Validation of 18F-fluoro-4-thia-palmitate as a PET probe for myocardial fatty acid oxidation: Effects of hypoxia and composition of exogenous fatty acids

Timothy R DeGrado, Mehmet T. Kitapci, Shuyan Wang, Jun Ying, Gary D. Lopaschuk

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Fatty acid oxidation (FAO) is the predominant energy-producing pathway in the healthy heart. Abnormalities in FAO are associated with many ischemic and nonischemic disease states. The aim of the present study was to further validate 16-[18F]-fluoro-4-thia-palmitate (18F-FTP) as a metabolically trapped FAO probe in the isolated perfused rat heart model by examining both the effects of hypoxia and the effects of changes in exogenous fatty acid availability. Methods: Hearts were excised from Sprague-Dawley rats and perfused in the Langendorff mode with Krebs-Henseleit solution under the following conditions: palmitate at 0.4 mmol/L with 95% oxygen, palmitate at 0.4 mmol/L with 35% oxygen, palmitate at 0.2 mmol/L plus oleate at 0.2 mmol/L with 95% oxygen, and palmitate at 0.2 mmol/L plus oleate at 0.2 mmol/L with 35% oxygen. Hearts were paced at 270 beats per minute, and the rate of left ventricular pressure change (LV dP/dt) was monitored. 18F-FTP in the perfusion medium was administered for 20 min, and this step was followed by a 20-min washout period without tracer in the perfusion medium. 18F kinetics in the whole heart were monitored externally, and the time-activity curves were analyzed to determine the fractional trapping rate for 18F-FTP (FTRFTP). A "lumped constant" (LC) was defined as the ratio of FTRFTP to the fractional rate of oxidation of fatty acid in the perfusion medium. Results: The kinetic data for 18F-FTP demonstrated metabolic trapping of 18F radioactivity that was insensitive to changes in the mixture of fatty acids in the perfusion medium but that was sensitive to the inhibition of mitochondrial FAO by hypoxia. LV dP/dt was reduced 47%-67% in hypoxic hearts relative to hearts with normal oxygenation (controls). FAO rates for palmitate and oleate were similar in group 3 (palmitate alone) and group 4 (palmitate and oleate). FAO was decreased 70%-76% with hypoxia, whereas FTRFTP was reduced 86%-88%, demonstrating hypersensitivity of a change in 18F-FTP retention to FAO inhibition by oxygen deprivation. The 18F-FTP LC was approximately 2 in myocardium with normal oxygenation and fell to 1.0-1.2 in hypoxic myocardium. Conclusion: The results confirm 18F-FTP to be a metabolically trapped palmitate analog that is capable of indicating rates of myocardial oxidation of exogenous long-chain fatty acids. The heterogeneous nature of fatty acids in plasma does not alter the quantitative analysis of 18F-FTP kinetics. However, the decreased LC value in hypoxic myocardium suggests the need to develop an understanding of the relationship of 18F-FTP processing to natural fatty acids at key limiting transport and metabolism processes, analogous to previous studies examining the LC values for radiolabeled deoxyglucose tracers used to estimate the glucose metabolic rate.

Original languageEnglish (US)
Pages (from-to)173-181
Number of pages9
JournalJournal of Nuclear Medicine
Volume47
Issue number1
StatePublished - Jan 1 2006
Externally publishedYes

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Palmitates
Fatty Acids
Oleic Acid
Oxygen
Perfusion
Myocardium
Hypoxia
16-fluoro-4-thiapalmitic acid
Deoxyglucose
Ventricular Pressure
Radioactivity
Sprague Dawley Rats
Hypersensitivity

Keywords

  • F-FTP
  • Fatty acid oxidation
  • PET
  • Quantitative evaluation

ASJC Scopus subject areas

  • Radiological and Ultrasound Technology

Cite this

Validation of 18F-fluoro-4-thia-palmitate as a PET probe for myocardial fatty acid oxidation : Effects of hypoxia and composition of exogenous fatty acids. / DeGrado, Timothy R; Kitapci, Mehmet T.; Wang, Shuyan; Ying, Jun; Lopaschuk, Gary D.

In: Journal of Nuclear Medicine, Vol. 47, No. 1, 01.01.2006, p. 173-181.

