It is a long-standing belief that cardiomyocytes in mammals lose their proliferative potential early after birth and that each myocyte survives and continuously beats throughout the life of the organism. Hence， it has been accepted that dead cardiac muscle will never be replaced by newly formed myocytes. Thus， ventricular assisting devises and/or heart transplantation were considered as the exclusive therapeutic options for uncontrollable heart failure.
However， several lines of evidence have been accumulated which question this theory. In sex-mismatched heart transplantation， Y chromosome was found in female donor heart transplanted to a male patient. In patients with aortic constriction， myocyte hyperplasia， which corresponds to an increase in cardiomyocyte number， accompanies cellular hypertrophic response. 

    These observations led to the recent discovery of resident c-kit-positive cardiac stem cells (CSCs)， which not only challenged the long-lasting biological dogma but also revealed the possibility of a totally new therapeutic approach for the devastating disease of heart failure. 

    CSCs can be isolated from adult myocardium obtained from different species including rodents， cats， dogs， pigs and humans. CSCs do not express hematopoietic lineage markers and possess the fundamental properties of stem cells; they are self renewing， clonogenic and multipotent.

    In the adult heart， CSCs are organized in clusters and localized in cardiac niches， in which primitive cells at various stages are connected through gap and adherens junctions with supporting cells， i.e. cardiac myocytes and fibroblasts. CSCs divide symmetrically or asymmetrically to generate daughter stem cells or a committed progeny， maintaining the homeostasis of the heart. CSCs differentiate into cardiomyocytes， smooth muscle cells， endothelial cells and fibroblasts to substitute old senescent cells. In fact， cardiac muscle consists of a heterogeneous population of myocytes. It contains small young myocytes as well as large senescent ones. 

    When isolated CSCs are injected in the non-damaged heart through the epicardial surface， they do not engraft and disappear quickly as there is no need of them. When CSCs are treated with growth factors prior to injection to the heart without damage， they engraft and survive but rarely differentiate in the host myocardium. Administration of CSCs in the border zone of an acutely infarcted heart， however， results in massive regeneration of viable cardiac muscle and vessels in the infarcted region and improved cardiac function. When human CSCs are injected in infarcted rodent heart， newly formed human cardiomyocytes are physically and functionally integrated in the border zone with the surrounding viable host myocytes. Importantly， cell fusion events do not play a major role in this process. 

    Such an effect is also observed when cell implantation is carried out through the coronary circulation in rats and larger animals. CSCs in coronary capillary eventually exit the lumen and invade the interstitium of damaged regions promoting tissue regeneration. 

    Alternatively， endogenous CSCs in the diseased heart can be stimulated by intramyocardial administration of growth factors and induced to migrate and replace areas of injury. Although cardiac niches exist throughout the heart， they accumulate preferentially in atria and apex， which therefore represent the reservoir of CSCs. When insulin-like growth factor-1 (IGF-1) and hepatocyte growth factor (HGF) are injected to induce migration of resident CSCs from their reservoir to damaged areas， these cells produce matrix metalloproteinase (MMP)， digest interstitial tissue and move through a tunnel of fibronectin heading to the regions， where they form new myocardium.

    Similar approaches are effective in chronic infarction， which is more relevant to the clinical setting of human diseases and treatments. In rats， both CSC injection and growth factor administration successfully result in partial but significant replacement of scarred tissue with viable myocardium and improvement of global function of the infarcted heart.
Additionally， injection of CSCs， following pretreatment with growth factors， in close proximity of the ligature of coronary artery causes the formation of a biological coronary bypass. The newly formed vessels include all segments of the coronary circulation， from large conductive arteries to capillary structures， and are connected with preexisting coronary arteries. Interestingly， this process occurs mainly through the mechanism of vasculogenesis rather than angiogenesis since newly formed vessels do not show incorporation of host-derived cells to generate chimeric structures.
Finally， aging cardiomyopathy， caused by progressive senescence and apoptosis of cardiomyocytes， is partially reversed by the stimulation of resident CSCs. Although the primitive cell compartment also becomes senescent as a function of age， there are groups of cells which are still functionally competent and responsive to activating factors. Treatment with growth factor injection in aged rat hearts resulted in replacement of senescent cardiac cells， improvement of cardiac function and， more importantly， prolongation of the expected life span of the old animals. 

    Collectively， CSCs would provide a powerful tool to treat a large variety of cardiovascular diseases. Further characterization of the cells will allow optimization of the treatment and the development of individualized strategies based on the type of disease and the cardiac region affected.