Detection of viable myocardium with p-iodophenyl-9-(R,S)-methylpentadecanoic acid in ischemic rat myocardium

BACKGROUND: The methyl-branched free fatty acid analog 15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid (9MPA) is metabolized more rapidly than 15-(p-iodophenyl)-3(beta)-(R,S)-methylpentadecanoic acid. This study investigates whether myocardial ischemic injury to beta-oxidation and viable myocardium can be detected with the use of 9MPA in a rat myocardial ischemia model. METHODS AND RESULTS: In the acute study the left coronary arteries were occluded for 15 or 45 minutes and then reperfused; the rats were killed after 2 hours. Iodine 125 and iodine 123 9MPA was injected 60 minutes (delayed images) and 3 minutes (early images), respectively, before the rats were killed. In the subacute study the left coronary arteries were either occluded for 45 minutes and then reperfused or occluded and not reperfused. One week later, I-125 and I-123 9MPA was injected 60 minutes and 3 minutes, respectively, before the rats were killed. The distribution of 9MPA was examined with the use of dual-tracer autoradiography. In the acute study the delayed images showed a higher uptake in viable regions at risk than in normal areas and nonviable regions. In the subacute study a difference in uptake between viable regions at risk and normal areas was visible on the early images, but this difference disappeared on the delayed images. CONCLUSIONS: 9MPA is a useful tracer for detecting viable regions of ischemic myocardium during acute and subacute disease stages.     

Scintigraphic evaluation of myocardial ischaemia using a new fatty acid analogue: iodine-123-labelled 15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid (9MPA)

Iodine-123-labelled 15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid (9MPA) is a branched fatty acid analogue for myocardial imaging, which has been recently designed for medium washout rates from the myocardium. The purpose of this study was to assess the clinical feasibility of use of 9MPA for the evaluation of myocardial ischaemia. Twenty-one patients were injected with 9MPA at rest, and sequential single-photon emission tomography (SPET) acquisitions were performed 5, 45 and 240 min after administration to calculate washout rates from the myocardium. The findings of 9MPA images were analysed in comparison with those of perfusion images with thallium-201 or sestamibi, coronary angiography and left venticulography. In general, reduction of 9MPA uptake was more remarkable than that of perfusion tracers. The findings of 9MPA early images correlated better with those of exercise perfusion images than with the rest images. Measured washout rates of 9MPA from ischaemic myocardium were significantly slower than those from normal myocardium. The majority of areas with abnormal 9MPA distribution manifested wall motion abnormality, while all areas with normal tracer distribution presented normal wall motion. The detectability of myocardial ischaemia was improved by adding mid and delayed images in six cases. However, both washout and fill-in patterns were encountered in ischaemic lesions, rendering the interpretation of images difficult. In conclusion, the results of this study indicated that 9MPA has acceptable myocardial uptake, that its use is feasible for the detection of ischaemia and that the abnormal distribution of the tracer correlates well with wall motion abnormality reflecting metabolic disorders. Received 6 March and in revised form 28 April 1999     

Scintigraphic evaluation of myocardial ischaemia using a new fatty acid analogue: iodine-123-labelled 15-(p-iodophenyl)-9-(R, S)-methylpentadecanoic acid (9MPA).

Iodine-123-labelled 15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid (9MPA) is a branched fatty acid analogue for myocardial imaging, which has been recently designed for medium washout rates from the myocardium. The purpose of this study was to assess the clinical feasibility of use of 9MPA for the evaluation of myocardial ischaemia. Twenty-one patients were injected with 9MPA at rest, and sequential single-photon emission tomography (SPET) acquisitions were performed 5, 45 and 240 min after administration to calculate washout rates from the myocardium. The findings of 9MPA images were analysed in comparison with those of perfusion images with thallium-201 or sestamibi, coronary angiography and left venticulography. In general, reduction of 9MPA uptake was more remarkable than that of perfusion tracers. The findings of 9MPA early images correlated better with those of exercise perfusion images than with the rest images. Measured washout rates of 9MPA from ischaemic myocardium were significantly slower than those from normal myocardium. The majority of areas with abnormal 9MPA distribution manifested wall motion abnormality, while all areas with normal tracer distribution presented normal wall motion. The detectability of myocardial ischaemia was improved by adding mid and delayed images in six cases. However, both washout and fill-in patterns were encountered in ischaemic lesions, rendering the interpretation of images difficult. In conclusion, the results of this study indicated that 9MPA has acceptable myocardial uptake, that its use is feasible for the detection of ischaemia and that the abnormal distribution of the tracer correlates well with wall motion abnormality reflecting metabolic disorders.     

