Background-Red blood cell transfusion can both benefit and harm. To inform decisions about transfusion, we aimed to quantify associations of transfusion with clinical outcomes and cost in patients having cardiac surgery. Methods and Results-Clinical, hematology, and blood transfusion databases were linked with the UK population register.Additional hematocrit information was obtained from intensive care unit charts. Composite infection (respiratory or wound infection or septicemia) and ischemic outcomes (myocardial infarction, stroke, renal impairment, or failure) were prespecified as coprimary end points. Secondary outcomes were resource use, cost, and survival. Associations were estimated by regression modeling with adjustment for potential confounding.

BACKGROUNDWhether a restrictive threshold for hemoglobin level in red-cell transfusions, as compared with a liberal threshold, reduces postoperative morbidity and health care costs after cardiac surgery is uncertain. METHODSWe conducted a multicenter, parallel-group trial in which patients older than 16 years of age who were undergoing nonemergency cardiac surgery were recruited from 17 centers in the United Kingdom. Patients with a postoperative hemoglobin level of less than 9 g per deciliter were randomly assigned to a restrictive transfusion threshold (hemoglobin level <7.5 g per deciliter) or a liberal transfusion threshold (hemoglobin level <9 g per deciliter). The primary outcome was a serious infection (sepsis or wound infection) or an ischemic event (permanent stroke [confirmation on brain imaging and deficit in motor, sensory, or coordination functions], myocardial infarction, infarction of the gut, or acute kidney injury) within 3 months after randomization. Health care costs, excluding the index surgery, were estimated from the day of surgery to 3 months after surgery. RESULTSA total of 2007 patients underwent randomization; 4 participants withdrew, leaving 1000 in the restrictive-threshold group and 1003 in the liberal-threshold group. Transfusion rates after randomization were 53.4% and 92.2% in the two groups, respectively. The primary outcome occurred in 35.1% of the patients in the restrictive-threshold group and 33.0% of the patients in the liberal-threshold group (odds ratio, 1.11; 95% confidence interval [CI], 0.91 to 1.34; P = 0.30); there was no indication of heterogeneity according to subgroup. There were more deaths in the restrictive-threshold group than in the liberal-threshold group (4.2% vs. 2.6%; hazard ratio, 1.64; 95% CI, 1.00 to 2.67; P = 0.045). Serious postoperative complications, excluding primary-outcome events, occurred in 35.7% of participants in the restrictive-threshold group and 34.2% of participants in the liberal-threshold group. Total costs did not differ significantly between the groups. CONCLUSIONSA restrictive transfusion threshold after cardiac surgery was not superior to a liberal threshold with respect to morbidity or health care costs.

Background-Clinical trials in ischemic patients showed the safety and benefit of autologous bone marrow progenitor cell transplantation. Non-bone marrow progenitor cells with proangiogenic capacities have been described, yet they remain clinically unexploited owing to their scarcity, difficulty of access, and low ex vivo expansibility. We investigated the presence, antigenic profile, expansion capacity, and proangiogenic potential of progenitor cells from the saphenous vein of patients undergoing coronary artery bypass surgery. Methods and Results-CD34-positive cells, negative for the endothelial marker von Willebrand factor, were localized around adventitial vasa vasorum. After dissection of the vein from surrounding tissues and enzymatic digestion, CD34-positive/CD31-negative cells were isolated by selective culture, immunomagnetic beads, or fluorescence-assisted cell sorting. In the presence of serum, CD34-positive/CD31-negative cells gave rise to a highly proliferative population that expressed pericyte/mesenchymal antigens together with the stem cell marker Sox2 and showed clonogenic and multilineage differentiation capacities. We called this population "saphenous vein-derived progenitor cells" (SVPs). In culture, SVPs integrated into networks formed by endothelial cells and supported angiogenesis through paracrine mechanisms. Reciprocally, endothelial cell-released factors facilitated SVP migration. These interactive responses were inhibited by Tie-2 or platelet-derived growth factor-BB blockade. Intramuscular injection of SVPs in ischemic limbs of immunodeficient mice improved neovascularization and blood flow recovery. At 14 days after transplantation, proliferating SVPs were still detectable in the recipient muscles, where they established N-cadherin-mediated physical contact with the capillary endothelium. Conclusions-SVPs generated from human vein CD34-positive/CD31-negative progenitor cells might represent a new therapeutic tool for angiogenic therapy in ischemic patients. (Circulation. 2010;121:1735-1745.)Key Words: CD34 antigen Ⅲ pericytes Ⅲ angiogenesis factors Ⅲ ischemia Ⅲ cell therapy R ecent evidence indicating the presence of progenitor cells in arteries and veins has inspired hope for their application in regenerative vascular medicine. [1][2][3] In fetal and postnatal vessels, putative proangiogenic progenitors reside in the vasculogenic niche, which comprises adventitial stromal cells and mature vascular cells of the vasa vasorum. 3 We previously showed that CD34-positive (CD34 pos ) cells from the human fetal aorta coexpress stem cell markers such as CD133 and c-Kit, are clonogenic, and give rise to vascular cells and skeletal myocytes. 2 Local implantation of fetal aorta-derived CD34 pos /CD133-positive (CD133 pos ) cells promoted reparative neovascularization in models of ischemia and diabetic ulcers through incorporation into nascent vessels and paracrine stimulation of resident vascular cells. 2,4 Ethical concerns and immunogenic/tumorigenic problems limit the clinical use of embr...

