Prolongation of the QT interval and post-extrasystolic augmentation of the TU-wave during emotional stress

We present a case of a 25-year-old woman with multiple blackouts and no structural heart disease, with abnormal T-U waves and borderline QT interval on her resting electrocardiogram. During emotional stress she developed frequent monomorphic ventricular premature beats, with characteristic changes of the sinus complexes immediately following the premature beats, namely augmentation and greater degree of merging of the T and U waves and QTc interval prolongation. The changes alert about the possibility of congenital long QT syndrome, specifically genotype 2 or 1.     

Single-Channel Characteristics of Wild-Type IKs Channels and Channels formed with Two MinK Mutants that Cause Long QT Syndrome

I_Ks channels are voltage dependent and K⁺ selective. They influence cardiac action potential duration through their contribution to myocyte repolarization. Assembled from minK and KvLQT1 subunits, I_Ks channels are notable for a heteromeric ion conduction pathway in which both subunit types contribute to pore formation. This study was undertaken to assess the effects of minK on pore function. We first characterized the properties of wild-type human I_Ks channels and channels formed only of KvLQT1 subunits. Channels were expressed in Xenopus laevis oocytes or Chinese hamster ovary cells and currents recorded in excised membrane patches or whole-cell mode. Unitary conductance estimates were dependent on bandwidth due to rapid channel “flicker.” At 25 kHz in symmetrical 100-mM KCl, the single-channel conductance of I_Ks channels was ∼16 pS (corresponding to ∼0.8 pA at 50 mV) as judged by noise-variance analysis; this was fourfold greater than the estimated conductance of homomeric KvLQT1 channels. Mutant I_Ks channels formed with D76N and S74L minK subunits are associated with long QT syndrome. When compared with wild type, mutant channels showed lower unitary currents and diminished open probabilities with only minor changes in ion permeabilities. Apparently, the mutations altered single-channel currents at a site in the pore distinct from the ion selectivity apparatus. Patients carrying these mutant minK genes are expected to manifest decreased K⁺ flux through I_Ks channels due to lowered single-channel conductance and altered gating.     

Ablation of Premature Ventricular Complexes Triggering Ventricular Fibrillation in a Patient with Long QT Syndrome

We describe the case of a patient with long QT syndrome and recurrent ventricular fibrillation, triggered by premature ventricular complexes (PVCs) with a left bundle branch block pattern and inferior axis of the QRS. Activation mapping demonstrated the origin of the PVCs to be in the right ventricular outflow tract. Ventricular fibrillation (VF) was successfully treated by catheter ablation of the triggering PVCs and there has been no recurrence of VF during a follow-up period of 14 months.     

Never Out of the Woods: Onset of Events in Long QT Syndrome Late in Life Provoked by Atrial Arrhythmias

The assessment of risk in the asymptomatic patient with long QT syndrome can often be a challenging task, particularly when the available evidence is limited to relatively small retrospective registries, not to mention the need to consider the effect of individual patient factors which are often difficult to quantitate. We describe the relatively uncommon case of a man with a long-standing diagnosis of Long QT 2 syndrome who suffered his first cardiac event in his late 60''s, likely precipitated by the development of paroxysmal atrial tachycardia. A brief review of the available literature on risk assessment in adults with genetically confirmed long QT syndrome who have remained asymptomatic late into adulthood will follow the case.     

Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long‐QT syndrome

Patient‐specific induced pluripotent stem cells (iPSCs) will assist research on genetic cardiac maladies if the disease phenotype is recapitulated in vitro. However, genetic background variations may confound disease traits, especially for disorders with incomplete penetrance, such as long‐QT syndromes (LQTS). To study the LQT2‐associated c.A2987T (N996I) KCNH2 mutation under genetically defined conditions, we derived iPSCs from a patient carrying this mutation and corrected it. Furthermore, we introduced the same point mutation in human embryonic stem cells (hESCs), generating two genetically distinct isogenic pairs of LQTS and control lines. Correction of the mutation normalized the current (I_Kr) conducted by the HERG channel and the action potential (AP) duration in iPSC‐derived cardiomyocytes (CMs). Introduction of the same mutation reduced I_Kr and prolonged the AP duration in hESC‐derived CMs. Further characterization of N996I‐HERG pathogenesis revealed a trafficking defect. Our results demonstrated that the c.A2987T KCNH2 mutation is the primary cause of the LQTS phenotype. Precise genetic modification of pluripotent stem cells provided a physiologically and functionally relevant human cellular context to reveal the pathogenic mechanism underlying this specific disease phenotype.     

