RESUMO
The Canadian Cardiovascular Society (CCS) atrial fibrillation (AF) guidelines program was developed to aid clinicians in the management of these complex patients, as well as to provide direction to policy makers and health care systems regarding related issues. The most recent comprehensive CCS AF guidelines update was published in 2010. Since then, periodic updates were published dealing with rapidly changing areas. However, since 2010 a large number of developments had accumulated in a wide range of areas, motivating the committee to complete a thorough guideline review. The 2020 iteration of the CCS AF guidelines represents a comprehensive renewal that integrates, updates, and replaces the past decade of guidelines, recommendations, and practical tips. It is intended to be used by practicing clinicians across all disciplines who care for patients with AF. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system was used to evaluate recommendation strength and the quality of evidence. Areas of focus include: AF classification and definitions, epidemiology, pathophysiology, clinical evaluation, screening and opportunistic AF detection, detection and management of modifiable risk factors, integrated approach to AF management, stroke prevention, arrhythmia management, sex differences, and AF in special populations. Extensive use is made of tables and figures to synthesize important material and present key concepts. This document should be an important aid for knowledge translation and a tool to help improve clinical management of this important and challenging arrhythmia.
Le programme de lignes directrices de la Société canadienne de cardiologie (SCC) en matière de fibrillation auriculaire (FA) a été élaboré pour aider les cliniciens à prendre en charge ces patients complexes, ainsi que pour orienter les décideurs politiques et les systèmes de soins de santé sur des questions connexes. La dernière édition complète des lignes directrices de la SCC en matière de FA a été publiée en 2010. Depuis lors, des mises à jour périodiques ont été publiées, traitant de domaines en évolution rapide. Cependant, en 2020, un grand nombre de développements s'y étaient ajoutés, couvrant un large éventail de domaines, ce qui a motivé le comité à créer une refonte complète des lignes directrices. L'édition 2020 des lignes directrices de la SCC en matière de FA représente un renouvellement complet qui intègre, met à jour et remplace les lignes directrices, les recommandations et les conseils pratiques des dix dernières années. Elle est destinée à être utilisée par les cliniciens praticiens de toutes les disciplines qui s'occupent de patients souffrant de FA. L'approche GRADE (Gradation des Recommandations, de l'Appréciation, du Développement et des Évaluations) a été utilisée pour évaluer la pertinence des recommandations et la qualité des résultats. Les domaines d'intérêt incluent : la classification et les définitions de la FA, son épidémiologie, sa physiopathologie, l'évaluation clinique, le dépistage de la FA, la détection et la gestion des facteurs de risque modifiables, l'approche intégrée de la gestion de la FA, la prévention des accidents vasculaires cérébraux, la gestion de l'arythmie, les différences entre les sexes et la FA dans des populations particulières. Des tableaux et figures ont été largement utilisés pour synthétiser les éléments importants et présenter les concepts clés. Ce document devrait représenter une aide importante pour l'intégration des connaissances et un outil pour aider à améliorer la gestion clinique de cette arythmie importante et difficile à traiter.
Assuntos
Humanos , Masculino , Feminino , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/terapia , Fibrilação Atrial/classificação , Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/epidemiologia , Grupos de Risco , Algoritmos , Fatores Sexuais , Fatores de Risco , Procedimentos Clínicos , Acidente Vascular Cerebral/prevenção & controleRESUMO
Histone H3 serine 28 (H3S28) phosphorylation and de-repression of polycomb repressive complex (PRC)-mediated gene regulation is linked to stress conditions in mitotic and post-mitotic cells. To better understand the role of H3S28 phosphorylation in vivo, we studied a Drosophila strain with ectopic expression of constitutively-activated H3S28A, which prevents PRC2 binding at H3S28, thus mimicking H3S28 phosphorylation. H3S28A mutants showed prolonged life span and improved resistance against starvation and paraquat-induced oxidative stress. Morphological and functional analysis of heart tubes revealed smaller luminal areas and thicker walls accompanied by moderately improved cardiac function after acute stress induction. Whole-exome deep gene-sequencing from isolated heart tubes revealed phenotype-corresponding changes in longevity-promoting and myotropic genes. We also found changes in genes controlling mitochondrial biogenesis and respiration. Analysis of mitochondrial respiration from whole flies revealed improved efficacy of ATP production with reduced electron transport-chain activity. Finally, we analyzed posttranslational modification of H3S28 in an experimental heart failure model and observed increased H3S28 phosphorylation levels in HF hearts. Our data establish a critical role of H3S28 phosphorylation in vivo for life span, stress resistance, cardiac and mitochondrial function in Drosophila. These findings may pave the way for H3S28 phosphorylation as a putative target to treat stress-related disorders such as heart failure.