Time course of discordant BMIPP and thallium uptake after ischemia and reperfusion in a rat model.

Serial changes in fatty acid metabolism or use associated with acute ischemia and reperfusion were examined in rat hearts. METHODS: Male Wistar rats were subjected to occlusion of the left coronary artery for 20 min followed by reperfusion. After release of the occlusion, groups of animals were allowed to recover for intervals of 20 min (n = 9), 1 d (n = 9), 3 d (n = 6), 7 d (n = 6), or 30 d (n = 6). Hearts were excised 15-20 min after injection of 0.74 MBq of (125)I-15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) and 14.8 MBq of (201)Tl. One minute before resection, the left coronary artery was reoccluded and 185 MBq of (99m)Tc-sestamibi were injected to document the area at risk. Triple-tracer autoradiography was performed to assess tracer uptake. Uptake ratios of BMIPP and (201)Tl in the area at risk were calculated on the basis of the count density in the lesion divided by that in the normally perfused area. RESULTS: (201)Tl uptake did not change throughout the observation period (P = 0.25). In contrast, BMIPP uptake increased early in the acute phase (20 min and 1 d), decreased during the subacute phase (7 d), and subsequently recovered in the chronic phase (30 d). CONCLUSION: The present investigation clearly illustrated that BMIPP uptake is higher than (201)Tl uptake in the acute phase, that BMIPP uptake is lower than (201)Tl uptake in the subacute phase, and that BMIPP uptake and (201)Tl uptake are similar in the chronic phase. These results yield data essential to the precise interpretation of BMIPP images.     

Myocardial fatty acid imaging with 123I-labelled 9-methyl-branched pentadecanoic acid (9MPA) using SPET

123I-labelled 15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid (9MPA) is a modified long-chain fatty acid that shows some beta-oxidation. Some basic aspects of this fatty acid, including myocardial uptake, distribution, clearance and differences from 201Tl myocardial perfusion, have yet to be evaluated. An average of 150 MBq of 123I-9MPA was injected intravenously into 16 patients with coronary artery disease. Planar images were obtained 45, 120 and 240 min post-injection, and single photon emission tomography (SPET) was performed at the initial (5 min), middle (45 min) and late (120 min) phases after injection. Myocardial uptake and clearance were evaluated by planar imaging, and a segmental comparison between 123I-9MPA and reinjection or resting 201Tl was performed on the SPET images. 123I-9MPA showed good uptake between 5 and 60 min, but a severe decrease was seen after 120 min in three (19%) patients. The heart-to-mediastinum ratio was 1.68 +/- 0.19, 1.55 +/- 0.19 and 1.40 +/- 1.40 at 45, 120 and 240 min, respectively. The washout rate after background subtraction was 28% for 45 min to 2 h and 47% for 45 min to 4 h. The segmental comparison (n = 182) between 123I-9MPA and 201Tl showed complete agreement of 72, 75 and 65% at 10, 45 and 120 min, respectively. The grading of the uptake of 123I-9MPA was less than that of 201Tl in 20-30% of the segments indicating myocardial fatty acid metabolic impairment relative to perfusion. The regional clearance from 5 to 120 min in the reduced-count region was lower than that in the normal region (28 +/- 7% vs 36 +/- 8%, P < 0.01). All 123I-9MPA SPET images showed good contrast if the data were acquired within 60 min. Based on the clearance of 123I-9MPA from the myocardium, imaging within 120 min is desirable. A mismatch of fatty acids and perfusion was seen in one-quarter of patients, and differential regional clearance may be clinically significant and should be investigated.     

