Early occurrence of anti-muscarinic autoantibodies and abnormal vagal modulation in Chagas disease.

BACKGROUND: Autoimmunity and dysautonomia are established features of Chagas disease (ChD) that could be related to its pathogenesis. Our objective was to assess heart rate variability (HRV) and levels of anti-M2 receptors autoantibodies in ChD patients with and without left ventricular (LV) dysfunction, in order to establish if these abnormalities occur early and concomitantly in the course of the illness. METHODS: ChD patients (n=75) and healthy controls (n=14) underwent a standardized protocol including Doppler echocardiogram, Holter monitoring, HRV analysis, and measurement of anti-M2 receptors autoantibodies (ELISA). ChD patients were divided accordingly by the absence (group 1, n=45) or presence (group 2, n=30) of LV dysfunction, defined as reduced LV ejection fraction (<55%) or regional wall motion abnormalities (including ventricular aneurysm). RESULTS: Both ChD groups displayed increased optical density values of anti-M2 cholinergic autoantibodies (Median (IQR): control=1.98(0.51); ChD 1=2.76(0.97); ChD 2=2.72(1.34), p<.001) and reduced HF power of spectral analysis of HRV when compared to controls (Median (IQR) in ms2: control=1087(2284); ChD 1=286(763); ChD 2=285(763), p<.001). M2 levels were significantly correlated with HF power values (r=-0.32, p=0.023), but not with LV ejection fraction. CONCLUSIONS: Anti-muscarinic autoantibodies and abnormal vagal modulation occur early in ChD patients, independently of the presence of LV dysfunction. Levels of antibodies against M2 muscarinic receptors were significantly and negatively correlated with HRV index HF power, suggesting an inhibitory effect of autoantibodies in vagal function.

Human chagasic IgGs bind to cardiac muscarinic receptors and impair L-type Ca2+ currents.

OBJECTIVES: Antibodies against cardiac G protein-coupled receptors have been reported in sera from chronic chagasic patients (CChP) and other non-parasitic cardiomyopathies, but the effects and underlying mechanism of interaction between these antibodies and heart cells are not fully established. To address this point, binding of antibodies purified from sera of CChP patients and normal blood donors (NBD) to cardiac muscarinic acetylcholine receptors (mAChR) and their effect on L-type Ca(2+) currents were examined. METHODS AND RESULTS: Saturation [3H]NMS binding experiments with porcine atrial membranes showed that B(max) in the presence of CChP-immunoglobulin G (IgG) decreased from 280.2+/-16.08 fmol/mg (control) to 91.00+/-5.98 fmol/mg, with no apparent change in K(D), while NBD-IgG did not significantly alter these parameters. At the single channel level, CChP-IgG decreased both the fast and slow mean open times and P(o) (from 0.074+/-0.023 to 0.025+/-0.007) without changes in single channel conductance. I/V plots of isoproterenol-stimulated whole-cell L-type Ca(2+) currents (I(Ca)) from rabbit ventricular cardiomyocytes showed a significant reduction in peak I(Ca) during perfusion with CChP-IgG (at 0 mV: from 10.61+/-2.97 to 8.45+/-2.54 pA/pF). NBD-IgGs had no effect on I(Ca). A CChP-IgG purified against a peptide corresponding to the second extracellular loop of the M(2) receptor also impaired L-type Ca(2+) currents. All effects of CChP-IgG were blocked by atropine. CONCLUSIONS: Our results show that antibodies from CChP bind to mAChR in a non-competitive manner and are able to activate the receptor in an agonist-like form resulting in L-type Ca(2+) current inhibition.