Opposing cardiac effects of autoantibody activation of beta-adrenergic and M2 muscarinic receptors in cardiac-related diseases.

摘要

BACKGROUND: Activating autoantibodies to beta-adrenergic receptors (AAbeta1/2AR) and M2 muscarinic receptors (AAM2R) have been reported in several cardiac diseases and may have pathophysiologic relevance. However, the interactions and relative effects of AAbeta1AR, AAbeta2AR and AAM2R on contractile function have not been characterized. METHODS: The inotropic effects of IgG from 18 selected patients with cardiomyopathy and/or atrial tachyarrhythmias positive by ELISA for antibodies to beta1/2AR were studied using an isolated canine Purkinje fiber contractility assay. M2R-blockade was tested using atropine while selective beta1AR and beta2AR blockade used CGP-20712A and ICI-118551 respectively. RESULTS: Fifteen of the 18 anti-beta1/2AR ELISA-positive samples demonstrated evidence for negative inotropic muscarinic effects which were blocked using atropine. Atropine failed to uncover a positive inotropic response in 2 of the 18 IgG samples (false positive ELISA for AAbetaAR). In the remaining 16 AAbetaAR true-positive subjects, the beta1AR-induced increase in contractility (concurrent M2/beta2 blockade) was augmented to 140.5+/-12.2% of baseline compared to 127.4+/-7.2% of baseline with M2 blockade (atropine) only (p<0.001, n=16). The beta2AR-induced increase in contractility (concurrent M2/beta1 blockade) was only 114.5+/-4.3% of baseline (p<0.001, n=16). Combined M2 and beta1/beta2 blockade eliminated any increase in contractility. CONCLUSIONS: The inherently positive inotropic effect of AAbeta1AR was negatively modulated by AAM2R and AAbeta2AR. These opposing effects of receptor-activating autoantibodies may alter cardiac performance and influence clinical outcome depending on their receptor type and relative contractile activity.