Listed in this section are current examples of pharmacological therapies targeted at protecting the myocardium from damage caused by ischemia and reperfusion injury.
6.1. Na+/H+ Exchange Blockers
Although activation of the Na+/H+ exchanger (NHE) in response to acidosis is a feedback mechanism that enables the myocardial cell to maintain a fairly stable pH range, NHE activation may not always be beneficial. During ischemia, there is often a buildup of metabolic products that is caused by the anaerobic breakdown of ATP; the production of lactate and high CO2 levels drive the intra-cellular pH below a tolerable level. However, a comparable decrease in the extracellular pH occurs during low-flow and no-flow ischemia, and importantly, NHE activity is inhibited. Then, when blood flow is reestablished to the ischemic region, this inhibition is removed, and both the NHE and the Na-HCO3- symport are simultaneously activated in an attempt to restore the internal pH rapidly (32). With the normalization of intracellular pH via the NHE, there is an increase in internal Na+. Under normal conditions, cells primarily extrude Na+ via Na+-K+ATPase; however, because of depleted energy reserves, the postischemic cell relies on the Na+-Ca2+ exchanger for Na+ normalization. Importantly, this results in increased intracellular Ca2+ levels, which, as mentioned in Section 5, significantly contribute to the pathology of reperfusion injury (Fig. 4).
In experimental animals, various NHE inhibitors have been observed to be beneficial when administered either prior to ischemia or prior to reperfusion. Specifically, cariporide (NHE-1 specific) has been reported to reduce postischemic edema, arrhythmias, apoptosis, infarct size, contracture, enzyme efflux, and hypertrophy and prevent free-radical damage, preserve ATP, and enhance myocardial preservation following prolonged storage (33-40). In the GUARDIAN (Guard During Ischemia Against Necrosis) clinical trial, cariporide pretreatment prior to coronary artery bypass grafting resulted in a 25% reduction in mortality or myocardial infarction following surgery (41). Further supporting its use during routine cardiac surgery, Myers and Karmazyn (42) found that hypothermia potentiated the benefits of cariporide, specifically when cariporide was administered during reperfusion.
However, in a clinical trial (the ESCAMI trial [Evaluation of the Safety and Cardioprotective Effects of Eniporide in Acute Myocardial Infarction]) in which eniporide (another NHE-1 inhibitor) was administered on reperfusion to patients undergoing percutaneous transluminal coronary angioplasty or thrombolysis for acute myocardial infarction, eniporide failed to show any significant reduction in either infarct size or occurrence of clinical events following treatment (43). Furthermore, cariporide administration, during reperfusion following global hypothermic ischemia, failed to show any beneficial hemodynamic effects relative to control hearts (unpublished data from our laboratory).
Although the use of NHE blockers is still considered experimental, their future use in cardiac surgery and following ischemia/reperfusion remains promising. Interestingly, the prospect of using them as a combined therapy with other cardioprotective therapies, such as ischemic preconditioning, is being addressed, and initial results have suggested that the combined therapies produce additive benefit (44).
Antioxidants are speculated to attenuate or prevent reperfusion injury by acting as: (1) free-radical scavengers; (2) inhibitors of free-radical generation; (3) metal chelators, thereby removing the free-radical-generating catalyst; (4) promoters of endogenous antioxidant production; or (5) inhibitors of apoptosis via the upregulation of Bcl-2 (a gene involved in the apoptosis signaling pathway) (45). However, experimental animal models and human clinical trials have together provided conflicting results concerning the therapeutic benefits of antioxidants to attenuate reperfusion injury. Interestingly, many typical thiol-containing drugs commonly used for treating both coronary artery disease and heart failure have also been shown to exhibit antioxidantlike effects within the myocardium; these include p-adrenergic antagonists propanolol (46), metoprolol (47), and carvedilol (48), as well as angio-tensin-converting enzyme inhibitors, iron-chelating agents, and Ca2+ channel blockers (45).
Experimentally, the administration of a calcium channel antagonist is believed to help preserve myocardial function and metabolism in case studies employing normothermic ischemia, crystalloid cardioplegia, or blood cardioplegia (1). More specifically, their use was reported to prevent ATP hydrolysis and calcium influx during ischemia and improve cardioplegia delivery by coronary vasodilation. However, the potential use of calcium channel blockers for myocardial protection is considered limited because of their negative inotro-pic and dromotropic effects, which could be specifically problematic in patients with preoperative poor ventricular function. Hence, further studies are needed to determine the potential utility of newer calcium channel antagonists such as amlodipine and felodipine, agents that may elicit fewer side effects in very ill patients. The current applications of calcium channel antagonists are in patients with normal preoperative function who are at risk for postoperative hypertension, tachycardia, coronary spasm, and/or ischemia (1).
Perioperative depletion of myocardial glycogen stores has been correlated with a higher incidence of arrhythmias, low output syndrome, and/or infarction (49). Consequently, in one study, Iyengar et al. (49) preoperatively dosed patients with a glucose-insulin-potassium solution and a bolus of exogenous glucose and found zero incidences of perioperative ischemic complications (compared to a 44% occurrence in patients not receiving the solutions). This beneficial effect was attributed to increased preoperative glycogen stores, enhanced perioperative aerobic metabolism, and reduced free fatty acid circulation in the hypoxic hearts, all of which are mediated by glucose and insulin. Future studies are needed to validate such a therapy.
The administration of growth factors for cardioprotective means is typically done in attempts to minimize or prevent apoptosis, which is known to occur in addition to necrosis during (prolonged) myocardial ischemia and reperfusion. In general, it is thought that reperfusion injury accelerates apoptosis in viable postischemic cells, adding to the overall necrosis (50). A link was described between apoptosis and reperfusion in humans following acute myocardial infarctions in which apoptosis was significant in cells within and bordering the infarcted region (51). Experimental animal studies have shown infarct-reducing benefits of several growth factor proteins when given during ischemia or during reperfusion, including transforming growth factor-pi (52), insulin (53), insulin-like growth factor 1 (54), fibroblast growth factor (55), and cardiotrophin 1 (56).
The amino acids glutamate and aspartate, when added to the cardiopulmonary bypass circuit, have been shown to reduce lipid peroxidation and preserve myocardial function following tissue reoxygenation (57). Similarily, the addition of amino acids to cardioplegia has yielded similar positive results (58). Although most of the benefits were attributed to the ability of the amino acids to produce ATP anaerobically via substrate phosphorylation, evidence has further linked their benefits to inhibition of free-radical production and better retention of endogenous antioxidants (57).
In addition to being a potent vasodilator, nitric oxide (NO) reduces platelet aggregation and neutrophil adherence and is considered to act as a free-radical scavenger. NO is synthesized from the amino acid l-arginine by nitric oxide synthase. It is thought that l-arginine levels decline during ischemia, leading to lower NO production and thus a greater injury potential (1). Although the addition of NO donors to cardioplegia solutions has been shown to beneficially increase ischemic NO levels (59), there are conflicting opinions regarding the benefits of NO because of its negative inotropic effects.
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