Increased cytosolic calcium buffering contributes to a cellular arrhythmogenic substrate in iPSC-cardiomyocytes from patients with dilated cardiomyopathy
2022-05-02 | journal article; research paper. A publication with affiliation to the University of Göttingen.
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Increased cytosolic calcium buffering contributes to a cellular arrhythmogenic substrate in iPSC-cardiomyocytes from patients with dilated cardiomyopathy
Jung, P.; Seibertz, F.; Fakuade, F. E.; Ignatyeva, N.; Sampathkumar, S.; Ritter, M. & Li, H. et al. (2022)
Basic Research in Cardiology, 117(1) pp. 5. DOI: https://doi.org/10.1007/s00395-022-00912-z
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- Authors
- Jung, Philipp; Seibertz, Fitzwilliam; Fakuade, Funsho E.; Ignatyeva, Nadezda; Sampathkumar, Shrivatsan; Ritter, Melanie; Li, Housen; Mason, Fleur E.; Ebert, Antje ; Voigt, Niels
- Abstract
- Dilated cardiomyopathy (DCM) is a major risk factor for heart failure and is associated with the development of life-threatening cardiac arrhythmias. Using a patient-specific induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model harbouring a mutation in cardiac troponin T (R173W), we aim to examine the cellular basis of arrhythmogenesis in DCM patients with this mutation. iPSC from control (Ctrl) and DCM-TnT-R173W donors from the same family were differentiated into iPSC-CM and analysed through optical action potential (AP) recordings, simultaneous measurement of cytosolic calcium concentration ([Ca2+]i) and membrane currents and separately assayed using field stimulation to detect the threshold for AP- and [Ca2+]i-alternans development. AP duration was unaltered in TnT-R173W iPSC-CM. Nevertheless, TnT-R173W iPSC-CM showed a strikingly low stimulation threshold for AP- and [Ca2+]i-alternans. Myofilaments are known to play a role as intracellular Ca2+ buffers and here we show increased Ca2+ affinity of intracellular buffers in TnT-R173W cells, indicating increased myofilament sensitivity to Ca2+. Similarly, EMD57033, a myofilament Ca2+ sensitiser, replicated the abnormal [Ca2+]i dynamics observed in TnT-R173W samples and lowered the threshold for alternans development. In contrast, application of a Ca2+ desensitiser (blebbistatin) to TnT-R173W iPSC-CM was able to phenotypically rescue Ca2+ dynamics, normalising Ca2+ transient profile and minimising the occurrence of Ca2+ alternans at physiological frequencies. This finding suggests that increased Ca2+ buffering likely plays a major arrhythmogenic role in patients with DCM, specifically in those with mutations in cardiac troponin T. In addition, we propose that modulation of myofilament Ca2+ sensitivity could be an effective anti-arrhythmic target for pharmacological management of this disease.
- Issue Date
- 2-May-2022
- Journal
- Basic Research in Cardiology
- Project
- SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz
EXC 2067: Multiscale Bioimaging - Working Group
- RG Ebert (Cardiovascular Cell Biology and Systems Medicine)
RG Voigt (Molecular Pharmacology) - ISSN
- 0300-8428
- eISSN
- 1435-1803
- Language
- English