The use of 123I-labeled heptadecanoic acid (HDA) as metabolic tracer: preliminary report

The feasibility of using 123I-heptadecanoic acid (HDA) as a metabolic tracer was studied. Different administration routes of HDA were compared. An intracoronary bolus injection was given to calves (n = 3), and an intravenous injection was given to patients (n = 4). In addition, we examined the influence of 4-h halothane anesthesia in calves and in patients the impact of an insulin (1.5 IU/kg) + glucose (1.5 g/kg) infusion on the myocardial kinetics of HDA. Data were accumulated with a scintillation probe in calves (t = 50 min) and a gamma camera in patients (t = 70 min). In calves after an intracoronary bolus injection of HDA the myocardial time-activity curve could be described by two exponentials. The mean elimination half-time of the initial phase (ta 1/2) was 7.3 min and that of the second phase (tb 1/2) was 35 min. The ratio of the size of the initial and second component at to was 0.93. Halothane anesthesia prolonged the elimination half-times and reduced the component ratio. The biphasic behavior of the myocardial time-activity curve was maintained in patients after intravenous administration of HDA under basal conditions (initial ta 1/2 = 8.4 min). However, during infusion of insulin + glucose the decline in the myocardial activity was prolonged and monoexponential. This data shows that insulin glucose, interfering with fatty acid metabolism, influences the myocardial washout of HDA, and thus support its use as a metabolic tracer.     

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.     

Myocardial scintigraphy with I-123 heptadecanoic acid as a test for coronary heart disease

We have evaluated ¹²³I-heptadecanoic acid for myocardial scintigraphy in the diagnosis of coronary heart disease by comparing the results obtained with it in subject groups with high and low probabilities of disease. We conclude that although some patients in the former group can be identified, the test is neither sufficiently sensitive nor specific for routine clinical use.     

Myocardial scintigraphy with I-123 heptadecanoic acid as a test for coronary heart disease

We have evaluated 123I-heptadecanoic acid for myocardial scintigraphy in the diagnosis of coronary heart disease by comparing the results obtained with it in subject groups with high and low probabilities of disease. We conclude that although some patients in the former group can be identified, the test is neither sufficiently sensitive nor specific for routine clinical use.     

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.     

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.     

The influence of glucose on the myocardial time-activity curve during 17-iodo-123 heptadecanoic acid scintigraphy

The lipid pools of the heart (i.e. the triglyceride and phospholipid pool) participate in the free fatty acid metabolism. The degree of involvement, for instance will be determined by the available substrate in the blood. Scintigraphy with 17-iodo-123 heptadecanoic acid was performed to study free fatty acid kinetics in the normal human myocardium during control and glucose infusion (n = 9). In both situations the derived time-activity curves, measured during a period of 75 min, obeyed a monoexponential plus a constant curve fitting [A(t) = A(o)exp(-tln2/T1/2)+C]. During glucose infusion the half-time values did not change but the lipid storage increased in favour of the oxidation pool. In the three protocols used, hypoglycaemic responses were observed, therefore these protocols cannot be advocated.     

Demonstration of the thoracic duct by 123I heptadecanoic acid. Report of a case

The thoracic duct was visualized following ingestion of 123I heptadecanoic acid in a healthy volunteer and in a patient with a growing chyle cyst. The visualization indicated that operative removal of the cyst would not interfere with the lymphatic drainage from the intestines.     

Dual tracer autoradiographic study of beta-methyl-(1-14C) heptadecanoic acid and 15-p-(131I)-iodophenyl-beta-methylpentadecanoic acid in normotensive and hypertensive rats

The myocardial distribution of 15-p-[131I]iodophenyl-3-(R,S)-methylpentadecanoic acid (BMPDA) and 1[14C]-3-(R,S)-methylheptadecanoic acid (BMHDA) was compared in normotensive and hypertensive rats using quantitative dual tracer autoradiographic techniques. The myocardial distribution of carbon-14 [14C] BMHDA and iodine-131 [131I] BMPDA was nearly homogeneous in the normotensive rats, while both tracers showed similar, though very heterogeneous, distribution in hypertensive hearts with decreased uptake in the endocardial region. Our data demonstrate that myocardial distribution of [131I]BMPDA was essentially the same as [14C]BMHDA, and thus single photon emission computed tomographic imaging with 123I-labeled BMPDA could be useful for the detection of regional changes of myocardial fatty acid uptake in patients with prolonged and severe hypertension.     

