Stem Cell Therapy after Acute Myocardial Infarction—The Emperor’s New Clothes?

Abstract

Ever since the pioneer studies of Abraham Trembley in 1740, who had documented that “a tiny piece of an older hydra could grow into the entire animal just the way the embryo did” (1), the amazing potential of multipotent cells in lower species to regenerate organs and body parts provoked great interest. In the recent past, the recognition that even in higher species circulating progenitor cells are capable of amazing organ repair (2) has led to a scientific revolution with fast-moving frontiers and intense efforts to translate basic findings to the clinical setting. One area where great hopes exist in the therapeutic potential of stem cells is the treatment of acute myocardial infarction (3,4). In clinical studies, bone marrow–derived cells were either administered via intracoronary infusion or were mobilized from the bone marrow via administration of cytokines such as granulocyte colony stimulating factor (G-CSF) or stem cell factor (5). After early reperfusion strategies have markedly lowered the early mortality of myocardial infarction, the major challenge for stem cell therapy is the prevention or attenuation of postinfarction heart failure. As it so happens, two recent communications reported long-term outcomes in sizable cohorts of patients. In the first study, after acute myocardial infarction patients received either autologous bone marrow cells infused into the infarct-related artery by stop-flow balloon catheter technique or placebo (6)—the so-called BOOST trial (Bone Marrow Transfer to Enhance ST Elevation Infarct Regeneration). The other study assessed the late outcome in patients with acute myocardial infarction in whom stem cells had been mobilized by administration of G-CSF (7); with a grain of excess optimism the trial was called REVIVAL-2 study (Regenerate Vital Myocardium by Vigorous Activation of Bone Marrow Stem Cells). The long-term results of either study are somewhat sobering. In agreement with several small, less well-controlled trials or trials not specifically designed for this purpose (8), the initial results of the BOOST study had been promising indeed (6): within 6 months a significant improvement of global as well as regional left ventricular ejection fractions (LVEF) had been noted (6). This was accompanied by evidence of improved diastolic function (9). There had been no major side effects. The 18-month long-term results, however, which are presented now, are not earth-shaking: the difference in LVEF, which had been significant at 6 months, was no longer significant after 18 months, although the speed of recovery had obviously been faster (10). How about the competing procedure, stem cell mobilization by G-CSF in patients with ST-segment elevation acute myocardial infarction (STEMI)? G-CSF was administered with the rationale that stem cells mobilized by the cytokine home in to the site of myocardial injury. Previous small studies had suggested benefit (11,12); they can all be criticized, however, for one reason or another, e.g., problems with control patients, randomization, blinding, sample size, etc. (13). The hypothesis that mobilizing bone marrow–derived precursors provides a clinically relevant benefit was subjected to a rigorous test in an adequately-sized randomized study, comprising more patients than all preceding studies taken together. The trial included patients with STEMI who had been successfully reperfused within 12 h after onset of symptoms. They received either placebo or 10 μg/kg G-CSF for 5 d. The primary end point was reduction of left ventricular (LV) infarct size by Tc99m sestamibi scintigraphy at baseline and after 4 as well as 6 months. Secondary end points were, among others, improvement of LVEF (by magnetic resonance imaging) and restenosis (by angiography). Not surprisingly, the patients receiving G-CSF experienced an increase in CD34+ cells (marker of bone marrow–derived precursors) and white blood cells, a decrease in platelets, and an increase in C-reactive protein, lactate dehydrogenase, and alkaline phosphatase. They experienced slightly more general side effects than the placebo group. There were no differences of infarct size between the groups at baseline or at follow-up after 4 and 6 months. LV function, evaluated as LVEF using magnetic resonance imaging, and the values of the LV end-systolic volume index were absolutely identical between the groups. Finally, angiography showed no difference of restenosis rate between the groups, at least in patients with bare (i.e., non–drug-coated) stents. In contrast with previous reports (11), there was no evidence of excess restenosis. Thus, the good news is that there were no serious side effects. The bad news is that there was no demonstrable benefit either. Several possibilities may account for the negative outcome. Acute myocardial infarction releases progenitor cells from the bone marrow by upregulating the secretion of cytokines (14). It is possible, therefore, that the functional consequences of a further increase caused by exogenous cytokines is limited. After mobilization from the bone marrow, the progenitor cells may also have not been able to properly home to the damaged cardiac tissue (this shortcoming is circumvented by intracoronary administration) (6). A further possibility is that the cytokine took too much time to mobilize stem cells: in experimental studies homing was seen only in the first days immediately after myocardial infarction (15–18). That the time window may be an important limitation is also suggested by the first observations in the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial (4) that improvement in LV function is correlated to the time interval between acute event and intracoronary stem cell administration. If this is the explanation, intracoronary administration would obviously be the way to go. Is this negative study outcome the requiem for stem cell therapy in general? We hope not. The authors of this negative study did an excellent job in recruiting an adequately-sized cohort of randomized patients and in applying state-of-the art methodology to evaluate heart function. It is plausible that past investigators might have been fooled by the spontaneous improvement of LV function, which is well documented in the placebo group of Zohlnhöfer et al. Factors such as reversal of myocardial stunning, removal of necrotic tissue, edema or infiltrating cells, and finally contraction of collagen may change the infarct tissue in such a fashion that this is easily confounded with treatment success (13). One reason why it has become so difficult to improve outcomes is that modern early-reperfusion techniques have reduced early mortality so much that it is difficult to do better. After the acute window is closed, the main challenge is to improve the long-term outcome over and above today’s success rates with blockade of the renin-angiotensin system, statins, and antiplatelet regimens—not an easy task. The initial, perhaps naïve, idea of how stem cells operate was direct transdifferentiation of bone marrow–derived precursors into mature cardiomyocytes (19), an idea which is not supported by experimental data (20,21) A more likely explanation, well known to nephrologists from what happens in the repair phase of acute renal failure (22), is the idea that stem cells act by paracrine secretions, thus creating a proangiogenic, antiapoptotic, and proproliferative environment (15,23,24). Bone marrow–derived mononuclear cells were, for instance, shown to express VEGF, basic fibroblast growth factor, and angiopoietins (25–27). Another current unknown is whether it is possible to modulate the (limited) number of multipotent resident cardiac stem cells (28). Although the results of the G-CSF stem cell mobilization study are outright negative, and the long-term outcome of the BOOST trial—despite initially positive results—are sobering, it would be too early to count the stem cell approach out. But after these studies the task will be much tougher.