Atrial Fibrillation in Hyperthyroidism: Active Antibodies to Autonomic Receptors

描述(由申请人提供)： 绝大多数老年自身免疫性Graves甲亢和房颤患者同时存在抗β1肾上腺素能受体(B1AR)和M2受体(M2R)的激活型自身抗体(AA)。肾上腺素能和毒扁豆碱能激动剂已知可增加发生房颤的可能性。假设：甲亢心脏老化的AA促进和/或引起房颤。在Graves‘甲亢合并房颤患者中，这两种自身抗体的阳性率均为83%，而在正常窦性心律的Graves’病患者中，这两种自身抗体的阳性率分别为10%(P&lt；0.001)。所有的房颤患者都至少有两种AA中的一种。这些自身抗体改变了肺静脉心房袖状细胞的电生理活动，如在实验模型中易患房颤；支持我们的观点，即Aabar和AAM2R以及甲状腺激素升高是房颤的主要危险因素。建议：我们将使用翻译和机制研究来检验作为房颤病因的甲状腺激素、年龄和激活自身抗体之间的电生理相互关系。方法：(规范)目的a)扩大流行病学研究，以确定自身抗体在非Graves甲亢和房颤中的患病率和功能；目的：在犬肺静脉心房袖状组织制备的体外标本中，鉴定年龄和甲状腺激素依赖的异位动作电位在靶点特异性自主神经AA存在下的触发；目的研究幼兔(6个月)和老年(5岁)兔在不加和不加甲状腺激素的条件下免疫产生靶向性AAB1AR和/或AAM2R后房颤的发生。然后，我们将使用复杂的电生理学研究结合右房神经节刺激来测量诱发房颤的肺静脉心房袖状细胞阈值。该模型将确定Aabar和AAM2R对房颤时心房基质的联合作用。方法还包括基于FRET的微量cAMP分析，以检查AA的变构效应。这个测试将有助于确定这些AA是否作为激动剂，以及它们是否也作为其正常工作的正构体配体的部分拮抗剂。我们的研究是新颖的，因为他们将识别心脏中一系列激活的自身抗体，并证明它们在免疫介导机制(S)中的作用，从而导致甲状腺功能亢进症的房颤。我们的数据不仅与甲亢有关，而且还将有助于更好地理解其他更常见的房颤的机制，这些房颤经常与再障共存。对退伍军人医疗保健的潜在影响：在我们老龄化的退伍军人群体中，房颤是中风和心力衰竭的重要风险因素，并导致死亡率和发病率的增加。本研究解决了这一问题，并可能有助于确定未来的治疗方案。 公共卫生相关性： 心率不齐(房颤)的存在与普通人群中三分之一的中风有关，并与心功能下降和年龄增加有关。在退伍军人中，心房颤动是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会导致心房颤动，需要血液稀释，需要仔细的医疗护理，而且仍然不能总是预防中风。我们发现，某些抗体是针对心脏的，几乎100%的房颤患者都存在这种抗体。它们似乎会导致心房颤动，并使其难以治疗。拟议的研究将检查这些信号抗体与过量的甲状腺激素和衰老导致节律不齐所起的作用。我们的研究旨在建立这种与房颤的联系，并开发未来的预防措施和治疗方法。

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.