Fibroblasts in heart scar tissue directly regulate cardiac excitability and arrhythmogenesis.

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  • Additional Information
    • Source:
      Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 0404511 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-9203 (Electronic) Linking ISSN: 00368075 NLM ISO Abbreviation: Science Subsets: MEDLINE
    • Publication Information:
      Publication: : Washington, DC : American Association for the Advancement of Science
      Original Publication: New York, N.Y. : [s.n.] 1880-
    • Subject Terms:
      Arrhythmias, Cardiac*/genetics ; Arrhythmias, Cardiac*/physiopathology ; Cicatrix*/pathology ; Cicatrix*/physiopathology ; Fibroblasts*/physiology ; Myocytes, Cardiac*/physiology ; Channelrhodopsins*/genetics ; Channelrhodopsins*/physiology; Animals ; Mice ; Optogenetics ; Connexin 43/genetics ; Connexin 43/physiology ; Gene Knockout Techniques
    • Abstract:
      After heart injury, dead heart muscle is replaced by scar tissue. Fibroblasts can electrically couple with myocytes, and changes in fibroblast membrane potential can lead to myocyte excitability, which suggests that fibroblast-myocyte coupling in scar tissue may be responsible for arrhythmogenesis. However, the physiologic relevance of electrical coupling of myocytes and fibroblasts and its impact on cardiac excitability in vivo have never been demonstrated. We genetically engineered a mouse that expresses the optogenetic cationic channel ChR2 (H134R) exclusively in cardiac fibroblasts. After myocardial infarction, optical stimulation of scar tissue elicited organ-wide cardiac excitation and induced arrhythmias in these animals. Complementing computational modeling with experimental approaches, we showed that gap junctional and ephaptic coupling, in a synergistic yet functionally redundant manner, excited myocytes coupled to fibroblasts.
    • Comments:
      Comment in: Nat Rev Cardiol. 2023 Dec;20(12):795. (PMID: 37848629)
      Comment in: J Cardiovasc Aging. 2023 Oct;3(4):. (PMID: 38235057)
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    • Grant Information:
      R01 HL152176 United States HL NHLBI NIH HHS; R01 HL149658 United States HL NHLBI NIH HHS; R01 HL169217 United States HL NHLBI NIH HHS; R01 HL157116 United States HL NHLBI NIH HHS; R01 DK132735 United States DK NIDDK NIH HHS; R01 HL152296 United States HL NHLBI NIH HHS; R01 HL139829 United States HL NHLBI NIH HHS; R01 HL134346 United States HL NHLBI NIH HHS; R01 HL149687 United States HL NHLBI NIH HHS; R01 HL134709 United States HL NHLBI NIH HHS; R01 AR075867 United States AR NIAMS NIH HHS
    • Accession Number:
      0 (Channelrhodopsins)
      0 (Connexin 43)
    • Publication Date:
      Date Created: 20230928 Date Completed: 20231023 Latest Revision: 20240523
    • Publication Date:
      20240524
    • Accession Number:
      PMC10768850
    • Accession Number:
      10.1126/science.adh9925
    • Accession Number:
      37769108