Assuntos
Drosophila melanogaster/genética , Expressão Ectópica do Gene , Coração/fisiologia , Histonas/genética , Longevidade/genética , Mutação , Estresse Fisiológico/genética , Alelos , Animais , Drosophila melanogaster/fisiologia , Histonas/metabolismo , Fosforilação/genética , Transcrição GênicaRESUMO
The Canadian Cardiovascular Society (CCS) Atrial Fibrillation (AF) Guidelines Committee provides periodic reviews of new data to produce focused updates that address clinically important advances in AF management. This 2016 Focused Update deals with: (1) the management of antithrombotic therapy for AF patients in the context of the various clinical presentations of coronary artery disease; (2) real-life data with non-vitamin K antagonist oral anticoagulants; (3) the use of antidotes for the reversal of non-vitamin K antagonist oral anticoagulants; (4) digoxin as a rate control agent; (5) perioperative anticoagulation management; and (6) AF surgical therapy including the prevention and treatment of AF after cardiac surgery. The recommendations were developed with the same methodology used for the initial 2010 guidelines and the 2012 and 2014 Focused Updates. Using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) standards, individual studies and literature were reviewed for quality and bias; the literature review process and evidence tables are included in the Supplementary Material, and on the CCS Web site. The section on concomitant AF and coronary artery disease was developed in collaboration with the CCS Antiplatelet Guidelines Committee. Details of the updated recommendations are presented, along with their background and rationale. This document is linked to an updated summary of all CCS AF Guidelines recommendations, from 2010 to the present 2016 Focused Update
Assuntos
Humanos , Fibrilação Atrial , Fibrilação Atrial/terapia , Complicações Pós-Operatórias/prevenção & controle , Fibrilação Atrial/complicações , Algoritmos , Doença da Artéria Coronariana/complicações , Inibidores da Agregação Plaquetária , Inibidores da Agregação Plaquetária/uso terapêutico , Estimulação Cardíaca Artificial , Cardiotônicos , Cardiotônicos/administração & dosagem , Cardiotônicos/efeitos adversos , Ablação por Cateter , Apêndice Atrial/cirurgia , Acidente Vascular Cerebral/prevenção & controle , Digoxina , Digoxina/administração & dosagem , Digoxina/efeitos adversos , Quimioterapia Combinada , Síndrome Coronariana Aguda/terapia , Fibrinolíticos/uso terapêutico , Intervenção Coronária Percutânea , Inibidores do Fator Xa , Inibidores do Fator Xa/uso terapêutico , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Hemorragia/induzido quimicamente , Hemorragia/prevenção & controle , Magnésio , Magnésio/uso terapêutico , Anticoagulantes , Anticoagulantes/uso terapêuticoRESUMO
Cardiac experimental electrophysiology is in need of a well-defined Minimum Information Standard for recording, annotating, and reporting experimental data. As a step towards establishing this, we present a draft standard, called Minimum Information about a Cardiac Electrophysiology Experiment (MICEE). The ultimate goal is to develop a useful tool for cardiac electrophysiologists which facilitates and improves dissemination of the minimum information necessary for reproduction of cardiac electrophysiology research, allowing for easier comparison and utilisation of findings by others. It is hoped that this will enhance the integration of individual results into experimental, computational, and conceptual models. In its present form, this draft is intended for assessment and development by the research community. We invite the reader to join this effort, and, if deemed productive, implement the Minimum Information about a Cardiac Electrophysiology Experiment standard in their own work.
Assuntos
Fenômenos Eletrofisiológicos , Coração/fisiologia , Disseminação de Informação/métodos , Modelos Biológicos , Projetos de Pesquisa/normas , Animais , Humanos , Padrões de Referência , Reprodutibilidade dos TestesRESUMO
BACKGROUND AND PURPOSE: Both parasympathetic tone and atrial tachycardia (AT) remodelling of ion channels play important roles in atrial fibrillation (AF) pathophysiology. Different muscarinic cholinergic receptor (mAChR) subtypes (M2, M3, M4) in atrial cardiomyocytes are coupled to distinct K+-currents (called IKM2, IKM3, IKM4, respectively). Pulmonary veins (PVs) are important in AF and differential cholinergic current responses are a potential underlying mechanism. This study investigated AT-induced remodelling of mAChR subtypes and K+-currents in left-atrial (LA) and PV cardiomyocytes. EXPERIMENTAL APPROACH: Receptor expression was assayed by western blot. IKM2, IKM3 and IKM4 were recorded with whole-cell patch-clamp in LA and PV cardiomyocytes of nonpaced control dogs and dogs after 7 days of AT-pacing (400 bpm). KEY RESULTS: Current densities of IKM2, IKM3 and IKM4 were significantly reduced by AT-pacing in LA and PV cardiomyocytes. PV cardiomyocyte current-voltage relations were similar to LA for all three cholinergic currents, both in control and AT remodelling. Membrane-protein expression levels corresponding to M2, M3 and M4 subtypes were decreased significantly (by about 50%) after AT pacing. Agonist concentration-response relations for all three currents were unaffected by AT pacing. CONCLUSIONS AND IMPLICATIONS: AT downregulated all three mAChR-coupled K+-current subtypes, along with corresponding mAChR protein expression. These changes in cholinergic receptor-coupled function may play a role in AF pathophysiology. Cholinergic receptor-coupled K+-currents in PV cardiomyocytes were similar to those in LA under control and AT-pacing conditions, suggesting that differential cholinergic current properties do not explain the role of PVs in AF.
