Heterogeneous myocardial distribution of iodine-123 15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) in patients with hypertrophic cardiomyopathy

It has been proposed that iodine-123 15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (¹²³I-BMIPP) is an agent for myocardial fatty acid metabolism in animal models. The aim of the present study was to determine whether alterations in fatty acid uptake and/or utilization in patients with hypertrophic cardiomyopathy (HCM) could be detected by ¹²³I-BMIPP. Myocardial imaging with ¹²³I-BMIPP and thallium-201 (²⁰¹Tl) was performed in 14 fasted patients. A dose of 111 MBq of ¹²³I-BMIPP was administered intravenously at rest, and myocardial emission computed tomography was obtained 20 min and 3 h after injection. The ²⁰¹Tl imaging was also performed within 1 week after the ¹²³I-BMIPP study. The regional myocardial uptake and clearance of ¹²³I-BMIPP and ²⁰¹Tl were assessed quantitatively. The myocardial distribution of ¹²³I-BMIPP was more heterogeneous than that of ²⁰¹Tl in patients with HCM. The myocardial uptake of ¹²³I-BMIPP was lower in the anteroseptal region of the left ventricle than in the posterolateral region (74% vs. 85%, P < 0.001). The anteroseptal wall showed a faster clearance of ¹²³I-BMIPP than the posterolateral wall (33% vs. 27%, P < 0.01). Both a decreased uptake and rapid clearance of ¹²³I-BMIPP were observed in the hypertrophied myocardium of the anteroseptal wall, where ²⁰¹Tl uptake was normal or even increased. Myocardial segments with a markedly increased thickness showed a lower uptake and faster clearance of ¹²³I-BMIPP than those with mild hypertrophy (uptake 73% vs. 82%, P < 0.05; clearance 30% vs. 25%, P < 0.05). Myocardial imaging with ¹²³I-BMIPP was thus applicable to patients with HCM for detecting myocardial regions with altered fatty acid metabolism.Supported in part by Grants-in-Aid for Scientific Research (nos. 02454259, 03268224) from the Ministry of Education, Science and Culture, Japan, a grant for Research on Cardiovascular Disease (1S-1) from the Ministry of Health and Welfare, Japan, and a grant from Uehara, Memorial Foundation. Offprint requests to: Y Takeishi     

Iodine-123-labelled fatty acids for myocardial single-photon emission tomography: current status and future perspectives

Renewed interest in the clinical use of iodine-123-labelled fatty acids is currently primarily focused on the use of iodine-123-labelled 15-(p-iodophenyl)pentadecanoic acid (IPPA) and modified fatty acid analogues such as 15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) which show delayed myocardial clearance, thus permitting single-photon emission tomographic imaging. Interest in the use of BMIPP and similar agents results from the differences which have often been observed in various types of heart disease between regional myocardial uptake patterns of [¹²³I]BMIPP and flow tracer distribution. Although the physiological basis is not completely understood, differences between regional fatty acid and flow tracer distribution may reflect alterations in important parameters of metabolism which can be useful for patient management or therapy planning. These tracers may also represent unique metabolic probes for correlation of energy substrate metabolism with regional myocardial viability. The two agents currently most widely used clinically are¹²³I-labelled IPPA and BMIPP. While [¹²³I]IPPA is commercially available as a radiopharmaceutical in Europe (Cygne) and Canada (Nordion), multicenter trials are in progress in the United States as a prelude to approval for broad use. [¹²³I]BMIPP was recently introduced as Cardiodine for commercial distribution in Japan (Nihon Medi-Physics, Inc.). [¹²³I]BMIPP is also being used in clinical studies on an institutional approval basis at several institutions in Europe and the United States. In this review, the development of a variety of radioiodinated fatty acids is discussed. The results of clinical trials with [¹²³I]IPPA and [¹²³I]BMIPP are discussed in detail, as are the future prospects for fatty acid imaging.     

Prognosis of hypertrophic cardiomyopathy: Assessment by123I-BMIPP (β-methyl-p-(123I)iodophenyI pentadecanoic acid) myocardial single photon emission computed tomography

