Atrial Fibrillation in Hyperthyroidism: Active Antibodies to Autonomic Receptors

甲状腺功能亢进症中的心房颤动：自主神经受体的活性抗体

• 批准号: 8046711
• 负责人: David Kem
• 金额: --
• 依托单位: OKLAHOMA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8046711
• 关键词: Action Potentials; Acute; Address; Adrenergic Agents; Adrenergic Agonists; Age; Aging; Animal Model; Animals; Antibodies; Anticoagulants; Atrial Fibrillation; Autoantibodies; Autoimmune Process; Biological Assay; Canis familiaris; Cardiac; Cells; Chronic; Cyclic AMP; Data; Databases; Development; Electrocardiogram; Epidemiologic Studies; Experimental Models; Fluorescence; Fluorescence Resonance Energy Transfer; Functional disorder; Future; Ganglia; General Population; Healthcare; Heart; Heart Atrium; Heart Diseases; Heart Rate; Heart failure; Human; Hyperactive behavior; Hyperthyroidism; Immune; In Vitro; Lead; Ligands; Maps; Measures; Mediating; Modeling; Morbidity - disease rate; Muscarinic Antagonists; Muscarinic M2 Receptor; Optics; Oryctolagus cuniculus; Patients; Perfusion; Population; Prevalence; Property; Pulmonary veins; Risk Factors; Role; Serum; Signal Transduction; Sinus; Source; Stroke; Stroke prevention; Tachyarrhythmias; Telemetry; Therapeutic; Thyroid Hormones; Veterans; adrenergic; age related; base; fluorescence imaging; in vivo; insight; medical attention; mortality; normal aging; older patient; receptor; tissue preparation

DESCRIPTION (provided by applicant): The large majority of older patients with autoimmune Graves' hyperthyroidism and atrial fibrillation (AF) have coexisting activating autoantibodies (AA) to the beta1-adrenergic (B1AR) and M2 muscarinic receptors (M2R). Adrenergic and muscarinic agonists are known to enhance the likelihood for developing AF. HYPOTHESIS: AA in the aging thyrotoxic heart facilitates and/or causes AF. We have demonstrated AABAR) in 94% and AAM2R in 88%; and both autoantibodies in 83% in Graves' hyperthyroidism + AF compared to 10% of Graves' patients in normal sinus rhythm (P<0.001). All patients with AF had at least one of the two AA. These autoantibodies altered electrophysiological activity in pulmonary vein atrial sleeve cells such as predisposes to AF in experimental models; supporting our concept that elevated AABAR and AAM2R as well as thyroid hormone are major risk factors for AF. PROPOSAL: We will use translational and mechanistic studies to examine the electrophysiological interrelationships of thyroid hormone, age and activating autoantibodies as a cause of AF. METHODS: (Spec. Aim A) Expansion of epidemiological studies to identify the prevalence and function of autoantibodies in non-Graves" hyperthyroidism and AF; (Spec. Aim Bi) Identify age and thyroid hormone dependent triggering of ectopic action potentials in the presence of target-specific autonomic AA in a canine pulmonary vein atrial sleeve tissue preparation in vitro; (Spec. Aim Bii) Study the development of AF (by ECG telemetry) in young (6 mo) and old (>5yrs) rabbits immunized to produce target-specific AAB1AR and/or AAM2R without and with thyroid hormone. We will then use sophisticated electrophysiological studies incorporating right atrial ganglia stimulation to measure the pulmonary vein atrial sleeve cell threshold for induction of AF. This model will determine the combined effects of AABAR and AAM2R on the atrial substrate for AF. METHODS also include a FRET-based micro-cAMP assay to examine the allosteric effects of AA. This assay will assist in determining whether these AA act as agonists and whether they also serve as partial antagonists to their normally operative orthosteric ligands. Our studies are NOVEL in that they will identify a spectrum of activating autoantibodies in the heart and demonstrate their role in immune-mediated mechanism(s) leading to AF in hyperthyroidism. Our data are relevant not only to hyperthyroidism but will also lead to a better understanding of these mechanisms in other and more common forms of AF which frequently coexist with AA. POTENTIAL IMPACT ON VETERANS HEALTH CARE: AF is an important risk factor for stroke and heart failure in our aging veteran population and leads to increased mortality and morbidity. The present study addresses this issue and may permit identification of future therapeutic options. PUBLIC HEALTH RELEVANCE: The presence of an irregular heart rate (atrial fibrillation) is associated with 1/3 of the strokes in the general population and is related to decreased cardiac function and with increasing age. Atrial fibrillation is a significant source of strokes and heart failure in the veteran population. An overactive thyroid in older veterans frequently causes atrial fibrillation and requires blood thinning, careful medical attention and still does not always prevent strokes. We have discovered certain antibodies are directed toward the heart and are present in almost 100% of these patients with atrial fibrillation. They appear to contribute to atrial fibrillation and make it difficult for treatment. The proposed studies will examine the role that these signaling antibodies have with excess thyroid hormone and aging to cause the irregular rhythm. Our studies are directed toward establishing this association with atrial fibrillation and to develop future preventative measures and treatment.

