Myocardial ischemia tolerance

Myocardial ischemia tolerance is a physiological phenomenon representing the intrinsic ability of the heart muscle to withstand periods of restricted blood flow and subsequent reperfusion injury. Rather than being a single molecular target, it is a complex biological state mediated by various intracellular signaling pathways, including the Reperfusion Injury Salvage Kinase (RISK) and Survivor Activator Factor Enhancement (SAFE) cascades. These pathways involve the activation of specific mediators like protein kinase C epsilon (PKC-ε) and the opening of mitochondrial ATP-sensitive potassium channels, which together serve to protect cardiomyocytes from necrosis and apoptosis. In clinical practice, this tolerance can be modulated by pharmacological agents such as nitrates, beta-blockers, and volatile anesthetics like sevoflurane, which mimic the protective effects of ischemic preconditioning. Understanding and enhancing myocardial ischemia tolerance is critical for reducing infarct size and improving outcomes in patients with coronary artery disease or those undergoing cardiac surgery. However, the translation of experimental preconditioning mimetics into effective clinical therapies has proven difficult, and certain drugs may inadvertently reduce this tolerance, a concept known as occult cardiotoxicity.

Other names

Cardiac ischemic toleranceIschemic toleranceMyocardial ischemic resistanceIntrinsic cardiac tolerance

Modulation of myocardial ischemia tolerance involves the activation of endogenous cardioprotective signaling pathways, most notably the Reperfusion Injury Salvage Kinase (RISK) and Survivor Activator Factor Enhancement (SAFE) pathways. These cascades lead to the activation of effectors such as protein kinase C epsilon (PKC-ε) and the opening of mitochondrial ATP-sensitive potassium (mitoKATP) channels, which collectively preserve mitochondrial integrity and inhibit the opening of the mitochondrial permeability transition pore (mPTP) during reperfusion.