RESUMO
Isolated congenital heart block may be associated with autoimmune disorder such as Sjögren Syndrome and systemic lupus erythematosus. In this work we demonstrate circulating autoantibodies against neonatal heart M1 muscarinic acetylcholine receptor (mAChR) in the sera of children with congenital heart block. This antibody were able to react with the second extracellular loop of the human M1 mAChR as demonstrated using a synthetic peptide in enzyme immune assay and binding assay. Affinity purified anti-peptide IgG as well as total IgG from children with congenital heart block, interfered with the specific radioligand occupancy from neonatal heart M1 mAChR, interacting irreversibly. The antipeptide antibodies also displayed an 'agonist-like' activity, i.e. decreased contractility, activated nitric oxide synthase activity and increased production of cyclic GMP. All of these effects were selectively blunted by pirenzepine and neutralized by the synthetic M1 peptide. Both binding and biological effects were obtained using neonatal rat heart instead adult heart and were independent of Ro/SS-A and La/SS-B antibodies and were also absent in the sera of normal children. A clinical relevance of these findings is demonstrated by a strong association between the existence of circulating M1 mAChR antipeptide antibodies and the presence of isolated congenital heart block, making these antibodies a proper marker of this disease.
Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Bloqueio Cardíaco/imunologia , Receptores Muscarínicos/imunologia , Sequência de Aminoácidos , Animais , Autoanticorpos/sangue , Criança , Pré-Escolar , GMP Cíclico/imunologia , Coração , Bloqueio Cardíaco/sangue , Bloqueio Cardíaco/complicações , Cardiopatias Congênitas/sangue , Cardiopatias Congênitas/imunologia , Humanos , Lactente , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Dados de Sequência Molecular , Óxido Nítrico Sintase/imunologia , Peptídeos/imunologia , Ratos , Receptor Muscarínico M1RESUMO
The purpose of a sensor-driven pacing system is to physiologically correct chronotropic incompetence (CI). The aim of this study was to evaluate the changes in heart rate provided by a sympathetically driven pacemaker (PM) compared with normal sinus function (NSF). Nine men and six women (age 37-80 years) with AV block and a PM controlled by a closed-loop system were studied. Group I included eight patients with CI, and group II included seven patients with NSF. All patients underwent Valsalva maneuver and tilt table testing with measurements of plasma catecholamines and renin activity. Pacing was initially programmed in the DDDC mode at a lower rate (60 ppm) and upper rate limit (0.85 x [220 - age]), then in DDDR in group I and VVIR in group II. The second phase of the study consisted of nitroglycerin and phenylephrine infusions, and the third phase of physiological provocative maneuvers. The second and third phases were performed in three patients from each group with sensor activity On and Off. In group I, heart rate changed during tilt only in the DDDR mode. In group II, heart rate changes were comparable in both modes. Catecholamine levels in group I were higher during DDDC than during DDDR pacing (P < 0.05). In group I, heart rate did not change during phases II and IV of the Valsalva maneuver in the DDDC mode, but behaved nearly physiologically after sensor activation. A late and a paradoxical response to nitroglycerin was observed in groups I and II and to phenylephrine in group I. During physiological maneuvers, significantly greater variations in heart rate were observed during DDDR than during DDDC pacing. Sympathetic SDP provides physiological modulations of the heart rate were provided by a sympathetically driven pacing system in patients with AV block and CI.