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Peripheral arterial disease (PAD) is an inflammatory process. The association between white blood cell (WBC) count and PAD in those with and without traditional risk factors is not clear. We examined data from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004. A total of 5260 participants were included. The result showed that the prevalence of PAD rose from 2.8% +/- 0.5% in the lowest quartile of plasma WBC count to 8.0% +/- 1.2% in the highest quartile. In subgroup analysis, the graded association between WBC count and PAD was significant in patients without hypertension, diabetes, smoking, chronic kidney disease (CKD), and in patients with or without hypercholesterolemia but not significant in patients with hypertension, smoking, diabetes, or CKD. In those without hypertension, diabetes, smoking, or CKD, the cutoff value for WBC count was 6.75 x 10(9)/L. We concluded that the positive association between WBC count and PAD can be demonstrated in this national survey.

Objectives: This 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)., Background: The role of mineralocorticoid in the pathogenesis of AF is unknown., Methods: We 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., Results: We 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., Conclusions: Expression 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., (Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Controversies exist regarding the indications for unicompartmental knee arthroplasty. The objective of this study is to report the mid-term results and examine predictors of failure in a metal-backed unicompartmental knee arthroplasty design., Methods: At a mean follow-up of 60 months, 80 medial unicompartmental knee arthroplasties (68 patients) were evaluated. Implant survivorship was analyzed using Kaplan-Meier method. The Knee Society objective and functional scores and radiographic characteristics were compared before surgery and at final follow-up. A Cox proportional hazard model was used to examine the association of patient's age, gender, obesity (body mass index > 30 kg/m2), diagnosis, Knee Society scores and patella arthrosis with failure., Results: There were 9 failures during the follow up. The mean Knee Society objective and functional scores were respectively 49 and 48 points preoperatively and 95 and 92 points postoperatively. The survival rate was 92% at 5 years and 84% at 10 years. The mean age was younger in the failure group than the non-failure group (p < 0.01). However, none of the factors assessed was independently associated with failure based on the results from the Cox proportional hazard model., Conclusion: Gender, pre-operative diagnosis, preoperative objective and functional scores and patellar osteophytes were not independent predictors of failure of unicompartmental knee implants, although high body mass index trended toward significance. The findings suggest that the standard criteria for UKA may be expanded without compromising the outcomes, although caution may be warranted in patients with very high body mass index pending additional data to confirm our results., Level of Evidence: IV.

Patients with spastic quadriplegia secondary to cerebral palsy manifest with severe spasticity and often with neuromuscular scoliosis. In order to optimize treatment and minimize morbidity in selected cases, the authors present a surgical option concurrently addressing these problems. This study reviews one case and describes the surgical technique in detail where intrathecal baclofen pump implantation and posterior spinal fusion are concomitantly performed to manage spasticity and scoliosis, respectively.

Brugada syndrome is a life-threatening, inherited arrhythmia disorder associated with autosomal dominant mutations in SCN5A, the gene encoding the human cardiac Na+ channel alpha subunit (Nav1.5). Here, we characterized the biophysical properties of a novel Brugada syndrome-associated Nav1.5 mutation, A551T, identified in a proband who was successfully resuscitated from an episode of ventricular fibrillation with sudden collapse. Whole-cell currents through wild-type (WT) Nav1.5 and mutant (A551T) channels were recorded and compared in the human embryonic kidney cell line HEK293T transfected with SCN5A cDNA and SCN1B cDNA, using the patch-clamp technique. Current density was decreased in the A551T mutant compared to the WT. In addition, the A551T mutation reduced Nav1.5 activity by promoting entry of the channel into fast inactivation from the closed state, thereby shifting the steady-state inactivation curve by -5 mV. Furthermore, when evaluated at -90 mV, the resting membrane potential, but not at the conventionally used -120 mV, both the percentage, and rate, of channel recovery from inactivation were reduced in the mutant. These results suggest that the DI-DII linker may be involved in the stability of inactivation gating process. This study supports the notion that a reduction in Nav1.5 channel function is involved in the pathogenesis of Brugada syndrome. The structural-functional study of the Nav1.5 channel advances our understanding of its pathophysiolgocial function.

Parathyroid hormone (PTH) regulation of mitogen-activated protein kinases (MAPK) ERK1/2 contributes to PTH regulation of osteoblast growth and apoptosis. We investigated the mechanisms by which PTH inhibits ERK1/2 activity in osteoblastic UMR 106-01 cells. Treatment with PTH significantly inhibited phosphorylated ERK1/2 between 5 and 60 min. Transient transfection of cells with a cDNA encoding MAPK phosphatase-1 (MKP-1) resulted in 30-40% inhibition of pERK1/2; however MKP-1 protein levels were only significantly stimulated by PTH after 30 mins, suggesting another mechanism for the early phase of pERK1/2 inhibition. The active upstream kinase c-Raf phosphorylation at serine 338 (ser(338)) was significantly inhibited by PTH treatment within 5 min and transfection of the cells with constitutively-active c-Raf blocked PTH inhibition of pERK1/2. Inhibition of pERK1/2 and phosphor-c-Raf were seen when cells were treated with PTH(1-34) or PTH(1-31) analogues that stimulate cAMP, but not with PTH(3-34), PTH(7-34) or PTH(18-48) that do not stimulate cAMP. Stimulation of the cells with forskolin or 8BrcAMP also inhibited pERK1/2 and c-Raf.p338. Our results suggest that rapid PTH inhibition of ERK1/2 activity is mediated by PKA dependent inhibition of c-Raf activity and that stimulation of MKP-1 may contribute to maintaining pERK1/2 inhibition over prolonged time., ((c) 2009 John Wiley & Sons, Ltd.)

