Numerous in vitro studies and clinical observations have demonstrated non-myocytes, including fibroblasts, can electrically couple to myocytes. However, definitive evidence demonstrating that current can passively spread across scar tissue has yet to be obtained in the intact heart. It was hypothesized that electrotonic conduction occurs across non-myocyte gaps in the heart and is mediated by the gap junctional protein Cx43. To investigate whether cells in scar tissue are electrically connected to surrounding myocardial tissue, transmural lesions were induced to the right or left ventricular free walls of wild-type mice. Electrical coupling between the scar tissue and healthy myocardium was demonstrated by injecting current into healthy tissue and recording depolarization in the lesion through high resolution optical mapping. Microelectrode recordings from cells within the scar showed significantly decreased amplitude (p=0.009), depolarized resting membrane potential (p=0.0013), increased duration (p=0.006 at 50% repolarization) and reduced upstroke velocity (p=0.0013) compared to surrounding myocytes (n=6). These results were further validated by 2D in silico simulations. Optical mapping of left ventricular lesions demonstrated that current delivered within the scar could excite surrounding myocardium (n=5), and that the lesion cells exhibited a significantly greater length constant than the myocardium (p=9.5×10−7, n=3). Cx43 immunoreactivity was present in the cells within the scar. Furthermore, mice with fibroblast-specific protein-1 deletion of Cx43 exhibited significantly reduced electrotonic coupling in lesions compared to littermate controls (p=0.001, n=6–8), and microelectrode recordings from the lesions of these mice demonstrated that electrotonic signals were absent (n=5). These data demonstrate non-myocytes in injured regions are electrically coupled to myocytes, and this activity is at least partially dependent on Cx43 expression.
|Advisor:||Morley, Gregory E.|
|Commitee:||Coetzee, William, Cohen, Ira, Delmar, Mario, Ramasamy, Ravi, Skolnik, Edward|
|School:||New York University|
|Department:||Basic Medical Science|
|School Location:||United States -- New York|
|Source:||DAI-B 76/12(E), Dissertation Abstracts International|
|Subjects:||Cellular biology, Physiology|
|Keywords:||Ablation lesion, Coupling, Electrotonic conduction, Fibroblast, Heart, Myocardial infarction, Non-myocyte|
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