¹²³I-BMIPP (β-methyl-iodophenyl pentadecanoic acid) has shown unique properties for potential use in assessing myocardial metabolism. Previous basic and clinical studies demonstrated that the disturbances of myocardial metabolism precede the occurrence of myocardial perfusion abnormalities by using²⁰¹Tl in hypertrophic myocardium. The present study was therefore undertaken to determine whether or not¹²³I-BMIPP myocardial SPECT is useful in predicting the prognosis of hypertrophic cardiomyopathy (HCM) in 65 patients in 6 facilities. There were 33 patients with non-obstructive HCM, 12 with obstructive HCM, 12 with apical HCM and 8 with dilated-phase HCM. Fasted patients at rest received an intravenous injection of 111 MBq of¹²³I-BMIPP. Twenty to thirty minutes later, myocardial SPECT was carried out. The BMIPP severity score (BMIPP SS) was evaluated semiquantitatively by using representative short axial SPECT images. We followed up the incidence of cardiac events for a mean period of 3.0 ± 0.6 years. Cardiac events occurred in 13 patients. Of these, 11 developed heart failure and 6 died (4 from heart failure and 2 from sudden death). The BMIPP SS in the dilated-phase HCM was significantly higher than that in the remaining HCM patients. The BMIPP SS for the survivors was significantly lower than that for the non-survivors. The BMIPP SS was particularly high in patients with fatal heart failure. Furthermore, there was a close negative correlation between the BMIPP SS and percent fractional shortening measured by echocardiography (r = ?0.49). Finally, the mortality over the three years increased according to the extent of the BMIPP SS. In conclusion, these results indicate that the BMIPP SS is useful in evaluating the severity of HCM. We conclude that¹²³I-BMIPP is a valuable metabolic tracer in predicting the outcome of HCM.     

Fatty acid myocardial imaging using 123I-β-methyl-iodophenyl pentadecanoic acid (BMIPP): comparison of myocardial perfusion and fatty acid utilization in canine myocardial infarction (Occlusion and reperfusion model)

To evaluate the relationship between myocardial perfusion and fatty acid metabolism in canine myocardial infarction, 16 dogs were studied using thallium and ¹²³I--methyl-iodophenyl pentadecanoic acid (BMIPP). Eight dogs (group A) had left anterior coronary arterial occlusion (6 h ligation), 6 dogs (group B) had reperfusion (3 h ligation and 1 h reperfusion) and 2 dogs served as the normal control. Myocardial imaging with BMIPP was excellent, owing to its higher uptake and longer retention in myocardium and rapid blood disappearance in addition to diminished liver and lung uptake. The mean half time value which was generated from the BMIPP myocardial washout curve, was significantly larger in the reperfused myocardium. The gamma camera imaging showed uncoupling of BMIPP and thallium (BMIPP uptake greater than thallium uptake) in five dogs in group B. On the other hand, all dogs in group A had a persistent defect in BMIPP and thallium uptake. Our findings indicate that the combination of BMIPP and thallium for myocardial imaging supply different information about the zone of infarction and ischemia, which may be useful for the assessment of myocardial viability.     

Myocardial metabolism of 123I-BMIPP under low-dose dobutamine infusion: implications for clinical SPECT imaging of ischemic heart disease

Purpose ¹²³I-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (¹²³I-BMIPP) is a fatty acid analog for single-photon emission computed tomography (SPECT) imaging that is mainly stored in the triglyceride pool. Low-dose dobutamine infusion has been reported to improve BMIPP uptake in the stunned myocardium, but the mechanism underlying this effect remains unclear. The purpose of this study was therefore to investigate the myocardial metabolism of ¹²³I-BMIPP in the stunned myocardium under low-dose dobutamine infusion, and to elucidate the mechanism by which dobutamine improves BMIPP uptake.Methods Using open-chest dogs, stunned myocardium was induced by occlusion of the left anterior descending artery (LAD) for 30 min, with subsequent reperfusion (ischemia group, n=6). After direct injection of BMIPP into the LAD, myocardial extraction and retention were examined and metabolites evaluated (using high-performance liquid chromatography) during dobutamine infusion. The results in the ischemia group were compared with findings obtained in a control group under dobutamine infusion (n=6).Results Dobutamine infusion significantly increased both the rapid extraction (within 30 s) of BMIPP into the myocardium (control vs ischemia group: 48±19% vs 66±14%, p<0.05) and its subsequent retention (73±13% vs 85±8%, p<0.05). The metabolites from the myocardium consisted of back diffusion of nonmetabolized BMIPP, the alpha-oxidation metabolite, intermediate metabolites, and the full-oxidation metabolite. Among these metabolites, the full-oxidation metabolite decreased significantly (from 34.0±20.0% to 15.8±9.3%, p<0.05) in the stunned regions, though back diffusion of nonmetabolized BMIPP increased (from 51.3±21.9% to 71.3±10.1%, p<0.05).Conclusion These results indicate that increased uptake of BMIPP in stunned myocardium is mainly due to decreased beta-oxidation in tissue and increased shunt retention of BMIPP in the triglyceride pool, and thereby provide further insight into the pathophysiology of stunned myocardium.An erratum to this article can be found at     

