Antiadrenergic autoimmunity in postural tachycardia syndrome

作者：Fedorowski Artur^*; Li Hongliang; Yu Xichun; Koelsch Kristi A; Harris Valerie M; Liles Campbell; Murphy Taylor A; Quadri Syed M S; Scofield Robert Hal; Sutton Richard; Melander Olle; Kem David C

来源：Europace, 2017, 19(7): 1211-1219.

DOI：10.1093/europace/euw154

• Autoimmunity
• Postural tachycardia syndrome
• Vasovagal syncope
• Adrenergic receptors
• Allosteric activation

Postural tachycardia syndrome (POTS), a common and debilitating cardiovascular disorder, is characterized by an exaggerated heart rate increase during orthostasis and a wide spectrum of adrenergic-related symptoms. To determine the aetiology of POTS, we examined a possible pathophysiological role for autoantibodies against alpha 1-adrenergic (alpha 1AR) and beta 1/2-adrenergic receptors (beta 1/2AR).
Immunoglobulin G (IgG) derived from 17 POTS patients, 7 with recurrent vasovagal syncope (VVS), and 11 normal controls was analysed for its ability to modulate activity and ligand responsiveness of alpha 1AR and beta 1/2AR in transfected cells and to alter contractility of isolated rat cremaster arterioles in vitro. Immunoglobulin G activation of alpha 1AR and beta 1/2AR was significantly higher in POTS compared with VVS and controls in cell-based assays. Eight, 11, and 12 of the 17 POTS patients possessed autoantibodies that activated alpha 1AR, beta 1AR and beta 2AR, respectively. Pharmacological blockade suppressed IgG-induced activation of alpha 1AR and beta 1/2AR. Eight of 17 POTS IgG decreased the alpha 1AR responsiveness to phenylephrine and 13 of 17 POTS IgG increased the beta 1AR responsiveness to isoproterenol irrespective of their ability to directly activate their receptors. Postural tachycardia syndrome IgG contracted rat cremaster arterioles, which was reversed by alpha 1AR blockade. The upright heart rate correlated with IgG-mediated beta 1AR and alpha 1AR activity but not with beta 2AR activity.
These data confirm a strong relationship between adrenergic autoantibodies and POTS. They support the concept that allosteric-mediated shifts in the alpha 1AR and beta 1AR responsiveness are important in the pathophysiology of postural tachycardia.

• 出版日期2017-7