Autologous cell-based therapies for vascular disease

Strategies that enhance the number of endothelial cells (ECs) in the vessel wall following injury may limit complications such as thrombosis, vasospasm, and neointimal formation through reconstitution of a luminal barrier and cellular secretion of paracrine factors. Proof of principle has been demonstrated by studies in which mature ECs, culture expanded from harvested vascular tissue, were seeded in the arterial wall following balloon injury. The recent identification of circulating cells capable of developing an endothelial phenotype, including progenitor cells, has raised the possibility of using blood-derived cells as therapeutic agents. This article reviews data suggesting that such cells confer vascular protective effects after injury, raising the potential for novel, autologous approaches to the treatment of vascular disease.     

New gene and cell-based therapies for lung cancer

Lung cancer is the leading cause of cancer-related mortality in men and women in the United States, in part, because of the poor treatment options available. New treatment strategies that specifically target discreet steps in the molecular and cellular pathogenesis of this disease are under development. This review highlights many of the basic defects that result in the cellular transformation and subsequent progression of lung cancer, and how the understanding of those fundamental defects lead to the formulation of rational gene-based or cell-based therapies.     

Evolving cell-based therapies for heart failure patients

Heart failure (HF) represents the only cardiovascular disease (CVD) whose incidence continues to rise in the developed world. With recent advances in device and drug therapies, the prognosis is improving. Nevertheless, the mortality associated with HF remains high, with more than 50% of patients dying within 5 years after initial diagnosis. The loss of cardiac cells is a major contributor to the development and progression of HF, thus therapeutic interventions to repair or regenerate lost cardiac cells hold tremendous promise. During the past several years, cell-based therapy for CVD has moved at a rapid pace from animal studies to clinical trials. To date, populations enrolled in cell-based therapy trials have comprised patients with coronary artery disease and myocardial infarction, with a limited number of trials conducted in patients with congestive HF. Also, most trials have used autologous skeletal myoblasts or bone marrow cells (whole bone marrow or subpopulations). The outcomes from these studies have been largely mixed, ranging from clear beneficial effects of cell therapy to no observed improvement, although all trials demonstrated a reasonable degree of safety, at least within the study period. Several critical issues, such as the type of cells, number of cells, timing, delivery methods, and the mechanisms of action involved, remain to be elucidated. This article reviews the current status of the emerging field of cell-based therapies for CVD, with particular focus on HF treatment.     

Plasmid-mediated gene therapy for cardiovascular disease

Gene transfer within the cardiovascular system was first demonstrated in 1989 yet, despite extensive basic-science and clinical research, unequivocal benefit in the clinical setting remains to be demonstrated. Potential reasons for this include the fact that recombinant viral vectors, used in the majority of clinical studies, have inherent problems with immunogenicity that are difficult to circumvent. Attention has turned therefore to plasmid vectors, which possess many advantages over viruses in terms of safety and ease of use, and many clinical studies have now been performed using non-viral technology. This review will provide an overview of clinical trials for cardiovascular disease using plasmid vectors, recent developments in plasmid delivery and design, and potential directions for this modality of gene therapy.     

Present status and perspectives of cell-based therapies for liver diseases

In recent years the interest in liver cell therapy has been increasing continuously, since the demand for whole liver transplantations in human beings far outweighs the supply. From the clinical point of view, transplantation of hepatocytes or hepatocyte-like cells may represent an alternative to orthotopic liver transplants in acute liver failure, for the correction of genetic disorders resulting in metabolically deficient states, and for late stage liver disease such as cirrhosis. Although the concept of cell therapy for various diseases of the liver is widely accepted, the practical approach in humans often remains difficult. An international expert panel critically discussed the recent published data on clinical and experimental hepatocyte transplantation and the possible role of stem cells in liver tissue repair. This paper aims to summarise the present status of cell based therapies for liver diseases and to identify areas of future preclinical and clinical research.     

Systemic gene therapy for cardiovascular disease

Systemic gene therapy involves the transfer into the body of a gene whose protein product reaches the blood and has a beneficial effect on a patient. Both retroviral and adenovirus-associated viral vectors have resulted in stable but only moderate systemic levels of blood proteins. Adenoviral vectors have resulted in very high levels of expression that diminishes over days or weeks. Hepatic gene therapy has achieved levels of the anticoagulant protein C in blood that would protect against spontaneous thromboses in homozygous protein-C deficiency, and levels of tissue plasminogen activator that can lyse pulmonary emboli. Hypercholesterolemia has been ameliorated transiently by transfer of the low-density lipoprotein receptor gene into the livers of animals with familial hypercholesterolemia or by promoting lipid transfer via a variety of alternative mechanisms. Hypertension has been reduced by the transfer of genes for kallikrein or atrial natriuretic peptide into the liver, or by expressing antisense for the angiotensin II type I receptor after intravenous injection in neonates. Finally, fasting but not fed hyperglycemia has been ameliorated in animal models of diabetes by transfer of an insulin gene into the liver or by expression of insulin from implanted fibroblasts. Gene therapy has the potential to treat these cardiovascular diseases. However, improvements in levels of long-term expression and the ability to regulate expression in response to physiologic changes will be required before this approach will be implemented for most of these disorders in humans.     