Impairment of regional fatty acid uptake in relation to wall motion and thallium-201 uptake in ischaemic but viable myocardium: Assessment with iodine-123-labelled beta-methyl-branched fatty acid

In coronary artery disease, discrepancy in the uptake of thallium-201 and of methyl-branched fatty acid at rest has been described. The purpose of this study was to evaluate iodine-123 labelled beta-methylbranched fatty acid (BMIPP) myocardial uptake and wall motion at rest in segments with stress-induced ischaemia identified by stress²⁰¹Tl tomography in patients with chronic coronary artery disease.¹²³I-BMIPP myocardial tomography was performed at rest and was compared with the findings of exercise-reinjection²⁰¹Tl tomography in 45 patients with chronic coronary artery disease. Regional wall motion was evaluated by contrast left ventriculography in 36 patients. Among 237 segments with reversible²⁰¹Tl defects, equally decreased uptake on both reinjection²⁰¹Tl and BMIPP images was observed in 93 (39%), more severely decreased uptake of BMIPP in 118 (50%) and more severely decreased uptake of reinjection²⁰¹Tl in 26 (11%). On the other hand, among 90 segments with non-reversible²⁰¹Tl defects, each pattern was observed in 71 (79%), 6 (7%) and 13 (14%) segments, respectively. When comparing the ischaemic segments with and without more severely reduced uptake of BMIPP than of reinjection²⁰¹Tl, wall motion was impaired to a greater extent in the segments with more severely reduced uptake of BMIPP than of reinjection²⁰¹Tl [severe hypo- or dyskinesis was present in 64 (70%) of 91 segments and in 24 (22%) of 110 segments, respectively,P<0.005]. In patients with chronic coronary artery disease, resting fatty acid uptake was frequently more reduced than reinjection²⁰¹Tl in the segments with stress-induced ischaemia, while in most of the fixed perfusion defects BMIPP and reinjection²⁰¹Tl uptake decreased concordantly. In ischaemic myocardium, wall motion was impaired to a greater extent in those segments which showed more severely reduced uptake of BMIPP than of reinjection²⁰¹Tl. In ischaemic but viable myocardium, discordant BMIPP uptake less than reinjection²⁰¹Tl uptake may indicate metabolic alterations and wall motion abnormality at rest independent of perfusion abnormalities. In conclusion, the combination of resting BMIPP and stress-reinjection²⁰¹Tl imaging may provide information on metabolic alterations and wall motion abnormality at rest independent of perfusion abnormalities.     

Evaluation of cellular viability by quantitative autoradiographic study of myocardial uptake of a fatty acid analogue in isoproterenol-induced focal rat heart necrosis

Previous studies led us to hypothesize that a fatty acid analogue, 15-p-iodophenyl--methyl pentadecanoic acid (IMPPA or BMIPP), which is taken up but not quickly metabolized by heart cells, would be a more suitable tracer of cellular viability than thallium-201. Biodistribution studies of 1-¹⁴C-IMPPA in conscious, freely moving rats showed that the concentration ratio of radioactivity in the heart with respect to the blood was about 8 for at least 60 min after intravenous administration, permitting its use as a putative tracer in these conscious, freely moving rats. Thereafter, the myocardial uptake of¹⁴C-IMPPA was studied in isoproterenol-treated rats (daily treatment for 10 days in order to induce cardiac hypertrophy and necrotic foci) with respect to control ones. Comparison of myocardial localizations by quantitative autoradiography of the uptake of²⁰¹Tl and¹⁴C-IMPPA with that of triphenyltetrazolium chloride (TTC) staining enabled comparative evaluation of nutritional blood flow, localization and uptake of¹⁴C-IMPPA and necrotic foci size. Distributions of¹⁴C-IMPPA and²⁰¹1 T1 in control rats' hearts were homogeneous, like TTC staining. In infarcted hearts, areas of decreased¹⁴C-IMPPA uptake were nearly the same (100%±5%) as those unstained by TTC. These areas were larger than those showing a decrease in thallium uptake (about 70%±5% of the total scar size). Therefore, IMPPA seems to be a more accurate and sensitive indicator of necrosis localization compared with thallium. It may be a useful agent for assessment of myocardial viability by single photon emission tomography (SPET) imaging.     