描述（由申请人提供）： 绝大多数患有自身免疫性坟墓的老年患者的甲状腺功能亢进和心房颤动（AF）具有与BetA1-肾上腺素能（B1AR）和M2毒蕈碱受体（M2R）共存的自身抗体（AA）。众所周知，肾上腺素能力和毒蕈碱激动剂会增强发生AF的可能性。假设：衰老的甲状腺毒性心脏中的AA促进和/或原因。我们已经证明了Aabar）为94％，AAM2R占88％；在坟墓的甲状腺功能亢进症中，这两种自身抗体在83％中，而正常窦性心律中的坟墓患者中有10％（p <0.001）。所有AF患者至少具有两个AA中的一个。这些自身抗体改变了肺静脉心房袖细胞中的电生理活性，例如在实验模型中对AF的AF。支持我们升高Aabar和AAM2R以及甲状腺激素的概念是AF的主要危险因素。提案：我们将使用翻译和机械研究来检查甲状腺激素，年龄和激活自身抗体的电生理相互关系作为AF的原因。方法：（规格a）扩展流行病学研究，以确定非刺激性自身抗体的流行和功能“甲状腺功能亢进和AF；犬类肺静脉袖子组织在体外制备（Spec。AimBii）的靶标特异性AA研究年轻（6个月）和旧（> 5年）的AF（ECG遥测）的发育 - 没有甲状腺激素的特异性AAB1AR和/或AAM2R。 AF的心房基质还包括基于FRET的微型训练学测定，以检查AA的变构效应。正常配体。我们的研究是新颖的，因为它们将确定激活心脏中自身抗体的范围，并证明它们在免疫介导的机制中的作用，导致AF在甲状腺功能亢进症中。我们的数据不仅与甲状腺功能亢进有关，而且还将更好地理解这些机制的其他和更常见的AF形式，这些AF经常与AA共存。对退伍军人卫生保健的潜在影响：AF是我们老年退伍军人人口中中风和心力衰竭的重要危险因素，导致死亡率和发病率提高。本研究解决了这个问题，可以识别未来的治疗选择。 公共卫生相关性： 心率不规则（心房颤动）的存在与一般人群中的1/3中风有关，并且与心脏功能降低和年龄增加有关。心房颤动是老兵中风和心力衰竭的重要来源。老年退伍军人的甲状腺过度活跃，经常引起心房颤动，需要血液稀疏，仔细的医疗护理，并且并不总是阻止中风。我们发现某些抗体针对心脏，并且在这些心房颤动的患者中，几乎100％存在。它们似乎有助于心房颤动，并使其难以接受治疗。拟议的研究将检查这些信号抗体与甲状腺激素过多的和衰老导致不规则节奏的作用。我们的研究旨在建立与房颤的关联，并开发未来的预防措施和治疗。