Therapeutic angiogenesis for coronary artery disease

Therapeutic angiogenesis may be a realistic approach in treating ischemic heart disease. VEGF is a major angiogenic factor involved in physiological as well as pathological angiogenesis. The ability of VEGF to promote angiogenesis in animal and clinical studies has been studied extensively. However, it is becoming clear that VEGF alone may not be sufficient to effectively complete the angiogenesis process. The use of more than one growth factor may be more pertinent in creating a sustainable angiogenic effect with clinically significant outcome. The challenge is to find complementary partners in angiogenesis to better affect the outcome of the process. To this end, we have been studying the effects of other angiogenic factors such as angiopoietin-1 (Ang-1) in a chronic ischemic porcine model. Single intramyocardial introduction of adenovirus-mediated gene transfer of Ang-1 into the left ventricle free wall has been found to enhance angiogenesis by augmenting the formation of new capillaries that manifested in improved total blood flow in the myocardium. A combined therapeutic angiogenesis study involving VEGF and Ang-1 is currently underway. Due to their unique complementary properties, it is expected that the combination will not merely enhance angiogenesis but will also lead to healthy and mature vascular network in the ischemic myocardium.     

Therapeutic angiogenesis in the ischemic canine heart induced by myocardial injection of naked complementary DNA plasmid encoding hepatocyte growth factor

OBJECTIVE: We investigated the efficacy of directly injecting a plasmid with complementary DNA encoding human hepatocyte growth factor into ischemic canine myocardium to induce angiogenesis. METHODS: Four weeks after ligation of the left anterior descending coronary artery, 125 microg of a complementary DNA plasmid encoding the gene for either hepatocyte growth factor (n = 8) or LacZ (transfection control group, n = 8) was injected directly into the myocardium at the border between the normal tissue and the infarction. Eight other dogs were used as a sham control group. Regional thickening fraction, which indicated contractile function, and blood flow in the normal (circumflex branch territory) and ischemic areas were evaluated under dobutamine administration just before and 4 weeks after transfection. The animals were killed, and capillary numbers in both areas were assessed. These data in the ischemic area were evaluated as the percentage of those in the normal. RESULTS: The number of myocardial capillaries in the ischemic area was successfully increased to approximately 140% of usual in the hepatocyte growth factor group, whereas no change was observed in the other groups (P =.0017 by analysis of variance). Furthermore, regional thickening fraction and blood flow in the ischemic area, which had deteriorated after coronary ligation, showed significant improvement in the hepatocyte growth factor group relative to the other groups (thickening fraction P <.0001 by analysis of variance, blood flow P =.0005 by analysis of variance). CONCLUSIONS: These results support the efficacy of the direct injection of plasmid complementary DNA encoding human hepatocyte growth factor to induce therapeutic angiogenesis in the ischemic myocardium.     

Potentials of regenerative medicine for liver disease

Liver transplantation is still the only effective treatment for end-stage liver disease. However, because of the serious worldwide shortage of donated organs, an alternative cellular therapy would be desirable. Animal studies and preclinical trials have indicated that hepatocyte transplantation can serve as an alternative to liver transplantation. Unfortunately, however, the harvesting of hepatocytes is associated with the same problem as organ transplantation, i.e., a lack of a suitable cell source. Therefore, current stem cell technology, which is attempting to establish an unlimited supply of hepatocytes, would facilitate the clinical application of hepatocyte transplantation. This review summarizes current knowledge of embryonic and adult stem cell differentiation into hepatocytes and discusses how liver stem cells could be applied clinically in the future.     

Therapeutic angiogenesis in cardiovascular disease

Atherosclerotic disease of the arteries is a major cause of coronary artery disease, peripheral vascular disease and stroke. Some patients are however not candidate for the standard treatment of angioplasty or bypass surgery. Hence there is tremendous enthusiasm for the utilization of angiogenesis as a therapeutic modality for atherosclerotic arterial disease. This augmentation of physiological neo-vascularization in cardiovascular disease can be achieved through different pathways. In this article we are reviewing the Use of Gene therapy, Protein therapy and cellular therapy.     