Incremental predictive value of myocardial scintigraphy with<Superscript> 123</Superscript>I-BMIPP in patients with acute myocardial infarction treated with primary percutaneous coronary intervention

Purpose It is unclear whether ¹²³I-labelled -methyl iodophenyl pentadecanoic acid (¹²³I-BMIPP) myocardial scintigraphy adds further predictive value for future cardiac events compared with the variables obtained during cardiac catheterisation in patients with acute myocardial infarction (AMI) treated with primary percutaneous coronary intervention (PCI). We therefore investigated whether ¹²³I-BMIPP imaging in patients with AMI treated by primary PCI was useful in predicting future cardiac events.Methods One hundred and fifty-nine patients with AMI who were treated with primary PCI and underwent left ventriculography (LVG) on admission underwent ²⁰¹Tl and ¹²³I-BMIPP myocardial scintigraphy. Scintigrams were visually classified, and the total defect score (TDS) was calculated. Major adverse cardiac events (MACE) were defined as cardiac death including sudden death, congestive heart failure and recurrence of acute coronary syndrome. Patients were followed up for a mean of 34.5 months (12–63 months).Results Twenty-six patients had MACE. Kaplan-Meier analysis indicated that patients with the top 50% of ¹²³I-BMIPP TDSs had a significantly higher rate of MACE (P=0.007). Patients with mismatch between ²⁰¹Tl and ¹²³I-BMIPP images also had significantly more MACE (P=0.02). In the prediction of MACE, the global chi-square value was 5.2 (P=0.001) based on LVEF (<45%) and the number of diseased vessels (two or three). Adding ¹²³I-BMIPP TDS and the mismatch improved the global chi-square value ( ²=7.2)Conclusion Myocardial scintigraphy using ²⁰¹Tl and ¹²³I-BMIPP predicts future cardiac events in patients with AMI treated with primary PCI, and provides additional predictive value compared with the variables obtained with cardiac catheterisation alone.     

Therapeutic effect of co-enzyme Q10 on idiopathic dilated cardiomyopathy: assessment by iodine-123 labelled 15-(p-iodophenyl)-3(R, S)-methylpentadecanoic acid myocardial single-photon mission tomography

It has been reported that myocardial mitochondrial function can be improved by the administration of co-enzyme Q10 (CoQ10). Recently, iodine-123 labelled 15-(p-iodophenyl)-3-(R, S)-methylpentadecanoic acid (BMIPP) was developed for metabolic imaging using single-photon emission tomography (SPET). This study was conducted to determine whether the therapeutic effects of CoQ10 on idiopathic dilated cardiomyopathy can be evaluated by BMIPP myocardial SPET. Fifteen patients, comprising 14 men and one woman (mean age: 64±12 years), were examined. CoQ10 was administered at 30 mg/day for a period of 35.7±12.4 days. BMIPP myocardial SPET was carried out belote and after CoQ 10 treatment. The count ratio of the heart (H) to the upper mediastinum (M) (H/M ratio) was calculated using a region of interest method with anterior planar imaging. Representative short-axis tomograms were divided into 27 segments (three slicesxnine segments). Each segmental score was analysed semiquantitatively using a four-point scoring system (normal=0, mild low uptake=1, severe low uptake=2, defect=3). The H/M ratio showed a significant improvement., from 2.39±0.39 to 2.54±0.47, after treatment (P<0.05). The BMIPP total defect score after CoQ10 treatment was significantly decreased to 10.1±43, compared to 13.9±4.5 without CoQ10 treatment (P<0.001). However, the percent fractional shortening measured using echocardiography was not significantly different before and alter CoQ treatment (19.2±8.1 vs 19.7±7.1). BMIPP myocardial SPET was confirmed to be sensitive in evaluating the therapeutic effects of CoQ 10 in patients with idiopathic dilated cardiomyopathy. This method is unique, since the therapeutic effects can be estimated from the perspective of metabolic SPET imaging.     

Comparison of [123I]ß-CIT and [123I]IPCIT as single-photon emission tomography radiotracers for the dopamine transporter in nonhuman primates

Single-photon emission tomographic (SPET) imaging with the radiotracer [¹²³I]2-carbomethoxy-3-(4-iodophenyl)tropane ([¹²³I]-CIT) has been reported to be a useful in vivo measure of dopamine (DA) transporters. However, in addition to its high DA transporter affinity,-CIT also binds with high affinity to serotonin (5-HT) transporters. 2-Carboisopropoxy-3-(4-iodophenyl)tropane (IPCIT) has been demonstrated by in vitro studies to have higher selectivity for the DA transporter. We compared [¹²³I]-CIT and [¹²³I]IPCIT SPET imaging and plasma metabolite analyses in baboons to evaluate the potential advantages of [¹²³I]IPCIT for quantitative in vivo measurements of DA transporter densities. Both tracers had low levels (2% of total plasma¹²³I activity) of lipophilic radiolabeled metabolites at 420 min. [¹²³I]IPCIT had significantly higher binding to plasma proteins. The average percent free (nonprotein bound) [¹²³I]-CIT and [¹²³I]IPCIT were 52%±7% and 14%±6%, respectively. Region of interest uptake data were normalized by injected dose and body weight. Consistent with the high density of 5-HT transporters in the midbrain and the lower 5-HT transporter affinity of IPCIT, the normalized peak specific midbrain uptake of [¹²³I]-CIT (1.7±0.5) was higher than that of [¹²³I]IPCIT (0.4±0.2). Consistent with its greater lipophilicity, [¹²³I]IPCIT had higher nonspecific uptake, such that normalized cerebellar uptake of [¹²³I]IPCIT was about twice that of [¹²³I]-CIT. The ratio of specific to nonspecific uptake in striatum was greater for [¹²³I]-CIT compared to [¹²³I]IPCIT; however, striatal binding potentials and distribution volumes were not significantly different. In conclusion, [¹²³I]IPCIT demonstrated in vivo a higher DA transporter selectivity and higher level of nonspecific uptake.     

