遗传性心律失常的基因检测

自1995年发现遗传性心律失常第一个离子通道致病基因以来,心律失常的遗传学研究取得了长足的进展,发现了近30个致病基因和近千个致病突变位点.2011年,美国心律学会/欧洲心律学会发布了《心脏离子通道病与心肌病基因检测专家共识》,2013年,美国心律学会/欧洲心律学会/亚太心律学会共同发布了《遗传性原发心律失常综合征患者的诊断治疗专家共识》[1-2].目前发达国家对遗传性心律失常的基因检测已用于辅助诊断.中华医学会心血管病学分会和中华心血管病杂志编辑委员会专家组根据国外的进展和自己的观点发布了相应的中国专家共识,其中重点阐述了基因检测在遗传性心律失常中的价值,评估了基因检测结果对不同种类的遗传性心律失常的诊断、预后、治疗和预防的影响,为我国遗传性心律失常基因检测提供了指导性意见.     

Emerging drugs for irritable bowel syndrome

Irritable bowel syndrome is extremely common and its severity is widely underestimated. Unfortunately, the current pharmacological treatment of this condition is far from satisfactory which might suggest that it would be an area in which the pharmaceutical industry would take a great interest. However, drug development in this field, especially in relation to 5-hydroxytryptamine (5-HT), has been beset by difficulties with side effects and, what some authorities would claim, an unnecessarily strict regulatory climate based on the perception that irritable bowel syndrome is not a particularly serious condition. This has resulted in a rapid withdrawal from the scene by a number of companies although with the identification of some potential new therapeutic targets, the area has not been totally abandoned.     

Repolarization abnormalities unmasked with exercise in sudden cardiac death survivors with structurally normal hearts

1 Background

Models of cardiac arrhythmogenesis predict that nonuniformity in repolarization and/or depolarization promotes ventricular fibrillation and is modulated by autonomic tone, but this is difficult to evaluate in patients. We hypothesize that such spatial heterogeneities would be detected by noninvasive ECG imaging (ECGi) in sudden cardiac death (SCD) survivors with structurally normal hearts under physiological stress.

2 Methods

ECGi was applied to 11 SCD survivors, 10 low‐risk Brugada syndrome patients (BrS), and 10 controls undergoing exercise treadmill testing. ECGi provides whole heart activation maps and >1,200 unipolar electrograms over the ventricular surface from which global dispersion of activation recovery interval (ARI) and regional delay in conduction were determined. These were used as surrogates for spatial heterogeneities in repolarization and depolarization. Surface ECG markers of dispersion (QT and Tpeak‐end intervals) were also calculated for all patients for comparison.

3 Results

Following exertion, the SCD group demonstrated the largest increase in ARI dispersion compared to BrS and control groups (13 ± 8 ms vs. 4 ± 7 ms vs. 4 ± 5 ms; P = 0.009), with baseline dispersion being similar in all groups. In comparison, surface ECG markers of dispersion of repolarization were unable to discriminate between the groups at baseline or following exertion. Spatial heterogeneities in conduction were also present following exercise but were not significantly different between SCD survivors and the other groups.

4 Conclusion

Increased dispersion of repolarization is apparent during physiological stress in SCD survivors and is detectable with ECGi but not with standard ECG parameters. The electrophysiological substrate revealed by ECGi could be the basis of alternative risk‐stratification techniques.     

Contemporary updates on ventricular arrhythmias: from mechanisms to management

Ventricular arrhythmias (VAs) are a group of heart rhythm disorders that can be life-threatening and cause significant morbidity. VA in the presence of structural heart disease (SHD) has distinct prognostic implications and requires a comprehensive and multifaceted approach for investigation and management. Early specialist referral should be considered for all patients with VA. Particular urgency is recommended in patients with syncope, nonsustained/sustained VA on Holter monitor and SHD on cardiac imaging because of the heightened risk of sudden cardiac death. Comprehensive phenotyping is recommended for most patients with VA, encompassing noninvasive cardiac functional testing, multimodality imaging and genetic testing in select circumstances. Management of idiopathic VA is guided heavily by symptom burden and the presence of ventricular systolic impairment. In SHD, guideline-directed heart failure therapy and device implantation are critical considerations. Whilst commonly used and well-established, antiarrhythmic drugs can be hampered by toxicity and failure of adequate arrhythmia control. Catheter ablation is increasingly being considered a feasible first-line alternative to medical therapy, where outcomes are influenced by disease aetiology and scar burden in SHD. Catheter ablation is associated with reduced arrhythmia recurrence and burden and improved quality of life at follow-up.     

