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Abstract
Ventricular tachycardia (VT) is the most common and potentially lethal complication following myocardial infarction (MI). Biological correction of the conduction inhomogeneity that underlies re-entry could be a major advance in infarction therapy. As minimal increases in conduction of infarcted tissue markedly influence VT susceptibility, we reasoned that enhanced propagation of the electrical signal between non-excitable cells within a resolving infarct might comprise a simple means to decrease post-infarction arrhythmia risk. We therefore tested lentivirus-mediated delivery of the gap-junction protein Connexin 43 (Cx43) into acute myocardial lesions. Cx43 was expressed in (myo)fibroblasts and CD45+ cells within the scar and provided prominent and long lasting arrhythmia protection in vivo. Optical mapping of Cx43 injected hearts revealed enhanced conduction velocity within the scar, indicating Cx43-mediated electrical coupling between myocytes and (myo)fibroblasts. Thus, Cx43 gene therapy, by direct in vivo transduction of non-cardiomyocytes, comprises a simple and clinically applicable biological therapy that markedly reduces post-infarction VT.
Highlights
Ventricular tachycardia (VT) is the most common and potentially lethal complication following myocardial infarction (MI)
Connexin 43 (Cx43) transduction efficiency is likely greater than indicated by EGFP expression due to incomplete translational efficiency of the internal ribosome entry site (IRES) element; Cx43 immunostaining was prominent in the membrane of all EGFP+ cells (Fig. 1b)
We sought to determine whether lentivirus-mediated Cx43 transduction of SKM results in formation of functional gap junctions in vivo and post-MI VT protection equivalent to our earlier studies indicating that engraftment of skeletal muscle cells (SkM) harvested from transgenic mice overexpressing Cx43 under control of a SkM promoter protected against post-MI VT in vivo
Summary
Ventricular tachycardia (VT) is the most common and potentially lethal complication following myocardial infarction (MI). EGFP (EGFP-SkM) and EGFP-IRES-Cx43 (Cx43-SkM) transduced SkM (200,000 cells) were injected into cryoinjured mice immediately after the lesion and the electrical vulnerability tested in vivo 12 to 14 days later by applying burst and extrastimulus protocols
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