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

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

Journal: Signal transduction and targeted therapy 2026;11(1):

PMID: 42918751

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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 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.

Address: Clinic for Cardiology and Pneumology, University Medical Centre Göttingen, Göttingen, Germany.; Institute for Cardiomyopathies (ICH), University Clinic Heidelberg, Heidelberg, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Göttingen, Germany.; Clinic for Cardiology and Pneumology, University Medical Centre Göttingen, Göttingen, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Göttingen, Germany.; Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany.; Clinic for Cardiology and Pneumology, University Medical Centre Göttingen, Göttingen, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Göttingen, Germany.; Institute of Pharmacology and Toxicology, University Medical Centre Göttingen, Georg-August-University Göttingen, Göttingen, Germany.; Institute of Human Genetics, University Medical Centre Göttingen, Göttingen, Germany.; Centre for Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland.; Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.; Department of Cardiology, University Hospital Zurich, Zurich, Switzerland.; DZHK (German Centre for Cardiovascular Research), partner site North, Hamburg, Lübeck, Kiel, Greifswald, Germany.; Centre for Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland.; Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.; DZHK (German Centre for Cardiovascular Research), partner site North, Hamburg, Lübeck, Kiel, Greifswald, Germany.; Clinic for Cardiology and Pneumology, University Medical Centre Göttingen, Göttingen, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Göttingen, Germany.; Medical Clinic I, Cardiology and Angiology, Justus-Liebig-University, Gießen, Germany.; Department of Cardiology, Campus Kerckhoff, Bad Nauheim, Germany.; Cardio-Pulmonary Institute (CPI), Gießen, Germany.; Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg, Würzburg, Germany.; Medical Clinic and Polyclinic I, University Clinic Würzburg, Würzburg, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Göttingen, Germany.; Institute of Pharmacology and Toxicology, University Medical Centre Göttingen, Georg-August-University Göttingen, Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells' (MBExC), University Medical Centre Göttingen, Göttingen, Germany.; Department of Pharmacology and Toxicology, European Center for Angioscience, University Heidelberg, Mannheim, Germany.; DZHK (German Centre for Cardiovascular Research), partner site North, Hamburg, Lübeck, Kiel, Greifswald, Germany.; Institute for Experimental Cardiovascular Research, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Göttingen, Germany.; Institute of Human Genetics, University Medical Centre Göttingen, Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells' (MBExC), University Medical Centre Göttingen, Göttingen, Germany.; German Centre for Child and Adolescent Health (DZKJ), partner site Göttingen, Göttingen, Germany.; Clinic for Cardiology and Pneumology, University Medical Centre Göttingen, Göttingen, Germany. [email protected].; DZHK (German Centre for Cardiovascular Research), partner site Lower Saxony, Göttingen, Germany. [email protected].; Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany. [email protected].; Medical Clinic I, Cardiology and Angiology, Justus-Liebig-University, Gießen, Germany. [email protected].

DOI: 10.1038/s41392-026-03000-z

MeSH Terms: Humans, Induced Pluripotent Stem Cells, Myocytes, Cardiac, Takotsubo Cardiomyopathy, Cyclic Nucleotide Phosphodiesterases, Type 4, Heart Atria, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Isoproterenol, Phospholamban, Calcium, Sarcoplasmic Reticulum, Calcium-Binding Proteins, Genetic Variation, Arrhythmias, Cardiac, Atrial Fibrillation