Effects of amiodarone on short QT syndrome variant 3 in human ventricles: a simulation study.

Background Short QT syndrome (SQTS) is a newly identified clinical disorder associated with atrial and/or ventricular arrhythmias and increased risk of sudden cardiac death (SCD). The SQTS variant 3 is linked to D172N mutation to the KCNJ2 gene that causes a gain-of-function to the inward rectifier potassium channel current (I K1), which shortens the ventricular action potential duration (APD) and effective refractory period (ERP). Pro-arrhythmogenic effects of SQTS have been characterized, but less is known about the possible pharmacological treatment of SQTS. Therefore, in this study, we used computational modeling to assess the effects of amiodarone, class III anti-arrhythmic agent, on human ventricular electrophysiology in SQT3. Methods The ten Tusscher et al. model for the human ventricular action potentials (APs) was modified to incorporate I K1 formulations based on experimental data of Kir2.1 channels (including WT, WT-D172N and D172N conditions). The modified cell model was then implemented to construct one-dimensional (1D) and 2D tissue models. The blocking effects of amiodarone on ionic currents were modeled using IC50 and Hill coefficient values from literatures. Effects of amiodarone on APD, ERP and pseudo-ECG traces were computed. Effects of the drug on the temporal and spatial vulnerability of ventricular tissue to genesis and maintenance of re-entry were measured, as well as on the dynamic behavior of re-entry. Results Amiodarone prolonged the ventricular cell APD and decreased the maximal voltage heterogeneity (δV) among three difference cells types across transmural ventricular wall, leading to a decreased transmural heterogeneity of APD along a 1D model of ventricular transmural strand. Amiodarone increased cellular ERP, prolonged QT interval and decreased the T-wave amplitude. It reduced tissue’s temporal susceptibility to the initiation of re-entry and increased the minimum substrate size necessary to sustain re-entry in the 2D tissue. Conclusions At the therapeutic-relevant concentration of amiodarone, the APD and ERP at the single cell level were increased significantly. The QT interval in pseudo-ECG was prolonged and the re-entry in tissue was prevented. This study provides further evidence that amiodarone may be a potential pharmacological agent for preventing arrhythmogenesis for SQT3 patients

Cardiac Arrhythmias

The most intimate mechanisms of cardiac arrhythmias are still quite unknown to scientists. Genetic studies on ionic alterations, the electrocardiographic features of cardiac rhythm and an arsenal of diagnostic tests have done more in the last five years than in all the history of cardiology. Similarly, therapy to prevent or cure such diseases is growing rapidly day by day. In this book the reader will be able to see with brighter light some of these intimate mechanisms of production, as well as cutting-edge therapies to date. Genetic studies, electrophysiological and electrocardiographyc features, ion channel alterations, heart diseases still unknown , and even the relationship between the psychic sphere and the heart have been exposed in this book. It deserves to be read

Murine Electrophysiological Models of Cardiac Arrhythmogenesis

Cardiac arrhythmias can follow disruption of the normal cellular electrophysiological processes underlying excitable activity and their tissue propagation as coherent wavefronts from the primary sinoatrial node pacemaker, through the atria, conducting structures and ventricular myocardium. These physiological events are driven by interacting, voltage-dependent, processes of activation, inactivation, and recovery in the ion channels present in cardiomyocyte membranes. Generation and conduction of these events are further modulated by intracellular Ca$^{2+}$ homeostasis, and metabolic and structural change. This review describes experimental studies on murine models for known clinical arrhythmic conditions in which these mechanisms were modified by genetic, physiological, or pharmacological manipulation. These exemplars yielded molecular, physiological, and structural phenotypes often directly translatable to their corresponding clinical conditions, which could be investigated at the molecular, cellular, tissue, organ, and whole animal levels. Arrhythmogenesis could be explored during normal pacing activity, regular stimulation, following imposed extra-stimuli, or during progressively incremented steady pacing frequencies. Arrhythmic substrate was identified with temporal and spatial functional heterogeneities predisposing to reentrant excitation phenomena. These could arise from abnormalities in cardiac pacing function, tissue electrical connectivity, and cellular excitation and recovery. Triggering events during or following recovery from action potential excitation could thereby lead to sustained arrhythmia. These surface membrane processes were modified by alterations in cellular Ca$^{2+}$ homeostasis and energetics, as well as cellular and tissue structural change. Study of murine systems thus offers major insights into both our understanding of normal cardiac activity and its propagation, and their relationship to mechanisms generating clinical arrhythmias.Medical Research Council, Wellcome Trust, McVeigh Benefaction, British Heart Foundation, Helen Kirkland Trust, Sudden Arrhythmic Death Syndrome - SADS U