Background and Purpose: Piceatannol is more potent than resveratrol in free radical scavenging in association with antiarrhythmic and cardioprotective activities in ischaemic-reperfused rat hearts. The present study aimed to investigate the antiarrhythmic efficacy and the underlying ionic mechanisms of piceatannol in rat hearts., Experimental Approach: Action potentials and membrane currents were recorded by the whole-cell patch clamp techniques. Fluo-3 fluorimetry was used to measure cellular Ca2+ transients. Antiarrhythmic activity was examined from isolated Langendorff-perfused rat hearts., Key Results: In rat ventricular cells, piceatannol (3-30 micromol.L(-1)) prolonged the action potential durations (APDs) and decreased the maximal rate of upstroke (V(max)) without altering Ca2+ transients. Piceatannol decreased peak I(Na) and slowed I(Na) inactivation, rather than induced a persistent non-inactivating current, which could be reverted by lidocaine. Resveratrol (100 micromol.L(-1)) decreased peak I(Na) without slowing I(Na) inactivation. The inhibition of peak I(Na) or V(max) was associated with a negative shift of the voltage-dependent steady-state I(Na) inactivation curve without altering the activation threshold. At the concentrations more than 30 micromol.L(-1), piceatannol could inhibit I(Ca,L), I(to), I(Kr), Ca2+ transients and Na+-Ca2+ exchange except I(K1). Piceatannol (1-10 micromol.L(-1)) exerted antiarrhythmic activity in isolated rat hearts subjected to ischaemia-reperfusion injury., Conclusions and Implications: The additional hydroxyl group on resveratrol makes piceatannol possessing more potent in I(Na) inhibition and uniquely slowing I(Na) inactivation, which may contribute to its antiarrhythmic actions at low concentrations less than 10 micromol.L(-1).

Ebstein's anomaly is a rare, congenital cardiac anomaly that may result in cyanosis, right heart failure, and tachyarrhythmia during the newborn stage or after adolescence. This study investigated the data of 77 patients diagnosed between 1980 and 2006 at a tertiary care center in Taiwan. Patients were grouped into either an early group or a late group. Survival declined rapidly within the newborn stage in the early group, but declined only during the third decade in the late group. Surgical results were poor (20% success rate) for neonatal systemic-to-pulmonary shunts in those cases with associated pulmonary atresia, but were satisfactory for other surgical modes. Supraventricular tachyarrhythmia occurred in 31 (41%) patients at a median age of 10 years and could be eliminated by radiofrequency ablation (81% success rate), though the recurrence rate was high (41%). In conclusion, other than those cases requiring shunts at the newborn stage, the long-term outcome was favorable.

Background: Many patients with chordae tendineae rupture (CTR) of the mitral valve have obscure aetiologies. The association between pre-existing hypertension and idiopathic CTR was investigated., Methods: 494 patients with CTR were identified by searching the computer database. For each patient with idiopathic CTR, three matched controls without CTR who were admitted to the same hospital for bone fractures were included., Results: Among the 494 patients with CTR, 351 patients (71%) had idiopathic CTR, and 143 patients (29%) had secondary CTR. The prevalence of pre-existing hypertension was significantly higher in the idiopathic than in the secondary CTR group (50.9% vs 14.6%, p<0.001). The odds ratio was 6.0 (95% CI 3.6 to 10.1). The percentage of patients without adequate blood pressure control was also higher in the idiopathic than in the secondary CTR group (23.1% vs 4.9%, p<0.001). When compared with the fracture group, patients with idiopathic CTR also had a significantly higher prevalence of hypertension (50.9% vs 14.9%, p<0.001), and the odds ratio was 5.9 (95% CI 4.5 to 7.8). After correction for age, the odds ratio of having hypertension was 3.6 (95% CI 2.1 to 6.3) and 6.6 (p<0.001, 95% CI 5.0 to 8.8) when compared with the secondary CTR group and fracture group respectively., Conclusions: There is a strong association between pre-existing hypertension and idiopathic CTR. Whether or not this disease can be prevented by controlling hypertension deserves further investigation.

Background: Metformin has been reported to reduce cardiovascular complications in diabetic patients. The purpose of the present study was to investigate the anti-inflammatory effects of metformin on endothelial cells and the related molecular mechanisms., Methods: Human umbilical vein endothelial cells (HUVEC) were used for the experiments. The effects of metformin on TNF-alpha-induced IL-6 production were investigated. Modulation of AMPK and related signal transduction pathways were also performed., Results: TNF-alpha increased IL-6 secretion by HUVEC in a dose-dependent manner but inhibitors of NF-kappaB abolished the TNF-alpha-induced IL-6 production. Pre-treatment with metformin (100-1000 micromol/L) also inhibited TNF-alpha-induced IL-6 production, phosphorylation of IkappaB kinase (IKK) alpha/beta and IkappaB-alpha degradation. Metformin increased phosphorylation of AMP-activated kinase (AMPK) but wortmannin, a PI3K inhibitor, negated its effects on AMPK phosphorylation and TNF-alpha-induced IkappaB-alpha degradation. AICAR, a direct AMPK activator, had inhibitory effects on TNF-alpha-induced IL-6 production, similar to that of metformin. Transfection of siRNA against alpha1-AMPK eradicated the inhibitory effects of metformin on TNF-alpha-induced IL-6, implying the essential role of AMPK., Conclusions: Metformin had anti-inflammatory effects on endothelial cells and inhibited TNF-alpha-induced IKKalpha/beta phosphorylation, IkappaB-alpha degradation and IL-6 production in HUVEC. This effect was related to PI3K-dependent AMPK phosphorylation.

Adipose tissue is now accepted by the scientific and medical community to be a genuine endocrine organ, in addition to its classical role as an energy store. Adiponectin is one of the many adipocytokines that are secreted almost exclusively by adipose tissue. Alteration in blood adiponectin concentrations has been linked to many human diseases in numerous cross-sectional and prospective studies. In this review, we describe briefly the biological effects of adiponectin as revealed by basic scientific investigations. We also summarize the principles of blood adiponectin assays. Overall, lower blood adiponectin concentration is found in subjects with obesity, type 2 diabetes mellitus, dyslipidemia, and hypertension. These medical conditions are components of the metabolic syndrome and major risk factors for accelerated atherosclerosis. Plasma adiponectin levels are also expected to be lower in subjects with cardiovascular diseases, such as coronary artery disease, ischemic stroke and peripheral artery disease. Congestive heart failure (CHF) and cardiac arrhythmia are common end points in cardiovascular diseases. Surprisingly, higher blood adiponectin levels are frequently reported to predict mortality associated with CHF. Few human data regarding adiponectin and cardiac arrhythmia are available. Higher blood adiponectin level has been documented only in atrial fibrillation. We also summarize data on the role of the high molecular weight (HMW) isoforms of adiponectin and the effects of clinical treatment on the levels of total or HMW adiponectin. Whether adiponectin is a risk marker or a risk factor for the diseases reviewed in this article, and in many other human diseases, and their detailed pathogenic links awaits further investigation.