Detection of coronary artery disease by iodine-123-labeled iodophenyl-9-methyl pentadecanoic acid SPECT: Comparison with thallium-201 and iodine-123 BMIPP SPECT

To evaluate the ability to detect coronary artery disease (CAD) with a new iodine-123 labeled branched fatty acid analog, iodophenyl-9-methyl pentadecanoic acid (9MPA), we performed 9MPA, iodine-123 BMIPP and thallium-201 SPECT in patients with CAD. Twenty-four patients (11 with effort angina and 13 with myocardial infarction) were studied. In all patients, 9MPA SPECT was obtained at 15 min after injection. Twenty-three patients underwent stress-redistribution 201Tl SPECT and 9 patients also underwent BMIPP myocardial fatty acid imaging. The regional uptakes of 9MPA, BMIPP and 201Tl were scored semiquantitatively and the segmental agreements were compared among them. In the segment-to-segment comparison, 9MPA showed reduced activity in comparison to stress-redistribution 201Tl imaging. The defect score of 9MPA was significantly greater than that of redistribution 201Tl images (p < 0.001). In addition, segmental 9MPA uptake was lower than BMIPP and its defect score was significantly greater than that of BMIPP (p < 0.05). When coronary angiography was used as the criterion, 9MPA showed higher sensitivity and lower specificity than stress-redistribution 201Tl (p < 0.01). In conclusion, fatty acid metabolic imaging with 9MPA is a sensitive but nonspecific detector of CAD.     

Fatty acid imaging with 123I-15-(p-iodophenyl)-9-R,S-methylpentadecanoic acid in acute coronary syndrome.

123I-15-(p-iodophenyl)-9-R,S-methylpentadecanoic acid (9-MPA) has recently been developed as a tracer for myocardial fatty acid uptake. The aim of this study, which was performed as part of a phase III clinical trial of 9-MPA, was to test the usefulness of 9-MPA for the assessment of myocardial viability in patients with acute coronary syndrome (ACS). METHODS: Fifteen patients with ACS who had undergone direct percutaneous transluminal coronary angioplasty were examined. Myocardial SPECT with 9-MPA and 99mTc-sestamibi and low-dose dobutamine echocardiography were performed within 2 wk after onset. The 9-MPA images were obtained 10 and 60 min after tracer administration, and sestamibi imaging was begun 60 min after the injection. The left ventricle was divided into 9 segments, and 9-MPA and sestamibi uptake were scored from 0 (normal) to 3 (no activity) in each segment. Lower uptake of 9-MPA than of sestamibi was defined as a mismatch. Myocardial segments showing improvement in wall motion during low-dose dobutamine infusion (5-10 microg/kg/ min) were considered viable. RESULTS: The 9-MPA images were of high quality for all patients. Myocardial uptake of 9-MPA was lower in ischemic myocardium than in nonischemic myocardium (58.2%+/-14.2% versus 91.9%+/-6.5%, P<0.0001). Clearance of 9-MPA from ischemic myocardium was slower than that from nonischemic myocardium (10.2%+/-11.7% versus 19.1%+/-5.9%, P<0.01). A mismatch was seen in 10 of 15 patients, and 18 of 20 (90%) mismatched segments were defined as viable by dobutamine echocardiography. Conversely, 18 of 20 (90%) matched segments did not show any improvement in function during dobutamine stimulation (P<0.0001). Uptake of 9-MPA in nonviable segments was lower than that in dysfunctional but viable segments (P<0.05), and 9-MPA clearance from nonviable segments was slower than that from viable segments (P<0.05). CONCLUSION: The imaging characteristics of 9-MPA for SPECT are excellent, allowing noninvasive assessment of myocardial fatty acid uptake. Myocardial imaging with 9-MPA may reveal impaired fatty acid uptake in dysfunctional but viable myocardium and thus provide useful information for clinical decision making in ACS.     

