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.     

心脏钠通道疾病

自从心脏钠离子通道 基因 (SC N 5A )突变 被首次鉴定 以来,人们对 SC N 5A 突变进行 了一系列研 究.SC N 5A突 变是在 两种明 显不同但 都与突 发性死 亡相关 联的疾病 ———长 Q T 波综合 症 (LQ T3)的 一种形 式和 B rugada 综合症 中被 鉴定的.后来 ,Lev-Lenegre 综 合症 进行 性的 心脏传 导缺 陷)也增 加到 LQ T3中.基因型 和表 型相 互关 系的 (研 究以及体外 表达研究提 供证据认为 SC N 5A 蛋白的结构 和功能相互 关系远比最 初预期的复 杂.心脏钠通 道的生物 物理特征与不同 的表型相关, 基因型和表型 相互关系的研究 使我们注意到 即使是单个 氨基酸的置换 都可能显而 易见的影响心脏 的兴奋性 .由 隐藏有 SC N 5A 突变的病 人提供的证 据以及临床呈 现 “重叠”现象的证 据显示已经 需要对上述提及 的疾病的传统 分类进行修改 .现在认为 钠通道综合症”作 为唯一的临 床称谓表示这 类疾病可 “能 的表型范围更合 适 .     

面向短QT综合征的药物作用建模与仿真研究

短QT综合征(short QT syndrome,SQTS)是以心电图QT间期、心室和心房不应期明显缩短为主要显性特征,并伴有晕厥、高发心源性猝死(sudden cardiac death,SCD)和恶性心律失常风险的一类遗传性心肌离子通道病.据目前资料信息,关于SQTS致病机理的报道比较多,而对SQTS药物治疗的报道罕见.为了揭示在SQTS下的药物作用,本文通过计算机仿真构建人体心室细胞和组织的药物作用模型,利用该模型,从亚细胞、细胞、组织三个尺度,模拟SQT1、SQT2和SQT3下的普罗帕酮药物作用过程,并仿真心电图的变化情况.仿真结果表明:在SQT1下普罗帕酮延长了动作电位时程(action potential duration,APD)和心电图QT间期,并降低T波幅值;相反,在SQT2和SQT3下普罗帕酮缩短了APD和QT间期.计算使用药物前后细胞间膜电压和APD空间离散度的变化,定量分析了普罗帕酮降低T波振幅的原因.总之,对SQT1,普罗帕酮有效;对SQT2和SQT3,普罗帕酮没有改变其致心律失常的危险.仿真结果为普罗帕酮用于临床治疗SQTS提供理论参考.     

Presence of Macrovolt T Wave Alternans and Short Coupled PVC Simultaneously in a Patient with Long QT Syndrome

This report presents a patient with macrovolt T wave alternans, PVC with R on T or a long-short sequence followed by torsades de pointes.     

Circadian rhythm in QT interval is preserved in mice deficient of potassium channel interacting protein 2

Potassium Channel Interacting Protein 2 (KChIP2) is suggested to be responsible for the circadian rhythm in repolarization duration, ventricular arrhythmias, and sudden cardiac death. We investigated the hypothesis that there is no circadian rhythm in QT interval in the absence of KChIP2. Implanted telemetric devices recorded electrocardiogram continuously for 5 days in conscious wild-type mice (WT, n = 9) and KChIP2^?/? mice (n = 9) in light:dark periods and in complete darkness. QT intervals were determined from all RR intervals and corrected for heart rate (QT₁₀₀ = QT/(RR/100)^1/2). Moreover, QT intervals were determined from complexes within the RR range of mean-RR ± 1% in the individual mouse (QT_mean-RR). We find that RR intervals are 125 ± 5 ms in WT and 123 ± 4 ms in KChIP2^?/? (p = 0.81), and QT intervals are 52 ± 1 and 52 ± 1 ms, respectively(p = 0.89). No ventricular arrhythmias or sudden cardiac deaths were observed. We find similar diurnal (light:dark) and circadian (darkness) rhythms of RR intervals in WT and KChIP2^?/? mice. Circadian rhythms in QT₁₀₀ intervals are present in both groups, but at physiological small amplitudes: 1.6 ± 0.2 and 1.0 ± 0.3 ms in WT and KChIP2^?/?, respectively (p = 0.15). A diurnal rhythm in QT₁₀₀ intervals was only found in WT mice. QT_mean-RR intervals display clear diurnal and circadian rhythms in both WT and KChIP2^?/?. The amplitude of the circadian rhythm in QT_mean-RR is 4.0 ± 0.3 and 3.1 ± 0.5 ms in WT and KChIP2^?/?, respectively (p = 0.16). In conclusion, KChIP2 expression does not appear to underlie the circadian rhythm in repolarization duration.     

