Extracellular Kir2.1C122Y Mutant Upsets Kir2.1-PIP2 Bonds and Is Arrhythmogenic in Andersen-Tawil Syndrome.

BACKGROUND: Andersen-Tawil syndrome type 1 is a rare heritable disease caused by mutations in the gene coding the strong inwardly rectifying K+ channel Kir2.1. The extracellular Cys (cysteine)122-to-Cys154 disulfide bond in the channel structure is crucial for proper folding but has not been associated with correct channel function at the membrane. We evaluated whether a human mutation at the Cys122-to-Cys154 disulfide bridge leads to Kir2.1 channel dysfunction and arrhythmias by reorganizing the overall Kir2.1 channel structure and destabilizing its open state. METHODS: We identified a Kir2.1 loss-of-function mutation (c.366 A>T; p.Cys122Tyr) in an ATS1 family. To investigate its pathophysiological implications, we generated an AAV9-mediated cardiac-specific mouse model expressing the Kir2.1C122Y variant. We employed a multidisciplinary approach, integrating patch clamping and intracardiac stimulation, molecular biology techniques, molecular dynamics, and bioluminescence resonance energy transfer experiments. RESULTS: Kir2.1C122Y mice recapitulated the ECG features of ATS1 independently of sex, including corrected QT prolongation, conduction defects, and increased arrhythmia susceptibility. Isolated Kir2.1C122Y cardiomyocytes showed significantly reduced inwardly rectifier K+ (IK1) and inward Na+ (INa) current densities independently of normal trafficking. Molecular dynamics predicted that the C122Y mutation provoked a conformational change over the 2000-ns simulation, characterized by a greater loss of hydrogen bonds between Kir2.1 and phosphatidylinositol 4,5-bisphosphate than wild type (WT). Therefore, the phosphatidylinositol 4,5-bisphosphate-binding pocket was destabilized, resulting in a lower conductance state compared with WT. Accordingly, on inside-out patch clamping, the C122Y mutation significantly blunted Kir2.1 sensitivity to increasing phosphatidylinositol 4,5-bisphosphate concentrations. In addition, the Kir2.1C122Y mutation resulted in channelosome degradation, demonstrating temporal instability of both Kir2.1 and NaV1.5 proteins. CONCLUSIONS: The extracellular Cys122-to-Cys154 disulfide bond in the tridimensional Kir2.1 channel structure is essential for the channel function. We demonstrate that breaking disulfide bonds in the extracellular domain disrupts phosphatidylinositol 4,5-bisphosphate-dependent regulation, leading to channel dysfunction and defects in Kir2.1 energetic stability. The mutation also alters functional expression of the NaV1.5 channel and ultimately leads to conduction disturbances and life-threatening arrhythmia characteristic of Andersen-Tawil syndrome type 1.

Atrial Cardiomyopathy Revisited - Evolution of a Concept. A Clinical Consensus Statement of the European Heart Rhythm Association (EHRA) of the ESC, the Heart Rhythm Society (HRS), the Asian Pacific Heart Rhythm Association (APHRS), and the Latin American Heart Rhythm Society (LAHRS).

Developed in partnership with the European Heart Rhythm Association (EHRA), (a registered branch of the European Society of Cardiology (ESC)) the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin America Heart Rhythm Society (LAHRS).

Kir2.1-NaV1.5 channelosome and its role in arrhythmias in inheritable cardiac diseases.

