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Aims: The study assessed 4-year outcomes of intramyocardial injections of autologous bone marrow-derived mesenchymal stromal cells (MSCs) in patients with ischaemic heart failure.Methods and Results: The MSC-HF trial was a randomized, double-blind, placebo-controlled trial. Patients were randomized 2:1 to intramyocardial injections of MSCs or placebo. The primary endpoint was change in left ventricular end-systolic volume (LVESV), measured by magnetic resonance imaging or computed tomography. Sixty patients aged 30-80 years with ischaemic heart failure, New York Heart Association class II-III, left ventricular ejection fraction (LVEF) <45% and no further treatment options were randomized. Patients were followed clinically for 12 months and in addition 4-year data of hospitalizations and survival were retrieved. After 12 months, LVESV was significantly reduced in the MSC group and not in the placebo group, with difference between groups of 17.0 ± 16.2 mL (95% confidence interval 8.3-25.7, P = 0.0002). There were also significant improvements in LVEF of 6.2% (P < 0.0001), stroke volume of 16.1 mL (P < 0.0001) and myocardial mass (P = 0.009) between groups. A significant dose-response effect was also observed. Moreover, a significant reduction in the amount of scar tissue and quality of life score in the MSC group but not in the placebo group was observed. After 4 years, there were significantly fewer hospitalizations for angina in the MSC group and otherwise no differences in hospitalizations or survival. No side effects were identified.Conclusions: Intramyocardial injections of autologous bone marrow-derived MSCs improved myocardial function and myocardial mass in patients with ischaemic heart failure. [ABSTRACT FROM AUTHOR]

A matched cohort study was conducted comparing patients with first-time acute coronary syndromes infected with human immunodeficiency virus (HIV) to non-HIV-infected patients with and without diabetes matched for smoking, gender, and type of acute coronary syndrome who underwent first-time coronary angiography. A total of 48 HIV-infected patients were identified from a national database. Coronary angiography showed that the HIV-infected patients had significantly fewer lesions with classification B2/C than the 2 control groups (p <0.001) but the same extent of multivessel disease. The HIV-infected patients were a decade younger than the non-HIV-infected controls and had significantly higher concentrations of total cholesterol (6.3 vs 4.8 and 4.5 mmol/L, p <0.0001), low-density lipoprotein (4.0 vs 2.9 and 2.5 mmol/L, p <0.001), and triglycerides (2.8 vs 1.0 and 1.4 mmol/ L, p <0.01) compared to the nondiabetic and diabetic non-HIV-infected groups, respectively. In conclusion, HIV-infected patients with first-time acute coronary syndromes have fewer complex lesions than non-HIV-infected patients. This finding supports the idea that the pathogenesis of atherosclerotic disease in HIV patients is different from that in the general population. [ABSTRACT FROM AUTHOR]

Background. YKL-40 is a glycoprotein secreted by macrophages and neutrophils in tissues with inflammation. Plasma YKL-40 is increased in patients with coronary artery disease (CAD) and associated with cardiovascular and all-cause mortality. Furthermore, plasma YKL-40 seems related to the number of diseased main vessels in patients with stable CAD. The aim was to further study the relation between YKL-40 and stenosis degree, stenosis type and actual ischemia in stable CAD patients. Methods. Plasma YKL-40 and hsCRP levels were determined from 206 consecutive patients with stable angina pectoris admitted for coronary angiography. Plasma YKL-40 in 245 healthy subjects was used for comparison. In addition to one to three vessel stenosis scores, two new scores for evaluating coronary angiographies were established for discriminating between focal and diffuse CAD and the extent of myocardial ischemia. Results. YKL-40 levels in CAD patients (median: 52 μg/L and quartiles: 37-85 μg/L) were significantly increased ( p < 0.001) compared to the healthy controls. In univariate analyses plasma YKL-40 was significantly associated with ischemic myocardium score, age, hypertension, peripheral vascular disease and serum creatinine levels. In multivariate analyses YKL-40 was related to hsCRP, peripheral artery disease, hypertension, and statin treatment. Conclusions. Plasma YKL-40 was increased in patients with CAD compared to controls. YKL-40 was related to the ischemic myocardium, but not to degree of CAD using different scoring systems. Therefore, YKL-40 is not related to the extent of CAD, but to some other pathophysiological mechanisms of importance for the prognosis. [ABSTRACT FROM AUTHOR]