QRS、QT、QTc及LVEF预测心源性猝死的价值分析

摘要 目的：探讨QRS时限值（QRS）、QT间期延长（QT）、QTc间期（QTc）及左室射血分数（LVEF）预测心源性猝死的价值分析。方法：选择2018年1月至2019年12月川北医学院附属医院心血管内科治疗的356例心源性猝死患者进行研究,设为病例组,并选择同期体检的健康人200例作为对照组,分析QRS、QT、QTc及LVEF水平变化情况及其预测价值。结果：病例组QRS、QTc水平显著高于对照组,QT、LVEF水平显著低于对照组,差异显著（P＜0.05）;轻度QRS、QTc显著低于中度、重度患者,QT、LVEF水平显著高于中度、重度患者;中度患者QRS、QTc显著低于重度患者,QT、LVEF水平显著高于重度患者,差异显著（P＜0.05）;ROC结果显示,QRS预测心源性猝死的AUC为0.989,灵敏度△为84.59%,特异度为87.68%,截断值为115.59ms;QT预测心源性猝死的AUC为0.944,灵敏度85.12%,特异度为88.45%,截断值为21.69ms;QTc预测心源性猝死的AUC为0.984,灵敏度为86.05%,特异度为88.61%,截断值为416.39ms,LVEF预测心源性猝死的AUC为0.997,灵敏度87.15%,特异度为89.05%,截断值为45.63%,（P＜0.05）。结论：QRS、QT、QTc及LVEF在心源性猝死患者中检查,可显著提高心源性猝死临床诊断效能。     

QT Dispersion in Uncomplicated Human Obesity

Objective: Because obese patients generally may be prone to ventricular arrhythmias, this study was designed to measure the interval between Q‐ and T‐waves of the electrocardiogram (QT) interval dispersion (QTD) in uncomplicated overweight and obese patients. QTD is an electrocardiographic parameter whose prolongation is thought to be predictive of the possibility of sudden death caused by ventricular arrhythmias. To better evaluate the association between obesity per se and QTD, the study population was intentionally selected because they were free of complications. Research Methods and Procedures: QTD (defined as the difference between the maximum and the minimum QT corrected interval [QTc] across the 12‐lead electrocardiogram) was measured manually in 54 obese patients (Group A: mean body mass index [BMI] of 38.1 ± 0.9 kg/m² [SEM], 15 males and 39 females), 35 overweight patients (Group B: mean BMI of 27.3 ± 0.2 kg/m², 10 males and 25 females), and 57 normal weight healthy control subjects (Group C: mean BMI of 21.9 ± 0.2 kg/m², 17 males and 40 females). The obese and overweight patients had no heart disease, hypertension, diabetes, or impaired glucose tolerance and did not have any hormonal, hepatic, renal or electrolyte disorders. The study subjects were matched in terms of age (mean age 38.4 ± 1.2 years) and sex. Results: The QTDs were comparable among the three groups: Group A, 56.4 ± 2.6 ms; Group B, 56.7 ± 2.1 ms; and Group C, 59.4 ± 2.1 ms; not significant. The QTc intervals of Group A and Group B were similar to that of Group C (411.8 ± 3.3, 407.2 ± 3.9, and 410.3 ± 3.9 ms, respectively [not significant]) and did not correlate with BMI. An association was found between QTD and QTc (r = 0.24, p < 0.005). Using multivariate stepwise regression analysis of the study population, QTD did not correlate with age, BMI, waist circumference, or abdominal sagittal diameter. Discussion: These data suggest that QTD in uncomplicated obese or overweight subjects is comparable with that in age‐ and sex‐matched normal weight healthy controls. In this study population, no association was found between QTD and anthropometric parameters reflecting body fat distribution.     

