Radiolabeled acetate as a tracer of myocardial tricarboxylic acid cycle flux.

Abstract

The kinetics of [1-14C]acetate oxidation in isolated perfused rat hearts have been determined over a range of perfusion conditions. Effluent measurements demonstrated that 14CO2 cleared biexponentially over 50 minutes after bolus injection of [1-14C]acetate into normoxic hearts perfused with 5 mM glucose and 10 mU/ml insulin. The clearance half-time (t1/2) for the predominant initial clearance phase was 3.1 +/- 0.5 minutes (n = 4). MVO2 was varied over a fourfold range by hypoxia and phenylephrine stimulation (t1/2, 7.2 +/- 1.2 and 2.2 +/- 0.2 minutes, respectively) and in the presence of alternate substrates (lactate, 2 mM; DL-3-hydroxybutyrate, 20 mM; and palmitate, 0.1 mM), which did not modify either tricarboxylic acid (TCA) cycle flux or acetate kinetics. A good correlation (r = 0.93) was observed between k, the rate constant for the initial phase of 14CO2 clearance, and TCA cycle flux, estimated from oxygen consumption. In contrast to results with [1-14C]acetate, lactate (2 mM) increased t1/2 for 14CO2 clearance from a bolus injection of [1-14C]palmitate from 3.0 +/- 0.4 minutes (n = 3) at control to 4.3 +/- 0.2 minutes (n = 3, p less than 0.01). Addition of acetate in nontracer amounts (0.5 or 5 mM) caused significant underestimation of TCA cycle flux when estimated with [1-14C]acetate. 14CO2 clearance accounted for 88-98% of total effluent 14C between 10 and 20 minutes after [1-14C]acetate bolus injection; rate constants for clearance of 14CO2 and total 14C clearance were very similar during this period, and these two rate constants did not differ significantly from each other under any conditions tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Direct noninvasive estimation of myocardial tricarboxylic acid cycle flux in vivo using hyperpolarized 13C magnetic resonance

“…Based on this hypothesis and using the previously determined citrate concentration (1.48 μmol/g dry weight) [49], V TCA was estimated to be 6.7 ± 1.7 μmol · g − 1 · min − 1 (dry weight). Although this value is comparable to previously published fluxes determined from 13 C MRS or radioactive labeled carbon experiments performed during a long acetate infusion in perfused heart or in vivo and typically leading to V TCA comprised between 7.4 and 14 μmol · g −1 · min −1 (dry weight) [3,15,16,61], the values estimated in the present work correspond to the lower end of the range. This might at first appear counter-intuitive since the RPP recorded in this in vivo study (~50 k mm Hg min −1 ; Table 1) was significantly larger than the reported RPP in earlier studies (~20 k to 30 k mm Hg min − 1 ) [3,15], and a larger V TCA is usually expected with increased RPP.…”

“…Although reporting similar V TCA , the obtained MVO 2 varied between 16 (in vivo [15]) and 29 to 31 μmol · g −1 · min − 1 (dry weight) (in perfused heart [3,16,61]), suggesting a more efficient energy conversion in vivo. Future studies should incorporate such a comparison to validate the estimated values of V TCA obtained in the present study.…”

Validation of [1-11C]acetate as a tracer for noninvasive assessment of oxidative metabolism with positron emission tomography in normal, ischemic, postischemic, and hyperemic canine myocardium.

“…3 There was a close correlation between the slope of the rapid clearance phase and the tricarboxylic acid (TCA) cycle flux under varying work load conditions. In contrast to results with labeled palmitate, changes in substrate supply did not alter the tissue kinetics of [1-1'4C]acetate except after administration of acetate in nontracer amounts, equivalent to nonphysiologically high acetate serum levels.…”

The Future of Cardiovascular Imaging in the Diagnosis and Management of Heart Failure, Part 1

“…39 The early rapid clearance of acetate correlates closely with myocardial oxygen consumption, and the relationship of myocardial 11 C-labeled acetate kinetics to cardiac work offers a noninvasive parameter for cardiac efficiency that can be used to demonstrate the effect of pharmacological and pacing interventions on cardiac energetics. 40,41 Fluorine 18-labled fluorodeoxyglucose ( 18 F-FDG) traces cellular glucose uptake and phosphorylation and can be used to quantify regional glucose metabolism.…”