Therapeutic potential of chitosan and its derivatives in regenerative medicine

BACKGROUND: Cell-based transplantation, tissue engineering and gene therapy are important therapeutic strategies for present and future regenerative medicine. One challenge is to present the target cells in a suitable matrix to allow the cells to survive the wound contraction, tissue repair, and remodeling in certain tissues. Recently, functional biomaterial research has been directed towards the development of improved scaffolds and new drug delivery systems for regenerative medicine. MATERIALS AND METHODS: A literature survey was performed in basic and clinic publications relevant to the therapeutic potential of chitosan and its derivatives in regenerative medicine. In this review the functional properties and potential applications of chitosan and its derivatives in regenerative medicine are presented and discussed. RESULTS: Chitosan can be obtained by alkaline deacetylation of chitin and is found to be a natural-based nontoxic, biocompatible, and biodegradable polymer with anti-microbial activity. Chitosan and its derivatives could accelerate wound healing by enhancing the functions of inflammatory cells and repairing cells. Recent studies further indicated that chitosan and its derivatives also are novel scaffold materials for tissue engineering and are-promising non-viral vectors for gene delivery. CONCLUSIONS: Regenerative medicine has entered a new era with the development of modern science and technology. The novel properties of chitosan make it a versatile biomaterial for cell therapy, tissue engineering and gene therapy. It is hoped that these diverse approaches for regenerative medicine will translate from "bench to bedside" in the future.     

Overview: Japanese guidelines for myocardial revascularization to treat stable ischemic heart disease 2012

Since its introduction in the early 1970s, coronary artery bypass grafting (CABG) has become an established surgical treatment for coronary artery disease (CAD). Percutaneous coronary intervention (PCI), first clinically applied in 1977, was promoted as an alternative to CABG during the mid-1980s. Along with the nationwide expansion of PCI, the ratio of PCI to CABG has exceeded 6–7:1. The Japanese Circulation Society (JCS) published “Guidelines on elective coronary intervention, including coronary artery bypass grafting (CABG), for ischemic heart disease in 2000” and “Guidelines on the selection of bypass conduits and operative procedures in coronary artery bypass grafting for ischemic heart disease”. The society intended to revise these guidelines in 2010 and to issue two new guidelines specific either to PCI or CABG. They also planned to issue joint guidelines for myocardial revascularization and PCI/CABG, which are primary indications for patients with stable CAD, especially with those with more complex left main trunk disease and/or multi-vessel disease. The scientific committee of JCS established the “Council for myocardial revascularization” that consisted of experts including interventional and non-interventional cardiologists, cardiac surgeons and physicians specialized in diabetes or nephrology selected by medical and surgical societies. After over 10 rounds of meetings, the Council prepared primary guidelines for myocardial revascularization to treat stable CAD, PCI/CABG. These guidelines consist of (1) Statements about myocardial revascularization, (2) Interpretation of the statements and (3) Indications for PCI/CABG including a table.     

Cell-based therapeutic angiogenesis for the treatment of ischemic disease

Cell-based therapy has been the recent focus of attention for repairing injured organs. Several cell sources, derived from peripheral blood, bone marrow, or embryonic stem cells, have been used to induce angiogenesis successfully in various experimental ischemic models, which might be related to angiogenic cytokine production and endothelial incorporation from implanted cells within the targeted ischemic tissues after implantation. Clinical trials have also reported the feasibility and found some efficacy of therapeutic angiogenesis induced by the implantation of autologous bone marrow-(or peripheral blood)-derived cells in patients with ischemic heart disease and peripheral artery disease. Although many questions regarding the effectiveness and safety, optimal cell number and route of delivery, and mechanisms remain, cell-based therapeutic angiogenesis may be a novel and promising treatment option for ischemic disease.     

Clinical aspects of indirect myocardial revascularization in patients with ischemic heart disease

The article analyses the experience in surgical treatment of patients with ischemic heart disease (504 cases) by indirect revascularization of the myocardium by creating aseptic mediastino-exo-pericarditis. Clinical characteristic of the patients is given, 81.1% of them had a history of myocardial infarction; 57.7% were invalids; the diagnosis was confirmed by coronarography in 56.2%; 92.1% of patients who underwent operation were related to III-IV functional classes. Late-5-year results showed marked improvement of the condition in 47.3%, moderate improvement in 31.6% and absence of an effect in 21.1% of patients. Postoperative lethality was 1.1%.     

