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(Circulation. 1999;99:1272-1276.)
© 1999 American Heart Association, Inc.

Correspondence

Variability of the Lumped Constant for [¹⁸F]2-Deoxy-2-fluoroglucose and the Experimental Isolated Rat Heart Model: Clinical Perspectives for the Measurement of Myocardial Tissue Viability in Humans

Christopher G. Rhodes; Paolo G. Camici

MRC Cyclotron Unit, Imperial College School of Medicine, Hammersmith Hospital Campus, London, UK

To the Editor:

The recent publication of findings on the utilization rate for glucose (MR_glu) in the ischemic and reperfused isolated rat heart¹ concludes that the lumped constant (LC) for [¹⁸F]2-deoxy-2-fluoroglucose (FDG) is variable under conditions in which free fatty acids (FFAs) are the main metabolic substrate. The article thus signals a cautionary message to those workers using FDG in the fasted state. However, what is not stated in the take-home message is the important finding that the LC is unaffected by ischemia and reperfusion when circulating FFAs are low.

The authors assert that the coadministration of glucose and FFAs results in a far more physiological condition than glucose alone, and thus they pay scant attention to the equally physiological condition in which insulin levels are increased and FFA concentrations greatly diminished. This is unfortunate, because many cardiac studies are now performed using the euglycemic glucose clamp,² whereby a true physiological steady state is preserved by maintaining glucose at normal levels in the presence of increased insulin concentrations and almost negligible concentrations of circulating FFAs.

Clearly, the in vivo assessment of glucose utilization with FDG will always require recognition of the prevailing metabolic state of the myocardium. This is illustrated by the work of Bøtker et al,³ who showed variations in the in vivo value of the LC in humans. However, this variation of the LC appears to have minimal clinical relevance to the body of scientific knowledge resulting from studies using FDG protocols with the euglycemic clamp.^{2 4} A replotting of the data presented by Bøtker et al for a value of LC=1.0 (the value used by our group and others) indicates minimal systematic error in MR_glu for a wide range of plasma insulin values.

Worrisome aspects of the data produced with use of the isolated heart preparation exist. A complete lack of an increase in FDG uptake with the coadministration of insulin is associated with this model.⁵ This is never the case with in vivo investigation with the glucose clamp. In the recent publication in Circulation,¹ there is a troubling variability in the uptake of FDG during the acute period of ischemia, and a significant and unexplained loss of tracer during the first half of the reperfusion period; is this an experimental issue? Moreover, the clinical significance of a value for LC with such large variability (0.86±0.50) is not clear.

These uncertainties overshadow the other important issues, such as the assertion that hibernating myocardium is ischemic. Blood flow to hibernating myocardium has been shown to be within normal limits in most patients.⁴

The findings of the work in the isolated heart have begun to answer the question as to whether FDG can be used noninvasively to identify meaningful differences in MR_glu in various pathological conditions in humans. The LC for FDG has been shown to be invariant during the administration of epinephrine, increased workload, and acute ischemia and reperfusion after acute ischemia at low FFA levels. The LC for FDG is clearly affected by nutritional changes, but the euglycemic clamp represents a physiologically appropriate methodological intervention to obviate this problem and allow FDG PET to be used for the assessment of tissue viability.

References

1. Doenst T, Taegtmeyer H. Profound underestimation of glucose uptake by [¹⁸F]2-deoxy-2-fluoroglucose in reperfused rat heart muscle. Circulation. 1998;97:2454–2462.
   
2. Marinho NVS, Keogh BE, Costa DC, Lammertsma AA, Ell PJ, Camici PG. Pathophysiology of chronic left ventricular dysfunction: new insights from the measurement of absolute myocardial blood flow and glucose utilization. Circulation. 1996;93:737–744.
   
3. Bøtker HE, Bötcher M, Schmitz O, Gee A, Hansen SB, Cold GE, Nielsen TT, Gjedde A. Glucose uptake and lumped constant variability in normal human hearts determined with [¹⁸F]fluorodeoxyglucose. J Nucl Cardiol. 1997;4:124–132.
   
4. Camici PG, Wijns W, Borgers M, De Silva R, Ferrari R, Knuuti J, Lammertsma AA, Liedtke AJ, Paternostro G, Vatner SF. Pathophysiological mechanisms of chronic reversible left ventricular dysfunction due to coronary artery disease (hibernating myocardium). Circulation. 1997;96:3205–3214.
   
5. Hariharan R, Bray M, Ganin R, Doenst T, Goodwin GW, Taegtmeyer H. Fundamental limitations of [¹⁸F]2-deoxy-2-fluoro-D-glucose for assessing myocardial glucose uptake. Circulation. 1995;91:2435–2444.
   

Response

Heinrich Taegtmeyer, MD, DPhil

UT-Houston Medical School Houston, Tex

Torsten Doenst, MD

Department of Cardiovascular Surgery University of Freiburg, Freiburg, Germany

Drs Rhodes and Camici are correct when they question the clinical significance of our in vitro observations on the tracer/tracee relation of FDG and glucose. We were careful to point out in the discussion of our article that protocols more closely reflecting clinical circumstances will have to be investigated.¹

The issue is not a comparison between in vivo and in vitro models for the noninvasive assessment of glucose uptake. The issue is to recognize that the LC is not a static but rather a dynamic value, as our experiments have shown. The change of the LC precludes the quantitative measurement of myocardial glucose uptake with FDG. Without quantitation, it is in turn not possible to address mechanisms regulating glucose uptake by the normal, ischemic, and reperfused myocardium. At present, quantitation remains an elusive goal. Moreover, lack of quantitation is a major obstacle for the use of FDG as a research tool in cardiac metabolism.²

References

1. Doenst T, Taegtmeyer H. Profound underestimation of glucose uptake by [¹⁸F]2-deoxy-2-fluoroglucose in reperfused rat heart muscle. Circulation. 1998;97:2454–2462.
   
2. Taegtmeyer H. Utility and limitations of [¹⁸F]2-deoxy-2-fluoro-D-glucose for the assessment of flux through metabolic pathways in heart muscle: a critical appraisal. In: Schwaiger M, ed. Cardiac Positron Emission Tomography. Boston, Mass: Kluwer Academic Publishers; 1996:79–95.
   

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