ABSTRACT
INTRODUCTION AND OBJECTIVES: HCN4 variants have been reported to cause combined sick sinus syndrome (SSS) and left ventricular noncompaction (LVNC) cardiomyopathy. This relationship has been proven in few cases and no previous patients have associated left atrial dilatation (LAD). Our objective was to study a familial disorder characterized by SSS, LAD, and hypertrabeculation/LVNC and to identify the underlying genetic and electrophysiological characteristics. METHODS: A family with SSS and LVNC underwent a clinical, genetic, and electrophysiological assessment. They were studied via electrocardiography, Holter recording, echocardiography, and exercise stress tests; cardiac magnetic resonance imaging was additionally performed in affected individuals. Genetic testing was undertaken with targeted next-generation sequencing, as well as a functional study of the candidate variant in Chinese hamster ovary cells. RESULTS: Twelve members of the family had sinus bradycardia, associated with complete criteria of LVNC in 4 members and hypertrabeculation in 6 others, as well as LAD in 9 members. A HCN4 c.1123C>T;(p.R375C) variant was present in heterozygosis in all affected patients and absent in unaffected individuals. Electrophysiological analyses showed that the amplitude and densities of the HCN4 currents (IHCN4) generated by mutant p.R375C HCN4 channels were significantly lower than those generated by wild-type channels. CONCLUSIONS: The combined phenotype of SSS, LAD, and LVNC is associated with the heritable HCN4 c.1123C>T;(p.R375C) variant. HCN4 variants should be included in the genetic diagnosis of LVNC cardiomyopathy and of patients with familial forms of SSS, as well as of individuals with sinus bradycardia and LAD.
Subject(s)
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels , Sick Sinus Syndrome , Animals , Bradycardia/diagnosis , Bradycardia/genetics , CHO Cells , Cricetinae , Cricetulus , Dilatation , Humans , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics , Muscle Proteins/genetics , Phenotype , Potassium Channels/genetics , Sick Sinus Syndrome/diagnosis , Sick Sinus Syndrome/geneticsABSTRACT
No disponible
Subject(s)
Humans , Anti-Arrhythmia Agents/therapeutic use , Atrial Fibrillation/drug therapy , Heart Rate/drug effects , Catheter AblationABSTRACT
INTRODUCCIÓN Y OBJETIVOS: La ivabradina es un inhibidor de la corriente If, principal determinante de la función marcapasos del nódulo sinusal, aprobado como antianginoso y para tratar la insuficiencia cardiaca. Existen indicios sobre su capacidad para inhibir la conducción a través del nódulo auriculoventricular (NAV). Sobre esta base, el proyecto BRAKE-AF plantea el uso de ivabradina como agente cronotrópico negativo en fibrilación auricular (FA). MÉTODOS: Se realizará un ensayo clínico multicéntrico de fase III, aleatorizado, abierto, en paralelo, con diseño de no inferioridad, para comparar la ivabradina frente a la digoxina en 232 pacientes con FA permanente no controlada con bloqueadores beta o antagonistas del calcio; el objetivo primario es la reducción de la frecuencia cardiaca media diurna en un Holter de 24 h a los 3 meses. El ensayo se apoyará en un estudio electrofisiológico que analizará el efecto de la ivabradina en el potencial de acción del NAV humano, utilizando un modelo experimental en células de ovario de hámster chino transfectadas con el ADN que codifica la expresión de los distintos canales que componen dicho potencial de acción, registrando las corrientes iónicas mediante la técnica del parche de membrana. RESULTADOS: Se obtendrá información tanto del efecto de la ivabradina en las corrientes iónicas y el potencial de acción del NAV como de su eficacia y su seguridad en pacientes con FA permanente. CONCLUSIONES: Los resultados del proyecto BRAKE-AF podrían permitir que la ivabradina se incluyera en el limitado arsenal de fármacos disponibles actualmente para el control de frecuencia en la FA
INTRODUCTION AND OBJECTIVES: Ivabradine is an inhibitor of the If channel, the main determinant of the pacemaker function of the sinus node. The drug has been approved for the treatment of angina and heart failure. There is some evidence of its role as an inhibitor of atrial-ventricular node (AVN) conduction. The aim of the BRAKE-AF project is to assess ivabradine use for rate control in atrial fibrillation (AF). METHODS: A multicenter, randomized, parallel, open-label, noninferiority phase III clinical trial will be conducted to compare ivabradine vs digoxin in 232 patients with uncontrolled permanent AF despite beta-blockers or calcium channel blockers. The primary efficacy endpoint is the reduction in daytime heart rate measured by 24-hour Holter monitoring at 3 months. This clinical trial will be supported by an electrophysiological study of the effect of ivabradine on the action potential of the human AVN. To do this, an experimental model will be used with Chinese hamster ovarium cells transfected with the DNA encoding the expression of the t channels involved in this action potential and recording of the ionic currents with patch clamp techniques. RESULTS: New data will be obtained on the effect of ivabradine on the human AVN and its safety and efficacy in patients with permanent AF. CONCLUSIONS: The results of the BRAKE-AF project might allow inclusion of ivabradine within the limited arsenal of drugs currently available for rate control in AF