Combined surgery for valvular and ischemic heart disease

Combined coronary artery bypass (CAB) and valve surgery is one of the most challenging surgical procedures, but the operative results have improved over the years. We discuss several important points in combined surgery. The first point is cardioplegia, which should be perfect in such complex operations. Sufficient antegrade cold blood cardioplegia should be used in combined CAB and mitral valve surgery. Continuous retrograde cardioplegia is required in CAB and aortic valve surgery. The second point is the prosthesis and grafts. A mechanical prosthesis and arterial grafts should be used in younger patients, while a bioprosthesis and vein grafts with a left internal thoracic artery graft should be used in older ones. Finally, the choice of valve repair or replacement must be considered in mitral surgery with CAB. Valve repair is the choice in patients with mitral prolapse due to chordal rupture, because a perfect repair can be achieved using a well-known procedure. In cases in which repair appears difficult, replacement must be carried out as soon as possible. In mitral valve replacement the continuity between the papillary muscles and the mitral ring must be preserved for good left ventricular performance.     

Experience in the perfecting of direct myocardial revascularization inpatients with ischemic heart disease

The first 100 operations for aortocoronary and mammary-coronary shunting in patients with ischemic heart disease are analysed. The operations were carried out on patients aged from 36 to 59 years who had no severe concomitant diseases. Angina pectoris of effort was encountered in 47%, angina of effort and of rest in 33%, and unstable angina in 20% of patients. The operations were performed under conditions of extracorporeal circulation. In 100 patients 184 arteries were shunted (1.8 shunt per one patient). A mammary-coronary shunt was established in 13 patients; the left internal thoracic artery was used in all of them for shunting the anterior interventricular branch. Improvement was recorded in 88.5% of patients after the operation. Thirteen (13.0%) patients died. It is concluded that patients should be chosen with great care for aortocoronary shunting with due regard for the risk factors.     

Combined operation for renovascular hypertension and ischemic heart disease

We have experienced two patients of ischemic heart disease associated with renovascular hypertension. Patient 1 (60-year-old man) underwent LV aneurysmectomy and triple aortocoronary bypass grafting (saphenous vein to diagonal branch, left internal mammary artery to obtuse marginal branch, and right gastroepiploic artery to right coronary artery). Seventy five days after the initial cardiac surgery endarterectomy for the left renal artery and bifurcated Dacron graft implantation for the iliac artery obstruction were performed. Patient 2 (62-year-old woman) underwent simultaneous operation of both right nephrectomy and triple aortocoronary bypass grafting (saphenous vein grafts to obtuse marginal branch and right coronary artery, and left internal mammary artery to left anterior descending artery). Their postoperative courses were uneventful except unstable and high blood pressure for four to seven days after the operation. It appears that it should be decided to achieve either simultaneous or two stage approach for ischemic heart disease associated with renovascular hypertension based on the preoperative cardiac function. And both postoperative cardiac function and hypertension should be carefully managed until the blood pressure becomes stable after the surgery.     

Biomedical research frontier for regenerative medicine

Making much of self-renew potential of the living body, "Regenerative Medicine" is sure to play an essential role providing an innovation in treating many human disorders. Although there has been remarkable advances in this field, they are successful only in certain tissues such like vessels or bone/cartilage. When think about the solid organs, i.e. liver or pancreas, it still remains as a huge research frontier. By combining the usage of flow-cytometry and fluorescence-labeled monoclonal antibodies, we had established an elegant methodology of single cell isolation which opened up the way to challenge this "frontier" and it finally led us to the success in identifying/characterizing the stem cells in such organs. Now our research enterprise covers through further understanding of the core stem cell biology to the development of basic technology to realize "Regenerative Medicine" so that we will be able to get reach the achievement to meet the increasing demands of patients suffering these tissues and organs.     

Stem cell-derived chondrocytes for regenerative medicine

The regenerative capacity of cartilage is limited. Transplantation methods used to treat cartilage lesions are based mainly on primary cultures of chondrocytes, which dedifferentiate during cultivation in vitro and lose their functional properties. Stem cells are considered as an alternative source to generate cells for two reasons: first, they can almost indefinitely divide in culture, and second, they are able to differentiate into various mature cell types. Herein, we asked the question whether chondrocytes could be differentiated from mouse embryonic stem (ES) cells to a state suitable for regenerative use. When cultivated as embryoid bodies (EBs), murine ES cells differentiate into mesenchymal progenitor cells, which progressively develop into mature, hypertrophic chondrocytes and transdifferentiate into calcifying cells recapitulating all of the cellular processes of chondrogenesis. Chondrocytes isolated from EBs exhibit a high regenerative capacity. They dedifferentiate initially in culture, but later reexpress stable characteristics of mature chondrocytes. However, in cultures of chondrocytes isolated from EBs, additional mesenchymal cell types can be observed. Mesenchymal stem (MS) cells from bone marrow have already been used in tissue engineering settings. We compared the chondrogenic differentiation of MS and ES cells.