Myocardin regulates BMP10 expression and is required for heart development.

Myocardin is a muscle lineage-restricted transcriptional coactivator that has been shown to transduce extracellular signals to the nucleus required for SMC differentiation. We now report the discovery of a myocardin/BMP10 (where BMP10 indicates bone morphogenetic protein 10) signaling pathway required for cardiac growth, chamber maturation, and embryonic survival. Myocardin-null (Myocd) embryos and embryos harboring a cardiomyocyte-restricted mutation in the Myocd gene exhibited myocardial hypoplasia, defective atrial and ventricular chamber maturation, heart failure, and embryonic lethality. Cardiac hypoplasia was caused by decreased cardiomyocyte proliferation accompanied by a dramatic increase in programmed cell death. Defective chamber maturation and the block in cardiomyocyte proliferation were caused in part by a block in BMP10 signaling. Myocardin transactivated the Bmp10 gene via binding of a serum response factor-myocardin protein complex to a nonconsensus CArG element in the Bmp10 promoter. Expression of p57kip2, a BMP10-regulated cyclin-dependent kinase inhibitor, was induced in Myocd-/- hearts, while BMP10-activated cardiogenic transcription factors, including NKX2.5 and MEF2c, were repressed. Remarkably, when embryonic Myocd-/- hearts were cultured ex vivo in BMP10-conditioned medium, the defects in cardiomyocyte proliferation and p57kip2 expression were rescued. Taken together, these data identify a heretofore undescribed myocardin/BMP10 signaling pathway that regulates cardiomyocyte proliferation and apoptosis in the embryonic heart.

In vivo evaluation of a biolimus eluting nickel titanium self expanding stent with overlapping balloon expandable drug eluting and bare metal stents in a porcine coronary model.

AIMS: Long lesions and complex vessel anatomy frequently require the use of overlapping stents to treat a lesion. The purpose of this study was to evaluate the long-term effects of overlapping the Axxess Biolimus A9 eluting stent (BES) with two of the most commonly used, commercially available drug eluting stents. These stents were compared to BxVelocity bare metal (BMS) stents in a porcine coronary stent-injury model. METHODS AND RESULTS: Nineteen juvenile farm swine, 25-35 kg in weight, 3-6 months in age were utilised. Each animal received an Axxess stent to their coronary artery as permitted by the individual animal's anatomy. A second stent, either a Cypher, sirolimus eluting stent (SES) or, a Taxus, paclitaxel eluting stent (PES), or a BxVelocity bare metal stent (BMS) were implanted in an overlapped fashion. The animals were then followed for either 28 or 180 days as specified by a randomisation scheme. At the end of each follow-up period, they were euthenised, and the vessels containing the overlapping stents were harvested, processed into histological sections, and analysed. Compared to bare metal stents, overlapped segments using DES exhibited delayed vascular healing compared to both the proximal and distal non-overlap sites at each of the follow-up time point. Overall, in the non-overlap stent segments, SES induced significantly more inflammation and neointimal hyperplasia compared to PES and BMS. CONCLUSIONS: In this study of BMS and two different types of DES overlapped with the Axxess Biolimus A9 eluting stent, we found that while there was a delay in the degree of vascular healing with DES compared to BMS, the specific type of DES that was overlapped with BES did not affect the behaviour of the overlap zone in terms of most of the histomorphometric measures at 28 or 180 days. This was true whether the stent was drug eluting or bare metal. More inflammation with delayed healing was seen in the SES compared to PES and BMS.

Long-term effects of novel biolimus eluting DEVAX AXXESS plus nitinol self-expanding stent in a porcine coronary model.

OBJECTIVE: The purpose of this study was to evaluate the long-term effects of the DEVAX AXXESS biolimus eluting stent (BES) in a porcine coronary model, compared with those of bare metal stent (BMS) and polymer only stent (POS) controls. BACKGROUND: Excessive neointimal growth has been identified as a major cause of late failure of percutaneous coronary interventions. The effect of drug eluting from self-expanding stents for prevention of neointimal hyperplasia has not been studied before. The DEVAX AXXESS is a self-expanding nickel titanium stent, coated with antiproliferative compound-biolimus. METHODS: Twenty juvenile farm swine, 25-35 kg in weight, 3-6 months in age were used. Each animal received a stent to the left anterior descending artery, left circumflex or right coronary arteries as permitted per anatomy. The chronic vascular response after BES implantation was compared with that after BMS and POS implantation at 28, 90, and 180 days follow-up. RESULTS: The 28-day outcome by quantitative coronary angiography (QCA) showed significant increase in minimal luminal diameter (MLD) in the BES (MLD: 2.90 +/- 0.97, 2.39 +/- 0.90, 1.59 +/- 0.91; P = 0.009) compared with BMS and POS, respectively. By histomorphometric analysis, there was also a corresponding significant reduction in neointimal tissue proliferation in the BES (average neointimal area: 2.78 +/- 0.07, 5.46 +/- 0.66, 8.42 +/- 0.85; P = 0.002) compared with that in BMS and POS controls, respectively at 28-days follow-up. At 90 and 180 days, the mean neointimal area was not significantly different between the BES and the controls. CONCLUSIONS: BES favorably modulates the neointimal tissue formation for 28 days, in the porcine coronary model. Long-term inhibition of neointimal hyperplasia is not sustained most likely because of the delayed cellular proliferation and inflammation in the vessel wall.