receptor dependent mitochondrial transcription factors A and B2. Conclusions: Aldosterone impairs vascular smooth muscle cell function and suppresses SERCA 2a expression.
    No preview · Article · Sep 2015 · The Journal of Clinical Endocrinology and Metabolism
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    ABSTRACT: Whether the spironolactone treatment remains effective for the prevention of atrial fibrillation (AF) in dialysis patients is unclear. We used a database from the Registry for Catastrophic Illness from the National Health Research Institute. All dialysis patients aged 18 or older without history of AF before ESRD were incorporated. A total of 113,191 dialysis patients were enrolled in the study. The median follow-up time was 4.17years. We collected information on prescribed drug dosage, number of days of treatment and the total number of pills dispensed from the outpatient pharmacy prescription database. All individuals in the study cohort with the first occurrence of AF were included as cases. In spironolactone group, the incidence of developing new AF was significantly lower than that in the control group both before (0.8% vs. 3.3%, P=0.019) and after PS matching (1.2% vs. 3.0%, P=0.019). Before PS matching, Cox's proportional hazard regression analyses showed that spironolactone was associated with 60% reduction of new AF (HR=0.372 [0.200-0.692], P=0.002) and the protective effect is dose-responsive in accumulated dose, treatment duration and mean daily dose. After PS matching, the overall AF prevention effect remained significant (HR=0.400 [0.179-0.895], P=0.026) while the dose-response relationship became borderline significant. Subgroup analyses showed that the protective effect was more evident in some specific subgroup patients. Our study showed that spironolactone therapy was associated with lower risk of developing AF in a dose-responsive manner in patients with dialysis. Further randomized study is needed to confirm this observation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    No preview · Article · May 2015 · International Journal of Cardiology
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    ABSTRACT: Left ventricular diastolic dysfunction (LVDD) is common among patients undergoing peritoneal dialysis (PD). We examined the relationship between LVDD, major adverse cardiovascular events (MACE), and mortality in PD patients. A total of 149 patients undergoing PD with preserved left ventricular systolic function were included and followed for 3.5 years. LVDD was diagnosed (according to the European Society of Cardiology guidelines) by conventional and tissue Doppler echocardiography. Serum high-sensitivity C-reactive protein (hsCRP) was measured. The location and volume of adipose tissue were assessed by computed tomography (CT) at the level of the fourth lumbar vertebra. Subjects with LVDD had higher levels of hsCRP, and more visceral and peritoneal fat than controls. The relationship between adjusted visceral adipose tissue and LVDD became nonsignificant when hsCRP and baseline demographic data were introduced into the logistic regression model (odds ratio = 1.52, P = 0.07). Subsequent hierarchical multivariate Cox regression analysis showed that LVDD was one of the most powerful determinants of MACE and mortality after adjusting for all confounding factors (hazard ratio [HR]: 1.71, 95% confidence interval [CI]: 1.43-3.51, P = 0.02 and HR: 2.25, 95% CI: 1.45-2.91, P = 0.04, respectively). Systemic inflammation (hsCRP) was also significantly associated with MACE and mortality (HR: 2.03, P = 0.03 and HR: 2.16, P = 0.04, respectively). LVDD is associated with systemic inflammation and increased visceral fat in patients undergoing PD. LVDD is also a sensitive, independent indicator of future MACE and mortality in PD patients.
    Full-text · Article · May 2015 · Medicine
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    ABSTRACT: Current evidence suggests that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) reduce the incidence of new atrial fibrillation (AF) in a variety of clinical conditions, including the treatment of left ventricular dysfunction or hypertension. Here we assessed whether ACEIs and ARBs could decrease incidence of new-onset AF in patients with end-stage renal disease (ESRD). We identified patients from the Registry for Catastrophic Illness, a nation-wide database encompassing almost all of the patients receiving dialysis therapy in Taiwan from 1995 to 2008. Propensity score matching and Cox proportional hazards regression models were used to estimate hazard ratios for new-onset AF. Among 113,186 patients, 13% received ACEIs, 14% received ARBs therapy, and 9% received ACEIs or ARBs alternatively. After a median follow-up of 1524 days, the incidence of new-onset AF significantly decreased in patients treated with ACEIs (hazard ratio 0.587, 95% confidence interval 0.519-0.663), ARBs (0.542, 0.461-0.637), or ACEIs/ARBs (0.793, 0.657-0.958). The prevention of new-onset AF was significantly better in patients taking longer duration of ACEI or ARB therapy. The effect remained robust in subgroup analyses. Thus both ACEIs and ARBs appear to be effective in the primary prevention of AF in patients with ESRD. Hence, renin-angiotensin system inhibition may be an emerging treatment target for the primary prevention of AF.Kidney International advance online publication, 25 March 2015; doi:10.1038/ki.2015.96.
