N-13 ammonia as an indicator of myocardial blood flow.

Abstract

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+.

Initial Characterization of an 18F-Labeled Myocardial Perfusion Tracer

“…The SPECT tracer 99m Tc-sestamibi has an average myocardial extraction fraction of 0.38 (SD 5 0.09) for a flow range of 0.52-3.19 mL/min/g (26). For 13 N-ammonia, an extraction fraction of 0.82 (SD 5 0.06) has been found at a control flow after injection into the left circumflex coronary artery (27); lower extraction fractions have been found at higher flows (in mL/min/100 g; calculated as extraction fraction 5 1 2 0.607 2125/flow ). For 82 Rb, a value of 0.42 (SD 5 0.06) has been found after injection into the femoral vein at normal resting flow rates (0.75-1.5 mL/min/g) (28).…”

Effect of Reconstruction Algorithms on Myocardial Blood Flow Measurement with 13N-Ammonia PET

“…13 N-NH 3 is frequently used in clinical cardiac PET. Tracer kinetic models have been developed to describe the exchange of NH 3 between the vascular space and myocardial tissue to quantify MBF (1,2). MBF as determined by cardiac PET with 13 N-NH 3 has been validated against blood flow measurements by microspheres in animal experiments (3), by PET with 15 O-water (4), and by argon inert gas in humans (5).…”

Assessment of Severity of Coronary Artery Stenosis in a Canine Model Using the PET Agent 18F-Fluorobenzyl Triphenyl Phosphonium: Comparison with 99mTc-Tetrofosmin

“…The behavior of 18 F-FBnTP is more desirable for stress-rest studies because it increases the contrast of flow defect. However, further studies are needed to directly quantify the 18 F-FBnTP extraction fraction in the myocardium, using first-pass models (9,15,22,23).…”

“…To date, despite these important advantages, PET is rarely used to assess myocardial perfusion clinically. 15 O-Water and 13 N-ammonia are excellent PET perfusion tracers and may provide a good quantitative estimate of coronary blood flow (8,9). However, the use of 15 O-water and 13 N-ammonia has been limited to a small number of medical centers with an on-site cyclotron because of their short half-lives.…”