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Many changes occur during reperfusion of the myocardium after ischemic damage. Necrosis and apoptosis appear to be ongoing during ischemia, while apoptosis is boosted by the reperfusion event. In the past 10 years, distinct intracellular pathways important for hypertrophy, apoptosis, cardiac failure, ischemic preconditioning and reperfusion damage have been recognized. The eventual response of the cardiomyocyte will depend on energy and time available as well as changes in pH and ion handling and the delicate balance of activation of signaling molecules and transcription factors. There is agreement on the central role of mitochondria and nitric oxide (NO) in programmed cell death. However, although many groups analyzed the contribution of NO to cell death, still the circumstances and levels required for cardioprotection or death are unclear. Growth factors, cytokines, and downstream signaling molecules have been shown to influence programmed cell death through mechanisms reminiscent of preconditioning. Here, the role of apoptosis in ischemia reperfusion-related cell death is reviewed. Important data have been obtained in isolated cells, intact hearts and intact animals. Both pharmacological as well as genetic interventions are discussed. Proof for apoptosis in man post-myocardial infarction (MI) treated through primary Percutaneous Trans-luminal Coronary Angioplasty or other reperfusion therapy is reviewed. Finally, the currently available quantification methods for apoptosis post-MI are mentioned.

Regeneration of the myocardium by transplantation of cardiomyocytes is an emerging therapeutic strategy. Human embryonic stem cells (HESC) form cardiomyocytes readily but until recently at low efficiency, so that preclinical studies on transplantation in animals are only just beginning. Here, we show the results of the first long-term (12 weeks) analysis of the fate of HESC-derived cardiomyocytes transplanted intramyocardially into healthy, immunocompromised (NOD-SCID) mice and in NOD-SCID mice that had undergone myocardial infarction (MI). Transplantation of mixed populations of differentiated HESC containing 20-25% cardiomyocytes in control mice resulted in rapid formation of grafts in which the cardiomyocytes became organized and matured over time and the noncardiomyocyte population was lost. Grafts also formed in mice that had undergone MI. Four weeks after transplantation and MI, this resulted in significant improvement in cardiac function measured by magnetic resonance imaging. However, at 12 weeks, this was not sustained despite graft survival. This suggested that graft size was still limiting despite maturation and organization of the transplanted cells. More generally, the results argued for requiring a minimum of 3 months follow-up in studies claiming to observe improved cardiac function, independent of whether HESC or other (adult) cell types are used for transplantation.

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