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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.

This paper reports the shallow trench isolation (STI)-related narrow channel effect (NCE) on the kink behaviour of the 40 nm PD SOI NMOS device. As verified by the experimentally measured data, with a smaller channel width, the onset of the kink effect behaviour occurs at a higher drain voltage and the breakdown voltage is also larger due to the weaker parasitic bipolar device in the floating thin film as a result of a smaller electron recombination lifetime caused by the STI-related defect effect.

Background Little evidence is available regarding the impact of genetic polymorphisms on the risk of stroke in patients with atrial fibrillation (AF). Angiotensin II plays a pathophysiologic role in prothrombotic atrial endocardial remodeling. Objective The purpose of this study was to investigate the effect of polymorphisms of renin–angiotensin system genes on the incidence of stroke in a prospective cohort of patients with AF. Methods A total of 712 AF patients were longitudinally followed-up for 10.3 ± 2.7 years. Eight polymorphisms of renin–angiotensin system genes were genotyped. Results Patients carrying the G-6 allele in the promoter of the angiotensinogen gene, which was associated with higher promoter activity, were more likely to develop stroke than were noncarriers (hazard ratio 2.54, 95% confidence interval [1.26–5.12], P = .009 after adjustment for CHADS 2 score). G-6A polymorphism provides information additional to CHADS 2 on stroke risk prediction ( C -statistic 0.672 vs 0.724, P = .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 = .004). G-217/G-6 haplotype carriers were even more likely to develop stroke than were noncarriers (hazard ratio 2.78, 95% confidence interval 1.37–5.64, P = .003 after multivariable adjustment). In pharmacogenetic analysis, the increased risk of stroke in subjects carrying G-6 was eliminated by concomitant treatment with an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker ( P = .012 for interaction). Conclusion In addition to the CHADS 2 score, angiotensinogen gene polymorphisms may be considered an additional genetic predictor of stroke in patients with AF. Genotyping of the angiotensinogen gene is helpful to determine which AF patients may benefit from treatment with an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker.

Being the chamber receiving systemic venous return, the right atrium is a structure of morphological mosaic, comprising the smooth vestibule, the septum, the trabeculated appendage and junctional crista terminalis, the Eustachian ridge, the fanning pectinate muscle, and the tendon of Todaro. The mosaic milieu by itself predisposes to the formation of reentrant atrial tachyarrhythmias. Meanwhile, the right atrium is also common with secondary isthmus structures resulting from surgical iatrogenic scars or stretch-related spontaneous scars. Inside the heterogenous scars, between adjacent scars, and between natural structural barriers and the scars, there are also facilitated opportunities of creating clinical microreentrant (focal) and macroreentrant atrial tachyarrhythmias.

Background 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. Methods and Results 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. Conclusions 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.

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.

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.

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 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.

OBJECTIVES: 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). METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

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 12years. 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.

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

To investigate the signaling pathways involved in thrombin-induced connective tissue growth factor (CTGF) expression in rat vascular smooth muscle cells (VSMCs).Experiments were preformed on primary rat aortic smooth muscle cells (RASMCs) and a rat VSMC line (A10). CTGF protein levels were measured using Western blotting. Luciferase reporter genes and dominant negative mutants (DNs) were used to investigate the signaling pathways mediating the induction of CTGF expression by thrombin.Thrombin (0.3-3.0 U/mL) caused a concentration- and time-dependent increase in CTGF expression in both RASMCs and A10 cells. Pretreating A10 cells with the protease-activated receptor 1 (PAR-1) antagonist SCH79797 (0.1 μmol/L) significantly blocked thrombin-induced CTGF expression, while the PAR-4 antagonist tcY-NH(2) (30 μmol/L) had no effect. The PAR-1 agonist SFLLRN-NH(2) (300 μmol/L) induced CTGF expression, while the PAR-4 agonist GYPGQV-NH(2) (300 μmol/L) had no effect. Thrombin (1 U/mL) caused time-dependent phosphorylation of c-Jun N-terminal kinase (JNK). Pretreating with the JNK inhibitor SP600125 (3-30 μmol/L) or transfection with DNs of JNK1/2 significantly attenuated thrombin-induced CTGF expression. Thrombin (0.3-3.0 U/mL) increased activator protein-1 (AP-1)-luciferase activity, which was inhibited by the JNK inhibitor SP600125. The AP-1 inhibitor curcumin (1-10 μmol/L) concentration-dependently attenuated thrombin-induced CTGF expression.Thrombin acts on PAR-1 to activate the JNK signaling pathway, which in turn initiates AP-1 activation and ultimately induces CTGF expression in VSMCs.

Objective 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. Methods 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. Results 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). Conclusions We identified a SNP (rs2290149) among the tagging SNP set that was significantly associated with early DHF in a Chinese population.

Background: A recent study in individuals of European ancestry demonstrated a significant association of the single nucleotide polymorphism (SNP) rs13376333 in potassium intermediate/small conductance calcium-activated channel, subfamily N, member 3 (KCNN3) on chromosome 1q21 with lone atrial fibrillation (AF), indicating a common genetic basis for AF. The aim of the present study was to investigate whether this association between SNP rs13376333 and AF also exists in Taiwanese subjects. Methods and Results: The SNP rs13376333 was compared in 214 lone AF patients (58.3±11.4 years) vs. 214 controls (57.7±13.2 years), and in 322 structural AF patients (69.6±13.7 years) vs. 322 controls (68.4±14.2 years) in a Taiwanese population, in a case-control design. The associations between SNP rs13376333 in KCNN3 and structural or lone AF were significant. In the lone AF group, the frequency of the minor allele of SNP rs13376333 was 8.6% compared with 3.0% in the controls (P

