Reperfusion injury in the heart can occur either as a result of transient arterial occlusion (eg, due to vasospasm or thrombus formation with spontaneous lysis) or as an iatrogenic consequence of thrombolytic or angioplastic therapy. A basic research objective is to delineate pathogenesis in order to devise effective prevention and/or treatment strategies. This, of course, applies to most biomedical research, and one general approach to this and other conditions is a reductionist model in which the responses of isolated cell types are investigated in tissue culture. This experimental approach has the advantage of distinguishing primary responses to the stimulus from those that are secondary to the responses of other cell types within the organ. Not only the target cell but also the inciting stimulus can be well defined in cell culture. Arterial occlusion leads to ischemia, which involves deprivation of energy substrates (glucose and oxygen) and accumulation of toxic metabolites (H+ and K+), as well as secondary alterations in endothelial and inflammatory cell function. In contrast, cultured cells (eg, cardiac myocytes) can be subjected to anoxia/hypoxia under highly controlled conditions. Furthermore, the expression of specific proteins can be experimentally manipulated in an attempt to establish molecular mechanisms. Two obvious limitations of tissue culture systems involve the analysis of responses that are not cell autonomous (ie, involve more than one cell type) and those that are cell-type or developmental-stage specific (eg, adult versus neonatal cardiomyocytes). Thus, the relevance of responses in tissue culture to organ function in vivo must be confirmed experimentally, eg, by the use of transgenic or knockout mouse models.

Webster et al1 have used cultured neonatal rat cardiac myocytes to explore the mechanisms of cell death triggered by hypoxia and reoxygenation. They recently reported that under their culture conditions these cells undergo apoptosis via a p53-independent pathway, in contrast to a previous study that implicated p53 in this process. 2 They also used Langendorff-perfused hearts from wild-type and p53-knockout mice to provide compelling evidence that cell death