Ageing,the autonomic nervous system and arrhythmia: From brain to heart

An ageing myocardium possesses significant electrophysiological alterations that predisposes the elderly patient to arrhythmic risk. Whilst these alterations are intrinsic to the cardiac myocytes, they are modulated by the cardiac autonomic nervous system (ANS) and consequently, ageing of the cardiac ANS is fundamental to the development of arrhythmias. A systems-based approach that incorporates the influence of the cardiac ANS could lead to better mechanistic understanding of how arrhythmogenic triggers and substrates interact spatially and temporally to produce sustained arrhythmia and why its incidence increases with age. Despite the existence of physiological oscillations of ANS activity on the heart, pathological oscillations can lead to defective activation and recovery properties of the myocardium. Such changes can be attributable to the decrease in functionality and structural alterations to ANS specific receptors in the myocardium with age. These altered ANS adaptive responses can occur either as a normal ageing process or accelerated in the presence of specific cardiac pathologies, such as genetic mutations or neurodegenerative conditions. Targeted intervention that seek to manipulate the ageing ANS influence on the myocardium may prove to be an efficacious approach for the management of arrhythmia in the ageing population.     

Antibody therapeutics targeting ion channels: are we there yet?

The combination of technological advances, genomic sequences and market success is catalyzing rapid development of antibody-based therapeutics. Cell surface receptors and ion channel proteins are well known drug targets, but the latter has seen less success. The availability of crystal structures, better understanding of gating biophysics and validation of physiological roles now form an excellent foundation to pursue antibody-based therapeutics targeting ion channels to treat a variety of diseases.     

The usual suspects in sudden cardiac death of the young: a focus on inherited arrhythmogenic diseases

Up to 14,500 young individuals die suddenly every year in Europe of cardiac pathologies. The majority of these tragic events are related to a group of genetic defects that predispose the development of malignant arrhythmias (inherited arrhythmogenic diseases [IADs]). IADs include both cardiomyopathies (hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy) and channelopathies (long QT syndrome, short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia). Every time an IAD is identified in a patient, other individuals in his/her family may be at risk of cardiac events. However; if a timely diagnosis is made, simple preventative measures may be applied. Genetic studies play a pivotal role in the diagnosis of IADs and may help in the management of patients and their relatives.     

The Timothy syndrome mutation differentially affects voltage- and calcium-dependent inactivation of CaV1.2 L-type calcium channels

Calcium entry into excitable cells is an important physiological signal, supported by and highly sensitive to the activity of voltage-gated Ca²⁺ channels. After membrane depolarization, Ca²⁺ channels first open but then undergo various forms of negative feedback regulation including voltage- and calcium-dependent inactivation (VDI and CDI, respectively). Inactivation of Ca²⁺ channel activity is perturbed in a rare yet devastating disorder known as Timothy syndrome (TS), whose features include autism or autism spectrum disorder along with severe cardiac arrhythmia and developmental abnormalities. Most cases of TS arise from a sporadic single nucleotide change that generates a mutation (G406R) in the pore-forming subunit of the L-type Ca²⁺ channel Ca_V1.2. We found that the TS mutation powerfully and selectively slows VDI while sparing or possibly speeding the kinetics of CDI. The deceleration of VDI was observed when the L-type channels were expressed with β₁ subunits prominent in brain, as well as β₂ subunits of importance for the heart. Dissociation of VDI and CDI was further substantiated by measurements of Ca²⁺ channel gating currents and by analysis of another channel mutation (I1624A) that hastens VDI, acting upstream of the step involving Gly⁴⁰⁶. As highlighted by the TS mutation, CDI does not proceed to completeness but levels off at ≈50%, consistent with a change in gating modes and not an absorbing inactivation process. Thus, the TS mutation offers a unique perspective on mechanisms of inactivation as well as a promising starting point for exploring the underlying pathophysiology of autism.     