Context: Primary aldosteronism (PA) is associated with a higher incidence of cardiovascular events, probably through mineralocorticoid receptor (MR)-dependent endothelial cell dysfunction, in comparison with essential hypertension (EH). Objective: Our objective was to investigate the number and function of endothelial progenitor cells (EPC) in PA and the relationship with arterial stiffness and disease progression. Design and Setting: We conducted a prospective study of the change of EPC number and outcome of PA patients after treatment at a tertiary medical center. Primary Outcomes: Changes in arterial stiffness and EPC number after treatment and the curability of hypertension were assessed. Patients: A total of 113 PA patients (87 patients diagnosed with aldosterone-producing adenoma, 26 with idiopathic hyperaldosteronism) and 55 patients with EH participated. Results: PA patients had higher arterial stiffness than EH patients (P = 0.006), with a lower numbers of circulating EPC and endothelial colony-forming units (P < 0.05). The differences were ameliorated at 6 months after unilateral adrenalectomy or treatment with spironolactone. Expression of MR was identified in the EPC. The number of circulating EPC was inversely correlated with the plasma aldosterone concentration (P = 0.021), arterial stiffness (P = 0.029) and serum high-sensitivity C-reactive protein (P = 0.03). High-dose aldosterone (10−5 and 10−6m) attenuated EPC proliferation and angiogenesis in vitro. Among the 45 patients who underwent unilateral adrenalectomy, 32 (71%) were cured of hypertension. The preoperative number of EPC [log(EPC number percent) >−3.6] predicted the curability of hypertension after adrenalectomy (P = 0.003). Conclusions: The relative deficiency of EPC in PA patients may contribute to aldosterone vasculopathy, which can be reversed by adrenalectomy and spironolactone. High aldosterone levels attenuated EPC proliferation and angiogenesis. Circulating EPC number may be a valuable biomarker to identify PA patients with a high incidence of arterial stiffness and to predict postoperative residual hypertension of aldosterone-producing adenoma.

Background: Atrial fibrosis is a feature of structural remodeling in atrial fibrillation (AF). Connective tissue growth factor (CTGF) is a potent profibrotic factor, but its role of CTGF in AF is not yet fully understood. Methods and Results: Right atrial appendages were obtained from 20 patients who underwent cardiac surgery (10 with sinus rhythm, 10 with AF). The mRNA level, protein level and immunohistochemical staining of CTGF were significantly increased in AF patients. In a porcine AF model, tissue angiotensin II (Ang II) and CTGF levels were significantly upregulated in both atria. In perfused rat hearts, Ang II stimulation increased CTGF expression, which could be inhibited by Ang II type I receptor antagonist. In a cell culture system, both atrial fibroblasts and myocytes were responsible for the increased CTGF expression under Ang II treatment. Ang II type I receptor antagonist could inhibit the Ang II-induced CTGF expression. Treating with recombinant CTGF, atrial fibroblasts expressed an increased level of collagen I. Furthermore, the CTGF level was highly correlated with tissue Ang II content in AF pigs. Conclusions: AF patients and animals exhibited a significantly increased expression of CTGF. Ang II stimulation upregulated CTGF expression in both atrial fibroblasts and myocytes. Ang II-induced CTGF expression might be involved in atrial substrate remodeling. (Circ J 2011; 75: 1592-1600)

The purpose of this study was to investigate the associations among central obesity, inflammation, and left ventricular (LV) diastolic dysfunction by structural equation modeling. Echocardiographic parameters were assessed in 102 otherwise-healthy adults over age 30. The participants were classified as having LV diastolic dysfunction by echocardiographic findings including mitral inflow E/A ratio1, deceleration time220 cm/s, or decreased peak annular early diastolic velocity in tissue Doppler imaging or otherwise the control group. Serum C-reactive protein (CRP) and lipid profile were also measured. The homeostasis model of insulin resistance (HOMA) was calculated. Central obesity was assessed by computerized tomography (CT) at the L4 level. In a multivariate regression analysis, the relationship between visceral adipose tissue (VAT) and LV diastolic dysfunction became insignificant when CRP was introduced into the model, although CRP itself was significantly associated with LV diastolic dysfunction (odds ratio (OR): 1.32, 95% confidence interval (CI): 1.01-1.72, P = 0.04). A significant correlation was also found between VAT and CRP (r = 0.70; P0.001). We then performed path analysis as illustrated by the structural equation model. This proved our hypotheses that VAT might affect LV diastolic dysfunction through the effect of CRP (total fat load with inflammation (B = 1.133, P0.001) and that inflammation might affect LV diastolic dysfunction (B = 0.373. P0.001)). Using structural equation modeling, we concluded that higher amounts of VAT were associated with low-grade inflammation and this may lead to subclinical LV diastolic dysfunction in otherwise-healthy subjects.

Objectives The purpose of this study was to investigate the effect of stretch (the major risk factor for atrial fibrillation [AF]) on spatial and temporal alternations of action potential duration (APD-ALT) and calcium transient in cultured atrial myocyte monolayer. Background How rapid firings or premature beats trigger AF is not completely understood. Discordant repolarization alternans, characterized by simultaneous prolongation and shortening of APD in different myocardial regions, is central to the genesis of ventricular fibrillation. We hypothesized that repolarization alternans also is central to the initiation of multiple re-entry circuits and AF. Methods Confluent HL-1 atrial myocyte monolayer with spontaneous depolarization was cultured in silicone membrane and subjected to mechanical stretch. Rapid field pacing was used to induce alternans. A high-resolution dual optical mapping system was used to record action potentials and calcium transients. Results High-rate pacing induced APD-ALT and calcium transient in atrial myocyte monolayer. Mechanical stretch significantly decreased the thresholds for APD-ALT and calcium transient. Mechanical stretch decreased the expression of sarcoplasmic reticulum adenosine triphosphatase 2, and thus slower calcium reuptake kinetics, which was responsible for the susceptibility to alternans. Mechanical stretch did not alter the APD restitution kinetics. Mechanical stretch also enhanced spatially discordant alternans. Overexpression of sarcoplasmic reticulum adenosine triphosphatase 2 reversed all the effects of stretch on susceptibility to alternans. In intact atrium, mechanical stretch also enhanced discordant alternans. Conclusions Mechanical stretch increased the susceptibility to alternans in atrial myocytes, which may explain the susceptibility to AF in conditions of atrial stretch, such as mitral valvular heart disease, heart failure, and hypertension.

