Partial inhibition of fatty acid oxidation increases regional contractile power and efficiency during demand-induced ischemia

Margaret P. Chandler, Pedro N. Chavez, Tracy A. McElfresh, Hazel Huang, Charles S. Harmon, William C. Stanley

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Objective: Clinical trials in patients with stable angina show that drugs that partially inhibit myocardial fatty acid oxidation reduce the symptoms of demand-induced ischemia, presumably by reducing lactate production and improving regional systolic function. We tested the hypothesis that partial inhibition of fatty acid oxidation with oxfenicine (a carnitine palmitoyl transferase-I inhibitor) reduces lactate production and increases regional myocardial power during demand-induced ischemia. Methods: Demand-induced ischemia was produced in anesthetized open-chest swine by reducing flow by 20% in the left anterior descending coronary artery and increasing heart rate and contractility with dobutamine (15 μg kg-1 min-1 i.v.) for 20 min. Glucose and fatty acid oxidation were measured with an intracoronary infusion of [U-14C] glucose and [9,10-3H] oleate, and hearts were treated with oxfenicine (2 mmol l-1; n=7) or vehicle (n=7). Regional anterior wall power was assessed from the left ventricular pressure-anterior free wall segment length loops. Results: During demand-induced ischemia, the oxfenicine group had a higher rate of glucose oxidation (6.9±1.1 vs. 4. 7±0.8 μmol min-1; P<0.05), significantly lower fatty acid uptake, but no change in total or active PDH activity. The oxfenicine group had significantly lower lactate output integrals (1.11±0.23 vs. 0.60±0.11 mmol) and glycogen depletion (66±6 vs. 43±8%), and higher anterior wall power index (0.95±0.17 vs. 1.30±0.11%) and anterior wall energy efficiency index (91±17 vs. 129±10%). Conclusions: Partial inhibition of fatty acid oxidation reduced non-oxidative glycolysis and improved regional contractile power and efficiency during demand-induced ischemia.

Original languageEnglish (US)
Pages (from-to)143-151
Number of pages9
JournalCardiovascular Research
Volume59
Issue number1
DOIs
StatePublished - Jul 1 2003

Fingerprint

Fatty Acids
Ischemia
Lactic Acid
Glucose
Myocardial Contraction
Dobutamine
Stable Angina
Carnitine
Glycolysis
Ventricular Pressure
Oleic Acid
Transferases
Glycogen
Coronary Vessels
Swine
Thorax
Heart Rate
Clinical Trials
4-hydroxyphenylglycine
Pharmaceutical Preparations

Keywords

  • Angina
  • Dobutamine
  • Energy metabolism
  • Heart

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Partial inhibition of fatty acid oxidation increases regional contractile power and efficiency during demand-induced ischemia. / Chandler, Margaret P.; Chavez, Pedro N.; McElfresh, Tracy A.; Huang, Hazel; Harmon, Charles S.; Stanley, William C.

In: Cardiovascular Research, Vol. 59, No. 1, 01.07.2003, p. 143-151.

Research output: Contribution to journalArticle

Chandler, Margaret P. ; Chavez, Pedro N. ; McElfresh, Tracy A. ; Huang, Hazel ; Harmon, Charles S. ; Stanley, William C. / Partial inhibition of fatty acid oxidation increases regional contractile power and efficiency during demand-induced ischemia. In: Cardiovascular Research. 2003 ; Vol. 59, No. 1. pp. 143-151.
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abstract = "Objective: Clinical trials in patients with stable angina show that drugs that partially inhibit myocardial fatty acid oxidation reduce the symptoms of demand-induced ischemia, presumably by reducing lactate production and improving regional systolic function. We tested the hypothesis that partial inhibition of fatty acid oxidation with oxfenicine (a carnitine palmitoyl transferase-I inhibitor) reduces lactate production and increases regional myocardial power during demand-induced ischemia. Methods: Demand-induced ischemia was produced in anesthetized open-chest swine by reducing flow by 20{\%} in the left anterior descending coronary artery and increasing heart rate and contractility with dobutamine (15 μg kg-1 min-1 i.v.) for 20 min. Glucose and fatty acid oxidation were measured with an intracoronary infusion of [U-14C] glucose and [9,10-3H] oleate, and hearts were treated with oxfenicine (2 mmol l-1; n=7) or vehicle (n=7). Regional anterior wall power was assessed from the left ventricular pressure-anterior free wall segment length loops. Results: During demand-induced ischemia, the oxfenicine group had a higher rate of glucose oxidation (6.9±1.1 vs. 4. 7±0.8 μmol min-1; P<0.05), significantly lower fatty acid uptake, but no change in total or active PDH activity. The oxfenicine group had significantly lower lactate output integrals (1.11±0.23 vs. 0.60±0.11 mmol) and glycogen depletion (66±6 vs. 43±8{\%}), and higher anterior wall power index (0.95±0.17 vs. 1.30±0.11{\%}) and anterior wall energy efficiency index (91±17 vs. 129±10{\%}). Conclusions: Partial inhibition of fatty acid oxidation reduced non-oxidative glycolysis and improved regional contractile power and efficiency during demand-induced ischemia.",
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T1 - Partial inhibition of fatty acid oxidation increases regional contractile power and efficiency during demand-induced ischemia

