Opioid Preconditioning of Normal and Dystrophic Heart Muscle

Principal Investigator: Paul Iaizzo, Ph.D.

Duchenne muscular dystrophy (DMD) is an x-linked disease that is characterized by the loss of the muscle protein, dystrophin. This protein is part of the dystroglycan complex that links the cytoskeleton to the extracellular matrix and is therefore integral in the contractile properties of the striated muscle. Muscle fibers are easily damaged in dystrophic muscle, and regeneration results in a gradual replacement of muscle fibers with connective tissue. It is a progressive disease that almost exclusively affects males. Clinical symptoms start appearing at 2-3 years of age. Mobility becomes increasingly limited and patients are often wheelchair bound by the time they reach their teens. In addition, cardiomyopathy and respiratory insufficiency affect DMD patients, and normally constitute the main cause of death. DMD patients often need to undergo surgeries to ameliorate symptoms of the disease such as joint stiffness or scoliosis. In a few rare cases, heart transplants have been performed due to this associated cardiomyopathy. Yet, any such surgical procedure can be dangerous because anesthetic complications often result with these patients. More specifically, the use of certain agents, such as succinylcholine, can trigger malignant hyperthermic-like episodes or even sudden cardiac death and thus should not be used. Opioid-based anesthesia may be an attractive alternative for DMD patients because it avoids the complications that may result from other anesthetics and also has a preconditioning effect on muscle. Preconditioning protects muscle from damage (mostly ischemic damage) by reducing the intracellular concentrations of calcium and oxygen free radicals. This protective effect has been seen in both skeletal and cardiac muscle, both of which are affected in DMD patients. The goal of this research project is to better define the potential benefits of specific opioid-based anesthesia so it may be best applied to the DMD patient. To do so, we will study both in vitro and in situ the potential benefits of opioid agonist preconditioning on striated (skeletal and cardiac) muscles.