The inflammatory process is associated with cardiac diastolic dysfunction, which has been demonstrated to be an independent prognostic marker for the mortality of critically ill patients. We investigated the association among inflammatory cytokines (tumor necrosis factor-α and interleukin-6), diastolic heart failure, and the possible molecular mechanism.Prospective case-controlled cohort and molecular studies.University hospital and research laboratory.Patients with a diagnosis of diastolic heart failure by echocardiography and matched control subjects from the general population (study group 1) and also subjects from the intensive care unit (study group 2). Sarcoplasmic reticulum Ca2+-ATPase (SERCA2) gene expression and diastolic calcium decay in HL-1 cardiomyocytes were used as molecular phenotypes of diastolic heart failure.Soluble plasma levels of tumor necrosis factor-α and interleukin-6 were measured in all subjects. An approximate 1.75-kb promoter of the SERCA2 gene was cloned to the pGL3 luciferase reporter. The effect of tumor necrosis factor-α and interleukin-6 on SERCA2 gene expression and diastolic calcium decay of HL-1 cardiomyocytes were investigated.Patients with diastolic heart failure had significantly higher plasma levels of tumor necrosis factor-α and interleukin-6 than the control subjects. Significant correlations (p.01 for each) were found for tumor necrosis factor-α and E/Em (r = .87) and E/A (r = -0.69), and for interleukin-6 and E/Em (r = .80) and E/A (r = -0.65). Cytokine levels were also correlated with diastolic function in critically ill patients (study group 2), and diastolic function improved significantly in association with decrease of cytokines. Tumor necrosis factor-α, interleukin-6, and sera from critically ill patients downregulated the expression of the SERCA2 gene. Tumor necrosis factor-α and interleukin-6 also delayed the diastolic calcium reuptake and decay in cardiomyocytes.Through downregulation of SERCA2 gene expression, inflammatory cytokines may cause cardiac diastolic dysfunction by decreasing diastolic calcium reuptake. Our study may suggest novel therapeutic strategies for diastolic heart failure and critically ill patients by modulating inflammatory reactions.

Atrial fibrillation (AF) is a risk factor for ischemic stroke. Stroke-prevention strategies based on risk schemes have been developed but most of the data are from western people. Our goal is to investigate the risk factors of ischemic stroke in Taiwanese with AF in a nation-wide database.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. By using ambulatory and inpatient claim data, we included subjects with AF and were above 20 years old. We excluded those who had ever taken warfarin or aspirin or had valvular heart diseases.A total of 7920 patients (3633 women, 4287 men) were included in the final analyses. Cox regression analysis showed that the risk factors for ischemic stroke were age (OR=1.338 for age 65-74 years vs. age 20-64 years, P=0.014; OR=1.652 for age over 75 years vs. age 20-64 years, P0.001), hypertension (HTN) (OR=2.656, P0.001), diabetes mellitus (DM) (OR=1.341, P=0.005), heart failure (OR=1.611, P0.001), previous ischemic stroke or transient ischemic accident (TIA) (OR=2.752, P0.001) and peripheral arterial disease (PAD) (OR=1.814, P=0.006). The gender, coronary artery disease, history of myocardial infarction and chronic renal insufficiency were not associated with ischemic stroke. The rate of ischemic stroke was much lower in current cohort as compared with that in whites. Frequent used risk schemes including CHADS₂ and CHA₂DS₂-VASC had comparable but only limited ability to predict ischemic stroke in subjects with AF.Compare with western people, hypertension plays a more important role in ischemic stroke in Taiwanese with AF and the incidence is lower. A substantial number of ischemic strokes cannot be accurately predicted by current risk schemes.

Aims We investigated the molecular mechanism of rapid-depolarization-induced atrial fibrosis. Methods and results We used a direct atrial myocyte–fibroblast contact co-culture and a fibroblast-specific transforming growth factor β1 (TGF-β1), connective tissue growth factor (CTGF) and procollagen type I α-1 (COL1A1) luciferase reporter system to investigate the possible molecular mechanism of rapid-depolarization-induced atrial fibrosis. Mouse atrial fibroblasts were first transfected with promoter–luciferase reporters, and then co-cultured with HL-1 atrial myocytes. Rapid depolarization of atrial myocytes by rapid electrical field stimulation induced increased TGF-β1, CTGF and COL1A1 promoter activities in the co-cultured atrial fibroblasts (2.4 ± 0.3-fold increase, P = 0.008 for TGF-β1; 2.9 ± 0.4-fold increase, P < 0.001 for CTGF; and 2.1 ± 0.2-fold increase, P = 0.008 for COL1A1). Rapid depolarization of atrial myocytes increased paracrine secretion of angiotensin II (Ang II) and reactive oxygen species in the co-culture medium. Rapid electrical field stimulation-induced ROS generation in atrial myocytes was attenuated by the membrane NADPH oxidase inhibitor, apocynin. Atrial myocyte-induced expression of TGF-β1, CTGF and COL1A1 in atrial fibroblasts was attenuated by co-treatment with the Ang II receptor blocker, losartan, and apocynin. Atrial myocyte-induced COL1A1 expression in atrial fibroblasts was attenuated by anti-TGF-β1 antibody and RNA interference knockdown of the TGF-β1 receptor. Conclusion We first demonstrated that tachycardia of atrial myocytes induced paracrine secretion of Ang II and reactive oxygen species, which in turn induced expression of CTGF and procollagen in co-cultured atrial fibroblasts through increasing TGF-β1 expression. The results may imply that use of an Ang II receptor blocker, in combination with an anti-oxidant, blocks rapid-depolarization-induced atrial fibrosis.

Angiotensin II (AngII) has been implicated in the mechanism of atrial fibrillation (AF). There may be calcium-dependent pro-fibrillatory effect of AngII on atrial myocytes. We used cultured confluent HL-1 atrial myocyte monolayer with spontaneously propagated depolarization to study direct pro-fibrillatory effect of AngII and its molecular mechanism. AngII stimulation induced fibrillatory-like complex electrogram and calcium wave propagation. AngII shortened action potential duration and augmented calcium transient, thus increasing electrochemical gradient of forward-mode sodium-calcium exchanger (NCX) current and induced frequent irregular afterdepolarizations. AngII increased expression of sodium-calcium exchanger (NCX), further increasing calcium-membrane voltage coupling gain. The fibrillatory effect of AngII was attenuated by NCX blocker SEA0400 and NCX siRNA knockdown. AngII increased expression of L-type calcium channel and augmented calcium transient through PKC and CREB. The fibrillatory effect of AngII was also attenuated by PKC inhibitor chelerythrine and dominant negative form of CREB. In conclusions, AngII itself may electrically contribute to the mechanism of AF through increasing NCX expression and augmenting calcium transient, which is PKC and CREB dependent. Specific genetic knockdown of NCX attenuated calcium mediated afterdepolarization and complex electrogram.

