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Despite advancements in treatment options, ischemic heart failure (IHF) remains the leading cause of morbidity and mortality in the Western world.1 Therefore, the search for new therapeutic strategies to prevent adverse ventricular remodeling after acute myocardial infarction (AMI) and subsequent development of IHF is ongoing. More than a decade after a patient with an AMI was first treated with intracoronary infusion of unfractioned bone marrow-derived mononuclear cells (BMMNCs), 2 numerous clinical studies have investigated cell-based therapy as an adjuvant treatment in patients with AMI. These studies have repeatedly shown that stem cell therapy is safe and feasible. However, although initial results were promising with significant improvement in left ventricular (LV) function and volumes, [3][4][5] other studies showed ambiguous or even negative results. [6][7][8][9] This controversy resulted in a continued search for new cell types and methods to improve outcomes, but still many questions remain.Thus far, it has been difficult to make solid statements on efficacy and long-term effects on clinical outcomes of cellular therapy because of the limited number of treated patients and the relatively short follow-up period. However, recently, some larger studies reported their primary results, whereas other studies presented long-term follow-up data. 5,[10][11][12] Several meta-analysis regarding BMMNCs for the treatment of AMI and IHF have been published to date. [13][14][15] These analyses showed an improvement of only 2% to 3% on LV ejection fraction (LVEF) and a significant reduction of major adverse cardiac and cerebrovascular events (MACCE; eg, all-cause mortality; odds ratio [OR], 0.39; 95% confidence interval [CI], 0.27-0.55).14 However, these publications only evaluated the use of autologous BMMNC on cardiac repair, whereas several other cell types have now been investigated. Moreover, in the most cited meta-analysis of Jeevanantham et al, 14 data of AMI and IHF patientsBackground-Several cell-based therapies for adjunctive treatment of acute myocardial infarction have been investigated in multiple clinical trials, but the benefits still remain controversial. This meta-analysis aims to evaluate the efficacy of bone marrow-derived mononuclear cell (BMMNC) therapy in patients with acute myocardial infarction, but also explores the effect of newer generations of stem cells. Methods and Results-A random-effects meta-analysis was performed on randomized controlled trials investigating the effects of stem cell therapy in patients with acute myocardial infarction that were published between January 2002 and September 2013. The defined end points were left ventricular (LV) ejection fraction, LV end-systolic and end-diastolic volumes, infarct size, and major adverse cardiac and cerebrovascular event rates. Also, several subgroup analyses were performed on BMMNC trials. Overall, combining the results of 22 randomized controlled trials (RCTs), LV ejection fraction increased by +2.10% (95% confidence interval [CI], 0...

their subpopulations might be more effective. [4][5][6] Mesenchymal precursor cells (MPCs) constitute a Stro-3 immune-selected, immature subfraction of bone marrow-derived MSCs. Objective: This study assessed the safety, feasibility, and efficacy of intracoronary delivery of allogeneic MPCs directly after acute myocardial infarction in sheep. Methods and Results:

Background-New vessel formation contributes to organ development during embryogenesis and tissue repair in response to mechanical damage, inflammation, and ischemia in adult organisms. Early angiogenesis includes formation of an excessive primitive network that needs to be reorganized into a secondary vascular network with higher hierarchical structure. Vascular pruning, the removal of aberrant neovessels by apoptosis, is a vital step in this process. Although multiple molecular pathways for early angiogenesis have been identified, little is known about the genetic regulators of secondary network development. Methods and Results-Using a transcriptomics approach, we identified a new endothelial specific gene named FYVE, RhoGEF, and PH domain-containing 5 (FGD5) that plays a crucial role in vascular pruning. Loss-and gain-of-function studies demonstrate that FGD5 inhibits neovascularization, indicated by in vitro tube-formation, aortic-ring, and coated-bead assays and by in vivo coated-bead plug assays and studies in the murine retina model. FGD5 promotes apoptosis-induced vaso-obliteration via induction of the hey1-p53 pathway by direct binding and activation of cdc42. Indeed, FGD5 correlates with apoptosis in endothelial cells during vascular remodeling and was linked to rising p21 Key Words: angiogenesis-inducing agents Ⅲ apoptosis Ⅲ endothelium Ⅲ FGD5 Ⅲ models, animal V ascularization during development and regeneration plays a vital role in adult disease progression, including tumor growth and metastasis, arthritis, diabetic retinopathy, and cardiovascular disease. Vascular growth in both development and disease consists of a strictly orchestrated, multistep process that requires integrated activation of several molecular pathways. During early vascular growth, a dense primary vascular network without functional arterial and venous distinction is formed in response to low-oxygen conditions. This primitive system, consisting of small capillaries, is relatively unstable, with tip and stalk cell vessel structures expanding and collapsing at a high rate. Transition of this primary network into a stable secondary vasculature with a defined arterial/venous hierarchy of larger vessels that branch into a restricted capillary field requires intensive vascular remodeling, a late angiogenic process that includes neovessel stabilization and pruning of redundant vessel structures. 1,2 Editorial see p 3063 Clinical Perspective on p 3158The molecular regulation by angiogenic factors such as vascular endothelial growth factor (VEGF)-A and fibroblast growth factor that promote growth of the primary vasculature has been studied extensively. In contrast, the key molecular pathways that regulate the reorganization of this early network into the more mature secondary vascular structure are still largely undefined. For the process of vascular pruning, vaso-obliteration by apoptosis induced by hyperoxia has been described, 3 but little is known about the molecular regulation of this important aspect in vascular remodeling that dete...

