Abstract 15115: Autoimmune Allosteric Basis for Postural Tachycardia Syndrome
Background: We have demonstrated that patients with postural tachycardia syndrome (POTS) have an exaggerated orthostatic tachycardia associated with the concurrence of functional autoantibodies (AA) to the α1AR and β1/2 adrenergic receptors (AR). It is not clear how the allosteric effects of these AA interact with their orthosteric ligand counterparts on their respective GPCR to produce the POTS phenotype.
Methods: Sera from POTS patients (n=3) and from healthy control subjects (n=3) were examined for their ability to alter phenylephrine activation of α1AR-AA mediated contractility and isoproterenol induced β2AR vasodilation using an isolated perfused rat cremaster arteriole assay. Receptor-transfected cell-based assays similarly were used to examine isoproterenol activation of β1AR and β2AR autoantibodies. Data were expressed as % ±SD of baseline.
Results: As previously reported, the POTS patients demonstrated marked arteriolar contractile activity; and this activity was suppressed by α1AR blockade with prazosin. POTS sera significantly (p<0.01) shifted the phenylephrine contractility curve >ten-fold to the right (inhibitory allosteric effect). By contrast, POTS sera shifted the isoproterenol -induced cremaster β2AR mediated dilatory effect 10 fold to the left compatible with a positive allosteric effect. POTS IgG shifted isoproterenol response curves to the left both in β1 and in β2 transfected CHO cells (p<0.01) confirming the cremaster β1/2AR data.
Conclusions: POTS patients have elevated α1AR autoantibodies that exert a negative allosteric effect resulting in partial antagonism requiring higher doses of agonist (e.g. norepinephrine) for vasoconstriction. Conversely, β1/2AR-AA exert a positive allosteric effect that will enhance the endogenous norepinephrine chronotropic activity on the heart. These findings provide a pathophysiological basis for an autoimmune induction of the marked tachycardia observed in POTS patients.
- Immunologic factors
- Receptor-mediated signaling
- Alpha-adrenergic receptor blockers
- Beta-adrenergic receptor agonists
- Reflexes, cardiovascular
- © 2013 by American Heart Association, Inc.