ObjectivesThis study was designed to evaluate the status of steroidogenesis proteins and de novo synthesis of aldosterone in the atrium, and relationships of these factors to atrial fibrillation (AF).BackgroundThe role of mineralocorticoid in the pathogenesis of AF is unknown.MethodsWe studied atrial expression of steroidogenesis proteins and aldosterone level in patients with and without AF, and in HL-1 atrial myocytes. We also investigated the electrophysiologic effects and signal transduction of aldosterone on atrial myocytes.ResultsWe found basal expressions of mineralocorticoid receptors (MRs), glucocorticoid receptors, and 11-beta-hydroxysteroid dehydrogenase type 2 (11bHSD2) but not 11-beta-hydroxylase (CYP11B1) or aldosterone synthase (CYP11B2) in human atria and HL-1 myocytes. There was no significant difference of mean atrial aldosterone level between patients with AF and those with normal sinus rhythm. However, patients with AF had a significantly higher atrial MR expression compared with those with normal sinus rhythm (1.73 ± 0.24-fold, p < 0.001). Using mouse HL-1 atrial myocytes as a cellular AF model, we found that rapid depolarization increased MR expression (1.97 ± 0.72-fold, p = 0.008) through a calcium-dependent mechanism, thus augmenting the genomic effect of aldosterone signaling as evaluated by MR reporter. Aldosterone increased intracellular oxidative stress through a nongenomic pathway, which was attenuated by nicotinamide adenine dinucleotide phosphate oxidase inhibitor diphenyleneiodonium, but not by MR-blockade spironolactone. Aldosterone increased expression of the alpha-1G and -1H subunits of the T-type calcium channel and thus increased the T-type calcium current (–13.6 ± 2.9 pA/pF vs. –4.5 ± 1.6 pA/pF, p < 0.01) and the intracellular calcium load through a genomic pathway, which were attenuated by spironolactone, but not by diphenyleneiodonium.ConclusionsExpression of MR increased in AF, thus augmenting the genomic effects of aldosterone. Aldosterone induced atrial ionic remodeling and calcium overload through a genomic pathway, which was attenuated by spironolactone. These results suggest that aldosterone may play a role in AF electrical remodeling and provide insight into the treatment of AF with MR blockade.

This double-blind, active- and randomized-controlled study compared the efficacy and safety of a fixed-dose combination of valsartan/hydrochlorothiazide 80 mg/12.5 mg once daily ( n = 32) with amlodipine monotherapy 5 mg once daily ( n = 33) for 8 weeks in patients with mild to moderate hypertension. Non-inferiority of valsartan/hydrochlorothiazide to amlodipine was demonstrated by comparable reductions in sitting systolic blood pressure (SBP), sitting diastolic blood pressure (DBP), and daytime, night-time and 24-h SBP and DBP on ambulatory blood pressure monitoring. Between-group comparisons of adverse events and changes in laboratory parameters did not reach statistical significance, except for uric acid which showed a significant increase in the valsartan/hydrochlorothiazide group compared with the amlodipine group, but was still below the laboratory's upper limit of normal. In conclusion, the use of the fixed-dose combination of valsartan/hydrochlorothiazide 80 mg/12.5 mg once daily as a starting regimen in patients with mild to moderate hypertension was shown to have non-inferior efficacy and comparable safety for daily practice compared with amlodipine 5 mg once daily monotherapy.

Niemann-Pick type C1-like 1 (NPC1L1) protein is responsible for intestinal cholesterol absorption. The aim of the study was to identify genetic polymorphisms of the NPC1L1 gene as well as their functional significance. The method involved screening of promoter and coding regions of the NPC1L1 gene for genetic polymorphisms by direct DNA sequencing of genomic DNA from 50 individuals. Functional studies on promoter polymorphisms were performed using luciferase assay. Association between the polymorphisms and serum cholesterol levels were investigated in 224 individuals. The results showed that in total, 11 single nucleotide polymorphisms were identified. Among them, a promoter polymorphism, g.-762TC, and a synonymous polymorphism, g.1679CG, were common (34 and 36%, respectively). These two polymorphisms were highly linked (D' value=0.7459, P-value0.00001). For the g.-762TC promoter polymorphism, luciferase assay in HepG2 cell line demonstrated that the -762C allele had a significantly higher promoter activity than the -762T allele (1.30+/-0.22 vs 0.37+/-0.06, 3.5-fold, P0.05). We also showed that the NPC1L1 promoter activity was downregulated by cholesterol content in both genotypes. When association studies were performed, we found that -762C allele was associated with significantly higher serum total cholesterol and LDL-cholesterol content levels in a recessive model (LDL-cholesterol value=131.2+/-8.1 vs 116.4+/-2.2 mg dl(-1); total cholesterol value=214.7+/-9.0 mg dl(-1) vs 196.9+/-2.6, P-value0.05, n=224). In conclusion, the C allele at -762 position of the NPC1L1 gene was common in people of Chinese ethnicity. The -762C allele had a higher promoter activity and was associated with a higher serum total cholesterol and LDL-cholesterol level.

The Brugada syndrome is characterized by ST segment elevation in the right precodial leads V1-V3 on surface ECG accompanied by episodes of ventricular fibrillation causing syncope or even sudden death. The molecular and cellular mechanisms that lead to Brugada syndrome are not yet completely understood. However, SCN5A is the most well known responsible gene that causes Brugada syndrome. Until now, more than a hundred mutations in SCN5A responsible for Brugada syndrome have been described. Functional studies of some of the mutations have been performed and show that a reduction of human cardiac sodium current accounts for the pathogenesis of Brugada syndrome. Here we reported three novel SCN5A mutations identified in patients with Brugada syndrome in Taiwan (p.I848fs, p.R965C, and p.1876insM). Their electrophysiological properties were altered by patch clamp analysis. The p.I848fs mutant generated no sodium current. The p.R965C and p.1876insM mutants produced channels with steady state inactivation shifted to a more negative potential (9.4 mV and 8.5 mV respectively), and slower recovery from inactivation. Besides, the steady state activation of p.1876insM was altered and was shifted to a more positive potential (7.69 mV). In conclusion, the SCN5A channel defect related to Brugada syndrome might be diverse but all resulted in a decrease of sodium current.

