Nature Clinical Practice. Cardiovascular Medicine最新文献

The potential therapeutic use of embryonic stem cells (ESCs) has gathered the attention of the scientific and medical communities recently. We report that in addition to their unique capacity to populate defective cardiac tissues, ESCs secrete factors that correct gene expression profiles in the defective neighboring cells. Id (inhibitor of DNA binding) gene knockout (KO) mouse embryos die at midgestation because of multiple cardiac defects, but injection of ESCs into preimplantation Id KO embryos prevents these defects and corrects gene expression profiles throughout the heart. ESCs injected into expectant mothers only partially rescue cardiac defects in the Id KO embryos. Two secreted factors are implicated in the rescue process: insulin-like growth factor I accounts for the long-range action of the ESCs, and Wnt5a, a short-range factor, corrects gene expression profiles in the Id KO hearts. Future studies are discussed.

Mesenchymal lineage precursors can be reproducibly isolated from adult mammalian bone marrow and grown in culture. Immunoselection with monoclonal antibodies against STRO-1 and vascular-cell-adhesion molecule 1 (VCAM1/CD106) prior to expansion results in a 1,000-fold enrichment of mesenchymal precursors compared to standard isolation techniques. Intramyocardial injection of human STRO-1-selected precursors in an athymic rat model of acute myocardial infarction results in induction of vascular network formation and arteriogenesis coupled with global functional cardiac recovery.

Autologous skeletal myoblast (ASM) transplantation is being explored as a possible therapy for patients who have suffered a myocardial infarction. Our initial experience with direct injection during coronary artery bypass grafting demonstrated that this method of delivery was both feasible and safe. In addition, proof of concept of the engraftment and survival of ASMs was shown. However, since many patients who have survived a myocardial infarction are not candidates for surgery, a less invasive delivery method is preferred. We implemented a series of translational research steps to bring catheter-based technology to a clinical application. This included assessing the biocompatibility of the ASM and a novel needle injection catheter using a 3-dimensional endoventricular navigation system, the bioretention and biodistribution of ASMs in a porcine model of myocardial infarction, and the safety and efficacy of ASM transplantation for cardiac function in the porcine model. After catheter functionality had been demonstrated, electromechanical mapping was used to assess the viability in the region of ASM transplantation, and echocardiography, electrocardiogram, and angiography tests were used to assess cardiac function 2 months after ASM transplantation. The results from these preclinical studies were used as a foundation for application of these concepts to a human clinical trial. Here we review the results from our preclinical experiments and surgical delivery clinical trial, and describe the recent clinical studies undertaken to assess the safety and feasibility of catheter-based ASM transplantation into human subjects.

Previous studies have shown that local angiogenic gene therapy acts, in part, by recruiting endothelial progenitor cells (EPCs) to ischemic tissue. Recent data indicate that patients with the most severe vascular disease may have insufficient or deficient EPCs and the poorest response to angiogenic therapy. Accordingly, we hypothesized that combining human CD34(+) cell implantation with local vascular endothelial growth factor 2 (phVEGF2) gene therapy might overcome these deficiencies. The addition of VEGF2 to EPC cultures resulted in significant and dose-dependent decreases in EPC apoptosis. Phosphorylated Akt (p-Akt) was increased in VEGF2-treated EPCs. In vivo, myocardial infarction (MI) was induced by ligation of the left anterior descending coronary artery in 34 immunodeficient rats. The animals were then randomized to one of four treatment groups: cell therapy alone with human CD34(+) cells; VEGF2 gene therapy alone; combination therapy with CD34(+) cells plus phVEGF2; or CD34(-) cells and 50 microg empty plasmid. Four weeks after MI, animals treated with combination therapy showed improved fractional shortening, increased capillary density, and reduced infarct size compared with the other three groups. Combination therapy was also associated with an increased number of circulating EPCs 1 week after MI. Combined subtherapeutic doses of cell and gene therapy result in a significant therapeutic effect compared to monotherapy. This approach may overcome therapeutic failures (e.g. inability of certain patients to mobilize sufficient EPCs) and may also offer safety advantages by allowing lower dosing strategies.

Regenerative therapy is a rapidly growing branch of science and medicine, which could have an important impact on the treatment of heart failure, a major cause of disability and death. Regeneration of the damaged myocardium in heart failure can be achieved through different strategies aimed at 'reviving' existing malfunctioning cells, repopulating the myocardium by new cells from exogenous or endogenous sources, altering the extracellular matrix, or increasing blood supply by enhancing vasculogenesis. To date, the clinical application of some of these strategies has had minimal or no impact on the global epidemic of chronic heart failure. However, several small clinical trials have reported varying degrees of functional improvement which could be considerable in some cases. We here review recent progress in the field, suggest an integrated approach, and outline the many gaps in our knowledge which need to be resolved by intensive laboratory research if regenerative therapy for chronic heart failure is to achieve its future potential.

