Enhanced myocardial glucose use in patients with a deficiency in long-chain fatty acid transport (CD36 deficiency). (1/444)

CD36 is a multifunctional, 88 kDa glycoprotein that is expressed on platelets and monocytes/macrophages. CD36 also has high homology with the long-chain fatty acid (LFA) transporter in the myocardium. Although platelet and monocyte CD36 levels can indicate a CD36 deficiency, they cannot predict specific clinical manifestations in the myocardium of a given person. We examined the hypothesis that a deficiency in LFA transport augments myocardial glucose uptake in patients with a type I CD36 deficiency. METHODS: Seven fasting patients with a type I CD36 deficiency and 9 controls were assessed by cardiac radionuclide imaging using beta-methyl-p-iodophenyl-pentadecanoic acid (BMIPP) as a LFA tracer and by PET with 18F-fluorodeoxyglucose (FDG). RESULTS: None of the patients with a CD36 deficiency showed myocardial uptake of BMIPP. The percentage dose uptake of BMIPP in these subjects was significantly lower than that in normal controls (1.31+/-0.24 versus 2.90+/-0.2; P < 0.005). PET studies revealed that myocardial FDG accumulation was substantially increased in patients with a CD36 deficiency. Quantitative analysis showed that the percentage dose uptake of FDG in patients with a CD36 deficiency was significantly higher than that in normal controls (1.28+/-0.35 versus 0.43+/-0.22; P< 0.01). CONCLUSION: CD36 functions as a major myocardial LFA transporter and its absence may cause a compensatory upregulation of myocardial glucose uptake.  (+info)

Myocardial metabolism of 123I-BMIPP in a canine model with ischemia: implications of perfusion-metabolism mismatch on SPECT images in patients with ischemic heart disease. (2/444)

123I-(rho-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) is a fatty acid analog for SPECT imaging. This radiopharmaceutical possesses the unique property, that is, perfusion-metabolism mismatch on SPECT images in patients with ischemic heart disease. However, the reason of this mechanism remains unclear. METHODS: Using open-chest dogs under anesthesia, we made a system to release all the blood of the great cardiac vein outside without recirculation, if necessary. Left anterior descending artery (LAD) was occluded for 30 min after reperfusion. After the injection of BMIPP into LAD, blood samplings from the cardiac vein and abdominal aorta (6 dogs) or serial biopsy specimens from the LAD region (5 dogs) were performed, and then compared with the normal control. The catabolites of BMIPP, including backdiffusion of nonmetabolized BMIPP, were evaluated with high-performance liquid chromatography (HPLC) in the efflux study. Thin-layer chromatography (TLC) technique was introduced in the tissue analytical study. RESULTS: Although the rapid extraction of BMIPP from the plasma into the myocardium and the subsequent retention were unchanged, the early washout (8 min) of radioactivity significantly increased (51% +/- 12% to 65% +/- 7%; P < 0.05) with ischemia. The metabolites from the myocardium consisted of backdiffusion of nonmetabolized BMIPP, alpha, intermediate, and full oxidation metabolites. Among these metabolites, backdiffusion of nonmetabolized BMIPP in blood significantly increased (27.9% +/- 7.7% to 42.3% +/- 8.1%; P < 0.05), especially in the early phase with ischemia. In tissue, the radioactivity was concentrated in the triglyceride pool even in the early phase, and in addition, BMIPP and alpha-oxidized metabolite significantly decreased in the early phase with ischemia (t = 1 min after BMIPP injection, 25.9% +/- 8.6% to 14.5% +/- 2.1%, P < 0.01; t = 2 min, 8.9% +/- 5.0% to 4.5% +/- 1.7%, P < 0.05). CONCLUSION: These results show that backdiffusion of nonmetabolized BMIPP from the myocardium increased and BMIPP (long-chain fatty acids) in tissue decreased with ischemia, suggesting backdiffusion of nonmetabolized BMIPP might play an important role in myocardial perfusion-metabolism mismatch on SPECT images in patients with ischemic heart disease.  (+info)