Sudden cardiac death in children and young adults is a relatively rare but tragic event whose pathophysiology is unknown at the molecular level. Evidence indicates that the main cardiac sodium channel (NaV1.5) and the strong inward rectifier potassium channel (Kir2.1) physically interact and form macromolecular complexes (channelosomes) with common partners, including adapter, scaffolding, and regulatory proteins that help them traffic together to their eventual membrane microdomains. Most important, dysfunction of either or both ion channels has direct links to hereditary human diseases. For example, certain mutations in the KCNJ2 gene encoding the Kir2.1 protein result in Andersen-Tawil syndrome type 1 and alter both inward rectifier potassium and sodium inward currents. Similarly, trafficking-deficient mutations in the gene encoding the NaV1.5 protein (SCN5A) result in Brugada syndrome and may also disturb both inward rectifier potassium and sodium inward currents. Moreover, gain-of-function mutations in KCNJ2 result in short QT syndrome type 3, which is extremely rare but highly arrhythmogenic, and can modify Kir2.1-NaV1.5 interactions in a mutation-specific way, further highlighting the relevance of channelosomes in ion channel diseases. By expressing mutant proteins that interrupt or modify Kir2.1 or NaV1.5 function in animal models and patient-specific pluripotent stem cell-derived cardiomyocytes, investigators are defining for the first time the mechanistic framework of how mutation-induced dysregulation of the Kir2.1-NaV1.5 channelosome affects cardiac excitability, resulting in arrhythmias and sudden death in different cardiac diseases.

The Kir2.1E299V mutation increases atrial fibrillation vulnerability while protecting the ventricles against arrhythmias in a mouse model of short QT syndrome type 3.

AIMS: Short QT syndrome type 3 (SQTS3) is a rare arrhythmogenic disease caused by gain-of-function mutations in KCNJ2, the gene coding the inward rectifier potassium channel Kir2.1. We used a multidisciplinary approach and investigated arrhythmogenic mechanisms in an in-vivo model of de-novo mutation Kir2.1E299V identified in a patient presenting an extremely abbreviated QT interval and paroxysmal atrial fibrillation. METHODS AND RESULTS: We used intravenous adeno-associated virus-mediated gene transfer to generate mouse models, and confirmed cardiac-specific expression of Kir2.1WT or Kir2.1E299V. On ECG, the Kir2.1E299V mouse recapitulated the QT interval shortening and the atrial-specific arrhythmia of the patient. The PR interval was also significantly shorter in Kir2.1E299V mice. Patch-clamping showed extremely abbreviated action potentials in both atrial and ventricular Kir2.1E299V cardiomyocytes due to a lack of inward-going rectification and increased IK1 at voltages positive to -80 mV. Relative to Kir2.1WT, atrial Kir2.1E299V cardiomyocytes had a significantly reduced slope conductance at voltages negative to -80 mV. After confirming a higher proportion of heterotetrameric Kir2.x channels containing Kir2.2 subunits in the atria, in-silico 3D simulations predicted an atrial-specific impairment of polyamine block and reduced pore diameter in the Kir2.1E299V-Kir2.2WT channel. In ventricular cardiomyocytes, the mutation increased excitability by shifting INa activation and inactivation in the hyperpolarizing direction, which protected the ventricle against arrhythmia. Moreover, Purkinje myocytes from Kir2.1E299V mice manifested substantially higher INa density than Kir2.1WT, explaining the abbreviation in the PR interval. CONCLUSION: The first in-vivo mouse model of cardiac-specific SQTS3 recapitulates the electrophysiological phenotype of a patient with the Kir2.1E299V mutation. Kir2.1E299V eliminates rectification in both cardiac chambers but protects against ventricular arrhythmias by increasing excitability in both Purkinje-fiber network and ventricles. Consequently, the predominant arrhythmias are supraventricular likely due to the lack of inward rectification and atrial-specific reduced pore diameter of the Kir2.1E299V-Kir2.2WT heterotetramer.

Practical approach for atrial cardiomyopathy characterization in patients with atrial fibrillation.

