Cardiac M-2 muscarinic cholinoceptor activation by human chagasic autoantibodies: association with bradycardia

Objective-To assess whether exposure of cardiac muscarinic acetylcholine re ceptors (mAChR) to activating chagasic anti-myocardial immunoglobulins resu lts in bradycardia and other dysautonomic symptoms associated with the regu lation of heart rate. Methods-Trypanosoma cruzi infected patients with bradycardia and other abno rmalities in tests of the autonomic nervous system were studied and compare d with normal subjects. Antipeptide antibodies in serum were demonstrated b y an enzyme linked immunosorbent assay using a synthetic 24-mer-peptide cor responding antigenically to the second extracellular loop of the human hear t M-2 mAChR. The functional effect of affinity purified antipeptide IgG fro m 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 a ntibodies in chagasic patients and the presence of basal bradycardia and an altered Valsalva manoeuvre (basal bradycardia: chi(2) = 37.5, p < 0.00001; Valsalva manoeuvre: chi(2) = 70.0, p < 0.00001) The antipeptide autoantibo dies also showed agonist activity, decreasing the rate of contraction and c AMP production. The effects on rat atria resembled the effects of the authe ntic agonist and those of the total polyclonal chagasic IgG, being selectiv ely blunted by atropine and AF-DX 116, and neutralised by the synthetic pep tide corresponding in amino acid sequence to the second extracellular loop of the human M-2 mAChR. Conclusions-There is an association between circulating antipeptide autoant ibodies in chagasic patients and the presence of bradycardia and other dysa utonomic symptoms. Thus these autoantibodies are a marker of autoimmune car diac autonomic dysfunction. The results support the hypothesis that autoimm une mechanisms play a role in the pathogenesis of chagasic cardioneuro-myop athy.