Objective: Bilirubin is a potent antioxidant and a cyroprotectant. Low serum bilirubin is associated with atherosclerosis. Little is known about its role in metabolic syndrome (MS) among children and adolescents., Methods: We examined 4723 children and adolescents aged 12-17 years with reliable measures of various serum hepatic profiles and metabolic risks from Health and Nutrition Examination Survey 1999-2004., Results: The results showed that the prevalence of the MS was from 6.6+/-1.2% in the lowest quartile to 2.1+/-1.9% in the highest quartile of the concentration of total bilirubin. The graded association remained significant after the adjustment of other co-variates. The odds ratios for the MS were around 0.29 (0.08-0.99) and 0.23 (0.08-0.65) for the upper two quartiles when using the lowest quartile as reference for the concentration of total bilirubin. The quartiles of the serum total bilirubin levels were inversely correlated with the homeostasis model assessment (HOMA-IR) and insulin while not associated with the serum C-reactive protein (CRP) levels., Conclusions: The serum total bilirubin levels are inversely correlated with the prevalence of the MS. The mechanism of the association between MS and total bilirubin may be related to the insulin resistance status.

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.-762T>C, and a synonymous polymorphism, g.1679C>G, were common (34 and 36%, respectively). These two polymorphisms were highly linked (D' value=0.7459, P-value <0.00001). For the g.-762T>C 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, P<0.05). 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-value <0.05, 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.

This study examined the seasonal birth patterns of patients with cerebral palsy (CP) in North Carolina. Data regarding live births in North Carolina were obtained for years 1980 to 2002 from the National Center for Health Statistics. Data from a pediatric orthopaedic multidisciplinary cerebral palsy clinical database at a regional medical center were weighted against the live births data. The results showed that despite slight fluctuations throughout the year, there was no significant difference between the actual monthly distribution of CP births and the expected monthly distribution (p = .68). There was no significant difference between the actual and expected seasonal distributions for overall CP births (p = .40). In conclusion, the monthly and seasonal distributions of cerebral palsy births are similar to those of live births in North Carolina. This study failed to identify any seasonal birth patterns specific for cerebral palsy.

There is increasing evidence suggesting the importance of evaluating gene-environment interactions in the genetic study of coronary artery disease (CAD). We investigated the association of multiple single nucleotide polymorphisms in the angiotensinogen (AGT) gene with CAD, considering the interaction between the genetic and non-genetic factors, using a larger and ethnically homogeneous angiographic cohort. A total of 1254 consecutive patients who underwent cardiac catheterization (735 with CAD and 519 without) were recruited. T174M (rs4762), M235T (rs699), G-6A, A-20C, G-152A, and G-217A polymorphisms of the AGT gene were genotyped. We used a regression approach based on a generalized linear model to evaluate haplotype effects defined by the multilocus data and detection of gene-environment interaction by incorporating interaction terms in the model. We found significant differences in global AGT gene haplotype profile between patients with and without CAD (the global score statistic=25.411, P=0.008). Significant interactions between AGT gene haplotypes, gender and hypertension were detected. We also used haplotype counting to directly estimate the odds ratio of each AGT gene haplotype, and found that the effects of haplotypes were markedly different in subgroups defined by gender and hypertension, providing strong evidence of gene-environment interaction. Female gender synergistically enhances (or male gender reverses) the effects of AGT gene haplotypes on the risk of CAD in the presence of hypertension. In conclusion, the effect of AGT gene haplotypes on the risk of CAD was significantly increased in women with hypertension, which highlights the importance of evaluating gene-environment interactions in the genetic study of CAD.

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.

In recent years, metal-on-metal hip resurfacing has become an increasingly popular treatment for patients needing hip arthroplasty. Important factors to consider for a successful outcome include proper patient selection and surgical technique, including approach, component positioning, and cementing technique. This review will serve as guide to both those who are learning the technique of hip resurfacing and to more experienced surgeons.

Remodeling of atrial extracellular matrix (ECM) in atrial fibrillation (AF) involves changes in the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs). The contributions of MMPs and TIMPs to the pathogenesis of AF development have not been clearly defined. This study evaluated the in situ activity and expression of gelatinases (MMP-2 and MMP-9) and their relationship with TIMP-1 or TIMP-3 in atria undergoing rapid atrial pacing for the induction of AF (4 weeks' pacing followed by 2 weeks of maintained AF) in pigs. In AF atria, in situ gelatinase activity was mainly localized in the interstitium of atrial myocardium, and was significantly larger than that of sinus rhythm control (i.e., sham control). The significant increase of MMP-9 in its pro-form and mRNA level, but not MMP-2, was shown to be responsible for the increased gelatinase activity in atria with AF. The inhibitory activities of glycosylated TIMP-1 and TIMP-3, but not TIMP-2, in AF tissues were markedly elevated and also localized in the atrial interstitium. TIMP-1 was found to be mostly colocalized with gelatinase activity over the AF tissues, implying the coexistence of gelatinase activity and TIMP-1, but TIMP-3 appeared only partially colocalized and discontinued the gelatinase activity surrounding the cardiomyocytes. TIMP-1 and TIMP-3 may play differential roles in the inhibition of gelatinase activity in vivo. Together with the survey of several MMPs transcripts and the level of transforming growth factor-beta1 (TGF-beta1), we proposed that the increased activity of gelatinase (i.e., MMP-9), TIMP-1 and TIMP-3 and their interaction may contribute to atrial ECM remodeling of AF.

Background: Diastolic heart failure (DHF) refers to an abnormality of diastolic distensibility, filling or relaxation of the left ventricle. The genetic study of DHF is scarce in the literature. The association of renin-angiotensin system (RAS) and DHF are well known. We hypothesized that RAS genes might be the susceptible genes for DHF and conducted a case-control study to prove the hypothesis., Materials and Methods: A total of 1452 consecutive patients were analysed and 148 patients with a diagnosis of DHF confirmed by echocardiography were recruited. We had two control populations. The first controls consisted of 286 normal subjects while the second were 148 matched controls selected on a 1-to-1 basis by age, sex, hypertension, diabetes and medication use. The angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism; multilocus polymorphisms of the angiotensinogen gene; and the A1166C polymorphisms of the angiotensin II type I receptor (AT(1)R) gene were genotyped., Results: In a single-locus analysis, the odds ratios (ORs) for DHF were significant with the ACE DD genotype and the AT(1)R 1166 CC plus AC genotype. In addition, the concomitant presence of ACE DD and AT(1)R 1166 CC/AC genotypes synergistically increased the predisposition to DHF., Conclusions: Genetic variants in the RAS genes may determine an individual's risk to develop DHF. There is also a synergistic gene-gene interaction between the RAS genes in the development of DHF.

