The nonspecific term cardiomyopathy is clinically characterized by cardiomegaly with or without left ventricular hypertrophy, electrocardiographic abnormalities, and signs and symptoms of congestive heart failure which cannot be attributed to hypertensive, coronary, valvular or congenital heart disease. The condition, which exists in both congestive and hypertrophic forms, is an important cause of heart failure which can lead to functional decompensation and death. Only a few studies have attempted to assess myocardial metabolic function in animals or humans with this disease. Strains of the Syrian hamster have been developed which autosomal-recessively inherit and exhibit either the congestive or hypertrophic cardiomyopathy in 100% of the animals. These animals are the most frequently used animal model of this disease and, thus, will be used in the proposed study. Data is currently available to suggest that utilization of long chain fatty acids, the primary energy source in normal hearts, is significantly decreased in cardiomyopathy. Furthermore, myocardial levels of L-carnitine, a cofactor needed for long chain fatty acid oxidation, are also decreased in these hearts. The long term objective of this project is to test the hypothesis that the basic metabolic defect in cardiomyopathy is lower energy production due to decreased long chain fatty acid utilization. Furthermore, studies will be done to define the relationship of the low tissue L-carnitine levels to the decreased fatty acid oxidation and determine if these decreased levels are secondary to decreased L-carnitine transport into the myocardial cell.
The specific aims are to: 1.) characterize glucose and fatty acid metabolism in the hearts of cardiomyopathic Syrian hamsters, and 2.) test the therapeutic efficacy of exogenous L-carnitine as a therapeutic agent in this animal model. The hearts will be perfused via the isolated, working heart technique in order to maximally stress them while providing various exogenous substrates. Glycolytic and oxidative rats will be estimated using radioisotopic techniques and selected metabolic intermediates will be determined by established enzymatic assay techniques of the hearts. Actual L-carnitine transport rates will be determined utilizing a [14C]-L-carnitine technique. Further definition of any metabolic deficits will be assessed later in the project using isolated mitochondrial studies of substrate utilization and enzymatic activities. Knowledge gained from these various investigations will help define any metabolic causes of this disease and, thus, hopefully facilitate the development of treatment regimens directed at the cellular basis of this often fatal disease entity.
| Whitmer, J T; Kumar, P; Solaro, R J (1988) Calcium transport properties of cardiac sarcoplasmic reticulum from cardiomyopathic Syrian hamsters (BIO 53.58 and 14.6): evidence for a quantitative defect in dilated myopathic hearts not evident in hypertrophic hearts. Circ Res 62:81-5 |
| Whitmer, J T (1987) L-carnitine treatment improves cardiac performance and restores high-energy phosphate pools in cardiomyopathic Syrian hamster. Circ Res 61:396-408 |
