cardiac treatment - NATURE|Vol 451|21 February...

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Ischaemic heart disease — characterized by reduced blood supply to the heart muscle — is the primary cause of death throughout the world, including most low-income and middle-income countries 1 . Obstruction of coronary arteries leads to myocardial infarction (heart attack) with the associated death of cardiomyocytes. This overloads the surviving myocardium and eventually leads to heart failure (see page 919). Other causes of heart failure, including chronic high blood pressure, are also characterized by a gradual loss of cardiomyocytes 2 , and experimental inhibition of programmed cell death can improve cardiac function 3 . The only standard therapy for heart failure that addresses the fundamental problem of cardiomyocyte loss is cardiac transplantation. New discoveries on the regenerative potential of stem cells and progenitor cells for treating and preventing heart failure have transformed experimental research and led to an explosion in clinical investigation. The crucial point at which it is decided that laboratory evidence sufficiently supports clinical experimentation is particularly controversial in stem-cell therapy for heart failure, so it is timely to consider the current state of this field. In this review, we discuss the current knowledge of regeneration in the adult mammalian heart. We also consider the various stem-cell and progenitor-cell types that might regenerate the myocardium and review the major challenges to such therapy. Cardiac regeneration Few questions in cardiac regeneration are definitively resolved. But it is widely agreed that the regenerative capacity of human myocardium is grossly inadequate to compensate for the severe loss of heart muscle presented by catastrophic myocardial infarction or other myocardial diseases. By contrast, skeletal muscle in mammals can regenerate effi- ciently, even after widespread injury 4,5 . Satellite cells and other types of myoblast reside in skeletal muscle and form large numbers of new myo- tubes within days of muscle injury. However, a regenerative response does occur in the hearts of some vertebrates, such as zebrafish and newts, after injury 6,7 . In the normal state, newt cardiomyocytes, like those of mice and humans, rarely divide. But after a substantial injury, remaining cardiomyocytes initiate DNA synthesis and re-enter the cell cycle 6 . Division of existing cardiomyocytes seems to be the most impor- tant factor for cardiac regeneration in this animal. Dedifferentiation of cardiomyocytes near the injured zone occurs before their proliferation and is characterized by loss of expression of cardiac contractile proteins such as α-myosin heavy chain and troponin T (ref. 6). Cardiac regenera- tion in zebrafish might be initiated predominantly by undifferentiated stem or progenitor cells from the outer (epicardial) layer of the heart 8 .
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