One of the most common complications after total hip arthroplasty is instability. This study reviewed the recent literature concerning the indications, contraindications, and results of recent studies using both constrained liners and large femoral heads to treat instability after total hip arthroplasty. We also report on the results of a series of 41 patients (52 hips) considered being at high risk for dislocation who were treated with large-diameter metal-on-metal bearings and who were compared with a matched group of hips treated with standard-size metal-on-polyethylene bearings. The large-diameter femoral head group had no dislocations at a minimum follow-up of 24 months, whereas the standard-size group had 2 dislocations. We support the use of large femoral heads to treat instability in a wide variety of patients because of the increased stability, decreased wear of modern metal-on-metal designs, increased range of motion, and variety of revision options.

Mutations of the KCNH2 with decreased channel activity lead to congenital long QT syndrome (LQTS). We studied the electrophysiological, glycosylation, trafficking and assembly properties of three novel KCNH2 mutations identified in Taiwanese patients with LQTS (p.N633D, p.R744fs, and p.P923fs). When expressed in HEK293T cells, p.N633D and p.R744fs HERG channels displayed no HERG current while p.P923fs HERG channel showed HERG current with significantly lower (34%) current density and faster inactivation kinetics. In Western blot analysis, pR744fs was the only one with glycosylation defect, which was in consistence with the confocal microscopic findings showing that p.R744fs-GFP was the only one with trafficking defect. However, p.R744fs-GFP differed from pR744fs in being fully glycosylated while p.R744fs fusion with GFP at the N-terminus revealed glycosylation defect. To access the assembly capacity of each mutant, co-immunoprecipitation was conducted. Wild type (WT), p.N633D, and p.P923fs HERG protein showed assembly ability while p.R744fs failed to assemble with neither WT nor itself. In conclusion, we identified three novel LQTS-related KCNH2 mutations and each had a distinct mechanism of channel defect. For p.R744fs mutant, adding GFP to the C-terminus rescued the glycosylation defect but the channel was still assembly defective indicating a dissociation between glycosylation and assembly defects.

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: This study was designed to evaluate the joint effects of plasma C-reactive protein (CRP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) vs coronary angiographic severity on cardiovascular risk stratification., Methods and Results: A total of 345 patients with stable coronary artery disease (CAD) were recruited after successful percutaneous coronary intervention (PCI). Endpoints were major adverse cardiovascular events (MACE) and cumulative clinical restenosis rate after 18-36-month follow-up. Plasma NT-proBNP and CRP levels were among the strongest predictors of MACE. Adjusted hazard ratios of MACE according to combined biomarkers were 2.4 (p=0.05) for elevated CRP only, 5.22 (p<0.001) for elevated NT-proBNP only, and 7.04 (p<0.001) for elevation of both. The differential capacity using both plasma CRP and NT-proBNP in a receiver-operating-characteristics curve analysis (area under curve, AUC: 0.82) was significantly higher than using either biomarker alone or conventional risk factors (AUC: 0.67). Significant predictors of clinical restenosis were plasma NT-proBNP and the Gensini score. The combination of NT-proBNP and the Gensini score was the strongest predictor (AUC: 0.77) for clinical restenosis., Conclusions: Plasma NT-proBNP, CRP, and the Gensini score are complementary in risk stratification. Combined use of these biomarkers has provided substantial extra information to conventional risk factors in stable CAD patients.

Background: Hip resurfacing is a technically demanding procedure in which accurate positioning of the femoral component is critical to the avoidance of early implant failures. The purpose of this study was to assess the accuracy of computer-assisted placement of the femoral component and to evaluate the impact of computer-assisted surgery on the learning curve associated with this procedure., Methods: The accuracy of positioning the femoral component was analyzed radiographically in hips undergoing resurfacing procedures performed by surgeons assigned to four different study groups: Group 1, in which the operations were performed with use of computer-assisted surgery by a fellowship-trained surgeon who was experienced in performing resurfacing arthroplasty (surgical experience, more than 250 hip resurfacings); Group 2, in which the operations were performed with use of computer-assisted surgery by senior residents who were inexperienced in performing resurfacing arthroplasty and who were closely supervised by faculty; Group 3, in which the operations were performed with use of conventional instruments by fellowship-trained faculty members; and Group 4, in which the operations were performed with use of computer-assisted surgery by a lesser experienced fellowship-trained faculty member (surgical experience, more than forty but less than seventy-five hip resurfacings) from Group 3., Results: The range of error in varus or valgus angulation that was observed for navigated procedures was 6 degrees in Group 1, 7 degrees in Group 2, and 5 degrees in Group 4. Compared with the preoperative neck-shaft angle value, the mean postoperative stem-shaft angle value increased by a mean of 4.7 degrees in Group 1, 7.2 degrees in Group 2, 6.5 degrees in Group 3, and 11.6 degrees in Group 4. When compared with the use of standard instrumentation, the use of computer-assisted surgery reduced the number of outliers and facilitated valgus insertion., Conclusions: In the present study, computer-assisted surgery resulted in improved accuracy and precision in positioning the femoral component. In addition, computer-assisted surgery led to a reduction in the length of the learning curve for beginners in hip resurfacing and improved the surgeon's ability to perform this procedure safely.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. There is genetic predisposition for the development of AF. Recently, by linkage analysis, several loci have been mapped for monogenetic AF, including 11p15.5, 21q22, 17q, 7q35-36, 5p13, 6q14-16, and 10q22. Some of these loci encode for subunits of potassium channels (KCNQ1, KCNE2, KCNJ2, and KCNH2 genes), and the remaining are yet unidentified. All of the known mutations are associated with a gain of function of repolarization potassium currents, resulting in a shortening of action potential duration and atrial refractory period, which facilitate multiple re-entrant circuits in AF. In addition to familial AF, common AF often occurs in association with acquired diseases such as hypertension, valvular heart disease, and heart failure. By genetic association study, some genetic variants or polymorphisms related to the mechanism of AF have been found to be associated with common AF, including genes encoding for subunits of potassium or sodium channels, sarcolipin gene, renin-angiotensin system gene, connexin-40 gene, endothelial nitric oxide synthase gene, and interleukin-10 gene. These observations suggest that genes related to ionic channels, calcium handling protein, fibrosis, conduction and inflammation play important roles in the pathogenesis of common AF. The complete elucidation of genetic loci for common AF is still in its infancy. However, the availability of genomewide scans with hundreds or thousands of polymorphisms has made it possible. However, challenges and pitfalls exist in association studies, and consideration of particular features of study design is necessary before making definite conclusions from these studies.

