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Robert A. Pooley - One of the best experts on this subject based on the ideXlab platform.
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Myocardial Uptake of the Fatty Acid Analog 14-Fluorine-18-Fluoro-6-Thia-Heptadecanoic Acid in Comparison to Beta-Oxidation Rates by Tritiated Palmitate
Journal of nuclear medicine : official publication Society of Nuclear Medicine, 1998Co-Authors: Charles K. Stone, Timothy R. Degrado, Robert A. Pooley, Robert J. Nickles, Britta Renstrom, Stephen H. Nellis, A. James Liedtke, James E. HoldenAbstract:UNLABELLED The fatty Acid tracer 14-18F-fluoro-6-thia-Heptadecanoic Acid (FTHA) is a metabolically trapped tracer of exogenous fatty Acid utilization. The objectives of this study were to determine the relationship of FTHA uptake to changes in perfusion and fatty Acid oxidation and to confirm the retention of FTHA in the mammalian heart. METHODS Six pigs with extracorporeal perfusion of the left anterior descending artery (LAD) and cannulation of the LAD vein were studied. The extraction fraction (EF) of FTHA, measured from LAD arterial and venous blood samples, was compared to beta-oxidation rates, determined by water production from tritiated palmitate. After a baseline period, changes in FTHA EF were measured in 15-min periods of hyperemia, control (baseline flow rate) and lactate infusion. After the lactate infusion, FTHA infusion was terminated, and a 15-min washout period was observed. RESULTS Beta-oxidation rate was unchanged from the baseline period during the hyperemic and control periods. With lactate infusion, the expected myocardial preference for lactate was noted, with a decline in exogenous fatty Acid oxidation. Fluorine-18-FTHA EF paralleled the changes in beta-oxidation, with a decrease in EF during lactate infusion. Increase in perfusion was associated with a decrease in FTHA EF, compared to control, such that the product of flow and extraction was maintained. A linear relationship of FTHA EF to fractional tritiated water production was found. Washout analysis confirmed minimal washout of tracer at 15 min after termination of infusion. Organic solvent extraction of tissue samples suggested that the majority of tissue radioactivity was protein-bound. CONCLUSION In the extracorporeally perfused mammalian heart, FTHA EF declined during suppression of beta-oxidation with lactate infusion and alteration in perfusion without change in fatty Acid oxidation rate. The linear relationship of FTHA EF with fractional water production from tritiated palmitate further confirms a correlation of the uptake of FTHA with fatty Acid beta-oxidation rate and supports the utility of FTHA in the noninvasive determination of fatty Acid oxidation rate. Furthermore, the trapped nature of the tracer may allow the use of graphical analysis for the quantification of beta-oxidation rates.
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evaluation of 14 r s 18f fluoro 6 thia Heptadecanoic Acid ftha as a positron emission tomography fatty Acid tracer of beta oxidation in the heart
Medical Physics, 1996Co-Authors: Robert A. PooleyAbstract:The radiolabeled long‐chain fatty Acid analog, 14(R,S)‐[18F]fluoro‐6‐thia‐Heptadecanoic Acid (FTHA), was designed (DeGrado, 1991) to undergo metabolic trapping subsequent to its commitment to the beta‐oxidation (β‐ox) pathway. FTHA was evaluated under various conditions in two animal models for heart research: isolated perfused working rat heart and open‐chest extracorporeally perfused swine heart. FTHA was infused into working rat hearts. Linear radioactivity accumulation was measured by external coincidence detection; the slope was used to determine an estimate for the rate of β‐ox and was compared to the rate determined from the standard tracer, 3H‐palmitate (3H‐PA). Experiments were conducted under conditions of low and high workload, fed and fasted states, suppression of β‐ox, and various perfusate concentrations of palmitate and glucose. Swine LAD artery was cannulated and perfused from the femoral artery through a perfusion pump. FTHA and 3H‐PA were simultaneously infused during three 15 min segments of hyperemia, control, and β‐ox suppression. Blood samples were collected and assayed for 3H2O and 18F concentrations. Results indicate that FTHA uptake is specifically sensitive to β‐ox, sensitive to changes in energy demand, independent of flow, and can accurately determine in vivorates of β‐ox in the normal clinical range of fatty Acid concentrations. At concentrations higher than this range, FTHA showed a decreased sensitivity to β‐ox, indicating the required use of a correction factor in the clinic.
