Resynchronization of separated rat cardiomyocyte fields with genetically modified human ventricular scar fibroblasts

Article

关键词: MESENCHYMAL STEM-CELLS;    CARDIAC RESYNCHRONIZATION;    HEART-FAILURE;    ION CHANNELS;    THERAPY;    CONDUCTION;    TISSUE;    REPOLARIZATION;    MYOCARDIUM;    EXPRESSION;   

DOI  :  10.1161/CIRCULATIONAHA.107.712935

来源: SCIE

【 摘 要 】

Background - Nonresponse to cardiac resynchronization therapy is associated with the presence of slow or nonconducting scar tissue. Genetic modification of scar tissue, aimed at improving conduction, may be a novel approach to achieve effective resynchronization. Therefore, the feasibility of resynchronization with genetically modified human ventricular scar fibroblasts was studied in a coculture model. Methods and Results - An in vitro model was used to study the effects of forced expression of the myocardin (MyoC) gene in human ventricular scar fibroblasts (hVSFs) on resynchronization of 2 rat cardiomyocyte fields separated by a strip of hVSFs. Furthermore, the effects of MyoC expression on the capacity of hVSFs to serve as pacing sites were studied. MyoC-dependent gene activation in hVSFs was examined by gene and immunocytochemical analysis. Forced MyoC expression in hVSFs decreased dyssynchrony, expressed as the activation delay between 2 cardiomyocyte fields (control hVSFs 27.6 +/- 0.2 ms [n=11] versus MyoC-hVSFs 3.6 +/- 0.3 ms [n=11] at day 8, P < 0.01). Also, MyoC-hVSFs could be stimulated electrically, which resulted in simultaneous activation of the 2 adjacent cardiomyocyte fields. Forced MyoC expression in hVSFs led to the expression of various connexin and cardiac ion channel genes. Intracellular measurements of MyoC-hVSFs coupled to surrounding cardiomyocytes showed strongly improved action potential conduction. Conclusions - Forced MyoC gene expression in hVSFs allowed electrical stimulation of these cells and conferred the ability to conduct an electrical impulse at high velocity, which resulted in resynchronization of 2 separated cardiomyocyte fields. Both phenomena appear mediated mainly by MyoC-dependent activation of genes that encode connexins, strongly enforcing intercellular electrical coupling.

【 授权许可】

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