Genetic predisposition for sudden cardiac death in myocardial ischaemia: the Arrhythmia Genetics in the NEtherlandS study

Sudden cardiac death from ventricular fibrillation during myocardial infarction is a leading cause of total and cardiovascular mortality. This multifactorial, complex condition clusters in families, suggesting a substantial genetic cause. We carried out a genomewide association study (GWAS) for sudden cardiac death, in the AGNES (Arrhythmia Genetics in the Netherlands) population, consisting of patients with (cases) and without (controls) ventricular fibrillation during a first ST-elevation myocardial infarction. The most significant association was found at chromosome 21q21 (rs2824292; odds ratio = 1.78, 95% CI 1.47–2.13, P = 3.3 × 10⁻¹⁰), 98 kb proximal of the CXADR gene, encoding the Coxsackie and adenovirus receptor. This locus has not previously been implicated in arrhythmia susceptibility. Further research on the mechanism of this locus will ultimately provide novel insight into arrhythmia mechanisms in this condition.     

Taxol,a microtubule stabilizer,prevents ischemic ventricular arrhythmias in rats

Microtubule integrity is important in cardio‐protection, and microtubule disruption has been implicated in the response to ischemia in cardiac myocytes. However, the effects of Taxol, a common microtubule stabilizer, are still unknown in ischemic ventricular arrhythmias. The arrhythmia model was established in isolated rat hearts by regional ischemia, and myocardial infarction model by ischemia/reperfusion. Microtubule structure was immunohistochemically measured. The potential mechanisms were studied by measuring reactive oxygen species (ROS), activities of oxidative enzymes, intracellular calcium concentration ([Ca²⁺]_i) and Ca²⁺ transients by using fluorometric determination, spectrophotometric assays and Fura‐2‐AM and Fluo‐3‐AM, respectively. The expression and activity of sarcoplasmic reticulum Ca²⁺‐ATPase (SERCA2a) was also examined using real‐time polymerase chain reaction, Western blot and pyruvate/Nicotinamide adenine dinucleotide‐coupled reaction. Our data showed that Taxol (0.1, 0.3 and 1 μM) effectively reduced the number of ventricular premature beats and the incidence and duration of ventricular tachycardia. The infarct size was also significantly reduced by Taxol (1 μM). At the same time, Taxol preserved the microtubule structure, increased the activity of mitochondrial electron transport chain complexes I and III, reduced ROS levels, decreased the rise in [Ca²⁺]_i and preserved the amplitude and decay times of Ca²⁺ transients during ischemia. In addition, SERCA2a activity was preserved by Taxol during ischemia. In summary, Taxol prevents ischemic ventricular arrhythmias likely through ameliorating abnormal calcium homeostasis and decreasing the level of ROS. This study presents evidence that Taxol may be a potential novel therapy for ischemic ventricular arrhythmias.     

瑞舒伐他汀对兔心肌梗死后心室重构及细胞凋亡的影响

目的:观察瑞舒伐他汀对新西兰大白兔心肌梗死后左室重构及心肌细胞凋亡的影响。方法:45只雄性新西兰大白兔随机分成三组,即:假手术组(S,n=15),心肌梗死对照组(MI,n=15),心肌梗死瑞舒伐他汀干预组(R,n=15)MI组和R组大鼠结扎左冠状动脉前降支建立AMI模型。心肌梗死对照组及假手术组术后24h灌等量的生理盐水。瑞舒伐他汀干预组于术后24h直接灌胃法给药,给药剂量以10mg/kg*d计算。干预2周后,进行心脏超声测定,随即处死新西兰大白兔、取出心脏,观察病理组织形态,并通过Western blot方法检测Bcl-2,Bax在心肌梗死边缘区的蛋白表达。结果:①心脏超声检测表明干预组左室舒张末内径(LVEDD)、左室收缩末内径(LVESD)较心肌梗死对照组降低而左室射血分数(LVEF)较心肌梗死对照组增高②干预组心肌梗死边缘区Bax表达与心肌梗死对照组比较未见统计学差异,而Bcl-2表达高于心肌梗死对照组。结论:瑞舒伐他汀上调Bcl-2的表达,改善心室重构     

Effects of PFOS and PFOA on L-type Ca2+ currents in guinea-pig ventricular myocytes

Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are amphiphiles found ubiquitously in the environment, including wildlife and humans, and are known to have toxic effects on physiological functions of various tissues. We investigated the effects of PFOS and PFOA on action potentials and L-type Ca(2+) currents, I(CaL), in isolated guinea-pig ventricular myocytes using whole-cell patch-clamp recording. In current-clamp experiments, PFOS significantly decreased the rate of spike, action potential duration, and peak potential at doses over 10 microM. In voltage-clamp experiments, PFOS increased the voltage-activated peak amplitude of I(CaL), and shifted the half-activation and inactivation voltages of I(CaL) to hyperpolarization. PFOA had similar effects PFOS, but showed significantly lower potency. These findings are consistent with previous observations for anionic n-alkyl surfactants, suggesting that PFOS and PFOA may change membrane surface potential, thereby eliciting general effects on calcium channels. These findings provide further insights into the mechanisms of PFOA and PFOS toxicities.     

Phase singularities and filaments: simplifying complexity in computational models of ventricular fibrillation

In the whole heart, millions of cardiac cells are involved in ventricular fibrillation (VF). Experimental studies indicate that VF is sustained by re-entrant activity, and that each re-entrant wave rotates around a filament of phase singularity. Filaments act as organising centres, and offer a way to simplify and quantify the complex spatio-temporal behaviour observed in VF. Where a filament touches the surface of fibrillating myocardium re-entrant activity can be observed, however the behaviour of filaments within bulk ventricular myocardium is difficult to observe directly using present experimental techniques. Large scale computational simulations of VF in three-dimensional (3D) tissue offer a tool to investigate the properties and behaviour of filaments, and the aim of this paper is to review recent advances in this area as well as to compare recent computational studies of fibrillation in whole ventricle geometries.     

The Virtual Ventricular Wall: A Tool for Exploring Cardiac Propagation and Arrhythmogenesis

Methods for the experimental and clinical investigation of cardiac arrhythmias are limited to inferring propagation within the myocardium, from surface measurements, or from electrodes at a few sites within the cardiac wall. Biophysically and anatomically detailed computational models of cardiac tissues offer a powerful way for studying the electrical propagation processes and arrhythmias within the virtual heart. We use virtual tissues to study and visualise the effects of patho- and physiological conditions, and pharmacological interventions on transmural propagation in the virtual ventricular walls. Class III drug actions are quantitatively explained by changes induced in the transmural dispersion of action potential duration. We illustrate the automated construction of a virtual anisotropic ventricle from Diffusion Tensor MRI for individual hearts, and use it to explore mechanisms leading to ventricular fibrillation. The virtual ventricular wall provides an effective tool for exploring, evaluating and visualising processes during the initiation and maintenance of ventricular arrhythmias.     

Remote monitoring in implantable defibrillator therapy

The major device manufacturers have introduced systems for remote patient monitoring. These remote monitoring systems promise more efficient patient management, especially in today’s clinical setting with the growing number of defibrillator implantations. The aim of this article is to present the role of remote patient monitoring in implantable cardioverter-defibrillator follow-up, its potential benefits and its barriers to widespread diffusion. (Neth Heart J 2008;16:53-6.)     

Radial glia and neural stem cells

During the last decade, the role of radial glia has been radically revisited. Rather than being considered a mere structural component serving to guide newborn neurons towards their final destinations, radial glia is now known to be the main source of neurons in several regions of the central nervous system, notably in the cerebral cortex. Radial glial cells differentiate from neuroepithelial progenitors at the beginning of neurogenesis and share with their ancestors the bipolar shape and the expression of some molecular markers. Radial glia, however, can be distinguished from neuroepithelial progenitors by the expression of astroglial markers. Clonal analyses showed that radial glia is a heterogeneous population, comprising both pluripotent and different lineage-restricted neural progenitors. At late-embryonic and postnatal stages, radial glial cells give rise to the neural stem cells responsible for adult neurogenesis. Embryonic pluripotent radial glia and adult neural stem cells may be clonally linked, thus representing a lineage displaying stem cell features in both the developing and mature central nervous system. This work was supported by AIRC (Associazione Italiana per la Ricerca sul Cancro) NUSUG grant (In vivo screening for genes implicated in glioma formation and development of new animal models of glial tumors) and by Fondazione CARIGE grant (Basi molecolari e cellulari dei gliomi: individuazione di marcatori diagnostici e di nuovi bersagli terapeutici).