Reversible defect of 123I-15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid indicates residual viability within infarct-related area

To evaluate the relationship between the reversible defect of 123I-15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid (9MPA) and residual viability within an infarct-related area, we performed resting single photon emission computed tomography (SPECT) with 9MPA and positron emission tomography (PET) with 18F-deoxyglucose (FDG) and 13N-ammonia (NH3) in 7 patients with prior myocardial infarction. 9MPA-SPECT was obtained 2 min (early) and 50 min (delayed) after tracer injection. Tomographic images of the left ventricle were divided into 13 segments to correlate the regional uptake of each tracer. Residual viability within an infarct-related segment was confirmed by NH3- and FDG-PET. Twenty-six infarct-related segments, confirmed by NH3-PET, showed reduced uptake of 9MPA on early images. In these 26 segments, 6 showed reversible defect of 9MPA and 20 showed fixed defect on delayed images. Residual viability was present in all segments exhibiting reversible 9MPA defect and 7 segments (35%) exhibiting fixed defect (p < 0.05). The sensitivity, specificity and accuracy of reversible 9MPA defect for the detection of myocardial viability were 46%, 100%, and 73%, respectively. Myocardial clearance of 9MPA was significantly slower in non-viable segments than in ischemic but viable segments (4.9+/-5.1% vs. 10.1+/-5.3%; p < 0.05). These data suggest that a reversible 9MPA defect indicates residual viability within the infarct-related area.     

Myocardial distribution of iodine-123-iodophenyl-9-methyl-pentadecanoic acid (9MPA) in patients with acute myocardial infarction: comparison with regional wall motion obtained from technetium-99m-sestamibi gated SPECT]

123I-iodophenyl-9-methyl-pentadecanoic acid (9MPA) is a modified long-chain (15 carbons) fatty acid with a methyl branch on its 9 carbon location. Myocardial SPECT images (two sets, 10 min each) were obtained starting 10 min (early phase) and 50 min (delay phase) after the injection of 160 MBq 123I-9MPA at rest in 10 patients with acute myocardial infarction. The segmental myocardial uptake (% uptake) and clearance (% washout) from early to delay image were calculated by the SPECT data. ECG-gated myocardial SPECT with 99mTc-sestamibi was also performed and segmental left ventricular (LV) wall motion was evaluated using QGS (quantitative gated SPECT) program. The % uptake of LV segments with hypokinetic or akinetic wall motion were significantly lower than those with normokinesis (p < 0.01) for both early and delay phases. The % washout of hypokinetic segments were significantly lower than those of normokinetic regions (p < 0.01), while the % washout of akinetic segments were significantly higher than those of severely hypokinetic segments (p < 0.05). Thus, 123I-9MPA myocardial distribution and clearance thought to be associated with left ventricular regional wall motion.     

Impaired myocardial accumulation of 15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid in a patient with hypertrophic cardiomyopathy and exercise-induced ischemia due to vasospasm

We encountered a patient with hypertrophic cardiomyopathy complicated with exercise-induced myocardial ischemia. Exercise-stress 99mTc-tetrofosmin imaging demonstrated reversible ischemia in the lateral wall, whereas resting fatty acid imaging with a new beta-methyl branched fatty acid analogue, I-123-15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid (123I-9-MPA), showed impaired uptake and accelerated washout kinetics in the inferoapical and posteroseptal walls but not in the ischemia-related region. These findings suggest that the metabolic derangement is closely related to cardiomyopathy per se rather than exercise-induced myocardial ischemia in this patient with hypertrophic cardiomyopathy and a spastic coronary lesion so that myocardial perfusion and 123I-9-MPA imagings may contribute to clarifying the etiological background of impaired myocardial fatty acid metabolism.     