Research output: Contribution to journalArticle

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title = "Validation of 18F-fluoro-4-thia-palmitate as a PET probe for myocardial fatty acid oxidation: Effects of hypoxia and composition of exogenous fatty acids",
abstract = "Fatty acid oxidation (FAO) is the predominant energy-producing pathway in the healthy heart. Abnormalities in FAO are associated with many ischemic and nonischemic disease states. The aim of the present study was to further validate 16-[18F]-fluoro-4-thia-palmitate (18F-FTP) as a metabolically trapped FAO probe in the isolated perfused rat heart model by examining both the effects of hypoxia and the effects of changes in exogenous fatty acid availability. Methods: Hearts were excised from Sprague-Dawley rats and perfused in the Langendorff mode with Krebs-Henseleit solution under the following conditions: palmitate at 0.4 mmol/L with 95{\%} oxygen, palmitate at 0.4 mmol/L with 35{\%} oxygen, palmitate at 0.2 mmol/L plus oleate at 0.2 mmol/L with 95{\%} oxygen, and palmitate at 0.2 mmol/L plus oleate at 0.2 mmol/L with 35{\%} oxygen. Hearts were paced at 270 beats per minute, and the rate of left ventricular pressure change (LV dP/dt) was monitored. 18F-FTP in the perfusion medium was administered for 20 min, and this step was followed by a 20-min washout period without tracer in the perfusion medium. 18F kinetics in the whole heart were monitored externally, and the time-activity curves were analyzed to determine the fractional trapping rate for 18F-FTP (FTRFTP). A {"}lumped constant{"} (LC) was defined as the ratio of FTRFTP to the fractional rate of oxidation of fatty acid in the perfusion medium. Results: The kinetic data for 18F-FTP demonstrated metabolic trapping of 18F radioactivity that was insensitive to changes in the mixture of fatty acids in the perfusion medium but that was sensitive to the inhibition of mitochondrial FAO by hypoxia. LV dP/dt was reduced 47{\%}-67{\%} in hypoxic hearts relative to hearts with normal oxygenation (controls). FAO rates for palmitate and oleate were similar in group 3 (palmitate alone) and group 4 (palmitate and oleate). FAO was decreased 70{\%}-76{\%} with hypoxia, whereas FTRFTP was reduced 86{\%}-88{\%}, demonstrating hypersensitivity of a change in 18F-FTP retention to FAO inhibition by oxygen deprivation. The 18F-FTP LC was approximately 2 in myocardium with normal oxygenation and fell to 1.0-1.2 in hypoxic myocardium. Conclusion: The results confirm 18F-FTP to be a metabolically trapped palmitate analog that is capable of indicating rates of myocardial oxidation of exogenous long-chain fatty acids. The heterogeneous nature of fatty acids in plasma does not alter the quantitative analysis of 18F-FTP kinetics. However, the decreased LC value in hypoxic myocardium suggests the need to develop an understanding of the relationship of 18F-FTP processing to natural fatty acids at key limiting transport and metabolism processes, analogous to previous studies examining the LC values for radiolabeled deoxyglucose tracers used to estimate the glucose metabolic rate.",
keywords = "F-FTP, Fatty acid oxidation, PET, Quantitative evaluation",
author = "DeGrado, {Timothy R} and Kitapci, {Mehmet T.} and Shuyan Wang and Jun Ying and Lopaschuk, {Gary D.}",
year = "2006",
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pages = "173--181",
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TY - JOUR

T1 - Validation of 18F-fluoro-4-thia-palmitate as a PET probe for myocardial fatty acid oxidation

T2 - Effects of hypoxia and composition of exogenous fatty acids

AU - DeGrado, Timothy R

AU - Kitapci, Mehmet T.

AU - Wang, Shuyan

AU - Ying, Jun

AU - Lopaschuk, Gary D.