Dizzy Spells in a Patient with Hypertrophic Obstructive Cardiomyopathy and a Pacemaker

Pacemaker syndrome represents the clinical consequences of the haemodynamic adverse effects of atrioventricular asynchrony during pacing. Patients suffering from hypertrophic cardiomyopathy may be particularly sensitive to these effects because of the importance of atrial systolic contribution to left ventricular diastolic filling. In this case report, we describe the symptoms and cause of pacemaker syndrome in a patient with hypertrophic obstructive cardiomyopathy.     

Genotype and clinical characteristics of congenital long QT syndrome in Thailand

Background

Congenital long QT syndrome (LQTS) is an inheritable arrhythmic disorder which is linked to at least 17 genes. The clinical characteristics and genetic mutations may be variable among different population groups and they have not yet been studied in Thai population.

心衰与低T3综合征的研究进展

研究发现,慢性心力衰竭时常伴甲状腺功能紊乱,主要表现为＂低T3综合征＂,而甲状腺激素代谢紊乱的严重程度与心衰患者病情发展、预后及远期生存率关系密切,本文着重就心衰伴＂低T3综合征＂的临床现状及治疗策略的最新研究进展作一综述。     

MinK subdomains that mediate modulation of and association with KvLQT1

KvLQT1 is a voltage-gated potassium channel expressed in cardiac cells that is critical for myocardial repolarization. When expressed alone in heterologous expression systems, KvLQT1 channels exhibit a rapidly activating potassium current that slowly deactivates. MinK, a 129 amino acid protein containing one transmembrane-spanning domain modulates KvLQT1, greatly slowing activation, increasing current amplitude, and removing inactivation. Using deletion and chimeric analysis, we have examined the structural determinants of MinK effects on gating modulation and subunit association. Coexpression of KvLQT1 with a MinK COOH-terminus deletion mutant (MinK DeltaCterm) in Xenopus oocytes resulted in a rapidly activated potassium current closely resembling currents recorded from oocytes expressing KvLQT1 alone, indicating that this region is necessary for modulation. To determine whether MinK DeltaCterm was associated with KvLQT1, a functional tag (G55C) that confers susceptibility to partial block by external cadmium was engineered into the transmembrane domain of MinK DeltaCterm. Currents derived from coexpression of KvLQT1 with MinK DeltaCterm were cadmium sensitive, suggesting that MinK DeltaCterm does associate with KvLQT1, but does not modulate gating. To determine which MinK regions are sufficient for KvLQT1 association and modulation, chimeras were generated between MinK and the Na(+) channel beta1 subunit. Chimeras between MinK and beta1 could only modulate KvLQT1 if they contained both the MinK transmembrane domain and COOH terminus, suggesting that the MinK COOH terminus alone is not sufficient for KvLQT1 modulation, and requires an additional, possibly associative interaction between the MinK transmembrane domain and KvLQT1. To identify the MinK subdomains necessary for gating modulation, deletion mutants were designed and coexpressed with KvLQT1. A MinK construct with amino acid residues 94-129 deleted retained the ability to modulate KvLQT1 gating, identifying the COOH-terminal region critical for gating modulation. Finally, MinK/MiRP1 (MinK related protein-1) chimeras were generated to investigate the difference between these two closely related subunits in their ability to modulate KvLQT1. The results from this analysis indicate that MiRP1 cannot modulate KvLQT1 due to differences within the transmembrane domain. Our results allow us to identify the MinK subdomains that mediate KvLQT1 association and modulation.     

hERG1a/1b heteromeric currents exhibit amplified attenuation of inactivation in variant 1 short QT syndrome

Potassium channels encoded by hERG (human ether-à-go-go-related gene) underlie the cardiac rapid delayed rectifier K⁺ current (I_Kr) and hERG mutations underpin clinically important repolarization disorders. Virtually all electrophysiological investigations of hERG mutations have studied exclusively the hERG1a isoform; however, recent evidence indicates that native I_Kr channels may be comprised of hERG1a together with the hERG1b variant, which has a shorter N-terminus. Here, for the first time, electrophysiological effects were studied of a gain-of-function hERG mutation (N588K; responsible for the ‘SQT1’ variant of the short QT syndrome) on current (I_hERG1a/1b) carried by co-expressed hERG1a/1b channels. There were no significant effects of N588K on I_hERG1a/1b activation or deactivation, but N588K I_hERG1a/1b showed little inactivation up to highly positive voltages (?+80 mV), a more marked effect than seen for hERG1a expressed alone. I_hERG1a/1b under action potential voltage-clamp, and the effects on this of the N588K mutation, also showed differences from those previously reported for hERG1a. The amplified attenuation of I_hERG inactivation for the N588K mutation reported here indicates that the study of co-expressed hERG1a/1b channels should be considered when investigating clinically relevant hERG channel mutations, even if these reside outside of the N-terminus region.     

