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  1. Article ; Online: High-throughput methods for cardiac cellular electrophysiology studies: the road to personalized medicine.

    Seibertz, Fitzwilliam / Voigt, Niels

    American journal of physiology. Heart and circulatory physiology

    2024  Volume 326, Issue 4, Page(s) H938–H949

    Abstract: Personalized medicine refers to the tailored application of medical treatment at an individual level, considering the specific genotype or phenotype of each patient for targeted therapy. In the context of cardiovascular diseases, implementing ... ...

    Abstract Personalized medicine refers to the tailored application of medical treatment at an individual level, considering the specific genotype or phenotype of each patient for targeted therapy. In the context of cardiovascular diseases, implementing personalized medicine is challenging due to the high costs involved and the slow pace of identifying the pathogenicity of genetic variants, deciphering molecular mechanisms of disease, and testing treatment approaches. Scalable cellular models such as human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) serve as useful in vitro tools that reflect individual patient genetics and retain clinical phenotypes. High-throughput functional assessment of these constructs is necessary to rapidly assess cardiac pathogenicity and test new therapeutics if personalized medicine is to become a reality. High-throughput photometry recordings of single cells coupled with potentiometric probes offer cost-effective alternatives to traditional patch-clamp assessments of cardiomyocyte action potential characteristics. Importantly, automated patch-clamp (APC) is rapidly emerging in the pharmaceutical industry and academia as a powerful method to assess individual membrane-bound ionic currents and ion channel biophysics over multiple cells in parallel. Now amenable to primary cell and hiPSC-CM measurement, APC represents an exciting leap forward in the characterization of a multitude of molecular mechanisms that underlie clinical cardiac phenotypes. This review provides a summary of state-of-the-art high-throughput electrophysiological techniques to assess cardiac electrophysiology and an overview of recent works that successfully integrate these methods into basic science research that could potentially facilitate future implementation of personalized medicine at a clinical level.
    MeSH term(s) Humans ; Induced Pluripotent Stem Cells ; Precision Medicine ; Myocytes, Cardiac ; Action Potentials/physiology ; Electrophysiology
    Language English
    Publishing date 2024-01-26
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 603838-4
    ISSN 1522-1539 ; 0363-6135
    ISSN (online) 1522-1539
    ISSN 0363-6135
    DOI 10.1152/ajpheart.00599.2023
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Vicious Twins: RyR2 Dysfunction and Structural Remodeling.

    Voigt, Niels / Seibertz, Fitzwilliam / Fakuade, Funsho E

    Circulation research

    2023  Volume 133, Issue 2, Page(s) 193–195

    MeSH term(s) Ryanodine Receptor Calcium Release Channel/genetics ; Ryanodine Receptor Calcium Release Channel/metabolism ; Myocytes, Cardiac/metabolism ; Calcium Signaling ; Calcium/metabolism ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Sarcoplasmic Reticulum/metabolism
    Chemical Substances Ryanodine Receptor Calcium Release Channel ; Calcium (SY7Q814VUP) ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 (EC 2.7.11.17)
    Language English
    Publishing date 2023-07-06
    Publishing country United States
    Document type Editorial ; Research Support, Non-U.S. Gov't ; Comment
    ZDB-ID 80100-8
    ISSN 1524-4571 ; 0009-7330 ; 0931-6876
    ISSN (online) 1524-4571
    ISSN 0009-7330 ; 0931-6876
    DOI 10.1161/CIRCRESAHA.123.323144
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Recording ten-fold larger I

    Bloothooft, Meye / Verbruggen, Bente / Seibertz, Fitzwilliam / van der Heyden, Marcel A G / Voigt, Niels / de Boer, Teun P

    Frontiers in physiology

    2024  Volume 15, Page(s) 1298340

    Abstract: Background: ...

    Abstract Background:
    Language English
    Publishing date 2024-01-24
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2564217-0
    ISSN 1664-042X
    ISSN 1664-042X
    DOI 10.3389/fphys.2024.1298340
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Single-Cell Optical Action Potential Measurement in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

    Seibertz, Fitzwilliam / Reynolds, Martyn / Voigt, Niels

    Journal of visualized experiments : JoVE

    2020  , Issue 166

    Abstract: Conventional intracellular microelectrode techniques to quantify cardiomyocyte electrophysiology are extremely complex, labor intensive, and typically carried out in low throughput. Rapid and ongoing expansion of induced pluripotent stem cell (iPSC) ... ...