Assuntos
Átrios do Coração/metabolismo , Miócitos Cardíacos/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Veias Pulmonares/metabolismo , Receptores Muscarínicos/metabolismo , Taquicardia Atrial Ectópica/metabolismo , Animais , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Western Blotting , Estimulação Cardíaca Artificial , Células Cultivadas , Modelos Animais de Doenças , Cães , Regulação para Baixo , Técnicas Eletrofisiológicas Cardíacas , Potenciais Evocados , Átrios do Coração/patologia , Miócitos Cardíacos/patologia , Técnicas de Patch-Clamp , Veias Pulmonares/patologia , Receptores Muscarínicos/biossíntese , Taquicardia Atrial Ectópica/fisiopatologia , Fatores de TempoRESUMO
Drugs that suppress beta-adrenergic signaling by competitively inhibiting agonist binding to beta-adrenergic receptors ("beta-blockers") have important antiarrhythmic properties. They differ from most other antiarrhythmic agents by not directly modifying ion channel function; rather, they prevent the arrhythmia-promoting actions of beta-adrenergic stimulation. beta-Blockers are particularly useful in preventing sudden death due to ventricular tachyarrhythmias associated with acute myocardial ischemia, congenital long QT syndrome, and congestive heart failure. They are also quite valuable in controlling the ventricular rate in patients with atrial fibrillation. This chapter reviews the properties of beta-adrenoceptor signaling, the basic mechanisms of cardiac arrhythmias on which beta-blockers act, the ion channel mediators of beta-adrenergic responses, the evidence for clinical antiarrhythmic indications for beta-blocker therapy and the specific pharmacodynamic and pharmacokinetic properties of beta-blockers that differentiate the various agents of this class.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Antiarrítmicos/farmacologia , Potenciais de Ação/efeitos dos fármacos , Antagonistas Adrenérgicos beta/farmacocinética , Antagonistas Adrenérgicos beta/uso terapêutico , Animais , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/etiologia , Canais de Cálcio Tipo L/efeitos dos fármacos , Canais de Cálcio Tipo L/fisiologia , Canais de Cloreto/efeitos dos fármacos , Canais de Cloreto/fisiologia , Coração/fisiologia , Humanos , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/fisiologia , Receptores Adrenérgicos beta 1/fisiologia , Receptores Adrenérgicos beta 2/fisiologia , Trocador de Sódio e Cálcio/efeitos dos fármacos , Trocador de Sódio e Cálcio/fisiologiaRESUMO
The "leading circle model" was the first detailed attempt at understanding the mechanisms of functional reentry, and remains a widely-used notion in cardiac electrophysiology. The "spiral wave" concept was developed more recently as a result of modern theoretical analysis and is the basis for consideration of reentry mechanisms in present biophysical theory. The goal of this paper is to present these models in a way that is comprehensible to both the biophysical and electrophysiology communities, with the idea of helping clinical and experimental electrophysiologists to understand better the spiral wave concept and of helping biophysicists to understand why the leading circle concept is so attractive and widely used by electrophysiologists. To this end, the main properties of the leading circle and spiral wave models of reentry are presented. Their basic assumptions and determinants are discussed and the predictions of the two concepts with respect to pharmacological responses of arrhythmias are reviewed. A major difference between them lies in the predicted responses to Na(+)-channel blockade, for which the spiral wave paradigm appears more closely to correspond to the results of clinical and experimental observations. The basis of this difference is explored in the context of the fundamental properties of the models.
Assuntos
Antiarrítmicos/farmacologia , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/fisiopatologia , Sistema de Condução Cardíaco/fisiopatologia , Modelos Cardiovasculares , Bloqueadores dos Canais de Sódio/farmacologia , Potenciais de Ação/fisiologia , Fenômenos Biofísicos , Biofísica , Simulação por Computador , Condutividade Elétrica , Técnicas Eletrofisiológicas CardíacasRESUMO
Understanding of the considerable variation in action potential (AP) shape throughout the heart is necessary to explain normal and pathological cardiac function. Existing mathematical models reproduce typical APs, but not all measured APs, as fitting the sets of non-linear equations is a tedious process. The study describes the integration of a pre-existing mathematical model of an atrial cell AP with a genetic algorithm to provide an automated tool to generate APs for arbitrary cells by fitting ionic channel conductances. Using the Nygren model as the base, the technique was first verified by starting with random values and fitting the Nygren model to itself with an error of only 0.03%. The Courtemanche model, which has a different morphology from that of the Nygren model, was successfully fitted. The AP duration restitution curve generated by the fit matched that of the target model very well. Finally, experimentally recorded APs were reproduced. To match AP duration restitution behaviour properly, it was necessary simultaneously to fit over several stimulation frequencies. Also, fitting of the upstroke was better if the stimulating current pulse replicated that found in situ as opposed to a rectangular pulse. In conclusion, the modelled parameters were successfully able to reproduce any given atrial AP. This tool can be useful for determining parameters in new AP models, reproducing specific APs, as well as determining the locus of drug action by examining changes in conductance values.
