Mathematical model of the metabolism of 123I-16-iodo-9-hexadecenoic acid in an isolated rat heart. Validation by comparison with experimental measurements

The aim of the present study was to demonstrate that it is possible to estimate the intracellular metabolism of a fatty acid labelled with iodine using external radioactivity measurements. ¹²³I-16-iodo-9-hexadecenoic acid (IHA) was injected close to the coronary arteries of isolated rat hearts perfused according to the Langendorff technique. The time course of the cardiac radioactivity was measured using an INa crystal coupled to an analyser. The obtained curves were analysed using a four-compartment mathematical model, with the compartments corresponding to the vascular-IHA (O), intramyocardial free-IHA (1), esterified-IHA (2) and iodide (3) pools. Curve analysis using this model demonstrated that, as compared to substrate-free perfusion, the presence of glucose (11 mM) increased IHA storage and decreased its oxidation. These changes were enhanced by the presence of insulin. A comparison of these results with measurements of the radioactivity levels within the various cellular fractions validated our proposed mathematical model. Thus, using only a mathematical analysis of a cardiac time-activity curve, it is possible to obtain quantitative information about IHA distribution in the different intracellular metabolic pathways. This technique is potentially useful for the study of metabolic effects of ischaemia or anoxia, as well as for the study of the influence of various substrates or drugs on IHA metabolism in isolated rat hearts.     

Measurement of myocardial fatty acid metabolism: kinetics of iodine-123 heptadecanoic acid in normal dog hearts

To define the potential of iodine-123 heptadecanoic acid (IHA) for the noninvasive assessment of myocardial fatty acid metabolism with gamma camera imaging, the influence of myocardial oxygen consumption (MVO2) and blood flow (MBF) on extraction and half-times of IHA were investigated in dogs. Following IHA injection into the left circumflex coronary artery, extraction fraction and half-times were derived from the peak and slope of the IHA time activity curve, which consisted of a vascular, early, and late phase. Single-pass extraction fraction of IHA averaged 0.53 +/- 0.11 s.d. at control and was not influenced by MVO2 and MBF. The half-time of the early phase (T = 9.3 min +/- 2.8 s.d. in controls) as well as the ratio between the size of the early and late phase increased with MVO2 (r = 0.82, r = 0.87, respectively). Thus, early phase intracellular turnover of IHA increased, yet clearance of 123I activity was slowed by augmented cardiac work. Preliminary data of HPLC and electrophoretic analysis of myocardial arterial and venous blood samples over time indicate that the early phase is characterized by a decreasing washout of IHA and a relative increase of radioiodine washout. The half-time of the late phase (T = 245 min +/- 156 s.d. at control) was not related to MVO2 and MBF. In conclusion, myocardial fatty acid metabolism cannot be measured from the half-time of the early phase but might be analyzed from the ratio between the size of the early and late phase when using IHA.     

Do iodinated fatty acids undergo a nonspecific deiodination in the myocardium?

The intracellular and subcellular distribution of 16-(123I)-iodo-9-hexadecenoic acid were studied in isolated rat hearts, perfused with or without glucose. At various time intervals after injection, cardiac lipids were extracted and the activity was determined for all fractions and all lipid classes. The total cardiac activity was maximal within 1 min postinjection and most of the activity was in the aqueous phase. The presence of glucose in the perfusion medium induced an increase of total cardiac and organic fraction activities. In the latter fraction, activity was very low for FFA, but high for triglycerides (TG), and especially polar lipids. The presence of an exogenous substrate, led to a more active esterification of fatty acids. Coronary effluent analysis showed, in the hydrophilic phase, a lower activity spike in the presence than in the absence of glucose. In the mitochondrial fraction most activity occurred in the organic phase, especially as polar lipids. In the nonmitochondrial fraction, activity was much higher in the aqueous phase. At 90 s postinjection of 1-14C-palmitic acid, over 80% of the myocardial activity was found in the hydrophilic fraction, which indicates, as for the iodo-fatty acid (IFA), an immediate and important oxidation, especially without glucose. These data seem to prove that IFA is taken up by the myocardial cell, subsequently enters the mitochondria and, without an early deiodination, is oxidized with iodide release. Changes in IFA metabolism, consecutive to modifications of glucose concentration in the perfusion medium can be observed by external detection of the myocardial activity curve. Omega-Iodinated fatty acids do not undergo a nonspecific deiodination and are therefore well suited for an external study of myocardial metabolism.     