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Evaluation of 14(R,S)‐[18F]fluoro‐6‐thia‐Heptadecanoic Acid (FTHA) as a positron emission tomography fatty Acid tracer of beta‐oxidation in the heart
Medical Physics, 1996Co-Authors: Robert A. PooleyAbstract:The radiolabeled long‐chain fatty Acid analog, 14(R,S)‐[18F]fluoro‐6‐thia‐Heptadecanoic Acid (FTHA), was designed (DeGrado, 1991) to undergo metabolic trapping subsequent to its commitment to the beta‐oxidation (β‐ox) pathway. FTHA was evaluated under various conditions in two animal models for heart research: isolated perfused working rat heart and open‐chest extracorporeally perfused swine heart. FTHA was infused into working rat hearts. Linear radioactivity accumulation was measured by external coincidence detection; the slope was used to determine an estimate for the rate of β‐ox and was compared to the rate determined from the standard tracer, 3H‐palmitate (3H‐PA). Experiments were conducted under conditions of low and high workload, fed and fasted states, suppression of β‐ox, and various perfusate concentrations of palmitate and glucose. Swine LAD artery was cannulated and perfused from the femoral artery through a perfusion pump. FTHA and 3H‐PA were simultaneously infused during three 15 min segments of hyperemia, control, and β‐ox suppression. Blood samples were collected and assayed for 3H2O and 18F concentrations. Results indicate that FTHA uptake is specifically sensitive to β‐ox, sensitive to changes in energy demand, independent of flow, and can accurately determine in vivorates of β‐ox in the normal clinical range of fatty Acid concentrations. At concentrations higher than this range, FTHA showed a decreased sensitivity to β‐ox, indicating the required use of a correction factor in the clinic.
Timothy R. Degrado - One of the best experts on this subject based on the ideXlab platform.
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An Evaluation of Myocardial Fatty Acid and Glucose Uptake Using PET with [18F]Fluoro-6-Thia-Heptadecanoic Acid and [18F]FDG in Patients with Congestive Heart Failure
Journal of nuclear medicine : official publication Society of Nuclear Medicine, 2001Co-Authors: Michael R. Taylor, Timothy R. Degrado, Thomas R. Wallhaus, Douglas C. Russell, Peter Stanko, Robert J. Nickles, Charles K. StoneAbstract:UNLABELLED Understanding the metabolic consequences of heart failure is important in evaluating potential mechanisms for disease progression and assessing targets for therapies designed to improve myocardial metabolism in patients with heart failure. PET is uniquely suited to noninvasively evaluate myocardial metabolism. In this study, we investigated the kinetics of 14(R,S)-[18F]fluoro-6-thia-Heptadecanoic Acid (FTHA) and [18F]FDG in patients with stable New York Heart Association functional class III congestive heart failure and a left ventricular ejection fraction of no more than 35%. METHODS Twelve fasting patients underwent dynamic PET studies using [18F]FTHA and FDG. From the dynamic image data, the fractional uptake rates (Ki) were determined for [18F]FTHA and FDG. Subsequently, serum free fatty Acid and glucose concentrations were used to calculate the myocardial free fatty Acid and glucose uptake rates, respectively. Uptake rates were compared with reported values for [18F]FTHA and FDG in subjects with normal left ventricular function. RESULTS The average Ki for [18F]FTHA was 19.7 +/- 9.3 mL/100 g/min (range, 7.2-36.0 ml/100 g/min). The average myocardial fatty Acid use was 19.3 +/- 2.3 mmol/100 g/min. The average Ki for FDG was 1.5 +/- 0.37 mL/100 g/min (range, 0.1-3.3 mL/100 g/min), and the average myocardial glucose use was 12.3 +/- 2.3 mmol/100 g/min. CONCLUSION Myocardial free fatty Acid and glucose use in heart failure can be quantitatively assessed using PET with [18F]FTHA and FDG. Myocardial fatty Acid uptake rates in heart failure are higher than expected for the normal heart, whereas myocardial glucose uptake rates are lower. This shift in myocardial substrate use may be an indication of impaired energy efficiency in the failing heart, providing a target for therapies directed at improving myocardial energy efficiency.