The presence of multiple affected offspring from apparently non-carrier parents is caused by germ line mosaicism. Although germ line mosaicism has been reported for many diseases, figures for recurrence risks are known for only a few of them. In X-linked Duchenne and Becker muscular dystrophies (DMD/BMD), the recurrence risk for non-carrier females due to germ line mosaicism has been estimated to be between 14% and 20% (95% confidence interval 3-30) if the risk haplotype is transmitted. In this study, we have analyzed 318 DMD/BMD cases in which the detected mutation was de novo with the aim of obtaining a better estimate of the 'true' number of germ line mosaics and a more precise recurrence risk. This knowledge is essential for genetic counseling. Our data indicate a recurrence risk of 8.6% (4.8-12.2) if the risk haplotype is transmitted, but there is a remarkable difference between proximal (15.6%) (4.1-27.0) and distal (6.4%) (2.1-10.6) deletions. Overall, most mutations originated in the female. Deletions occur more often on the X chromosome of the maternal grandmother, whereas point mutations occur on the X chromosome of the maternal grandfather. In unhaplotyped de novo DMD/BMD families, the risk of recurrence of the mutation is 4.3%.

Background-Toll-like receptor (TLR)-

AimsThe Genous™ Bio-engineered R™ stent (GS) aims to promote vascular healing by capture of circulatory endothelial progenitor cells (EPCs) to the surface of the stent struts, resulting in accelerated re-endothelialization. Here, we assessed the function of the GS in comparison to bare-metal stent (BMS), when exposed to the human and animal circulation.Methods and resultsFirst, 15 patients undergoing coronary angiography received an extracorporeal femoral arteriovenous (AV) shunt containing BMS and GS. Macroscopical mural thrombi were observed in BMS, whereas GS remained visibly clean. Confocal and scanning electron microscopic (SEM) analysis of GS showed an increase in strut coverage. Quantitative polymerase chain reaction (qPCR) analysis of captured cells on the GS demonstrated increased expression of endothelial markers KDR/VEGFR2 and E-selectin, and a decrease in pro-thrombogenic markers tissue factor pathway inhibitor and plasminogen activator inhibitor-1 compared with BMS. Secondly, a similar primate AV shunt model was used to validate these findings and occlusion of BMS was observed, while GS remained patent, as demonstrated by live imaging of indium-labelled platelets. Thirdly, in an in vitro cell-capture assay, GS struts showed increased coverage by EPCs, whereas monocyte coverage remained similar to BMS. Finally, the assessment of re-endothelialization was studied in a rabbit denudation model. Twenty animals received BMS and GS in the aorta and iliac arteries for 7 days. Scanning electron microscopic analysis showed a trend towards increased strut coverage, confirmed by qPCR analysis revealing increased levels of endothelial markers (Tie2, CD34, PCD31, and P-selectin) in GS.ConclusionIn this proof-of-concept study, we have demonstrated that the bio-engineered EPC-capture stent, Genous™ R™ stent, is effective in EPC capture, resulting in accelerated re-endothelialization and reduced thrombogenicity.

R egenerative stem cell therapy to promote cardiac repair has been a target of interest in the past 10 years to prevent heart failure after an acute myocardial infarction (AMI). 1,2 Various different stem cells have been investigated for their ability to repair the heart.3 Mesenchymal stem cells (MSCs) seem to be a potent candidate to date. The mechanism of action of MSC is primarily based on the release of paracrine factors to the myocardium. 4 However, retention and survival of stem cells in the myocardium after intracoronary infusion remains an issue in cell-based therapy, because only a limited number of surviving stem cells remain in the myocardium, thereby limiting the potential benefit of the therapy. [5][6][7] CellBeads, which consist of alginate-encapsulated MSCs (eMSCs; BTG International Germany GmbH, Alzenau, Germany), were developed to improve survival of cells in the myocardium, thereby elongating the release of cardioprotective proteins into the infarcted myocardium. These eMSCs secrete endogenous paracrine factors that include vascular endothelial growth factor, monocyte chemotactic protein-1, interleukin (IL)-6, IL-8, glial-derived neurotrophic factor, and neurotrophin-3 and are genetically modified to produce glucagon-like peptide-1 (GLP-1) fusion protein, which comprises 2 GLP-1 molecules bound by an intervening peptide, extending its half-life in vivo. [8][9][10][11][12] Among its beneficial effectsBackground-Engraftment and survival of stem cells in the infarcted myocardium remain problematic in cell-based therapy for cardiovascular disease. To overcome these issues, encapsulated mesenchymal stem cells (eMSCs) were developed that were transfected to produce glucagon-like peptide-1, an incretin hormone with known cardioprotective effects, alongside MSC endogenous paracrine factors. This study was designed to investigate the efficacy of different doses of intracoronary infusion of eMSC in a porcine model of acute myocardial infarction (AMI). Methods and Results-One hundred pigs were subjected to a moderate AMI (posterolateral AMI; n=50) or a severe AMI (anterior AMI; n=50), whereupon surviving animals (n=36 moderate, n=33 severe) were randomized to receive either intracoronary infusion of 3 incremental doses of eMSC or Ringers' lactate control. Cardiac function was assessed using invasive hemodynamics, echocardiography, and histological analysis. A trend was observed in the moderate AMI model, whereas in the severe AMI model, left ventricular ejection fraction improved by +9.3% (P=0.004) in the best responding eMSC group, because of a preservation of left ventricular end-systolic volume. Arteriolar density increased 3-fold in the infarct area (8.4±0.9/mm 2 in controls versus 22.2±2.6/mm 2 in eMSC group; P<0.001). Although not statistically significant, capillary density was 30% higher in the border zone (908.1±99.7/mm 2 in control versus 1209.0±64.6/mm 2 in eMSC group; P=ns). Conclusions-eMSCs enable sustained local delivery of cardioprotective proteins to the heart, thereby enhancing angio...