    Full-text · Article · Mar 2015 · Kidney International
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    ABSTRACT: TNF-alpha (TNF-α) causes left ventricular diastolic dysfunction. Down-regulation of sarcoplasmic reticulum Ca(2+)-ATPase 2a protein (SERCA2a) expression is one of the major mechanisms underlying diastolic dysfunction. We investigated whether TNF-α modulates SERCA2a expression and alters cardiac diastolic function, and its detailed signalling pathway. We used both in vitro cellular cardiomyocyte model and in vivo rat model to address this issue. We found that TNF-α decreased the levels of both SERCA2a mRNA and protein in the cardiomyocytes, with corresponding impairment of diastolic calcium reuptake, a cellular phenotype of cardiac diastolic function. An ∼2 kb promoter of the SERCA2a gene (atp2a2) along with its serial deletions was cloned into the luciferase reporter system. TNF-α significantly decreased the promoter activity, and truncation of the SERCA2a gene promoter with the putative nuclear factor kappa-B (NF-κB) response element abolished TNF-α-induced SERCA2a gene suppression. Chromatin immunoprecipitation and gel retardation also confirmed the binding of NF-κB to this putative-binding site. TNF-α increased the phosphorylation of IKK and the degradation of IκB, resulted in NF-κB nuclear translocation, and decreased SERCA2a gene promoter activity. This process was attenuated by NF-κB blockers and simvastatin. In the in vivo rat model, lipopolysaccharide treatment significantly elevated the serum TNF-α level, as well as phosphorylation of IKK, resulting in a decrease in myocardial SERCA2a expression, diastolic calcium reuptake, and diastolic dysfunction. Oral treatment with simvastatin led to an increase in SERCA2a expression, alleviation, and prevention of the diastolic dysfunction. TNF-α suppresses SERCA2a gene expression via the IKK/IκB/NF-κB pathway and binding of NF-κB to the SERCA2a gene promoter, and its effect is blocked by simvastatin, demonstrating the potential therapeutic effect of statins in treating inflammation-related diastolic dysfunction. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.
    No preview · Article · Mar 2015 · Cardiovascular Research
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    ABSTRACT: We tested the acute effects of resynchronization in heart failure patients with a normal (>50%) left ventricular (LV) ejection fraction (HFNEF) and mechanical dyssynchrony. Twenty-four HFNEF patients (72 ± 6 years, 5 male) with mechanical dyssynchrony (standard deviation of electromechanical time delay among 12 LV segments >35 ms) were studied with temporary pacing catheters in the right atrium, LV, and right ventricle (RV), and high-fidelity catheters for pressure recording. Using selected atrioventricular (AV) intervals of 60, 90, 120, 150, and 180 ms to optimize transmitral flow during simultaneous biventricular pacing, the RV-LV (VV) interval was then evaluated at RV30, RV15, 0, LV15, LV30, and LV45 (RV or LV indicates which ventricle was paced first, the number indicates by how many ms). During simultaneous pacing, longer AV intervals were associated with improved LV pressure-derivative minimums and increased aortic pressures (p < 0.05 vs. normal sinus rhythm). In the VV interval from RV30 to LV45, there was a graded increase in the aortic velocity time integral and a decrease in dyssynchrony during simultaneous or LV-first pacing (p < 0.05 vs. normal sinus rhythm). For HFNEF patients with mechanical dyssynchrony, acute simultaneous biventricular or LV-first pacing with longer AV intervals reduced mechanical dyssynchrony and improved diastolic and systolic hemodynamics. © 2015 S. Karger AG, Basel.
