No abstract

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...