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An estimated 15% of patients with ischemic heart disease are not amenable to conventional methods of revascularization (1-3), and an additional 12-22% may be limited to incomplete percutaneous coronary intervention (PCI) or surgical procedures (1,4-7). These so-called no-option patients often progress to end-stage ischemic cardiomyopathy with an annual mortality in excess of 30% (8). Treatment options for this group remain limited to multidrug medical management, myocardial reduction surgery, left-ventricular (LV) assist device placement, or cardiac transplantation. The current estimation is that 100,000 patients per year in this group would potentially benefit from alternative therapies (2,3,9). Over the past decade, cardiac angiogenesis and myogenesis have emerged as such alternatives. [ABSTRACT FROM AUTHOR]

Numerous patients with coronary artery disease have been successfully treated with conventional methods, such as coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI), but a significant and increasing number of patients have exhausted the ability to undergo these procedures repeatedly because of the diffuse nature of their coronary artery disease. As a result, they have chronic disabling angina that is often refractory to medical therapy. Transmyocardial laser revascularization (TMR) was developed to treat these patients. Although Mirhoseini et al. (1,2) and Okada et al. (3,4) pioneered the use of a laser to perform this type of revascularization in conjunction with CABG in the early 1980s, the use of a laser as sole therapy required advancements in the technology to establish its efficacy. Since then, more than 15,000 patients have been treated with TMR around the world and results from individual institutions, multicenter studies, and prospective randomized control trials have been reported (5-18). [ABSTRACT FROM AUTHOR]

Coronary heart disease remains the single largest killer of American men and women. The American Heart Association statistics show that approx 1.1 million Americans suffer a myocardial infarction (MI) annually. Of those who survive, 22% of men and 46% of women are disabled with heart failure (1). Although cardiomyocytes of infarcted or failing human hearts have been shown to undergo mitoses (2,3), this regenerative capacity is by far too limited to compensate for the loss of cardiac cells resulting from a large infarct. In areas of ischemia, cell death ensues and scar forms in the place of myocardium. The remaining myocardial cells respond to mitotic signals by hypertrophy rather than hyperplasia. Necrotized myocardial cells are replaced by fibroblasts. If no viable myocardium is present, scar formation ensues with ventricular wall thinning and dilation of the ventricular cavity. This leads to symptoms of heart failure in a significant number of patients. For conventional coronary revascularization to be beneficial, viable myocardium must be present. The prognosis for these patients is poor, with a 1-yr mortality rate of 20% and a 5-yr mortality rate of close to 50% (1). [ABSTRACT FROM AUTHOR]

Congestive heart failure remains the leading cause of death in developed countries. Myocardial infarction (MI) results in the loss of heart muscle cells, which is the main contributor to the development of heart failure. Classical medical therapy and mechanical left-ventricular assist devices are available for physicians to improve the prognosis of patients with MI and heart failure, but only half of the patients with end-stage heart failure survive the following year (1). At the present time, allogeneic heart transplantation to extend life span and to improve the quality of daily life is probably the preferred alternative treatment for patients with end-stage heart failure, but extreme organ shortage and chronic cardiac rejection limit the therapy. In recent years, research on stem cells is leading scientists to investigate the possibility of cell-based therapies for cardiac repair, often referred to as regenerative or reparative medicine. Stem cell-based cellular cardiomyoplasty (CCM) for cardiomyocyte replacement/regeneration has been evaluated in animal settings (2-6) and clinical trials (7-9). Transplantation of exogenous stem cells could regenerate damaged myocardium and improve cardiac function in failing hearts. Such efforts may offer exciting novel options for treating patients with end-stage heart failure. [ABSTRACT FROM AUTHOR]

Coronary artery disease remains the leading cause of death in developing countries. In the United States, up to 12 million Americans have a history of myocardial infarction, angina pectoris, or both (1). Although recent advances in medical treatment and interventional procedures have reduced the mortality in patients with coronary artery disease (2), the number of patients with refractory myocardial ischemia and congestive heart failure is rapidly increasing. In a significant proportion of these patients, percutaneous coronary intervention or surgical bypass revascularization is either not feasible or incomplete as a result of patients' comorbidity, total occlusion, or poor distal vessels. After a myocardial infarction, some cardiomyocytes are lost and others hibernate because of insufficient myocardial perfusion. Therefore, therapeutic approaches aimed at promoting blood vessel formation (angiogenesis) and growing new heart muscle fibers (myocardial regeneration) are attractive alternatives. Accumulating evidence suggests that bone marrow cells have the potential of contributing to tissue revascularization and cardiac regeneration after myocardial injury. This chapter summarizes the current status of bone marrow cell transplantation for myocardial regeneration and therapeutic angiogenesis. [ABSTRACT FROM AUTHOR]

Angiogenesis, the growth and proliferation of blood vessels from existing vascular structures, is a tightly regulated process in adult tissues. Abnormalities in angiogenesis are associated with a number of pathological states. Strategies designed to promote angiogenesis to treat disorders of inadequate tissue perfusion, such as occurs in peripheral arterial disease, have led to the area of therapeutic angiogenesis. Angiogenic growth factors of varying types and preparations are being investigated to promote therapeutic angiogenesis and reduce the sequelae of atherosclerotic disease. In addition to promoting blood vessel growth, these angiogenic growth factors have the potential to influence important biological processes such as the response to injury and cell survival. This chapter reviews the use of angiogenic growth factors for therapeutic angiogenesis in peripheral arterial disease. [ABSTRACT FROM AUTHOR]