Requirement for the heart-type fatty acid binding protein in cardiac fatty acid utilization. (3/444)

Nonenzymatic cytosolic fatty acid binding proteins (FABPs) are abundantly expressed in many animal tissues with high rates of fatty acid metabolism. No physiological role has been demonstrated for any FABP, although these proteins have been implicated in transport of free long-chain fatty acids (LCFAs) and protection against LCFA toxicity. We report here that mice lacking heart-type FABP (H-FABP) exhibit a severe defect of peripheral (nonhepatic, non-fat) LCFA utilization. In these mice, the heart is unable to efficiently take up plasma LCFAs, which are normally its main fuel, and switches to glucose usage. Altered plasma levels of LCFAs, glucose, lactate and beta-hydroxybutyrate are consistent with depressed peripheral LCFA utilization, intensified carbohydrate usage, and increased hepatic LCFA oxidation; these changes are most pronounced under conditions favoring LCFA oxidation. H-FABP deficiency is only incompletely compensated, however, causing acute exercise intolerance and, at old age, a localized cardiac hypertrophy. These data establish a requirement for H-FABP in cardiac intracellular lipid transport and fuel selection and a major role in metabolic homeostasis. This new animal model should be particularly useful for investigating the significance of peripheral LCFA utilization for heart function, insulin sensitivity, and blood pressure.  (+info)

Influence of methodology on the presence and extent of mismatching between 99mTc-MIBI and 123I-BMIPP in myocardial viability studies. (4/444)

Discordant uptake (mismatching) of 123I-labeled beta-methyl-piodophenyl-pentadecanoic acid (BMIPP) less than 99mTc-labeled methoxyisobutyl isonitrile (MIBI) is a good predictor of myocardial viability. However, methodological factors can influence assessment of the presence of mismatching because of differences in background activity between the tracers. In this study, we investigated the influence of methodological parameters on the mismatching between BMIPP and MIBI in patients with chronic ischemic heart disease. METHODS: Polar maps were created to quantify the extent of mismatched tissue measured in 10 patients with myocardial infarction according to three methods for data processing: no correction, subtraction of background activity measured in the left ventricle cavity and dual-window scatter correction. Mismatching was expressed as a percentage of the surface of the left ventricle globally as well as for each arterial territory using a BMIPP uptake of at least 10% less than MIBI as the threshold. The results of dobutamine stress echocardiography and the evolution of the regional contractility at 6-mo follow-up were used as references. RESULTS: Mean background activity in the ventricle cavity was 9.3% of the maximum activity for MIBI and 21.4% for BMIPP before, and 2.8% and 8.3% after scatter correction. Fourteen arterial vascular territories demonstrated baseline wall-motion abnormalities; 9 territories showed contractile reserve with dobutamine stress echocardiography. Significant mismatching was found in 5 of 14 regions without correction, 9 of 14 after scatter correction and 13 of 14 after background subtraction. Compared with the evolution of resting regional contractility at follow-up, optimal results were found when using the scatter-corrected data. Without correction, mismatching between BMIPP and MIBI was partially disguised because of the higher noise level in the iodine images. On the contrary, subtraction of background measured by means of a single region of interest overestimated the magnitude of mismatching due to the heterogeneous background distribution in the ventricular cavity. CONCLUSION: In quantifying the presence and extent of mismatching between MIBI and BMIPP in chronic ischemic heart disease, significant differences in the detection of viability are noted according to the acquisition and processing methods used. Scatter correction of the acquisition data is the most accurate and reliable method for identifying viable myocardium.  (+info)

Assessment of myocardial viability using 123I-labeled iodophenylpentadecanoic acid at sustained low flow or after acute infarction and reperfusion. (5/444)

