Published online before print October 15, 2007, doi: 10.1161/CIRCULATIONAHA.107.712935
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(Circulation. 2007;116:2018-2028.)
© 2007 American Heart Association, Inc.
Arrhythmia/Electrophysiology |
Resynchronization of Separated Rat Cardiomyocyte Fields With Genetically Modified Human Ventricular Scar Fibroblasts
From the Departments of Cardiology (D.A.P., J.v.T., R.W.G., A.v.d.L., D.L.Y., D.E.A., M.J.S.) and Molecular Cell Biology (J.v.T., A.A.F.d.V.), Leiden University Medical Center, Leiden, The Netherlands.
Correspondence to Douwe E. Atsma, MD, PhD, Department of Cardiology, Leiden University Medical Center, PO Box 9600, 2300RC Leiden, the Netherlands.
Received May 2, 2007; accepted August 31, 2007.
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.