Nature Clinical Practice. Cardiovascular Medicine最新文献

The human heart has a limited capacity for self-repair because, unlike most other cells, cardiomyocytes do not regenerate. Therefore, if a substantial number of myocytes is lost after a myocardial infarction, the performance of the heart may become severely limited, leading to a condition of heart failure. Recently, cell transplantation has emerged as a potential therapy for patients with end-stage heart failure. Of the various cell types being investigated for this purpose, skeletal myoblasts are an attractive option, because they are readily available from muscle biopsies and, if autologous cells are used, immunosuppression is not required and ethical issues are avoided. Several studies have shown that the cells can survive and differentiate after transplantation, and promising clinical results have been reported. However, effects of this therapy on left ventricular function remain largely unknown. In the present study, we investigated the long-term hemodynamic effects of intramyocardial injection of autologous skeletal myoblasts in patients with ischemic heart failure. Our findings indicate hemodynamic improvement after follow-up for up to 1 year, which is especially promising in view of the expected decline in left ventricular function in these patients.

Permanent loss of cardiomyocytes after ischemic injury often initiates the development of heart failure and adversely affects clinical outcome. The concept of progenitor-cell transfer for enhancing cardiac repair has raised new therapeutic prospects. Promising results have been reported in early studies in rodents, using various modalities of progenitor-cell transfer in the dysfunctional heart, although underlying mechanisms remain ill defined. Despite ongoing controversies over whether or not stem cells can autonomously adapt cardiomyocyte-like behavior after genetic reprogramming or whether they merely fuse with native host cardiomyocytes, early-phase clinical trials have shown a reassuring safety profile and suggest a functional benefit. However, identification of the intrinsic value of stem cell transfer in patients after myocardial infarction will require carefully designed randomized, placebo-controlled, blinded studies. While these are becoming available, a number of critical questions about the choice of progenitor-cell type, dosage regimen, and timing of administration need to be considered, and end points for future clinical trials need to be chosen carefully. There is great enthusiasm for this novel treatment paradigm in patients with ischemic cardiomyopathy, but only carefully conducted clinical trials paralleled by preclinical studies in relevant animal models will ultimately identify the best conditions and indications for cell transfer.

Simple ex vivo or in vitro models are most useful for testing putative cell therapy protocols, as they allow quick and controlled screening of variants and possible improvements. We discuss here three different models: coculture of precursors of human bone marrow cells (BMCs) with mouse heart slices bearing a cryogenic lesion; coculture of human BMCs and rat cardiomyocytes separated by a porous membrane that allows passage of soluble substances but prevents migration of nuclear material; and injection of human BMCs in developing chick heart bearing burn lesions. Our results indicate that the damaged areas express specific genes such as MPC1 and SDF1, and that some human BMCs migrate and graft near the lesion, where they can originate cells with a cardiac phenotype that produce human cardiac proteins. The frequency of this transformation is, however, very low. Understanding the factors that determine and regulate nuclear reprogramming and transdifferentiation would be crucial to appraising the contribution of these phenomena to cardiac regeneration and, eventually, to modulating them with therapeutic intent.

Skeletal myoblast transplantation has now entered the clinical arena as a potential means of restoring function to scarred myocardium. While the current experience derived from phase I trials suggests that cell implantation during coronary artery bypass operations is a straightforward and safe procedure, routine use of myoblast transplantation would certainly be premature. Two major issues have not yet been addressed: firstly, the risk-benefit ratio needs to be assessed, specifically whether the potential proarrhythmic risk associated with myoblast transplantation is supported by the results of an ongoing large, randomized study, and if so, whether this risk is offset by a benefit in terms of improvement of left ventricular function and patient outcome. Secondly, this putative benefit will then have to be weighed against the financial burden inherent to this type of procedure, to assess whether the cost-effectiveness ratio is favorably shifted and supports the expanded indication of myoblast transplantation during coronary artery revascularization in patients with severe ischemic heart failure.

Increasing experimental evidence indicates that skeletal myoblasts can be considered as a possible source of cells for regeneration of contractile performance in chronic postinfarction myocardial injury. In experimental models, the observed functional benefit of transplanting skeletal myoblasts into an area of chronic fibrotic myocardial scar has led to the development of clinical trials to evaluate the potential use of autologous skeletal myoblasts for myocardial regeneration in patients with postinfarction heart failure. We conducted an independent, phase I clinical trial to evaluate myoblast transplantation during coronary artery bypass grafting. In addition, to test whether the effect of transplanted cells on myocardial contractility was independent of revascularization, we performed a clinical study of percutaneous transvenous myoblast transplantation-the POZNAN trial. These trials have shown the feasibility of myoblast transplantation during cardiac surgery and via a percutaneous route, as well as the safety of both procedures when performed with concurrent prophylactic administration of amiodarone. Here, we review the details of our observations from both of these phase I clinical trials in the context of the clinical work in cardiovascular cell transplantation performed by others.

