β1 -Adrenoceptor autoantibodies increase the susceptibility to ventricular arrhythmias involving abnormal repolarization in guinea-pigs.

Abstract

What is the central question of this study? High titres of autoantibodies against the second extracellular loop of the β1 -adrenergic receptor (β1 -AAs) can be detected in the sera of patients with ventricular arrhythmias, but a causal relationship between β1 -AAs and ventricular arrhythmias has not been established. What is the main finding and its importance? Monoclonal β1 -AAs (β1 -AR mAbs) were used in the experiments. We showed that β1 -AR mAbs increased susceptibility to ventricular arrhythmias and induced repolarization abnormalities. Antibody adsorption of β1 -AAs will be a potential new therapeutic strategy for ventricular arrhythmias in patients with high titres of β1 -AAs. High titres of autoantibodies against the second extracellular loop of the β1 -adrenergic receptor (β1 -AAs) can be detected in sera from patients with ventricular arrhythmias, but a causal relationship between β1 -AAs and ventricular arrhythmias has not been established. In this work, ECGs of guinea-pigs and isolated guinea-pig hearts were recorded. Ventricular tachycardia (VT) and ventricular fibrillation (VF) were evoked by programmed electrical stimulation of the left ventricular epicardium of isolated guinea-pig hearts. The monophasic action potential and effective refractory period of the left ventricle were recorded in paced isolated guinea-pig hearts. Furthermore, to increase the specificity, monoclonal autoantibodies against the second extracellular loop of the β1 -adrenergic receptor (β1 -AR mAbs) were used in all experiments. The results showed that β1 -AR mAbs induced premature ventricular contractions in guinea-pigs and isolated guinea-pig hearts. In addition, β1 -AR mAbs decreased the threshold of VT/VF and prolonged the duration of VT/VF. Furthermore, β1 -AR mAbs shortened the corrected QT interval and effective refractory period, and prolonged late-phase repolarization of the monophasic action potential (MAPD90-30 ). These changes in electrophysiological parameters might be attributed, at least in part, to the arrhythmogenicity of β1 -AR mAbs.