AU - Chandler, Margaret P.

AU - Chavez, Pedro N.

AU - McElfresh, Tracy A.

AU - Huang, Hazel

AU - Harmon, Charles S.

AU - Stanley, William C.

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N2 - Objective: Clinical trials in patients with stable angina show that drugs that partially inhibit myocardial fatty acid oxidation reduce the symptoms of demand-induced ischemia, presumably by reducing lactate production and improving regional systolic function. We tested the hypothesis that partial inhibition of fatty acid oxidation with oxfenicine (a carnitine palmitoyl transferase-I inhibitor) reduces lactate production and increases regional myocardial power during demand-induced ischemia. Methods: Demand-induced ischemia was produced in anesthetized open-chest swine by reducing flow by 20% in the left anterior descending coronary artery and increasing heart rate and contractility with dobutamine (15 μg kg-1 min-1 i.v.) for 20 min. Glucose and fatty acid oxidation were measured with an intracoronary infusion of [U-14C] glucose and [9,10-3H] oleate, and hearts were treated with oxfenicine (2 mmol l-1; n=7) or vehicle (n=7). Regional anterior wall power was assessed from the left ventricular pressure-anterior free wall segment length loops. Results: During demand-induced ischemia, the oxfenicine group had a higher rate of glucose oxidation (6.9±1.1 vs. 4. 7±0.8 μmol min-1; P<0.05), significantly lower fatty acid uptake, but no change in total or active PDH activity. The oxfenicine group had significantly lower lactate output integrals (1.11±0.23 vs. 0.60±0.11 mmol) and glycogen depletion (66±6 vs. 43±8%), and higher anterior wall power index (0.95±0.17 vs. 1.30±0.11%) and anterior wall energy efficiency index (91±17 vs. 129±10%). Conclusions: Partial inhibition of fatty acid oxidation reduced non-oxidative glycolysis and improved regional contractile power and efficiency during demand-induced ischemia.

AB - Objective: Clinical trials in patients with stable angina show that drugs that partially inhibit myocardial fatty acid oxidation reduce the symptoms of demand-induced ischemia, presumably by reducing lactate production and improving regional systolic function. We tested the hypothesis that partial inhibition of fatty acid oxidation with oxfenicine (a carnitine palmitoyl transferase-I inhibitor) reduces lactate production and increases regional myocardial power during demand-induced ischemia. Methods: Demand-induced ischemia was produced in anesthetized open-chest swine by reducing flow by 20% in the left anterior descending coronary artery and increasing heart rate and contractility with dobutamine (15 μg kg-1 min-1 i.v.) for 20 min. Glucose and fatty acid oxidation were measured with an intracoronary infusion of [U-14C] glucose and [9,10-3H] oleate, and hearts were treated with oxfenicine (2 mmol l-1; n=7) or vehicle (n=7). Regional anterior wall power was assessed from the left ventricular pressure-anterior free wall segment length loops. Results: During demand-induced ischemia, the oxfenicine group had a higher rate of glucose oxidation (6.9±1.1 vs. 4. 7±0.8 μmol min-1; P<0.05), significantly lower fatty acid uptake, but no change in total or active PDH activity. The oxfenicine group had significantly lower lactate output integrals (1.11±0.23 vs. 0.60±0.11 mmol) and glycogen depletion (66±6 vs. 43±8%), and higher anterior wall power index (0.95±0.17 vs. 1.30±0.11%) and anterior wall energy efficiency index (91±17 vs. 129±10%). Conclusions: Partial inhibition of fatty acid oxidation reduced non-oxidative glycolysis and improved regional contractile power and efficiency during demand-induced ischemia.

KW - Angina

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KW - Energy metabolism

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