Occult Cardiotoxicity—Toxic Effects on Cardiac Ischemic Tolerance

Abstract

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.

Uremia Aggravates Left Ventricular Remodeling after Myocardial Infarction

“…We therefore concluded that ischemia tolerance is reduced in uremia [14,15]. There is growing evidence that 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 [30,31,32]. In line with our previous results [14,15] an increased area of myocardial necrosis was reproducible in the present study.…”

Interaction of Risk Factors, Comorbidities, and Comedications with Ischemia/Reperfusion Injury and Cardioprotection by Preconditioning, Postconditioning, and Remote Conditioning

“…Very little is known on the possible unwanted effect of medications on the ischemic heart and endogenous cardioprotection, which may result in a latently developing cardiotoxicity (Golomb et al, 2009), and which is now termed as "hidden cardiotoxicity." Hidden cardiotoxicty of a medication may not be seen in the healthy heart but may manifest in only the ischemic heart as an increased tissue injury due to an increased sensitivity to an ischemic challenge or a decreased capability to adapt to an ischemic challenge.…”

Non-proliferative and Proliferative Lesions of the Cardiovascular System of the Rat and Mouse

“…Some xenobiotics may have little direct effect on the cardiovascular system but may elicit “toxicity” by complicating or exacerbating pre-existing cardiovascular disease (Feenstra et al 1999; Golomb et al 2007; Golomb et al 2009). …”