In our study, the main finding is that the intracoronary administration of autologous purified BM-derived MSCs at 1 month after STEMI is tolerable without serious complications and provides modest improvement in LVEF at 6-month follow-up by SPECT.
The stem cell therapy for AMI increased LVEF by 2.99% (95% confidence interval [CI], 1.26%-4.72%, P
=0.0007) in meta-analysis (4
). In chronic ischemic heart failure, STAR-Heart study demonstrated that intracoronary BM cell therapy improved ventricular performance, quality-of-life and even survival (13
). Our results met the primary endpoint of ≥4.3% improvement in LVEF compared with the control group. However, it is uncertain whether the relatively small increase in systolic function is meaningful in real-life situations (and not just a statistical difference).
In terms of safety, intracoronary administration of MSCs showed no serious adverse events, although periprocedural MI was developed in 2 patients. It seems to be a safe method to deliver stem cells via intracoronary route, since its introduction by Strauer et al. (22
). Moreover, ischemic pre-conditioning induced by transient balloon occlusion seems to be important to recruit MSCs into the infarcted myocardium (24
Numerous in vitro and in vivo studies have shown the pleiotropic effects of MSCs such as antifibrotic, immunomodulatory, antiapototic and proangiogenic features as well as the impact of inflammation/cytokine expression on the different aspects of homing, including chemokine-chemokine receptor interactions, adhesion on endothelial cells, transendothelial migration, and invasion through the extracellular matrix (26
). Stromal cell-derived factor (SDF)-1α is a major chemotactic paracrine factor for homing stem cells. SDF-1α-modified MSCs enhanced the tolerance of engrafted MSCs to hypoxic injury in vitro and improved their viability in a rat model of infarcted hearts, thus helping preserve the contractile function and attenuate LV remodeling (27
). Moreover, MSC-conditioned medium directly inhibited the function of cardiac fibroblasts and resulted in a decrease of myocardial fibrosis with the consequent improvement of cardiac function by secreting antifibrotic factors such as adrenomedullin (28
One of the main concerns is the time limitation for using autologous MSCs in acute setting. It is impossible to use autologous MSCs immediately because it takes time to harvest and culture cells for over 3 weeks. However, the optimal time for stem-cell therapy was not precisely identified. The temporal window of opportunity to maximize efficacy seems to be between the acute inflammatory response and scar formation. Several experimental studies and clinical subgroup analyses provided important clues that stem cell therapy might be effective within the first month after AMI, but not in very acute phase (24 hr after AMI) (29
). Further clinical randomized trials need to confirm the optimal time to treatment.
The use of statin may ameliorate the microenvironment of injured myocardium and protect implanted MSCs. Animals treated with atorvastatin showed the improvement of myocardial perfusion and contractility compared with untreated animals by Yang et al. (30
). The combined treatment of atorvastatin with MSCs reduced myocardial apoptosis, oxidative stress and expression of the inflammatory cytokines (30
). Nearly 90% of our patients were prescribed statin at discharge. This synergic effect of statin might contribute to the functional recovery of damaged myocardium in our study.
The total ischemic time from symptom to treatment is the most important factor related to adverse outcomes. Mortality reduction was greatest in the first 2-3 hr after the onset of AMI, as a consequence of myocardial salvage (31
). However, there was no mortality benefit by opening the occluded artery after 6 hr (31
). Our subgroup analysis supports that BM-derived MSCs may help damaged myocardium to recover, if treated within 6 hr after AMI.
Our study has several limitations. First, our study enrolled relatively small number of patients. This limitation may attenuate the efficacy of intracoronary purified MSCs. Further large-scale randomized trials are needed. Second, there may be a technical problem for the assessment of LVEF. Although CMR was considered to be the "gold standard" for evaluation of LV function, it was impossible to use CMR at all institutions for the first time. We therefore measured LVEF with SPECT because we concluded that software-based automated analysis using SPECT could minimize inter-observer variability. Hovland et al. provided good evidence that SPECT showed the improvement of inter-observer agreement compared with echocardiography despite the possibility of an overestimation (32
). Third, many patients were excluded from this study. Total patients of exclusion were 22/80 (27.5%). Ten of 40 (25%) in treatment group and 12/40 (30%) in control group were excluded. It was larger than we had anticipated. After randomization, 11 of 69 (15.9%) patients were excluded and the main cause was poor image quality. More patients in control group (5/36, 13.9%) were excluded than those in treatment group (1/33, 3.0%). However, there may be little possibility for selection bias, because radiologists were blinded to treatment information. The selection of inappropriate images was left at the discretion of radiologists. The final decision was confirmed by the agreement of investigators in each participating center. Fourth, we did not use diverse assessment tools such as the 6-min walking distance, exercise tolerance, pulmonary function test and quality of life. Finally, we did not evaluate the inter- and intra-observer variability in radiographic measurements. Sixth, there was no death in either group. Our study group showed a relatively preserved LV systolic function and low risk profiles. Long-term follow-up is needed to define the safety and beneficial effect of MSCs.
In conclusion, this pilot study was designed to identify the safety and practical efficacy of intracoronary purified autologous BM-derived MSCs in patients with STEMI. Intracoronary administration of autologous BM-derived MSCs at 1 month is tolerable and safe with modest improvement in LVEF at 6-month follow-up.