Novel interventions for cardioprotection.

Abstract

The restoration of blood flow to an ischemic region is associated with complex events that lead to tissue injury greater than that attributable to the original ischemic insult, a phenomenon referred to as reperfusion injury. Reperfusion injury is associated with generation of reactive oxygen species (ROS), activation of the innate immune system (complement), and infiltration of inflammatory cells. The endothelial glycocalyx is recognized as an important first site of damage. Therefore I hypothesized that pharmacological agents that might protect the glycocalyx may in turn reduce reperfusion injury. Treatment of rabbits with the glycosaminoglycan sulodexide significantly reduced myocardial infarct size after 30 minutes of coronary artery occlusion and 4 hours of reperfusion. The plasma concentration of cardiac-specific troponin I (cTnI), a marker of cardiac damage, was also reduced. Deposition of C-reactive protein (CRP) and the complement membrane attack complex (MAC) within the myocardium was attenuated in sulodexide-treated rabbits. No change was observed in activated partial thromboplastin time indicating that administration of the drug had little effect on systemic coagulation parameters, a consequence common among glycosaminoglycans. Infarct size was also reduced by pretreatment of a carotenoid, disodium disuccinate astaxanthin (DDA). Plasma levels of cTnI and deposition of CRP and MAC were decreased as well. Serum complement activity was diminished in rabbits pretreated with DDA suggesting the compound possesses anti-inflammatory properties in addition to its role as an antioxidant. Finally, I investigated the role of DDA in a canine model of arterial thrombosis. Accumulating evidence suggests that generation of ROS is required for proper platelet activation. I hypothesized that the antioxidant DDA would inhibit thrombus formation by reducing ROS. After lysis of a stable thrombus, DDA decreased the incidence of rethrombosis compared to control. DDA administration also improved arterial blood flow while reducing thrombus weight. Many anticoagulants increase the risk of bleeding at sites of injury. Tongue bleeding times, however, demonstrated no difference between dogs treated with DDA or saline. The results reported in this dissertation suggest that after completion of more rigorous pharmacology and toxicology studies, these compounds may one day find clinical utility in the treatment of cardiovascular diseases.