Arrhythmic events and genetic variants as drivers for Takotsubo Syndrome: a patient-specific atrial stem-cell model
Year: 2026
Type: article
Abstract: 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 Ca 2+ transient amplitude, reduced diastolic Ca 2+ , 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 Ca 2+ current density, but reduced Ca 2+ transient amplitude with increased resting Ca 2+ 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.
Authors: Charlotte Brand, Clarissa Zinke, Gideon Syed Ali, Daniela Hübscher, Karim Ajmail, Aylin Seedorf, Pauline Steinker, Franziska Treu, Philipp Jung, Hanna Eberl, Yun Li, Nataliya Dybkova, Lukas Feld, Jelena R. Ghadri, Christian Templin, Samuel Sossalla, Christoph Maack, Niels Voigt, Viacheslav O. Nikolaev, Bernd Wollnik, Katrin Streckfuss-Bömeke
Institutions: University Hospital Heidelberg, Universitätsmedizin Göttingen, German Centre for Cardiovascular Research, University of Würzburg, University of Göttingen, University of Zurich, Universitätsmedizin Greifswald, University Hospital Zurich, Justus-Liebig-Universität Gießen, Kerckhoff Klinik, Cardio-Pulmonary Institute, Universitätsklinikum Würzburg, Heidelberg University, Multiscale Bioimaging, University Medical Center Hamburg-Eppendorf
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,790
Awards: G1105311255, G1905259079, G1992554820, G2204319727, G2347632252, G2732538412, NAD Metabolismus in hereditären Kardiomyopathien, G5890406466, G6054371019, Untersuchung von funktionellen und molekularen Mechanismen der Arrhythmieinduzierten Kardiomyopathie (AIC): Effekte von Vorhofflimmern auf den linken Ventrikel, Die Bedeutung der mitochondrialen CalciumHomöostase bei der Arrhythmogenese bei Patienten mit Vorhofflimmern., SFB 1525: Kardioimmune Schnittstellen, G973360009
OpenAlex ID: W7223226584