Identification of a Kir3.4 Mutation in Congenital Long QT Syndrome

Congenital long QT syndrome (LQTS) is a hereditary disorder that leads to sudden cardiac death secondary to fatal cardiac arrhythmias. Although many genes for LQTS have been described, the etiology remains unknown in 30%–40% of cases. In the present study, a large Chinese family (four generations, 49 individuals) with autosomal-dominant LQTS was clinically evaluated. Genome-wide linkage analysis was performed by using polymorphic microsatellite markers to map the genetic locus, and positional candidate genes were screened by sequencing for mutations. The expression pattern and functional characteristics of the mutated protein were investigated by western blotting and patch-clamp electrophysiology. The genetic locus of the LQTS-associated gene was mapped to chromosome 11q23.3-24.3. A heterozygous mutation (Kir3.4-Gly387Arg) was identified in the G protein-coupled, inwardly rectifying potassium channel subunit Kir3.4, encoded by the KCNJ5 gene. The Kir3.4-Gly387Arg mutation was present in all nine affected family members and absent in 528 ethnically matched controls. Western blotting of human cardiac tissue demonstrated significant Kir3.4 expression levels in the cardiac ventricles. Heterologous expression studies with Kir3.4-Gly387Arg revealed a loss-of-function electrophysiological phenotype resulting from reduced plasma membrane expression. Our findings suggest a role for Kir3.4 in the etiology of LQTS.     

Device Therapy to Prevent Sudden Death in Patients with Structural Heart Disease

The advent of the implantable cardioverter defibrillator has provided clinicians with a potential tool to prevent sudden arrhythmic death. When considering patients with structural heart disease, long-term follow-up data have suggested that this is indeed an important cause of late mortality. It is essential therefore to undertake follow-up studies to identify high risk individuals or disease categories that are associated with sudden cardiac death (SCD), and to elucidate the specific risk factors that may be associated with this complication. We provide a brief update on the current state of knowledge in this challenging and rapidly developing field.     

Transformation of Fusarium virguliforme, the Causal Agent of Sudden Death Syndrome of Soybean

Fusarium virguliforme is a soil-borne pathogen that causes sudden death syndrome (SDS) in soybean. SDS is an important disease that causes significant losses in soybean growing areas worldwide. Little is known about the interaction between F. virguliforme and soybean. We have developed a protoplast-based fungal transformation system for F. virguliforme . One of the applications of the transformation system was the production of a green fluorescent protein (GFP)-expressing fungal transformant. The GFP-expressing fungus can be used to study fungal infection processes including fungal penetration, colonization, and spread, especially at the early stages of disease development. Furthermore, in an attempt to increase the genetic resources available to identify and characterize fungal virulence genes involved in the F. virguliforme -soybean system, we generated random insertional mutations in F. virguliforme using restriction enzyme mediated integration.     

Repolarisation and vulnerability to re-entry in the human heart with short QT syndrome arising from KCNQ1 mutation--a simulation study