Background/purpose: Desmosome gene mutations have been reported in patients with arrhythmogenic right ventricular dysplasia (ARVD). However, there are hardly any genetic studies in Asians. We studied the clinical characteristics, cardiac manifestations and desmosome gene mutations in ARVD patients in Taiwan., Methods: Medical records of five ARVD patients were reviewed and genomic DNA was obtained from peripheral blood samples. Mutation screening in desmoplakin (DSP), plakophilin-2, desmoglein-2 (DSG2) and desmocollin-2 genes was performed using polymerase chain reaction and DNA sequencing techniques., Results: Among the five patients, three presented with palpitations followed by loss of consciousness, and the other two had palpitations or chest tightness without loss of consciousness. Electrocardiogram (ECG), magnetic resonance imaging and signal averaged ECG results were similar to those reported in Western countries. Mutations in the desmosome genes were identified in four of the five patients (three with a DSG2 mutation and one with a DSP mutation). Five gene mutations were noted in four patients and all mutations were novel (one patient had a DSG2 double mutation). The mutation types were missense in four and splicing mutation in one., Conclusion: Patients with ARVD in Taiwan had similar clinical and cardiac manifestations as reported in the Western literature. More than half of the patients had desmosome gene mutations.

Background: Increasing evidence suggests that atrial fibrillation (AF) is an inflammatory disease. Statins is an anti-inflammatory agent. The present study was conducted to test the efficacy of atorvastatin in preventing paroxysmal AF or atrial high rate episodes (AHEs) in patients with bradyarrhythmias and implantation of an atrial-based or dual-chamber pacemaker., Methods: The effect of atorvastatin on time to the first attack of AF or AHE (> or =180 per minute and > or =1 or 10 minutes), which was accurately detected by pacemaker interrogation, was evaluated in an open-label prospective randomized design for 1 year of follow-up., Results: Fifty-two patients (23 males, 70 +/- 13 years old) were randomized to the statin group (atorvastatin 20 mg/d) and 54 (25 males, 72 +/- 13 years old) to the nonstatin group. Event-free survivals from AHE > or =1 minute were not significantly different between the 2 groups (log-rank P = .410). However, patients in the nonstatin group were more likely to develop AHE > or =10 minutes than those in the statin group (log-rank P = .028). Atrial high rate episode > or =10 minutes occurred in 3 (5.8%) of 51 patients in the statin group after 1 year of follow-up, and 10 (19.2%) of 52 patients (odds ratio 0.26, P = .041) in the nonstatin group. The mean left atrial volume of the statin group was significantly lower than that of the nonstatin group at the end of follow-up (39.7 +/- 1.7 vs 43.7 +/- 1.9 mL, P < .0001)., Conclusions: The present study demonstrated the efficacy of atorvastatin in preventing significant AF (> or =10 minutes) and left atrial enlargement in patients with bradyarrhythmias and implantation of a pacemaker.

The sympathetic nervous system has been demonstrated to have a role in regulating bone remodeling through beta-adrenergic receptors (beta-AR) expressed on osteoblasts. Studies using beta(2)-adrenergic receptor agonists in vivo have also suggested an effect on endochondral bone development; however, it was not clear if this effect was mediated through osteoblasts or chondrocytes. To more thoroughly examine the role of beta-AR in chondrocytes we characterized the expression and signal transduction systems activated by beta-AR in growth plate chondrocytes prepared from ribs of embryonic E18.5 mice. Using RT-PCR and immunohistochemistry we found that the chondrocytes expressed only beta(2)-AR. The receptors were coupled to stimulation of adenylyl cyclase, phosphorylation of the cyclic AMP response element binding protein (CREB) and extracellular signal-regulated kinase (ERK1/2). Stimulation of ERK1/2 was transient and limited by the concomitant stimulation of the mitogen-activated protein kinase phosphatase (MKP-1). Isoproterenol stimulated the growth of chondrocytes as assessed by increased incorporation of [(3)H]-thymidine into the cells. The cellular expression of two markers of chondrocyte differentiation, Indian hedgehog, expressed in pre-hypertrophic cells and collagen type X, expressed in hypertrophic chondrocytes, were both significantly inhibited after incubation with isoproterenol. Collectively, these findings demonstrate regulation of chondrocytes through beta(2)-AR expressed on the cells that stimulate their growth and inhibit their differentiation, indicating that the sympathetic nervous system may be an important regulator of embryonic cartilage development., (Copyright 2007 Wiley-Liss, Inc.)

Objective: Heart rate recovery (HRR) is a marker for survival. Little is known about the association between HRR and metabolic risks in healthy children or adolescents., Research Design and Methods: We examined 993 healthy children and adolescents aged 12-19 years with reliable measures of cardiovascular fitness from the National Health and Nutrition Examination Survey 1999-2002. HRR parameters 1-3 min after exercise were calculated from exercise test results. Anthropometric and metabolic risk factors as well as metabolic Z score were obtained., Results: The HRR parameters were inversely correlated with most of the metabolic risks, including waist circumference, systolic blood pressure (SBP), serum triglycerides, and serum C-reactive protein (CRP) levels, and were positively correlated with serum HDL levels. In multiple linear regression analysis, among the metabolic risks, waist circumference was the only parameter associated with HRR parameters (P = 0.038, 0.001, and 0.001 for 1-, 2-, and 3-min HRR, respectively) in boys. In girls, waist circumference (P = 0.001 and <0.001 for 2- and 3-min HRR, respectively), SBP (P = 0.029 for 1-min HRR), serum glucose (P = 0.021 for 2-min HRR), and serum CRP (P = 0.007 for 2-min HRR) levels were the most important determinants of HRR parameters. The adjusted 1-min HRR did not change across four quartiles of metabolic Z score, while the adjusted 3-min HRR decreased significantly with four quartiles of metabolic Z score., Conclusions: Metabolic risks are inversely associated with HRR in healthy children and adolescents. Our finding suggests that there is a link between metabolic risks and autonomic nervous system functions in healthy young ages.