A new model for separation between brain dopamine and serotonin transporters in <Superscript>123</Superscript>I-β-CIT SPECT measurements: normal values and sex and age dependence

¹²³I--CIT is a radioactive ligand for single-photon emission computed tomography (SPECT) imaging of the pre-synaptic (transporter) re-uptake sites for dopamine (DAT) and serotonin (5HTT), and it is widely used to visualize monoamine turnover. Since ¹²³I--CIT uptake occurs at 5HTT and DAT sites in conjunction with the presence of freely soluble ¹²³I--CIT in brain tissue, adequate separation of these three components is necessary. However, only partial separation is possible with current methods. Two main strategies have previously been used for ¹²³I--CIT component separation, based on the following considerations: (1) the faster uptake rate for 5HTT compared with DAT enables temporal separation by performing 5HTT imaging at 1–2 h and DAT imaging at 20–24 h; (2) blocking the 5HTT re-uptake with citalopram renders ¹²³I--CIT imaging DAT (non-5HTT) specific. In a new analytical model, we combined these two approaches with methods to isolate the passively dissolved ¹²³I--CIT in brain tissue from the monoamine transporter uptake, and to correct the 5HTT and DAT values for concomitant uptake. The new analytical model was used to study brain 5HTT and DAT in 23 normal subjects, with the aim of clarifying the effect of age and sex. A significant correlation between 5HTT and DAT values was found only in the thalamus, indicating successful component separation. Negative correlations between age and DAT were found for basal ganglia, thalami, brain stem and temporal lobes, but not for the frontal, parietal or occipital regions. No correlation with age was found for 5HTT. We found no sex difference for 5HTT or DAT.     

Prediction of cardiac events in patients with dilated cardiomyopathy using <Superscript>123</Superscript>I-BMIPP and <Superscript>201</Superscript>Tl myocardial scintigraphy

Objective Various clinical trials for dilated cardiomyopathy (DCM) have demonstrated that the prognosis as well as cardiac function is improved by the administration of beta-blocker therapy. On the other hand, ¹²³I-betamethyl-p-iodophenyl-pentadecanoic acid (BMIPP) reflects myocardial fatty acid metabolism and is considered to be a more sensitive tracer than perfusion tracers. In this study, the efficacy of DCM for the evaluation of myocardial damage and the prediction of cardiac events was studied using ¹²³I-BMIPP and ²⁰¹TI (Tl) myocardial scintigraphy. Methods Study subjects comprised 33 DCM patients, divided into a cardiac event group (event, n = 9) and an event-free group (event free, n = 24). An extent score (ES) and severity score (SS) were calculated for each BMIPP image. BMIPP and Tl images were divided into 17 segments, and total defect scores (TDS) were calculated for each. The TDS of the BMIPP and Tl images were compared with score differences greater than or equal to 4 and less than 4 defined as mismatch and non-mismatch, respectively. Results The TDS of BMIPP was significantly higher in the event group than in the event-free group (P < 0.05). The ES and SS were significantly higher in the event group than in the event-free group (P < 0.01). The comparison in the 2 × 2 contingency tables showed that the occurrence of non-mismatch was significantly higher in the event-free group (χ² test; P < 0.01). The ES of BMIPP was a significant predictor of cardiac events in the multivariate analysis (P < 0.01). Conclusions These results suggest that the ES for BMIPP is useful as a predictor of cardiac events in DCM.     