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Myocardial Uptake of the Fatty Acid Analog 14-Fluorine-18-Fluoro-6-Thia-Heptadecanoic Acid in Comparison to Beta-Oxidation Rates by Tritiated Palmitate
Journal of nuclear medicine : official publication Society of Nuclear Medicine, 1998Co-Authors: Charles K. Stone, Timothy R. Degrado, Robert A. Pooley, Robert J. Nickles, Britta Renstrom, Stephen H. Nellis, A. James Liedtke, James E. HoldenAbstract:UNLABELLED The fatty Acid tracer 14-18F-fluoro-6-thia-Heptadecanoic Acid (FTHA) is a metabolically trapped tracer of exogenous fatty Acid utilization. The objectives of this study were to determine the relationship of FTHA uptake to changes in perfusion and fatty Acid oxidation and to confirm the retention of FTHA in the mammalian heart. METHODS Six pigs with extracorporeal perfusion of the left anterior descending artery (LAD) and cannulation of the LAD vein were studied. The extraction fraction (EF) of FTHA, measured from LAD arterial and venous blood samples, was compared to beta-oxidation rates, determined by water production from tritiated palmitate. After a baseline period, changes in FTHA EF were measured in 15-min periods of hyperemia, control (baseline flow rate) and lactate infusion. After the lactate infusion, FTHA infusion was terminated, and a 15-min washout period was observed. RESULTS Beta-oxidation rate was unchanged from the baseline period during the hyperemic and control periods. With lactate infusion, the expected myocardial preference for lactate was noted, with a decline in exogenous fatty Acid oxidation. Fluorine-18-FTHA EF paralleled the changes in beta-oxidation, with a decrease in EF during lactate infusion. Increase in perfusion was associated with a decrease in FTHA EF, compared to control, such that the product of flow and extraction was maintained. A linear relationship of FTHA EF to fractional tritiated water production was found. Washout analysis confirmed minimal washout of tracer at 15 min after termination of infusion. Organic solvent extraction of tissue samples suggested that the majority of tissue radioactivity was protein-bound. CONCLUSION In the extracorporeally perfused mammalian heart, FTHA EF declined during suppression of beta-oxidation with lactate infusion and alteration in perfusion without change in fatty Acid oxidation rate. The linear relationship of FTHA EF with fractional water production from tritiated palmitate further confirms a correlation of the uptake of FTHA with fatty Acid beta-oxidation rate and supports the utility of FTHA in the noninvasive determination of fatty Acid oxidation rate. Furthermore, the trapped nature of the tracer may allow the use of graphical analysis for the quantification of beta-oxidation rates.
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Kinetics of 14(R,S)-fluorine-18-fluoro-6-thia-Heptadecanoic Acid in normal human hearts at rest, during exercise and after dipyridamole injection.
Journal of nuclear medicine : official publication Society of Nuclear Medicine, 1994Co-Authors: Andreas Ebert, Timothy R. Degrado, Heinz H. Coenen, Gerhard Stöcklin, Hans Herzog, Michael M. Henrich, Ludwig E. FeinendegenAbstract:UNLABELLED The myocardial uptake kinetics of 14(R,S)-[18F]fluoro-6-thia-Heptadecanoic Acid (FTHA) were evaluated in humans with PET. The relationship between human myocardial FTHA uptake kinetics and the rate-pressure product (RPP) as an index of myocardial oxygen consumption was investigated in seven normal subjects under fasting conditions. METHODS Seven studies were performed at rest and under submaximal continuous supine bicycle exercise with elevated RPP. An additional five studies were performed after dipyridamole injection to increase myocardial blood flow independent of the myocardial energy requirement. RESULTS In all studies, rapid tracer uptake was found within 2-3 min after injection, which remained nearly constant during the 30-min study. Patlak plots of myocardial FTHA kinetics showed a linear increase, indicating metabolic trapping. The mean uptake rate constant, Ki, obtained from Patlak plot analysis was 0.11 +/- 0.02 ml/g/min at rest and increased significantly to 0.26 +/- 0.06 ml/g/min during exercise. The dipyridamole study yielded a comparatively small elevation with a mean Ki of 0.15 +/- 0.02 ml/g/min, which was not significant in the analysis of variance and the Duncan range test. There was a significant correlation between Ki and RPP, with r = 0.85 (p < 0.01). CONCLUSION Analysis of FTHA uptake kinetics with PET may be useful for noninvasive assessment of myocardial utilization of exogenous long-chain fatty Acids in general and of beta oxidation in the fasting state.