The impact of antidiabetic therapies on cardiovascular disease

Cardiovascular disease disproportionately affects people with diabetes and is a leading cause of death. Glycemic control has so far not been conclusively shown to decrease cardiovascular events. The therapeutic agents used in treating glycemia have different effects on cardiovascular risks and, therefore, may have different effects on outcome. Insulin sensitizers impact cardiovascular risk factors, including dyslipidemia and fibrinolysis. Metformin is the only oral antidiabetic medication shown to decrease cardiovascular events independent of glycemic control. Thiazolidinediones improve insulin resistance and lower insulin concentrations, which is beneficial because hyperinsulinemia is an independent predictor of cardiovascular disease. Insulin therapy acutely reduces cardiovascular mortality and morbidity in patients with diabetes and known coronary artery disease and also in patients with hyperglycemia when critically ill, but the long-term effects are unclear. In contrast, insulin secretagogues have very little effect on both cardiovascular risk factors and outcomes.     

Vectors for gene therapy of cardiovascular disease

Several phase I/II clinical trials are currently ongoing in gene therapy of cardiovascular disease. Whereas the indications vary, including peripheral artery disease, ischemic heart disease, post-angioplasty restenosis, and vein graft failure, these trials are mostly based on the use of adenoviral vectors and nonviral vectors. Novel vectors aimed at improving the efficacy and safety of gene delivery in target organs, such as heart, skeletal muscle, vasculature and liver, have been recently generated. Some of them have already been successfully validated in preclinical m odelsof cardiovascular disease. This review focuses on the most recent advances in vector development that could substantially increase the spectrum of cardiovascular pathologies amenable to gene transfer-based treatments.     

Use of complementary therapies in patients with cardiovascular disease

Previous studies have suggested that patients with chronic medical conditions use complementary and alternative medicine (CAM) at a higher rate than the general population. Despite recent interest in CAM for cardiovascular disease, few data are available regarding patterns of use in patients with cardiovascular disease in the United States. This study used the 2002 National Health Interview Survey and analyzed data on CAM use in 10,572 respondents with cardiovascular disease. Among those with cardiovascular disease, 36% had used CAM (excluding prayer) in the previous 12 months. The most commonly used therapies were herbal products (18%) and mind-body therapies (17%). Among herbs, echinacea, garlic, ginseng, ginkgo biloba, and glucosamine with or without chondroitin were most commonly used. Among mind-body therapies, deep-breathing exercises and meditation were most commonly used. Overall, CAM was used most frequently for musculoskeletal complaints (24% of respondents who used mind-body therapies, 22% who used herbs, 45% who used any CAM). Mind-body therapies were also used for anxiety or depression (23%) and stress or emotional health and wellness (16%). Herbs were commonly used for head and chest colds (22%). Fewer respondents (10%) used CAM specifically for their cardiovascular conditions (5% for hypertension, 2% for coronary disease, 3% for vascular insufficiency, < 1% for heart failure or stroke). Most, however, who used CAM for their cardiovascular condition perceived the therapies to be helpful (80% for herbs, 94% for mind-body therapies). CAM use was more common in younger respondents, women, Asians, and those with more education and greater incomes. In conclusion, CAM use, particularly herbs and mind-body therapies, is common in the United States in patients with cardiovascular disease and mirrors use in the general population. CAM use specifically to treat cardiovascular conditions, however, is less common.     

Novel lipid-modifying therapies addressing unmet needs in cardiovascular disease

Cardiovascular disease(CVD) remains a major cause of morbidity and mortality worldwide. Currently, it is well established that dyslipidemia is one of the major risk factors leading to the development of atherosclerosis and CVD. Statins remain the standard-of-care in the treatment of hypercholesterolemia and their use has significantly reduced cardiovascular morbidity and mortality. In addition, recent advances in lipid-modifying therapies, such as the development of proprotein convertase subtilisin/kexin type 9 inhibitors, have further improved cardiovascular outcomes in patients with hypercholesterolemia.However, despite significant progress in the treatment of dyslipidemia, there is still considerable residual risk of recurring cardiovascular events. Furthermore, in some cases, an effective therapy for the identified primary cause of a specific dyslipidemia has not been found up to date. Thus, a number of novel pharmacological interventions are under early human trials, targeting different molecular pathways of lipid formation, regulation and metabolism. This editorial aims to discuss the current clinical and scientific data on new promising lipidmodifying therapies addressing unmet needs in CVD, which may prove beneficial in the near future.     

