Abstract 5655: Autoantibodies Against Endothelin-1 Receptors Are Involved in the Pathogenesis of Pulmonary Arterial Hypertension
Background In patients with pulmonary arterial hypertension (PAH) production of endothelin-1 (ET-1) is increased and elevated ET-1 plasma levels correlate with PAH severity. After repeated detection of agonistic antibodies against the ET-1 A receptor (ETA) in PAH patients’ sera we assessed their prevalence and properties.
Methods Using spontaneously beating rat neonatal cardiomyocytes as bioassay we analyzed sera of PAH patients for the presence of autoantibodies (AABs) against ETA receptors. AABs were purified by affinity chromatography.
Results At the time of AAB testing, the pulmonary vascular resistance (PVR) in the 58 evaluated PAH patients varied between 500 and 1920 dyn • sec • cm−5 (median 1088 dyn • sec • cm−5) and 45 (77.6%) were in functional NYHA/WHO class ≥ III. Of these 58 patients 44 (78.7%) tested positive for AABs against ETA receptors. ET-1 and the AABs against ETA exerted agonistic negative chronotropic effects on the neonatal cardiomyocytes (decrease in pulsation rate), which were blocked by the ETA antagonist BQ610, but not by the ET-1 B receptor blocker BQ788. The AABs induced permanent stimulation without desensitization of the receptor mediated signal cascade and the effect increases with higher AAB concentrations. First attempts to eliminate by immunoadsorption these AABs (which appeared to belong to the IgG2 subclass) in 5 PAH patients showed encouraging results. After AAB removal, which was well tolerated by all patients, at the first controls performed 3 and 6 weeks later all 5 patients showed reduction in right ventricular diameters, lower pulmonary arterial pressure, higher cardiac index and improved exercise tolerance (increase in both VO2max and 6 minute walk distance). In one patient the AABs reappeared after 2 months and this AAB reappearance was associated with clinical worsening and PVR increase.
Conclusions The majority of patients with advanced PAH tested positive for functional serum AABs against ETA These AABs activate the receptors, like ET-1, but prevent the desensitization of the receptor-mediated signal cascade normally seen with ongoing receptor stimulation. Our results suggest that these AABs could be involved in PAH pathogenesis. AAB removal by immunoadsorption might be a possible new therapeutic approach.