Reduced gap junction coupling amplifies the effects of cardiomyocyte variability and destabilizes the heartbeat
Abstract Cardiomyocytes exhibit significant cell‐to‐cell variability due to differences in protein expression and post‐translational modifications in the cell membrane and the intracellular machinery. Resulting variability in action potential propagation and configuration is proposed to promote arrh...
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Wiley
2025-07-01
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| Series: | Physiological Reports |
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| Online Access: | https://doi.org/10.14814/phy2.70461 |
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| author | Karoline Horgmo Jæger William E. Louch Aslak Tveito |
| author_facet | Karoline Horgmo Jæger William E. Louch Aslak Tveito |
| author_sort | Karoline Horgmo Jæger |
| collection | DOAJ |
| description | Abstract Cardiomyocytes exhibit significant cell‐to‐cell variability due to differences in protein expression and post‐translational modifications in the cell membrane and the intracellular machinery. Resulting variability in action potential propagation and configuration is proposed to promote arrhythmia. However, such effects may be suppressed by tight electrical coupling of cells in the healthy heart, but not during pathological conditions where gap junction function is impaired. To investigate this, we employed a cell‐based mathematical model of cardiac electrophysiology, in which we systematically modified properties of individual cells and intercellular electrical connectivity (gap junctions). Despite the inclusion of marked variation in properties between cells, we observed electrical homogeneity when cells were well coupled. In contrast, lower and/or more variable gap junction connectivity resulted in nonhomogeneous action potential configuration and irregular timing of the depolarizing and repolarizing electrical wavefronts. Pro‐arrhythmic early after depolarizations also occurred under these conditions. These effects were effectively dampened in highly coupled cells. Nevertheless, differences in calcium homeostasis were not negated by gap junction coupling, indicating a limit to which electrical connections can homogenize mechanical function. Our findings underscore the critical role of intercellular coupling in maintaining cardiac stability and highlight the importance of studying cardiomyocytes within a syncytium rather than in isolation. |
| format | Article |
| id | doaj-art-6ec04e0aa3ea4ba59238ca8b452de879 |
| institution | Kabale University |
| issn | 2051-817X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Physiological Reports |
| spelling | doaj-art-6ec04e0aa3ea4ba59238ca8b452de8792025-08-20T03:27:44ZengWileyPhysiological Reports2051-817X2025-07-011313n/an/a10.14814/phy2.70461Reduced gap junction coupling amplifies the effects of cardiomyocyte variability and destabilizes the heartbeatKaroline Horgmo Jæger0William E. Louch1Aslak Tveito2Simula Research Laboratory Oslo NorwayInstitute for Experimental Medical Research Oslo University Hospital and University of Oslo Oslo NorwaySimula Research Laboratory Oslo NorwayAbstract Cardiomyocytes exhibit significant cell‐to‐cell variability due to differences in protein expression and post‐translational modifications in the cell membrane and the intracellular machinery. Resulting variability in action potential propagation and configuration is proposed to promote arrhythmia. However, such effects may be suppressed by tight electrical coupling of cells in the healthy heart, but not during pathological conditions where gap junction function is impaired. To investigate this, we employed a cell‐based mathematical model of cardiac electrophysiology, in which we systematically modified properties of individual cells and intercellular electrical connectivity (gap junctions). Despite the inclusion of marked variation in properties between cells, we observed electrical homogeneity when cells were well coupled. In contrast, lower and/or more variable gap junction connectivity resulted in nonhomogeneous action potential configuration and irregular timing of the depolarizing and repolarizing electrical wavefronts. Pro‐arrhythmic early after depolarizations also occurred under these conditions. These effects were effectively dampened in highly coupled cells. Nevertheless, differences in calcium homeostasis were not negated by gap junction coupling, indicating a limit to which electrical connections can homogenize mechanical function. Our findings underscore the critical role of intercellular coupling in maintaining cardiac stability and highlight the importance of studying cardiomyocytes within a syncytium rather than in isolation.https://doi.org/10.14814/phy2.70461cardiac electrophysiologycardiac myocytescell‐based modelingcellular variabilityheterogeneity |
| spellingShingle | Karoline Horgmo Jæger William E. Louch Aslak Tveito Reduced gap junction coupling amplifies the effects of cardiomyocyte variability and destabilizes the heartbeat Physiological Reports cardiac electrophysiology cardiac myocytes cell‐based modeling cellular variability heterogeneity |
| title | Reduced gap junction coupling amplifies the effects of cardiomyocyte variability and destabilizes the heartbeat |
| title_full | Reduced gap junction coupling amplifies the effects of cardiomyocyte variability and destabilizes the heartbeat |
| title_fullStr | Reduced gap junction coupling amplifies the effects of cardiomyocyte variability and destabilizes the heartbeat |
| title_full_unstemmed | Reduced gap junction coupling amplifies the effects of cardiomyocyte variability and destabilizes the heartbeat |
| title_short | Reduced gap junction coupling amplifies the effects of cardiomyocyte variability and destabilizes the heartbeat |
| title_sort | reduced gap junction coupling amplifies the effects of cardiomyocyte variability and destabilizes the heartbeat |
| topic | cardiac electrophysiology cardiac myocytes cell‐based modeling cellular variability heterogeneity |
| url | https://doi.org/10.14814/phy2.70461 |
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