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Ann Thorac Surg 1996;61:1411-1412
© 1996 The Society of Thoracic Surgeons
Eric Lipman Laboratories of Molecular and Cellular Cardiology, Division of Cardiology, Medical College of Virginia, Richmond, VA 23298
When living cells are subjected to a short elevation in temperature, certain proteins, known as heat-stress or heat-shock proteins (HSPs), are synthesized. These proteins have been shown to subsequently protect the myocyte from not only further heat stress, but other metabolic insults, including ischemia/reperfusion injury [1, 2]. The induction of these HSPs has been shown to protect the myocardium from ischemic damage in a number of different models and species. The effects have included a reduction in infarct size as demonstrated by tetrazolium staining, reduced release of creatine kinase, and improvement in contractile functions. Increased levels of HSP have been associated with preservation of tissue adenosine triphosphate after ischemia-reperfusion and decreased production of oxygen-derived free radicals after reperfusion [3]. However, whether one or a combination of these mechanisms is mediated through HSP resulting in myocardial protection remains unknown.
In the study, Amrani and associates investigated postischemic recovery of mechanical and endothelial cell function in a model of hypothermic cardioplegic arrest and correlated this with the synthesis of inducible form of HSP 70. Their results demonstrate that maximal levels of HSP 70 correlated with postischemic recovery observed at 24, 26, and 30 hours after hypothermic cardioplegic arrest. For other time intervals, the postischemic functional recovery was comparable with control, although the levels of HSP 70 were still detectable.
This study raises a very important question: what is the critical threshold of HSP 70 to induce protection in the heart? Although the cellular levels of HSP 70 were significantly increased at several time intervals (18, 20, 36, and 48 hours after heat shock), apparently the level of protein was not high enough to protect the myocardium against hypothermic cardioplegic arrest. The results of this study differ somewhat from other studies. For example, Currie and associates [1] reported increased expression of HSP 71 correlated with cardioprotection at 24 hours but not 40 hours after heat shock. A preliminary study by Shipley and colleagues [4] demonstrated rapid induction and accumulation of both HSP 27 and HSP 72 four hours after heat stress. Interestingly, no myocardial protection was afforded until 24 hours after heat stress, and protection was gone by 30 hours after heat stress. The synthesis of HSP after heat stress was rapid, reaching more than 80% of maximum within 4 hours of initial insult. These results suggested that the myocardial protection afforded by heat stress cannot be solely explained on the basis of HSP expression, and may be dependent on posttranslational modification of translocation of HSP, or may be dependent on other as yet unidentified factors. Clearly, there is considerable controversy in this important area, and rigorous studies are required to further elucidate the mechanisms of heat stress induced cardiac protection.
Nevertheless, Amrani and colleagues deserve compliments for investigating the role of HSP 70 in this unique model of hypothermic cardioplegic arrest. To borrow a term from our high-tech colleagues, if cardioplegia represented the first generation of cardiac protection, preconditioning represents the second generation. Obviously heat shock, being nonphysiologic, is only a model, but the race is on in the laboratory on two fronts: first, the development of clinically applicable preconditioning either metabolically or pharmacologically, and second, the isolation and characterization of these unique HSPs. The prolonged ischemic time associated with cardiac transplantation appears to be a logical initial problem to begin this second generation approach. If a direct cause and effect relationship could be established for expression of HSP 70 versus protection of ischemic myocardium, the protein will open the door to new therapeutic options to reduce damage caused by ischemic heart disease of multiple etiologies.
References
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