The traditional processes for designing and verifying a new device need a long time. First, the customized requirement is converted to a prototype which would be followed a series of tests to verify the specifications. Then the software system is added to the prototype and re-verify. When all functions of the system hardware and software are validated, a real test will be performed on the physical system. This study is to design a developing platform for speeding the process of building a customization apparatus in the application of physiological measurement system. The platform includes (1) a module socket together with different physiological measurement units, (2) a control system of hardware device composed of a microcontroller and a Bluetooth module, and (3) a human interface of software device as a control panel and signal display. These components have been produced and are ready to constitute different apparatus according to user’s requirement. Through the platform, it enables users to quickly construct the prototype and verify all functions of desired system with hardware and software. This study was focus on the applications of physiological measurement apparatus by the platform. A customized design of this platform has been successfully utilized in a bi-directional wireless transmission system, which was used for ECG detection and electronic stimulation in an animal experiment.

In this work, we explore the utility of a complex adaptive systems approach for studying epistasis, the nonlinear effects among genes that contribute to different disease outcomes. Due to the nonlinear interactions among the genes, data such as this is difficult to model using traditional epidemiological tools. Thus, we have developed EpiSwarm, a Swarm-based system for investigating complex genetic diseases. EpiSwarm uses genetic algorithms evolution on agents that function as condition-action rules to explain the data in their vicinity. These agents migrate and evolve as they cluster data in a two-dimensional world. Thus, EpiSwarm uses a genetic algorithms component to model genetic data. Although this system does not embody linkage learning explicitly, the goal of the system to identify genetic epistasis is an important process in linkage learning research. In EpiSwarm, the decision variables are biological genes, and identifying the epistasis is the core task.

Angiotensin II plays an important role in diastolic heart failure (DHF). However, genetic studies of DHF are scarce in the literature. We hypothesized that RAS genes might be the susceptible genes for DHF and conducted a propensity score-based case-control study to prove this hypothesis. A total of 666 subjects (285 diagnosed with DHF confirmed by echocardiography and 381 without diastolic dysfunction) were recruited. Genotyped were: the angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism; the T174M, M235T, G-6A, A-20C, G-152A and G-217A polymorphisms of the angiotensinogen (AGT) gene; and the A1166C polymorphisms of the angiotensin II type I receptor (AT1R) gene. Propensity scores (PS) were used to find patients with and without DHF with equalized characteristics. We also assembled another set of PS matched groups for all characteristics except left ventricular mass (LVM) to detect the genetic association with DHF through the effect of left ventricular hypertrophy. PS matched 210 patients with DHF to 210 without. In a single-locus analysis, the odds ratios (ORs) for DHF were significant with the ACE DD genotype (OR=1.30, 95% CI=1.13-1.49, permuted P=0.003) and the AT1R 1166 CC genotype (OR=2.61, 95% CI=1.52-4.45, permuted P

Local atrial tissue angiotensin II (AngII) level is elevated in atrial fibrillation (AF), but the mechanism is unknown. We hypothesized that atrial myocytes express all components of the renin-angiotensin system (RAS) and investigated whether rapid depolarization alone is sufficient to increase paracrine AngII production by up-regulating RAS component expression.In the HL-1 atrial cell line, rapid depolarization was induced by rapid field electrical stimulation (RES) at 1.0 V/cm and 600/min (10 Hz) in atrial HL-1 cells. In a pig model of AF, AF was induced by atrial pacing at 600/min in 10 adult pigs and 10 sham-operated pigs for comparison.In atrial myocytes, RES induced a sustained elevation of intracellular calcium, and up-regulation of angiotensin-converting enzyme (ACE), chymase and angiotensinogen, resulting in increased AngII production. RES-induced AngII production was attenuated by enalapril [ACE inhibitor (ACEI)] and chymostatin (chymase inhibitor). Conditioned medium from RES-stimulated atrial myocytes increased [3H]leucine uptake and atrial natriuretic peptide expression in atrial myocytes, and [3H]proline uptake and collagen type 1 alpha 1 expression in atrial fibroblasts. Both were attenuated by co-incubation with the AngII type 1 receptor blocker (ARB) losartan. In the porcine model, significant structural changes and a similar pattern of changes of RAS components were noted in AF pigs.Atrial cells expressed all components of RAS and rapid depolarization alone was sufficient to up-regulate RAS components, increase paracrine AngII production and induce atrial structural changes, which are attenuated by ACEI, ARB and chymase inhibitor.

Background Angiotensin II and its downstream mitogen-activated protein kinase signaling pathways are involved in the pathogenesis of AF. Pro-inflammatory JAK/STAT is another downstream signaling pathway of Angiotensin II, and its status in AF remains unknown. Objective The aim of this study was to characterize the status of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways in pacing-induced sustained atrial fibrillation (AF). Methods AF was induced by atrial pacing at 600/min in 10 adult pigs (AF group), while 10 sham-operated pigs served as the control group. Results Significant structural and inflammatory changes were noted in the AF group. Atrial tissue angiotensin II level was elevated and STAT1 and STAT3 were activated in the AF group. Nuclear translocation of activated STAT3 and binding to STAT3 consensus DNA sequence were also increased in the AF group. Rac1, the molecular target of statin, which mediates the activation of STAT3 by angiotensin II, was also activated in the AF group. The tissue levels of interleukin-6, leukemia inhibitory factor (LIF) and cardiotrophin-1 (CT-1), which are known to activate STATs through membrane gp130 and JAKs, were not increased in the AF group. Membrane gp130 and JAKs were also not activated in the AF group. Conclusion Activated angiotensin II/Rac1/STAT may be associated with or perhaps contribute to the structural and inflammatory changes in pacing-induced sustained trial fibrillation. It may further imply the therapeutic option of combination of angiotensin receptor blocker and statin.

Background— Recently, activation of the local renin-angiotensin system and mitogen-activated protein kinase pathways in atrial myocardium has been found to play an important role in atrial structural remodeling related to atrial fibrillation. Another important mediator of the angiotensin II (Ang II) effect is the Janus kinase/signal transducers and activators of transcription (STAT) pathway, which has never been characterized in the atrium. Methods and Results— In cultured atrial myocytes and fibroblasts, Ang II induced tyrosine phosphorylation of STAT3 through a Rac1-dependent mechanism, which was inhibited by dominant-negative Rac1, losartan, and simvastatin. In atrial myocytes, activation of STAT3 by Rac1 was mediated by direct association of Rac1 with STAT3; however, in atrial fibroblasts, it was mediated by an indirect paracrine effect. Constitutively active STAT3 increased protein synthesis, and dominant-negative STAT3 abrogated Ang II–induced protein synthesis in atrial myocytes and fibroblasts. Rats infused long term with Ang II exhibited higher levels of activated Rac1, phospho-STAT3, collagen synthesis, and atrial fibrosis in the atria, all of which were attenuated by oral losartan and simvastatin. In human atrial tissues from patients with atrial fibrillation, Ang II and phospho-STAT3 levels were also elevated. Conclusions— The Ang II/Rac1/STAT3 pathway is an important signaling pathway in the atrial myocardium to mediate atrial structural remodeling, and losartan and statin may be able to reverse Ang II–induced atrial structural remodeling in atrial fibrillation.

