Arrhythmic events and genetic variants as drivers for Takotsubo Syndrome: a patient-specific atrial stem-cell model

@article{brand2026arrhythmic,
  title = {{Arrhythmic events and genetic variants as drivers for Takotsubo Syndrome: a patient-specific atrial stem-cell model}},
  author = {Charlotte Brand and Clarissa Zinke and Gideon Syed Ali and Daniela Hübscher and Karim Ajmail and Aylin Seedorf and Pauline Steinker and Franziska Treu and Philipp Jung and Hanna Eberl and Yun Li and Nataliya Dybkova and Lukas Feld and Jelena R. Ghadri and Christian Templin and Samuel Sossalla and Christoph Maack and Niels Voigt and Viacheslav O. Nikolaev and Bernd Wollnik and Katrin Streckfuss-Bömeke},
  journal = {Signal Transduction and Targeted Therapy},
  year = {2026},
  month = oct,
  doi = {10.1038/s41392-026-03000-z},
  url = {https://doi.org/10.1038/s41392-026-03000-z},
  note = {CC BY},
}

TY  - JOUR
TI  - Arrhythmic events and genetic variants as drivers for Takotsubo Syndrome: a patient-specific atrial stem-cell model
AU  - Charlotte Brand
AU  - Clarissa Zinke
AU  - Gideon Syed Ali
AU  - Daniela Hübscher
AU  - Karim Ajmail
AU  - Aylin Seedorf
AU  - Pauline Steinker
AU  - Franziska Treu
AU  - Philipp Jung
AU  - Hanna Eberl
AU  - Yun Li
AU  - Nataliya Dybkova
AU  - Lukas Feld
AU  - Jelena R. Ghadri
AU  - Christian Templin
AU  - Samuel Sossalla
AU  - Christoph Maack
AU  - Niels Voigt
AU  - Viacheslav O. Nikolaev
AU  - Bernd Wollnik
AU  - Katrin Streckfuss-Bömeke
PY  - 2026
DA  - 2026/10/25
JO  - Signal Transduction and Targeted Therapy
DO  - 10.1038/s41392-026-03000-z
UR  - https://doi.org/10.1038/s41392-026-03000-z
AB  - Takotsubo Syndrome (TTS) is an acute, potentially life-threatening condition often complicated by ventricular dysfunction and arrhythmias. Atrial fibrillation (AF) is common in TTS patients and associated with increased mortality. However, the arrhythmic mechanisms, genetic variability underlying TTS, and personalised therapy remain unclear. We generated induced pluripotent stem cell-derived atrial and ventricular cardiomyocytes (iPSC-CMs) from TTS patients and provoked TTS-like events by isoprenaline (Iso) stimulation. Compared with controls, atrial TTS iPSC-CMs exhibited enhanced diastolic sarcoplasmic reticulum (SR) Ca²⁺ leak and increased arrhythmogenic potential following Iso exposure. Iso-induced stress further increased systolic Ca²⁺ transient amplitude and reduced phosphodiesterase 4 (PDE4) activity in TTS iPSC-CMs. Under baseline conditions, atrial TTS iPSC-CMs demonstrated unchanged Ca2+ transient amplitude, reduced diastolic Ca2+, elevated SERCA2 activity with faster Ca²⁺ decay compared to controls, which could be explained by increased phosphorylation of PKA-specific phospholamban S16. In contrast, ventricular TTS-iPSC-CM showed increased L-Type Ca2+ current density, but reduced Ca2+ transient amplitude with increased resting Ca2+ leak and reduced PDE4 activity post-Iso-exposure. In atrial TTS iPSC-CMs, the PDE4 activator MR-L2 restored PDE4 activity, normalised several defects in Ca²⁺ handling and prevented arrhythmias more efficiently than the β-blocker metoprolol. Genetic analyses identified variants in the Ca²⁺ handling genes AHNAK and CASQ2 in TTS. Using CRISPR/Cas9, we generated isogenic rescue and mutation-insertion lines, confirming a causal role of p.P5390T in catecholamine-induced arrhythmogenic phenotypes in atrial TTS iPSC-CMs. Our findings support a mechanistic link between genetic predisposition to an excessive catecholaminergic stress response, dysregulated PDE/cAMP signalling, and atrial arrhythmogenesis in TTS-CMs, identifying PDE4 as a potential therapeutic target in this critical condition.
SN  - 2059-3635
ER  -