Tissue Doppler imaging-derived intra-left ventricular (LV) contractile dyssynchrony is an evolving prognostic parameter for patients with systolic heart failure (HF). However, whether and how exercise could abolish the synchronicity in HF patients with narrow QRS remains less studied. We evaluated a total of 33 HF patients with impaired LV ejection fraction (<50%), QRS duration < or =120 ms, and baseline dyssynchrony index (DI; standard deviation of electromechanical delay of 12 LV segments by tissue Doppler imaging) <33 ms. After a 6-minute treadmill exercise by modified Bruce protocol, the absolute time difference from QRS onset to peak systolic myocardial velocity of each segment was recorded immediately. With similar DI at rest and peak heart rates during exercise, 11 patients (33%) developed dyssynchrony (DI > or =33 ms) after exercise, and the others did not (44.7 +/- 8.0 vs 16.2 +/- 8.3 ms, p <0.001). Patients with dyssynchrony after exercise had greater baseline mitral early diastolic velocity/annular early diastolic velocity (E/Ea) (19 +/- 17 vs 10 +/- 5, p <0.026). Multivariate analysis revealed mitral E/Ea >10 at rest, indicating higher LV filling pressure, independently predicted the exercise-evoked dyssynchrony (odds ratio 18, 95% confidence interval 2 to 163, p <0.012). In conclusion, exercise uncovered masked LV dyssynchrony in 1/3 of systolic HF patients with narrow QRS, and exercise-provoked dyssynchrony could be predicted by mitral E/Ea >10 at rest.

Objectives: 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., Methods: 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., Results: 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., Conclusions: 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: 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.

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. >or=386 pg/ml, was the interventricular contraction time difference (p = 0.01). Reprogramming 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., ((c) 2007 S. Karger AG, Basel.)

Spasticity, a common symptom accompanying cerebral palsy (CP), can severely affect patients' function and cause disability in childhood. Intrathecal baclofen (ITB) therapy is a widely used treatment to reduce spasticity in quadriparetic CP patients. Likewise, adults sustaining strokes and subsequent spastic hemiplegic have proven excellent candidates as well from ITB therapy. However, data on ITB treatment in pediatric patients with hemiplegic CP are lacking. This is the first report to present such a case. A nine-year old girl with spastic hemiplegic CP failed chemical denervation and serial casting of lower extremity spasticity and an associated equinovarus contracture. An ITB bolus test revealed an improvement in her Ashworth score from a mean of 2.8 to 1.2 on the involved side, whereas the unaffected side stayed constant from a mean of 1.3 to 1.2. The patient was subsequently treated with continuous ITB with improvement of Ashworth scores from a mean of 2.8 at baseline to 1.1 at 17 months after implantation of the ITB pump. Subsequent surgery was performed to correct the residual ankle deformity resulting in improvements in passive range of motion, gait function and brace tolerance. Hemiplegic CP pediatric patients can be successfully treated with ITB to reduce spasticity, improve function, and retain postoperative surgical correction without affecting the normal side.

Background: To evaluate the left atrial (LA) volume, and LA systolic (contractile) and diastolic (expansion) functions in different stages of hypertension with or without atrial fibrillation (AF), as well as the effects of good blood pressure control., Methods: A prospective observational study. Individuals including 22 normotensive controls, 23 patients with mild hypertension, 20 with severe hypertension, and 17 with hypertension and paroxysmal AF were recruited for paired echocardiography studies at baseline and 6 months after control of hypertension., Results: With increasing severity of hypertension, left ventricular (LV) diastolic function deteriorated with decreasing LV septal E'/A' and increasing E/E' ratios. LA expansion index was reduced in parallel. LA expansion index was correlated positively with LV E'/A' (r = 0.43, p = 0.022) and inversely with LV E/E' (r = 0.49, p = 0.009). Significant improvement of LV diastolic function and LA expansion index preceded the reduction of LA volume after blood pressure control. In patients with paroxysmal AF, LA volume reduction was more evident in patients receiving angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers., Conclusions: With progressive LV diastolic dysfunction in hypertension, there was a corresponding deterioration in LA diastolic function. Effective blood pressure control for 6 months improved LA diastolic function., (Copyright 2007 S. Karger AG, Basel.)

Objectives: The effects of HMG-CoA reductase inhibitors on C-reactive protein (CRP)-induced pro-inflammatory changes in endothelial cells remain unclear. We tested the hypothesis that simvastatin inhibited CRP-induced pro-inflammatory changes in endothelial cells by decreasing mevalonate pathway products., Methods: Human umbilical vein endothelial cells were incubated with CRP and measurement of CD32, nuclear factor kappaB (NF-kappaB) activation, vascular cell adhesion molecule-1 expression and monocyte adhesion assay were performed. The effects of simvastatin, siRNA against CD32 (siCD32) and mevalonate pathway products were also examined., Results: Pre-treatment with simvastatin significantly attenuated the CRP-induced CD32 expression and NF-kappaB activation in human umbilical vein endothelial cells. Simvastatin also decreased CRP-induced vascular cell adhesion molecule-1 expression and reduced monocyte adhesion on endothelial cells. The inhibitory effects of simvastatin were significantly reversed by adding mevalonate and geranylgeranyl pyrophosphate (GGPP), but not by adding farnesyl pyrophosphate. Pre-treatment with siCD32 also decreased CRP-induced CD32 expression and inhibitor of kappaB degradation. However, neither mevalonate nor GGPP reversed the effects of siCD32., Conclusions: CRP-induced CD32 expression and NF-kappaB activation were attenuated by simvastatin. A decrease in mevalonate and subsequent GGPP contributes to the inhibitory effects of simvastatin. These findings may provide an explanation of using statins on patients with high serum CRP levels., ((c) 2007 S. Karger AG, Basel.)

The purpose of this study is to report the short-term outcome of intrathecal baclofen therapy on the function of individuals with diplegic cerebral palsy (CP) and the health-related quality of life (HRQL) of their caregivers. Eight pediatric patients with spastic diplegia were treated with ITB following failed oral spasticity management and were followed for a minimum of 2 years. Physical and functional outcomes were assessed using Ashworth Scores (AS), Physician Rating Scale (PRS), and a subset of the Functional Independence Measure for children (WeeFIM). HRQL was assessed using SF-36, CES-D short form, Impact on Family Scale, Life Orientation Test, Rand Social Support Scale, and Social Desirability Scale. At final follow-up, AS was significantly reduced (all p ⩽ 0.03). The PRS scale showed statistically significant improvement in four out of six subscales: median gait pattern (p = 0.05), median hind foot strike (p = 0.03), median knee position (p = 0.03) and median hind foot gait (p = 0.05). The WeeFIM score improved significantly with a mean increase of 32% (p = 0.03). ITB therapy significantly reduced spasticity and improved the function of these eight children with diplegic CP. HRQL of the parents or the caregivers remained stable despite the surgical intervention and follow-up visits required for pump refills.