Assuntos
Função Atrial/fisiologia , Modelos Cardiovasculares , Potenciais de Ação , Algoritmos , Animais , Cães , Condutividade Elétrica , Processamento de Sinais Assistido por ComputadorRESUMO
Over the past 10 years, cDNAs encoding a wide range of pore-forming K(+)-channel alpha-subunits have been cloned and found to result in currents with many properties of endogenous cardiac K(+) channels upon homomeric expression in heterologous systems. However, a variety of remaining discrepancies have led to a search for other subunits that might be involved in the formation of native channels. Over the past few years, a series of accessory subunits has been discovered that modify current properties upon coexpression with alpha-subunits. One of these, the minimal K(+)-channel subunit minK, is essential for formation of the cardiac slow delayed-rectifier K(+) current, I(Ks), and may also interact in functionally important ways with other alpha-subunits. Another, the K(+)-channel interacting protein KChIP appears critical in formation of native transient outward current (I(to)) channels. The roles of 2 other accessory subunits, the minK-related peptide MiRP and the K(+)-channel accessory protein, KChAP, remain unclear. This article reviews the available knowledge regarding the accessory subunits minK, MiRP, KChIP and KChAP, dealing with their structure, effects on currents carried by coexpressed alpha-subunits, expression in cardiac tissues and potential physiological function. On the basis of the available information, we attempt to assess the potential involvement of these accessory K(+)-channel subunits in cardiac pathophysiology and in developing new therapeutic approaches.
Assuntos
Sistema de Condução Cardíaco/metabolismo , Canais de Potássio , Sequência de Aminoácidos , Animais , Antiarrítmicos/farmacologia , Humanos , Ativação do Canal Iônico , Camundongos , Dados de Sequência Molecular , Potássio/metabolismo , Canais de Potássio/química , Canais de Potássio/classificação , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/genética , Canais de Potássio/fisiologia , Subunidades Proteicas/química , Subunidades Proteicas/genética , Subunidades Proteicas/fisiologia , Ratos , Homologia de Sequência de Aminoácidos , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Atrial fibrillation is the most common sustained cardiac arrhythmia, and engenders significant health care costs. The impact of various treatment options for atrial fibrillation on hospital costs has not been evaluated in a randomized trial. METHODS: We analysed 1-year follow-up data on 392 patients randomized to low dose amiodarone (200 mg. day(-1)) or alternative first-line therapy (sotalol or propafenone) in a multicentre trial (Canadian Trial of Atrial Fibrillation, CTAF). RESULTS: Patients in the amiodarone group had fewer electrical cardioversions (65 vs 109 for patients in the sotalol/propafenone group, P<0.0001), and pacemaker insertions (4 vs 11, P=0.07). The average amiodarone patient spent fewer days in hospital (0.47 vs 0.97, P=0.01), and incurred lower costs ($532 vs $898, P=0.03), for admissions where atrial fibrillation was the admitting diagnosis. Average total hospital costs per patient for all admissions, as well as average combined hospital and physician costs per patient, showed wide variations within the treatment arms and were not significantly different between groups. CONCLUSION: For patients in whom antiarrhythmic drug therapy is indicated, low dose amiodarone significantly reduces atrial fibrillation-related costs by reducing the number of atrial fibrillation-related procedures.