Assessment of myocardial metabolism with iodine-123 heptadecanoic acid: effect of decreased fatty acid oxidation on deiodination

Terminally radioiodinated fatty acid analogs are of potential use for the noninvasive delineation of regional alterations of fatty acid metabolism by gamma imaging. Since radioactivity from extracted iodine-123 heptadecanoic acid [( 123I]HDA) is released from the myocardium in form of free radioiodide (123I-) the present study was performed to determine whether deiodination of [123I]HDA is related to free fatty acid metabolism. Myocardial production of free radioiodide was measured in rat hearts in vitro and in vivo both under control conditions and after inhibition of fatty acid oxidation. In isolated rat hearts perfused at constant flow with a medium containing [123I]HDA, release of 123I- was markedly reduced during cardioplegia and pharmacologic inhibition of mitochondrial fatty acid transfer with POCA by 67% (p less than 0.005) and 72% (p less than 0.005), respectively. In fasted rats in vivo, 1 min after i.v. injection of [123I]HDA, 51 +/- 5% of myocardial radioactivity was recovered in the aqueous phase, containing free iodide, of myocardial lipid extracts. Aqueous activity was significantly decreased in fed (20 +/- 2%; p less than 0.002) and POCA pretreated (30 +/- 3.7%; p less than 0.05) animals exhibiting reduced oxidation of [14C]palmitate. Thus, deiodination of [123I]HDA was consistently reduced during inhibition of fatty acid oxidation in vitro and in vivo. The results apply to the interpretation of myocardial clearance curves of terminally radioiodinated fatty acid analogs.     

I-123 heptadecanoic acid — value and limitations in comparison with C-11 palmitate

To define the potential of ¹²³I-labeled heptadecanoic acid (IHA) for the noninvasive assessment of myocardial free fatty acid (FFA) metabolism, the kinetics of IHA were compared to those of physiologic ¹¹C-palmitate (CPA). The single-pass myocardial extraction fraction of IHA was lower than that of CPA (0.53±0.11 vs 0.65±0.10 under control conditions). Following an intracoronary injection of IHA and CPA, the myocardial time-activity curves showed biphasic clearance of both tracers. While, for CPA, the half-time of the early phase of the time-activity curve was a function of myocardial oxygen consumption (MVO₂), this phase was not found to reflect the oxidative metabolism of IHA. However, for both tracers, the size of the early phase increased with augmented MVO₂, whereas the size of the late phase decreased. The late phase represents storage of both tracers in triglycerides and phospholipids. Hence, while quantitative measurement of CPA oxidation is possible from the early phase of the time-activity curve, only the ratio between the size of the early and late phase might be of value in assessing myocardial FFA metabolism using IHA.

     

Beta-oxidation of 1-[14C]-17-[131I]-iodoheptadecanoic acid following intracoronary injection in humans results in similar release of both tracers

Radioiodine labelled 17-iodo-heptadecanoic acid (IHA) is used for non-invasive study of myocardial metabolism in coronary heart disease and cardiomyopathy. Yet in the interpretation of in vivo myocardial tracer kinetics, it is controversial whether the intracellular degradation of IHA or the removal of iodide across cellular membranes is the rate-limiting step in iodide release from the myocardium. In five patients undergoing coronary sinus catheterization, a mixture of about 40 kBq of [¹²³I] NaI was injected into the left coronary artery. During the following 15-min period, frequent blood samples were taken from the aorta and the coronary sinus. In the aqueous phase of the venous blood, ¹⁴CO₂ and inorganic ¹³¹I appeared nearly in parallel, with a peak time of 4–5 min. Moreover, as shown by the AV difference, there was no significant back diffusion of IHA and no significant non-specific deiodination detectable over the period of observation. There was myocardial retention of inorganic iodide (¹²³I) injected into the left coronary artery. The data strongly support the premise that lipid turnover through -oxidation is the rate-limiting step in the externally measured release of iodide after IHA injection, provided that recirculating inorganic radioactive iodide is corrected for. In addition, 15 volunteers were studied using [¹¹C]palmitic acid and [¹²³I]IHA using PET and dynamic planar camera scintigraphy with iodide correction. There was no significant difference between the mean values of the elimination half-times, and also no significant correlation between half-times of both fatty acids for single individuals.     