Background. Patients with stable coronary artery disease (CAD) have a poor prognosis. The aim of the study was to evaluate the extent to which serum high-sensitivity C-reactive protein (hs-CRP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurement alone or together could be prognostic biomarkers in patients with stable CAD. Materials and methods. During the 2.6-year follow-up period 270 patients among the 4264 patients with stable CAD in the CLARICOR trial suffered myocardial infarction (MI) and 377 died (187 cardiovascular deaths (CVD)). Results. Serum NT-proBNP was significantly associated with MI (hazard ratio (HR), 1. 65 (refers to a 2.72 fold increase in serum level, p = 0.0005), CVD (HR, 2.42, p < 0.0005) and non-CVD (HR, 1.79, p < 0.0005). When correcting for hs-CRP, NT-proBNP was still significantly associated with MI (HR, 1.63, p = 0.0005), CVD (HR, 2.36, p < 0.0005) and non-CVD (HR, 1.66, p < 0.0005). Serum hs-CRP was compared to NT-proBNP less associated with MI (HR, 1.20, p = 0.001), CVD (HR, 1.39, p < 0.0005) and non-CVD (HR, 1.67, p < 0.0005). When corrected for NT-proBNP, hs-CRP was only associated with non-CVD (HR, 1.51, p < 0.0005). When adjusting for cardiovascular risk factors hs-CRP predicted non-CVD (HR, 1.46) and all-cause death (HR, 1.24) and NT-proBNP predicted MI (HR, 1.50), CVD (HR, 1.98), non-CVD (HR, 1.39), and all-cause death (HR, 1.62)( p < 0.0005 for all). Conclusion. Increased serum NT-proBNP was a stronger predictor of MI, cardiovascular death and non-cardiovascular death than hs-CRP in patients with stable CAD. Once NT-proBNP was taken into account, hs-CRP did not improve predictions. [ABSTRACT FROM AUTHOR]

Background. Platelet lysates (PL) represent a promising replacement for xenogenic growth supplement for adipose-derived stem cell (ASC) expansions. However, fresh platelets from human blood donors are not clinically feasible for large-scale cell expansion based on their limited supply. Therefore, we tested PLs prepared via three methods from outdated buffy coat-derived platelet concentrates (PCs) to establish an efficient and feasible expansion of ASCs for clinical use. Methods. PLs were prepared by the freeze-thaw method from freshly drawn platelets or from outdated buffy coat-derived PCs stored in the platelet additive solution, InterSol. Three types of PLs were prepared from outdated PCs with platelets suspended in either (1) InterSol (not manipulated), (2) InterSol + supplemented with plasma or (3) plasma alone (InterSol removed). Using these PLs, we compared ASC population doubling time, cell yield, differentiation potential and cell surface markers. Gene expression profiles were analyzed using microarray assays, and growth factor concentrations in the cell culture medium were measured using enzyme-linked immunosorbent assay (ELISA). Results. Of the three PL compositions produced from outdated PCs, removal of Intersol and resuspension in plasma prior to the first freezing process was overall the best. This specific outdated PL induced ASC growth kinetics, surface markers, plastic adherence and differentiation potentials comparable with PL from fresh platelets. ASCs expanded in PL from fresh versus outdated PCs exhibited different expressions of 17 overlapping genes, of which 10 were involved in cellular proliferation, although not significantly reflected by cell growth. Only minor differences in growth factor turnover were observed. Conclusion. PLs from outdated platelets may be an efficient and reliable source of human growth supplement allowing for large-scale ASC expansion for clinical use. [ABSTRACT FROM AUTHOR]

