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.     

遗传性心律失常心肌病:2007研究进展与专家共识

心脏电疾病的分类极端复杂,许多方面甚至相互矛盾.AHA在致心律失常心肌病的分类法中,建议把离子通道病合并到原发性心肌病中.2007年11月,美国国立心肺与血管研究所和罕见疾病办公室在Circulation杂志发表了关于由基因突变影响离子通道功能所致原发性心肌病的诊断、表型、分子机制和治疗手段的专家共识报告,针对这组日益复杂化的原发性心脏膜通道疾病提出了一个重要框架.现就其中的重点与新进展做一综述.内容包括:(1)Na 通道病;(2)K 通道突变引起的心律失常;(3)由于其它遗传性致心律失常机制引起的心律失常;(4)未来诊断和治疗的建议.     

Cardiac Arrhythmias in Africa: Epidemiology,Management Challenges,and Perspectives

Africa is experiencing an increasing burden of cardiac arrhythmias. Unfortunately, the expanding need for appropriate care remains largely unmet because of inadequate funding, shortage of essential medical expertise, and the high cost of diagnostic equipment and treatment modalities. Thus, patients receive suboptimal care. A total of 5 of 34 countries (15%) in Sub-Saharan Africa (SSA) lack a single trained cardiologist to provide basic cardiac care. One-third of the SSA countries do not have a single pacemaker center, and more than one-half do not have a coronary catheterization laboratory. Only South Africa and several North African countries provide complete services for cardiac arrhythmias, leaving more than hundreds of millions of people in SSA without access to arrhythmia care considered standard in other parts of the world. Key strategies to improve arrhythmia care in Africa include greater government health care funding, increased emphasis on personnel training through fellowship programs, and greater focus on preventive care.     

Phenylephrine-Induced Ventricular Arrhythmias in Dogs with Inherited Sudden Death

Dogs with Inherited Sudden Death. Introduction: Dogs with an inherited predisposition to sudden death display ventricular arrhythmias having certain characteristics, such as pause dependence, that are suggestive of early afterdepolarization-induced triggered activity. We hypothesized that α-adrenergic stimulation may facilitate the development of these arrhythmias by inducing a reflex bradycardia and by exerting a direct myocardial effect.
Methods and Results: Twenty affected dogs and 7 unaffected dogs were studied. The incidence and severity of ventricular arrhythmias were determined after administration of phenylephrine (0.01 mg/kg IV), with or without pretreatment with propranolol (0.1 to 0.3 mg/kg IV), atropine (0.04 mg/kg IV), or prazosin (0.5 mg/kg IV). Third-degree heart block was induced by AV nodal ablation in 4 affected dogs. Phenylephrine increased ventricular arrhythmias in affected dogs, with or without pretreatment with propranolol, but did not induce ventricular arrhythmias in unaffected dogs. In dogs with intact AV nodal conduction, atropine increased sinus rate, which suppressed baseline and phenylephrine-induced arrhythmias. In dogs with heart block, arrhythmias were increased during baseline and after phenylephrine with or without pretreatment with atropine. Prazosin and overdrive ventricular pacing suppressed phenylephrine-induced arrhythmias.
Conclusion: Phenylephrine increases ventricular arrhythmias in dogs with inherited sudden death via both an induction of reflex bradycardia and a direct myocardial effect. Superimposition of heightened α-adrenergic and vagal tone may facilitate the development of sudden death in these animals.     

Arrhythmias in Cardiac Amyloidosis: Challenges in Risk Stratification and Treatment