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synthesis of 14 r s 18f fluoro 6 thia Heptadecanoic Acid ftha
Journal of Labelled Compounds and Radiopharmaceuticals, 1991Co-Authors: Timothy R. DegradoAbstract:No-carrier-added (n.c.a) 14(R,S)-[18F]fluoro-6-thia-Heptadecanoic Acid (FTHA) has been synthesized for evaluation as a PET tracer for myocardial long chain fatty Acid utilization. The n.c.a. nucleophilic radiofluorination of benzyl 14(R,S)-tosyloxy-6-thia-heptadecanoate in acetonitrile utilized (cryptate 2.2.2/K)2CO3 for anion activation. The resulting [18F]fluoro-ester was quantitatively hydrolyzed with addition of aqueous KOH and the product purified by reversed phase HPLC. The radiochemical yield of purified FTHA was 35–65% (n=5) with a synthesis time of 50 min. Radiochemical purity was >99%.
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Synthesis of 14 (R,S)‐[18F]fluoro‐6‐thia‐Heptadecanoic Acid (FTHA)
Journal of Labelled Compounds and Radiopharmaceuticals, 1991Co-Authors: Timothy R. DegradoAbstract:No-carrier-added (n.c.a) 14(R,S)-[18F]fluoro-6-thia-Heptadecanoic Acid (FTHA) has been synthesized for evaluation as a PET tracer for myocardial long chain fatty Acid utilization. The n.c.a. nucleophilic radiofluorination of benzyl 14(R,S)-tosyloxy-6-thia-heptadecanoate in acetonitrile utilized (cryptate 2.2.2/K)2CO3 for anion activation. The resulting [18F]fluoro-ester was quantitatively hydrolyzed with addition of aqueous KOH and the product purified by reversed phase HPLC. The radiochemical yield of purified FTHA was 35–65% (n=5) with a synthesis time of 50 min. Radiochemical purity was >99%.
Jörgen Bergman - One of the best experts on this subject based on the ideXlab platform.
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Automated production of [18F]FTHA according to GMP
Journal of Labelled Compounds and Radiopharmaceuticals, 2018Co-Authors: Nina Savisto, Jörgen Bergman, Tapio Viljanen, Esa Kokkomäki, Olof SolinAbstract:14-(R,S)-[18 F]fluoro-6-thia-Heptadecanoic Acid is a tracer for fatty Acid imaging by positron emission tomography. High demand for this tracer required us to replace semiautomatic synthesis with a fully automated procedure. An automated synthesis device was constructed in-house for multistep nucleophilic 18 F-fluorination and a control system was developed. The synthesis device was combined with a sterile filtration unit and both were qualified. 14-(R,S)-[18 F]fluoro-6-thia-Heptadecanoic Acid was produced according to good manufacturing practice guidelines set by the European Union. The synthesis includes an initial nucleophilic labelling reaction, deprotection, preparative HPLC separation, purification of the final product, and formulation for injection. The duration and temperature of the reaction and hydrolysis were optimized, and the radiochemical stability of the formulated product was determined. The rotary evaporator used to evaporate the solvent after HPLC purification was replaced with solid phase extraction purification. We also replaced the human serum albumin used in the earlier procedure with a phosphate buffer-ascorbic Acid mixture in the final formulation solution. From 2011 to 2016, we performed 219 synthesis procedures, 94% of which were successful. The radiochemical yield of 14-(R,S)-[18 F]fluoro-6-thia-Heptadecanoic Acid, decay-corrected to the end of bombardment, was 13% ± 6.3%. The total amount of formulated end product was 1.7 ± 0.8 GBq at end of synthesis.
