Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function.

Left ventricular remodeling is a major cause of progressive heart failure and death after myocardial infarction. Although neoangiogenesis within the infarcted tissue is an integral component of the remodeling process, the capillary network is unable to support the greater demands of the hypertrophied myocardium, resulting in progressive loss of viable tissue, infarct extension and fibrous replacement. Here we show that bone marrow from adult humans contains endothelial precursors with phenotypic and functional characteristics of embryonic hemangioblasts, and that these can be used to directly induce new blood vessel formation in the infarct-bed (vasculogenesis) and proliferation of preexisting vasculature (angiogenesis) after experimental myocardial infarction. The neoangiogenesis resulted in decreased apoptosis of hypertrophied myocytes in the peri-infarct region, long-term salvage and survival of viable myocardium, reduction in collagen deposition and sustained improvement in cardiac function. The use of cytokine-mobilized autologous human bone-marrow-derived angioblasts for revascularization of infarcted myocardium (alone or in conjunction with currently used therapies) has the potential to significantly reduce morbidity and mortality associated with left ventricular remodeling.

Cell- and gene therapy for ischemic heart disease.

Despite advances in pharmacological therapies, cardiovascular surgery, use of mechanical assist devices, and organ transplantation, more than half of the patients with clinically evident heart failure die within 5 years of the initial diagnosis. The use of cellular cardiomyoplasty and gene therapy offer a promising approach for both the prevention and treatment of heart failure. This review will discuss the current state of these emerging fields and the prospects of introducing the methods into clinical practice. Since functional restoration of the damaged heart presents a formidable challenge, developing strategies for the prevention of post-infarct heart failure remains of utmost priority. New strategies to optimize cell delivery, homing and survival on the one side and safe and efficient application of gene therapy to the failing myocardium on the other side are indispensable in order to achieve myocardial recovery after acute infarction or chronic ischemic damage.

Combined heart and kidney transplantation using a single donor: a single center's experience with nine cases.

BACKGROUND: Simultaneous double-organ transplants comprising various organ combinations have become frequent. The purpose of this article is to report on a single center's experience of simultaneous heart and kidney transplantation (HNTX) with particular emphasis on selection criteria and patient outcome. METHODS: From September 1990 to January 1997, nine patients underwent HNTX, receiving both grafts from a single donor selected on ABO blood group compatibility and a negative lymphocytotoxic crossmatch, but without regard to HLA-antigen matching. RESULTS: One patient died of acute humoral rejection of the cardiac graft shortly after surgery. Eight patients are alive and well and have normal cardiac and renal function at a mean follow-up of 44+/-28 months. CONCLUSION: HNTX offers a compelling therapeutic solution in the treatment of advanced cardiac and renal failure in carefully selected patients. Because the heart and kidney rejection episodes were independent of each other, rejection surveillance should be carried out separately for each transplanted organ.

Cardiac transplantation and simultaneous surgical repair of an aortic aneurysm.

Simultaneous cardiac transplantation and surgical repair of an aortic aneurysm has not been reported previously. At our institution, a 59-year-old patient with an aneurysm of the ascending aorta and aortic arch required orthotopic cardiac transplantation for end-stage cardiomyopathy. He underwent successful surgical replacement of his ascending aorta and transverse arch (in circulatory arrest and deep hypothermia) at the time of heart transplantation.

Immediate, single stage, truly anatomic zirconia implant in lower molar replacement: a case report with 2.5 years follow-up.

This report demonstrates the clinical use of a modified, truly anatomic, root-analogue zirconia implant for immediate replacement of a two-rooted, left first mandibular molar. A 50-year-old female patient with chronic apical periodontitis of the left mandibulary first molar was referred and the tooth was extracted. The mesial root had to be removed surgically due to a root fracture. A truly anatomical, root identical, roughened zirconia implant modified by macro-retentions was manufactured and placed into the extraction socket by tapping 7 days later. After 4 months a composite crown was cemented in place. No complications occurred during the healing period. A good functional and aesthetic result was achieved with minimal bone resorption and soft tissue recession at 30 months follow-up. This report describes the successful clinical use of an immediate, single stage, truly anatomical root-analogue zirconia implant for replacement of a two-rooted tooth. Significant modifications such as macro-retentions yielded primary stability and excellent osseointegration. This novel approach is minimally invasive, respects the underlying anatomy, aids socket prevention, is time- and cost-saving with good patient acceptance as there is no need for bone drilling, sinus lift, bone augmentation or other traumatic procedures.

CCR3- and CXCR4-mediated interactions regulate migration of CD34+ human bone marrow progenitors to ischemic myocardium and subsequent tissue repair.