Evaluation of left ventricular function using electrocardiographically gated myocardial SPECT with (123)I-labeled fatty acid analog.

Electrocardiographically (ECG) gated myocardial SPECT with (99m)Tc-tetrofosmin has been used widely to assess left ventricular (LV) function. However, the accuracy of variables using ECG gated myocardial SPECT with beta-methyl-p-(123)I-iodophenylpentadecanoic acid (BMIPP) has not been well defined. METHODS: Thirty-six patients (29 men, 7 women; mean age, 61.6 +/- 15.6 y) with ischemic heart disease underwent ECG gated myocardial SPECT with (123)I-BMIPP and with (99m)Tc-tetrofosmin and left ventriculography (LVG) within 1 wk. LV ejection fraction (LVEF), LV end-diastolic volume (LVEDV), and LV end-systolic volume (LVESV) were determined on gated SPECT using commercially available software for automatic data analysis. These volume-related items on LVG were calculated with an area-length method and were estimated by 2 independent observers to evaluate interobserver validity. The regional wall motion with these methods was assessed visually. RESULTS: LVEF was 41.1% +/- 12.5% on gated SPECT with (123)I-BMIPP, 44.5% +/- 13.1% on gated SPECT with (99m)Tc-tetrofosmin, and 46.0% +/- 12.7% on LVG. Global LV function and regional wall motion between both gated SPECT procedures had excellent correlation (LVEF, r = 0.943; LVEDV, r = 0.934; LVESV, r = 0.952; regional wall motion, kappa = 0.92). However, the correlations of global LV function and regional wall motion between each gated SPECT and LVG were significantly lower. Gated SPECT with (123)I-BMIPP showed the same interobserver validity as gated SPECT with (99m)Tc-tetrofosmin. CONCLUSION: Gated SPECT with (123)I-BMIPP provides high accuracy with regard to LV function and is sufficiently applicable for use in clinical SPECT. This technique can simultaneously reveal myocardial fatty acid metabolism and LV function, which may be useful to evaluate various cardiac diseases.     

The myocardial elimination rate of radioiodinated heptadecanoic acid

To clarify the mechanism of the elimination of radioactivity after administration of radioiodinated heptadecanoic acid, dogs with and without coronary occlusion were studied. In myocardial tissue samples of normal and ischemic myocardium, the proportions of free radioiodide, radioiodinated heptadecanoic acid, and radioiodinated lipids were determined. Five minutes after intravenous injection of heptadecanoic acid 69% of the radioactivity was present as free iodine, 7% as unaltered heptadecanoic acid, and 24% as lipids. Even in ischemic myocardium 41% was free iodine and 47% lipids. After 2 h free iodine decreased to 48% and lipids increased to 44%. These results indicate that beta-oxidation is not the rate-limiting step in the elimination rate of heptadecanoic acid.     

The myocardial elimination rate of radioiodinated heptadecanoic acid

To clarify the mechanism of the elimination of radioactivity after administration of radioiodinated heptadecanoic acid, dogs with and without coronary occlusion were studied. In myocardial tissue samples of normal and ischemic myocardium, the proportions of free radioiodide, radioiodinated heptadecanoic acid, and radioiodinated lipids were determined. Five minutes after intravenous injection of heptadecanoic acid 69% of the radioactivity was present as free iodine, 7% as unaltered heptadecanoic acid, and 24% as lipids. Even in ischemic myocardium 41% was free iodine and 47% lipids. After 2 h free iodine decreased to 48% and lipids increased to 44%. These results indicate that beta-oxidation is not the rate-limiting step in the elimination rate of heptadecanoic acid.     

