Heart disease remains a leading cause of death worldwide. Owing to the limited regenerative capacity of heart tissue, cardiac regenerative therapy has emerged as an attractive approach. Direct reprogramming of human cardiac fibroblasts (HCFs) into cardiomyocytes may hold great potential for this purpose. We reported previously that induced cardiomyocyte-like cells (iCMs) can be directly generated from mouse cardiac fibroblasts in vitro and vivo by transduction of three transcription factors: Gata4, Mef2c, and Tbx5, collectively termed GMT. In the present study, we sought to determine whether human fibroblasts also could be converted to iCMs by defined factors. Our initial finding that GMT was not sufficient for cardiac induction in HCFs prompted us to screen for additional factors to promote cardiac reprogramming by analyzing multiple cardiac-specific gene induction with quantitative RT-PCR. The addition of Mesp1 and Myocd to GMT up-regulated a broader spectrum of cardiac genes in HCFs more efficiently compared with GMT alone. The HCFs and human dermal fibroblasts transduced with GMT, Mesp1, and Myocd (GMTMM) changed the cell morphology from a spindle shape to a rod-like or polygonal shape, expressed multiple cardiac-specific proteins, increased a broad range of cardiac genes and concomitantly suppressed fibroblast genes, and exhibited spontaneous Ca 2+ oscillations. Moreover, the cells matured to exhibit action potentials and contract synchronously in coculture with murine cardiomyocytes. A 5-ethynyl-2′-deoxyuridine assay revealed that the iCMs thus generated do not pass through a mitotic cell state. These findings demonstrate that human fibroblasts can be directly converted to iCMs by defined factors, which may facilitate future applications in regenerative medicine.cell fate conversion | regeneration | cardiogenesis C ardiovascular disease remains a leading cause of death worldwide, for which current therapeutic regimens remain limited. Given that adult human hearts have little regenerative capacity after injury, the demand is high for cardiac regenerative therapy. The recent discovery of induced pluripotent stem cells (iPSCs) allows the direct generation of specific cell types from differentiated somatic cells by overexpression of lineagespecific factors.Several previous studies have demonstrated that such direct lineage reprogramming can yield a diverse range of cell types, including pancreatic β cells, neurons, neural progenitors, blood progenitors, and hepatocyte-like cells (1-5). We previously reported that a minimum mixture of three cardiac-specific transcription factors-Gata4, Mef2c, and Tbx5 (GMT)-directly induced cardiomyocyte-like cells (iCMs) from mouse fibroblasts in vitro (6). Following our report, three other groups also reported generation of functional cardiomyocytes from mouse fibroblasts with various combinations of transcription factors, either with GMT plus Hand2 (GHMT) or Mef2c, Myocd, and Tbx5 or using microRNAs (7-9). Although full reprogramming into beating cardiomyocytes was not effic...

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Performing double-bar placement decreases postoperative pain. Therefore, surgeons should not hesitate to perform double-bar correction in patients in whom the deformity extends to multiple intercostal spaces, requiring correction of the thorax shape at multiple sites.

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A simple prognostic model was developed to predict mortality after surgical ventricular reconstruction. It can be useful in clinical practice to select treatment options for ischemic heart failure.