SUMMARY We have characterized N-13 ammonia as a myocardial blood flow imaging agent suitable for positron-emission computed tomography. However, the mechanisms of uptake and retention of this agent in myocardium are not known, and effects of altered metabolism were not considered. Therefore, we studied the uptake and retention of N-13 ammonia in myocardium under various hemodynamic and metabolic conditions in open-chest dogs. N-13 ammonia was extracted nearly 100% during its initial capillary transit, followed by metabolic trapping that competed with flow-dependent back diffusion. At control flows, the first capillary transit extraction fraction (E) of N-13 ammonia averaged 0.82 ± 0.06. It fell with higher flows by E = 1 -0.607 exp -125/F. Myocardial N-13 tissue clearance half-times were similarly inversely related to blood flow, and ranged from 110-642 minutes. Cardiac work and changes in the myocardial inotropic state induced by isoproterenol and propranolol did not affect E or the tissue clearance half-times. Low plasma pH reduced E by an average of 20%, while elevated plasma pH had no effect. Decreases in flow below control also were associated with a fall in E. Inhibition of glutamine synthetase with L-methionine sulfoximine impaired metabolic trapping of N-13 ammonia and implicates the glutamic acid-glutamine reaction as the primary mechanism for ammonia fixation. The product of E times flow predicts the myocardial N-13 tissue concentrations, which increased by 70% when flow was doubled. Thus, blood flow and metabolic trapping are the primary determinants of myocardial uptake and retention of N-13 ammonia. The relative constancy of metabolic trapping over a wide range of hemodynamic and metabolic conditions demonstrates the value of N-13 ammonia as a myocardial blood flow imaging agent. N-13 AMMONIA* has been characterized as an indicator for the noninvasive visualization of regional myocardial perfusion by positron computed tomography (PCT).' Use of N-13 ammonia has also permitted noninvasive detection of mild, 47% diameter coronary stenosis in the intact dog.2Because fixation of N-13 ammonia in myocardium occurs through metabolic pathways, alterations in both the hemodynamic and metabolic state of the heart could modify the uptake of N-13 ammonia, and hence, limit its value as a flow indicator. In blood, N-13 (NH3) ammonia exists primarily in its ionic species, NH4+, the ammonium ion, which apparently can substitute for K+ on the sodium-potassium transmembraneous exchange system in red blood cells.3 It thus may be actively transported into myocardium. On the other hand, NH3 can diffuse across cell membranes because of its lipid solubility and is rapidly replenished by conversion of NH4+ to NH3 as it leaves the vascular space.4" 5Transmembrane exchange therefore may occur through an active transport mechanism or *The term ammonia is used to refer to the chemical equilibrium of NH3 NH4+ in which the prominent form is NH4+.
Positron emission tomography (PET) was applied to the measurement of myocardial perfusion using the perfusion tracer 13N-labeled ammonia. 13N ammonia was delivered intravenously to 13 healthy volunteers both at rest and during supine bicycle exercise. Dynamic PET imaging was obtained in three cross-sectional planes for 10 minutes commencing with each injection. The left ventricle was divided into eight sectors, and a small region of interest was assigned to the left ventricular blood pool to obtain the arterial input function. The net extraction of 13N ammonia was obtained for each sector by dividing the tissue 13N concentration at 10 minutes by the integral of the input function from the time of injection to 10 minutes. With this approach for calculating net extractions, rest and exercise net extractions were not significantly different from each other. To obviate possible overestimation of the true 13N ammonia input function by contamination by '3N-labeled compounds other than 13N ammonia or by spillover from myocardium into blood pool, the net extractions were calculated using only the first 90 seconds of the blood and tissue time-activity curves. This approach for calculating net extractions yielded significant differences between rest and exercise, with an average ratio of exercise to rest of 1.38+0.34. Nonetheless, the increase was less than predicted from the average 2.7-2.8-fold increase in double product at peak exercise or the 1.7-fold increase in double product at 1 minute after exercise. However, when the first 90 seconds of dynamic data were fit with a two compartment tracer kinetic model, average perfusion rates of 0.75+±0.43 ml/min/g at rest and 1.50± 0.74 ml/min/g with exercise were obtained. This average increase in perfussion of 2.2-fold corresponded to similar average increases in double product. Thus, the noninvasive technique of PET imaging with 13N ammonia shows promise for future applications in determining absolute flows in patients with coronary artery disease. (Circulation 1989;80:1328-1337 T he reference standard for diagnosing coronary artery disease has long been considered to be coronary angiography. However, the limitations of this shadow technique, the variability of subjective readings of angiograms, and the variable relations of percent stenosis and coronary perfusion have emphasized the need for improved means to assess the functional severity of coronary