Absent myocardial accumulation of two different radioiodinated pentadecanoic acids

This article presents two cases with preserved myocardial²⁰¹Tl uptake and absent uptake of two kinds of radioiodinated fatty acids: iodine-123-labeled 15-(p-iodophenyl)-3-(R,S)-methyl-pentadecanoic acid (BMIPP) and iodine-123-labeled 15-(p-iodophenyl)-9-(R,S)-methyl-pentadecanoic acid (9MPA). Although coronary angiography showed no stenotic lesion and left ventriculography revealed no wall motion abnormality, no myocardial uptake of BMIPP and 9MPA was observed in the first case. In the second case, no myocardial accumulation was recognized even in the initial phase of dynamic SPECT acquired soon after the injection of 9MPA. The results suggest that the non-visualized myocardium was not specific for BMIPP imaging and that rather than the early back diffusion of the tracers from the myocardium, abnormality of the myocardial cell membrane was a possible mechanism accounting for the phenomenon.     

Assessment of myocardial viability using 123I-labeled iodophenylpentadecanoic acid at sustained low flow or after acute infarction and reperfusion.

123I-labeled iodophenylpentadecanoic acid (IPPA) is a synthetic fatty acid that may be useful for determination of myocardial viability. We investigated the uptake and clearance kinetics of this tracer in canine models of ischemia and infarction. METHODS: In protocol 1, 185 MBq (5 mCi) 123I-IPPA were injected intravenously in 19 dogs with 50% left anterior descending artery (LAD) flow reduction. In 9 dogs, 201TI was coinjected. In protocol 2, 5 dogs underwent LAD occlusion for 3 h, and 123I-IPPA was injected 60 min after reperfusion. All dogs had flow measured by microspheres, regional systolic thickening by ultrasonic crystals and measurements of postmortem risk area and infarct size. Tracer activities were quantified by gamma well counting and by serial imaging. RESULTS: In protocol 1 dogs with sustained low flow (50% +/- 4%) and absence of systolic thickening (-3.2% +/- 1%), 123I-IPPA defect magnitude (LAD/left circumflex artery [LCX] count ratios) decreased from 0.65 +/- 0.02 to 0.74 +/- 0.02 at 30 min and to 0.84 +/- 0.03 at 2 h (P < 0.01), indicative of rest redistribution. Final transmural 123I-IPPA LAD/LCX activity ratio (0.99 +/- 0.05) was significantly greater than the flow ratio (0.53 +/- 0.04) at injection, confirming complete rest redistribution. The final 123I-IPPA activity ratio was significantly greater than the 201TI ratio over the 2-h period (P < 0.01). In protocol 2 dogs that underwent 3 h of total LAD occlusion and reflow (infarct size = 51% +/- 13% of risk area), viability was overestimated with 123I-IPPA, because uptake averaged 64% of normal in the central necrotic region, where flow averaged < 10% of normal. CONCLUSION: These findings suggest that serial 123I-IPPA imaging may be useful for assessing myocardial viability under conditions of sustained low flow and myocardial asynergy, such as appears to exist in patients with chronic coronary artery disease and depressed left ventricular function. In contrast, 123I-IPPA given early after reperfusion following prolonged coronary occlusion overestimates the degree of viability and therefore may not provide useful information pertaining to the degree of myocardial salvage after reflow in the setting of acute myocardial infarction.     

Synthesis and initial evaluation of 17-(11)C-heptadecanoic acid for measurement of myocardial fatty acid metabolism.

Fatty acid oxidation defects are being increasingly identified as causes of abnormal heart function and sudden death in children. Children with medium-chain acyl-coenzyme A (acyl-CoA) dehydrogenase defects can metabolize fatty acids labeled in the carboxylic acid end of the compound. Accordingly, our goal was to label a long-chain fatty acid in the omega-position and evaluate its myocardial kinetics. METHODS: Heptadecanoic acid, a 17-carbon fatty acid, was labeled in the C-17 position with (11)C by the general process of coupling (11)C-methyliodide to t-butyl-15-hexadecanoate. Yield was approximately 5%-10% end-of-bombardment. Subsequently, evaluation studies were performed on isolated perfused rat hearts and in intact, anesthetized dogs. The myocardial uptake and efflux of 17-(11)C-heptadecanoic acid were compared with those of 1-(11)C-palmitate. RESULTS: With the exception of delayed efflux of tracer reflecting the temporal delay for beta-oxidation, the washout of 17-(11)C-heptadecanoic acid from the heart mirrored that of 1-(11)C-palmitate in isolated rat hearts and in intact dogs with PET. CONCLUSION: 17-(11)C-Heptadecanoic acid may be a useful tracer for the identification of defects in fatty acid metabolism in subjects with medium- and short-chain fatty acid oxidation defects.     