Background. Resynchronization therapy has been proven to improve exercise tolerance only in heart failure (HF) patients (pts) with profoundly impaired left ventricular ejection fraction (LVEF). Whether it could be useful to other spectrum of HF pts may depend on the existence of ventricular dyssynchrony, either at rest or exercise-induced. Methods. We studied clinical features, ECG, and echocardiography coupled with tissue Doppler imaging (TDI) in 70 pts (38 men and 32 women, mean age 62±13 years). Among them, 60 pts with compensated HF (functional class II–III) for at least 3 months were grouped into systolic HF (SHF; EF=35–50 %, N=30) and diastolic HF (DHF; EF=50 % plus diastolic dysfunction, N=30) groups. The other 10 pts had no systolic or diastolic dysfunction are the control group. Six-minutes (stage 2) treadmill exercise tests were performed for SHF pts by modified Bruce protocol and for DHF and control pts by Bruce protocol. Dyssynchrony index (DI) represented by standard deviation of electromechanical delays of 12 LV segments was measured before and immediately after exercise. Results. Except for diverse clinical features and conventional echo-parameters as expected, the QRS duration was similar (mean: 93±16 ms) between the 3 groups. TDI studies showed that baseline synchronized LV contraction remained unchanged after exercise (DI: 12.4±3.6 vs. 11.8±2.9 ms, p =ns) in control group. With regard to the DHF group, the preexisting ventricular dyssynchrony got significantly exacerbated (DI: 52.4±10.0 vs. 62.4±12.8 ms, p< 0.001) including 21 pts (70%) with a ≥ 10% increase of DI after exercise provocation. With a more complex response to exercise, the DI in SHF pts didn’t worsen significantly (27.0±19.2 vs. 32.8±20.6 ms, p< 0.06). However, the proportion of DI>33 ms, considered as presence of dyssynchrony, increased from 37% at baseline to 50% after exercise, including 6 pts (20%) with post-exercise new development and 2 pts (7%) with post-exercise disappearance of ventricular dyssynchrony. Conclusions. Exercise-exacerbated ventricular dyssynchrony in DHF pts, and a 50% incidence of post-exercise dyssynchrony in SHF pts with LVEF between 35 to 50% may support the potential utility of resynchronization therapy to these non-indicated HF groups.

BACKGROUND. Enlarged left atrial volume (LAV), resulting from multifactorial pathogenesis, carries a poorer prognosis to patients with atrial fibrillation (AF) even under well rhythm control. We hypothesized that the preexistence of intra-left ventricular (LV) contractile dyssynchrony impaired diastolic filling, which contribute to atrial remodeling in AF patients. METHODS. We investigated 40 patients (34 men and 6 women, mean age 60 ± 10 years) with paroxysmal or persistent AF who were converted mainly by catheter ablation-based circumferential pulmonary venous isolation and then pharmacologically maintained in sinus rhythm. Exclusion criteria included significant (>moderate) valvular heart disease, LV ejection fraction M ) and the time to peak S M (T S ) of the 6-basal and 6-mid LV segments were measured by tissue Doppler imaging (TDI). RESULTS. With similar AF duration before conversion, patients with LAV >40ml (n = 16) had similar baseline characteristics, cardiovascular medications, QRS width, and LV chamber sizes as those with LAV M was borderline lower (6.3 ± 1.2 vs. 7.1 ± 1.2 cm/s, p < 0.05), and the maximal intersegmental difference in T S (77 ± 43 vs. 40 ± 22 ms, p < 0.003) was greater in patients with larger LAV. The intersegmental difference in T S correlated positively with LAV (r = 0.41, p < 0.009), and LV filling pressure estimated by early transmitral flow velocity/annular diastolic velocity was significantly higher (12.3 ± 7.8 vs. 8.7 ± 2.2, p < 0.045) in patients with intersegmental difference in T S >65 ms. After adjusting for age, gender, and the diastolic parameters, intersegmental difference in T S >65ms emerged as an independent determinant of larger LAV in multivariate logistic analysis (OR=17; 95% CI=2–166, p < 0.016). CONCLUSIONS. Intraventricular dyssynchrony, which accompanied with elevated LV filling pressure, contributed independently to LA remodeling in AF patients converted into sinus rhythm by catheter ablation.

Many genetic diseases are not caused by the effects of a single gene, but rather, are due to multiple genes acting in concert. For complex diseases, looking at the effect of variation in a single gene may predict one disease outcome, while looking at the interactions of genetic variations across multiple genes gives us a richer understanding of the risk of disease, and may predict different outcomes. EpiSwarm is designed to model genetic epistasis (nonlinear effects among genes) using the swarm system. EpiSwarm rule agents act both as rules to explain epistatic phenomena as well as the machinery to organize the data into clusters of similar etiologies. The preliminary results reported here indicate that the system is a promising approach for visualizing and understanding clusters of disease outcomes for complex genetic diseases.

Objective: Debates about adverse effects of ventricular- vs. atrial-based pacing have never ended, especially regarding cardiovascular outcomes in common pacemaker populations. Methods: To investigate the contribution of right ventricular apical pacing to the left ventricular negative remodeling, we measured the inter- and intraventricular mechanical dyssynchrony by echocardiography as well as plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) level in 116 consecutive patients of symptomatic bradyarrhythmias including sinus node dysfunction (SND) in 80 and atrioventricular block in 36. Dual-chamber rate-modulated pacing (DDDR) pacemakers were implanted in 76 patients (SND, 40), and single-chamber ventricular rate-modulated pacing (AAIR) pacemakers in 40 (all SND). Clinical manifestations were retrospectively correlated. Results: After 3.5 years of pacing, DDDR pacemaker patients demonstrated higher plasma NT-proBNP concentration (503 ± 111 pg/ml) than AAIR patients (194 ± 42 pg/ml, p = 0.002) despite similar cardiovascular function at baseline. Multivariate regression analysis revealed that the only predictor of the highest quartile of plasma NT-proBNP, i.e. ≧386 pg/ml, was the interventricular contraction time difference (p = 0.01). Reprograming to minimize ventricular pacing percentage in 8 patients of SND caused parallel reduction of plasma NT-proBNP. Conclusion: Interventricular mechanical dyssynchrony, imposed mostly by right ventricular apical pacing, could lead to abnormal heightening of plasma NT-proBNP concentration after chronic DDDR pacing in common pacemaker patients with normal baseline left ventricular function.

