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Most organs in mammals, including the heart, show a certain level of plasticity and repair ability during gestation. This plasticity is, however, compromised for many organs in adulthood, resulting in the inability to repair organ injury, including heart damage produced by acute or chronic ischemic conditions. In contrast, lower vertebrates, such as fish or amphibians, retain a striking regenerative ability during their entire life, being able to repair heart injuries. There is a great interest in understanding both the mechanisms that allow heart plasticity during mammalian fetal life and those that permit adult cardiac regeneration in zebrafish. Here, we revise strategies for cardiomyocyte production during development and in response to injury and discuss differential regeneration ability of teleosts and mammals. Understanding these mechanisms may allow establishing alternative therapeutic approaches to cope with heart failure in humans. [ABSTRACT FROM AUTHOR]

Many forms of cardiovascular disease are associated with cardiomyocyte loss via necrosis and/or apoptosis. The cumulative loss of contractile cells ultimately results in diminished cardiac function. Numerous approaches have been employed to reduce the rate of cardiomyocyte loss, or alternatively, to repopulate the heart with new cardiomyocytes. Strategies aimed at repopulating the heart include cardiomyocyte cell therapy, myogenic stem cell therapy, and cell cycle activation therapy. All three approaches are based on the assumption that the de novo cardiomyocytes will participate in a functional syncytium with the surviving myocardium. This review will discuss the current status of interventions aimed at repopulating the heart with functional cardiomyocytes. [ABSTRACT FROM AUTHOR]

Regeneration of the diseased myocardium by cardiac cell transplantation is an attractive therapeutic modality. Yet, because the transplanted cardiomyocytes should functionally integrate within the diseased myocardium, it is preferable that their properties resemble those of the host. To determine the functional adaptability of human embryonic stem cell-derived cardiomyocytes (hESC-CM) to the host myocardium, the authors investigated the excitation-contraction (E-C) coupling and the responsiveness to common physiological stimuli. The main findings are: (1) hESC-CM readily respond to electrical pacing and generate corresponding [Ca2+ ]i transients (measured by fura-2 fluorescence) and contractions (measured by video edge detector). (2) In contrast to the mature myocardium, hESC-CM display negative force-frequency relations. (3) The hESC-CM contraction is dependent on [Ca 2+]o and blocked by verapamil. (4) Surprisingly, ryanodine, the sarcoplasmic-endoplasmic reticulum Ca 2 -ATPase inhibitor thapsigargin, and caffeine do not affect the [Ca2+]i transient or contraction. Collectively, these results indicate that at the developmental stage of 45 to 60 days, the contraction is largely dependent on [Ca2+]o rather than on sarcoplasmic reticulum (SR) Ca2+ stores. The results show for the first time that the E-C coupling properties of hESC-CM differ from the adult myocardium, probably due to immature SR function. Based on these findings, genetic manipulation of hESC-CM toward the adult myocardium should be considered. [ABSTRACT FROM AUTHOR]

Relaxin has been validated as a cardiotropic hormone, being produced by the heart and acting on specific heart receptors. Evidence is accumulating that it could hamper the pathophysiologic mechanisms of ischemic heart disease. Time is ripe to study relaxin as a cardiotropic drug, as recombinant human relaxin (hrRLX) is now available and previous clinical trials have shown a virtual lack of toxicity and adverse side effects, even at high doses. Our recent observations suggest that relaxin, besides being a preventative agent, may also be effective in the treatment of acute myocardial infarction and may be an adjuvant for precursor cell grafting to repair postinfarct myocardium. In a swine model of myocardial infarction currently used to test cardiotropic drugs due to its similarities with human ischemic heart disease, hrRLX, given at reperfusion upon 30 min of ischemia, markedly reduced serum and tissue markers of myocardial injury, cardiomyocyte apoptosis and leukocyte recruitment, resulting in overall improvement in cardiac performance compared with the controls. In in vitro mixed cultures of mouse skeletal myoblasts and adult rat cardiomyocytes, relaxin increased gap junction formation and potentiated gap junction-mediated intercellular exchanges and signaling between the coupled cells. In view of the therapeutic use of myoblast grafting for cardiac repair, relaxin could hence favor the electromechanical coupling of grafted myoblasts with the resident cardiomyocytes and facilitate their transdifferentiation towards a cardiac phenotype. Relaxin, therefore, shows promising therapeutic potential in cardiology and cardiac surgery. [ABSTRACT FROM AUTHOR]

Many forms of cardiovascular disease are associated with cardiomyocyte loss via apoptosis and/or necrosis. Although there is currently debate regarding the level at which adult cardiomyocytes can reenter the cell cycle and proliferate, it is clear that the intrinsic regenerative growth capacity is insufficient to reverse the progression to failure in badly injured hearts, The ability to reactivate cardiomyocyte proliferation in damaged hearts might permit regenerative growth, provided that the nascent cells are able to participate in a functional syncytium with the surviving myocardium. In this review, techniques commonly used to monitor cardiomyocyte cell cycle activity in normal and injured hearts are discussed. In addition, several genetic models are described wherein the expression of fundamental cell cycle regulatory proteins has been altered in cardiomyocytes. [ABSTRACT FROM AUTHOR]