External detection of regional myocardial metabolism with radioiodinated hexadecenoic acid in the dog heart

In a previous study we have demonstrated that terminally iodinated hexadecenoic acid (¹³¹I-HA) and Thallium-201 (²⁰¹Tl) are comparable in myocardial uptake and distribution in the ischemic dog heart (Westera et al. 1980). In the present study the potential value of ¹³¹I-HA was proved in determining regional myocardial metabolism in 19 dog experiments.In ten dogs, ¹³¹I-HA was administered 5 min after occlusion of a coronary artery (group II), in six dogs after a 90 min occlusion period (group III). Three dogs served as controls (group I). The turnover rates (t1/2) of ¹³¹I-HA were calculated from mono-exponential time-activity curves, obtained by external detection over ischemic and normally perfused areas during a 30 min period after IV injection of 0.7–1.5 mCi ¹³¹I-HA. The t1/2 values in ischemic regions were found to be significantly longer (group II, 25.1±2.6 min; group III, 22.6±1.8 min) than in nonischemic areas (group II, 12.5±1.8 min; group III, 14.2±1.4 min). The t1/2 values in the control dogs (group I, 13.4±1.4 min) were not significantly different from the turnover rates in the non-ischemic areas of the occluded hearts.We conclude that the study of turnover rates of radioiodinated free fatty acids allows the determination of regional myocardial metabolism and offers a means to distinguish normally perfused from ischemic myocardial tissue.     

Iodomethylated fatty acid metabolism in mice and dogs

The myocardial uptake of fatty acids labeled with radioactive iodine and injected i.v. can only be evaluated with SPECT if their oxidation kinetics is slow enough. For this reason, we evaluated different iodomethylated fatty acids in mice and dogs to determine which of them shows the highest myocardial uptake and the slowest oxidation. The most suitable was found to be 16-iodo-3-methyl hexadecanoic acid (mono beta) since its myocardial fixation was the same as that of the reference, i.e. 16-iodo-9-hexadecenoic acid (IHA), whereas it was degraded more slowly. Thirty min after injection of mono beta into dogs, the decrease in myocardial activity with respect to the maximum was two fold less than after IHA injection. The myocardial uptake of the two dimethylated fatty acids studied, i.e. 16-iodo-2,2-methyl hexadecanoic acid and 16-iodo-3,3-methyl hexadecanoic acid, was less than that of IHA in mice and dogs. In the latter, the myocardial uptake was so small that we were unable to study the time course of its activity. Consequently, these dimethylated fatty acids are not suitable for the study of the myocardial uptake of fatty acids in man.     

Standardized non-invasive assessment of myocardial free fatty acid kinetics by means of 15-(para-iodo-phenyl) pentadecanoic acid (123I-pPPA)scintigraphy: I. Method

Two simple mathematical functions have been applied for estimating myocardial perfusion and fatty acid metabolism from planar, dynamic 123I-para-phenylpentadecanoic acid (123I-pPPA) studies. The first one uses a modified gamma function and the latter one a biexponential fit. The reciprocal of mean transit time is assumed to represent myocardial blood flow and the fast phase (size and half-time) of the biexponential fit primarily accounts for beta oxidation of 123I-pPPA.     

Effect of impaired fatty acid oxidation on myocardial kinetics of 11C-and 123I-labelled fatty acids

Positron emission tomography with ¹¹C-palmitate and single photon imaging with terminally radioiodinated fatty acid analogues (¹²³I-FFA) were evaluated for the non-invasive assessment of regional myocardial fatty acid metabolism during ischaemia. Decreased uptake of tracer and delayed clearance of activity in the ischaemic myocardium were reported for both ¹¹C-and ¹²³I-labelled compounds. However, since during ischaemia both myocardial blood flow and oxidative metabolism are reduced concomitantly, either factor can be responsible for the changes observed. Experimental preparations in which fatty acid metabolism can be modified independently of flow are helpful for the characterization of the relationship between metabolism and myocardial kinetics of labelled fatty acids. Results obtained during flow-independent inhibition of fatty acid oxidation include the following observations:

• - In dogs with controlled coronary perfusion the rate of clearance of ¹¹ C-palmitate activity is decreased during diminished delivery of oxygen, regardless of whether myocardial perfusion is concomitantly reduced or not.

• - In isolated rabbit hearts perfused at normal flow, the extraction of ¹²³ I-FFA is decreased during hypoxia.

• - During pharmacological inhibition of fatty acid oxidation the deiodination of ¹²³ I_FFA is markedly reduced in rat hearts in vivo and in vitro.