Subject(s)
Humans , Animals , Female , Young Adult , Aged , Aged, 80 and over , Ivabradine/pharmacology , Atrial Fibrillation/drug therapy , Cardiovascular Agents/pharmacology , Digoxin/pharmacology , Anti-Arrhythmia Agents/pharmacology , Patch-Clamp Techniques , Action Potentials , Atrial Fibrillation/physiopathology , Heart Rate/drug effectsABSTRACT
INTRODUCTION AND OBJECTIVES: Ivabradine is an inhibitor of the If channel, the main determinant of the pacemaker function of the sinus node. The drug has been approved for the treatment of angina and heart failure. There is some evidence of its role as an inhibitor of atrial-ventricular node (AVN) conduction. The aim of the BRAKE-AF project is to assess ivabradine use for rate control in atrial fibrillation (AF). METHODS: A multicenter, randomized, parallel, open-label, noninferiority phase III clinical trial will be conducted to compare ivabradine vs digoxin in 232 patients with uncontrolled permanent AF despite beta-blockers or calcium channel blockers. The primary efficacy endpoint is the reduction in daytime heart rate measured by 24-hour Holter monitoring at 3 months. This clinical trial will be supported by an electrophysiological study of the effect of ivabradine on the action potential of the human AVN. To do this, an experimental model will be used with Chinese hamster ovarium cells transfected with the DNA encoding the expression of the t channels involved in this action potential and recording of the ionic currents with patch clamp techniques. RESULTS: New data will be obtained on the effect of ivabradine on the human AVN and its safety and efficacy in patients with permanent AF. CONCLUSIONS: The results of the BRAKE-AF project might allow inclusion of ivabradine within the limited arsenal of drugs currently available for rate control in AF. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Identifier: NCT03718273.
Subject(s)
Anti-Arrhythmia Agents/therapeutic use , Atrial Fibrillation/drug therapy , Cardiovascular Agents/therapeutic use , Digoxin/therapeutic use , Heart Rate/drug effects , Ivabradine/therapeutic use , Equivalence Trials as Topic , Heart Rate/physiology , Humans , Treatment OutcomeABSTRACT
La mejora en la supervivencia de los pacientes con cáncer ha puesto de manifiesto el impacto clínico que la cardiotoxicidad tiene en el pronóstico tanto cardiovascular como onco-hematológico, sobre todo cuando motiva la interrupción de terapias antitumorales altamente eficaces. La fibrilación auricular es una complicación frecuente en pacientes con cáncer activo y su tratamiento supone un gran reto. Estos pacientes tienen mayores riesgos tromboembólico y hemorrágico y, sin embargo, no se dispone de escalas específicas para guiar la atención clínica. El objetivo de este documento promovido por los grupos de Cardio-Onco-Hematología y Trombosis de la Sociedad Española de Cardiología y elaborado de manera conjunta con las diferentes áreas de conocimiento de la Sociedad Española de Cardiología y con expertos de la Sociedad Española de Oncología Médica, la Sociedad Española de Oncología Radioterápica y la Sociedad Española de Hematología y Hemoterapia, es proporcionar un enfoque multidisciplinario y práctico para la prevención y el tratamiento de la fibrilación auricular de pacientes con cáncer activo y basado en el consenso de expertos
Improvements in survival among cancer patients have revealed the clinical impact of cardiotoxicity on both cardiovascular and hematological and oncological outcomes, especially when it leads to the interruption of highly effective antitumor therapies. Atrial fibrillation is a common complication in patients with active cancer and its treatment poses a major challenge. These patients have an increased thromboembolic and hemorrhagic risk but standard stroke prediction scores have not been validated in this population. The aim of this expert consensus-based document is to provide a multidisciplinary and practical approach to the prevention and treatment of atrial fibrillation in patients with active cancer. This is a position paper of the Spanish Cardio-Oncology working group and the Spanish Thrombosis working group, drafted in collaboration with experts from the Spanish Society of Cardiology, the Spanish Society of Medical Oncology, the Spanish Society of Radiation Oncology, and the Spanish Society of Hematology