    Abstract Conventional intracellular microelectrode techniques to quantify cardiomyocyte electrophysiology are extremely complex, labor intensive, and typically carried out in low throughput. Rapid and ongoing expansion of induced pluripotent stem cell (iPSC) technology presents a new standard in cardiovascular research and alternate methods are now necessary to increase throughput of electrophysiological data at a single cell level. VF2.1Cl is a recently derived voltage sensitive dye which provides a rapid single channel, high magnitude response to fluctuations in membrane potential. It possesses kinetics superior to those of other existing voltage indicators and makes available functional data equivalent to that of traditional microelectrode techniques. Here, we demonstrate simplified, non-invasive action potential characterization in externally paced human iPSC derived cardiomyocytes using a modular and highly affordable photometry system.
    MeSH term(s) Action Potentials/physiology ; Cell Differentiation ; Cells, Cultured ; Coloring Agents/chemistry ; Data Analysis ; Electricity ; Humans ; Image Processing, Computer-Assisted ; Induced Pluripotent Stem Cells/cytology ; Myocytes, Cardiac/cytology ; Single-Cell Analysis
    Chemical Substances Coloring Agents
    Language English
    Publishing date 2020-12-22
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Video-Audio Media
    ZDB-ID 2259946-0
    ISSN 1940-087X ; 1940-087X
    ISSN (online) 1940-087X
    ISSN 1940-087X
    DOI 10.3791/61890
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Single-cell optical action potential measurement in human induced pluripotent stem cell-derived cardiomyocytes

    Seibertz, Fitzwilliam / Reynolds, Martyn / Voigt, Niels

    Journal of visualized experiments. 2020 Dec. 22, , no. 166

    2020  

    Abstract: Conventional intracellular microelectrode techniques to quantify cardiomyocyte electrophysiology are extremely complex, labor intensive, and typically carried out in low throughput. Rapid and ongoing expansion of induced pluripotent stem cell (iPSC) ... ...

    Abstract Conventional intracellular microelectrode techniques to quantify cardiomyocyte electrophysiology are extremely complex, labor intensive, and typically carried out in low throughput. Rapid and ongoing expansion of induced pluripotent stem cell (iPSC) technology presents a new standard in cardiovascular research and alternate methods are now necessary to increase throughput of electrophysiological data at a single cell level. VF2.1Cl is a recently derived voltage sensitive dye which provides a rapid single channel, high magnitude response to fluctuations in membrane potential. It possesses kinetics superior to those of other existing voltage indicators and makes available functional data equivalent to that of traditional microelectrode techniques. Here, we demonstrate simplified, non-invasive action potential characterization in externally paced human iPSC derived cardiomyocytes using a modular and highly affordable photometry system.
    Keywords action potentials ; cardiomyocytes ; dyes ; electric potential difference ; humans ; labor ; photometry ; stem cells
    Language English
    Dates of publication 2020-1222
    Size p. e61890.
    Publishing place Journal of Visualized Experiments
    Document type Article
    ZDB-ID 2259946-0
    ISSN 1940-087X
    ISSN 1940-087X
    DOI 10.3791/61890
    Database NAL-Catalogue (AGRICOLA)

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  6. Article: Adventures and Advances in Time Travel With Induced Pluripotent Stem Cells and Automated Patch Clamp.

    Rosholm, Kadla R / Badone, Beatrice / Karatsiompani, Stefania / Nagy, David / Seibertz, Fitzwilliam / Voigt, Niels / Bell, Damian C

    Frontiers in molecular neuroscience

    2022  Volume 15, Page(s) 898717

    Abstract: In the Hollywood blockbuster "The Curious Case of Benjamin Button" a fantastical fable unfolds of a man's life that travels through time reversing the aging process; as the tale progresses, the frail old man becomes a vigorous, vivacious young man, then ... ...