     

Myocardial metabolism of radioiodinated methyl-branched fatty acids

Methylated fatty acids labeled with radioactive iodine have been proposed as a means of studying regional myocardial uptake of fatty acids in man. To investigate the methylated fatty acid that is best adapted for an assessment of uptake, we have studied the influence of the number and the position of the methyl groups of IFA intracellular metabolism; 16-iodo-2-methyl-hexadecanoic (mono-alpha), 16-iodo-2,2-methyl hexadecanoic (di-alpha), 16-iodo-3-methyl-hexadecanoic (mono-beta), and 16-iodo-3,3-methyl-hexadecanoic (di-beta) acids were injected into the coronary arteries of isolated rat hearts. Intracellular analysis shows that the degradation of mono-alpha was always lower than that of IHA and the storage was always much higher. The differences between mono-beta and IHA were similar to those observed with mono-alpha, but were much more pronounced. With the two dimethylated IFAs there was an inhibition of both oxidation and esterification which led to an accumulation of free FAs in myocardial cells. In conclusion, mono-beta, di-alpha, and di-beta are potentially suitable for studying the cellular uptake of IFA since all of them, and particularly the dimethylated IFAs, have a low oxidation rate.     

Ischaemic memory imaging using metabolic radiopharmaceuticals: overview of clinical settings and ongoing investigations

“Ischaemic memory” is defined as a prolonged functional and/or biochemical alteration remaining after a particular episode of severe myocardial ischaemia. The biochemical alteration has been reported as metabolic stunning. Metabolic imaging has been used to detect the footprint left by previous ischaemic episodes evident due to delayed recovery of myocardial metabolism (persistent dominant glucose utilization with suppression of fatty acid oxidation). β-Methyl-p-[¹²³I]iodophenylpentadecanoic acid (BMIPP) is a single-photon emission computed tomography (SPECT) radiotracer widely used for metabolic imaging in clinical settings in Japan. In patients with suspected coronary artery disease but no previous myocardial infarction, BMIPP has shown acceptable diagnostic accuracy. In particular, BMIPP plays an important role in the identification of prior ischaemic insult in patients arriving at emergency departments with acute chest pain syndrome. Recent data also show the usefulness of ¹²³I-BMIPP SPECT for predicting cardiovascular events in patients undergoing haemodialysis. Similarly, SPECT or PET imaging with ¹⁸F-FDG injected during peak exercise or after exercise under fasting conditions shows an increase in FDG uptake in postischaemic areas. This article will overview the roles of ischaemic memory imaging both under established indications and in ongoing investigations.     

Sequential sampling: a new acquisition technique for fatty acid kinetics from quasi-simultaneous multiple projections

Studies of myocardial metabolism by rapidly catabolized fatty acids like omega-I-123-heptadecanoic acid (IHA) are usually limited to one planar view of require sophisticated equipment, such as bidirectional slant-hole collimators or seven-pinhole collimators for multiplane or tomographic views. To solve this problem a normal SPECT camera was utilized to acquire sequentially sampled dynamic studies from up to six different views. This was done by a periodically repeated sequence of acquisitions in different projections, which followed one another clockwise. This procedure overcomes the single-plane limitations of the usual IHA dynamic studies. It reveals regional myocardial patterns of tracer uptake and elimination not obtainable from any single viewing angle. In this way one methodological disadvantage relative to thallium perfusion studies is removed. Furthermore, the non-invasive diagnosis of cardiomyopathies, for which no other radioisotope procedure is appropriate, should be improved using this new method.     

PET measurements of myocardial glucose metabolism with 1-11C-glucose and kinetic modeling.

