Cardiac M2 muscarinic cholinoceptor activation by human chagasic autoantibodies: association with bradycardia

Abstract

Objective-To assess whether exposure of cardiac muscarinic acetylcholine receptors (mAChR) to activating chagasic antimyocardial immunoglobulins results in bradycardia and other dysautonomic symptoms associated with the regulation of heart rate. Methods-Trypanosoma cruzi infected patients with bradycardia and other abnormalities in tests of the autonomic nervous system were studied and compared with normal subjects. Antipeptide antibodies in serum were demonstrated by an enzyme linked immunosorbent assay using a synthetic 24-mer-peptide corresponding antigenically to the second extracellular loop of the human heart M 2 mAChR. The functional eVect of aYnity purified antipeptide IgG from chagasic patients on spontaneous beating frequency and cAMP production of isolated normal rat atria was studied.Results-There was a strong association between the finding of antipeptide antibodies in chagasic patients and the presence of basal bradycardia and an altered Valsalva manoeuvre (basal bradycardia: 2 = 37.5, p < 0.00001; Valsalva manoeuvre: 2 = 70.0, p < 0.00001). The antipeptide autoantibodies also showed agonist activity, decreasing the rate of contraction and cAMP production. The eVects on rat atria resembled the eVects of the authentic agonist and those of the total polyclonal chagasic IgG, being selectively blunted by atropine and AF-DX 116, and neutralised by the synthetic peptide corresponding in amino acid sequence to the second extracellular loop of the human M 2 mAChR. Conclusions-There is an association between circulating antipeptide autoantibodies in chagasic patients and the presence of bradycardia and other dysautonomic symptoms. Thus these autoantibodies are a marker of autoimmune cardiac autonomic dysfunction. The results support the hypothesis that autoimmune mechanisms play a role in the pathogenesis of chagasic cardioneuromyopathy. (Heart 1999;82:273-278)

Autoantibodies in Heart Failure and Cardiac Dysfunction

“…A number of other antigenic targets for autoantibodies have been described, but their pathogenic role is not understood (Table 1). [93][94][95][96][97][98][99][100][101][102][103] …”

Trypanosoma cruzi infection induces up-regulation of cardiac muscarinic acetylcholine receptors in vivo and in vitro

“…The possible agonistic activity of some anti-muscarinic and/or anti-nicotinic cholinergic receptor antibodies (11,12,17) could induce receptor functional subsensitivity and down-regulation of the post-synaptic cardiac muscle mAChR, due to an agonist-induced receptor desensitization phenomenon (20); however, this event in cardiac tissues of chagasic animals has not been observed or reported. In the scenario in which both phenomena (vagal denervation and muscarinic receptor modulation by autoantibodies) are supposed to occur simultaneously, each phenomenon could neutralize the other with no overall changes in mAChR expression.…”

“…Atropine neutralizes these effects by direct competition for the mAChR binding sites, while pertussis toxin acts by preventing the inhibition of cAMP (16). It has been reported that serum from chronic chagasic patients with complex cardiac arrhythmias is able to reduce cardiac rate (17) and induce auricular-ventricular conduction blockades, in isolated beating heart preparations, which is partially antagonized by atropine (18). Furthermore, the relationship between the immune system and the muscarinic cholinergic system is suggested by the report that activation of mAChR expressed on T cell receptor-activated T cells increases the production of IL-2 (19).…”

Muscarinic antibodies and heart rate responses to dynamic exercise and to the Valsalva maneuver in chronic chagasic patients

“…The findings of these clinical investigations have been conflicting and controversial. Nonetheless, parasympathetic effects on heart rate are currently considered, by most investigators, as being impaired by cardiac muscarinic auto-antibodies 14,[21][22][23]42,43 . We have postulated, on the contrary, that parasympathetic activity is enhanced by the allosteric effects of the muscarinic cardiac auto-antibodies 11,12 .…”

“…The second extracellular (o2) and the third intracellular loops (i3), of these receptors, are considered as autoimmune epitopes in patients with chronic Chagas' disease 22,40. The autoimmune response occurs early on the natural history of the disease and it is considered to be responsible for the abnormalities of parasympathetic control of heart rate 14,21,23,[41][42][43][44] . These investigations have demonstrated that, the chronotropic responses to cardiac autonomic tests are apparently impaired in the indeterminate form of the disease.…”