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14(R, S)-[18f]Fluoro-6-thia-Heptadecanoic Acid as a tracer of free fatty Acid uptake and oxidation in myocardium and skeletal muscle
European Journal of Nuclear Medicine and Molecular Imaging, 2002Co-Authors: Teemu Takala, Pirjo Nuutila, Vesa Oikonen, M. Luotolahti, Kari Pulkki, Tove J. Grönroos, Timo Savunen, Tommi Vähäsilta, Markku Kallajoki, Jörgen BergmanAbstract:14(R,S)-[18F]Fluoro-6-thia-Heptadecanoic Acid ([18F]FTHA) is a long-chain fatty Acid substrate for fatty Acid metabolism. [18F]FTHA has been used to study fatty Acid metabolism in human heart and skeletal muscle. It has been suggested that the rate of radioactivity accumulation in the myocardium reflects the beta-oxidation rate of free fatty Acids (FFAs). However, the net accumulation of FFAs in tissue always represents the sum of FFA oxidation and incorporation into triglycerides. The fraction of [18F]FTHA entering directly into mitochondria for oxidation has not been previously measured. Eight anaesthetized pigs were studied with [18F]FTHA and positron emission tomography (PET). Immediately after each PET experiment, tissue samples from myocardium and skeletal muscle were taken for the isolation of mitochondria and measurements of radioactivity accumulation, and for intracellular [18F]FTHA metabolite analysis. Fractional [18F]FTHA uptake rates were calculated both by graphical analysis of PET data and by measuring 18F in the tissue samples. Fractional [18F]FTHA uptake rates based on the analysis of tissue samples were 0.56±0.17 ml g–1 min–1 and 0.037±0.007 ml g–1 min–1 for myocardium and skeletal muscle (mean ± SD), respectively. The myocardial results obtained from the PET data (0.50±0.11 ml g–1 min–1) were similar to the values obtained from the tissue samples (r=0.94, P=0.002). We also found that 89%±23% (mean±SD, n=7) of the 18F entered mitochondria in myocardium, as compared with only 36%±15% (mean±SD, n=7) in skeletal muscle. Intracellular [18F]FTHA metabolite analysis showed that a major part of [18F]FTHA is metabolized in the mitochondria in the heart. Our data suggest that ~89% of [18F]FTHA taken up by the heart enters mitochondria. This supports the hypothesis that [18F]FTHA traces FFA beta-oxidation in the heart. In contrast to this, only ~36% of [18F]FTHA accumulated in skeletal muscle appears to directly enter mitochondria; the majority is taken up by the other cell fractions, suggesting that in skeletal muscle [18F]FTHA traces FFA uptake but not specifically FFA beta-oxidation.
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Impaired free fatty Acid uptake in skeletal muscle but not in myocardium in patients with impaired glucose tolerance: studies with PET and 14(R,S)-[18F]fluoro-6-thia-Heptadecanoic Acid.
Diabetes, 1999Co-Authors: Anu K. Turpeinen, M. Haaparanta, Pirjo Nuutila, M. Luotolahti, Teemu Takala, Jörgen Bergman, T. Axelin, Helena Hämäläinen, Hidehiro Iida, Maija MäkiAbstract:Free fatty Acids (FFAs) are an important substrate for myocardial and skeletal muscle metabolism, and increased availability and oxidation of FFA are suggested to be associated with insulin resistance. This study was undertaken to assess whether myocardial or muscle uptake of FFA is altered in patients with impaired glucose tolerance (IGT). Eight healthy men (control group; age 48+/-1 years, BMI 25+/-1 kg/m2, mean +/- SE) and eight men with IGT (glucose-intolerant group; age 49+/-1 years, BMI 29+/-1 kg/m2) were studied in the fasting state. Myocardial oxygen consumption and blood flow and myocardial and femoral muscle FFA uptake rates were measured with positron emission tomography (PET) and [15O]O2, [15O]H2O, [15O]CO, and 14(R, S)-[18F]fluoro-6-thia-Heptadecanoic Acid ([18F]FTHA), a fatty Acid tracer trapped into the cell after undergoing initial steps of beta-oxidation. Serum glucose and insulin concentrations were higher in the glucose-intolerant group during the PET study, but FFA concentrations were comparable between the groups. No differences between the groups were observed in the myocardial blood flow, oxygen consumption, fractional FTHA uptake rates, or FFA uptake indices (5.6+/-0.4 vs. 5.2+/-0.4 pmol x 100 g(-1) x min(-1), glucose-intolerant versus control, NS). In the femoral muscle, fractional FTHA uptake (0.0062+/-0.0003 vs. 0.0072+/-0.0003 min(-1), P = 0.044) and FFA uptake indices (0.30+/-0.02 vs. 0.43+/-0.04 min(-1), P = 0.020) were significantly lower in the glucose-intolerant group than in the control group. In conclusion, when studied at the fasting state and normal serum FFA concentrations, subjects with IGT have similar myocardial but lowered femoral muscle FFA uptake. This finding argues against the hypothesis that an increased oxidation of serum FFA, via the competition of glucose and FFA as fuel sources, is the primary cause for impaired peripheral glucose utilization and insulin resistance commonly observed in IGT.