Supplemental Digital Content is available in the text, 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.

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

Objectives: To test the association between renin-angiotensin system gene variants and atrial fibrillation (AF) using a regression approach. Methods: A total of 1,236 consecutive patients (227 with AF and 1,009 with normal sinus rhythm as controls) were recruited. Angiotensin-converting enzyme (ACE) gene I/D polymorphism; T174M, M235T, G–6A, A–20C, G–152A and G–217A polymorphisms of the angiotensinogen (AGT) gene, and A1166C polymorphism of the angiotensin II type I receptor (AT1R) gene were genotyped. We used a regression approach based on a generalized linear model to evaluate haplotype effects and to detect gene-gene interactions by incorporating interaction terms in the model. Results: In single-locus analyses, no locus was associated with AF. After adjustment for AF risk factors, we found significant differences in the global AGT gene haplotype profile (the global score statistic = 30.364, p = 0.001) and individual haplotype frequencies between AF patients and controls. Furthermore, significant 2-way gene-gene interactions between ACE I/D polymorphism and AGT gene haplotypes and between AT1R A1166C polymorphism and AGT gene haplotypes, and 3-way interaction between ACE I/D, AT1R A1166C and AGT gene haplotypes were detected. Conclusions: These results are compatible with the concept of multilocus and multigene effects in determining the risk of complex diseases such as AF, which would be missed with conventional single-locus approaches.

Patients with heart failure (HF) and a normal left ventricular ejection fraction usually present with diastolic dysfunction (DD). Whether intraleft ventricular contractile dyssynchrony (IVCD) coexists with DD and contributes to the clinical manifestations of HF remains unclear. The study investigated the IVCD at rest and after exercise in hypertensive patients with diastolic HF (DHF).Echocardiography was performed in 60 hypertensive patients with narrow QRS, left ventricular ejection fractionor = 50%, and no active ischemia. Patients were grouped as having DD (mitral E/A1 plus E deceleration time200 milliseconds, or mitral annular early diastolic velocity8 cm/s; n = 26), DD plus HF symptoms/signs (DHF, n = 13), or as non-DD (n = 21).At rest, the IVCD index (SD of 12 left ventricular segmental electromechanical delays) was greater in the DHF and DD groups than that in the non-DD group (52.2 +/- 10.7 and 39.1 +/- 23.6 vs 23.1 +/- 19.9 milliseconds; P.05 for both comparisons). Six-minute treadmill exercise induced exacerbation of dyssynchrony in the DHF group (67.0 +/- 12.9 vs 52.2 +/- 10.7 milliseconds; P.001). Multivariate analysis revealed that the combination of IVCD indexor = 35 milliseconds at rest andor = 50 milliseconds after exercise was independently associated with DHF (odds ratio = 20, 95% CI = 2-199, P = .009). Postexercise IVCD index correlated positively with plasma N-terminal pro-brain natriuretic peptide (r = 0.37, P = .004).Exercise would aggravate intraventricular dyssynchrony in hypertensive patients with DHF, implicating a potential contribution of systolic dyssynchrony to clinical manifestations.

There have been many reports regarding the association between renin-angiotensin system (RAS) gene polymorphisms and coronary artery disease (CAD) or acute myocardial infarction (AMI), but the results are inconsistent. In the present study, we used several new approaches with multilocus data to reappraise this issue in a large and relatively homogeneous Taiwanese population. A total of 1254 consecutive patients who underwent cardiac catheterization (735 with documented coronary artery disease and 519 without) between 1996 and 2003 were recruited. Angiotensin-converting enzyme gene insertion/deletion (I/D) polymorphism; T174M, M235T, G-6A, A-20C, G-152A and G-217A polymorphisms of the angiotensinogen gene; and A1166C polymorphism of the angiotensin II type I receptor gene were genotyped. In single-locus analyses, no locus was associated with CAD, history of AMI and three-vessel CAD, either with or without adjustment for conventional CAD risk factors. For multilocus analyses, we recreated a balanced population, with the controls individually matched to the cases regarding the conventional CAD risk factors. We found that the angiotensinogen gene haplotype profile was significantly different between the cases and controls (chi2=31.6, P=0.030) in haplotype analyses. Furthermore, significant three-locus (G-217A, M235T and I/D) gene-gene interactions were detected by multifactor-dimensionality reduction method (highest cross-validation consistency 10.0, lowest prediction error 40.56%, P=0.017) and many even higher order gene-gene interactions by multilocus genotype disequilibrium tests (16 genotype disequilibria exclusively found in the controls, all of which included at least two genes among AGT, ACE and AT1R genes). Our study is the first to demonstrate epistatic, high-order, gene-gene interactions between RAS gene polymorphisms and CAD. These results are compatible with the concept of multilocus and multi-gene effects in complex diseases that would be missed with conventional approaches.

Background: TheI823M polymorphism of the ATP-binding cassette transporter A1 (ABCA1) gene has been reported to affect plasmahigh-density lipoprotein cholesterol (HDL-C) level. Information about its relationship to coronary artery disease (CAD) is limited. Methods and Results: We included 205 patients with angiographically documented CAD and 201 controls from the general population. We found thatI823M polymorphism was a significant source of variation of HDL-C (p = 0.024 after adjustment for age, sex, body mass index, smoking and alcohol drinking). Subjects with M823/M823 homozygotes (n = 103) had a higher HDL-C than those with I823/I823 or I823/M823 genotype (n = 98) (50.5 ± 9.7 vs. 47.6 ± 10.1 mg/dl, p = 0.039). I823M polymorphism was not a predictor of CAD in multivariate analysis (adjusted odds ratio = 1.5 [0.9–2.5], p = 0.145). However, it interacted with low HDL-C level to increase the risk of CAD. The odds ratio of CAD with M823 homozygosity was 5.3 (2.0–20.0) in patients with HDL-C ≤35 mg/dl, but was only 1.0 (0.5–2.0) in those with HDL >40 mg/dl (p = 0.039 for interaction). Conclusions: M823 variant of the ABCA1 gene was associated with a higher HDL-C. Furthermore, I823M polymorphism interacted with low-HDL-C on the risk of CAD. It served as a marker to identify high-risk patients for CAD in subjects with low-HDL-C.