The aim of this study was to investigate whether compartmental modeling of 1-(11)C-glucose PET kinetics can be used for noninvasive measurements of myocardial glucose metabolism beyond its initial extraction. METHODS: 1-(11)C-Glucose and U-(13)C-glucose were injected simultaneously into 22 mongrel dogs under a wide range of metabolic states; this was followed by 1 h of PET data acquisition. Heart tissue samples were analyzed for (13)C-glycogen content (nmol/g). Arterial and coronary sinus blood samples (ART/CS) were analyzed for glucose (mumol/mL), (11)C-glucose, (11)CO(2), and (11)C-total acidic metabolites ((11)C-lactate [LA] + (11)CO(2)) (counts/min/mL) and were used to calculate myocardial fractions of (a) glucose and 1-(11)C-glucose extractions, EF(GLU) and EF((11)C-GLU); (b) (11)C-GLU and (11)C-LA oxidation, OF((11)C-GLU) and OF((11)C-LA); (c) (11)C-glycolsysis, GCF((11)C-GLU); and (d) (11)C-glycogen content, GNF((11)C-GLU). On the basis of these measurements, a compartmental model (M) that accounts for the contribution of exogenous (11)C-LA to myocardial (11)C activity was implemented to measure M-EF(GLU), M-GCF(GLU), M-OF(GLU), M-GNF(GLU), and the fraction of myocardial glucose stored as glycogen M-GNF(GLU)/M-EF(GLU)). RESULTS: ART/CS data showed the following: (a) A strong correlation was found between EF((11)C-GLU) and EF(GLU) (r = 0.92, P < 0.0001; slope = 0.95, P = not significantly different from 1). (b) In interventions with high glucose extraction and oxidation, the contribution of OF((11)C-GLU) to total oxidation was higher than that of OF((11)C-LA) (P < 0.01). In contrast, in interventions in which glucose uptake and oxidation were inhibited, OF((11)C-LA) was higher than OF((11)C-GLU) (P < 0.05). (c) A strong correlation was found between GNF((11)C-GLU)/EF(GLU) and direct measurements of fractional (13)C-glycogen content, (r = 0.96, P < 0.0001). Model-derived PET measurements of M-EF(GLU), M-GCF(GLU), and M-OF(GLU) strongly correlated with EF(GLU) (slope = 0.92, r = 0.95, P < 0.0001), GCF((11)C-GLU) (slope = 0.79, r = 0.97, P < 0.0001), and OF((11)C-GLU) (slope = 0.70, r = 0.96, P < 0.0001), respectively. M-GNF(GLU)/M-EF(GLU) strongly correlated with fractional (13)C-content (r = 0.92, P < 0.0001). CONCLUSION: Under nonischemic conditions, it is feasible to measure myocardial glucose metabolism noninvasively beyond its initial extraction with PET using 1-(11)C-glucose and a compartmental modeling approach that takes into account uptake and oxidation of secondarily labeled exogenous (11)C-lactate.     

Iodomethylated fatty acid metabolism in mice and dogs

The myocardial uptake of fatty acids labeled with radioactive iodine and injected i.v. can only be evaluated with SPECT if their oxidation kinetics is slow enough. For this reason, we evaluated different iodomethylated fatty acids in mice and dogs to determine which of them shows the highest myocardial uptake and the slowest oxidation. The most suitable was found to be 16-iodo-3-methyl hexadecanoic acid (mono ) since its myocardial fixation was the same as that of the reference, i.e. 16-iodo-9-hexadecenoic acid (IHA), whereas it was degraded more slowly. Thirty min after injection of mono into dogs, the decrease in myocardial activity with respect to the maximum was two fold less than after IHA injection. The myocardial uptake of the two dimethylated fatty acids studied, i.e. 16-iodo-2,2-methyl hexadecanoic acid and 16-iodo-3,3-methyl hexadecanoic acid, was less than that of IHA in mice and dogs. In the latter, the myocardial uptake was so small that we were unable to study the time course of its activity. Consequently, these dimethylated fatty acids are not suitable for the study of the myocardial uptake of fatty acids in man.     

Metabolism of beta-methyl-heptadecanoic acid in the perfused rat heart and liver

The metabolism of beta-methyl-[1-14C]heptadecanoic acid, a potential myocardial imaging agent, was investigated in perfused hearts and livers from rats. Hepatic uptake is approximately 4.5 times greater than cardiac uptake. In the heart, 66% of beta-methyl-heptadecanoic acid metabolism occurs via omega-oxidation, 33% by esterification and less than 1% via alpha-oxidation. In contrast, 53% of hepatic metabolism of beta-methyl-heptadecanoic acid occurs via alpha-oxidation, 27% via omega-oxidation, and 20% via esterification. Perfusion of hearts and livers with concentrations of beta-methyl-heptadecanoic acid 100 to 1000 times greater than that used for myocardial imaging does not alter any of the physiological and biochemical parameters measured. In the perfused liver, 3-methyl-[1-14C]glutarate was identified as the principal hydrosoluble catabolite of beta-methyl-heptadecanoic acid.     