Pirjo Nuutila - One of the best experts on this subject based on the ideXlab platform.
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Liver uptake of free fatty Acids in vivo in humans as determined with 14( R, S)-[18F]fluoro-6-thia-Heptadecanoic Acid and PET.
European Journal of Nuclear Medicine and Molecular Imaging, 2003Co-Authors: Patricia Iozzo, Pirjo Nuutila, Vesa Oikonen, Anu K. Turpeinen, Teemu Takala, Olof Solin, Ele Ferrannini, Juhani KnuutiAbstract:Increased delivery of circulating free fatty Acids (FFA) to the liver has been implicated in the pathogenesis and progression of diabetes. The liver is inaccessible for direct measurement in humans in vivo. We measured liver FFA uptake with positron emission tomography (PET) and 14(R,S)-[18F]fluoro-6-thia-Heptadecanoic Acid ([18F]FTHA) in healthy men. We evaluated the use of graphical analysis and linear fit to describe uptake data over time, and compared the use of metabolite-corrected vs uncorrected input functions. Rapid accumulation of tracer in the liver was observed with time, leading to progressively higher tissue to blood radioactivity ratios. Using metabolite-corrected input function curves, linear fit to the data (r value) exceeded 0.99 in all subjects, during each fitting time frame. Values of liver FFA influx rate constant and uptake were 0.34±0.01 ml min−1 ml−1 and 0.20±0.02 µmol min−1 ml−1, respectively, and were minimally affected by the choice of the fitting interval. Expressed per unit mass, liver FFA uptake was ~50 times higher than that reported in skeletal muscle; in the whole organ, FFA uptake was twice as high as in skeletal muscles. The use of metabolite-uncorrected input functions significantly worsened the spread of data around the fitted line and led to a remarkable underestimation of liver FFA uptake at all time intervals. In conclusion, our data provide non-invasive quantification of hepatic FFA uptake in humans, showing the liver to handle a high FFA flux. [18F]FTHA-PET appears a valuable tool for the investigation of hepatic FFA turnover in humans.
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14(R, S)-[18f]Fluoro-6-thia-Heptadecanoic Acid as a tracer of free fatty Acid uptake and oxidation in myocardium and skeletal muscle
European Journal of Nuclear Medicine and Molecular Imaging, 2002Co-Authors: Teemu Takala, Pirjo Nuutila, Vesa Oikonen, M. Luotolahti, Kari Pulkki, Tove J. Grönroos, Timo Savunen, Tommi Vähäsilta, Markku Kallajoki, Jörgen BergmanAbstract:14(R,S)-[18F]Fluoro-6-thia-Heptadecanoic Acid ([18F]FTHA) is a long-chain fatty Acid substrate for fatty Acid metabolism. [18F]FTHA has been used to study fatty Acid metabolism in human heart and skeletal muscle. It has been suggested that the rate of radioactivity accumulation in the myocardium reflects the beta-oxidation rate of free fatty Acids (FFAs). However, the net accumulation of FFAs in tissue always represents the sum of FFA oxidation and incorporation into triglycerides. The fraction of [18F]FTHA entering directly into mitochondria for oxidation has not been previously measured. Eight anaesthetized pigs were studied with [18F]FTHA and positron emission tomography (PET). Immediately after each PET experiment, tissue samples from myocardium and skeletal muscle were taken for the isolation of mitochondria and measurements of radioactivity accumulation, and for intracellular [18F]FTHA metabolite analysis. Fractional [18F]FTHA uptake rates were calculated both by graphical analysis of PET data and by measuring 18F in the tissue samples. Fractional [18F]FTHA uptake rates based on the analysis of tissue samples were 0.56±0.17 ml g–1 min–1 and 0.037±0.007 ml g–1 min–1 for myocardium and skeletal muscle (mean ± SD), respectively. The myocardial results obtained from the PET data (0.50±0.11 ml g–1 min–1) were similar to the values obtained from the tissue samples (r=0.94, P=0.002). We also found that 89%±23% (mean±SD, n=7) of the 18F entered mitochondria in myocardium, as compared with only 36%±15% (mean±SD, n=7) in skeletal muscle. Intracellular [18F]FTHA metabolite analysis showed that a major part of [18F]FTHA is metabolized in the mitochondria in the heart. Our data suggest that ~89% of [18F]FTHA taken up by the heart enters mitochondria. This supports the hypothesis that [18F]FTHA traces FFA beta-oxidation in the heart. In contrast to this, only ~36% of [18F]FTHA accumulated in skeletal muscle appears to directly enter mitochondria; the majority is taken up by the other cell fractions, suggesting that in skeletal muscle [18F]FTHA traces FFA uptake but not specifically FFA beta-oxidation.
