The radioidinated synthetic fatty acid iodine-123 phenylpentadecanoic acid (IPPA) has proven useful in the identification of regional abnormalities of cardiac metabolism in patients with myocardial ischemia. The present study was performed to test the hypothesis that the myocardial distribution and turnover of fatty acids, assessed noninvasively with IPPA, are altered in patients with cardiomyopathy. Nine normal volunteers and 19 patients with dilated cardiomyopathy of various etiologies underwent cardiac imaging with single-photon emission computed tomography (SPECT) after intravenous injection of IPPA. Apical short-axis and basal short-axis sections were reconstructed and quantitatively analyzed for relative IPPA activity distribution and washout. Patients with congestive cardiomyopathy demonstrated significantly greater heterogeneity of IPPA uptake than normal subjects (maximal percent variation of activity 27 +/- 11 vs 18 +/- 4, p less than 0.01). They also demonstrated a more rapid percent washout rate than control subjects (24 +/- 8 vs 17 +/- 6 for the apical short-axis section, p less than 0.05; 26 +/- 7 vs 18 +/- 5 for the basal short-axis section, p less than 0.01). These abnormalities of fatty acid distribution and turnover were independent of the etiology of the cardiomyopathy. The degree of heterogeneity of IPPA uptake was significantly related to the patients' New York Heart Association functional class (r = 0.64, p less than 0.01). Thus, compared with normal myocardium, the myocardium of patients with congestive cardiomyopathy demonstrates a more heterogeneous distribution of fatty acid uptake, which parallels the clinical severity of the disease. Furthermore, patients with congestive cardiomyopathy demonstrate a more rapid myocardial clearance of the labeled fatty acid, as assessed with SPECT imaging.