The usefulness of [1l-tC]acetate as a tracerof overall myocardial oxidative metabolism for use with positron emission tomography has been investigated in 12 closed-chest dogs. Myocardial ltC activity clearance kinetics after intravenous administration of [1-"C]acetate in dogs have been determined noninvasively by positron emission tomography. Biexponential fitting of regional myocardial`C time-activity curves was performed to give clearance half-times and fractional distribution. The rate constant kl for the early rapid phase of "C activity clearance was found to correlate linearly with myocardial oxygen consumption (y=0.0156x+0.039; SEE=0.023; r=0.95). kl was approximately 7% lower in septal sectors compared with the left ventricular free wall, suggesting that regional oxygen consumption in the septum was lower; a concomitant regional attenuation of blood flow in the septum relative to the left ventricular free wall was also observed. In dogs using carbohydrates as the predominant fuel, kl oxygen consumption was somewhat more than in dogs using predominantly free fatty acids (0.021±0.002 compared with 0.018+0.002, p <0.01), indicating that increased carbohydrate consumption is associated with a small increase in kl at constant oxygen consumption. It is concluded that measurement of myocardial [1-"Cjacetate kinetics allows noninvasive determination of cardiac oxygen consumption by positron emission tomography and that the technique is relatively insensitive to myocardial fuel selection. (Circulation 1989;79:134-142) P ositron emission tomography (PET) provides a unique opportunity for the noninvasive study of regional metabolism in vivo.1 While metabolic tracers currently in use for PET are
Experimental studies of animals have previously demonstrated the validity of [1-ttClacetate as a tracer of oxidative metabolism for use with positron emission tomography. The present study was undertaken to define in normal human volunteers the relation between myocardial clearance kinetics of [1-"C]acetate, and the rate-pressure product as an index of myocardial oxygen consumption. Twenty-two studies were performed of 12 volunteers. The rate-pressure product was increased with continuous supine bicycle exercise in six studies. Of the 16 resting studies, seven were performed in the fasted state and nine following an oral glucose load, to define possible effects of substrate availability on the tracer-tissue kinetics. Myocardial tissue time-activity curves were biexponential. Clearance of activity was homogeneous throughout the myocardium. The rate constants ki, obtained from biexponential fitting, and kn..n, obtained by monoexponential fitting of the initial linear portion of the time-activity curves, correlated well with the rate-pressure product. Although the correlation coefficient was higher for kl than for km.,, (0.95 vs. 0.91), analysis on a sectorial basis showed less regional variability in kn..O. This suggests that korno,0 which is more practical than kl because it requires shorter acquisition times, may be more clinically and experimentally useful for detection of myocardial segments with abnormal oxygen consumption. Overall, changes in myocardial substrate supply were without significant effect on the relation between the rate constants (kl and k...0) and the rate-pressure product, although a small decrease in km0,,0/rate-pressure product was observed following oral glucose by paired analysis in four subjects. It is concluded that [1-"C]acetate can be used for the noninvasive measurement of myocardial oxygen consumption in humans with positron emission tomography, and, thus, has clinical and experimental potential as a tool for the understanding and diagnosis of myocardial disease. (Circulation 1989;80:863-872) acid kinetics in myocardium.3-12 Although characteristic changes in uptake and clearance of labeled fatty acids have been observed in myocardial ischemia, these changes reflect the net effect of diminished oxygen supply on each of the steps in fatty acid utilization and are not specific for impairment of 3-oxidation.2 Uptake and clearance of labeled fatty acids are markedly affected by substrate availability,13-15 in addition to myocardial workload.16 To characterize more precisely the metabolic state of the myocardium, a selective tracer of mitochondrial oxidative function is required.In the early 1980s, [1-1"C]acetate was examined both in animal studies17 and in patients with coro-
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