Objectives-Recent clinical trials use cell therapy with bone marrow (BM) cells or endothelial progenitor cells (EPCs) for ischemic syndromes. We explored the effect of BM cell-or spleen cell-derived EPC transfer on plaque size and stability markers in the apolipoprotein E knockout (apoE KO) mouse model. Methods and Results-ApoE KO mice aged 10 weeks served as recipients. Labeled BM cells and spleen cell-derivedEPCs from age-matched apoE KO mice were injected intravenously to 2 groups of recipient mice each. Additional mice served as controls receiving saline. Both protocols were repeated 3 times at 2 weekly intervals. On killing, plaque size and character were studied, lipid profile analyzed, and serum and aortic cytokines assayed. Spleen cell-derived cells contained a significantly larger number of endothelial cell precursors. Labeled EPCs and BM cells were found abundantly in the spleens, yet also in the lesions of the recipient mice. Aortic sinus lesion size was significantly increased in mice receiving BM cells (nϭ10) in the EPC-treated group (nϭ10) compared with controls (nϭ10; a 54% and a 34% increase in aortic sinus plaque area, respectively). Mice receiving EPCs exhibited plaques with larger lipid cores and thinner fibrous caps and a higher number of infiltrating CD3 cells. RT-PCR analysis of aortas revealed reduced expression of mRNA for interleukin-10 (IL-10) in both cell transfer groups. Higher serum concentrations of IL-6 and monocyte chemoattractant protein-1 were found in sera from BM recipients, whereas lower IL-10 levels were found in mice transfused with spleen-derived EPCs. 1 It is probable that factors that govern the initiation of atherosclerosis, which involves less complex cellular crosstalk, are not identical to determinants of plaque progression, in which additional matrix components and cell types are prevalent. 2 In both these processes, ECs have been proposed to play a major role forming the attachment surface on which monocytes role and adhere. ECs participate in the early fatty streak formation and in constituting the vasa vasorum network that acts to supply the inner growing neointima in more advanced lesions. These actions are regulated by expression of a set of adhesion molecules on the EC surface and by synthesis and secretion of regulatory humoral factors. 1,2 Apparently, confounding data have been provided with regard to the effect of EC on plaque progression and phenotype. Atherosclerosis is a disorder with endothelial dysfunction, and it is thus conceivable that replenishment of ECs would result in attenuated EC activation with consequent inflammation. These findings are supported by a study by Rauscher et al 3 showing that transfer of bone marrow (BM) cells from young apolipoprotein E knockout (apoE KO) mice reduces atherosclerotic plaque size. However, it appears that the angiogenesis inhibitor TNP-470 and angiostatin acting to inhibit plaque neovascularization were found to suppress atherosclerotic lesion development, 4,5 whereas vascular endothelial growth factor promote...

OBJECTIVES We evaluated the association between pericardial fat and myocardial ischemia for risk stratification. BACK GROUND Pericardial fat volume (PFV) and thoracic fat volume (TFV) measured from noncontrast computed tomography (CT) performed for calculating coronary calcium score (CCS) are associated with increased CCS and risk for major adverse cardiovascular events. METHODS From a cohort of 1,777 consecutive patients without previously known coronary artery disease (CAD) with noncontrast CT performed within 6 months of single photon emission computed tomography (SPECT), we compared 73 patients with ischemia by SPECT (cases) with 146 patients with normal SPECT (controls) matched by age, gender, CCS category, and symptoms and risk factors for CAD. TFV was automatically measured. Pericardial contours were manually defined within which fat voxels were automatically identified to compute PFV. Computer-assisted visual interpretation of SPECT was performed using standard 17-segment and 5-point score model; perfusion defect was quantified as summed stress score (SSS) and summed rest score (SRS). Ischemia was defined by: SSS – SRS ≥4. Independent relationships of PFV and TFV to ischemia were examined. RESULTS Cases had higher mean PFV (99.1 ± 42.9 cm3 vs. 80.1 ± 31.8 cm3, p = 0.0003) and TFV (196.1 ± 82.7 cm3 vs. 160.8 ± 72.1 cm3, p = 0.001) and higher frequencies of PFV >125 cm3 (22% vs. 8%, p = 0.004) and TFV >200 cm3 (40% vs. 19%, p = 0.001) than controls. After adjustment for CCS, PFV and TFV remained the strongest predictors of ischemia (odds ratio [OR]: 2.91, 95% confidence interval [CI]: 1.53 to 5.52, p = 0.001 for each doubling of PFV; OR: 2.64, 95% CI: 1.48 to 4.72, p = 0.001 for TFV. Receiver operating characteristic analysis showed that prediction of ischemia, as indicated by receiver-operator characteristic area under the curve, improved significantly when PFV or TFV was added to CCS (0.75 vs. 0.68, p = 0.04 for both). CONCLUSIONS Pericardial fat was significantly associated with myocardial ischemia in patients without known CAD and may help improve risk assessment.

The number and properties of endothelial progenitor cells (EPC) in disease states is of considerable interest due to the importance attributed to this distinct cell population. However, there has been no study comparing each of the methods employed in the same sampled individuals. Herein, we performed an analysis of several methods used for circulating EPC assessment and correlated them with humoral factors known to influence their numbers. Thirty-eight individuals (mean age of 34 +/- 9 years) were tested. Peripheral blood mononuclear cells were obtained and stained for FACS analysis with antibodies to CD34, CD45, CD133, and KDR and the remaining cells grown under endothelial cell conditions for assessment of colony-forming unit (CFU) numbers and adhesive properties. Levels of circulating vascular endothelial growth factor (VEGF), erythropoietin (EPO), and C-reactive protein (CRP) were determined and correlated with each of the EPC markers. CFU numbers did not correlate with CD34/KDR or CD34/CD133/KDR and negatively correlated with CD34/ CD133 numbers. CD34/KDR numbers correlated with CD34/CD133/KDR, but not with CD34/ CD133. Only CD34/KDR and CD34/CD133/KDR correlated with VEGF serum levels. The number of EPC adhering to fibronectin and endothelial cells correlated with CFU numbers and not with either of the EPC membrane markers. Current methods for quantitatively assessing numbers of circulating EPC are not correlated. VEGF serum levels are associated only with CD34/KDR and CD34/ CD133/KDR, whereas CFU numbers correlate with EPC functional properties. These findings may suggest that CD34/KDR is more appropriate for the definition of circulating EPC, whereas CFU numbers are more likely to reflect their ability to proliferate.

Chronic Epo treatment is associated with an increase in the adhesive and proliferative properties of circulating EPC in patients with CHF.

No abstract

If confirmed in large-scale clinical studies, determination of circulating EPO levels may aid in predicting morbidity and mortality in patients with clinically controlled congestive CHF.

No abstract

No abstract