123I-labeled iodophenylpentadecanoic acid (IPPA) is a synthetic fatty acid that may be useful for determination of myocardial viability. We investigated the uptake and clearance kinetics of this tracer in canine models of ischemia and infarction. METHODS: In protocol 1, 185 MBq (5 mCi) 123I-IPPA were injected intravenously in 19 dogs with 50% left anterior descending artery (LAD) flow reduction. In 9 dogs, 201TI was coinjected. In protocol 2, 5 dogs underwent LAD occlusion for 3 h, and 123I-IPPA was injected 60 min after reperfusion. All dogs had flow measured by microspheres, regional systolic thickening by ultrasonic crystals and measurements of postmortem risk area and infarct size. Tracer activities were quantified by gamma well counting and by serial imaging. RESULTS: In protocol 1 dogs with sustained low flow (50% +/- 4%) and absence of systolic thickening (-3.2% +/- 1%), 123I-IPPA defect magnitude (LAD/left circumflex artery [LCX] count ratios) decreased from 0.65 +/- 0.02 to 0.74 +/- 0.02 at 30 min and to 0.84 +/- 0.03 at 2 h (P < 0.01), indicative of rest redistribution. Final transmural 123I-IPPA LAD/LCX activity ratio (0.99 +/- 0.05) was significantly greater than the flow ratio (0.53 +/- 0.04) at injection, confirming complete rest redistribution. The final 123I-IPPA activity ratio was significantly greater than the 201TI ratio over the 2-h period (P < 0.01). In protocol 2 dogs that underwent 3 h of total LAD occlusion and reflow (infarct size = 51% +/- 13% of risk area), viability was overestimated with 123I-IPPA, because uptake averaged 64% of normal in the central necrotic region, where flow averaged < 10% of normal. CONCLUSION: These findings suggest that serial 123I-IPPA imaging may be useful for assessing myocardial viability under conditions of sustained low flow and myocardial asynergy, such as appears to exist in patients with chronic coronary artery disease and depressed left ventricular function. In contrast, 123I-IPPA given early after reperfusion following prolonged coronary occlusion overestimates the degree of viability and therefore may not provide useful information pertaining to the degree of myocardial salvage after reflow in the setting of acute myocardial infarction.  (+info)

Cloning and characterization of Aplysia neutral endopeptidase, a metallo-endopeptidase involved in the extracellular metabolism of neuropeptides in Aplysia californica. (6/444)

Cell surface metallo-endopeptidases play important roles in cell communication by controlling the levels of bioactive peptides around peptide receptors. To understand the relative relevance of these enzymes in the CNS, we characterized a metallo-endopeptidase in the CNS of Aplysia californica, whose peptidergic pathways are well described at the molecular, cellular, and physiological levels. The membrane-bound activity cleaved Leu-enkephalin at the Gly3-Phe4 bond with an inhibitor profile similar to that of the mammalian neutral endopeptidase (NEP). This functional homology was supported by the molecular cloning of cDNAs from the CNS, which demonstrated that the Aplysia and mammalian NEPs share all the same amino acids that are essential for the enzymatic activity. The protein is recognized both by specific anti-Aplysia NEP (apNEP) antibodies and by the [125I]-labeled NEP-specific inhibitor RB104, demonstrating that the apNEP gene codes for the RB104-binding protein. In situ hybridization experiments on sections of the ganglia of the CNS revealed that apNEP is expressed in neurons and that the mRNA is present both in the cell bodies and in neurites that travel along the neuropil and peripheral nerves. When incubated in the presence of a specific NEP inhibitor, many neurons of the buccal ganglion showed a greatly prolonged physiological response to stimulation, suggesting that NEP-like metallo-endopeptidases may play a critical role in the regulation of the feeding behavior in Aplysia. One of the putative targets of apNEP in this behavior is the small cardioactive peptide, as suggested by RP-HPLC experiments. More generally, the presence of apNEP in the CNS and periphery may indicate that it could play a major role in the modulation of synaptic transmission in Aplysia and in the metabolism of neuropeptides close to their point of release.  (+info)

Metabolism of radioiodinated fatty acid analogs in ischemic and hypoxic canine myocardium. (7/444)