兴安落叶松结实规律与长短枝习性的关系

1987年5月,大兴安岭林区发生的特大森林火灾,实属世界罕见,火灾面积达1.0×10~6ha 多。大量的火烧迹地亟待更新、无论是人工更新还是人工促进天然更新,其中关键的问题之一是种子的来源,在大兴安岭地区,兴     

Impaired ion channel function related to a common KCNQ1 mutation — Implications for risk stratification in long QT syndrome 1

Long QT syndrome (LQTS) 1 is the most common type of inherited LQTS and is linked to mutations in the KCNQ1 gene. We identified a KCNQ1 missense mutation, KCNQ1 G325R, in an asymptomatic patient presenting with significant QT prolongation (QTc, 448–600 ms). Prior clinical reports revealed phenotypic variability ranging from the absence of symptoms to syncope among KCNQ1 G325R mutation carriers. The present study was designed to determine the G325R ion channel phenotype and its association with the clinical LQTS presentation. Electrophysiological testing was performed using the Xenopus oocyte expression system. KCNQ1 G325R channels were non-functional and suppressed wild type (WT) currents by 71.1%. In the presence of the native cardiac regulatory ß-subunit, KCNE1, currents conducted by G325R and WT KCNQ1 were reduced by 52.9%. Co-expression of G325R and WT KCNQ1 with KCNE1 shifted the voltage-dependence of I_Ks activation by 12.0 mV, indicating co-assembly of mutant and WT subunits. The dysfunctional biophysical phenotype validates the pathogenicity of the KCNQ1 G325R mutation and corresponds well with the severe clinical presentation revealed in some reports. However, the index patient and other mutation carriers were asymptomatic, highlighting potential limitations of risk assessment schemes based on ion channel data.     

Biophysical characterization of a new SCN5A mutation S1333Y in a SIDS infant linked to long QT syndrome

Various entities and genetic etiologies, including inherited long QT syndrome type 3 (LQT3), contribute to sudden infant death syndrome (SIDS). The goal of our research was to biophysically characterize a new SCN5A mutation (S1333Y) in a SIDS infant. S1333Y channels showed the gain of Na⁺ channel function characteristic of LQT3, including a persistent inward Na⁺ current and an enhanced window current that was generated by a −8 mV shift in activation and a +7 mV shift in inactivation. The correlation between the biophysical data and arrhythmia susceptibility suggested that the SIDS was secondary to the LQT3-associated S1333Y mutation.     

哮喘患者外周血Treg和Th1/Th2的变化及其与哮喘病情的关系

目的：探讨哮喘患者外周血调节性T细胞（Treg）以及辅助性T细胞（Th1/Th2）的比例的变化,探讨其在哮喘的临床治疗中的作用。方法：80例哮喘患者（哮喘组）按临床表现分为急性发作期组（54例）和缓解期组（26例）,同时选择50例健康体检者。应用流式细胞仪检测上述各组外周血CD4＋CD25＋Foxp3＋Treg、CD4＋IFN-γ＋Th1和CD4＋IL-4＋Th2细胞水平,并进行统计学分析。结果：哮喘组CD4＋CD25＋Foxp3＋Treg水平亦明显低于正常对照组（P〈0.05。其中急性发作期组Treg水平明显低于缓解期组和正常对照组（P〈0.05）。而哮喘组Th1/Th2比值显著低于对照组（P〈0.05）,且在哮喘急性发作组中Th1/Th2比值显著低于缓解期组和正常对照组（P〈0.05）。结论：提示Treg和Th在哮喘的发生和发展中起着重要的作用。     

一类S-I传染病模型行波解的存在性

本文研究了一类具有扩散且是非线性传染率的SI传染病模型,分析了模型的行波解的存在性条件,给出了最小波速与产生单调和振荡行波解的条件,并且进行了计算机仿真．     

Molecular Species of Phosphatidylcholine Containing Very Long Chain Fatty Acids in Human Brain: Enrichment in X-Linked Adrenoleukodystrophy Brain and Diseases of Peroxisome Biogenesis Brain

Molecular species of phosphatidylcholine containing unsaturated (i.e., monoenoic and polyenoic) 32- to 40-carbon (very long chain) fatty acids (VLCFA-PC) are present in normal human brain, the fatty acid composition changing significantly with development. There is a marked increase in the concentration and a change in the polyenoic VLCFA composition of these molecular species in brains of patients with inherited defects in peroxisomal biogenesis [Zellweger's syndrome, neonatal adrenoleukodystrophy (ALD), and infantile Refsum's disease]. In contrast, there is a marked increase in monoenoic VLCFA-PC in X-linked ALD whereas molecular species containing polyenoic VLCFA are minor components.     

一类时滞反应扩散方程的稳态解和行波解

本文讨论了一类造血生物模型在Dirichlet边值条件下稳态解的全局吸引性,并利用上、下解技术和单调迭代方法讨论了行波解的存在性.     