Diagnostic evaluation and arrhythmia mechanisms in survivors of unexplained cardiac arrest

Identifying the cause of unexplained cardiac arrest is critical for appropriate management of both survivors and their family members. Aborted cardiac arrests whose cause remains unknown following investigation with a surface ECG, echocardiogram, and coronary angiogram are deemed unexplained. Many of these unexplained arrests are felt to be secondary to concealed forms of cardiac channelopathies and latent or subtle cardiomyopathies. This recognition has led to evaluating a diagnostic role for a series of additional investigations, including advanced imaging, genetic testing, and provocative forms of testing, including sodium channel blockade and treadmill testing. Despite evidence of an improved diagnostic yield through their systematic usage, clinical guidelines have yet to endorse a formal algorithm delineating investigations that must be performed before assigning a label of idiopathic ventricular fibrillation, which has resulted in markedly variables thresholds for concluding this diagnosis. Debate remains regarding the need for an invasive electrophysiology study among these patients, though identification of arrhythmic culprits requiring intracardiac electrograms for diagnostic confirmation have suggested a potential role when an initial comprehensive evaluation is unrevealing. Although progress is being made, the sizeable portion of arrests that remain unexplained despite completion of a comprehensive evaluation highlights an ongoing need for further research and additional tools to help unravel the ongoing mysteries of these near fatal events.     

Value of short exercise and short exercise with cooling tests in the diagnosis of myotonic dystrophies (DM1 AND DM2)

Introduction: Standard electromyography (EMG) is useful in the diagnosis of myotonic dystrophy type 1 (DM1) and type 2 (DM2), but it does not differentiate between them. The aim of this study was to estimate the utility of the short exercise test (SET) and short exercise test with cooling (SETC) in differentiating between DM1 and DM2. Methods: SET and SETC were performed in 32 patients with DM1 (mean age 35.8 ± 12.7 years) and 28 patients with DM2 (mean age 44.5 ± 12.5 years). Results: We observed a significant decline in compound motor action potential (CMAP) amplitude in DM1 with both SET and SETC immediately after effort. In DM2, there was no marked change in CMAP amplitude with either SET or SETC. Conclusions: SET and SETC may serve as useful tools for clinical differentiation between DM1 and DM2, and they may be used as a guide for molecular testing. Muscle Nerve 49 : 277–283, 2014     

钾敏感型周期性麻痹一个家系研究

目的　探讨正常血钾型家族性周期性麻痹的临床、病理特点及可行的治疗方法。方法　对一个血钾正常的周期性麻痹患者家系进行临床及病理研究。结果　该家系 4代 1 8名有血缘关系的家庭成员中 ,共有 8名男女成员患病 ,符合常染色体显性遗传方式。受累成员均在 1 0岁前发病 ,表现为发作性四肢无力 ,持续 1～ 2周后逐渐恢复。间歇期基本正常。儿童期发作频繁 ,为每月数次 ,不能上学。青春期后发作减少 ,约每年数次。常见诱因有饥饿、寒冷、兴奋、剧烈运动后休息及进食西瓜等。发作时及发作后血钾均正常。钾负荷试验诱发出典型全身无力发作 ,静脉滴注葡萄糖及胰岛素能迅速缓解。肌电图检查支持周期性麻痹诊断。肌肉活检未发现明显病理学改变。使用已报道的治疗方法均不能有效缓解生活因素诱发的肌无力。结论　血钾正常的钾敏感型周期性麻痹很可能是高钾型周期性麻痹的变异型 ,但与已报道的家系又有诸多不同 ,需进一步研究其分子缺陷及离子通道特性。     

Neuroimaging and neurogenetics of epilepsy in humans

In the past decade, several genetic mutations have been associated with different forms of familial focal and generalized epilepsies. Most of these genes encode ion-channel subunits. Based on neurophysiological in vitro and in vivo animal studies, substantial progress has been made in understanding the functional consequences of gene defects associated with epilepsies. However, the knowledge transition from animal studies to patients carrying a mutation, or even suffering from a nonfamilial form of epilepsy, is very limited. This review will illustrate how neuroimaging studies in humans may help to bridge the gap between genotype and phenotype. We will be presenting examples of familial focal (autosomal dominant nocturnal frontal lobe epilepsy), idiopathic generalized epilepsies (severe myoclonic epilepsy of infancy). Such studies will help to better understand functional consequences of genetic alterations and may contribute to a better phenotype characterization.