Transient weakness and compound muscle action potential decrement in myotonia congenita

Twenty-five Turkish patients with recessive myotonia congenita (RMC), 16 of whom had genetic confirmation, were studied. Nineteen had transient weakness. In the upper extremities, onset age of transient weakness was usually in the early teens. All untreated RMC patients had a compound muscle action potential decrement of ⩾25%, usually above 50%, with repetitive nerve stimulation at 10/s for 5 s. Patients with other nondystrophic diseases with myotonia, except 1 patient with dominant myotonia congenita, had no transient weakness and a CMAP decrement below 25%. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:1334–1337, 1998.     

KCNJ2 mutation in short QT syndrome 3 results in atrial fibrillation and ventricular proarrhythmia

We describe a mutation (E299V) in KCNJ2, the gene that encodes the strong inward rectifier K⁺ channel protein (Kir2.1), in an 11-y-old boy. The unique short QT syndrome type-3 phenotype is associated with an extremely abbreviated QT interval (200 ms) on ECG and paroxysmal atrial fibrillation. Genetic screening identified an A896T substitution in a highly conserved region of KCNJ2 that resulted in a de novo mutation E299V. Whole-cell patch-clamp experiments showed that E299V presents an abnormally large outward I_K1 at potentials above −55 mV (P < 0.001 versus wild type) due to a lack of inward rectification. Coexpression of wild-type and mutant channels to mimic the heterozygous condition still resulted in a large outward current. Coimmunoprecipitation and kinetic analysis showed that E299V and wild-type isoforms may heteromerize and that their interaction impairs function. The homomeric assembly of E299V mutant proteins actually results in gain of function. Computer simulations of ventricular excitation and propagation using both the homozygous and heterozygous conditions at three different levels of integration (single cell, 2D, and 3D) accurately reproduced the electrocardiographic phenotype of the proband, including an exceedingly short QT interval with merging of the QRS and the T wave, absence of ST segment, and peaked T waves. Numerical experiments predict that, in addition to the short QT interval, absence of inward rectification in the E299V mutation should result in atrial fibrillation. In addition, as predicted by simulations using a geometrically accurate three-dimensional ventricular model that included the His–Purkinje network, a slight reduction in ventricular excitability via 20% reduction of the sodium current should increase vulnerability to life-threatening ventricular tachyarrhythmia.     

HCN通道相关性疾病在心脏中的表现

超极化激活环核苷酸门控阳离子通道(HCN)在心脏起搏细胞中呈高表达,并参与心脏起搏的产生及心率调控。而调控该通道蛋白的基因突变、错义均可导致心律失常的发生。目前已发现5种HCN基因突变所致的心律失常,且存在家族遗传性。不仅如此,该基因在心肌不同的微环境中可能呈现出不同的表达,进一步影响心律的变化。现对HCN通道生物生理特点及HCN通道相关性疾病的研究进展进行综述。     

Is there a role for potassium channel openers in neuronal ion channel disorders?

Malfunction in ion channels, due to mutations in genes encoding channel proteins or the presence of autoantibodies, are increasing being implicated in causing disease conditions, termed channelopathies. Dysfunction of potassium (K⁺) channels has been associated with the pathophysiology of a number of neurological, as well as peripheral, disorders (e.g., episodic ataxia, epilepsy, neuromyotonia, Parkinson’s disease, congenital deafness, long QT syndrome). K⁺ channels, which demonstrate a high degree of diversity and ubiquity, are fundamental in the control of membrane depolarisation and cell excitability. A common feature of K⁺ channelopathies is a reduction or loss of membrane potential repolarisation. The identification of K⁺ channel subtype specific openers will allow the recovery of the mechanism(s) responsible for counteraction of uncontrolled cellular depolarisation. Synthetic agents that demonstrate K⁺ channel opening properties are available for a variety of K⁺ channel subtypes (e.g., K_ATP, BK_Ca, GIRK and M-channel). This study reviews the realistic therapeutic potential that may be gained in a broad spectrum of clinical conditions by K⁺ channel openers. K⁺ channel openers would therefore identify dysfunctional K⁺ channel as therapeutic targets for clinical benefit, in addition being able to modulate normally functioning K⁺ channels to gain clinical management of pathophysiological events irrespective of the cause.