嗜血细胞综合征患儿外周血CD_4~+CD_(25)~+调节性T细胞变化及临床意义

目的观察嗜血细胞综合征(hemophagocytic syndrome,HPS)患儿外周血中调节性T细胞(RegulatoryTcells,Treg细胞)的变化,探讨其在HPS发病中的作用及临床意义。方法应用流式细胞仪检测17例初诊HPS患者(初诊组)、11例经诱导治疗后临床缓解者(缓解组)及20例健康人群(对照组)外周血中CD4+CD25+调节性T细胞。结果与对照组相比较,HPS患者初诊组及缓解组外周血CD4+CD25+调节性T细胞均升高(P0.05)。与初诊组相比较,缓解组CD4+CD25+Treg细胞降低(P0.05),但仍高于正常对照组(P0.05)。结论CD4+CD25+Treg细胞增多可能是HPS患者免疫功能受抑的重要原因之一,其变化对于HPS的预后判断有一定的意义。     

Comparative study of high sensitivity troponin T and heart-type fatty acid-binding protein in STEMI patients

Aim and background

Heart-type fatty acid-binding proteins (H-FABP) which are detected within 2–3 h of acute myocardial infarction are involved in uptake of free fatty acids in the myocardium. Our aim in the present study is to compare window periods of H-FABP to high sensitivity troponin T (hs-Trop T) in acute ST elevation myocardial infarction (STEMI).

Methods

160 STEMI diagnosed patient’s serum samples are analyzed for hs-Trop T and H-FABP. Different window periods of chest pain onset (<3 h, 3–6 h and >6 h) are compared with complications, in-hospital mortality and statistically analyzed.

Results

From 160 patients, 53 (33%) cases are presented in <3 h, 75 (47%) in 3–6, and 32 (20%) after >6 h respectively. Accordingly sensitivity of hs-Trop T was 92%, 94% and 97% while H-FABP was 75%, 88% and 84%, respectively. Overall sensitivity was 94% and 82% respectively. Statistically significant difference between mean hs-Trop T values with respect to window period <3, 3–6 and >6 h was 0.21, 0.35 and 0.80 ng/ml respectively, p value < 0.0001. No significant difference in H-FABP values was observed.Hs-Trop T positively correlated with age (r = 0.153, P = 0.05), window period (r = 0.363, P < 0.0001), TIMI score (r = 0.208, P = 0.008), ejection fraction (r = 0.191, P = 0.008), serum H-FABP (r = 0.229, P = 0.004), and serum hs-CRP (r = 0.326, p < 0.001). There was a statistically significant difference of mean hs-Trop T values with or without in hospital mortality (0.35 vs. 0.85 ng/ml, respectively, p = 0.008).No significant correlation to age, TIMI score, ejection fraction and hs-CRP values for H-FABP was observed.

Conclusion

It appears that hs-Trop T is a more sensitive marker than H-FABP in early hours of AMI and higher hs-Trop T predicts increase in-hospital mortality.     

Impaired Thymic Export and Increased Apoptosis Account for Regulatory T Cell Defects in Patients with Non-ST Segment Elevation Acute Coronary Syndrome

Regulatory T (Treg) cells play a protective role against the development of atherosclerosis. Previous studies have revealed Treg cell defects in patients with non-ST elevation acute coronary syndrome (NSTACS), but the mechanisms underlying these defects remain unclear. In this study, we found that the numbers of peripheral blood CD4⁺CD25⁺CD127^low Treg cells and CD4⁺CD25⁺CD127^lowCD45RA⁺CD45RO⁻ naive Treg cells were lower in the NSTACS patients than in the chronic stable angina (CSA) and the chest pain syndrome (CPS) patients. However, the number of CD4⁺CD25⁺CD127^lowCD45RA⁻CD45RO⁺ memory Treg cells was comparable in all of the groups. The frequency of CD4⁺CD25⁺CD127^lowCD45RO⁻CD45RA⁺CD31⁺ recent thymic emigrant Treg cells and the T cell receptor excision circle content of purified Treg cells were lower in the NSTACS patients than in the CSA patients and the CPS controls. The spontaneous apoptosis of Treg cells (defined as CD4⁺CD25⁺CD127^lowannexin V⁺7-AAD⁻) was increased in the NSTACS patients compared with the CSA and CPS groups. Furthermore, oxidized LDL could induce Treg cell apoptosis, and the oxidized LDL levels were significantly higher in the NSTACS patients than in the CSA and CPS groups. In accordance with the altered Treg cell levels, the concentration of TNF-α was increased in the NSTACS patients, resulting in a decreased IL-10/TNF-α ratio. These findings indicate that the impaired thymic output of Treg cells and their enhanced susceptibility to apoptosis in the periphery were responsible for Treg cell defects observed in the NSTACS patients.