Chapter 5 - Ischemic Heart Disease and its Consequences

Abstract

Ischemic heart disease remains a leading cause of morbidity and mortality in all industrialized nations, resulting from blockage of one or more coronary arteries. Although the treatment of myocardial ischemia continues to improve with more timely and effective reperfusion, no effective therapy exists to prevent or attenuate the resulting myocardial ischemia–reperfusion injury. Moreover, the major determinant of the long-term outcome is the amount of myocardium that is destroyed as a result of ischemic injury (i.e., the size of infarction). Thus, it is believed that a significant reduction in myocardial infarct size will decrease subsequent morbidity and mortality. As such, interventions designed to effectively reduce myocardial infarction are still needed. This chapter will open with a brief description of the pathophysiology of ischemia–reperfusion injury before transitioning into a discussion on the signaling cascades that have been associated with cardioprotection. Specifically, this chapter will highlight the Reperfusion Injury Salvage Kinase (RISK) pathway, the Survivor Activating Factor Enhancement (SAFE) pathway, and AMP-activated protein kinase (AMPK) signaling, which all confer cardioprotection when specifically activated at the onset of reperfusion following myocardial ischemia by signaling through the mitochondria. This chapter will also provide some insights into several therapeutic strategies, such as gasotransmitters (nitric oxide, hydrogen sulfide, carbon monoxide), micro-RNA, and stem cells, which have the ability to activate multiple cardioprotective signaling cascades. Finally, this chapter will provide a discussion on why therapeutic trials for new drugs designed to reduce ischemia–reperfusion injury have not been successful in the past.