Transcatheter Mitral Valve Repair Therapies: Evolution, Status and Challenges.

Mitral regurgitation is a common cardiac valve lesion, developing from primary lesions of the mitral valve or secondary to cardiomyopathies. Moderate or higher severity of mitral regurgitation imposes significant volume overload on the left ventricle, causing permanent structural and functional deterioration of the myocardium and heart failure. Timely correction of regurgitation is essential to preserve cardiac function, but surgical mitral valve repair is often delayed due to the risks of open heart surgery. Since correction of mitral regurgitation can provide symptomatic relief and halt progressive cardiac dysfunction, transcatheter mitral valve repair technologies are emerging as alternative therapies. In this approach, the mitral valve is repaired either with sutures or implants that are delivered to the native valve on catheters introduced into the cardiovascular system under image guidance, through small vascular or ventricular ports. Several transcatheter mitral valve technologies are in development, but limited clinical success has been achieved. In this review, we present a historical perspective of mitral valve repair, review the transcatheter technologies emerging from surgical concepts, the challenges they face in achieving successful clinical application, and the increasing rigor of safety and durability standards for new transcatheter valve technologies.

BMP2 rescues deficient cell migration in Tgfbr3(-/-) epicardial cells and requires Src kinase.

During embryogenesis, the epicardium undergoes proliferation, migration, and differentiation into several cardiac cell types which contribute to the coronary vessels. The type III transforming growth factor-ß receptor (TGFßR3) is required for epicardial cell invasion and development of coronary vasculature in vivo. Bone Morphogenic Protein-2 (BMP2) is a driver of epicardial cell migration. Utilizing a primary epicardial cell line derived from Tgfbr3(+/+) and Tgfbr3(-/-) mouse embryos, we show that Tgfbr3(-/-) epicardial cells are deficient in BMP2 mRNA expression. Tgfbr3(-/-) epicardial cells are deficient in 2-dimensional migration relative to Tgfbr3(+/+) cells; BMP2 induces cellular migration to Tgfbr3(+/+) levels without affecting proliferation. We further demonstrate that Src kinase activity is required for BMP2 driven Tgfbr3(-/-) migration. BMP2 also requires Src for filamentous actin polymerization in Tgfbr3(-/-) epicardial cells. Taken together, our data identifies a novel pathway in epicardial cell migration required for development of the coronary vessels.

Type III TGFß receptor and Src direct hyaluronan-mediated invasive cell motility.

During embryogenesis, the epicardium undergoes proliferation, migration, and differentiation into several cardiac cell types which contribute to the coronary vessels. This process requires epithelial to mesenchymal transition (EMT) and directed cellular invasion. The Type III Transforming Growth Factor-beta Receptor (TGFßR3) is required for epicardial cell invasion and coronary vessel development. Using primary epicardial cells derived from Tgfbr3(+/+) and Tgfbr3(-/-) mouse embryos, high-molecular weight hyaluronan (HMWHA) stimulated cellular invasion and filamentous (f-actin) polymerization are detected in Tgfbr3(+/+) cells, but not in Tgfbr3(-/-) cells. Furthermore, HMWHA-stimulated cellular invasion and f-actin polymerization in Tgfbr3(+/+) epicardial cells are dependent on Src kinase. Src activation in HMWHA-stimulated Tgfbr3(-/-) epicardial cells is not detected in response to HMWHA. RhoA and Rac1 also fail to activate in response to HMWHA in Tgfbr3(-/-) cells. These events coincide with defective f-actin formation and deficient cellular invasion. Finally, a T841A activating substitution in TGFßR3 drives ligand-independent Src activation. Collectively, these data define a TGFßR3-Src-RhoA/Rac1 pathway that is essential for hyaluronan-directed cell invasion in epicardial cells.