Arrhythmogenic and chronotropic effects of bronchodilator drugs on human cardiomyocytes

Introduction: An increasing number of patients with obstructive pulmonary diseases use combinations of bronchodilators, including beta-2-agonists, parasympatholytics, and methylxanthines as a chronic treatment. Chronic use of these drugs may result in the development of cardiomyopathy, arrhythmia, or sudden cardiac death. The direct effects of these bronchodilators on the function of human cardiomyocytes are not experimentally described sufficiently. Aims: We aimed to investigate in vitro effect of bronchodilator drugs on human-induced pluripotent stem cell-derived cardiomyocyte (hiPS-CMs) cell clusters. We focused on their chronotropic and inotropic effects. Methods: The measurements were performed on 3D clusters, embryoid bodies (EBs), of hiPS-CMs with spontaneous pacing and contraction ability. The effect of bronchodilators was measured using an atomic force microscope (AFM), which enables the real-time monitoring of EBs´ contraction frequency and is capable of measuring contractility. We choose three bronchodilators representatives: salbutamol, ipratropium, and aminophylline. Results: A total of 10 EBs were tested by AFM. We observed a neutral or negative chronotropic and inotropic effect in clinically relevant concentrations for all tested drugs. There was an apparent tendency for a positive chronotropic and inotropic effect in higher drug concentrations. We observed the direct arrhythmogenic effect of aminophylline in the human cardiomyocyte for the first time. These findings correspond to the previously described effects of caffeine. Conclusion: A combination of AFM and hiPS-CMs provides a reliable platform for further investigation of pulmonary drug effects in relation to the cardiovascular system.