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Impaired free fatty Acid uptake in skeletal muscle but not in myocardium in patients with impaired glucose tolerance: studies with PET and 14(R,S)-[18F]fluoro-6-thia-Heptadecanoic Acid.
Diabetes, 1999Co-Authors: Anu K. Turpeinen, M. Haaparanta, Pirjo Nuutila, M. Luotolahti, Teemu Takala, Jörgen Bergman, T. Axelin, Helena Hämäläinen, Hidehiro Iida, Maija MäkiAbstract:Free fatty Acids (FFAs) are an important substrate for myocardial and skeletal muscle metabolism, and increased availability and oxidation of FFA are suggested to be associated with insulin resistance. This study was undertaken to assess whether myocardial or muscle uptake of FFA is altered in patients with impaired glucose tolerance (IGT). Eight healthy men (control group; age 48+/-1 years, BMI 25+/-1 kg/m2, mean +/- SE) and eight men with IGT (glucose-intolerant group; age 49+/-1 years, BMI 29+/-1 kg/m2) were studied in the fasting state. Myocardial oxygen consumption and blood flow and myocardial and femoral muscle FFA uptake rates were measured with positron emission tomography (PET) and [15O]O2, [15O]H2O, [15O]CO, and 14(R, S)-[18F]fluoro-6-thia-Heptadecanoic Acid ([18F]FTHA), a fatty Acid tracer trapped into the cell after undergoing initial steps of beta-oxidation. Serum glucose and insulin concentrations were higher in the glucose-intolerant group during the PET study, but FFA concentrations were comparable between the groups. No differences between the groups were observed in the myocardial blood flow, oxygen consumption, fractional FTHA uptake rates, or FFA uptake indices (5.6+/-0.4 vs. 5.2+/-0.4 pmol x 100 g(-1) x min(-1), glucose-intolerant versus control, NS). In the femoral muscle, fractional FTHA uptake (0.0062+/-0.0003 vs. 0.0072+/-0.0003 min(-1), P = 0.044) and FFA uptake indices (0.30+/-0.02 vs. 0.43+/-0.04 min(-1), P = 0.020) were significantly lower in the glucose-intolerant group than in the control group. In conclusion, when studied at the fasting state and normal serum FFA concentrations, subjects with IGT have similar myocardial but lowered femoral muscle FFA uptake. This finding argues against the hypothesis that an increased oxidation of serum FFA, via the competition of glucose and FFA as fuel sources, is the primary cause for impaired peripheral glucose utilization and insulin resistance commonly observed in IGT.