Pharmacokinetic analysis of123I-labeled medium chain fatty acid as a radiopharmaceutical for hepatic function based on beta-oxidation

Beta-oxidation is the most important pathway to provide energy for the liver. Our recent findings indicated that radiolabeled medium chain fatty acid analogs could be used as radiopharmaceuticals in the liver, allowing us to monitor alterations in energy metabolism on the cellular level. In the present study, pharmacokinetical analysis of a radioiodinated medium chain fatty acid analog, 6-[123I]iodophenylenanthic acid ([123I]IPEA), was carried out in normal and hepatitis model rats to investigate the index for the measurement of beta-oxidation activity in hepatocytes. The rate constant for metabolism of [123I]IPEA in the liver showed a strong correlation with the ATP level, which was determined as an indicator of beta-oxidation activity in hepatocytes. The radioactivity profile in the liver after [123I]IPEA administration provided important information regarding hepatic viability, and the metabolic rate constant of [123I]IPEA calculated by a pharmacokinetic method was a useful criterion for hepatic diagnosis based on hepatic cellular energy metabolism.     

Preparation and use of 123I-labeled highly iodinated fibrinogen for imaging deep-vein thrombi.

A method for producing protein-iodination-grade 123I suitable for use with a compact bio-medical cyclotron is reported. The preparation of highly iodinated fibrinogen (25 123I atoms per molecule) is described, and its successful use as a thrombus-imaging agent in experimental animals is reported. This new agent clears from the blood faster than conventional radioiodinated fibrinogen and gives higher thrombus-to-blood activity ratios. Thus, the detection of deep-vein thrombi in areas of large blood pool is enhanced, and images can be obtained sooner after administration of the radiopharmaceutical. Induced 4--8-hr-old femoral-vien thrombi in dogs can be well visualized with a scintillation camera as early as 4 hr and as late as 15 hr after administration of 1 mCi of 123I-labeled highly iodinated fibrinogen.     

omega-123I-hexadecanoic acid metabolic probe of cardiomyopathy

The utility of omega-123I-hexadecanoic acid myocardial scintigraphy as a metabolic probe of cardiomyopathies was investigated. Sixteen patients with a variety of cardiomyopathies and myopathies that involve cardiac muscle and ten volunteers were imaged in the postabsorptive state in a 40 degrees LAO projection after a standard dose of omega-123I-hexadecanoic acid. An elimination T1/2 was calculated from the left ventricular myocardial time-activity curve. An uptake index, corrected for chest wall attenuation, was also computed in 7 of 10 volunteers and 8 of 16 patients. Of the 16 patients, only 2 had distinctly abnormal omega-123I-hexadecanoic acid myocardial tracer kinetics. The first patient had a metabolic disorder of which carnitine deficiency was one component. The second patient had endocardial fibroelastosis, a process which has been linked to disorders which deprive the myocardium of oxygen and energy. Therefore, the cardiomyopathy may have been caused by some abnormality of cardiac metabolism other than carnitine deficiency. Although of limited utility in the overall cardiomyopathic population, omega-123I-hexadecanoic acid myocardial scintigraphy should be further investigated as a screening test for carnitine deficiency and related metabolic abnormalities in patients at risk.     

15(p-[123I]Iodophenyl)pentadecanoic acid as tracer of lipid metabolism: comparison with [1-14C]palmitic acid in murine tissues

Uptake and turnover of 15-(p-[123I]iodophenyl)pentadecanoic acid (I-PPA), a radioiodinated free-fatty-acid analog, was examined in heart, lung, liver, kidneys, and spleen and compared with that of [1-14C]palmitic acid (PA). High cardiac uptake of both I-PPA (4.4% dose/g) and PA (2.8% dose/g) was followed by a two-component tracer clearance. Kinetics of I-PPA were linked to those of PA in tissues with primary oxidation of free fatty acids or their preferential storage. Tissue lipids of all organs investigated were labeled concordantly by both tracers. Fractional distributions of PA and I-PPA incorporation in tissue lipids were significantly correlated. Thus general pathways of FFA tissue metabolism are traced by this radioiodinated free-fatty-acid analog. High-quality metabolic imaging of the heart is possible by means of I-PPA with conventional scintigraphic equipment or cross-sectional imaging with single photon emission computerized tomography facilities.     