Biophysical Characterization of Three SCN5A Mutations Linked to Long QT Syndrome Type 3, Sudden Infant Death Syndrome, and Atrial Fibrillation

Le gène SCN5A encode la sous-unité principale du canal sodique cardiaque (Nav1.5). Ce canal est responsable de l'initiation et de la propagation du potentiel d'action cardiaque. Un dysfonctionnement de ce canal peut causer le syndrome du QT long de type 3 (LQT3) et la fibrillation auriculaire (AF). Les patients atteints du LQT3 sont à risques de développer des arythmies létales, particulièrement des torsades de pointes qui peuvent causer le syndrome de mort subite du nourrisson (SIDS). Objectifs : Le but de cette étude est de caractériser les propriétés biophysiques de trois mutations sur le gène SCN5A : Y1767C, S1333Y et K1493R. Ces trois mutations ont respectivement été retrouvées chez un patient souffrant du LQT3, chez un patient mort du SIDS et la dernière mutation chez un patient souffrant d'AF. Méthodes : Des cellules tsA 201 ont été transfectées avec le gène codant pour le canal sauvage et les gènes codant pour les canaux mutés. Par la suite, leurs caractéristiques biophysiques ont été étudiées par la méthode du patch-clamp en configuration cellule entière. Résultats : La mutation Y1767C est située dans le segment 6 du domaine IV (DIVS6). Cette mutation sur le canal produit un courant persistant et un courant de fenêtre augmenté, ces résultats expliquent les phénotypes cliniques des patients affectés de cette mutation. La ranolazine, un nouveau bloqueur des canaux Na+, peut bloquer efficacement le courant Na+ persistant et réduire le courant de fenêtre. Ces canaux mutés montrent aussi une augmentation de l'inhibition fréquence-dépendante ainsi qu'une réactivation lente. La mutation S1333Y est situé sur la boucle S4 et S5 du domaine III. L'étude fonctionnelle de ce canal montre un gain de fonction : un courant Na+ persistant et une augmentation du courant de fenêtre provoquée par un déplacement de -8 mV de l'activation et de +7mV de l'inactivation. La mutation K1493R est située sur la boucle entre les domaines III-IV. Cette mutation provoque un déplacement vers des potentiels plus dépolarisés de l'inactivation est entraîne une augmentation du courant de fenêtre. Conclusion : Les manifestations cliniques observées chez les patients sont probablement dues aux changements des propriétés biophysiques provoqués par les trois mutations sur Nav1.5 rapportées dans cette étude. Nous concluons donc que (1) Y1767C est une mutation provoquant le LQT3. L'effet observé par la ranolazine sur cette mutation (la ranolazine agit probablement comme un bloqueur des canaux ouverts) nous donne de nouveaux indices pour le traitement des patients porteurs de cette mutation. (2) La mort subite du nourrisson observé est probablement lié à un syndrome LQT3 associé à la mutation S1333Y. (3) La mutation K1493R provoque de la fibrillation auriculaire causée par une hyperexcitabilité des cardiomyocytes

Functional Studies of Genetic Variants in TRPM7 and AKAP9 – Two Candidate Genes for Stillbirth