Assuntos
Amiodarona/uso terapêutico , Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Idoso , Análise de Variância , Fibrilação Atrial/economia , Custos e Análise de Custo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Propafenona/uso terapêutico , Sotalol/uso terapêuticoAssuntos
Antiarrítmicos/farmacologia , Fibrilação Atrial/fisiopatologia , Canais Iônicos/metabolismo , Lidocaína/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/metabolismo , Regulação para Baixo , Condutividade Elétrica , Insuficiência Cardíaca/fisiopatologia , Humanos , Transporte de Íons/efeitos dos fármacos , Lidocaína/análogos & derivados , Lidocaína/uso terapêutico , Bloqueadores dos Canais de Potássio/farmacologia , Período Refratário Eletrofisiológico/efeitos dos fármacos , Taquicardia Atrial Ectópica/metabolismo , Taquicardia Atrial Ectópica/fisiopatologia , Torsades de Pointes/etiologiaRESUMO
Compensatory changes in ion transport mechanisms occur in response to a variety of cardiac disease processes. Recent work has demonstrated that these adaptive responses can produce the arrhythmogenic substrate for a variety of important cardiac rhythm disorders. Two important paradigms are atrial tachycardia-induced remodeling and ionic remodeling caused by congestive heart failure. Atrial tachycardia promotes cellular Ca(2)+ loading and downregulates a variety of ion channels, particularly L-type Ca(2)+ channels, thereby promoting the occurrence and maintenance of atrial fibrillation. Congestive heart failure alters the expression and function of a variety of membrane transport processes, including several K(+)-channels and key Ca(2)+-transport systems, favoring the occurrence of arrhythmogenic afterdepolarizations. An improved understanding of the mechanisms and consequences of arrhythmogenic ionic remodeling promises to lead to novel and improved therapeutic approaches.
Assuntos
Arritmias Cardíacas/etiologia , Arritmias Cardíacas/metabolismo , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/metabolismo , Transporte de Íons/fisiologia , Taquicardia/complicações , Taquicardia/metabolismo , Remodelação Ventricular/fisiologia , Animais , Cães , Humanos , Coelhos , Transdução de Sinais/fisiologiaRESUMO
OBJECTIVES: The goal of this research was to study the effect of locally delivered 17beta-estradiol (17beta-E) during angioplasty on endothelial function after percutaneous transluminal coronary angioplasty (PTCA) at four weeks. BACKGROUND: The endothelium plays a major role in the structural and functional integrity of coronary arteries and is damaged by PTCA. METHODS: Juvenile swine were subjected to PTCA, after which each artery was randomly-assigned to 600-microg 17beta-E delivered locally, an equal volume of vehicle (V) or PTCA alone. After four weeks, the improvement in endothelial function was assessed by angiography using intracoronary acetylcholine (Ach) infusion and by immunohistochemistry. RESULTS: At 10(-5) mol/l and 10(-4) mol/l Ach, significant vasoconstriction was noted in arteries treated with PTCA alone (p < 0.01 and p < 0.0001, respectively) and with PTCA plus V (p < 0.02 and p < 0.001, respectively). No significant vasoconstrictive response to Ach was observed in arteries treated with PTCA plus 17beta-E. Immunohistochemistry of vessels four weeks after PTCA revealed enhanced re-endothelialization (p < 0.0005) and endothelial nitric-oxide synthase (eNOS) expression (p < 0.0005) in PTCA plus 17beta-E-treated arteries compared with the other two treatment groups. Arteries treated with 17beta-E showed significantly lower neointima formation, which correlated inversely with the extent of re-endothelialization and eNOS expression. CONCLUSIONS: Locally delivered 17beta-E significantly enhances re-endothelialization and endothelial function after PTCA, possibly by improving the expression of eNOS. Since endothelial dysfunction can promote both restenosis and coronary spasm, local 17beta-E administration is a promising new approach to improve long-term results after PTCA.
Assuntos
Angioplastia Coronária com Balão/efeitos adversos , Doença das Coronárias/terapia , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/lesões , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/lesões , Estradiol/uso terapêutico , Acetilcolina/farmacologia , Angioplastia Coronária com Balão/métodos , Animais , Cateterismo Cardíaco , Terapia Combinada , Angiografia Coronária , Doença das Coronárias/diagnóstico , Doença das Coronárias/metabolismo , Vasoespasmo Coronário/etiologia , Vasoespasmo Coronário/prevenção & controle , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Vasos Coronários/fisiopatologia , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos , Endotélio Vascular/química , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Estradiol/farmacologia , Imuno-Histoquímica , Infusões Intra-Arteriais , Óxido Nítrico Sintase/análise , Distribuição Aleatória , Recidiva , Método Simples-Cego , Suínos , Resultado do Tratamento , Vasodilatadores/farmacologiaRESUMO
BACKGROUND: Lysophosphatidylcholine (LPC), a naturally occurring phospholipid metabolite, accumulates in the ischemic heart and causes extracellular K(+) accumulation and action potential shortening. LPC has been incriminated as a biochemical trigger of lethal cardiac arrhythmias, but the underlying mechanisms remain poorly understood. METHODS AND RESULTS: We studied the effect of 1-palmitoyl-LPC (Pal-LPC) on currents resulting from human ether-a-go-go-related gene (HERG) expression in human embryonic kidney (HEK) cells using whole-cell patch-clamp techniques. Bath application of Pal-LPC consistently and reversibly increased HERG current (I(HERG)). The effects of Pal-LPC were apparent as early as 3 minutes after application of the drug, reached maximum within 10 minutes, and were reversible on washout. Pal-LPC increased I(HERG) at voltages between -20 and +30 mV, with greater effects at stronger depolarization. However, Pal-LPC did not affect the voltage-dependence of I(HERG) activation. In contrast, Pal-LPC significantly shifted the inactivation curve toward more positive potentials, causing a mean 20.0+/-2.2 mV shift in half-inactivation voltage relative to control. CONCLUSIONS: Our results indicate that apart from being a well-recognized target for drug inhibition, I(HERG) can also be enhanced by natural substances. An increase in I(HERG) by Pal-LPC may contribute to K(+) loss, abnormal electrophysiology, and arrhythmia occurrence in the ischemic heart.