A Phase 1 study of beta-methyl-p-(123I)-iodophenyl-pentadecanoic acid (123I-BMIPP)

Phase 1 study of beta-methyl-p-(123I)-iodophenylpentadecanoic acid (123I-BMIPP), a new radiopharmaceutical developed for the evaluation of myocardial fatty acid metabolism, was performed in six normal volunteers to evaluate its biodistribution and safety. After intravenous injection of 111 MBq of 123I-BMIPP, the agent accumulated to the myocardium rapidly (5.4 +/- 0.6% at 1.5 hr after injection) and was washed-out slowly (5.1 +/- 0.4% at 3.0hr). 123I-BMIPP demonstrated no significant accumulation to any specific organs other than myocardium, liver and muscle. Myocardium was clearly visualized in the planar and SPECT images obtained 30 min and 3 hrs after injection. The absorption doses from 123I-BMIPP estimated by MIRD method were lower than those from 201Tl in all organs. Neither adverse reactions nor abnormal clinical laboratory findings were found in the safety evaluation. These results suggest 123I-BMIPP is a promising agent for evaluating myocardial fatty acid metabolism.     

Effect of myocardial perfusion and metabolic interventions on cardiac kinetics of phenylpentadecanoic acid (IPPA) I 123

The effect of regional myocardial perfusion and flow-independent adrenergic stimulation, as well as lactatemediated inhibition of cardiac lipolysis, on cardiac IPPA uptake and metabolism was examined in canine hearts (flow studies) and in the isolated perfused Langendorff rat heart (metabolic interventions). In both normal and ischaemic myocardium, local perfusion is a major determinant of cardiac IPPA uptake. In pacing-induced hyperaemia, the strict flow-dependence of cardiac IPPA uptake is not preserved. Adrenergic stimulation raises the rate of oxidation of both palmitic acid ¹⁴C and IPPA. This change is reflected by increased metabolite production released into the perfusate and radioactivity clearance recorded externally. Lactate in high concentrations exerts the opposite effect on cardiac free fatty acid oxidation. IPPA is stored in this condition preferentially in tissue phospholipids and triglycerides.

     

Diagnostic utility of myocardial imaging using 123I-labeled beta-methyl-iodophenyl pentadecanoic acid in ischemic heart disease]

We evaluated the myocardial metabolism in the acute and subacute phases of myocardial infarction or unstable angina using 123I-labeled beta-methyl-iodophenyl pentadecanoic acid (BMIPP). We then compared those findings with (1) myocardial perfusion images obtained with 201TlCl and (2) the regional and global left ventricular function determined by left ventriculography. Thirty-one patients were examined, consisting of 16 with acute myocardial infarction (6.8 +/- 2.6 days after onset), 8 with subacute myocardial infarction (35 +/- 3.0 days after onset) and 7 with unstable angina. The BMIPP images showed a larger uptake-defect than 201TlCl images in the patients in the acute or subacute phase of myocardial infarction. This finding was especially remarkable in the acute phase after successful coronary revascularization therapy. Moreover, in such cases, the myocardial BMIPP uptake improved to the same degree as 201TlCl one month later. The decrease in myocardial uptake of BMIPP agreed well with the decrease in regional wall motion in the acute and subacute phases of myocardial infarction. In contrast, the myocardial perfusion of 201TlCl did not always agree with the regional wall motion in stunned or hibernating myocardium, where BMIPP showed an uptake-defect in the acute phase but improved in the subacute phase. Thus, BMIPP is surmised to be able to depict fatty acid metabolism in in vivo myocardial imaging.