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Free Fatty Acid Uptake in the Myocardium and Skeletal Muscle Using Fluorine-18-Fluoro-6-Thia-Heptadecanoic Acid
Journal of nuclear medicine : official publication Society of Nuclear Medicine, 1998Co-Authors: Maija Mäki, M. Haaparanta, Pirjo Nuutila, Vesa Oikonen, M. Luotolahti, Olli Eskola, Juhani KnuutiAbstract:UNLABELLED 14(R,S)-[18F]fluoro-6-thia-Heptadecanoic Acid (FTHA) has been recently introduced as a new tracer for fatty Acid metabolism. Myocardial [18F]FTHA uptake is believed to reflect mainly beta-oxidation of the circulating free fatty Acids (FFAs), since it is trapped in the mitochondria because subsequent steps of beta-oxidation are inhibited by sulfur heteroatom. We investigated [18F]FTHA kinetics in myocardial and skeletal muscle in vivo. METHODS Two dynamic PET studies were performed in seven patients with stable coronary artery disease, once in the fasting state and once during euglycemic hyperinsulinemia (serum insulin approximately 60 mU/liter). The fractional [18F] FTHA uptake rates (Ki) were multiplied with serum FFA concentrations and were considered to represent FFA uptake. RESULTS Serum FFA concentration decreased by 80% during insulin clamp. After tracer injection, rapid myocardial uptake was identified both in the fasting state and during insulin stimulation. The cardiac image quality was excellent in both occasions. In addition, femoral muscles were clearly visualized in both studies. The fractional myocardial [18F]FTHA uptake rates (Ki) in the normal myocardial regions were similar in the fasting state (0.11 +/- 0.04 ml/g/min (mean +/- s.d.) and during insulin clamp (0.12 +/- 0.03 ml/g/min; ns). The calculated myocardial FFA uptake was four times higher in the fasting state than during insulin clamp (5.8 +/- 1.7 versus 1.4 +/- 0.5 micromol/100 g/min, p < 0.005). The femoral muscle fractional [18F]FTHA uptake rates (Ki) were lower (0.0071 +/- 0.0014 ml/g/min) in the fasting state than during insulin clamp (0.0127 +/- 0.0036 ml/g/min; p = 0.03), but the estimated femoral muscle FFA uptake was three times higher in the fasting state (0.38 +/- 0.09 micromol/100 g/min) as compared to that during insulin clamp (0.12 +/- 0.05 micromol/100 g/min, p < 0.005). CONCLUSION Fluorine-18-FTHA PET appears to be a feasible method to estimate fatty Acid kinetics in myocardial and skeletal muscle. Physiologically reasonable rates of FFA uptake in myocardium and skeletal muscle were obtained. Furthermore, the uptake rates were suppressed in response to insulin both in the myocardial and femoral muscle as expected.
Sam H Ridgway - One of the best experts on this subject based on the ideXlab platform.
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increased dietary intake of saturated fatty Acid Heptadecanoic Acid c17 0 associated with decreasing ferritin and alleviated metabolic syndrome in dolphins
PLOS ONE, 2015Co-Authors: Stephanie Vennwatso, Celeste Parry, Mark S Aird, Sacha Stevenso, Kevi P Carli, Risa Daniels, Cynthia R Smith, Randall S Wells, Richard O. Jones, Sam H RidgwayAbstract:Similar to humans, bottlenose dolphins (Tursiops truncatus) can develop metabolic syndrome and associated high ferritin. While fish and fish-based fatty Acids may protect against metabolic syndrome in humans, findings have been inconsistent. To assess potential protective factors against metabolic syndrome related to fish diets, fatty Acids were compared between two dolphin populations with higher (n = 30, Group A) and lower (n = 19, Group B) mean insulin (11 ± 12 and 2 ± 5 μIU/ml, respectively; P < 0.0001) and their dietary fish. In addition to higher insulin, triglycerides, and ferritin, Group A had lower percent serum Heptadecanoic Acid (C17:0) compared to Group B (0.3 ± 0.1 and 1.3 ± 0.4%, respectively; P < 0.0001). Using multivariate stepwise regression, higher percent serum C17:0, a saturated fat found in dairy fat, rye, and some fish, was an independent predictor of lower insulin in dolphins. Capelin, a common dietary fish for Group A, had no detectable C17:0, while pinfish and mullet, common in Group B’s diet, had C17:0 (41 and 67 mg/100g, respectively). When a modified diet adding 25% pinfish and/or mullet was fed to six Group A dolphins over 24 weeks (increasing the average daily dietary C17:0 intake from 400 to 1700 mg), C17:0 serum levels increased, high ferritin decreased, and blood-based metabolic syndrome indices normalized toward reference levels. These effects were not found in four reference dolphins. Further, higher total serum C17:0 was an independent and linear predictor of lower ferritin in dolphins in Group B dolphins. Among off the shelf dairy products tested, butter had the highest C17:0 (423mg/100g); nonfat dairy products had no detectable C17:0. We hypothesize that humans’ movement away from diets with potentially beneficial saturated fatty Acid C17:0, including whole fat dairy products, could be a contributor to widespread low C17:0 levels, higher ferritin, and metabolic syndrome.