Delineation of myocardial oxygen utilization with carbon-11-labeled acetate.

Although positron-emission tomography (PET) with labeled fatty acid delineates infarct size and permits qualitative assessment of fatty acid utilization, quantification of oxidative metabolism is limited by complex alterations in the pattern of utilization of fatty acid during ischemia and reperfusion. Because metabolism of acetate by myocardium is less complex than that of glucose or palmitate, we characterized kinetics of utilization of radiolabeled acetate in 37 isolated rabbit hearts perfused with modified Krebs-Henseleit buffer and performed a pilot tomographic study in man. Results of initial experiments with carbon-14-labeled acetate (14C-acetate) indicated that the steady-state extraction fraction of acetate averaged 61.5 +/- 4.0% in control hearts (n = 4), 93.6 +/- 0.9% in hearts rendered ischemic (n = 4), and 54.8 +/- 4.0% in hearts reperfused after 60 min of ischemia (n = 3). Oxidation of 14C-acetate, assessed from the rate of efflux of 14CO2 in the venous effluent, correlated closely with the rate of oxygen consumption under diverse metabolic conditions (r = .97, p less than .001). In addition, no significant differences were observed between rates of efflux of total 14C in all chemical species (reflecting total clearance of tracer from myocardium) and efflux of 14CO2. Clearance of 11C-acetate, measured externally with gamma probes in normal and ischemic myocardium, correlated closely with clearance of 14C-acetate measured directly in the effluent (r = .99, p less than .001) and with overall myocardial oxygen consumption (r = .95, p less than .001). Accumulation and clearance of 11C-acetate from human myocardium with PET demonstrated kinetics comparable to those seen with radiolabeled acetate in vitro. Thus externally detectable clearance of 11C-acetate provides a quantitative index of myocardial oxidative metabolism despite variation in the patterns of intermediary metabolism that confounds interpretation of results with conventionally used tracers such as glucose and fatty acid.

[1]  J. Williamson.  Effects of insulin and starvation on the metabolism of acetate and pyruvate by the perfused rat heart. , 1964, The Biochemical journal.

[2]  J. Fabricius,et al.  MYOCARDIAL UTILIZATION OF ACETATE, LACTATE AND FREE FATTY ACIDS AFTER INGESTION OF ETHANOL. , 1964, Clinical science.

[3]  V. Pike,et al.  Preparation of [1-11C]acetate--an agent for the study of myocardial metabolism by positron emission tomography. , 1982, The International journal of applied radiation and isotopes.

[4]  J. Williamson,et al.  Control of citric acid cycle activity in rat heart mitochondria. , 1970, The Journal of biological chemistry.

[5]  H. Taegtmeyer,et al.  Energy metabolism in reperfused heart muscle: metabolic correlates to return of function. , 1985, Journal of the American College of Cardiology.

[6]  D. Woo,et al.  Polymeric columns for liquid chromatography. , 1984, Journal of chromatographic science.

[7]  R. Huesman,et al.  Positron emission tomography of the heart. , 1983, The Physiologist.

[8]  R. Kattermann,et al.  Enzymatic determination of acetate in serum. , 1985, Journal of clinical chemistry and clinical biochemistry. Zeitschrift fur klinische Chemie und klinische Biochemie.

[9]  M J Welch,et al.  Quantification of Infarction in Cross Sections of Canine Myocardium In Vivo with Positron Emission Transaxial Tomography and 11C‐Palmitate , 1977, Circulation.

[10]  D. Gadian,et al.  Studies of metabolism in the isolated, perfused rat heart using 13C NMR , 1981, FEBS letters.

[11]  M. J. Coon,et al.  Enzymatic Breakdown and Synthesis of Acetoacetate , 1953, Nature.

[12]  W. J. Dyer,et al.  A rapid method of total lipid extraction and purification. , 1959, Canadian journal of biochemistry and physiology.

[13]  V. Pike,et al.  Positive labeling of ischemic myocardium: A new approach in patients with coronary disease , 1981 .

[14]  C. Fiol,et al.  Fatty acid and ketone metabolism. , 1985, Circulation.

[15]  L. Opie,et al.  Relative Rates of Oxidation of Glucose and Free Fatty Acids by Ischaemic and Non‐Ischaemic Myocardium after Coronary Artery Ligation in the Dog * , 1973, European journal of clinical investigation.

[16]  R. Shulman,et al.  In vivo carbon-13 nuclear magnetic resonance studies of heart metabolism. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[17]  B E Sobel,et al.  Positron emission tomography of the heart. , 1992, Progress in cardiovascular diseases.

[18]  E. S. Weiss,et al.  External Detection and Visualization of Myocardial Ischemia with 11C‐Substrates in Vitro and in Vivo , 1976, Circulation research.

[19]  B. Sobel,et al.  Efflux of metabolized and nonmetabolized fatty acid from canine myocardium. Implications for quantifying myocardial metabolism tomographically. , 1985, Circulation research.

[20]  F. Spener.  Fatty Acid Metabolism and its Regulation , 1985 .

[21]  M. Rovetto,et al.  Control of fatty acid metabolism in ischemic and hypoxic hearts. , 1978, The Journal of biological chemistry.

[22]  R. E. Clark,et al.  An improved isolated heart preparation for external assessment of myocardial metabolism. , 1979, The American journal of physiology.

[23]  J. Fleiss,et al.  Some Statistical Methods Useful in Circulation Research , 1980, Circulation research.

[24]  F. Collins,et al.  Principles of Biochemistry , 1937, The Indian Medical Gazette.

[25]  H A Krebs,et al.  Utilization of energy-providing substrates in the isolated working rat heart. , 1980, The Biochemical journal.

[26]  J. Williamson.  GLYCOLYTIC CONTROL MECHANISMS. I. INHIBITION OF GLYCOLYSIS BY ACETATE AND PYRUVATE IN THE ISOLATED, PERFUSED RAT HEART. , 1965, The Journal of biological chemistry.

[27]  P. Harris,et al.  The effects of acute hypoxia on lipid synthesis in the rat heart. , 1971, Cardiology.

[28]  B. Sobel,et al.  Substrate use in ischemic and reperfused canine myocardium: quantitative considerations. , 1987, The American journal of physiology.

[29]  J. Bremer,et al.  Chapter 5 Fatty acid oxidation and its regulation , 1984 .

[30]  R. Denton,et al.  Control of the tricarboxylate cycle and its interactions with glycolysis during acetate utilization in rat heart. , 1970, The Biochemical journal.

[31]  E. S. Weiss,et al.  Detection of Remote Myocardial Infarction in Patients with Positron Emission Transaxial Tomography and Intravenous “IC-Palmitate , 1977, Circulation.