Atrial fibrillation (AF) causes progressive structural and electrical changes in the atria that can be summarized within the general concept of atrial remodeling. In parallel, other clinical characteristics and comorbidities may also affect atrial tissue properties and make the atria susceptible to AF initiation and its long-term persistence. Overall, pathological atrial changes lead to atrial cardiomyopathy with important implications for rhythm control. Although there is general agreement on the role of the atrial substrate for successful rhythm control in AF, the current classification oversimplifies clinical management. The classification uses temporal criteria and does not establish a well-defined strategy to characterize the individual-specific degree of atrial cardiomyopathy. Better characterization of atrial cardiomyopathy may improve the decision-making process on the most appropriate therapeutic option. We review current scientific evidence and propose a practical characterization of the atrial substrate based on 3 evaluation steps starting with a clinical evaluation (step 1), then assess outpatient complementary data (step 2), and finally include information from advanced diagnostic tools (step 3). The information from each of the steps or a combination thereof can be used to classify AF patients in 4 stages of atrial cardiomyopathy, which we also use to estimate the success on effective rhythm control.

Selección de lo mejor del año 2016 en ablación con catéter / Selection of the best of 2016 in catheter ablation

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Principios básicos de las nuevas estrategias farmacológicas antiarrítmicas en fibrilación auricular / Basic mechanisms of the new antiarrhythmic drugs in atrial fibrillation

La fibrilación auricular (FA) es la arritmia crónica sostenida más frecuente en la población general. A pesar de los últimos avances tecnológicos y en el entendimiento de sus mecanismos, derivados de modelos experimentales, así como de los procedimientos de ablación en pacientes con FA, los fármacos antiarrítmicos siguen siendo la principal estrategia para la cardioversión y mantenimiento del ritmo sinusal. Nuevas generaciones de fármacos antiarrítmicos han llegado a la práctica clínica, y otros se encuentran en fase de experimentación. Los nuevos fármacos actúan de forma más específica sobre corrientes iónicas auriculares, y al mismo tiempo involucradas en el mantenimiento de la arritmia. Paralelamente, cada vez se da más importancia a la necesidad de actuar sobre el sustrato arritmogénico auricular y los factores que lo promueven, implicados en el mantenimiento a largo plazo de la arritmia (terapias upstream). La presente revisión tiene como objetivo exponer las actuales líneas de desarrollo en fármacos antiarrítmicos y terapias para prevención o retraso del remodelado auricular, con base a los conocimientos mecanísticos que hoy en día se involucran en el mantenimiento de la FA.

Atrial fibrillation (AF) is the most common sustained arrhythmia seen in clinical practice. Despite of new technological breakthroughs and the understanding of the mechanisms underlying AF, based on animal models and ablation procedures in patients, the antiarrhythmic drugs remain the main therapeutic strategy to restore and maintain the sinus rhythm. New antiarrhythmic drugs are already available in the clinical practice and many others are under development. The new antiarrhythmic drugs have the capability to block atrial-specific ionic currents, which are involved in the maintenance of the arrhythmia. Parallel, increasing evidence supports the use of compounds to regulate the arrhythmogenic atrial substrate involved in the long-term maintenance of the arrhythmia (upstream therapies). This article reviews the new antiarrhythmic drugs and upstream therapies, based on the current knowledge of the mechanisms involved in the maintenance of AF.

Retroalimentación mecanoeléctrica del miocardio isquémico: un juego que modula su capacidad fibrilatoria / Mechanoelectric feedback in the ischemic myocardium: an interplay that modulates susceptibility to fibrillation

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Arritmias y muerte súbita en la taquicardia ventricular catecolaminérgica de origen hereditario / Ventricular arrhythmias of catecholaminergic origin and sudden death

The hereditary disease known as polymorphic catecholaminergic ventricular tachycardia (PCVT) is highly lethal. Almost 30% of the affected patients die before 40 years old, mainly due to sudden cardiac death. We have used isolated hearts from mutant mice (type 2 ryanodine receptors, RyR2/RyR2(R4496C)) to investigate arrhythmia mechanisms that are adrenergic- and intracellular calcium ([Ca2+]o) levels-dependent. Our results corroborate that polymorphic and bidirectional ventricular arrhythmias, as well as ventricular fibrillation, occurs in 50% of RyR2/ RyR2(R4496C) mice, and in less than 12% of the non-affected mice. Our hypothesis suggests that the origin of catecholaminergic arrhythmias in animals, and possibly in humans, is conditioned by the focal activity that begins by late post-potentials in the Purkinje fibers.

