Metabolic impairment and perfusion abnormalities are known to occur in hypertensive heart disease (HHD) and in cardiomyopathies. Free fatty acid (FFA) extraction is severely inhibited in a number of pathobiochemical reactions. This parameter was assessed using the radiolabeled FFA analogue 123I-(p-iodo-phenyl-)-pentadecanoic acid (IPPA) and 201Tl as perfusion marker, both of them injected at maximal physical workload. The regional extraction fraction of IPPA (IPPA-EF) was estimated by relating the regional IPPA and 201Tl uptake to each other. In HHD (normal coronary arteries) with posterior wall thickness less than or equal to 12 mm IPPA-EF was 77 +/- 18% (SD) in septum and 92 +/- 17% in the posterolateral wall (N = 13), with thickness of greater than 12 mm 60 +/- 23% in septum and 61 +/- 20% in the posterolateral wall (N = 8) when compared with IPPA-EF in normal subjects (= 100%, N = 9). In hypertrophic cardiomyopathy (HCM) IPPA-EF averaged 51 +/- 20% in septum and 87 +/- 10% in the posterolateral wall (N = 11). In these patient groups no systematic regional changes in 201TI uptake were observed. In dilated cardiomyopathy (DCM) both IPPA-EF and 201Tl uptake showed distinct regional variations and a great interindividual variability with a mean IPPA-EF reduction of 12% (N = 9). Thus, IPPA uptake in primarily non-ischemic myocardial disease may already be compromised when 201Tl uptake is unchanged. The double-nuclide method for IPPA-EF determination allows to eliminate the influence of flow in FFA imaging and enhances the potential of scintigraphy in the differential diagnosis of HHD versus coronary artery disease.