Cardiac amyloidosis occurs secondarily to the deposition of insoluble protein fibrils in cardiac tissue leading to progressive myocardial dysfunction, clinical heart failure, and arrhythmia. In recent years, increasing awareness and improved screening have resulted in an increased prevalence of cardiac amyloidosis, with contemporary estimates reporting a prevalence of 18-55 cases per 100,000 person-years, accounting for > 13% of heart failure hospitalizations. The arrhythmic manifestations of cardiac amyloidosis can range from conduction-system disease and bradyarrhythmias to atrial fibrillation and sudden cardiac death. Bradyarrhythmias and conduction system disease may occur secondarily to amyloid infiltration, but the timing of pacemaker implantation remains unclear. When available, biventricular pacing should be considered in symptomatic patients, particularly in those expected to receive a high burden of ventricular pacing (> 40%). The management of atrial fibrillation can be challenging, because contemporary agents for rate and rhythm control may be poorly tolerated in patients with cardiac amyloidosis. Patients with cardiac amyloidosis also have a high rate of intracardiac thrombus and should be anticoagulated in the presence of atrial fibrillation (regardless of CHADS₂ score). We generally consider transesophageal echocardiography before cardioversion regardless of anticoagulation status or duration of arrhythmia. Ventricular arrhythmias may also occur in patients with cardiac amyloidosis, and decisions surrounding implantable cardioverter-defibrillator implantation should balance the risks of ventricular arrhythmia and sudden cardiac death with the competing risks of worsening heart failure and noncardiac death. In this review, we cover the primary arrhythmic manifestations of cardiac amyloidosis and discuss their management considerations.     

Nanomaterials for Inner Ear Diseases: Challenges,Limitations and Opportunities

The inner ear is located deep in the temporal bone and has a complex anatomy. It is difficult to observe and obtain pathological tissues directly. Therefore, the diagnosis and treatment of inner ear diseases have always been a major clinical problem. The onset of inner ear disease can be accompanied by symptoms such as hearing loss, dizziness and tinnitus, which seriously affect people’s lives. Nanoparticles have the characteristics of small size, high bioavailability and strong plasticity. With the development of related research on nanoparticles in inner ear diseases, nanoparticles have gradually become a research hotspot in inner ear diseases. This review briefly summarizes the research progress, opportunities and challenges of the application of nanoparticles in inner ear diseases.     

Late Sodium Current Inhibition in Acquired and Inherited Ventricular (dys)function and Arrhythmias

The late sodium current has been increasingly recognized for its mechanistic role in various cardiovascular pathologies, including angina pectoris, myocardial ischemia, atrial fibrillation, heart failure and congenital long QT syndrome. Although relatively small in magnitude, the late sodium current (I_NaL) represents a functionally relevant contributor to cardiomyocyte (electro)physiology. Many aspects of I_NaL itself are as yet still unresolved, including its distribution and function in different cell types throughout the heart, and its regulation by sodium channel accessory proteins and intracellular signalling pathways. Its complexity is further increased by a close interrelationship with the peak sodium current and other ion currents, hindering the development of inhibitors with selective and specific properties. Thus, increased knowledge of the intricacies of the complex nature of I_NaL during distinct cardiovascular conditions and its potential as a pharmacological target is essential. Here, we provide an overview of the functional and electrophysiological effects of late sodium current inhibition on the level of the ventricular myocyte, and its potential cardioprotective and anti-arrhythmic efficacy in the setting of acquired and inherited ventricular dysfunction and arrhythmias.     

Cost‐Effectiveness of Implanted Defibrillators in Young People with Inherited Cardiac Arrhythmias

Background: The implanted cardioverter‐defibrillator (ICD) has been shown to improve survival in adult patients with high risk acquired cardiac disease, with a cost‐effectiveness ratio in the range of $30,000 to $185,000 per quality‐adjusted‐life‐year saved. However, data on the benefit and cost‐effectiveness of device therapy in high‐risk patients with inherited cardiac disorders are limited. Methods: We developed two separate computer‐based analytical models to compare non‐ICD with ICD therapy in patients (age range: 10–75 years) with long QT syndrome (LQTS) and hypertrophic cardiomyopathy (HCM). In each disease entity patients were stratified into low‐risk (no known risk factors); high‐risk (known risk factors [primary prevention]); and very high‐risk (prior near‐fatal events [secondary prevention]). Net costs were defined as the difference between costs resulting from treatment of the disease and savings due to gained productivity attributable to prevention of sudden cardiac death. Outcome was defined as costs per quality‐adjusted life‐years saved. Results: In LQTS, defibrillator therapy was shown to be cost effective in high‐risk male patients (incremental cost‐effectiveness ratio [ICER]=$3328 per quality‐adjusted‐life‐year saved), and cost saving in high‐risk females (ICER =$7102 gained per quality‐adjusted‐life‐year saved) and very high‐risk males and females (ICER =$15,483 and 19,393 gained per quality‐adjusted‐life‐year saved, respectively). In HCM, defibrillator therapy was cost saving in both male and female high‐risk (ICER =$17,892 and $17,526 gained per quality‐adjusted‐life‐year saved, respectively) and very high‐risk (ICER =$22,944 and $22,329 gained per quality‐adjusted‐life‐year saved, respectively) patients. Defibrillator therapy was not shown to be cost effective in low‐risk patients with either LQTS or HCM (ICER in the range of $400,000 to $600,000 lost per quality‐adjusted‐life‐year saved). Sensitivity analyses were consistent with the results in each risk group. Conclusions: In appropriately selected patients with inherited cardiac disorders, early intervention with ICD therapy is cost‐effective to cost saving due to added years of gained productivity when the lifespan of an individual at risk is considered.     