It is still unclear whether the timing of intracoronary stem cell therapy affects the therapeutic response in patients with reperfused myocardial infarction. The natural course of healing the infarction and the presence of putative homing signals within the damaged myocardium appear to favor cell engraftment during the transendothelial passage in the early days after reperfusion. However, the adverse inflammatory environment, with its high oxidative stress, might be deleterious if cells are administered too early after reperfusion. In addition, current studies use mostly unfractionated cells and it remains to be addressed whether specific cell types, and their enrichment, would be better suited to augmenting the recovery at later time points. Here we highlight several aspects of the timing of intracoronary stem cell therapy and focus on time-related questions that are relevant to the design of future experimental and basic studies.

Clinical trials have begun to assess the feasibility, safety, and efficacy of administering progenitor cells to the heart in order to repair or perhaps reverse the effects of myocardial ischemia and injury. In contrast to surgical-based injections, which are often coupled with coronary bypass surgery, catheter-based injections are less invasive and make it possible to evaluate cell products used as sole interventions. The two methods that have been tested in humans are injecting cells directly into the ventricular wall with catheter systems dedicated to that purpose and infusing cells into coronary arteries with standard balloon angioplasty catheters. The catheters described in this article have been shown in both animal and clinical studies to be effective in cell delivery and to be safe. They are well-designed and user-friendly devices, but require further investigation to identify means for optimizing cell retention and to address other limitations. Randomized, placebo-controlled trials utilizing catheters for cell implantation are under way, and others are soon to follow. The results of these studies will help to shape the direction of future investigations, both clinical and basic. The spectrum of cardiac diseases, the variety of catheters for cell delivery, and the wide array of progenitor cell types open up this young field to creative discoveries.

There are several strategies for cell delivery in cardiac stem cell therapy. The cells can be delivered through coronary arteries, coronary veins, or peripheral veins. Alternatively, direct intramyocardial injection can be performed, using a surgical, transendocardial, or transvenous approach. In this article, we describe the most important conceptual aspects and the evidence for the use of these techniques, with emphasis on intramyocardial injections.

Stem cells have emerged as a next-generation therapy for cardiovascular disease. Initial clinical trials in patients with myocardial infarction document improved cardiac performance after administration of stem cells, translating their regenerative potential from the bench to the bedside. However, the promise of stem cell-based therapy has yet to be fully exploited, in part due to varying degrees of efficacy on follow-up. Contributing to the uncertain outcome is the variable cardiogenic potential of patient-derived stem cells. A strategy mimicking cardiogenic signaling was here formulated to transform mesenchymal stem cells, derived from human bone marrow, into cardiac progenitors. We identified a set of recombinant trophic factors capable of collectively inducing nuclear translocation of cardiac-specific transcription factors, engaging mesenchymal stem cells into cardiopoiesis, and ultimately securing a phenotype with functional excitation-contraction coupling. Maximizing the cardiogenic potential of human mesenchymal stem cells achieves a critical step in optimizing therapeutic translation.

The past decade has seen the emergence of paradigm shifts in concepts involving cardiovascular tissue regeneration, including the idea that adult stem cells originate in hematopoietic or bone marrow cells, the belief that even adult organs, such as the heart and nervous system, are capable of post-mitotic regeneration, and the concept of inherent plasticity in cells that have undergone limited lineage differentiation. There has consequently been a flurry of proposed regenerative strategies, and safety and limited efficacy data from both animal and limited human trials have been presented. The drive to push these advances from the bench to the bedside has created a unique environment where the therapeutic agents, delivery approaches, and methods of measuring efficacy (often imaging technology) are evolving practically in parallel. The encouraging results of recent cell-therapy trials should therefore be assessed cautiously and in consonance with an understanding of the advantages and limitations of delivery strategies and end points. Arguably, the use of imaging technologies to evaluate surrogate end points might help overcome the difficulty posed by large sample sizes required for hard end point trials in cardiovascular therapeutics. Cardiac magnetic resonance imaging is one of the most sensitive techniques available to assess spatial and temporal changes following local or systemic therapies, and the availability of a bevy of complementary techniques enables interrogation of physiology, morphology, and metabolism in one setting. We contend that cardiac magnetic resonance imaging is ideally suited to assess response to myocardial regeneration therapy and can be exploited to yield valuable insights into the mechanism of action of myocardial regeneration therapies.