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Despite great advances in the therapy of cardiovascular diseases within the past several decades, ischemic heart disease and congestive heart failure (CHF) continue to be leading causes of mortality and morbidity in the Western hemisphere.1 Myocyte loss as well as structural and functional abnormalities of the myocyte are observed in the syndrome of CHF, regardless of its cause.2 Although much of molecular cardiology over the past 2 decades has been devoted to the understanding of myocyte abnormalities in heart failure, only recently has regenerative therapy of the heart emerged as an exciting therapeutic modality.3 Unlike hearts of lower animals such as newts and zebrafish,4 which regenerate completely after injury, the human heart has been traditionally thought of as a terminally differentiated organ incapable of regeneration.5 This traditional line of thinking has been challenged recently by observations in animals and humans of the existence of cardiac6,7 and extracardiac progenitor cells (CPCs) capable of forming cardiomyocytes, endothelial as well as smooth muscle cells.8-14 These observations in turn have engendered clinical trials of stem cell therapy aimed at regenerating the heart after acute myocardial infarction (MI) and in chronic left ventricular failure.15

This chapter provides a brief overview of the emerging field of cardiac regenerative therapy. The chapter discusses the scientific basis for cardiac regenerative therapy, examines the types of stem cells used and mechanisms of action and mode of delivery, addresses safety concerns, reviews clinical trials of cardiac cell therapy, and finally summarizes the questions that confront the future of this rapidly developing field.

The concept of the heart as a terminally differentiated organ incapable of replacing myocytes has been an accepted paradigm over the past 50 years.3 However, several lines of evidence from animal and human studies have emerged over the past few years to challenge this existing paradigm. A number of experimental studies in animals supported the possibility of stem cell–based cardiac regeneration. Orlic et al8 demonstrated that bone marrow cells injected into the infarcted mouse heart regenerated infarcted myocardium and led to improvement in cardiac function. More recently, Beltrami and colleagues6 identified a resident CPC capable of differentiating into cardiomyocyte, endothelial, and smooth muscle lineages. Injection of these cells into the injured heart led to regeneration of functioning myocardium and improvement in cardiac function. Studies in human subjects supported the above-mentioned experimental observations. The presence of Y chromosome–positive cardiomyocytes in female hearts transplanted into male recipients directly pointed to the presence of putative progenitors capable of de novo cardiomyocyte formation (Fig.11–1A,B).11,14 Furthermore, the presence of chimeric cardiomyocytes, albeit at low numbers, in the hearts of patients who had undergone gender mismatched bone marrow transplantation strongly suggested the existence of bone marrow progenitors capable of contributing to cardiomyocyte formation in the adult human heart (Fig. 11–1C).10 Taken together, a large body of experimental evidence thus suggests the existence of progenitors capable of ...

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