    No preview · Article · Feb 2015 · Cardiology
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    ABSTRACT: The objective is to assess the effectiveness of statin use to prevent atrial fibrillation (AF) in dialysis patients. We used a database from the Registry for Catastrophic Illness from the National Health Research Institute (NHRI), which encompasses almost 100% of the patients receiving dialysis started from 1997 to 2008 in Taiwan. All dialysis patients aged 18 or older without history of cardiovascular events in 1997 and 1998 were incorporated. Finally, 113,191 dialysis patients were enrolled. We used propensity score (PS) matching method and Cox's proportional hazard regression models to estimate hazard ratios for AF events for statin users vs. nonusers. In statin group, the incidence of developing new AF was significantly lower than that in control group (1.1% vs. 3.8%, P<0.001). The PS-based selection process identified 2146 patients receiving statins and 2146 who did not receive statins. The incidence of developing AF remained lower in statin group than that in control group (2.4% vs. 4.9%, P<0.001). After PS matching, Cox's proportional hazard regression analyses showed that there was a protective effect of developing AF in a dose-responsive manner. The protective effect was more obvious in subjects with younger age, female gender, hyperlipidemia, coronary artery disease and peripheral artery disease and in subjects without taking angiotensin converting enzyme inhibitor and angiotensin receptor blocker. Our analyses showed that statin therapy was associated with lower risk of newly diagnosed AF in patients with dialysis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    No preview · Article · Jan 2015 · International Journal of Cardiology
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    ABSTRACT: Long-term benefit of using a renin-angiotensin-aldosterone system blocker such as an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) for patients already receiving dialysis remains undetermined. The aim of this study is to assess the efficacy and safety of ACEI or ARB use in dialysis patients. We performed a population-based cohort study with time-to-event analyses to estimate the relation between the use of ACEI/ARB and their outcomes. We used a nationwide database (Registry for Catastrophic Illnesses) for Taiwan, which has data from 1995 to 2008 nearly of all patients who received dialysis therapy. The records of all dialysis patients aged ≥18 with no evidence of cardiovascular (CV) events in 1997 and 1998 (133,564 patients) were examined. Users (n = 50,961) and nonusers (n = 59,913) of an ACEI/ARB were derived. We then used propensity score matching and Cox proportional hazards regression models to estimate adjusted hazard ratios (HRs) for all-cause mortality and CV events in users and nonusers of an ACRI/ARB. The 15,182 patients, who used an ACEI/ARB, and the 15,182 nonusers had comparable baseline characteristics during the 14 years of follow-up. The mortality was significantly greater in patients who did not use an ACEI/ARB (HR = 0.90, 95% confidence interval = 0.86-0.93). Subgroup analysis of 3 tertiles of patients who used different total amounts of ACEI/ARB during the study period indicated that CV events were more common in patients who used an ACEI/ARB for a short duration (tertile 1: HR = 1.63), but less common in those who used an ACEI/ARB for long durations (tertile 2: HR = 1.05; tertile 3: HR = 0.94; trend for declining HR from tertile 1 to 3: P < 0.001). The mortality benefit provided by use of an ACEI/ARB was consistent across most patient subgroups, as was the benefit of ARB monotherapy rather than ACEI monotherapy. Independent of traditional risk factors, overall mortality was significantly lower in dialysis patients who used an ACEI/ARB. In addition, subjects who used an ACEI/ARB for longer durations were significantly less likely to experience CV events.
    Full-text · Article · Jan 2015 · Medicine
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    ABSTRACT: Three dimensional (3D) echocardiography-derived measurements of myocardial deformation and twist have recently advanced as novel clinical tools. However, with the exception of left ventricular ejection fraction and mass quantifications in hypertension and heart failure populations, the prognostic value of such imaging techniques remains largely unexplored. We studied 200 subjects (mean age: 60.2±16 years, 54% female, female n = 107) with known hypertension (n = 51), diastolic heart failure (n = 61), or systolic heart failure (n = 30), recruited from heart failure outpatient clinics. Fifty-eight healthy volunteers were used as a control group. All participants underwent 3D-based myocardial deformation and twist analysis (Artida, Toshiba Medical Systems, Tokyo, Japan). We further investigated associations between these measures and brain natriuretic peptide levels and clinical outcomes. The global 3D strain measurements of the healthy, hypertension, diastolic heart failure, and systolic heart failure groups were 28.03%, 24.43%, 19.70%, and 11.95%, respectively (all p<0.001). Global twist measurements were estimated to be 9.49°, 9.77°, 8.32°, and 4.56°, respectively. We observed significant differences regarding 3D-derived longitudinal, radial, and global 3D strains between the different disease categories (p<0.05), even when age, gender, BMI and heart rate were matched. In addition, 3D-derived longitudinal, circumferential, and 3D strains were all highly correlated with brain natriuretic peptide levels (p<0.001). At a mean 567.7 days follow-up (25th-75th IQR: 197-909 days), poorer 3D-derived longitudinal, radial, and global 3D strain measurements remained independently associated with a higher risk of cardiovascular related death or hospitalization due to heart failure, after adjusting for age, gender, and left ventricular ejection fraction (all p<0.05). 3D-based strain analysis may be a feasible and useful diagnostic tool for discriminating the extent of myocardial dysfunction. Furthermore, it is able to provide a prognostic value beyond traditional echocardiographic parameters in terms of ejection fraction.