ApoE基因多态性与心血管疾病的研究进展

载脂蛋白E（ApoE）作为人体内一种广泛存在的调节蛋白,一直是心血管疾病领域的研究热点。目前,已有众多的研究证实ApoE与许多心血管疾病密切相关,并且可能通过脂代谢调节、炎症信号通路激活、抗氧化应激等机制产生作用,尤其是证明了其在冠状动脉粥样硬化性疾病中所发挥的独特作用。但是最近有研究表明,不同的ApoE基因表型在心血管疾病中表现出了不同的作用,甚至是相互矛盾的结果,而且在不同人种、民族、地域和生活习惯的人群中其作用也不尽相同。本文系统阐述了ApoE及其基因表型特征,并着重讨论了ApoE基因多态性在不同心血管疾病中的特殊作用,特别是为探索ApoE基因多态性对国人心血管疾病的影响奠定一定基础。     

Cardiac genes and gene databases for cardiovascular disease genetics

Genes play a very important role in the etiology of hypertension. This paper reviews the current pool of candidate genes for human hypertension. Some of the genes studied in rat models of hypertension are also discussed. The methods for studying the genetics of hypertension are reviewed. A discussion of the role of cardiac gene libraries and gene databases in the characterization of cardiovascular disease is also included. This review is concluded by a discussion on the future role of genomics and cardiovascular gene databases in medical research.     

Stem cells and their potential in cell-based cardiac therapies

Stem cells are potential agents for the treatment of myocardial infarcts among other heart diseases. Over the past decade, the scientific community has extensively used a wide variety of cells and examined their capacity to both regenerate the infarcted myocardium and improve functionally the diseased hearts. Some of the cells used include skeletal myoblasts, bone marrow-derived cells, adult cardiac resident stem cells, mesenchymal stem cells, and both mouse and human embryonic stem cells (Nat Biotechnol 2005;23:845-856). The reported cardiogenic capacity of the utilitized stem cells is assayed both in vitro through the use of differentiation paradigms and in vivo through transplantation into a variety of animal models of cardiac disease. The purpose of this review article is to summarize recent stem cell applications in cell-based cardiac therapies and their outcomes.     

Marrow cell therapies for cardiovascular diseases

The nascent field of regenerative medicine has taken root in cardiovascular disease. Preclinical data demonstrating hemangioblast potential of marrow cells and cardioprotective effects of growth factors served as the basis for numerous early phase clinical trials. With the first wave of safety and efficacy trials complete, much is still unknown regarding optimal cell dose and type, timing of injection, route of administration, mechanisms of action, and achievable response measures. The next generation of studies will aim to answers these questions and make way for cellular therapies that result in effective cardiac repair.     

Hormonal prostate cancer therapies and cardiovascular disease: a systematic review

Heart Failure Reviews - Therapeutic intervention for prostate cancer mostly relies on eliminating circulating androgen or antagonizing its effect at the cellular level. As the use of endocrine...     

Somatic gene therapy for cardiovascular disease Recent advances

The recent development of several novel approaches for in vivo gene transfer into the coronary arteries and myocardium has led to new possibilities for the treatment of both acquired and inherited cardiovascular diseases. This review summarizes the current state of the art of in vivo gene transfer into the heart and coronary arteries with particular emphasis on antisense oligonucleotide-mediated suppression of gene expression in vascular smooth muscle cells, liposome-mediated gene transfer into the vasculature, and percutaneous transluminal gene transfer (PTGT) into the heart with the use of replication-defective adenoviruses.     

Role of progenitor endothelial cells in cardiovascular disease and upcoming therapies.

The field of cell-based transplantation has expanded considerably and is poised to become an established cardiovascular therapy in the near future. In this review, we will focus on endothelial progenitor cells (EPCs), which are immature cells capable of differentiating into mature endothelial cells. EPCs share many surface marker antigens such as CD34, AC133, Flk-1, etc. with hematopoietic stem cells (HSCs) and the major source of EPCs as well as HSCs is the bone marrow (BM). BM-derived EPCs are mobilized into peripheral blood and recruited to the foci of pathophysiological neovascularization and reendothelialization, thereby contributing to vascular regeneration. Severe EPC dysfunction is an indicator of poor prognosis and severe endothelial dysfunction. Indeed, number of circulating EPCs and their migratory activity are reduced in patients with diabetes, coronary artery disease (CAD), or subjects with multiple coronary risk factors. Effective neovascularization induced by EPC transplantation for hindlimb, myocardial, and cerebral ischemia has been demonstrated in many preclinical studies, and early clinical trials of EPC transplantation in chronic and acute CAD indicate safety and feasibility of myocardial cell-based therapies. For therapeutic reendothelialization in patients undergoing percutaneous coronary intervention, CD34 antibody-coated stents have been used clinically to capture circulating EPCs at the injury sites and enhance reendothelialization and safety of stents. Further development in cell processing technology for efficient isolation, expansion, mobilization, recruitment, and transplantation of EPCs into target tissues are underway and expected to be tested in clinical trials in the near future.