Idiopathic short QT syndrome (SQTS) is a recently identified, genetically heterogeneous condition characterised by abbreviated QT intervals and an increased susceptibility to arrhythmia and sudden death. This simulation study identifies mechanisms by which cellular electrophysiological changes in the SQT2 (slow delayed rectifier, I_Ks, -linked) SQTS variant increases arrhythmia risk. The channel kinetics of the V307L mutation of the KCNQ1 subunit of the I_Ks channel were incorporated into human ventricular action potential (AP) models and into 1D and 2D transmural tissue simulations. Incorporating the V307L mutation into simulations reproduced defining features of the SQTS: abbreviation of the QT interval, and increases in T wave amplitude and T_peak–T_end duration. In the single-cell model, the V307L mutation abbreviated ventricular cell AP duration at 90% repolarisation (APD₉₀) and increased the maximal transmural voltage heterogeneity (δV) during APs; this resulted in augmented transmural heterogeneity of APD₉₀ and of the effective refractory period (ERP). In the intact tissue model, the vulnerable window for unidirectional conduction block was also increased. In 2D tissue the V307L mutation facilitated and maintained reentrant excitation. Thus, in SQT2 increases in transmural heterogeneity of APD, δV, ERP and an increased vulnerable window for unidirectional conduction block generate an electrical substrate favourable to reentrant arrhythmia.     

先天性脊柱侧弯采用后路半椎体切除短节段融合疗效分析

目的:探讨先天性脊柱侧弯采用后路半椎体切除短节段融合治疗的临床疗效。方法:选取2011年1月~2014年1月经我院治疗的120份先天性脊柱侧弯患者,采用后路半椎体切除短节段融合治疗法进行治疗,比较手术前后、最后一次随访的脊柱全长正侧位X线片,测量并记录治疗前后及随访期间脊柱侧弯程度及后凸的Cobb's角。结果:通过治疗患者脊柱侧弯得到明显改善,半椎体节段侧弯Cobb's角术前平均44.2°,术后平均15.1°,平均矫正率为65.8%,末次随访平均14.3°,矫正率64.2%;全主弯Cobb's角术后平均矫正率60.7%,末次随访平均矫正率65.6%;半椎体节段后凸Cobb's角术前平均15.3°,术后为正常范围值;术后和末次随访的头侧、尾侧代偿弯改善明显,5项指标手术前后对比差异有统计学意义(P0.05)。结论:先天性脊柱侧弯采用后路半椎体切除短节段融合治疗可以达到显著矫正先天性脊柱侧弯的效果。     

Risk stratification for sudden cardiac death in hypertrophic cardiomyopathy: Dutch cardiologists and the care of mutation carriers

Background. Patients with hypertrophic cardiomyopathy (HCM) and HCM mutation carriers are at risk of sudden cardiac death (SCD). Both groups should therefore be subject to regular cardiological testing – including risk stratification for SCD – according to international guidelines. We evaluated Dutch cardiologists' knowledge of and adherence to international guidelines on risk stratification and prevention of SCD in mutation carriers with and without manifest HCM. Methods. A questionnaire was sent to 1109 Dutch cardiologists (in training) containing case-based questions. Results. The response rate was 21%. Own general knowledge on HCM care was rated as insufficient by 63% of cardiologists. The percentage of correct answers (i.e. in agreement with international guidelines), on the case-based questions ranged from 37 to 96%, being lowest in cases with an unknown number of risk factors for SCD. A substantial portion of correct answers was based on the correct answer ‘ask an expert opinion’. Significantly more correct answers were provided in cases with manifest HCM. There was little difference between the answers of cardiologists with different self-reported levels of knowledge, with different numbers of HCM patients in their practice or with different numbers of carriers without manifest HCM. Conclusion. Knowledge on risk stratification and preventive therapy was mediocre, and knowledge gaps exist, especially on HCM mutation carriers without manifest disease. Fortunately, experts are frequently asked for their opinion which might bring patient care to an adequate level. Hopefully, our results will stimulate cardiologists to follow developments in this field, thereby increasing quality of care for HCM patients and mutation carriers. (Neth Heart J 2009:17:464–9.).     

