title: Autologous Skeletal Myoblast Sheet Therapy for Porcine Myocardial Infarction Without Increasing Risk of Arrhythmia.
abstract: Safety concerns of ventricular tachyarrhythmia have arisen from some clinical trials of autologous skeletal myoblast (SkM) injection therapy. This study examined the effect and safety of SkM sheet therapy in a pig model of chronic myocardial infarction. Minipigs underwent LAD occlusion using a balloon catheter for 2 h, followed by reperfusion. After 28 days, 12 SkM sheets were transplanted onto the infarcted myocardium (sheet group n = 8); the same number of cells was also injected into the myocardium (injection group n = 7), and sham operations were performed as a control (sham group n = 7). Implantable ECG loop recorders (ILR) were placed subcutaneously on the left thorax. At 28 days after transplantation, we assessed cardiac function with MDCT, interrogated ILR, and performed programmed ventricular stimulation (PVS), after which organs were harvested for histopathology. To assess the inflammatory and injury response, inflammation factors and high-sensitive CRP and troponin I were measured at 1, 3, 7, and 28 days after transplantation by the cytokine array method and ELISA, respectively. The sheet group showed an improvement in cardiac function compared with both the injection and sham groups (LVEF change: 5.8 ± 2.7%, -1.0 ± 2.6%, and -3.8 ± 1.8% in the sheet, injection, and sham groups, respectively, p < 0.05). VF was not detected in any group using ILR, while VT was detected in one pig from the injection group. VF was induced in 25.0%, 71.4%, and 28.6% of animals in the sheet, injection, and sham groups, respectively. In the injection group, anti-macrophage-positive cells were observed around the injected cells within the myocardium. Transmission electron microscopic images showed differentiated myofilaments, collagen layers, and a characteristic extracellular matrix surrounding the SkMs in the sheet group. Toroponin I and IL-6 levels were higher in the injection group compared with both the sheet and sham groups. SkM sheets transplanted onto infarcted myocardium improved cardiac function over SkM injection without increasing arrhythmogenicity.
authors: Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, TWIns, Tokyo, Japan; †Department of Cardiology, Tokyo Women's Medical University, Tokyo, Japan.
authors: Yutaka
authors: Y
authors: Terajima
authors: Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, TWIns , Tokyo , Japan.
authors: Tatsuya
authors: T
authors: Shimizu
authors: Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, TWIns , Tokyo , Japan.
authors: Shinpei
authors: S
authors: Tsuruyama
authors: Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, TWIns , Tokyo , Japan.
authors: Hidekazu
authors: H
authors: Sekine
authors: ‡ Department of Cardiovascular Surgery, Tokyo Women's Medical University , Tokyo , Japan.
authors: Hikaru
authors: H
authors: Ishii
authors: ‡ Department of Cardiovascular Surgery, Tokyo Women's Medical University , Tokyo , Japan.
authors: Kenji
authors: K
authors: Yamazaki
authors: † Department of Cardiology, Tokyo Women's Medical University , Tokyo , Japan.
authors: Nobuhisa
authors: N
authors: Hagiwara
authors: Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, TWIns , Tokyo , Japan.
authors: Teruo
authors: T
authors: Okano
keywords: Cell sheet; Heart failure; Regeneration therapy; Tissue engineering