Assuntos
Proteínas de Transporte de Cátions , Proteínas de Ligação a DNA , Transporte de Íons/fisiologia , Fosfolipídeos/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/genética , Canais de Potássio/metabolismo , Transativadores , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/metabolismo , Linhagem Celular , Ceramidas/farmacologia , Relação Dose-Resposta a Droga , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go , Expressão Gênica , Humanos , Transporte de Íons/efeitos dos fármacos , Rim/citologia , Rim/metabolismo , Lisofosfatidilcolinas/metabolismo , Lisofosfatidilcolinas/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Técnicas de Patch-Clamp , Canais de Potássio/efeitos dos fármacos , Regulador Transcricional ERGRESUMO
BACKGROUND: Atrial structural remodeling creates a substrate for atrial fibrillation (AF), but the underlying signal transduction mechanisms are unknown. This study assessed the effects of ACE inhibition on arrhythmogenic atrial remodeling and associated mitogen-activated protein kinase (MAPK) changes in a dog model of congestive heart failure (CHF). METHODS AND RESULTS: Dogs were subjected to various durations of ventricular tachypacing (VTP, 220 to 240 bpm) in the presence or absence of oral enalapril 2 mg. kg(-1). d(-1). VTP for 5 weeks induced CHF, local atrial conduction slowing, and interstitial fibrosis and prolonged atrial burst pacing-induced AF. Atrial angiotensin II concentrations and MAPK expression were increased by tachypacing, with substantial changes in phosphorylated forms of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38-kinase. Enalapril significantly reduced tachypacing-induced changes in atrial angiotensin II concentrations and ERK expression. Enalapril also attenuated the effects of CHF on atrial conduction (conduction heterogeneity index reduced from 3.1+/-0.4 to 1.9+/-0.2 ms/mm, P<0.05), atrial fibrosis (from 11.9+/-1.1% to 7.5+/-0.4%, P<0.01), and mean AF duration (from 651+/-164 to 218+/-75 seconds, P<0.05). Vasodilator therapy of a separate group of VTP dogs with hydralazine and isosorbide mononitrate did not alter CHF-induced fibrosis or AF promotion. CONCLUSIONS: CHF-induced increases in angiotensin II content and MAPK activation contribute to arrhythmogenic atrial structural remodeling. ACE inhibition interferes with signal transduction leading to the AF substrate in CHF and may represent a useful new component to AF therapy.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Fibrilação Atrial/tratamento farmacológico , Enalapril/farmacologia , Insuficiência Cardíaca/etiologia , Dinitrato de Isossorbida/análogos & derivados , Taquicardia Ventricular/complicações , Angiotensina II/metabolismo , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Animais , Fibrilação Atrial/etiologia , Fibrilação Atrial/metabolismo , Fibrilação Atrial/patologia , Cães , Eletrofisiologia , Enalapril/administração & dosagem , Fibrose Endomiocárdica/etiologia , Fibrose Endomiocárdica/metabolismo , Fibrose Endomiocárdica/patologia , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Hidralazina/farmacologia , Dinitrato de Isossorbida/farmacologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Sistema Renina-Angiotensina , Transdução de SinaisRESUMO
OBJECTIVES: Atrial tachycardia-induced remodeling (ATR) and ventricular tachypacing-induced heart failure (HF) create experimental substrates for atrial fibrillation (AF), and both have been reported to produce atrial dilation and hypocontractility. The relative importance of changes in atrial size and contractility in the two models is unknown. This study compared changes in atrial dimensions and emptying in ATR versus HF dog models and related them to AF promotion. METHODS: In ATR dogs (n=11), the right atrium (RA) was paced at 400/min for 42 days. In HF dogs (n=10), the right ventricle was paced at 240 bpm for 2 weeks, followed by 3 weeks at 220 bpm. Transthoracic echocardiography was performed at baseline and weekly thereafter. At a terminal electrophysiological study, RA effective refractory period (ERP) was recorded and AF induced repeatedly by atrial burst pacing to measure mean AF duration (DAF). RESULTS: Left atrial (LA) systolic area increased by 10.0% in ATR versus 48.2% in HF dogs (P=0.008), with significant time-dependent changes in HF (P=0.0001), but not ATR (P=0.16). LA diastolic area increased over time in both groups (P=0.004, 0.0001 for ATR and HF respectively), but increases were much larger in CHF (80.2%) compared to ATR (24.2%, P=0.0002). Similar findings were obtained for RA. Fractional area shortening (FAS) decreased by 19.4% (ATR) versus 41.8% (HF, P=0.007) in LA and 13.7% (ATR) versus 33.7% (HF, P=0.03) in RA. RA ERP correlated with DAF in ATR dogs (r=-0.79, P<0.001), but not in HF dogs (r=0.20, P=NS). DAF and diastolic areas of RA and LA were highly correlated (r=0.71, 0.77; P<0.01 for each) in HF dogs, but not in ATR dogs (r=-0.18, 0.29; P=NS). CONCLUSIONS: Remodeling of atrial size and emptying function is much greater in HF than in ATR. Whereas in ATR, electrophysiological remodeling is of prime importance in AF promotion, structural remodeling (as reflected in changes in atrial size and contraction) appears much more important in HF-induced AF.