The metabolism of 15-p-[123I]-iodophenylpentadecanoic acid in a surgically induced canine model of regional ischemia

The purpose of this study was to examine the longitudinal effect of gradual coronary occlusion on regional myocardial metabolism of 15-p-123I-iodophenylpentadecanoic acid [( 123I]IPPA). Adult dogs were imaged using [123I]IPPA and planar gamma imaging. A thoracotomy was performed and an ameroid constrictor of appropriate size permanently positioned on the left anterior descending coronary artery. The dogs were imaged after injection of 3-5 mCi [123I]IPPA at various times over a 2-week period. With imaging on days 7 and 14, the dogs were paced at a rate of 185. Time-activity curves were generated and t1/2 values calculated using monoexponential curve fitting. Results indicate a significant increase in t1/2 between control and 14 days after surgery in the apical wall (29 +/- 7 to 53 +/- 18 min; P less than 0.05). Although there was also an increased t1/2 in the lateral wall, this was not significant (27 +/- 8 to 78 +/- 99 min; P greater than 0.05). There was no significant change in t1/2 in the septal wall (27 +/- 9 to 33 +/- 8 min; P greater than 0.05). We conclude that [123I]IPPA is a useful indicator of developing myocardial ischemia.     

Sequential sampling: A new acquisition technique for fatty acid kinetics from quasi-simultaneous multiple projections

Studies of myocardial metabolism by rapidly catabolized fatty acids like -I-123-heptadecanoic acid (IHA) are usually limited to one planar view of require sophisticated equipment, such as bidirectional slant-hole collimators or seven-pinhole collimators for multiplane or tomographic views. To solve this problem a normal SPECT camera was utilized to acquire sequentially sampled dynamic studies from up to six different views. This was done by a periodically repeated sequence of acquisitions in different projections, which followed one another clockwise. This procedure overcomes the single-plane limitations of the usual IHA dynamic studies. It reveals regional myocardial patterns of tracer uptake and elimination not obtainable from any single viewing angle. In this way one methodological disadvantage relative to thallium perfusion studies is removed. Furthermore, the non-invasive diagnosis of cardiomyopathies, for which no other radioisotope procedure is appropriate, should be improved using this new method.     

Nonuniformity in myocardial accumulation of fluorine-18-fluorodeoxyglucose in normal fasted humans

In initial studies using fluorine-18-fluorodeoxyglucose (FDG) in normal fasted subjects, we observed disparities in the regional myocardial accumulation of this tracer. Accordingly, we systematically evaluated regional myocardial FDG accumulation in comparison with regional myocardial perfusion assessed with oxygen-15-water and oxidative metabolism assessed with carbon-11-acetate in nine normal subjects (four studied after a 5-hr fast and five studied both fasted and following glucose loading). Under fasting conditions, myocardial accumulation of FDG in the septum and anterior wall averaged 80% of that in the lateral and posterior walls (p less than 0.03). In contrast, after glucose loading the regional distribution of myocardial FDG accumulation became more homogeneous. Regional myocardial perfusion, oxidative metabolism, and accumulation of carbon-11-acetate were homogeneous under both conditions. Thus, under fasting conditions there are regional variations in myocardial accumulation of FDG, which are visually apparent, are not associated with concomitant changes in oxidative metabolism or perfusion, and cannot be attributed to partial-volume effects. This significant heterogeneity may limit the specificity of PET with FDG for detecting myocardial ischemia in fasting subjects.     

Metabolic myocardial imaging with 123I-labeled heptadecanoic acid in patients with angina pectoris

The potential value of ¹²³I-heptadecanoic acid (¹²³I-H^oA) in myocardial scintigraphy has recently been assessed in patients with acute myocardial infarction (AMI) by studying regional myocardial metabolism (Van der Wall et al. 1981 a). To determine the metabolic behavior of ¹²³I-H^oA in patients with stable angina pectoris (AP) as well, 30 patients with AP were included in this study: 18 patients were exercised and 12 patients were studied at rest.Regional myocardial metabolism was evaluated by generating background subtracted time-activity curves, acquired by external detection over normally perfused and ischemic regions during a 30-min period after intravenous injection of ¹²³I-H^oA. Following monoexponential curve-fitting, clearance rates were measured representing turnover rate (T_1/2) of ¹²³I-H^oA.The exercise group showed prolonged T1/2 values of 46.7±7.1 min (mean±SD) in ischemic regions and 28.7±3.6 min in normally perfused regions. The group at rest did not reveal any scintigraphic abnormalities and showed normal T1/2 values in all myocardial regions (29.1±4.7 min).Our observations of prolonged turnover rates in ischemic areas differ from the results of our recent study in patients with AMI, which demonstrated fast turnover rates in infarcted tissue. These data imply that ¹²³I-H^oA permits the study of myocardial metabolism in patients with AP and the discrimination of normally perfused, reversibly ischemic (AP) and irreversibly ischemic (AMI) myocardium.