The role of the atrium in the development of the Takotsubo Syndrome – investigation of a patient-specific atrial stem cell model

Abstract Background and aims The Takotsubo syndrome (TTS) is characterised by an acute left ventricular dysfunction without exhibiting signs of stenosis. TTS affects mainly the ventricle, however, its pathophysiology comprises transient impairments in atrium functions with a prevalence atrial fibrillation (AF) around 18% correlating higher heart rhythm disorders. In this study, we aimed to prove hypothesis that molecular cellular arrhythmic events contribute development under catecholamine stress test if currently clinically used β-blockers (Metoprolol) or PDE4 activator MR-L2 are suitable for cardiomyopathy vitro. Methods results We generated induced pluripotent stem cell-derived cardiomyocytes (TTS-iPSC-aCMs) from patients, confirmed marker expression (MLC2a, PItX2, NR2F2), treated them catecholamines (Iso) mimic TTS-phenotype. Using cytosolic Förster resonance energy transfer (FRET) based cAMP sensor, tested activity phosphodiesterases (PDEs) TTS-iPSC-aCMs observed after β-AR stimulation, strong effects family cytosol control cells were significantly decreased aCMs patients. This effect was rescued application line previously described downregulation human myocardium AF functional studies, Iso-induced increase systolic Ca2+ amplitude more pronounced iPSC-aCM compared controls. These both, approved β-blocker Metoprolol MR-L2. To analyse CMs, performed confocal microscope measurements demonstrated diastolic sarcoplasmic reticulum leak increased iPSC patients basal conditions Iso-treatment. addition, displayed faster kinetics cells, already conditions. underlined on level phospholamban phosphorylation iPSC-aCM. Subsequent treatment kinetic parameters calcium sparks all cell lines. Conclusion conclusion, able draw comprehensive picture role arrhythmias TTS. found TTS-patient-specific differences reduced activity, elevated enhanced reactions catecholamines, which could be drug partly Therefore, has proven effective option preliminary data demonstrate promising as new patient-specific therapeutic target catecholamine-stress. Funding Acknowledgement Type funding sources: Public grant(s) – National budget only. Main source(s): German centre cardiovascular research