Subject(s)
Humans , Atrial Fibrillation/drug therapy , Anticoagulants/therapeutic use , Neoplasms/complications , Thromboembolism/prevention & control , Atrial Fibrillation/complications , Antineoplastic Agents/therapeutic use , Consensus , Practice Patterns, Physicians'ABSTRACT
Improvements in survival among cancer patients have revealed the clinical impact of cardiotoxicity on both cardiovascular and hematological and oncological outcomes, especially when it leads to the interruption of highly effective antitumor therapies. Atrial fibrillation is a common complication in patients with active cancer and its treatment poses a major challenge. These patients have an increased thromboembolic and hemorrhagic risk but standard stroke prediction scores have not been validated in this population. The aim of this expert consensus-based document is to provide a multidisciplinary and practical approach to the prevention and treatment of atrial fibrillation in patients with active cancer. This is a position paper of the Spanish Cardio-Oncology working group and the Spanish Thrombosis working group, drafted in collaboration with experts from the Spanish Society of Cardiology, the Spanish Society of Medical Oncology, the Spanish Society of Radiation Oncology, and the Spanish Society of Hematology.
Subject(s)
Atrial Fibrillation/complications , Cardiology , Consensus , Medical Oncology , Neoplasms/complications , Societies, Medical , Thromboembolism/prevention & control , Anticoagulants/therapeutic use , Humans , Risk Factors , Spain , Thromboembolism/etiologyABSTRACT
No disponible
Subject(s)
Humans , Drug Interactions , Phosphorus/pharmacology , Phosphorus/pharmacokinetics , Renal Insufficiency, Chronic/drug therapyABSTRACT
Atrial fibrillation starts in the left atrium and from there the activity invades the atrial tissues and causes an inhomogeneous shortening the duration of atrial action potential duration and refractoriness. The purpose of this study was to compare the voltage-dependent potassium currents in human cells isolated from the right and left atria and to determine whether electrical remodeling produced by chronic atrial fibrillation (CAF) differentially affects voltage-dependent potassium currents involved in atrial repolarization in each atrium as compared to sinus rhythm (SR). The currents were recorded using the whole-cell configuration of the patch-clamp technique. We found that in atrial cardiomyocytes of patients both in SR and in CAF there are three types of cells according to their main voltage-dependent repolarizing potassium current: the Ca(2+)-independent 4-aminopyridine sensitive component of the transient outward current (I(to1)) and the ultrarapid (I(Kur)), rapid (I(Kr)) and slow (I(Ks)) components of the delayed rectifier current. CAF differentially modified the proportion of these 3 types of cells on each atrium: CAF reduced the I(to1) more markedly in the left than in the right atria, while I(Kur) was more markedly reduced in the right than in the left atria. Interestingly, in both atria, CAF markedly increased the I(Ks). This increase was enhanced by isoproterenol and suppressed by atenolol. These changes produce a non-uniform shortening of atrial repolarization that facilitates the reentry of the cardiac impulse and the perpetuation of the arrhythmia.
Subject(s)
Atrial Fibrillation/physiopathology , Ventricular Remodeling , Chronic Disease , Electrophysiologic Techniques, Cardiac , Heart Atria , HumansABSTRACT
Atrial fibrillation (AFb) is the most common sustained cardiac arrhythmia. Once initiated, AFb alters atrial electrical and structural properties (remodeling) that promotes its maintenance and recurrence. Treatment is directed to restore and maintain the sinus rhythm, to control the ventricular rate and to prevent thromboembolic complications. Recent evidence indicates that angiotensin converting enzyme inhibitors, angiotensin AT1 receptor antagonists and statins modify atrial remodeling and reduce the incidence of AFb, thus possibly representing a new alternative in the treatment of the arrhythmia.
Subject(s)
Atrial Fibrillation/drug therapy , Action Potentials/physiology , Adrenergic beta-Antagonists/therapeutic use , Aged , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Atrial Fibrillation/complications , Atrial Fibrillation/etiology , Atrial Fibrillation/physiopathology , Disease Models, Animal , Flecainide/therapeutic use , Humans , Hypolipidemic Agents/therapeutic use , Incidence , Randomized Controlled Trials as Topic , Swine , Thromboembolism/prevention & controlABSTRACT
No disponible
