Characterization of altered myocardial fatty acid metabolism in patients with inherited cardiomyopathy

Inherited defects in myocardial long-chain fatty acid metabolism are increa singly recognized as a cause of cardiomyopathy and sudden death in children . To evaluate whether the phenotypic expression of these genetic diseases c ould be delineated using positron emission tomography (PET), 11 patients wi th inherited defects in fatty acid metabolism were evaluated and results we re compared with those of 6 nonaffected siblings. Myocardial perfusion, myo cardial oxygen consumption (MVO2), and long-chain fatty acid metabolism wer e determined noninvasively with PET using quantitative mathematical models. There were no differences in haemodynamics, perfusion, MVO2 or plasma subs trate levels between groups. Patients with defects in enzymes of fatty acid beta -oxidation (acyl-CoA dehydrogenase and 3-hydroxyacyl-CoA dehydrogenas e deficiencies) n = 5 had diminished myocardial palmitate oxidation compare d with healthy siblings (3.2 +/- 3.0 vs 13.0 +/- 5.6 nmol/g per min, p < 0. 03) and a decrease in the percentage of MVO2 accounted for by palmitate (2% +/- 3% vs 9% +/- 5%), p > 0.04). In these patients, extracted palmitate wa s shunted into a slow-turnover compartment (predominantly reflecting esteri fication to triglycerides) with expansion of palmitate in that pool (185 +/ - 246 compared with 27 +/- 67 nmol/g in healthy siblings, p < 0.02). In con trast, myocardium of patients with carnitine deficiency (n = 6 (all on oral carnitine therapy) had normal palmitate extraction but expansion of the in terstitial/cytosolic fatty acid pool (617 +/- 399 vs 261 +/- 73 nmol/g in h ealthy siblings, p < 0.04), suggesting different mechanisms for handling up stream fatty acyl intermediates. Thus, PET can be used to noninvasively ass ess abnormal myocardial handling of fatty acids in patients with inherited defects of metabolism. This approach should be useful in the assessment of altered myocardial fatty acid metabolism associated with cardiomyopathy as well as for evaluating the efficacy of therapeutic interventions in affecte d patients.