PET Measurements of Myocardial Glucose Metabolism with 1-11C-Glucose and Kinetic Modeling

Herrero, Pilar; Kisrieva-Ware, Zulfia; Dence, Carmen S.; Patterson, Bruce W.; Coggan, Andrew R.; Han, Dong‐Ho; Ishii, Yôsuke; Eisenbeis, Paul; Gropler, Robert J.

doi:10.2967/jnumed.106.037598

Cited by 31 publications

(22 citation statements)

References 29 publications

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“…S2), suggesting that, under the conditions studied, secondarily labeled 11 C-lactate metabolites undergo minimal myocardial extraction and, therefore, should not interfere with noninvasive myocardial PET measurements of exogenous 11 C-lactate metabolism. These observations contrast with our recent study on measurements of glucose metabolism using 1-11 C-glucose, where myocardial contribution of secondarily labeled 11 C-lactate produced from 1-11 C-glucose was significant and had to be considered to accurately measure myocardial glucose metabolism beyond its initial uptake (24).…”

Section: Figurecontrasting

confidence: 54%

L-3-11C-Lactate as a PET Tracer of Myocardial Lactate Metabolism: A Feasibility Study

Herrero¹,

Dence²,

Coggan³

et al. 2007

Journal of Nuclear Medicine

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Lactate is a key myocardial energy source. Lactate metabolism is altered in a variety of conditions, such as exercise and diabetes mellitus. However, to our knowledge, noninvasive quantitative measurements of myocardial lactate metabolism have never been performed because of the lack of an adequate radiotracer. In this study we tested L-3-11 C-lactate ( 11 C-lactate) as such a tracer. Methods: Twenty-three dogs were studied under a wide range of metabolic interventions. 11 C-Lactate and 13 C-lactate were injected as boluses and PET data were acquired for 1 h. Concomitant arterial and coronary sinus (ART/CS) blood samples were collected to identify 13 C-lactate metabolites and to measure fractional myocardial extraction/production of 11 C metabolite fractions ( 11 C acidic: 11 CO 2 and 11 C-lactate; 11 C basic: 11 C-labeled amino acids; and 11 C neutral: 11 C-glucose). Lactate metabolism was quantified using 2 PET approaches: monoexponential clearance analysis (oxidation only) and kinetic modeling of PET 11 C-myocardial curves. Results: Arterial 11 C acidic, neutral, and basic metabolites were identified as primarily 11 C-labeled lactate 1 pyruvate, glucose, and alanine, respectively. Despite a significant contribution of 11 C-glucose (23%-45%) and 11 C-alanine (,11%) to total arterial 11 C activity, both were minimally extracted (1)/produced(2) by the heart (1.7% 6 1.0% and 20.12% 6 0.84%, respectively). Whereas extraction of 11 C-lactate correlated nonlinearly with that of unlabeled lactate extraction (r 5 0.86, P , 0.0001), 11 CO 2 production correlated linearly with extraction of unlabeled lactate (r 5 0.89, P , 0.0001, slope 5 1.20 6 0.13). In studies with physiologic free fatty acids (FFA) (415 6 216 nmol/mL), 11 C-lactate was highly extracted (32% 6 12%) and oxidized (26% 6 14%), and PET monoexponential clearance and kinetic modeling analyses resulted in accurate estimates of lactate oxidation and metabolism. In contrast, supraphysiologic levels of plasma FFA (4,111 6 1,709 nmol/mL) led to poor PET estimates of lactate metabolism due to negligible lactate oxidation (1% 6 2%) and complete backdiffusion of unmetabolized 11 C-lactate into the vasculature (28% 6 22%). Conclusion: Under conditions of net lactate extraction, L-3-11 Clactate faithfully traces myocardial metabolism of exogenous lactate. Furthermore, in physiologic substrate environments, noninvasive measurements of lactate metabolism are feasible with PET using myocardial clearance analysis (oxidation) or compartmental modeling. Thus, L-3-11 C-lactate should prove quite useful in widening our understanding of the role that lactate oxidation plays in the heart and other tissues and organs.

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Section: Figurecontrasting

confidence: 54%

L-3-11C-Lactate as a PET Tracer of Myocardial Lactate Metabolism: A Feasibility Study

Herrero¹,

Dence²,

Coggan³

et al. 2007

Journal of Nuclear Medicine

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“…MBF was measured using 15 O-water, FA fractional uptake, utilization and oxidation were measured using 1- 11 C-palmitate, and myocardial glucose utilization, glycolysis, glucose oxidation, and glycogen storage rates were measured using 1- 11 C-glucose, as previously described (9, 24). MBF was quantified in all 19 subjects, FA metabolism in all but 1 woman (there was a problem verifying the quality of the C-11 palmitate for that single study and the subject did not want to return for a repeat study), and glucose metabolism in 15 (8 men, 7 women).…”

Section: Methodsmentioning

confidence: 99%

“…Similarly, our group has validated the compartmental modeling that allows us to measure glucose uptake, glucose utilization, and the components of glucose utilization - glycolysis and glycogen storage rates (9). Glycolysis can also be further broken down using kinetic modeling into the portion accounted for by full glucose oxidation as detailed by Herrero et al.…”