    Abstract In the Hollywood blockbuster "The Curious Case of Benjamin Button" a fantastical fable unfolds of a man's life that travels through time reversing the aging process; as the tale progresses, the frail old man becomes a vigorous, vivacious young man, then man becomes boy and boy becomes baby. The reality of cellular time travel, however, is far more wondrous: we now have the ability to both
    Language English
    Publishing date 2022-06-22
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2452967-9
    ISSN 1662-5099
    ISSN 1662-5099
    DOI 10.3389/fnmol.2022.898717
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Acute antiarrhythmic effects of SGLT2 inhibitors-dapagliflozin lowers the excitability of atrial cardiomyocytes.

    Paasche, Amelie / Wiedmann, Felix / Kraft, Manuel / Seibertz, Fitzwilliam / Herlt, Valerie / Blochberger, Pablo L / Jávorszky, Natasa / Beck, Moritz / Weirauch, Leo / Seeger, Timon / Blank, Antje / Haefeli, Walter E / Arif, Rawa / Meyer, Anna L / Warnecke, Gregor / Karck, Matthias / Voigt, Niels / Frey, Norbert / Schmidt, Constanze

    Basic research in cardiology

    2024  Volume 119, Issue 1, Page(s) 93–112

    Abstract: In recent years, SGLT2 inhibitors have become an integral part of heart failure therapy, and several mechanisms contributing to cardiorenal protection have been identified. In this study, we place special emphasis on the atria and investigate acute ... ...

    Abstract In recent years, SGLT2 inhibitors have become an integral part of heart failure therapy, and several mechanisms contributing to cardiorenal protection have been identified. In this study, we place special emphasis on the atria and investigate acute electrophysiological effects of dapagliflozin to assess the antiarrhythmic potential of SGLT2 inhibitors. Direct electrophysiological effects of dapagliflozin were investigated in patch clamp experiments on isolated atrial cardiomyocytes. Acute treatment with elevated-dose dapagliflozin caused a significant reduction of the action potential inducibility, the amplitude and maximum upstroke velocity. The inhibitory effects were reproduced in human induced pluripotent stem cell-derived cardiomyocytes, and were more pronounced in atrial compared to ventricular cells. Hypothesizing that dapagliflozin directly affects the depolarization phase of atrial action potentials, we examined fast inward sodium currents in human atrial cardiomyocytes and found a significant decrease of peak sodium current densities by dapagliflozin, accompanied by a moderate inhibition of the transient outward potassium current. Translating these findings into a porcine large animal model, acute elevated-dose dapagliflozin treatment caused an atrial-dominant reduction of myocardial conduction velocity in vivo. This could be utilized for both, acute cardioversion of paroxysmal atrial fibrillation episodes and rhythm control of persistent atrial fibrillation. In this study, we show that dapagliflozin alters the excitability of atrial cardiomyocytes by direct inhibition of peak sodium currents. In vivo, dapagliflozin exerts antiarrhythmic effects, revealing a potential new additional role of SGLT2 inhibitors in the treatment of atrial arrhythmias.
    MeSH term(s) Humans ; Animals ; Swine ; Myocytes, Cardiac ; Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; Induced Pluripotent Stem Cells ; Anti-Arrhythmia Agents/pharmacology ; Anti-Arrhythmia Agents/therapeutic use ; Atrial Fibrillation ; Action Potentials ; Sodium ; Benzhydryl Compounds ; Glucosides
    Chemical Substances dapagliflozin (1ULL0QJ8UC) ; Sodium-Glucose Transporter 2 Inhibitors ; Anti-Arrhythmia Agents ; Sodium (9NEZ333N27) ; Benzhydryl Compounds ; Glucosides
    Language English
    Publishing date 2024-01-03
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 189755-x
    ISSN 1435-1803 ; 0300-8428 ; 0175-9418
    ISSN (online) 1435-1803
    ISSN 0300-8428 ; 0175-9418
    DOI 10.1007/s00395-023-01022-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Therapeutic efficacy of AAV-mediated restoration of PKP2 in arrhythmogenic cardiomyopathy.

    Kyriakopoulou, Eirini / Versteeg, Danielle / de Ruiter, Hesther / Perini, Ilaria / Seibertz, Fitzwilliam / Döring, Yannic / Zentilin, Lorena / Tsui, Hoyee / van Kampen, Sebastiaan J / Tiburcy, Malte / Meyer, Tim / Voigt, Niels / Tintelen, van J Peter / Zimmermann, Wolfram H / Giacca, Mauro / van Rooij, Eva

    Nature cardiovascular research

    2023  Volume 2, Issue 12, Page(s) 1262–1276

    Abstract: Arrhythmogenic cardiomyopathy is a severe cardiac disorder characterized by lethal arrhythmias and sudden cardiac death, with currently no effective treatment. Plakophilin 2 ( ...