Tiempo, espacio y frecuencia en la fibrilación ventricular / Time, space and frequency in ventricular fibrillation

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Corrientes iónicas y dinámica de la fibrilación ventricular / Ionic currents and ventricular fibrillation dynamics

La fibrilación ventricular es la causa principal de muerte súbita cardíaca. A diferencia de otras arritmias, en general se ha considerado farmacológicamente inabordable, dado que parece una sucesión de innumerables frentes eléctricos descoordinados que circulan de manera caótica desde su inicio. Durante varias décadas, su prevención se centró básicamente en la supresión de las extrasístoles ventriculares que pudieran precipitarla. Este enfoque terapéutico se tradujo en pésimos resultados clínicos. En la última década, gracias a los conceptos de la teoría de propagación de ondas en medios no lineales, la visión global de la fibrilación ventricular ha cambiado de manera radical. Se ha demostrado que la fibrilación está mediada por reentradas funcionales con forma helicoidal que rotan siguiendo una dinámica determinada por su pivote organizativo o rotor. Estos rotores se comportarían como el centro que genera los múltiples frentes de activación eléctricos. Los rotores, a su vez, están condicionados por las propiedades electrofisiológicas del miocardio, determinadas por la dinámica de las diferentes corrientes iónicas. Así, recientemente se han publicado numerosos trabajos experimentales y de simulación sobre el papel que desempeña cada corriente en la dinámica de los rotores y se han analizado los efectos de su bloqueo mediante antiarrítmicos. Esta revisión detalla los hallazgos de los principales trabajos publicados, así como los análisis teóricos que describen sus autores. De estos trabajos se desprenden nuevos enfoques terapéuticos farmacológicos que buscarían evitar no ya el latido desencadenante, sino el propio mantenimiento de la fibrilación (AU)

Nuevos conceptos sobre los mecanismos de la fibrilación ventricular / New Concepts on the Mechanisms of Ventricular Fibrillation

La fibrilación ventricular es la principal arritmia causante de muerte súbita cardíaca; sin embargo, su mecanismo detallado es aún difícil de explicar. La fibrilación ventricular ha sido definida como una actividad eléctrica cardíaca 'turbulenta', término que nos transmite la idea de una activación desorganizada y totalmente aleatoria de los ventrículos. En este artículo se discuten los resultados de experimentos publicados recientemente en los que se utilizó un nuevo algoritmo, la 'cartografía bidimensional de fases', que asigna un estado de fase a cada segmento del potencial de acción transmembrana y demuestra que la propagación de ondas durante la fibrilación ventricular no es aleatoria y puede, además, ser analizada cuantitativamente. Esta técnica se basa en la grabación en vídeo de imágenes de la fluorescencia de un colorante sensible a los cambios de voltaje, que permite observar simultáneamente, en corazones de conejos y ovejas, los cambios del potencial transmembrana de miles de puntos en la superficie epicárdica ventricular. En el análisis del electrocardiograma durante la fibrilación ventricular se observa un componente predominante de frecuencia cercano a los 500 lat/min. El mapa de fases revela que la fibrilación ventricular depende de la rotación de líneas convergentes alrededor de 'puntos singulares', en los que el estado de fase es indefinido, dando la apariencia de torbellinos eléctricos que rotan a frecuencias que pueden ser más altas que las que se observan en el electrocardiograma. Dichos puntos singulares, formados como consecuencia de la interacción de frentes de onda con obstáculos que encuentran en su camino, son escasos en número y de vida relativamente corta. La observación más importante es la existencia de un alto grado de organización, tanto espacial como temporal, en la fibrilación cardíaca. Estos resultados preparan el terreno para un mejor entendimiento de los mecanismos de la fibrilación ventricular, tanto en corazones sanos como enfermos (AU)