Atrial Fibrillation in Hyperthyroidism: Active Antibodies to Autonomic Receptors

描述（由申请人提供）： 大多数患有自身免疫性Graves甲状腺功能亢进症和房颤（AF）的老年患者同时存在β 1-肾上腺素能（B1 AR）和M2毒蕈碱受体（M2 R）的激活性自身抗体（AA）。我们已经证明，在94%的Graves甲亢+AF患者中，AA（AABAR）和AAM 2 R（AAM 2 R）促进和/或导致AF;在Graves甲亢+ AF患者中，这两种自身抗体的发生率为83%，而在正常窦性心律的Graves甲亢患者中，这两种自身抗体的发生率为10%（P<0.001）。所有AF患者至少有两种AA之一。这些自身抗体改变了肺静脉心房袖细胞的电生理活动，例如在实验模型中易患AF;支持我们的概念，即AABAR和AAM 2 R以及甲状腺激素升高是AF的主要危险因素。建议：我们将使用翻译和机制研究来检查甲状腺激素，年龄和激活自身抗体作为AF原因的电生理相互关系。（规范目的A）扩大流行病学研究，以确定自身抗体在非Graves甲亢和AF中的患病率和功能;（规范目的Bi）在体外犬肺静脉心房袖组织制备物中，在存在靶向特异性自主AA的情况下，鉴定异位动作电位的年龄和甲状腺激素依赖性触发;（Spec. Aim Bii）研究在不含和含甲状腺激素的情况下免疫以产生靶特异性AAB 1AR和/或AAM 2 R的年轻（6月龄）和老年（> 5岁）兔中AF的发展（通过ECG遥测）。然后，我们将使用复杂的电生理学研究，将右心房神经节刺激，以测量肺静脉心房袖细胞的阈值诱导AF。该模型将确定AABAR和AAM 2 R的心房基板AF的组合效果。方法还包括FRET为基础的微cAMP测定，以检查变构AA的影响。该测定将有助于确定这些AA是否作为激动剂，以及它们是否也作为其正常操作的正构配体的部分拮抗剂。我们的研究是新颖的，因为它们将识别心脏中的激活自身抗体谱，并证明它们在导致甲状腺功能亢进症AF的免疫介导机制中的作用。我们的数据不仅与甲状腺功能亢进症有关，而且还将有助于更好地了解经常与AA共存的其他更常见形式的AF的这些机制。对退伍军人医疗保健的潜在影响：AF是我们老年退伍军人人群中风和心力衰竭的重要风险因素，并导致死亡率和发病率增加。本研究解决了这个问题，并可能允许确定未来的治疗方案。

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.