PY - 2006/1/1

Y1 - 2006/1/1

N2 - Fatty acid oxidation (FAO) is the predominant energy-producing pathway in the healthy heart. Abnormalities in FAO are associated with many ischemic and nonischemic disease states. The aim of the present study was to further validate 16-[18F]-fluoro-4-thia-palmitate (18F-FTP) as a metabolically trapped FAO probe in the isolated perfused rat heart model by examining both the effects of hypoxia and the effects of changes in exogenous fatty acid availability. Methods: Hearts were excised from Sprague-Dawley rats and perfused in the Langendorff mode with Krebs-Henseleit solution under the following conditions: palmitate at 0.4 mmol/L with 95% oxygen, palmitate at 0.4 mmol/L with 35% oxygen, palmitate at 0.2 mmol/L plus oleate at 0.2 mmol/L with 95% oxygen, and palmitate at 0.2 mmol/L plus oleate at 0.2 mmol/L with 35% oxygen. Hearts were paced at 270 beats per minute, and the rate of left ventricular pressure change (LV dP/dt) was monitored. 18F-FTP in the perfusion medium was administered for 20 min, and this step was followed by a 20-min washout period without tracer in the perfusion medium. 18F kinetics in the whole heart were monitored externally, and the time-activity curves were analyzed to determine the fractional trapping rate for 18F-FTP (FTRFTP). A "lumped constant" (LC) was defined as the ratio of FTRFTP to the fractional rate of oxidation of fatty acid in the perfusion medium. Results: The kinetic data for 18F-FTP demonstrated metabolic trapping of 18F radioactivity that was insensitive to changes in the mixture of fatty acids in the perfusion medium but that was sensitive to the inhibition of mitochondrial FAO by hypoxia. LV dP/dt was reduced 47%-67% in hypoxic hearts relative to hearts with normal oxygenation (controls). FAO rates for palmitate and oleate were similar in group 3 (palmitate alone) and group 4 (palmitate and oleate). FAO was decreased 70%-76% with hypoxia, whereas FTRFTP was reduced 86%-88%, demonstrating hypersensitivity of a change in 18F-FTP retention to FAO inhibition by oxygen deprivation. The 18F-FTP LC was approximately 2 in myocardium with normal oxygenation and fell to 1.0-1.2 in hypoxic myocardium. Conclusion: The results confirm 18F-FTP to be a metabolically trapped palmitate analog that is capable of indicating rates of myocardial oxidation of exogenous long-chain fatty acids. The heterogeneous nature of fatty acids in plasma does not alter the quantitative analysis of 18F-FTP kinetics. However, the decreased LC value in hypoxic myocardium suggests the need to develop an understanding of the relationship of 18F-FTP processing to natural fatty acids at key limiting transport and metabolism processes, analogous to previous studies examining the LC values for radiolabeled deoxyglucose tracers used to estimate the glucose metabolic rate.

AB - Fatty acid oxidation (FAO) is the predominant energy-producing pathway in the healthy heart. Abnormalities in FAO are associated with many ischemic and nonischemic disease states. The aim of the present study was to further validate 16-[18F]-fluoro-4-thia-palmitate (18F-FTP) as a metabolically trapped FAO probe in the isolated perfused rat heart model by examining both the effects of hypoxia and the effects of changes in exogenous fatty acid availability. Methods: Hearts were excised from Sprague-Dawley rats and perfused in the Langendorff mode with Krebs-Henseleit solution under the following conditions: palmitate at 0.4 mmol/L with 95% oxygen, palmitate at 0.4 mmol/L with 35% oxygen, palmitate at 0.2 mmol/L plus oleate at 0.2 mmol/L with 95% oxygen, and palmitate at 0.2 mmol/L plus oleate at 0.2 mmol/L with 35% oxygen. Hearts were paced at 270 beats per minute, and the rate of left ventricular pressure change (LV dP/dt) was monitored. 18F-FTP in the perfusion medium was administered for 20 min, and this step was followed by a 20-min washout period without tracer in the perfusion medium. 18F kinetics in the whole heart were monitored externally, and the time-activity curves were analyzed to determine the fractional trapping rate for 18F-FTP (FTRFTP). A "lumped constant" (LC) was defined as the ratio of FTRFTP to the fractional rate of oxidation of fatty acid in the perfusion medium. Results: The kinetic data for 18F-FTP demonstrated metabolic trapping of 18F radioactivity that was insensitive to changes in the mixture of fatty acids in the perfusion medium but that was sensitive to the inhibition of mitochondrial FAO by hypoxia. LV dP/dt was reduced 47%-67% in hypoxic hearts relative to hearts with normal oxygenation (controls). FAO rates for palmitate and oleate were similar in group 3 (palmitate alone) and group 4 (palmitate and oleate). FAO was decreased 70%-76% with hypoxia, whereas FTRFTP was reduced 86%-88%, demonstrating hypersensitivity of a change in 18F-FTP retention to FAO inhibition by oxygen deprivation. The 18F-FTP LC was approximately 2 in myocardium with normal oxygenation and fell to 1.0-1.2 in hypoxic myocardium. Conclusion: The results confirm 18F-FTP to be a metabolically trapped palmitate analog that is capable of indicating rates of myocardial oxidation of exogenous long-chain fatty acids. The heterogeneous nature of fatty acids in plasma does not alter the quantitative analysis of 18F-FTP kinetics. However, the decreased LC value in hypoxic myocardium suggests the need to develop an understanding of the relationship of 18F-FTP processing to natural fatty acids at key limiting transport and metabolism processes, analogous to previous studies examining the LC values for radiolabeled deoxyglucose tracers used to estimate the glucose metabolic rate.

KW - F-FTP

KW - Fatty acid oxidation

KW - PET

KW - Quantitative evaluation

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