Preliminary evaluation of 15-[18F]fluoro-3-oxa-pentadecanoate as a PET tracer of hepatic fatty acid oxidation.

The liver is an important site of fat oxidation. Abnormalities of hepatic mitochondrial fatty acid oxidation (HMFAO) are associated with obesity, type II diabetes, alcoholic hepatitis, and nonalcoholic steatohepatitis. Noninvasive assessment of HMFAO by PET has been impeded by the lack of a specific radiotracer. METHODS: No-carrier-added 15-[18F]fluoro-3-oxa-pentadecanoate (FOP) was synthesized and evaluated in living rats and isolated rat livers. RESULTS: FOP showed high uptake and slow clearance of radioactivity from livers in living rats. Inhibition of HMFAO by pretreatment of fasting rats with the carnitine palmitoyltransferase-I (CPT-I) inhibitor reduced the liver-to-blood ratio by 64%. In isolated rat livers, perfused in normoxic (95% O2) and hypoxic (15% O2) conditions with glucose (5 mmol/L) and palmitate (0.15 mmol/L), the externally measured kinetics of FOP showed reversible binding in tissue. The kinetics were adequately fit by a catenary 2-compartment model for estimation of tracer distribution volumes (DVs). The DVs of both compartments were found to correlate with fractional palmitate oxidation rate (FPOR) in experiments in normoxic and hypoxic conditions. The correlation was particularly strong for the slower second compartment (DV2 [mL/g dry weight] = 34.1 FPOR [mL/min/g dry weight] - 0.7, r = 0.89). Relatively small levels of diffusible metabolites of FOP were formed in vivo and in isolated rat liver. CONCLUSION: The selective uptake of FOP by liver and the high sensitivity of hepatic FOP DV to changes of HMFAO with CPT-I inhibition and hypoxia suggests potential usefulness for the 3-oxa fatty acid analog in assessments of hepatic mitochondrial oxidation of exogenous fatty acids with PET. These data emphasize that further studies are required to clarify the intracellular disposition of FOP in the liver and test its validity as a tracer of HMFAO over a broad range of conditions.     

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.     

Substrate selection early after reperfusion of ischemic regions in the working rabbit heart

Several substrates are available in vivo for oxidation by the myocardium. Although substrate selection has been studied extensively in normoxic myocardium, relatively little is known about substrate preference very early during reperfusion after ischemia. Carbon-13 isotopomer analysis was used to study substrate usage by nonischemic and reperfused-ischemic myocardium in a working heart that was subjected to 15 min of regional ischemia and reperfused for 5 min. Compared with nonischemic myocardium, the contribution of acetoacetate to acetyl coenzyme A was increased in the reperfused-ischemic region, and the contribution of exogenous lactate was decreased. Free fatty acid oxidation, however, was not different in the two regions. These results indicate that (1) early during reperfusion, ketone body oxidation may be more significant than has been emphasized, (2) the relative contribution of fatty acids to acetyl coenzyme A is not sensitive to ischemia followed by reperfusion, and (3) Carbon-13 magnetic resonance spectroscopy methods may be used for analysis of spatial heterogeneity of metabolism in the heart.     

Myocardial metabolism of 123I-BMIPP in a canine model with ischemia: implications of perfusion-metabolism mismatch on SPECT images in patients with ischemic heart disease.