    Full-text · Article · Dec 2014 · PLoS ONE
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    ABSTRACT: The objective of this study was to test the effect of removal of a ureteral obstruction (renal calculus) from anesthetized patients on the perfusion index (PI), as measured by a pulse oximeter, and on the estimated glomerular filtration rate (eGFR). This prospective study enrolled 113 patients with unilateral ureteral obstructions (kidney stones) who were scheduled for ureteroscopy (URS) laser lithotripsy. One urologist graded patient hydronephrosis before surgery. A pulse oximeter was affixed to each patient's index finger ipsilateral to the intravenous catheter, and a non-invasive blood pressure cuff was placed on the contralateral side. Ipsilateral double J stents and Foley catheters were inserted and left indwelling for 24 h. PI and mean arterial pressure (MAP) were determined at baseline, 5 min after anesthesia, and 10 min after surgery; eGFR was determined at admission, 1 day after surgery, and 14 days after surgery. Patients with different grades of hydronephrosis had similar age, eGFR, PI, mean arterial pressure (MAP), and heart rate (HR). PI increased significantly in each hydronephrosis group after ureteral stone disintegration. None of the groups had significant post-URS changes in eGFR, although eGFR increased in the grade I hydronephrosis group after 14 days. The percent change of PI correlates significantly with the percent change of MAP, but not with that of eGFR. Our results demonstrate that release of a ureteral obstruction leads to a concurrent increase of PI during anesthesia. Measurement of PI may be a valuable tool to monitor the successful release of ureteral obstructions and changes of microcirculation during surgery. There were also increases in eGFR after 14 days, but not immediately after surgery.
    Preview · Article · Dec 2014 · PLoS ONE
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    ABSTRACT: Background 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. Methods We used an extreme trait design to sequence carefully selected probands with extreme phenotypes and their unaffected parents to identify rare de novo variants or mutations. Based on the hypothesis that common and rare variants may colocate in the same disease susceptibility gene, we used next-generation sequencing to sequence these nine published AF susceptibility genes identified by GWAS (a total of 179 exons) in 20 trios, 200 unrelated patients with AF and 200 non-AF controls. Results We identified a novel mutation in the 5′ untranslated region of the PITX2 gene, which localised in the transcriptionally active enhancer region. We also identified one missense exon mutation in KCNN3, two in ZFHX3 and one in SYNE2. None of these mutations were present in other unrelated patients with AF, healthy controls, unaffected parents and are thus novel and de novo (p<10−4). Functional study showed that the mutation in the 5′ untranslated region of the PITX2 gene significantly downregulated PITX2 expression in atrial myocytes, either in basal condition or during rapid pacing. In silico analysis showed that the missense mutation in ZFHX3 results in damage of the ZFHX3 protein structure. Conclusions The genetic architecture of subjects with extreme phenotypes of AF is similar to that of rare or Mendelian diseases, and mutations may be the underlying cause.
    Preview · Article · Nov 2014 · Journal of Medical Genetics
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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.
    Full-text · Article · Oct 2014 · Scientific Reports
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    ABSTRACT: Objective: 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. Methods: A universal national health insurance (NHI) program has been implemented in Taiwan since 1995. We used system sampling database from 1997 to 2008 with a total of 1,000,000 subjects. We included subjects with first episode of MI and were above 30 years old. Sudden death, cardiovascular mortality, and heart failure hospitalization were assessed in all included subjects. Anti-anxiety as well as other medications and risk factors were obtained. Cox regression analysis was used to evaluate the adjusted hazard ratio (HR) for all patients and subgroups. Results: The adjusted HRs of sudden death were significantly associated with increased benzodiazepam (BZD) dosage (HRs = 0.639, 1.003, 1.957 from Q2 to Q4 vs. Q1, p = .019 for trend) during approximately 4.8 years. For cardiac mortality and heart failure hospitalization, there was a J-curve dose-response relationship. The HRs for cardiac mortality were 0.255 (p < .001) and 0.385 (p < .001) for Q2 and Q3 vs. Q1, respectively. For patients receiving higher doses of daily BZDs (>5 mg), protective effects for cardiac mortality and heart failure hospitalization decreased and a J-curve dose-response relationship was seen. Conclusion: Anti-anxiety medications are independent associated with a decreased risk of cardiac mortality and heart failure hospitalization in patients after a new MI.
    No preview · Article · Jun 2014 · Atherosclerosis
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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.
    No preview · Article · Apr 2014 · Heart rhythm: the official journal of the Heart Rhythm Society
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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.
    No preview · Article · Apr 2014 · Chinese medical journal

Publication Stats

2k Citations
491.57 Total Impact Points

Institutions

  • 2011-2015
    • National Taiwan University Hospital
      Hsin-chu-hsien, Taiwan, Taiwan
  • 2007-2015
    • National Taiwan University
      T’ai-pei, Taipei, Taiwan
  • 2002-2015
    • National Taiwan University Hospital
      • Department of Internal Medicine
      T’ai-pei, Taipei, Taiwan
  • 2014
    • Taipei University
      T’ai-pei, Taipei, Taiwan
  • 2010-2014
    • Lotung Poh-Ai Hospital
      I-lan-hsien, Taiwan, Taiwan
  • 2013
    • Tamkang University
      • Department of Chemistry
      T’ai-pei, Taipei, Taiwan
  • 2006-2013
    • Taipei Medical University
      • Division of Cardiology
      T’ai-pei, Taipei, Taiwan