Statin Use and Ventricular Arrhythmias During Clinical Treadmill Testing

Background: Premature ventricular complexes (PVCs) during exercise are associated with adverse prognosis, particularly in patients with intermediate treadmill test findings. Statin use reduces the incidence of resting ventricular arrhythmias in patients with coronary artery disease; however, the relationship between statin use and exercise-induced ventricular arrhythmias has not been investigated.
Methods and Results: We evaluated the association between statin use and PVCs in 1,847 heart-failure-free patients (mean age 58, 95% male) undergoing clinical exercise treadmill testing between 1997 and 2004 in the VA Palo Alto Health Care System. PVCs were quantified in beats per minute and frequent PVCs were defined as PVC rates greater than the median value (0.43 and 0.60 PVCs per minute for exercise and recovery, respectively). Propensity-adjusted logistic regression was used to evaluate the odds of developing PVCs during exercise and recovery periods associated with statin use. There were 431 subjects who developed frequent PVCs during exercise and 284 subjects had frequent recovery PVCs. After propensity score adjustment, subjects treated with statins (n = 145) had 42% lower odds of developing frequent PVCs during exercise (odds ratio [OR] 0.58, 95% confidence interval [CI] 0.37–0.93) and 44% lower odds of developing frequent PVCs during recovery (OR 0.56, 95% CI 0.30–0.94). These effects were not modified by age, prior coronary disease, hypercholesterolemia, exercise-induced angina, or exercise capacity.
Conclusions: Statin use was associated with reduced odds of frequent PVCs during and after clinical exercise testing in a manner independent of associations with coronary disease or ischemia in our study population.     

2015年欧洲心脏病学会关于心肌病、遗传性心律失常、小儿和先天性心脏病患者室性心律失常治疗和心脏性猝死预防指南解读

本文解读2015年欧洲心脏病学会关于心肌病、遗传性心律失常、小儿和先天性心脏病患者室性心律失常治疗和心脏性猝死预防指南,指南全面评价了这些患者室性心律失常和心脏性猝死的风险因素;更新了风险分层和室性心律失常预防和治疗最佳策略推荐,以预防心脏性猝死和降低其他不良临床预后;最后指出临床证据的空白,明确今后研究的重点领域。     

Human iPSC-Derived Cardiomyocytes for Investigation of Disease Mechanisms and Therapeutic Strategies in Inherited Arrhythmia Syndromes: Strengths and Limitations

During the last two decades, significant progress has been made in the identification of genetic defects underlying inherited arrhythmia syndromes, which has provided some clinical benefit through elucidation of gene-specific arrhythmia triggers and treatment. However, for most arrhythmia syndromes, clinical management is hindered by insufficient knowledge of the functional consequences of the mutation in question, the pro-arrhythmic mechanisms involved, and hence the most optimal treatment strategy. Moreover, disease expressivity and sensitivity to therapeutic interventions often varies between mutations and/or patients, underlining the need for more individualized strategies. The development of the induced pluripotent stem cell (iPSC) technology now provides the opportunity for generating iPSC-derived cardiomyocytes (CMs) from human material (hiPSC-CMs), enabling patient- and/or mutation-specific investigations. These hiPSC-CMs may furthermore be employed for identification and assessment of novel therapeutic strategies for arrhythmia syndromes. However, due to their relative immaturity, hiPSC-CMs also display a number of essential differences as compared to adult human CMs, and hence there are certain limitations in their use. We here review the electrophysiological characteristics of hiPSC-CMs, their use for investigating inherited arrhythmia syndromes, and their applicability for identification and assessment of (novel) anti-arrhythmic treatment strategies.