Assuntos
Fibrilação Atrial/diagnóstico por imagem , Função Atrial , Átrios do Coração/diagnóstico por imagem , Animais , Fibrilação Atrial/fisiopatologia , Estimulação Cardíaca Artificial , Cães , Ecocardiografia , Eletrocardiografia , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Modelos AnimaisRESUMO
BACKGROUND: Cardiac Purkinje cells (PCs) are important for the generation of triggered arrhythmias, particularly in association with abnormal repolarization. The effects of congestive heart failure (CHF) on the ionic properties of PCs are unknown. METHODS AND RESULTS: PCs were isolated from false tendons of control dogs and dogs with ventricular tachypacing-induced CHF. CHF PCs were hypertrophied (capacitance, mean+/-SEM, 149+/-4 pF, n=130; versus 128+/-3 pF, n=150, control; P<0.001). Transient outward current density was reduced in CHF PCs without change in voltage dependence or kinetics. CHF also reduced inward-rectifier current density, with no change in form of the current-voltage relationship. Densities of L- and T-type calcium, rapid and slow delayed rectifier, and Na(+)-Ca(2+) exchange currents were unaltered by CHF, but L-type calcium current inactivation was slowed at positive potentials. Purkinje fiber action potentials from CHF dogs showed decreased phase 1 amplitudes and elevated plateau voltages and demonstrated twice as much prolongation on exposure to the rapid delayed rectifier blocker E-4031 as control Purkinje fibers. CONCLUSIONS: CHF causes remodeling of important K(+) and Ca(2+) currents in cardiac PCs, decreasing repolarization reserve and causing an exaggerated repolarization delay in response to a class III drug. These results have important potential implications regarding ventricular arrhythmogenesis, particularly related to triggered activity in PCs, in patients with CHF.
Assuntos
Insuficiência Cardíaca/metabolismo , Ramos Subendocárdicos/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Antiarrítmicos/farmacologia , Bário/farmacologia , Cálcio/metabolismo , Canais de Cálcio Tipo L/metabolismo , Canais de Cálcio Tipo T/metabolismo , Modelos Animais de Doenças , Cães , Insuficiência Cardíaca/patologia , Técnicas In Vitro , Transporte de Íons/efeitos dos fármacos , Técnicas de Patch-Clamp , Piperidinas/farmacologia , Potássio/metabolismo , Canais de Potássio/efeitos dos fármacos , Ramos Subendocárdicos/efeitos dos fármacos , Piridinas/farmacologia , Sódio/metabolismo , Trocador de Sódio e Cálcio/metabolismoRESUMO
INTRODUCTION: It has been suggested that the three-dimensional structure of the atria may be crucial in arrhythmogenesis; however, previous in vivo atrial activation mapping studies have been limited to either endocardial or epicardial approaches. METHODS AND RESULTS: To investigate the role of endocardial and epicardial structures and their interaction in atrial conduction and arrhythmias, we used five epicardial plaques and two intra-atrial balloon arrays to record a total of 368 unipolar electrograms from the entire epicardial and endocardial surface of both atria. During regular 1:1 pacing from the right atrial appendage, right atrial endocardial activation spread considerably faster than epicardial (total activation time 45+/-12 msec vs 60+/-19 msec, respectively [mean +/- SD]; P < 0.05), pointing to preferential conduction over structures like the crista terminalis and pectinate muscles. No such differences were noted in the left atrium. Transseptal spread occurred via discrete anterior and posterior pathways, causing separate breakthroughs in anterior and posterior atrial regions, respectively. Dissociation between septal pathways played a role in reentry during vagal atrial fibrillation. In 2 of 4 dogs with atrial fibrillation associated with congestive heart failure, single macroreentrant circuits involving endocardial and epicardial components were revealed during the arrhythmia. CONCLUSION: We conclude that activation mapping using simultaneous recording from both epicardial and endocardial surfaces provides potentially important insights into the mechanisms of atrial conduction and arrhythmogenesis.