For every 200 births in the UK, one will end in a stillbirth. Stillbirth is classified as a baby born dead after 24 weeks gestation. Mutations in genes that cause ion channelopathies are known to cause sudden cardiac death in adults and children. Prenatal diagnosis of LQT has been possible for decades, creating a disease spectrum where channelopathies may fatally influence pregnancy. We sequenced 35 candidate genes in 70 unexplained stillbirth cases. Thirty-nine cases harboured a predicted damaging protein missense variant. Two novel and two rare variants were observed in the transient receptor potential melastatin 7 (TRPM7) gene and five rare genetic variants were found in A-kinase anchor protein 9 (AKAP9). The aim of this PhD was to perform functional studies of these variants in TRPM7 and AKAP9. TRPM7 is an ion channel indispensable for mouse cardiogenesis. Two TRPM7 variants (p.G179V and p.T860M) showed significantly reduced current compared to wild-type channels. Conversely, cells expressing p.R494Q TRPM7, had a significant increase in current compared to WT channels, but only in CHO-K1 cells. Western blot analyses failed to detect full length TRPM7 in cells transfected with either p.G179V or p.T860M compared to wild-type expressing cells. Proteosomal inhibition using MG132 produced a small but visible band in p.T860M transfected cells. Expression of TRPM7 in iPSC-derived cardiomyocytes increases during cell maturation, and TRPM7-like current was measured in 20-23 day old cardiomyocytes. AKAP9 is required to couple adrenergic stimulation in the heart with faster cardiac repolarisation. Cells expressing WT AKAP9 alongside the KCNQ1/KCNE1 potassium channel responded to β-adrenergic stimulation, however those transfected with p.A3043T AKAP9 did not respond to treatment with forskolin. Our analyses supports two deleterious variants in TRPM7 and one in AKAP9 in unexplained stillbirth cases. These heterozygous variants could lead to haploinsufficiency and may be a cause of stillbirth

Prevalence, Clinical Significance and Time-Course of Neonatal ECG Abnormalities associated with Arrhythmias during Infancy: the experience of Brindisi

Background: Some rhythm disturbances may be detected on the surface electrocardiogram even during the neonatal period. Most of them are transitory and benign arrhythmias, others can constitute the first sign of cardiac disease or may become malignant and life-threatening. Furthermore, arrhythmogenic syndromes such as the Long QT syndrome and the Brugada syndrome can cause sudden death in infancy and may also contribute to SIDS (Sudden Infant Death Syndrome). The risk of fatal arrhythmias - which often manifest themselves in infancy, childhood or even at later age - justifies preventive measures. Since diagnosis in symptom-free patients requires electrocardiography, such a non invasive methodology must be available to provide early diagnosis and therapy. The Italian Ministry of Health has funded a prospective study in 50.000 neonates, involving 16 Italian centers, to assess the feasibility of a nationwide neonatal ECG screening. Aim: The purpose of this project was to assess prevalence and clinical significance of neonatal ECG abnormalities. This paper considers the data collected in Brindisi, at the “Perrino” Hospital, with the participation of ISBEM (Euro Mediterranean Scientific Biomedical Institute). Methods: From 2001 to 2006, electrocardiograms were recorded and the demographic data of newborns and of their parents were collected, as well as the clinical history of the newborn babies and of their mothers. All electrocardiographic parameters were measured according to the guidelines for the interpretation of the neonatal ECG. Data of all newborns enlisted in the study were entered into the neonatal ECG database. Newborns with clinically relevant ECG abnormalities were followed-up, according to the guidelines work-up section for clinical management of pathologies related to ECG anomalies. Results: Of the 2619 ECGs recorded, 418 (16%) presented abnormalities. Among the abnormalities 5 (0.2%) had a major clinical significance such as prolonged QT syndrome, Wolff-Parkinson-White syndrome and congenital heart disease. Conclusions: Although life-threatening arrhythmias are rare in infants, they are very serious and must be sought to avoid both short- and long-term morbidity and mortality. The electrocardiographic screening for neonates, as an additional measure of prevention, especially for the early identification of infants at risk of life-threatening arrhythmias, is available and relatively at low cost, and can also help detecting complex cardiac malformations