123I-(rho-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) is a fatty acid analog for SPECT imaging. This radiopharmaceutical possesses the unique property, that is, perfusion-metabolism mismatch on SPECT images in patients with ischemic heart disease. However, the reason of this mechanism remains unclear. METHODS: Using open-chest dogs under anesthesia, we made a system to release all the blood of the great cardiac vein outside without recirculation, if necessary. Left anterior descending artery (LAD) was occluded for 30 min after reperfusion. After the injection of BMIPP into LAD, blood samplings from the cardiac vein and abdominal aorta (6 dogs) or serial biopsy specimens from the LAD region (5 dogs) were performed, and then compared with the normal control. The catabolites of BMIPP, including backdiffusion of nonmetabolized BMIPP, were evaluated with high-performance liquid chromatography (HPLC) in the efflux study. Thin-layer chromatography (TLC) technique was introduced in the tissue analytical study. RESULTS: Although the rapid extraction of BMIPP from the plasma into the myocardium and the subsequent retention were unchanged, the early washout (8 min) of radioactivity significantly increased (51% +/- 12% to 65% +/- 7%; P < 0.05) with ischemia. The metabolites from the myocardium consisted of backdiffusion of nonmetabolized BMIPP, alpha, intermediate, and full oxidation metabolites. Among these metabolites, backdiffusion of nonmetabolized BMIPP in blood significantly increased (27.9% +/- 7.7% to 42.3% +/- 8.1%; P < 0.05), especially in the early phase with ischemia. In tissue, the radioactivity was concentrated in the triglyceride pool even in the early phase, and in addition, BMIPP and alpha-oxidized metabolite significantly decreased in the early phase with ischemia (t = 1 min after BMIPP injection, 25.9% +/- 8.6% to 14.5% +/- 2.1%, P < 0.01; t = 2 min, 8.9% +/- 5.0% to 4.5% +/- 1.7%, P < 0.05). CONCLUSION: These results show that backdiffusion of nonmetabolized BMIPP from the myocardium increased and BMIPP (long-chain fatty acids) in tissue decreased with ischemia, suggesting backdiffusion of nonmetabolized BMIPP might play an important role in myocardial perfusion-metabolism mismatch on SPECT images in patients with ischemic heart disease.     

Synthesis and preliminary evaluation of (18)F-labeled 4-thia palmitate as a PET tracer of myocardial fatty acid oxidation

Interest remains strong for the development of a noninvasive technique for assessment of regional fatty acid oxidation rate in the myocardium. (18)F-labeled 4-thia palmitate (FTP, 16-[(18)F]fluoro-4-thia-hexadecanoic acid) has been synthesized and preliminarily evaluated as a metabolically trapped probe of myocardial fatty acid oxidation for positron emission tomography (PET). The radiotracer is synthesized by Kryptofix 2.2.2/K(2)CO(3) assisted nucleophilic radiofluorination of an iodo-ester precursor, followed by alkaline hydrolysis and by purification by reverse phase high performance liquid chromatography. Biodistribution studies in rats showed high uptake and long retention of FTP in heart, liver, and kidneys consistent with relatively high fatty acid oxidation rates in these tissues. Inhibition of carnitine palmitoyl-transferase-I caused an 80% reduction in myocardial uptake, suggesting the dependence of trapping on the transport of tracer into the mitochondrion. Experiments with perfused rat hearts showed that the estimates of the fractional metabolic trapping rate (FR) of FTP tracked inhibition of oxidation rate of palmitate with hypoxia, whereas the FR of the 6-thia analog 17-[(18)F]fluoro-6-thia-heptadecanoic acid was insensitive to hypoxia. In vivo defluorination of FTP in the rat was evidenced by bone uptake of radioactivity. A PET imaging study with FTP in normal swine showed excellent myocardial images, prolonged myocardial retention, and no bone uptake of radioactivity up to 3 h, the last finding suggesting a species dependence for defluorination of the omega-labeled fatty acid. The results support further investigation of FTP as a potential PET tracer for assessing regional fatty acid oxidation rate in the human myocardium.     