Not long ago, it was assumed that mammalian hearts were so differentiated that regeneration of cardiac tissue was not possible, but now an increasing amount of information suggests that the intrinsic regenerative capacity of the heart can be encouraged by stimulating resident stem cells or transplanting extracardiac progenitor cells. In the future, cardiovascular stem cell therapy may be administered to all patients. Here, we review what has happened and look at where we are going.

Early reperfusion of occluded coronary arteries has significantly reduced early mortality and improved the long-term prognosis of patients with an acute myocardial infarction. However, the development of postinfarction heart failure remains a major challenge. Initial experimental studies indicated that mononuclear progenitor cells derived from the bone marrow may contribute to the functional regeneration of freshly infarcted myocardium and increase neovascularization of ischemic areas. A number of clinical pilot trials have now transferred the experimental approach into the clinical arena, aiming at regenerating myocardial function with infusion of bone-marrow-derived progenitor cells in patients after an acute myocardial infarction. While these initial trials using intracoronary infusion of bone-marrow-derived progenitor cells indeed suggested that such a strategy appears to be feasible and safe in patients with an acute myocardial infarction, there is definitely a pressing need for a proof-of-concept study documenting a potentially beneficial effect of progenitor cell therapy on cardiac function.

The application of stem cell biology to repair of the heart offers therapeutic potential. However, randomized, double-blind, controlled trials are required to clarify under what conditions it may be effective. The unprecedented nature of the discovery of a therapeutic role for autologous stem cells brings with it unprecedented challenges in clinical application of basic biology, ethics, funding and organization. It is suggested that the academic community should show leadership.

Emerging evidence suggests that bone-marrow-derived stem and progenitor cells can be used to improve cardiac function after acute myocardial infarction. We tested this concept in the randomized, controlled, BOOST (bone marrow transfer to enhance ST-elevation infarct regeneration) clinical trial. Following successful percutaneous coronary intervention for acute ST-elevation myocardial infarction, patients received an intracoronary transfer of autologous bone marrow cells (BMCs). After 6 months, global left ventricular ejection fraction, as determined by magnetic resonance imaging, was significantly improved in the BMC-treated group compared with the control group. BMC transfer enhanced left ventricular systolic function, primarily in myocardial segments adjacent to the infarcted area, and also had a positive effect on diastolic function. BMC transfer did not increase the risk of adverse clinical events and did not promote in-stent re-stenosis or proarrhythmic effects. In principle, the effects of BMC transfer on ejection fraction were sustained at 18-month follow-up. Notably, radioactive labeling of BMCs and positron emission tomography showed that these beneficial effects are achieved with limited cardiac homing of BMCs after intracoronary application. Taken together, our studies indicate that intracoronary transfer of autologous BMCs is a safe, promising, and novel approach to further improving systolic function in patients with successful reperfusion after acute myocardial infarction.

Recent experimental studies have shown that granulocyte-colony-stimulating factor (G-CSF) enhanced cardiac function after infarction. The concept of direct cytokine or cell-mediated effects on postischemic myocardial function was tested in the setting of human myocardial infarction subjected to percutaneous coronary intervention. In the FIRSTLINE-AMI study 50 consecutive patients with first ST-elevation myocardial infarction were randomly assigned to receive either 10 microg/kg G-CSF for 6 days after percutaneous coronary intervention in addition to standard medication, or standard care alone. G-CSF administration led to mobilization of CD34(+) mononuclear stem cells (MNC(CD34+)), with a 20-fold increase to 64 +/- 37 MNC(CD34+)/microl at day 6 without significant associated changes in rheology, blood viscosity or inflammatory reaction, or any major adverse effects. At 4 months the G-CSF group showed improved left ventricular ejection fraction of 54 +/- 8% versus 48 +/- 4% at baseline (P <0.001), and no evidence of left ventricular end-diastolic remodeling, with a diameter of 55 +/- 5 mm and improved segmental wall thickening (P <0.001); conversely, in control patients left ventricular ejection fraction was 43 +/- 5% at 4 months (P <0.001), with increased left ventricular end-diastolic dimension of 58 +/- 4 mm (P <0.001), and no segmental wall thickening. In conclusion, the FIRSTLINE-AMI study showed that G-CSF administration and mobilization of MNC(CD34+) after reperfusion of infarcted myocardium may offer a pragmatic strategy for preservation of human myocardium and prevention of remodeling without evidence of aggravated atherosclerosis.