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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2007.06.038 Byline: Rasmus Sejersten Ripa (a)(b), Jens Christian Nilsson (c), Yongzhong Wang (a), Lars SA[cedilla]ndergaard (a), Erik JA[cedilla]rgensen (a), Jens Kastrup (a) Abstract: Knowledge of the natural course after an ST-elevation myocardial infarction (STEMI) treated according to guidelines is limited because comprehensive serial magnetic resonance imaging (MRI) of systolic left ventricular function, edema, perfusion, and infarct size after STEMI has not been undertaken. The aim of this study was to evaluate effects of therapy for STEMI on left ventricular function and perfusion and to test the hypothesis that myocardial perfusion by MRI predicts recovery of left ventricular function. Author Affiliation: (a) Department of Cardiology, The Heart Centre, University Hospital Rigshospitalet, Copenhagen, Denmark (b) Department of Radiology, University Hospital Rigshospitalet, Copenhagen, Denmark (c) Danish Research Centre for Magnetic Resonance, University Hospital Hvidovre, Hvidovre, Denmark Article History: Received 29 March 2007; Accepted 27 June 2007 Article Note: (footnote) The STEMMI trial has been funded with grants from the Danish Heart Foundation (no. 0442B18-A1322141); Danish Stem Cell Research Doctoral School; Faculty of Health Sciences, Copenhagen University; Lundbeck Foundation; Raimond og Dagmar RinggA[yen]rd-Bohn's Fond; Aase og Ejnar Danielsens Fond; Erik og Martha Scheibels Legat; Fonden af 17.12.1981; and Arvid Nilssons Fond.

Abstract: Background: Granulocyte-colony stimulating factor (G-CSF) therapy after ST-elevation myocardial infarction (STEMI) have not demonstrated impact on systolic recovery compared to placebo. However, recent studies suggest that timing of G-CSF therapy is crucial. Methods: Timing of G-CSF treatment was analyzed in the STEMMI MRI subpopulation including 54 patients with STEMI treated with primary percutaneous coronary intervention (PCI) <12 h after symptom onset. Patients were randomized to double blind treatment with G-CSF (10 µg/kg/day) or placebo. Treatment was initiated from 17 to 65 h (mean 30) after PCI. Left ventricular ejection fraction (LVEF) was evaluated with MRI. Results: Recovery of LVEF from baseline to 6 months was not associated with time from PCI to G-CSF. An identical improvement in LVEF was found in the placebo group and the G-CSF group (p =0.8). There was no correlation between time from PCI to G-CSF and maximum plasma concentration of CD34+ cells (r =−0.3, p =0.1). Similar results were found from data on recovery of the infarction size and change in the systolic wall thickening. Conclusions: In the time window from 17 to 65 h after STEMI treated with PCI, the timing of G-CSF treatment does not seem to affect the recovery of LVEF. It remains to be determined if very early, or very late G-CSF treatment might be effective. [Copyright &y& Elsevier]

This review of adjunctive therapy with subcutaneous granulocyte-colony stimulating factor (G-CSF) to patients with acute myocardial infarction (AMI) focus on the cardioprotective effects and potential mechanisms of G-CSF and discuss the therapeutic potential of G-CSF. All clinical trials published in peer-reviewed journals identified through PubMed are discussed. G-CSF treatment seems to be safe, and initial unblinded trials in patients with AMI were encouraging. However, larger double-blind placebo-controlled trials have not been able to demonstrate improved myocardial recovery after G-CSF treatment. Current controversies in interpretation of the results include 1) importance of direct cardiac effect of G-CSF vs indirect through bone marrow stem and progenitor cell mobilization, 2) importance of timing of G-CSF therapy, 3) importance of G-CSF dose, and 4) importance of cell types mobilized from the bone-marrow. Cell-based therapies to improve cardiac function remain promising and further experimental and clinical studies are warranted to determine the future role of G-CSF. [Copyright &y& Elsevier]