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: Variations of coronary venous system in a dilated, failing heart may well be unpredictable. Noninvasive preview of coronary veins before left ventricular (LV) lead implantation for cardiac resynchronization therapy would facilitate successful procedure in chronic systolic heart failure (SHF) patients., Methods and Results: Multidetector computed tomography (MDCT) of the heart was investigated in 23 consecutive patients of chronic SHF with LV ejection fraction < or = 40%. Morphologic and topologic characteristics of coronary venous system were studied, and compared with 23 age-matched controls. All coronary veins including coronary sinus, posterior interventricular vein (PIV), LV posterior vein, left margin vein (LMV), and anterior interventricular vein (AIV) were clearly visible in all 23 SHF patients and 23 normal controls. Total coronary venous length (ie, from PIV to AIV) was directly correlated with LV volume (r = 0.65, P < .001). The main lengthened venous segment was between LMV and AIV. Ostial diameters of all coronary venous tributaries were larger in SHF patients, but the angle of branching was similar. However, the secondary angle of the coronary sinus relative to superior vena cava axis was more acute (30 +/- 7 degrees) in SHF patients than that in normal (44 +/- 8 degrees, P < .001). Local aneurysm locating at LV posterolateral wall could detour relevant coronary vein tributaries to the outer border of the aneurysm, compress venous dimensions throughout the cardiac cycle, and cause acute angulation of venous tributaries., Conclusions: Coronary venous system shown by MDCT in SHF patients with low LV ejection fraction manifested longer venous length between LMV and AIV, acute secondary CS angle, and usually topologically distorted by posterolateral LV aneurysms. A panoramic delineation of all coronary venous tributaries could help effective venous intervention.

Background/purpose: Chinese are more sensitive to beta-blockers than Caucasians. However, data regarding beta-blocker therapy in heart failure (HF) patients in Taiwan are lacking. We aimed to evaluate the improvement of left ventricular function and the potential predictors of response to beta-blocker therapy in Taiwanese HF patients., Methods: We enrolled 34 HF patients with baseline left ventricular ejection fraction (LVEF)

Background: 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)., Methods: Echocardiography was performed in 60 hypertensive patients with narrow QRS, left ventricular ejection fraction > or = 50%, and no active ischemia. Patients were grouped as having DD (mitral E/A < 1 plus E deceleration time > 200 milliseconds, or mitral annular early diastolic velocity < 8 cm/s; n = 26), DD plus HF symptoms/signs (DHF, n = 13), or as non-DD (n = 21)., Results: 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 index > or = 35 milliseconds at rest and > or = 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)., Conclusions: Exercise would aggravate intraventricular dyssynchrony in hypertensive patients with DHF, implicating a potential contribution of systolic dyssynchrony to clinical manifestations.

Background: Atrial fibrillation (AF) is characterized by structural remodeling of the extracellular matrix (ECM) in cardiac atrium., Objective: The purpose of this study was to gain further insight into atrial ECM remodeling at the molecular level and to test whether altered expression of ECM proteins was associated with the disease., Methods: Sustained AF was induced in nine adult pigs after 3-4 weeks of continuous rapid atrial pacing at a rate of 600 bpm. Histologic studies and immunohistochemical stain were performed to identify the potential pathologic substrate underlying abnormalities in atrial tissues with sustained AF., Results: In the pathologic findings, the fraction of myocardial ECM (ECM%) was measured, with a significantly greater ECM% found in the AF group compared with the sham operated group (n = 6; i.e., pigs with normal sinus rhythm [SR]). A set of 9,182 genes was screened with cDNA microarray analysis. In AF animals, expression of 121 genes increased and 24 genes decreased by > or =1.75-fold compared with SR animals. Significant up-regulation of fibronectin-1 (4.9-fold), fibrillin-1 (3.1-fold), and fibromodulin (1.9-fold) in the fibrillating atria was confirmed by quantitative real-time reverse transcriptase-polymerase chain reaction. Western blot analysis revealed significantly increased atrial fibronectin-1, fibrillin-1, and fibromodulin in the AF group compared with the SR group (1.5-, 2.7-, and 2.1-fold, respectively). Immunohistochemical staining of AF tissue displayed increased accumulation of fibronectin-1 and fibrillin-1 in the atrial interstitial space., Conclusion: Increased expression of ECM proteins in fibrillating atria supports the hypothesis that ECM metabolism contributes to the development of AF.

Angiotensin II (Ang II) is involved in the pathogenesis of atrial fibrillation (AF). L-type calcium channel (LCC) expression is altered in AF remodeling. We investigated whether Ang II modulates LCC current through transcriptional regulation, by using murine atrial HL-1 cells, which have a spontaneous calcium transient, and an in vivo rat model. Ang II increased LCC alpha1C subunit mRNA and protein levels and LCC current density, which resulted in an augmented calcium transient in atrial myocytes. An approximately 2-kb promoter region of LCC alpha1C subunit gene was cloned to the pGL3 luciferase vector. Ang II significantly increased promoter activity in a concentration- and time-dependent manner. Truncation and mutational analysis of the LCC alpha1C subunit gene promoter showed that cAMP response element (CRE) (-1853 to -1845) was an important cis element in Ang II-induced LCC alpha1C subunit gene expression. Transfection of dominant-negative CRE binding protein (CREB) (pCMV-CREBS133A) abolished the Ang II effect. Ang II (1 micromol/L, 2 hours) induced serine 133 phosphorylation of CREB and binding of CREB to CRE and increased LCC alpha1C subunit gene promoter activity through a protein kinase C/NADPH oxidase/reactive oxygen species pathway, which was blocked by the Ang II type 1 receptor blocker losartan and the antioxidant simvastatin. In the rat model, Ang II infusion increased LCC alpha1C subunit expression and serine 133 phosphorylation of CREB, which were attenuated by oral losartan and simvastatin. In summary, Ang II induced LCC alpha1C subunit expression via a protein kinase C-, reactive oxygen species-, and CREB-dependent pathway and was blocked by losartan and simvastatin.

