Occult Cardiotoxicity—Toxic Effects on Cardiac Ischemic Tolerance

The outcome of cardiac ischemic events depends not only on the extent and duration of the ischemic stimulus but also on the myocardial intrinsic tolerance to ischemic injury. Cardiac ischemic tolerance reflects myocardial functional reserves that are not always used when the tissue is appropriately oxygenated. Ischemic tolerance is modulated by ubiquitous signal transduction pathways, transcription factors and cellular enzymes, converging on the mitochondria as the main end effector. Therefore, drugs and toxins affecting these pathways may impair cardiac ischemic tolerance without affecting myocardial integrity or function in oxygenated conditions. Such effect would not be detected by current toxicological studies but would considerably influence the outcome of ischemic events. The authors refer to such effect as "occult cardiotoxicity." In this review, the authors summarize current knowledge about main mechanisms that determine cardiac ischemic tolerance, methods to assess it, and the effects of drugs and toxins on it. The authors offer a view that low cardiac ischemic tolerance is a premorbid status and, therefore, that occult cardiotoxicity is a significant potential source of cardiac morbidity. The authors propose that toxicologic assessment of compounds would include the assessment of their effect on cardiac ischemic tolerance.