OBJECTIVE: Hematopoietic progenitor cells are able to induce neovascularization of ischemic myocardium, inhibit apoptosis, and prevent heart failure. They express functional CC chemokine-binding receptor 3 (CCR3) and CXC chemokine-binding receptor 4 (CXCR4); however, the role of those receptors in migration of progenitor cells into the ischemic myocardium is unknown. METHODS: Myocardial infarction was surgically induced in athymic nude rats, and human bone marrow-derived CD34+ cells or saline was injected into the tail vein. Cell chemotaxis was studied in vitro using chemotaxis chambers with or without concomitant stimulation with eotaxin or stromal cell-derived factor-1. Cell migration into ischemic myocardium was evaluated by immunohistochemistry. CCR3 and CXCR4 antibodies or local injections of stromal cell-derived factor-1 were used to investigate the role of chemokine expression in the migration capacity of the injected cells. Morphologic analysis included evaluation of apoptosis and capillary density in the ischemic myocardium. RESULTS: Ischemic rat myocardium demonstrated induced messenger RNA expression for the CCR3-binding chemokines eotaxin, RANTES (regulated on activation, normal T expressed and secreted), and monocyte chemotactic protein-3, but not the CXCR4-binding chemokine stromal cell-derived factor-1. Migration of human angioblasts to ischemic rat myocardium was inhibited by a blocking anti-CCR3 monoclonal antibody, but not by a blocking anti-CXCR4 monoclonal antibody, which instead inhibited migration to bone marrow. Finally, intramyocardial injection of stromal cell-derived factor-1 redirected migration of human angioblasts to ischemic rat hearts, resulting in augmented neovascularization, enhanced cardiomyocyte survival, and functional cardiac recovery. CONCLUSIONS: CCR3-dependent chemokine interactions regulate endogenous migration of CD34+ progenitors from bone marrow to ischemic but not to normal myocardium. Manipulating CXCR4-dependent interactions could enhance the efficacy of cell therapy after myocardial infarction.

Myocardial homing and neovascularization by human bone marrow angioblasts is regulated by IL-8/Gro CXC chemokines.

In the adult, new blood vessel formation can occur either through angiogenesis from pre-existing mature endothelium or vasculogenesis mediated by bone marrow-derived endothelial precursors. We recently isolated endothelial progenitor cells, or angioblasts, in human adult bone marrow which have selective migratory properties for ischemic tissues, including myocardium, to where they home and induce vasculogenesis. Here we show that myocardial production of the IL-8/Gro-alpha CXC chemokine family is significantly increased after acute ischemia, and that this provides a chemoattractant gradient for bone marrow-derived endothelial progenitors, or angioblasts. This chemokine-mediated homing of bone marrow angioblasts to the ischemic heart regulates their ability to induce myocardial neovascularization, protection against cardiomyocyte apoptosis, and functional cardiac recovery. Together, our results indicate that CXC chemokines play a central role in regulating vasculogenesis in the adult, and suggest that manipulation of interactions between chemokines and their receptors on autologous human bone marrow-derived angioblasts could augment neovascularization of ischemic myocardial tissue.

Myocardial neovascularization by adult bone marrow-derived angioblasts: strategies for improvement of cardiomyocyte function.

In the pre-natal period, hemangioblasts derived from the human ventral aorta give rise to cellular elements involved in both hematopoiesis and vasculogenesis, resulting in formation of the primitive capillary network. Endothelial precursors with phenotypic and functional characteristics of embryonic hemangioblasts are also present in human adult bone marrow, and can be used to induce infarct bed vasculogenesis and angiogenesis after experimental myocardial infarction. The neovascularization results in decreased apoptosis of hypertrophied myocytes in the peri-infarct region, long-term salvage and survival of viable myocardium, reduction in collagen deposition, and sustained improvement in cardiac function. Autologous angioblasts may also be useful in cellular therapy strategies aiming to regenerate myocardial tissue after established heart failure. It is likely that protocols using cardiomyocyte/mesenchymal stem cells will require balanced co-administration of angioblasts to provide vascular structures for supply of oxygen and nutrients to both the chronically ischemic, endogenous myocardium and to the newly-implanted cardiomyocytes. Future studies will need to address the timing, relative concentrations, source and route of delivery of each of these cellular populations in animal models of acute and chronic myocardial ischemia.

Immunobiology of left ventricular assist devices.

The increasing use of implanted biomaterial devices has made it evident that no material is biologically inert. As a result of direct contact with elements of the blood circulation, such as during hemodialysis or after left ventricular assist device (LVAD) implantation, significant changes in systemic immunologic and thrombostatic functions occur. The clinical success of LVAD implantation has, nevertheless, been accompanied by complications arising from an aberrant state of monocyte and T-cell activation, leading to heightened susceptibility of circulating CD4 T cells to undergo activation-induced cell death; this results in progressive defects in cellular immunity and an increased risk of serious infection. Because of the increased state of T-cell activation and the selective loss of Th1 cytokine producing CD4 T cells, LVAD recipients also develop B-cell hyperreactivity and dysregulated immunoglobulin syntheses by unopposed production of Th2 cytokines and increased CD40 Ligand-CD40 interactions. LVADs are currently being evaluated as a permanent therapy for end-stage heart failure. Because these immune dysfunctions appear to be related to the effects of excessive biomaterial associated T-cell activation, future efforts will need to be directed at either altering the physical properties of the materials interacting with the host circulation or pharmacological intervention aimed at inhibiting T-cell activation.