This study demonstrates that ABMMC delivered by PRCSP in patients with CRA and stress-inducible ischemia was safe, may reduce anginal symptoms and improve exercise capacity. Stem cell transplantation by PRCSP is an alternative route of delivery to the myocardium for patients with coronary artery occlusion at their initial portions, or for patients with severe multivessel disease or occluded venous and arterial grafts. In this study we have demonstrated that, in patients with chronic ischemia with or without severely impaired LV function, that ABMMC injection enhances myocardial perfusion. In addition we observed that improved systolic LV function occurred only in patients with low ejection at baseline. Improvement and maintenance of the LV ejection fraction at 24 months follow-up was most likely a result of increased myocardial perfusion and global regional wall motion. This resulted in a reduced LV end-systolic volume. Consequently, the therapeutic effect appears to be more related to enhanced myocardial contractility rather than induction of LV reverse remodeling. The findings of the present study are consistent with the hypothesis that ABMMC promote angiogenesis, resulting in increased myocardial perfusion [
18]. The present study was not designed to assess the underlying cellular mechanism of bone marrow cell injection improving myocardial perfusion and LV function. Therefore, secretion of pro-angiogenic factors by the bone marrow cells and differentiation of bone marrow cells in endothelium cells, smooth muscle cells, or cardiomyocytes could have contributed to the described effect. The mechanism of angiogenesis could be caused by differentiation of bone marrow cells in endothelial and/or vascular smooth muscle cells or by the production of angiogenic cytokines, as previously proposed but has not been fully validated [
19]. ABMMC by the PRCSP has been proposed as a novel therapeutic option for patients with coronary artery disease. Until now most clinical studies investigating ABMMC were performed in patients with acute myocardial infarction. Data from patients with chronic ischemia are scarce. At present, only few studies in patients with chronic coronary artery disease have been published [
9‐
13]. The current results are in line with studies on the safety and feasibility of intramyocardial delivery of ABMMC in patients with chronic ischemia and angina pectoris. Tse et al
9 described a reduction in anginal symptoms, improved wall motion and improved wall thickening at 3 'months follow-up in 8 patients. In addition, the area of hypoperfused myocardium was reduced on SPECT. Fuchs et al reported a reduction in anginal symptoms and improved myocardial perfusion in 27 patients with a trend toward improved LV ejection fraction [
11]. Perin et al reported the same results in 21 patients [
12]. In a randomized controlled study Losordo et al demonstrated data that CD34 + after GCSF can be safely transplanted via intramyocardial injection and may improve perfusion and reduce symptoms in patients with advanced coronary disease [
14]. In this pilot trial ABMMC were successfully delivered in each patient without any major periprocedural events (i.e., death, myocardial infarction, ventricular arrhythmias, cardiac perforation, pericardial effusion or significant enzyme release) using PRCSP. The present study supports previously suggested beneficial effects in preclinical models of retrograde stem cells delivery for cardiac disease,[
21,
22] and the first to demonstrate improvement on symptoms, perfusion defects and LV function by PRVST in patients with preserved or decreased LV ejection fraction. However, we found similar improvements in patients with chronic ischemia with or without severely impaired LV function. This study suggests improvement and potential outcome durability of angina symptoms relief and better angina class, myocardial perfusion and contractility with this therapeutic approach in chronic refractory angina patients. We believe there may be clinical potential for this relatively novel method of cell delivery for patients suffering from refractory angina. We currently have a number of clinical trials using retrograde delivery of cells for both chronic refractory angina and heart failure based on this trial. Larger randomized trials will be needed to determine optimal cell numbers and to further understand the clinical outcomes.