Improved function and myocardial repair of infarcted heart by intracoronary injection of mesenchymal stem cell-derived growth factors.

Transplantation of mesenchymal stem cells (MSC) improves repair and function recovery following myocardial infarction (MI), but underlying mechanisms remain to be elucidated. We hypothesize that MSC could achieve protection by paracrine effects through released mediators rather than direct cardiac regeneration. We sought to characterize the effects of MSC-secreted growth factors on extent of early recovery from MI. Swine subjected to acute MI by temporary balloon occlusion of the left anterior descending coronary artery using percutaneous techniques received intracoronary injection of either concentrated MSC-derived growth factors or control medium. Animals were killed at 7 days to evaluate early effects. Treatment with MSC-derived factors significantly reduced cardiac troponin-T elevation and improved echocardiographic parameters, including fractional area shortening, stroke volume, cardiac output, and wall motion score index. Quantitative evaluation of fibrosis by Verhoff staining revealed a reduction of the fibrotic area in the infarcted zone. Similarly, Masson's trichrome staining revealed reduced myocardial damage as demonstrated by areas of relatively preserved myocardium in the infarcted area. TUNEL assay demonstrated less cardiomyocyte apoptosis. Protein array detected the presence of angiogenic (vascular endothelial growth factor, endothelin, and epiregulin), anti-apoptotic (Galectin-3, Smad-5, sRFP-1, and sRFP-4) and anti-remodeling factors. Reverse transcription polymerase chain reaction confirmed the expression of these factors. In summary, a single intracoronary injection of concentrated biologically active factors secreted by MSC could achieve early protection of ischemic myocardium and improve cardiac repair and contractility. MSC-derived growth factors injection (rather than MSC themselves) should be evaluated as a novel therapy to treat ischemic heart disease, avoiding many practical and technical issues of cell therapy.

COMPARE-AMI trial: comparison of intracoronary injection of CD133+ bone marrow stem cells to placebo in patients after acute myocardial infarction and left ventricular dysfunction: study rationale and design.

Stem cell therapy has emerged as a promising approach to improve healing of the infarcted myocardium, to treat or prevent cardiac failure, and to restore lost cardiac function. Despite initial excitement, recent clinical trials using nonhomogenous human stem cells preparations showed variable results, raising concerns about the best cell type to transplant. Selected CD133(+) hematopoietic stem cells are promising candidate cells with great potential. COMPARE-acute myocardial infarction (AMI) study is a phase II, randomized, double-blind, placebo-controlled trial evaluating the safety and effectiveness of intracoronary CD133(+)-enriched hematopoietic bone marrow stem cells in patients with acute myocardial infarction and persistent left ventricular dysfunction. Patients who underwent successful percutaneous coronary intervention and present a persistent left ventricular ejection fraction <50% will be eligible to have bone marrow aspiration and randomized for intracoronary injection of selected CD 133(+) bone marrow cells vs placebo. The primary end point is a composite of a safety and efficacy end points evaluating the change at 4 months in the coronary atherosclerotic burden progression proximal and distal to the coronary stent in the infarct related artery; and the change in global left ventricular ejection fraction at 4 months relative to baseline as measured by magnetic resonance imaging. The secondary end point will be the occurrence of a major adverse cardiac event. To date, 14 patients were successfully randomized and treated without any protocol-related complication. COMPARE-AMI trial will help identify the effect of a selected population of the bone marrow stem cells on cardiac recovery of infarcted myocardium.