title: β1-Adrenergic and M2 Muscarinic Autoantibodies and Thyroid Hormone Facilitate Induction of Atrial Fibrillation in Male Rabbits.
abstract: Activating autoantibodies to the β1-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 β1-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.
authors.affiliation: Department of Endocrinology (H.L., D.C.K., X.Y.) and Heart Rhythm Institute (H.L., T.M., L.Z., B.H., V.V., B.J.S., D.C.K., X.Y.), University of Oklahoma Health Sciences Center and Veterans Affairs Medical Center, Oklahoma City, Oklahoma 73104.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Endocrinology (H.L., D.C.K., X.Y.) and Heart Rhythm Institute (H.L., T.M., L.Z., B.H., V.V., B.J.S., D.C.K., X.Y.), University of Oklahoma Health Sciences Center and Veterans Affairs Medical Center, Oklahoma City, Oklahoma 73104.
authors.forename: Taylor
authors.initials: T
authors.lastname: Murphy
authors.affiliation: Department of Endocrinology (H.L., D.C.K., X.Y.) and Heart Rhythm Institute (H.L., T.M., L.Z., B.H., V.V., B.J.S., D.C.K., X.Y.), University of Oklahoma Health Sciences Center and Veterans Affairs Medical Center, Oklahoma City, Oklahoma 73104.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology (H.L., D.C.K., X.Y.) and Heart Rhythm Institute (H.L., T.M., L.Z., B.H., V.V., B.J.S., D.C.K., X.Y.), University of Oklahoma Health Sciences Center and Veterans Affairs Medical Center, Oklahoma City, Oklahoma 73104.
authors.forename: Bing
authors.initials: B
authors.lastname: Huang
authors.affiliation: Department of Endocrinology (H.L., D.C.K., X.Y.) and Heart Rhythm Institute (H.L., T.M., L.Z., B.H., V.V., B.J.S., D.C.K., X.Y.), University of Oklahoma Health Sciences Center and Veterans Affairs Medical Center, Oklahoma City, Oklahoma 73104.
authors.forename: Vineet
authors.initials: V
authors.lastname: Veitla
authors.affiliation: Department of Endocrinology (H.L., D.C.K., X.Y.) and Heart Rhythm Institute (H.L., T.M., L.Z., B.H., V.V., B.J.S., D.C.K., X.Y.), University of Oklahoma Health Sciences Center and Veterans Affairs Medical Center, Oklahoma City, Oklahoma 73104.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Scherlag
authors.affiliation: Department of Endocrinology (H.L., D.C.K., X.Y.) and Heart Rhythm Institute (H.L., T.M., L.Z., B.H., V.V., B.J.S., D.C.K., X.Y.), University of Oklahoma Health Sciences Center and Veterans Affairs Medical Center, Oklahoma City, Oklahoma 73104.
authors.forename: David C
authors.initials: DC
authors.lastname: Kem
authors.affiliation: Department of Endocrinology (H.L., D.C.K., X.Y.) and Heart Rhythm Institute (H.L., T.M., L.Z., B.H., V.V., B.J.S., D.C.K., X.Y.), University of Oklahoma Health Sciences Center and Veterans Affairs Medical Center, Oklahoma City, Oklahoma 73104.
authors.forename: Xichun
authors.initials: X
authors.lastname: Yu
mesh_terms: D058665:Adrenergic beta-1 Receptor Agonists / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D000941:Antigens / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D001281:Atrial Fibrillation / Q000139:chemically induced / Q000209:etiology* / Q000276:immunology / Q000517:prevention & control; D001323:Autoantibodies / Q000032:analysis / Q000096:biosynthesis / Q000737:chemistry; D054326:Coronary Sinus / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology; D004195:Disease Models, Animal; D006111:Graves Disease / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D006325:Heart Atria / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology; D006329:Heart Conduction System / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology; D008297:Male; D018721:Muscarinic Agonists / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D011817:Rabbits; D043585:Receptor, Muscarinic M2 / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D018342:Receptors, Adrenergic, beta-1 / Q000737:chemistry / Q000378:metabolism*; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D013610:Tachycardia / Q000139:chemically induced / Q000209:etiology*; D013974:Thyroxine / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology / Q000506:poisoning; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; D000941:Antigens; D001323:Autoantibodies; D018721:Muscarinic Agonists; D010446:Peptide Fragments; D043585:Receptor, Muscarinic M2; D018342:Receptors, Adrenergic, beta-1; D013974:Thyroxine