123I-mIBG Scintigraphy to predict risk for adverse cardiac outcomes in heart failure patients: Design of two prospective multicenter international trials

Background  ADMIRE-HF (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure) consists of two identical prospective open-label, multicenter, phase 3 studies (MBG311 and MBG312) evaluating the prognostic usefulness of ¹²³I-mIBG scintigraphy for identifying subjects with heart failure who will experience a major adverse cardiac event. Methods  Subjects with NYHA class II and III heart failure and left ventricular ejection fraction ≤35% were eligible for the trials. Subjects underwent planar and SPECT ¹²³I-mIBG myocardial imaging, as well as echocardiography and gated SPECT ^99mTc-tetrofosmin myocardial perfusion imaging. Subjects are then monitored on a regular basis for 2 years. Time to first occurrence of one of the following—NYHA class progression; potentially life-threatening arrhythmic event (including ICD discharge); or cardiac death, as verified by an independent adjudication panel—will be analyzed in comparison to quantitative parameters derived from ¹²³I-mIBG imaging. The primary efficacy analysis will employ the heart/mediastinum ratio on 4-hour delayed planar imaging, while secondary efficacy analyses will examine quantitative results from both planar and SPECT ¹²³I-mIBG images, as well as from ^99mTc-tetrofosmin SPECT and echocardiography. Conclusion  The results of the ADMIRE-HF trials will provide prospective validation of the potential role of ¹²³I-mIBG scintigraphy in assessing prognosis and developing management strategies for patients with heart failure. Funding Source: GE Healthcare.     

Comparison of myocardial fatty acid metabolism with left ventricular function and perfusion in cardiomyopathies: by<Superscript>123</Superscript>I-BMIPP SPECT and<Superscript>99m</Superscript>Tc-tetrofosmin electrocardiographically gated SPECT

Objective: To investigate myocardial fatty acid metabolism and its relationship with left ventricular (LV) function and perfusion in hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM).Methods: Thirty-nine patients with cardiomyopathies (58±14 y), comprising 15 DCM and 24 HCM, and 9 age-matched healthy controls were studied with¹²³I-15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) and^99mTc-tetrofosmin (TF) electrocardiographically gated SPECT. As parameters of myocardial fatty acid metabolism, the heart-to-mediastinum ratio (H/M) and global washout of BMIPP were calculated from early and delayed planar images, while regional BMIPP uptake and washout were calculated from SPECT. In TF study, the H/M (H/M-TF) and LV ejection fraction (LVEF) were calculated as global parameters of perfusion and function, while regional TF uptake and wall thickening index were calculated as regional parameters of perfusion and function using the Quantitative Gated SPECT software. The differences in the parameters and the correlations between the parameters from the 2 studies were investigated by one-way ANOVA and multiple linear regression analysis.Results: BMIPP uptake was decreased (p<0.05), and its washout was increased (p<0.05) in DCM and HCM. In multiple linear regression analysis, global BMIPP parameters showed no significant correlation with LVEF (p>0.05), but showed a significant correlation with H/M-TF (p<0.05) in DCM and HCM. According to the partial correlation coefficient, early H/M was the only significant factor (p<0.05) for predicting H/M-TF in DCM and HCM. Multiple linear regression analysis on regional parameters showed regional BMIPP parameters had no correlation with regional function (p>0.05) but had a significant correlation with regional perfusion (p<0.0001) in DCM. In HCM, regional BMIPP parameters showed significant multiple linear correlations with both regional function (p<0.005) and perfusion (p<0.0001). According to the partial correlation coefficients, delayed regional BMIPP uptake was the most significant factor for predicting regional function in HCM, while early regional BMIPP uptake was the only or the most significant factor for predicting regional perfusion in DCM and HCM, respectively.Conclusion: In DCM, BMIPP uptake and washout could not reflect LV function. In HCM, regional delayed BMIPP uptake might be useful for evaluating regional function. In DCM and HCM, early BMIPP uptake might be largely determined by myocardial perfusion.     

Effect of exercise induced hyperlactatemia on the biodistribution and metabolism of iodine-123-15-(p-iodophenyl)-3-R,S-methyl pentadecanoic acid in normal volunteers