    Abstract Arrhythmogenic cardiomyopathy is a severe cardiac disorder characterized by lethal arrhythmias and sudden cardiac death, with currently no effective treatment. Plakophilin 2 (
    Language English
    Publishing date 2023-12-07
    Publishing country England
    Document type Journal Article
    ISSN 2731-0590
    ISSN (online) 2731-0590
    DOI 10.1038/s44161-023-00378-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: A modern automated patch-clamp approach for high throughput electrophysiology recordings in native cardiomyocytes.

    Seibertz, Fitzwilliam / Rapedius, Markus / Fakuade, Funsho E / Tomsits, Philipp / Liutkute, Aiste / Cyganek, Lukas / Becker, Nadine / Majumder, Rupamanjari / Clauß, Sebastian / Fertig, Niels / Voigt, Niels

    Communications biology

    2022  Volume 5, Issue 1, Page(s) 969

    Abstract: Crucial conventional patch-clamp approaches to investigate cellular electrophysiology suffer from low-throughput and require considerable experimenter expertise. Automated patch-clamp (APC) approaches are more experimenter independent and offer high- ... ...

    Abstract Crucial conventional patch-clamp approaches to investigate cellular electrophysiology suffer from low-throughput and require considerable experimenter expertise. Automated patch-clamp (APC) approaches are more experimenter independent and offer high-throughput, but by design are predominantly limited to assays containing small, homogenous cells. In order to enable high-throughput APC assays on larger cells such as native cardiomyocytes isolated from mammalian hearts, we employed a fixed-well APC plate format. A broad range of detailed electrophysiological parameters including action potential, L-type calcium current and basal inward rectifier current were reliably acquired from isolated swine atrial and ventricular cardiomyocytes using APC. Effective pharmacological modulation also indicated that this technique is applicable for drug screening using native cardiomyocyte material. Furthermore, sequential acquisition of multiple parameters from a single cell was successful in a high throughput format, substantially increasing data richness and quantity per experimental run. When appropriately expanded, these protocols will provide a foundation for effective mechanistic and phenotyping studies of human cardiac electrophysiology. Utilizing scarce biopsy samples, regular high throughput characterization of primary cardiomyocytes using APC will facilitate drug development initiatives and personalized treatment strategies for a multitude of cardiac diseases.
    MeSH term(s) Animals ; Calcium ; Electrophysiological Phenomena ; Electrophysiology ; Humans ; Mammals ; Myocytes, Cardiac ; Patch-Clamp Techniques ; Swine
    Chemical Substances Calcium (SY7Q814VUP)
    Language English
    Publishing date 2022-09-15
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2399-3642
    ISSN (online) 2399-3642
    DOI 10.1038/s42003-022-03871-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Increased cytosolic calcium buffering contributes to a cellular arrhythmogenic substrate in iPSC-cardiomyocytes from patients with dilated cardiomyopathy.

    Jung, Philipp / Seibertz, Fitzwilliam / Fakuade, Funsho E / Ignatyeva, Nadezda / Sampathkumar, Shrivatsan / Ritter, Melanie / Li, Housen / Mason, Fleur E / Ebert, Antje / Voigt, Niels

    Basic research in cardiology

    2022  Volume 117, Issue 1, Page(s) 5

    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 ... ...

    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 ([Ca
    MeSH term(s) Arrhythmias, Cardiac/genetics ; Calcium ; Cardiomyopathy, Dilated/genetics ; Humans ; Induced Pluripotent Stem Cells ; Myocytes, Cardiac ; Troponin T/genetics ; Troponin T/pharmacology
    Chemical Substances Troponin T ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2022-05-02
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 189755-x
    ISSN 1435-1803 ; 0300-8428 ; 0175-9418
    ISSN (online) 1435-1803
    ISSN 0300-8428 ; 0175-9418
    DOI 10.1007/s00395-022-00912-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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