Assuntos
Mapeamento Potencial de Superfície Corporal/métodos , Endocárdio/fisiopatologia , Pericárdio/fisiopatologia , Análise por Ativação , Animais , Arritmias Cardíacas/fisiopatologia , Cães , Eletrofisiologia , Feminino , Átrios do Coração/inervação , Sistema de Condução Cardíaco/fisiopatologia , Masculino , Modelos CardiovascularesRESUMO
Experimental and clinical evidence suggests a critical role for the left atrium (LA) in atrial fibrillation (AF). In animal models, repolarization is faster in the LA than in the right atrium (RA), leading to more stable reentry circuits with a shorter intrinsic period in the LA. The ionic mechanisms underlying LA-RA repolarization differences are unknown. Therefore, we evaluated ionic currents and action potentials (APs) with the whole-cell patch clamp in isolated canine atrial myocytes. The density of the rapid delayed rectifier current (I(Kr)) was greater in the LA (eg, 1.83+/-0.10 pA/pF at +20 mV) than in the RA (1.15+/-0.07 pA/pF, P<0.01; n=16 cells per group). The slow and ultrarapid delayed rectifier, the inward rectifier, L-type Ca(2+), and transient outward K(+) currents were all comparable in the LA and RA. There were no differences in kinetic or voltage-dependent properties of currents in LA versus RA. Western blots of ether-a-go-go-related gene (ERG) protein in three RA and corresponding LA regions showed significantly greater ERG expression in LA. AP duration (APD) was shorter in the LA versus RA in both isolated cells and multicellular preparations, and the effective refractory period (ERP) was shorter in the LA compared with the RA in vivo. Dofetilide had significantly larger APD- and ERP-increasing effects in the LA compared with RA, and LA-RA repolarization differences were eliminated by exposure to dofetilide. We conclude that LA myocytes have larger I(Kr) than do RA myocytes, contributing importantly to the shorter APD and ERP in LA. The larger LA I(Kr) may participate in the ability of the LA to act as a "driver region" for AF, with potentially important implications for understanding AF mechanisms and antiarrhythmic therapy.
Assuntos
Função do Átrio Esquerdo/fisiologia , Função do Átrio Direito/fisiologia , Proteínas de Transporte de Cátions , Átrios do Coração/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Antiarrítmicos/farmacologia , Função do Átrio Esquerdo/efeitos dos fármacos , Função do Átrio Direito/efeitos dos fármacos , Cálcio/metabolismo , Canais de Cálcio Tipo L/metabolismo , Separação Celular , Cães , Canais de Potássio Éter-A-Go-Go , Potenciais Evocados/efeitos dos fármacos , Potenciais Evocados/fisiologia , Átrios do Coração/citologia , Átrios do Coração/efeitos dos fármacos , Immunoblotting , Técnicas In Vitro , Transporte de Íons/fisiologia , Miocárdio/citologia , Miocárdio/metabolismo , Especificidade de Órgãos , Técnicas de Patch-Clamp , Fenetilaminas/farmacologia , Potássio/metabolismo , Bloqueadores dos Canais de Potássio , Canais de Potássio/metabolismo , Sulfonamidas/farmacologiaRESUMO
Oxidative stress can cause significant cell death by apoptosis. We performed studies in L-cells to explore whether prior exposure to oxidative stress ("oxidative preconditioning") can protect the cell against the apoptotic consequences of subsequent oxidative insults and to establish the mediators in the preconditioning signaling cascade. Cells were preconditioned with three 5-min exposures to H(2)O(2), followed by 10-h recovery and subsequent exposure to 600 microm H(2)O(2) for 10 h. A single 10-h exposure to H(2)O(2) induced substantial apoptotic cell death (approximately 90%), as determined by enzyme-linked immunosorbent assay, TUNEL (terminal deoxyribonucleotide transferase-mediated dUTP nick end labeling), and Annexin V methods, but apoptosis was largely prevented in preconditioned cells. The degree of cytoprotection depended on the strength of preconditioning or H(2)O(2) concentration (20 approximately 600 microm). Transient increases in mitogen-activated protein kinase (MAPK), p38, and JNK/SAPK activities and sustained protein kinase B (Akt) activation, accompanied by drastically reduced caspase 3 activity, were seen after preconditioning. The expression levels of these kinases were unaltered. Inhibitors of p38 (SB203580) and phosphoinositide 3-kinase (PI3K, LY294002) pathways abolished the protection provided by preconditioning. We conclude that oxidative preconditioning protects cells against apoptosis and that this effect involves MAPK and PI3K/Akt pathways. This system may be important in regulating apoptotic cell death in development and disease states.