We have evaluated the biodistribution and metabolism of iodine-123-15-(p-iodophenyl)-3-R,S-methyl pentadecanoic acid (BMIPP) in the presence of increased lactate levels induced by short-term heavy exercise. Five healthy male subjects received 159 MBq (±13 MBq) ¹²³I-BMIPP at rest and a week later after they performed a maximal exercise test using a bicycle ergometer. Planar and tomographic images were obtained with a dual-head gamma camera up to 4 h after administration of the tracer. Multiple blood samples were taken at different time points for blood clearance, substrate concentration measurements and for HPLC analysis of metabolites. The exercise test did not alter plasma glucose and non-esterified fatty acid concentrations, but blood lactate increased from 1.12 mmol/l at rest to 9.26 mmol/l with maximal exercise. After exercise, BMIPP showed a significantly faster plasma clearance than at rest and the production of PIPA, the end metabolite of BMIPP oxidation, was reduced. Activity in the heart was similar after exercise and at rest on planar images 15 min after injection (4.83±0.50%ID vs 4.80±0.43%ID, P=NS), although the myocardium-to-cavity activity ratio, as determined on the SPET images 20 min after tracer injection, was slightly increased after the exercise test (4.20±0.63 vs 3.78±1.34 at rest, P=NS). Significantly increased activity was observed in a leg muscle region of interest after exercise (4.98±0.50%ID vs 3.93±0.44%ID at rest, P=0.02). Between early and late images, tracer washout from the myocardium increased from 20.72% at rest to 36.72% after exercise (P<0.05), but was unchanged for liver and leg muscles. The metabolic and physiological alterations induced by exercise do not degrade image quality of BMIPP scintigraphy. On the contrary, exercise-induced hyperlactatemia seems to enhance myocardium-to-cavity activity ratios on SPET images, although this effect does not reach statistical significance in this small group of normal subjects. These findings further support the robustness of BMIPP SPET in varied metabolic environments. Received 7 June and in revised form 7 August 1999     

Recovery of impaired left ventricular function in patients with acute myocardial infarction is predicted by the discordance in defect size on123I-BMIPP and201TI SPET images

A discrepancy between myocardial perfusion defect and wall motion abnormalities is frequently found early after coronary reperfusion in patients with acute myocardial infarction. The purpose of this study was to assess recovery of impaired left ventricular function by reference to the discordance in defect size between myocardial fatty acid uptake and myocardial perfusion using combined single-photon emission tomographic (SPET) imaging early after coronary perfusion therapy. In 37 patients with acute myocardial infarction, iodine-123 15(p-iodophenyl)-3(R, S)-methylpentadecanoic acid (BMIPP) and thallium-201 SPET scans were performed early after coronary reperfusion. A severity score was determined from the extent of the imaging defect with each tracer. Left ventricular wall motion score (WMS) and ejection fraction (EF) were obtained at admission and at 4 weeks after the onset of infarction. In 32 of the 37 patients, discordance in defect sizes delineated with the two SPET studies was found during the acute stage. The severity score for BMIPP was larger than that for²⁰¹Tl during the acute stage (7.7±2.4 vs 4.4±2.5,P <0.001). There was a fair correlation between the severity score for BMIPP and WMS (r=0.82,P <0.0001), but a poor correlation between that for²⁰¹Tl and WMS. The extent of discordance in severity scores between BMIPP and²⁰¹Tl during the acute stage correlated well with the extent of the improvement in WMS (r=0.86,P <0.0001) and that of EF (r=0.85,P <0.0001). We conclude that the discordance in defect size on BMIPP and²⁰¹TI SPET images during the acute stage of infarction is an early predictor of the viability of the myocardium at risk of infarction.     

Characterization of Japanese standards for myocardial sympathetic and metabolic imaging in comparison with perfusion imaging

Objective  The standard patterns of myocardial radiotracer distribution of ¹²³I-metaiodobenzylguanidine (MIBG) and ¹²³I-β-methyl-p-iodophenyl-pentadecanoic acid (BMIPP) should be defined in a Japanese population. The purpose of this study was to present and provide data on the characteristics of MIBG and BMIPP with respect to myocardial single photon emission computed tomography. Methods  The normal database included ¹²³I-MIBG and ¹²³I-BMIPP imaging and a ^99mTc-sestamibi/tetrofosmin myocardial perfusion study. The projection images were transferred by digital imaging and communications in medicine (DICOM) format and reconstructed and analyzed with polar maps. Results  The projection data from multiple centers were successfully transferred to a common format for SPECT reconstruction. When the average values were analyzed using a 17-segment model, MIBG uptake in the inferior and apical wall appeared to be slightly lower than anterior uptake (P < 0.05). The inferior and apical uptake of MIBG has a larger standard deviation (10.7 units in males, 12.6 units in females). BMIPP uptakes in the septal wall have higher than that of ^99mTc-tracer uptake (P < 0.05). Conclusion  Myocardial sympathetic nerve and metabolic scintigraphy data that were specific for the Japanese population were generated and found to be different from that of perfusion tracers. The normal database can serve as a standard for nuclear cardiology work conducted in Japan.     

