β1-Adrenergic and M2 Muscarinic Autoantibodies and Thyroid Hormone Facilitate Induction of Atrial Fibrillation in Male Rabbits
β1-Adrenergic and M2 Muscarinic Autoantibodies and Thyroid Hormone Facilitate Induction of Atrial Fibrillation in Male Rabbits
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DOI：
10.1210/en.2015-1655
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发表时间：
2016-01-01
期刊：
影响因子：
4.8
通讯作者：
Yu, Xichun
中科院分区：
文献类型：
--
作者：
Li, Hongliang;Murphy, Taylor;Yu, Xichun
非常高比例的格雷夫斯病和心房颤动 (AF) 患者体内存在针对 β1-肾上腺素能受体和 M2 毒蕈碱受体的激活自身抗体。本研究的目的是开发一种可重复的动物模型，从而检查这些内分泌样自身抗体单独使用以及与甲状腺激素联合使用对诱发甲状腺相关房性快速心律失常的影响。五只新西兰白兔用来自 β1-肾上腺素能和 M2 毒蕈碱受体第二个细胞外环的肽进行共免疫，以产生拟交感神经和拟副交感神经抗体。在免疫和随后的甲状腺激素治疗前后对麻醉兔子进行了基于导管的电生理学研究。抗体表达促进持续窦性心动过速、交界性心动过速和房性心动过速的诱发，但不促进房颤的诱发。添加过量的甲状腺激素会导致所有动物出现持续性房颤。尽管甲状腺功能亢进持续存在，但由于这些抗体与免疫原性肽的中和作用，房颤的诱导被严重阻断。作为房颤倾向参数之一的心房有效不应期在免疫后显着缩短，并通过肽中和而急剧逆转。添加甲状腺激素后，没有观察到有效不应期进一步缩短，这表明甲状腺激素的其他心脏作用可能有助于其在房颤诱发中的作用。这项研究表明，自主神经自身抗体和甲状腺激素会加剧心脏对房颤的脆弱性，而这种脆弱性可以通过诱饵肽疗法来逆转。这些数据有助于满足 Witebsky 的假设，即格雷夫斯甲状腺功能亢进症和房颤的自身免疫/内分泌基础增加。
Activating autoantibodies to the beta 1-adrenergic and M2 muscarinic receptors are present in a very high percentage of patients with Graves' disease and atrial fibrillation (AF). The objective of this study was to develop a reproducible animal model and thereby to examine the impact of these endocrine-like autoantibodies alone and with thyroid hormone on induction of thyroid-associated atrial tachyarrhythmias. Five New Zealand white rabbits were coimmunized with peptides from the second extracellular loops of the beta 1-adrenergic and M2 muscarinic receptors to produce both sympathomimetic and parasympathomimetic antibodies. A catheter-based electrophysiological study was performed on anesthetized rabbits before and after immunization and subsequent treatment with thyroid hormone. Antibody expression facilitated the induction of sustained sinus, junctional and atrial tachycardias, but not AF. Addition of excessive thyroid hormone resulted in induced sustained AF in all animals. AF induction was blocked acutely by the neutralization of these antibodies with immunogenic peptides despite continued hyperthyroidism. The measured atrial effective refractory period as one parameter of AF propensity shortened significantly after immunization and was acutely reversed by peptide neutralization. No further decrease in the effective refractory period was observed after the addition of thyroid hormone, suggesting other cardiac effects of thyroid hormone may contribute to its role in AF induction. This study demonstrates autonomic autoantibodies and thyroid hormone potentiate the vulnerability of the heart to AF, which can be reversed by decoy peptide therapy. These data help fulfill Witebsky's postulates for an increased autoimmune/endocrine basis for Graves' hyperthyroidism and AF.