Detection and assessment by positron emission tomography of a genetically determined defect in myocardial fatty acid utilization (long-chain acyl-CoA dehydrogenase deficiency)

Abstract

Genetic defects in fatty acid oxidation are important, inherited causes of cardiomyopathy, skeletal myopathies, and childhood sudden death. The clinical manifestations and their severity vary widely among affected subjects and different age groups. Although measurement of serum and urinary fatty acid intermediary metabolites and enzymatic assays establish the diagnosis of a defect in fatty acid oxidation, they do not predict the specific clinical manifestations nor their severity in a given subject. To determine whether impaired myocardial fatty acid utilization, indicative of cardiac phenotypic expression of a specific genetic abnormality in fatty acid oxidation, can be detected, cardiac positron emission tomography with the metabolic tracers carbon-11-labeled palmitate and acetate was performed in 6 patients with long-chain acyl-CoA dehydrogenase (ACD) deficiency and in 9 control subjects. The myocardial extraction of both tracers was similar in patients and controls. The rate of clearance of palmitate from myocardium was significantly prolonged in patients compared with that in control subjects (0.022 +/- 0.012 vs 0.061 +/- 0.033 min-1; p < 0.025), indicative of a decreased rate of oxidation of long-chain fatty acids. Furthermore, the extent of diminution of clearance of palmitate, quantified in terms of the rate of clearance for palmitate divided by that for acetate (to correct for individual differences in overall mitochondrial oxidative metabolic flux), correlated with the clinical severity of the long-chain ACD deficiency. Accordingly, noninvasive evaluation with positron emission tomography may not only facilitate diagnosis, but also enable assessment of the pathogenetic impact and effects of therapeutic interventions in the hearts of subjects with specific, inherited defects in fatty acid oxidative metabolism.