Abstract: Background: Angiogenic growth factors and stem cell therapies have demonstrated varying results in patients with chronic coronary artery disease. A reason could be that these mechanisms are already up-regulated due to reduced blood supply to the myocardium. The objective of this study was to examine if plasma concentrations of circulating stem cells and angiogenic cytokines in patients with severe stable chronic coronary artery disease were correlated to the clinical severity of the disease. Methods: Fifty-four patients with severe coronary artery disease and reversible ischemia at stress myocardial perfusion scintigraphy were prospectively included. The severity of the disease was quantified by an exercise tolerance test, Canadian Cardiovascular Society angina classification, and Seattle Angina Pectoris Questionnaire. Fifteen persons without coronary artery disease served as control subjects. Results: Plasma concentration of VEGF-A, FGF-2, SDF-1, and circulating CD34+ and CD34−/CD45−cells were similar in the two groups, but early stem cell markers (CD105, CD73, CD166) and endothelial markers (CD31, CD144, VEGFR2) were significantly different between patients and control subjects (p <0.005−0.001). Diabetic patients had higher concentration of SDF-1 (2528 vs. 2150 pg/ml, p =0.004). We found significant correlations between both VEGF-A, FGF-2, and CD34+ to disease severity, including degree of reversible ischemia, angina stability score, and exertional dyspnoea. Conclusions: Plasma concentrations of circulating stem cells and angiogenic cytokines have large inter-individual variations, which probably exclude them from being useful as indicators of myocardial ischemic burden. [Copyright &y& Elsevier]

Abstract: Background: Lectin complement pathway (LP) activation is an important mechanism in myocardial ischemia reperfusion injury (IRI). LP is activated via the recognition molecules mannose-binding lectin (MBL), ficolins-2 and-3 and is regulated by MBL/Ficolin-associated Protein-1 (MAP-1). Also, C-reactive protein (CRP) and ficolin-2 interact in vitro, but the role of the ficolins in IRI is unknown. Methods and results: In 55 patients with ST segment elevation myocardial infarction, we investigated the association of LP components and CRP in plasma samples with left ventricular (LV) end systolic and diastolic volumes (ESV and EDV) and infarct size, assessed by cardiac magnetic resonance early at 1–3 days after primary percutaneous coronary intervention and at 6 months follow-up. Opposed to MBL, ficolin-3 and MAP-1, ficolin-2 levels were low at baseline. At baseline, ficolin-2>median was associated with ESV and EDV increases by 7.83ml/m2 (p =0.004) and 14.04ml/m2 (p <0.001). MBL and MAP-1 were not associated with LV dilatation, yet ficolin-2 and MBL worked synergistically and the combination of their levels>median was associated with ESV (11.21ml/m2; p =0.017) and EDV increases (14.72ml/m2; p =0.006). MAP-1median had the greatest LV dilatation (17.61ml/m2). The ficolin-2×CRP interaction variable was positively associated with infarct size and inversely associated with EDV change over 6 months (p =0.006). There was no interaction between CRP and the other LP molecules. Conclusion: The LP initiator molecule ficolin-2 and combinations of ficolin-2, MBL and MAP-1 are associated with LV dilatation after myocardial infarction. Interaction of ficolin-2 and CRP was associated with infarct size and LV remodeling, indicating a potential role for LP and LP-pentraxin cross-activation in IRI and LV remodeling. [Copyright &y& Elsevier]

Objectives: The objective of this meta-analysis was to evaluate the effect of stem cell mobilization by granulocyte colony-stimulating factor (G-CSF) on myocardial regeneration on the basis of a synthesis of the data generated by randomized, controlled clinical trials of G-CSF after acute myocardial infarction (AMI). Background: Experimental studies and early-phase clinical trials suggest that stem cell mobilization by G-CSF may have a positive impact on cardiac regeneration after AMI. The role of G-CSF in patients with AMI remains unclear considering the inconsistent results of several clinical trials. Methods: For our analysis, PubMed, the Cochrane Central Register of Controlled Trials, conference proceedings from major cardiology meetings, and Internet-based sources of information on clinical trials in cardiology from January 2003 to August 2007 served as sources. Two reviewers independently identified studies and abstracted data on sample size, baseline characteristics, and outcomes of interest. Eligible studies were randomized trials with stem cell mobilization by G-CSF after reperfused AMI that reported data regarding the change in left ventricular ejection fraction (LVEF) at follow-up. Results: Ten trials using stem cell mobilization by G-CSF, including 445 patients, met the inclusion criteria. Significant improvement in LVEF at follow-up was observed in both the G-CSF and placebo groups. Compared with placebo, stem cell mobilization by G-CSF did not enhance the improvement of LVEF at follow-up (mean difference 1.32% [95% confidence interval −1.52 to 4.16; p = 0.36]). Moreover, the mean difference of reduction of infarct size between the treatment and placebo groups was −0.15 (95% confidence interval −0.38 to 0.07, p = 0.17). Conclusions: Cumulatively, available evidence does not support a beneficial effect of G-CSF in patients with AMI after reperfusion. [Copyright &y& Elsevier]