Genetic variation in exon 5 of troponin - I gene in hypertrophic cardiomyopathy cases

BACKGROUND:

Cardiomyopathies are a heterogeneous group of heart muscle disorders and are classified as 1) Hypertrophic Cardiomyopathy (HCM) 2) Dilated cardiomyopathy (DCM) 3) Restrictive cardiomyopathy (RCM) and 4) Arrhythmogenic right ventricular dysplasia (ARVD) as per WHO classification, of which HCM and DCM are common. HCM is a complex but relatively common form of inherited heart muscle disease with prevalence of 1 in 500 individuals and is commonly associated with sarcomeric gene mutations. Cardiac muscle troponin I (TNNI-3) is one such sarcomeric protein and is a subunit of the thin filament-associated troponin-tropomyosin complex involved in calcium regulation of skeletal and cardiac muscle contraction. Mutations in this gene were found to be associated with a history of sudden cardiac death in HCM patients.

AIM:

Therefore the present study aims to identify for mutations associated with troponin I gene in a set of HCM patients from Indian population.

MATERIALS AND METHODS:

Mutational analyses of 92 HCM cases were carried out following PCR based SSCP analysis.

RESULTS:

The study revealed band pattern variation in 3 cases from a group of 92 HCM patients. This band pattern variation, on sequencing revealed base changes, one at nt 2560 with G>T transversion in exon-5 region with a wobble and others at nt 2479 and nt 2478 with G>C and C>G transversions in the intronic region upstream of the exon 5 on sequencing. Further analysis showed that one of the probands showed apical form of hypertrophy, two others showing asymmetric septal hypertrophy. Two of these probands showed family history of the condition.

CONCLUSIONS:

Hence, the study supports earlier reports of involvement of TNNI-3 in the causation of apical and asymmetrical forms of hypertrophy.     

The role of the unfolded protein response in arrhythmias

Human heart failure is characterized by arrhythmogenic electrical remodeling consisting mostly of ion channel downregulations. Reversing these downregulations is a logical approach to antiarrhythmic therapy, but understanding the pathophysiological mechanisms of the reduced currents is crucial for finding the proper treatments. The unfolded protein response (UPR) is activated by endoplasmic reticulum (ER) stress and has been found to play pivotal roles in different diseases including neurodegenerative diseases, diabetes mellitus, and heart disease. Recently, the UPR is reported to regulate multiple cardiac ion channels, contributing to arrhythmias in heart disease. In this review, we will discuss which UPR modulators and effectors could be involved in regulation of cardiac ion channels in heart disease, and how the understanding of these regulating mechanisms may lead to new antiarrhythmic therapeutics that lack the proarrhythmic risk of current ion channel blocking therapies.     

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.     

Cardiac Arrhythmias In Congenital Heart Diseases

Arrhythmias figure prominently among the complications encountered in the varied and diverse population of patients with congenital heart disease, and are the leading cause of morbidity and mortality. The incidence generally increases as the patient ages, with multifactorial predisposing features that may include congenitally malformed or displaced conduction systems, altered hemodynamics, mechanical or hypoxic stress, and residual or postoperative sequelae. The safe and effective management of arrhythmias in congenital heart disease requires a thorough appreciation for conduction system variants, arrhythmia mechanisms, underlying anatomy, and associated physiology. We, therefore, begin this review by presenting the scope of the problem, outlining therapeutic options, and summarizing congenital heart disease-related conduction system anomalies associated with disorders of the sinus node and AV conduction system. Arrhythmias encountered in common forms of congenital heart disease are subsequently discussed. In so doing, we touch upon issues related to risk stratification for sudden death, implantable cardiac devices, catheter ablation, and adjuvant surgical therapy.     

When Rare Illuminates Common: How Cardiocutaneous Syndromes Transformed Our Perspective on Arrhythmogenic Cardiomyopathy

Abstract

The classic cardiocutaneous syndromes of Naxos and Carvajal are rare. The myocardial disorder integral to their pathology – arrhythmogenic cardiomyopathy – is arguably not uncommon, with a prevalence of up to 1 in 1,000 despite almost certain under-recognition. Yet the study of cardiocutaneous syndromes has been integral to evolution of the contemporary perspective of arrhythmogenic cardiomyopathy – its clinical course, disease spectrum, genetics, and cellular and molecular mechanisms. Here we discuss how recognition of the association of hair and skin abnormalities with underlying heart disease transformed our conception of a little-understood but important cause of sudden cardiac death.