Rationale: Pericytes are key regulators of vascular maturation, but their value for cardiac repair remains unknown. Objective: We investigated the therapeutic activity and mechanistic targets of saphenous vein-derived pericyte progenitor cells (SVPs) in a mouse myocardial infarction (MI) model. Methods and Results: SVPs have a low immunogenic profile and are resistant to hypoxia/starvation (H/S).Transplantation of SVPs into the peri-infarct zone of immunodeficient CD1/Foxn-1 nu/nu or immunocompetent CD1 mice attenuated left ventricular dilatation and improved ejection fraction compared to vehicle. Moreover, SVPs reduced myocardial scar, cardiomyocyte apoptosis and interstitial fibrosis, improved myocardial blood flow and neovascularization, and attenuated vascular permeability. SVPs secrete vascular endothelial growth factor A, angiopoietin-1, and chemokines and induce an endogenous angiocrine response by the host, through recruitment of vascular endothelial growth factor B expressing monocytes. The association of donor-and recipient-derived stimuli activates the proangiogenic and prosurvival Akt/eNOS/Bcl-2 signaling pathway. Moreover, microRNA-132 (miR-132) was constitutively expressed and secreted by SVPs and remarkably upregulated, together with its transcriptional activator cyclic AMP response element-binding protein, on stimulation by H/S or vascular endothelial growth factor B. We next investigated if SVP-secreted miR-132 acts as a paracrine activator of cardiac healing. In vitro studies showed that SVP conditioned medium stimulates endothelial tube formation and reduces myofibroblast differentiation, through inhibition of Ras-GTPase activating protein and methyl-CpG-binding protein 2, which are validated miR-132 targets. Furthermore, miR-132 inhibition by antimiR-132 decreased SVP capacity to improve contractility, reparative angiogenesis, and interstitial fibrosis in infarcted hearts. Key Words: pericytes-based cell therapy Ⅲ myocardial infarction Ⅲ angiogenesis Ⅲ VEGF-B Ⅲ microRNA-132 W ith myocardial infarction (MI) remaining a major cause of morbidity and mortality worldwide, cell therapy now aims to offer a novel option for cardiac repair. 1 Clinical trials showed that administration of bone marrowderived progenitor cells (PCs) improves left ventricular (LV) function in patients with coronary artery disease. 2-4 However, more specialized cells are warranted to fulfill specific regenerative needs of the ischemic myocardium. ConclusionPericytes provide the physical strength and nurturing signals that instruct neovessels to organize in a stable and efficient tubular network. 5 On the other hand, ischemic disease and associated risk factors may impair pericyte recruitment. 6 -8 Therefore, a supply-side approach with fresh pericytes from exogenous sources could be helpful therapeutically. However, difficulties in isolating and expanding bona-fide pericytes from accessible human tissues have so far precluded clinical applications.Two main mural cell populations, probably originating from a common emb...

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Propensity score (PS) methods offer certain advantages over more traditional regression methods to control for confounding by indication in observational studies. Although multivariable regression models adjust for confounders by modelling the relationship between covariates and outcome, the PS methods estimate the treatment effect by modelling the relationship between confounders and treatment assignment. Therefore, methods based on the PS are not limited by the number of events, and their use may be warranted when the number of confounders is large, or the number of outcomes is small. The PS is the probability for a subject to receive a treatment conditional on a set of baseline characteristics (confounders). The PS is commonly estimated using logistic regression, and it is used to match patients with similar distribution of confounders so that difference in outcomes gives unbiased estimate of treatment effect. This review summarizes basic concepts of the PS matching and provides guidance in implementing matching and other methods based on the PS, such as stratification, weighting and covariate adjustment.

As compared with the use of saphenous-vein grafts, the use of radial-artery grafts for CABG resulted in a lower rate of adverse cardiac events and a higher rate of patency at 5 years of follow-up. (Funded by Weill Cornell Medicine and others.).

Background-These studies examined the early time course of plaque development and destabilization in the brachiocephalic artery of the apolipoprotein E-knockout mouse, the effects of pravastatin thereon, and the effects of pravastatin on established unstable plaques. Methods and Results-Male apolipoprotein E-knockout mice were fed a high-fat, cholesterol-enriched diet from the age of 8 weeks. Animals were euthanized at 1-week intervals between 4 and 9 weeks of fat feeding. Acutely ruptured plaques were observed in the brachiocephalic arteries of 3% of animals up to and including 7 weeks of fat feeding but in 62% of animals after 8 weeks, which suggests that there is a sharp increase in the number of plaque ruptures at 8 weeks. These acute plaque ruptures then appear to heal and form buried fibrous caps; after 9 weeks of fat feeding, mice had 1.05Ϯ0.15 buried fibrous caps at a single site in the brachiocephalic artery. Pravastatin (40 mg/kg of body weight per day for 9 weeks; resultant plasma concentration 16Ϯ4 nmol/L) had no effect on plasma cholesterol concentration in fat-fed apolipoprotein E-knockout mice but reduced the number of buried fibrous caps by 43% (PϽ0.0001). In longer-term experiments, the delay of pravastatin treatment until unstable plaques had developed reduced the incidence of acute plaque rupture by 36% (PϽ0.0001). Conclusions-Plaque rupture occurs at high frequency in the brachiocephalic arteries of male apolipoprotein E-knockout mice after 8 weeks of fat feeding. Pravastatin treatment inhibits early plaque rupture and is also effective when begun after unstable plaques have developed.