The Role of Leukocyte-Generated Oxidants in Left Ventricular Remodeling

The cellular injury that results from irreversible ischemia leads to the alteration of tissue function responsible for the phenomenon that we call left ventricular remodeling. Oxidative stress and inflammation are key elements of this process; in mice as in humans, elevation of markers of inflammation at the time of myocardial infarction (MI) is a predictor of the development of ischemic myopathy and of adverse clinical outcomes. Several leukocyte-derived enzyme systems are responsible for the release of oxidizing agents into the myocardium after ischemic injury and provide a means of better understanding MI. By identifying the oxidation products present after inflammation, the responsible leukocyte-generating oxidant systems can be elucidated. Interestingly, a key leukocyte-derived marker, myeloperoxidase (MPO), was formerly measured routinely by older-generation hematology analyzers. Patients with lower levels of MPO were noted to be at lower risk for untoward cardiovascular events, suggesting that humans are more genomically “hardwired” than previously thought. Studies with genetic knockout mice confirm the importance of these leukocyte-generated oxidants in the pathophysiologic consequences of ischemia. This clearly affects the anatomic extent of damage, the hemodynamic consequences, and ultimately, the clinical correlates and potential outcomes. An understanding of these oxidative processes and their relation to inflammation will be extremely useful in the development and understanding of potential therapeutic agents.