Background/purpose: Elevation of C-reactive protein (CRP) level is associated with increased risk of cardiovascular events. The 1059 G>C polymorphism in exon 2 of the CRP gene has been shown to affect plasma concentration of CRP. We want to elucidate the effect of this polymorphism on the development of coronary artery disease (CAD) among the Chinese population in Taiwan., Methods: We scrutinized 536 patients undergoing coronary angiography (365 patients with CAD and 171 controls with patent coronaries) and evaluated the association of CRP gene 1059 G>C polymorphism with CAD. Genotyping of the polymorphism was performed by polymerase chain reaction and MaeIII restriction enzyme digestion., Results: The CC genotype was associated with lower plasma CRP concentration (GG, 6.5+/-5.8; GC, 3.3+/-4.4; CC, 2.3+/-3.1 mg/L; p=0.02). Subjects with CAD or myocardial infarction (MI) had significantly higher plasma CRP concentration than that in controls (CAD vs. controls, 8.9+/-18.9 vs. 3.3+/-7.2 mg/L; p<0.001), while patients with MI showed higher CRP when compared to those with chronic stable angina (13.5+/-22.9 vs. 5.2+/-14.1 mg/L; p<0.001). However, this polymorphism was not associated with CAD in our population., Conclusion: Our data suggest that human CRP gene 1059 G>C polymorphism is associated with plasma CRP concentration among Chinese in Taiwan receiving coronary angiography.

Amiodarone-related pneumonitis is a potentially limiting factor for amiodarone usage. However, it is believed that amiodarone-related pneumonitis is unlikely to occur during low-dose and short courses of therapy. We report three patients who received low-dose amiodarone, 200 mg/day, for an average of 6.6 months and who developed amiodarone-related pneumonitis. All patients were male with age of 75, 93 and 85, respectively, and had the habit of cigarette smoking. The initial presentation was dyspnea without symptoms and signs of heart failure. Their chest radiographs showed diffuse interstitial pneumonitis pattern and chest computed tomography scan also confirmed interstitial pneumonitis. Treatment included cessation of amiodarone and corticosteroid usage. All patients improved symptomatically by early detection and early treatment. This case report implies that old age and possible pre-existing pulmonary abnormalities caused by smoking could be associated with amiodarone-related pulmonary toxicity. Clinicians must remain alert to detect amiodarone-related pneumonitis even under low dosage and short duration of amiodarone usage. Immediate withdrawal of amiodarone and prompt steroid therapy will ensure full recovery.

Left ventricular lead positioning is always the critical step in cardiac resynchronization therapy because of the complex anatomy of coronary sinus branches. We describe the case of a 46-year-old man with dilated cardiomyopathy and complete left bundle branch block presenting with heart failure. The placing of the left ventricular lead into the posterolateral branch was hampered by an angulated portion at the proximal branch even with the assistance of anchor wire technique and one to two additional parallel wires' support. The use of three buddy wires facilitated the advancement of the left ventricular lead.

Background: 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., Methods: 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., Results: 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, P<0.001). 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 (P<0.006, 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 (P<0.004) 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., Conclusions: 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.

Atrial fibrillation (AF) is the most common progressive disease in patients with cardiac arrhythmia. AF is accompanied by complex atrial remodeling and changes in gene expression, but only a limited number of transcriptional regulators have been identified. Using a low-density cDNA array, we identified 31 genes involved in transcriptional regulation, signal transduction or structural components, which were either significantly upregulated or downregulated in porcine atria with fibrillation (induced by rapid atrial pacing at a rate of 400-600 bpm for 4 weeks that was then maintained without pacing for 2 weeks). The genes for four and a half LIM domains protein-1 (FHL1), transforming growth factor-beta (TGF-beta)-stimulated clone 22 (TSC-22), and cardiac ankyrin repeat protein (CARP) were significantly upregulated, and chromosome 5 open reading frame gene 13 (P311) was downregulated in the fibrillating atria. FHL1 and CARP play important regulatory roles in cardiac remodeling by transcriptional regulation and myofilament assembly. Induced mRNA expression of both FHL1 and CARP was also observed when cardiac H9c2 cells were treated with an adrenergic agonist. Increasing TSC-22 and marked P311 deficiency could enhance the activity of TGF-beta signaling and the upregulated TGF-beta1 and -beta2 expressions were identified in the fibrillating atria. These results implicate that observed alterations of underlying molecular events were involved in the rapid-pacing induced AF, possibly via activation of the beta-adrenergic and TGF-beta signaling.

Atrial fibrillation (AF), the most common cardiac arrhythmia, is frequently accompanied by atrial interstitial fibrosis. Angiotensin II (Ang II) dependent signaling pathways have been implicated in interstitial fibrosis during the development of AF. However, Ang II could be further degraded by angiotensin converting enzyme II (ACE2). We examined expression of ACE2 in the fibrillating atria of pigs and its involvement in fibrotic pathogenesis during AF. Nine adult pigs underwent continuous rapid atrial pacing to induce sustained AF and six pigs were sham controls (i.e., sinus rhythm; SR). In the histological examinations, extensive accumulation of extracellular matrix in the interstitial space of the atria, as evidenced by Masson's trichrome stain, were found in fibrillating atria. The relative amount of collagen type I in the atria with AF was significantly increased as compared with that in the SR. Local ACE activity in the fibrillating atria was also markedly higher than that in the SR subjects. ACE2 gene and protein expression in the AF subjects were significantly decreased compared with those in the SR subjects, whereas expression of mitogen-activated/ERK kinase 1/2 (MEK1/2), extracellular signal-regulated protein kinase 2 (ERK2), and activated ERK2 were significantly greater in the AF subjects. We propose that decreasing ACE2 expression during AF may affect the Ang II-dependent signaling pathway. In addition, our results suggest that atrial fibrosis in AF may be induced by antagonistic regulation between ACE and ACE2 expression.

The association between the endothelial nitric oxide synthase (eNOS) gene with vascular diseases in Western populations and with severe preeclampsia (PE) in the Japanese population have been demonstrated, lacing the data in Chinese population. The authors examine the association between PE and 2 polymorphisms of the eNOS gene in a Chinese population, consisting of 92 pregnant women with PE and 256 healthy controls. All were genotyped for the Glu298Asp polymorphism in exon 7 and the number of 27 base pair repeats in intron 4 of the eNOS gene. The frequencies of both the variant T allele and eNOS 4a (small allele with 4 repeats of 27 bp) were significantly lower in the PE group than in the control group. The genotype distribution of Glu298Glu, Glu298Asp, and Asp298Asp in eNOS exon 7 and bb type and ab type in eNOS intron 4 revealed statistically significant differences between control and PE groups. This is the first study to evaluate the association between 2 polymorphisms in the maternal eNOS gene with PE simultaneously in a Chinese population. Similar to the findings in Western populations, polymorphisms in the eNOS gene may be protective against PE in a Chinese population, in contrast to the results in the Japanese population.