Myocardial metabolism of 17-[123I]-iodoheptadecanoic acid (IHDA), 15-(p-[131I]-iodophenyl)pentadecanoic acid (pIPPA) and 15-(p-[125I]-iodophenyl)-3,3-dimethylpentadecanoic acid (DMIPP) was assessed during ischemia and hypoxia. The simultaneous investigation allowed us to evaluate differences in metabolic handling of these three fatty acids. METHODS: In 17 open-chest dogs, the left ascending coronary artery was cannulated and extracorporeal bypass (ECB) perfused. In 3 dogs, ECB flow was kept normal, and these control experiments showed that kinetics of the radioiodinated fatty acids were not affected by the ECB technique itself. In 9 dogs, ECB flow was reduced to one third (ischemia), and in 5 dogs, the ECB area was perfused with venous blood and was kept at control values (hypoxia). After simultaneous intravenous injection of IHDA, pIPPA and DMIPP, seven paired biopsy specimens from the native and ECB-perfused myocardium were taken over an assay period of 35 min. Total activity and the distribution in the aqueous phase and lipid fractions were determined, and time-activity curves were constructed. RESULTS: In ischemic (Is) but not in hypoxic (Hy) myocardium, peak total activity of IHDA, pIPPA and DMIPP decreased significantly versus normal (N) myocardium (IHDA: N = 700 +/- 267 versus Is = 335 +/- 158 dpm/mg/mCi; pIPPA: N = 988 +/- 318 versus Is = 438 +/- 180 dpm/mg/mCi; DMIPP: N = 352 +/- 146 versus Is = 179 +/- 82 dpm/mg/mCi; all P values < 0.001). The relative decrease was similar for IHDA, pIPPA or DMIPP. Half-time values of total activity were prolonged for IHDA and pIPPA but were shortened for DMIPP in ischemic and hypoxic myocardium (IHDA: N = 22, Is = 44 and Hy = 50 min; pIPPA: N = 24, Is = 95 and Hy = 169 min; DMIPP: N = 528, Is = 409 and Hy = 115 min). The aqueous phase activity for IHDA, pIPPA and DMIPP decreased significantly versus normal myocardium in both ischemic (IHDA: N = 71% +/- 9% versus Is = 36% +/- 9%, P < 0.001; pIPPA: N = 62% +/- 10% versus Is = 25% +/- 8%, P < 0.001; DMIPP: N = 26% +/- 11% versus Is = 18% +/- 3%, P < 0.05) and hypoxic (IHDA: N = 76% +/- 8% versus Hy = 62% +/- 8%, P < 0.05; pIPPA: N = 66% +/- 8% versus Hy = 46% +/- 10%, P < 0.05; DMIPP: N = 32% +/- 6% versus Hy = 24% +/- 4%, P < 0.05) myocardium. The relative decrease was significantly highest for pIPPA and lowest for DMIPP. Incorporation into triacylglycerols increased significantly for IHDA, pIPPA and DMIPP in both ischemic and hypoxic myocardium. In normal myocardium, DMIPP was already mainly incorporated into triacylglycerols. Activity of IHDA and pIPPA in acylcarnitine increased significantly in ischemic and hypoxic myocardium. CONCLUSION: Kinetics of the radioiodinated fatty acid analogs in myocardium are altered during oxygen deprivation in a similar fashion as documented in literature for natural fatty acids. However, the changes were different between IHDA, pIPPA and DMIPP, suggesting different metabolic handling and thus reflecting different aspects of myocardial fatty acid metabolism.  (+info)

Iodomycin and iodipine, a structural analogue of azidopine, bind to a common domain in hamster P-glycoprotein. (8/444)

Both the overexpression of P-glycoprotein and the broad range of substrates of this ATP-binding cassette (ABC) transporter induce the phenomenon of multidrug resistance, one major cause of the failure of cancer chemotherapy in humans. This study reports that [125I]iodipine, a structural analogue of the 1,4-dihydropyridine azidopine, shares a common binding site with iodomycin, a Bolton-Hunter derivative of the anthracycline daunomycin. This binding site is different from that described for iodoarylazidoprazosin, which is presumed to share a common binding site with azidopine. Edman sequencing revealed that [125I]iodipine had photolabelled the same peptide as iodomycin and spans the primary sequence of hamster isoform pgp1 from amino acid 230 to amino acid 312.  (+info)

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