Metabolic fate of extracted glucose in normal human myocardium.

Wisneski, Judith A.; Gertz, Edward W.; Neese, Richard A.; Gruenke, Larry D.; Morris, D. Lynn; Craig, J. Cymerman

doi:10.1172/jci112174

Cited by 182 publications

(110 citation statements)

References 69 publications

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“…3B). These results are consistent with results of earlier studies in humans using arteriovenous measurements of 1-14 C-lactate and L-U-13 C-lactate (19,25). Greater myocardial extraction of tracer than unlabeled lactate was observed in these studies because of the simultaneous release of unlabeled lactate produced from glycolysis of unlabeled glucose.…”

Section: Figuresupporting

confidence: 92%

“…To identify the 11 C-metabolites present in ART and CS blood samples, 50 mmol/kg of L-3-13 C-bolus (sodium salt; Cambridge Isotope Laboratories, Inc.) were injected into 8 dogs (2 IL, 1 CLAMP, 2 LACTATE, and 3 LAC/PHEN) immediately after the 11 C-lactate bolus injection. Simultaneous ART and CS blood samples were obtained at 5,10,15,20,25,30,45, and 60 min after 11 C-and 13 C-lactate administration for the measurement of 11 C-lactate, 11 CO 2 (an indicator of lactate oxidation), 11 C-neutral, and 11 C-basic metabolites (17), as well as for measurements of ART 13 C-labeled lactate, pyruvate, glucose, and alanine. Paired ART/CS blood samples were also collected to determine blood gases, plasma substrates (glucose, free fatty acids [FFA], lactate), and insulin at baseline, before 11 C, and 30 and 60 min of imaging.…”

Section: Imaging and Art/cs Sampling Protocolmentioning

confidence: 99%

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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: Figuresupporting

confidence: 92%

Section: Imaging and Art/cs Sampling Protocolmentioning

confidence: 99%

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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“…Also, it is calculated under the assumption that all substrates taken up by the myocardium undergo complete oxidation in the steady state. Recent isotope-labeled substrate studies have shown that this is not exactly true (41,53,54). OER overestimates the glucose utilization because -13% is released as lactate (41), whereas lactate and fatty acid utilizations are underestimated.…”

Section: Discussionmentioning

confidence: 99%

Myocardial Carbohydrate, Ketone, and Fatty Acid Uptake in Conscious Lambs with Aortopulmonary Shunts1

et al. 1992

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ABSTRACT. A left to right shunt increases myocardial work and is often accompanied by increased catecholamine levels. Because both increased myocardial work and increased catecholamine levels may induce increased fatty acid utilization, which could increase resting myocardial oxygen consumption and therefore unfavorably affect coronary reserve, we studied myocardial uptake of glucose, pyruvate, lactate, &OH-butyrate, acetoacetate, FFA, and triglycerides in 12 7-wk-old lambs with aortopulmonary left to right shunts (58 f 2% of left ventricular output, mean f SEM) and in 10 control lambs 2 wk after surgery. Despite the shunt, systemic blood flow in the shunt lambs was maintained at the same level as in the control lambs. This was accomplished by an increased heart rate and stroke volume. Furthermore, the shunt was accompanied by an increased myocardial oxygen consumption in the shunt lambs (834 f 70 versus 528 f 43 pmol 02-mine' -100 g-I; p c 0.05). There were no significant differences in arterial substrate concentrations between the two groups. The same was true for arteriovenous differences across the myocardium, with the exception of lactate, which was substantially higher in shunt than in control lambs (72 f 25 versus 18 f 23 pmol/L; p < 0.05). As a consequence, myocardial lactate uptake in the shunt lambs was increased 15-fold (18 2 6 versus 1 f 2 pmol. min-I. 100 g-I; p c 0.02), whereas uptake of the other substrates merely paralleled the increased myocardial blood flow. Our data demonstrate that myocardial substrate uptake is not substantially different between shunt and control lambs, with the exception of lactate, of which the extraction is 10-fold higher than in control lambs. We speculate that the increased myocardial lactate utilization may reflect an increase of lactate and pyruvate dehydrogenase activities. A left to right shunt through a ventricular septa1 defect or ductus arteriosus imposes an increased work load on the heart because of its effect on left ventricular wall stress, external work, contractility, and heart rate (1-3). This effect is accompanied by an increased myocardial oxygen consumption (3), which reflects increased oxidation of substrates to meet the increased ATP demand (4). Often, an increased work load leads not only to increased substrate uptake, but also to a change in the pattern of myocardial substrate utilization (5), as has been shown in hearts with increased afterload (6), contractility (7), and thyroxineinduced volume load (8, 9) and during exercise (5,(10)(11)(12). Furthermore, catecholamines are often increased in the presence of a substantial left to right shunt (13), and they are also known to affect myocardial metabolism (14,15). Through their effect on myocardial performance, catecholamines stimulate glucose and fatty acid utilization by the myocardium, and, through activation of lipoprotein lipase, they enhance fatty acid utilization (5, [14][15][16].These considerations suggest that a left to right shunt could lead to a change in myocardial substrate metabolism....

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“…In isolated working rat heart perfused with glucose as sole substrate, a small part of extracellular glucose taken up by the cell is incorporated into glycogen before entering the glycolytic pathway, 31 whereas this incorporation rate is significantly greater in vivo, when hormones and competing substrates are present. 32 At the other end of the spectrum, glycogen is rapidly broken down when glycogen phosphorylase is stimulated by epinephrine or glucagon. 31 Glycogen phosphorylase is the main regulator of glycogenolysis and one of the best-studied enzymes.…”

Section: Glycogen Metabolismmentioning

confidence: 99%