Introduction. To evaluate survival and engraftment of mesenchymal stromal cells (MSCs) in vivo, it is necessary to track implanted cells non-invasively with a method, which does not influence cellular ultrastructure and functional characteristics. Iron-oxide particles have been applied for cell tracking for years, but knowledge regarding possible cytotoxic ultrastructural changes subsequent to iron-oxide particle labeling is limited. Hence, the purpose of this study was to label MSCs with dextran-coated ultrasmall super-paramagnetic iron-oxide (USPIO) particles conjugated with the transduction sequence of trans-activator of transcription (TAT) (IODEX-TAT) and evaluate the effect of labeling on ultrastructure, viability, phenotype and proliferative capacity of the cells. Materials and methods. MSCs were labeled with 5 and 10 µg IODEX-TAT/105 cells for 2, 6 and 21 hours. IODEX-TAT uptake and cellular ultrastructure were determined by electron microscopy. Cell viability was determined by propidium iodide staining and cell proliferation capacity by 5-bromo-2-deoxyuridine (BrdU) incorporation. Maintenance of stem cell surface markers was determined by flow cytometry. Results. IODEX-TAT labeling for 2, 6 and 21 h did not influence cellular ultrastructure or viability. Moreover, neither stem cell surface markers nor cell proliferation capacity was affected by labeling with IODEX-TAT. Conclusion. Our results demonstrate that labeling of MSCs for 21 h with a clinically relevant dose of 10 µg IODEXTAT/105 cells is feasible and does not affect MSC ultrastructure, viability, phenotype or proliferation capacity. [ABSTRACT FROM AUTHOR]

Aims. We evaluated the feasibility, safety and efficacy of intra-myocardial injection of autologous mesenchymal stromal cells derived endothelial progenitor cell (MSC) in patients with stable coronary artery disease (CAD) and refractory angina in this first in man trial. Methods and results. A total of 31 patients with stable CAD, moderate to severe angina and no further revascularization options, were included. Bone marrow MSC were isolated and culture expanded for 6--8 weeks. It was feasible and safe to establish in-hospital culture expansion of autologous MSC and perform intra-myocardial injection of MSC. After six months follow-up myocardial perfusion was unaltered, but the patients increased exercise capacity (p < 0.001), reduction in CCS Class (p < 0.001), angina attacks (p < 0.001) and nitroglycerin consumption (p < 0.001), and improved Seattle Angina Questionnaire (SAQ) evaluations (p < 0.001). For all parameters there was a tendency towards improved outcome with increasing numbers of cells injected. In the MRI substudy: ejection fraction (p < 0.001), systolic wall thickness (p == 0.03) and wall thickening (p == 0.03) all improved. Conclusions. The study demonstrated that it was safe to treat patients with stable CAD with autologous culture expanded MSC. Moreover, MSC treated patients had significant improvement in left ventricular function and exercise capacity, in addition to an improvement in clinical symptoms and SAQ evaluations. [ABSTRACT FROM AUTHOR]

An abstract of the paper "Myocardium Area at Risk Measured With Delayed Enhancement After Scar Remodelling Compared With T2-Weighted Cardiac Magnetic Resonance Imaging," by Niels Vejlstrup and colleagues is presented.

Abstract: Introduction: Aim was to compare absolute myocardial perfusion using cardiac magnetic resonance imaging (CMRI) based on Tikhonov's procedure of deconvolution and rubidium-82 positron emission tomography (Rb-82 PET). Materials and methods: Fourteen patients with coronary artery stenosis underwent rest and adenosine stress imaging by 1.5-Tesla MR Scanner and a mCT/PET 64-slice Scanner. CMRI were analyzed based on Tikhonov's procedure of deconvolution without specifying an explicit compartment model using our own software. PET images were analyzed using standard clinical software. CMRI and PET data was compared with Spearman's rho and Bland–Altman analysis. Results: CMRI results were strongly and significantly correlated with PET results for the absolute global myocardial perfusion differences (r =0.805, p =0.001) and for global myocardial perfusion reserve (MPR) (r =0.886, p <0.001). At vessel territorial level, CMRI results were also significantly correlated with absolute PET myocardial perfusion differences (r =0.737, p <0.001) and MPR (r =0.818, p <0.001). Each vessel territory had similar strong correlation for absolute myocardial perfusion differences (right coronary artery (RCA): r =0.787, p =0.001; left anterior descending artery (LAD): r =0.796, p =0.001; left circumflex artery (LCX): r =0.880, p <0.001) and for MPR (RCA: r =0.895, p <0.001; LAD: r =0.886, p <0.001; LCX: r =0.886, p <0.001). Conclusion: On a global and vessel territorial basis, CMRI-measured absolute myocardial perfusion differences and MPR were strongly and significantly correlated with the Rb-82 PET findings. [Copyright &y& Elsevier]