Over the last quarter-century, numerous advances have been made in the understanding of the molecular and cellular processes that lead to the development of atherosclerosis. The respective roles of the endothelium, inflammatory mediators, and thrombosis in the pathogenesis of vascular disease are beginning to be better understood. As more is learned about the initiation of atherosclerotic cardiovascular disease, new targets for systemic therapies are being discovered. Several classes of medications have been shown to be beneficial in preventing adverse cardiovascular events in patients with cardiovascular disease. These medications include platelet inhibitors (aspirin and thienopyridines), angiotensin-converting enzyme inhibitors, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors ("statins"). [ABSTRACT FROM AUTHOR]

Improvements in pharmacological therapy and revascularization procedures have greatly increased the life expectancy of patients with coronary artery disease (CAD) in the last few decades. As a result of these improvements in cardiovascular care and the aging of the population, anincreasing number of patients have incomplete revascularization or recurrent myocardial ischemia and are suboptimal candidates for surgical (coronary artery bypass grafting [CABG]) or percutaneous (percutaneous coronary intervention [PCI]) revascularization (1,2). In an analysis of 500 consecutive patients at a tertiary referral center, 12% had myocardial ischemia and were not optimal candidates for CABG or PCI (3). In patients with two- and three-vessel CAD, complete revascularization was successful in only 23% and 9% of cases, respectively (2). In fact, up to 20-37% of patients with CAD are either poor candidates for CABG or PCI or receive incomplete revascularization with current revascularization strategies (4-6). As a result, many of these patients have residual symptoms and limited quality of life despite maximal medical therapy (frequently described as "refractory angina pectoris") (7,8). Therefore, an alternative revascularization strategy is required and has stimulated intense interest in and excitement about novel approaches to myocardial revascularization. [ABSTRACT FROM AUTHOR]

Rapid advancements in molecular biology have expanded the candidate treatments aiming to modify blood supply without surgery. Laser treatments (1), growth factors, and gene therapies have been touted as capable of improving blood supply sufficient to resolve symptoms and/or reduce the risks of damage. Pro-angiogenic growth factors that induce the growth and development of blood vessels may prove useful in (1) protecting myocardium from cell death, (2) protecting extremities from ischemic ulcers and other damage leading to limb loss, (3) providing relief from ischemic symptoms, and/or (4) improving functional capacity. Antiangiogenic agents may prove valuable in slowing or stopping cancers. [ABSTRACT FROM AUTHOR]

Resistance circulation of the heart is important in regulating the delivery of blood and nutrients to the myocardium. There has been a longstanding interest in studying its properties; however, prior to the mid-1980s, technical limitations made it difficult to directly study coronary microvessels either in situ or in vitro. Traditionally, studies of the coronary microcirculation had been limited to indirect assessments using measurements of coronary flow and calculations of coronary resistance, which provided a great deal of insight into the properties of the intact coronary circulation. Significantly more has been learned in the last 15 yr as new in vivo and in vitro approaches have been developed for direct study of coronary microvessels (1-4). Furthermore, development of microangiography methods allowed for visualization of the coronary microcirculation in mammals (5,6). The most important finding of these studies was the inhomogeneity of the resistance vessels (7). [ABSTRACT FROM AUTHOR]

In the last decade, therapeutic angiogenesis in cardiovascular diseases has been extensively investigated using a variety of animal models. Recently, there have been great efforts to begin such research in human trials. There is still, however, an ongoing need for continued preclinical investigations to illuminate the complexity of angiogenic agents. Therapeutic modalities including autologous stem cell transplantation, targeted protein delivery, prolonged protein half-life, and various combination therapies are only some of the areas that require further investigation. [ABSTRACT FROM AUTHOR]

Until recently, the transcription factors necessary for regulating vascular development were largely unknown. This is in sharp contrast with other developmental processes, such as hematopoiesis and myogenesis, in which several cell- or tissue-specific transcription factors have been identified. Vascular development requires the differentiation of endothelial cells from pluripotent stem cells. Progress in identifying the molecular mechanisms underlying vascular development has lagged considerably, in large part the model systems for studying vascular blood vessel development are more limited. The identification of several vascular-specific genes involved in vasculogenesis and the genomic regulatory regions required for directing their expression over the past decade has facilitated the identification of the transcriptional mechanisms required for vascular-specific gene expression. Targeted disruption of additional transcription factors that have been associated with vascular defects led to the elucidation of a role for these factors in vascular development. Angiogenesis, the development of additional blood vessels from a primary vascular network, may recapitulate many of the molecular events occurring during vascular development. [ABSTRACT FROM AUTHOR]

Despite advances in preventive health care, medical management, interventional cardiology, and cardiovascular surgery, atherosclerotic disease remains the leading cause of morbidity and mortality in the Western Hemisphere. Cardiovascular disease accounted for 38.5% of all deaths or 1 of every 2.6 deaths in the United States in 2001. Cardiovascular disease mortality was about 60% of "total mortality," i.e., of over 2,400,000 deaths from all causes, cardiovascular disease was listed as a primary or contributing cause on about 1,408,000 death certificates. Since 1900, cardiovascular disease has been the number one killer in the United States every year except 1918 (1). Treatment of coronary artery disease (CAD) includes risk factor modification, use of antiplatelet agents, medical therapy by decreasing myocardial oxygen demand and coronary vasodilation, and restoring myocardial perfusion using percutaneous coronary interventions (PCI) and coronary artery bypass grafting (CABG). Although significant advances have reduced the mortality of cardiovascular disease, the number of cardiac interventions continues to grow: a total of 1.3 million inpatient cardiac catheterizations, 561,000 percutaneous transluminal coronary angioplasty (PTCA) procedures, and 519,000 coronary artery bypass procedures were performed in 2000 in the United States alone (1). [ABSTRACT FROM AUTHOR]