Abstract 5429: Autoantibody Activation of Beta-Adrenergic and Muscarinic receptors Contributes to an “Autoimmune” Postural Hypotension
Background: Dysautonomic orthostatic hypotension is characterized by an inadequate autonomic response to upright posture. Activating autoantibodies to β-adrenergic receptors (AAβAR) and M2 muscarinic receptor (AAM2R) can produce pathophysiologic changes that would contribute to or complicate postural hypotension.
Methods: We have studied 6 patients with unexplained chronic postural hypotension (drop of diastolic blood pressure >10 mmHg and pulse increase <10/min). Purified IgG from sera of these patients and from 10 healthy controls were analyzed by ELISA for the presence of autoantibodies to βAR and M2R. The functional properties of these activating autoantibodies were studied in an isolated canine cardiac Purkinje fiber contractility assay. The contractile response was examined before and after addition of either buffer (baseline) or IgG from each subject. Atropine was used to block the AAM2R component of IgG. An increase in contractility over baseline with IgG plus atropine represented the AAβAR effect. The difference in IgG effect on contractility between the presence and absence of atropine was a surrogate marker of the AAM2R inhibitory effect.
Results: All patients had ELISA titers to βAR and M2R ranging from 1:3,200 to 1:25,600 with controls from 1:400–1:1,600. IgG from 4 of the 6 patients demonstrated evidence for both AAβAR and AAM2R, 1 for AAβAR only and 1 for AAM2R only by the Purkinje fiber assay. βAR activity (% over baseline) was elevated significantly in 5 of the 6 patients (26.8±5.0%, n=5, vs. control 1.0±1.0%, n=10, p<0.0001). M2R activity was also increased in 5 of the 6 patients (12.8±2.1%, n=5 vs. control 0.6±1.3%, n=10, p=0.0002).
Conclusions: These data confirm the presence of significant levels of AAβAR and AAM2R in a subgroup of patients with postural hypotension. These activating autoantibodies have selective activity in vitro at concentrations compatible with an in vivo effect. High levels of AAβAR can cause vasodilation of visceral arteries and have little impact on peripheral arteries since they do not have α1R agonist effects. AAM2R negatively modulate the positive inotropic effect of AAβAR. These data may provide new insight into the pathophysiology of this disease.
This research has received full or partial funding support from the American Heart Association, AHA South Central Affiliate (Arkansas, New Mexico, Oklahoma & Texas).