Background-Pulmonary hypertension (PH) is a life-threatening disease. Bone marrow cell transplantation is reported to reduce the development of PH by increasing vascular beds in pulmonary circulation. However, adenoviral overexpression of endothelial nitric oxide synthase (eNOS) in the lung is also known to reduce PH. Because mesenchymal stem cells (MSCs) are potential cell sources for neovascularization, the implantation of MSCs overexpressing eNOS (MSCs/eNOS) may further improve the surgical results. We evaluated the efficacy of MSCs/eNOS implantation in monocrotaline (MCT)-induced PH rats. Methods and Results-MSCs were isolated from rat bone marrow. PH was induced in rats by subcutaneous injection of MCT. One week after MCT administration, the rats received 3 different treatments: MSCs (MSC group), MSCs/eNOS (MSC/eNOS group), or nontreatment (PH group). As the negative control, rats received saline instead of MCT (control group). Right ventricular (RV) hypertrophy and the elevation of RV systolic pressure (RVSP) were evaluated 3 weeks after MCT administration. Moreover, the effects of MSCs/eNOS on survival were investigated in PH induced by MCT 3 weeks earlier. RVSP in both the MSC and MSC/eNOS groups was significantly lower than the PH group. RVSP in the MSC/eNOS group was significantly lower than the MSC group. The RV weight to body weight ratio was significantly lower in the MSC and MSC/eNOS groups than the PH group. The survival time of rats receiving MSCs/eNOS was significantly longer than the nontreatment rats. Conclusion-Intravenous

NSE and tau are better associated with NCD and less influenced by cardiotomy suction compared with S-100beta. Inflammatory and oxidative stress is associated with NCD post-CPB.

Background-Ischemic heart disease is the most common cause of mortality in diabetic patients. Although therapeutic angiogenesis is an attractive option for these patients, they appear to have reduced collateral formation in response to myocardial ischemia. The aims of this study were to establish a large animal model of diabetes and chronic myocardial ischemia, evaluate the effects of diabetes on the angiogenic response, and elucidate the molecular pathways involved. Methods and Results-Diabetes was induced in male Yucatan miniswine using a pancreatic ␤-cell specific toxin, alloxan (150 mg/kg; nϭ8). Age-matched swine served as controls (nϭ8). Eight weeks after induction, chronic ischemia was induced by ameroid constrictor placement around the circumflex coronary artery. Myocardial perfusion and function were assessed at 3 and 7 weeks after ameroid placement using isotope-labeled microspheres. Endothelial cell density and myocardial expression of angiogenic mediators was evaluated. Diabetic animals exhibited significant endothelial dysfunction. Collateral dependent perfusion and LV function were significantly impaired in diabetic animals. Diabetic animals also demonstrated reduced endothelial cell density (173Ϯ14 versus 234Ϯ23 cells/hpf, Pϭ0.03). Expression of VEGF, Ang-1, and Tie-2 was reduced, whereas antiangiogenic proteins, angiostatin (4.4Ϯ0.9-fold increase, PϽ0.001), and endostatin (2.9Ϯ0.4-fold increase, Pϭ0.03) were significantly elevated in the diabetic myocardium. Conclusions-Diabetes

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Background-Although 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) can restore endothelial function in coronary disease, in vitro and murine studies have shown their effects on myocardial angiogenesis to be biphasic and dose dependent. We investigated the functional and molecular effects of high-dose atorvastatin on the endogenous angiogenic response to chronic myocardial ischemia in hypercholesterolemic swine. Methods and Results-Yucatan pigs were fed either a normal (NORM group; nϭ7) or high-cholesterol diet, with (CHOL-ATR group; nϭ7) or without (CHOL group; nϭ6) atorvastatin (3 mg/kg per day) for 13 weeks. Chronic ischemia was induced by ameroid constrictor placement around the circumflex artery.

Background— Cardioplegic arrest (CA) using cold blood cardioplegia (CBC) has been reported to reduce ischemia-reperfusion (IR)-induced myocardial injury via apoptosis. We studied key apoptotic mediators via the caspase-dependent and intrinsic pathways as well as poly(ADP)-ribosylating protein (PARP) activity in myocardial and peripheral tissues after CA and cardiopulmonary bypass (CBP). Methods and Results— Right atrial (RA) and skeletal muscle(SM) was harvested from cardiac surgical patients with similar baseline characteristics (N =6) before and after CPB and CBC. Total and modified caspase-3, Bcl-2, Bad, apoptosis-inducing factor (AIF), and PARP were quantified by immunoblotting. Terminal caspase-3 activity was assessed and immunohistochemistry was performed for PARP and AIF. TUNEL staining was used for identification of apoptotic cells. Microarray gene expression analysis was performed using Affymetrix U95 GeneChip. In RA tissue, CA with CBC significantly increased phosphorylation of Bcl-2 (Ser 70 ), Bad (Ser 112 ) (2.63±0.4 and 1.77±0.3-fold respectively; P <0.05), and cleavage of the downstream caspase 3 (1.45±0.1-fold; P <0.05). There was no significant change in total protein levels. Also, there was an increase in mature AIF (57 kDa) levels (1.22±0.01-fold; P <0.05) and a trend toward nuclear translocation on histological staining. Caspase 3 activity was increased 1.5±0.14-fold ( P <0.05). The number of apoptotic cells in atrial tissue increased after compared with before CPB/CA using TUNEL staining (1.55±0.66 versus 0.325±0.05%, respectively; P =0.03). In contrast, SM samples did not show any of the changes observed in RA tissue after CPB. Conclusion— Despite optimal current surgical myocardial protection, we found that CA with CBC induced both programmed cell death and survival signaling in myocardial tissue.