There is evidence showing that genetic factors contribute to the pathogenesis of atrial fibrillation (Af). We investigated the association between Af and polymorphisms of the connexin 40 (Cx40) gene, which is important in the electrical coupling between atrial myocytes.We performed an association study between two Cx40 single nucleotide polymorphisms (SNPs) (Cx40 -44 and +71 allele) and Af. We enrolled 173 patients with Af, and the control group consisted of 232 patients without Af. The luciferase assay was performed to evaluate the promoter activities of different Cx40 haplotypes in cultured atrial myocytes.We found that the two SNPs were both significantly associated with Af. In pairwise linkage disequilibrium analysis, the two SNPs were completely linked (Cx40 -44G always associated with Cx40 +71A; Cx40 -44A associated with Cx40 +71G, P0.001). In haplotype analysis, we demonstrated that the frequency of Cx40 (-44A,+71G) was significantly higher in the Af group than that in the control group (P0.006, odds ratio=1.514, 95% confidence interval 1.13-2.04). We also performed genotype analysis using several genetic models, finding that the recessive model showed the lowest P value (P0.004) and the largest odds ratio (2.53, 95% confidence interval 1.23-5.19). In promoter activity studies using luciferase as the reporter, Cx40 (-44A,+71G) had significantly lower promoter activity than that of the Cx40 (-44G,+71A) in atrial myocytes.The two SNPs in the promoter region of the Cx40 gene were significantly associated with Af. The Cx40 (-44A +71G) haplotype was associated with a higher risk for Af. This haplotype also had significantly lower promoter activity in atrial myocytes.

Little information about the ICD is available from the Asian Pacific region. The purpose of this study was to characterize the clinical features in ICD patients in Taiwan and to compare these features with those in patients in the Western populations, mainly the Canadian Implantable Defibrillator Study (CIDS), the Antiarrhythmics versus Implantable Defibrillator (AVID) trial, and the Cardiac Arrest Study Hamburg (CASH) trial. From February 1995 to October 2001, 101 ICDs were implanted in 92 patients (78 [84%] men) in 12 hospitals. Clinical presentations included sudden cardiac death due to VF/VT in 35 (38%) patients, syncopal VT in 25 (27%), drug refractory nonsyncopal VT in 27 (29%), and unexplained syncope with inducible sustained VT/VF in 5 (6%). The mean age was significantly younger than that in CIDS or AVID (59 +/- 16 vs 63 +/- 9 years in CIDS, P = 0.02; vs 65 +/- 11 years in AVID, P < 0.001), but was comparable to that in CASH (59 +/- 16 vs 58 +/- 11 years in CASH, P = 0.75). The mean LVEF was significantly higher than that in CIDS or AVID (48 +/- 19% vs 34 +/- 15% in CIDS, P < 0.001; vs 32 +/- 13% in AVID, P < 0.001), but was comparable to that in CASH (48 +/- 19 vs 46 +/- 19% in CIDS, P = 0.83). The ICD patients in the current study also showed a higher incidence of normal heart (23 vs 4% in CIDS, P < 0.001; vs 3% in AVID, P < 0.001; vs 9% in CASH, P < 0.001) and cardiomyopathy (41% vs 10% in CIDS, P < 0.001; vs 15% in AVID, P < 0.001; vs 11% in CASH, P < 0.001), but a lower incidence of coronary artery disease (29% vs 83% in CIDS, P < 0.001; vs 82% in AVID, P < 0.001; vs 73% in CASH, P < 0.001). During a mean follow-up of 28 +/- 24 months, 13 (14%) patients died. Older age was the only factor associated with poorer survival after ICD implantation. Forty-seven (51%) patients received appropriate ICD discharges during follow-up. History of prior myocardial infarction was the only factor associated with an earlier first appropriate ICD discharge and LVEF < 0.35 the only factor associated with subsequent poorer survival after the first ICD discharge. In conclusion, this study demonstrated many distinct clinical features in our ICD population that were different from those in the Western populations.

There are many reports demonstrating the association of renin-angiotensin system gene polymorphisms with hypertension in different populations. In the present study, we used haplotype analyses of the angiotensinogen gene with a new permutation-based hypothesis testing method to determine the association between multilocus angiotensinogen gene polymorphisms and hypertension in a relatively homogeneous Taiwanese population. We also genotyped angiotensin-converting enzyme gene insertion/deletion polymorphism and angiotensin II type 1–receptor gene A1166C polymorphism to detect epistatic gene-gene interactions. There were 408 patients with hypertension (hypertensives) and 286 controls. The angiotensinogen gene haplotype frequencies were significantly different between hypertensives and controls, and this finding was only present in subjects with angiotensin-converting enzyme gene II genotypes when the analysis was stratified by genotype of this polymorphism. In addition, the angiotensinogen gene haplotype structure of hypertensives was more heterogeneous than that of controls. Our results showed that angiotensinogen gene haplotypes were associated with hypertension and might act synergistically with I allele of the angiotensin-converting enzyme gene.

We studied whether the 27 base pair (bp) tandem repeat polymorphism in intron 4 of the endothelial nitric oxide synthase (eNOS) gene was associated with coronary artery disease (CAD) in a hospital-based Taiwanese population. We included 219 consecutive patients who underwent coronary angiography at our institution. Two alleles, containing 4 (eNOS4a) and 5 repeats (eNOS4b), were identified after polymerase chain reaction amplifying intron 4 of the eNOS gene. The genotype frequencies for eNOS4b/b, eNOS4a/b and eNOS4a/a were 77.9, 21.5 and 0.6% in CAD subjects, and 80, 20 and 0% in control subjects (Fisher’s exact test, p = 0.90), respectively. The odds ratio (OR) for CAD in patients with at least one eNOSa allele was 1.2 (0.5–2.9) after adjustment for classical CAD risk factors. The eNOS4a allele was not associated with the severity of CAD (Fisher’s exact test, p = 0.90) and the occurrence of acute myocardial infarction (AMI) or unstable angina (adjusted OR 0.6, 0.3–1.6) in patients with CAD. In conclusion, the 27-bp repeat polymorphism of the eNOS gene was not associated with CAD and the occurrence of AMI or unstable angina in a hospital-based Taiwanese population.