Detection of cardiomyocyte death in a rat model of ischemia and reperfusion using 99mTc-labeled annexin V.

There is increasing evidence that cell death after myocardial ischemia and reperfusion may begin as apoptosis rather than necrosis. To determine the time course, location, and extent of this process, we studied groups of rats after a 20-min interval of coronary occlusion and reperfusion. METHODS: After thoracotomy, the left coronary artery was occluded for 20 min. After release and before study, groups of animals were allowed to recover for various intervals: 0.5 h (n = 6), 1.5 h (n = 7), 6 h (n = 7), 1 d (n = 8), 3 d (n = 8), or 2 wk (n = 5). At the time of study, the rats were injected with 99mTc-annexin V (80-150 MBq). One hour later, to verify the area at risk, 201Tl (0.74 MBq) was injected intravenously just after the left coronary artery reocclusion and the rats were sacrificed 1 min later. Dual-tracer autoradiography was performed to assess 99mTc-annexin V uptake and the area at risk. RESULTS: Extensive 99mTc-annexin V uptake was observed in the mid myocardium after 0.5-1.5 h of reperfusion. The area of annexin uptake had expanded in the subendocardial and subepicardial layers at 6 h after reperfusion and then gradually lessened over 3 d. At 0.5 and 1.5 h of reperfusion, 99mTc-annexin V uptake ratios were 7.36 +/- 2.95 and 6.34 +/- 2.24 (mean +/- SD), respectively. The uptake ratios gradually decreased at 6 h, 1 d, 3 d, and 2 wk after reperfusion (4.65 +/- 1.93, 3.27 +/- 0.92 [P < 0.01 vs. 0.5 h], 1.84 +/- 0.55 [P < 0.001 vs. 0.5 h, P < 0.005 vs. 1.5 h], and 1.65 +/- 0.31 [P < 0.001 vs. 0.5 h, P < 0.005 vs. 1.5 h], respectively). CONCLUSION: These data indicate that annexin binding commences soon after ischemia and reperfusion in the mid myocardium within the area at risk and expands to include the subendocardial and subepicardial layers at 6 h after reperfusion, followed by gradual reduction of activity over 3 d.     

The temporal pattern of recovery of myocardial perfusion and metabolism delineated by positron emission tomography after coronary thrombolysis

Recovery of mechanical function by ischemic myocardium is dependent on the restoration of nutritive blood flow and oxidative metabolism subsequent to reperfusion. To characterize the time course and extent of recovery of perfusion and metabolism, we used positron emission tomography with 15O-labeled water and 11C-labeled palmitate to sequentially study six dogs after 2 hr of ischemia followed by reperfusion for 4 wk. Myocardial blood flow in the ischemic region increased from 15 +/- 8% of normal during coronary occlusion to 82 +/- 25% 1 hr after reperfusion. Despite maintained coronary patency documented angiographically, flow was reduced after 24 hr to 37 +/- 16% of normal. This decrease was temporary, with flow returning to 66 +/- 11%, 62 +/- 7%, and 64 +/- 18% of normal after 1, 2, and 4 wk of reperfusion, respectively. Uptake of 11C-labeled palmitate paralleled alterations in perfusion during ischemia and early reperfusion, averaging 32 +/- 15% of normal during ischemia, and 67 +/- 22% and 36 +/- 10% after 1 and 24 hr of reperfusion. After that, palmitate uptake was more variable. Flow and fatty acid uptake after 4 wk of reperfusion were not related to collateral flow during ischemia or the extent of initial reperfusion. However, uptake of palmitate 1 hr after reperfusion was a strong predictor of the uptake of palmitate 4 wk after reperfusion (r = 0.86, p less than 0.03). The results indicate that positron emission tomography with 15O-labeled water and 11C-labeled palmitate may be useful for assessing the success of recanalization in restoring nutritive perfusion and fatty acid metabolism and that the uptake of [11C]palmitate early after reperfusion predicts the ultimate salvage of myocardium.