Section: Methodsmentioning

confidence: 99%

Sex affects myocardial blood flow and fatty acid substrate metabolism in humans with nonischemic heart failure

Kadkhodayan

Lin

Coggan

et al. 2017

Journal of Nuclear Cardiology

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In animal models of heart failure (HF), myocardial metabolism shifts from the normal preference for high-energy fatty acid (FA) metabolism towards the more efficient fuel, glucose. However, FA (vs. glucose) metabolism generates more ATP/mole; thus FA metabolism may be especially advantageous in HF. Sex modulates myocardial blood flow (MBF) and substrate metabolism in normal humans. Whether sex affects MBF and metabolism in patients with HF is unknown. We studied 19 well-matched men and women with nonischemic HF with similar ejection fractions (all ≤ 35%). MBF and myocardial substrate metabolism were quantified using positron emission tomography. Women had higher MBF (mL/g/min), FA uptake (mL/g/min), utilization (nmol/g/min) (P<0.005, <0.005, <0.05, respectively) and trended towards higher FA oxidation than men (P=0.09). These findings were independent of age, obesity, and insulin resistance. There were no sex-related differences in fasting myocardial glucose uptake or metabolism. In an exploratory analysis of the longitudinal follow-up of these subjects (mean 7 y), we found that 4 men had a major cardiovascular event, while one woman died of non-cardiac causes. Higher MBF related to improved event-free survival (HR=0.31, P=0.02). In sum, in nonischemic HF, women have higher MBF and FA uptake and metabolism than men, and these changes are not due to differences in other variables that can affect myocardial metabolism (e.g., age, obesity, or insulin resistance). Moreover, higher MBF portends a better prognosis. These sex-related differences should be taken into account in the development and targeting of novel agents aimed at modulating in MBF and metabolism in HF.

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“…Purpose-bred mongrel dogs weighing 20–25 kg were fasted overnight, anesthetized, and instrumented as previously described 10,11. Briefly, catheters were placed in the thoracic aorta (via a femoral artery) for monitoring of blood pressure and for sampling of arterial blood and in both femoral veins for tracer and drug administration, respectively.…”

Section: Methodsmentioning

confidence: 99%

Measurement of myocardial fatty acid esterification using [1-11C]palmitate and PET: comparison with direct measurements of myocardial triglyceride synthesis

Coggan

Kisrieva-Ware

Dence

et al. 2009

Journal of Nuclear Cardiology

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The purpose of the present study was to assess the accuracy of non-invasive estimates of the rate of myocardial fatty acid esterification (MFAE) obtained using positron emission tomography (PET).Methods-Sixteen dogs were studied after an overnight fast (FAST), during a euglycemic hyperinsulinemic clamp (CLAMP), or during infusion of Intralipid (IL) or IL plus dobutamine (IL/ DOB) (n=4/group). The rate of MFAE was quantified using a bolus injection of [1-11 C]palmitate and compartmental modeling as described by Bergmann et al. 3 and compared to the rate of triglyceride (TG) synthesis measured directly using a continuous infusion of [1-13 C]palmitate and tissue sampling.Results-Across groups, mean plasma free fatty acid (FFA) concentration varied ~20-fold, with this variation in FFA availability accompanied by a ~20-fold range in directly-measured TG synthesis (i.e., from 7±1 nmol/min/g in CLAMP to 128±75 nmol/min/g in IL). PET-based estimates of MFAE varied to a similar degree (i.e., from 22±9 nmol/min/g in CLAMP to 543±551 nmol/min/g in IL), and were significantly correlated with TG synthesis (i.e., R=0.77, P<0.001). MFAE, however, was 3-to 4-fold higher than TG synthesis in FAST, CLAMP, and IL, but comparable when cardiac work was increased in IL/DOB, suggesting that MFAE reflects, in part, the incorporation of label into amino acids via TCA cycle exchange reactions (e.g., α-ketoglutarate ↔ glutamate) as well as the synthesis of TG and other lipids.Conclusions-Changes in the rate of MFAE as determined using PET and the compartmental model of Bergmann et al. 3 parallel changes in the rate of TG synthesis, at least in the basal state. Although such measurements are not as robust as rates of myocardial FFA uptake and oxidation as estimated by the model, this method should still be useful for quantifying acute changes in FFA storage by the heart in various pathophysiological states.

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PET Measurements of Myocardial Glucose Metabolism with 1-11C-Glucose and Kinetic Modeling

Cited by 31 publications

References 29 publications

L-3-11C-Lactate as a PET Tracer of Myocardial Lactate Metabolism: A Feasibility Study

L-3-11C-Lactate as a PET Tracer of Myocardial Lactate Metabolism: A Feasibility Study

Sex affects myocardial blood flow and fatty acid substrate metabolism in humans with nonischemic heart failure

Measurement of myocardial fatty acid esterification using [1-11C]palmitate and PET: comparison with direct measurements of myocardial triglyceride synthesis

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