Combinatorial G-CSF/AMD3100 treatment in cardiac repair after myocardial infarction.

Several studies suggest that circulating bone marrow derived stem cells promote the regeneration of ischemic tissues. For hematopoietic stem cell transplantation combinatorial granulocyte-colony stimulating factor (G-CSF)/Plerixafor (AMD3100) administration was shown to enhance mobilization of bone marrow derived stem cells compared to G-CSF monotherapy. Here we tested the hypothesis whether combinatorial G-CSF/AMD3100 therapy has beneficial effects in cardiac recovery in a mouse model of myocardial infarction.We analyzed the effect of single G-CSF (250 µg/kg/day) and combinatorial G-CSF/AMD3100 (100 µg/kg/day) treatment on cardiac morphology, vascularization, and hemodynamics 28 days after permanent ligation of the left anterior descending artery (LAD). G-CSF treatment started directly after induction of myocardial infarction (MI) for 3 consecutive days followed by a single AMD3100 application on day three after MI in the G-CSF/AMD3100 group. Cell mobilization was assessed by flow cytometry of blood samples drawn from tail vein on day 0, 7, and 14.Peripheral blood analysis 7 days after MI showed enhanced mobilization of white blood cells (WBC) and endothelial progenitor cells (EPC) upon G-CSF and combinatorial G-CSF/AMD3100 treatment. However, single or combinatorial treatment showed no improvement in survival, left ventricular function, and infarction size compared to the saline treated control group 28 days after MI. Furthermore, no differences in histology and vascularization of infarcted hearts could be observed.Although the implemented treatment regimen caused no adverse effects, our data show that combinatorial G-CSF/AMD therapy does not promote myocardial regeneration after permanent LAD occlusion

Influence of fibre diameter and orientation of electrospun copolyetheresterurethanes on smooth muscle and endothelial cell behaviour

Polymers exhibiting cell-selective effects represent an extensive research field with high relevance for biomedical applications e.g. in the cardiovascular field supporting re-endothelialization while suppressing smooth muscle cell overgrowth. Such an endothelial cell-selective effect could be recently demonstrated for a copolyetheresterurethane (PDC) containing biodegradable poly(p-dioxanone) and poly(epsilon-caprolactone) segments, which selectively enhanced the adhesion of human umbilical vein endothelial cells (HUVEC) while suppressing the attachment of smooth muscle cells (SMC). In this study we investigated the influence of the fibre orientation (random and aligned) and fibre diameter (2 mu m and 500 nm) of electrospun PDC scaffolds on the adhesion, proliferation and apoptosis of HUVEC and SMC. Adhesion, viability and proliferation of HUVEC was diminished when the fibre diameter was reduced to a submicron scale, while the orientation of the microfibres did only slightly influence the cellular behaviour. In contrast, a submicron fibre diameter improved SMC viability. In conclusion, PDC scaffolds with micron-sized single fibres could be promising candidate materials for cell-selective stent coatings

Cumulative Kaplan-Meier survival analysis.

<p>Kaplan-Meier survival curve of control MI and drug-treated mice during the observation period of 28 days after MI. Treatment of mice with G-CSF or G-CSF/AMD did not improve the (<b>A</b>) overall survival and did not alter (<b>B</b>) the mortality of mice that survived the first 4 days after MI.</p

Cardiac histology of infarcted hearts 28 days after MI.

<p>Overview of Masson trichrome stained heart section <b>(upper panel)</b> and higher magnification images <b>(lower panels)</b> of border zone (BZ), infarcted region (IF) and remote area (RA). Images show no evident alteration of collagen deposition in designated areas between treatment groups. Bar: 100 µm.</p

TTC and Masson trichrome staining of infarcted cardiac tissue for assessment of infarction size and fibrosis.

<p>Infarction size expressed as percentage of left ventricular area of control MI and drug treated mice assessed by TTC (<b>A, B</b>) and Masson trichrome (<b>C</b>) staining 28 days after MI. (<b>D, E</b>) Masson trichrome staining of sequential heart sections of control MI, G-CSF and G-CSF/AMD treated mice reveals no difference in left ventricular dilation, infarction size and fibrosis.</p

A Randomized, Double-Blind, Placebo-Controlled Trial on Restenosis Prevention by the Receptor Tyrosine Kinase Inhibitor Imatinib

ObjectivesThe aim of the present double-blind, placebo-controlled study was to evaluate the efficacy of a systemic imatinib treatment, a potent platelet-derived growth factor (PDGF) receptor kinase inhibitor, for the prevention of recurrent restenosis in patients with in-stent restenosis (ISR).BackgroundNeointima proliferation after stent placement has been associated with the effect of potent mitogenes such as PDGF, and their inhibition has resulted in reduction of neointima formation in experimental models.MethodsA total of 180 patients with either symptoms or a positive stress test in the presence of angiographically signficiant ISR were randomly assigned to two treatment arms: imatinib treatment or placebo. Patients received imatinib (600 mg/day) for 10 days starting 2 days before repeat intervention. Angiographic restenosis at follow-up angiography was the primary end point of the study.ResultsRepeat angiography was performed in 160 of 180 patients (88.9%). The combined rate of death or MI at one year was 1.0% in patients randomized to either group (p = 0.67). Compared with the placebo group, imatinib treatment did not affect the angiographic restenosis rate (38.8% with imatinib vs. 41.3% with placebo; p = 0.75). Similarily, the need for target lesion revascularization did not differ between both groups (28.1% with imatinib vs. 28.6% with placebo; p = 0.94).ConclusionsSystemic imatinib therapy does not affect the risk of recurrence in patients with ISR

Left ventricular hemodynamics recorded by pressure-volume catheterization in the closed chest 28 days after LAD ligation.

<p>Values are means ± SEM. HR, heart rate; EF, ejection fraction; SW, stroke work; dP/dt max, maximum first derivative of change in pressure rise with respect to time; dP/dt min, maximum first derivative of change in pressure fall with respect to time; SV, Stroke volume; CO, cardiac output; Ves, end-systolic volume; Ved, end-diastolic volume; One-way ANOVA post hoc Tukey's Multiple Comparison Test # p<0.05 vs. sham; no significant differences vs. control MI.</p