Noninvasive identification of anthracycline cardiotoxicity: Comparison of123I-MIBG and123I-BMIPP imaging

To test the feasibility of myocardial¹²³I-MIBG and¹²³I-BMIPP imaging for the early detection of anthracycline cardiotoxicity, 13 patients who had received anthracycline anticancer chemotherapeutic agents were studied. Two-dimensional echocardiography and myocardial imaging with both¹²³I-MIBG and¹²³I-BMIPP were performed in 13 patients treated with anthracycline (group A) and 10 normal control subjects (group C). Anterior myocardial images were obtained 15 minutes and 3 hours after the injection of isotopes. The heart-to-mediastinum ratio (H/M ratio) was used to quantify cardiac¹²³I-MIBG and¹²³I-BMIPP uptake. The left ventricular shortening fraction (%SF) and the ratio of peak mitral flow velocity in early diastole to that at the time of atrial systole (E/A ratio) were measured by echocardiography. The H/M ratio of¹²³I-MIBG was lower in group A than in group C (1.5 ± 0.2 vs. 1.9 ± 0.2, p < 0.01). The patients in group A had faster clearance of¹²³I-MIBG from the myocardium than those in group C (27 ± 10% vs. 22 ± 4%, p < 0.05). However, the H/M ratio and clearance of¹²³I-BMIPP were similar between the two groups (H/M ratio: 2.1 ± 0.2 vs. 2.0 ± 0.2, clearance: 24 ± 6% vs. 26 ± 6%). The %SF (37 ± 8% vs. 36 ± 7%) and E/A ratio (1.4 ± 0.4 vs. 1.6 ± 0.3) were comparable in groups A and C. The present findings indicated that myocardial imaging with¹²³I-MIBG could detect myocardial damage in patients treated with anthracycline in the early stage when cardiac systolic and diastolic function was still preserved. Early detection of anthracycline cardiotoxicity by¹²³I-MIBG would reduce the incidence and severity of heart failure.     

Myocardial metabolism of 123I-BMIPP during low-flow ischaemia in an experimental model: comparison with myocardial blood flow and 18F-FDG

Risk stratification of coronary artery disease may provide a basis for selection of treatment to prevent myocardial events and to assist functional recovery. Iodine-123 (A-iodophenyl)-3-R,S-methylpentadecanoic acid (¹²³I-BMIPP) is a radioiodinated fatty acid analogue for single-photon emission tomographic (SPET) imaging, and several reports have demonstrated that the abnormal uptake of ¹²³I-BMIPP is associated with wall motion abnormality and severe coronary artery stenosis. Clarification of the contribution of fatty acids to myocardial metabolism would be highly valuable in recognising this critical condition. In this study, we investigated the myocardial uptake of ¹²³I-BMIPP under low-flow ischaemia, and compared it with the uptake of fluorine-18 fluorodeoxyglucose (¹⁸F-FDG). Using open chest dogs, the flow of the left anterior descending coronary artery was controlled using a pneumatic occluder in order to maintain a 30%-40% reduction of Doppler flow. ¹²³I-BMIPP and ¹⁸F-FDG were injected into the left atrium after 90 min of ischaemia (protocols 1 and 3). Canine hearts were excised after 120 min of ischaemia for the measurement of radioactivity. In protocol 2, ¹²³I-BMIPP alone was injected and hearts were excised 8 min after the injection. A time-course biopsy study was also performed at the same time (protocol 3). Wall thickening was evaluated using a wall tracker module. The uptake of ¹⁸F-FDG increased significantly in the ischaemic region (232%끏% vs non-ischaemic, P<0.05 in protocol 1) even on mild reduction of myocardial blood flow (MBF). The increased uptake of ¹⁸F-FDG did not correlate well with the severity of MBF. On the other hand, ¹²³I-BMIPP uptake decreased gradually (78.9%ᆫ.6%, P<0.05 in protocol 1, and 85.9%ᆬ.3% in protocol 2) in the ischaemic region, specifically in the endocardium (64.0%ᆰ.9%, P<0.05 in protocol 1, and 75.1%ᆰ.8%, P<0.05 in protocol 2), and correlated strongly with MBF (r=0.93 in protocol 1 and r=0.97 in protocol 2) as a logarithmic function. This indicated that the abnormal uptake of ¹²³I-BMIPP was associated not only with wall motion abnormality but also with the severity of MBF. In the biopsy study (protocol 3), the radioactivity of either ¹²³I-BMIPP or ¹⁸F-FDG correlated well with the MBF at the time of tracer injection and was similar to post-mortem analysis. It is concluded that ¹⁸F-FDG is a valid tool for identifying ischaemic myocardium even in its earliest stages. On the other hand, ¹²³I-BMIPP might be used to detect moderately to severely ischaemic myocardium such as hibernation, suggesting the potential value of ¹²³I-BMIPP in the risk stratification of patients with severe coronary artery disease who require revascularisation without delay.     

Reduced 123I-BMIPP uptake implies decreased myocardial flow reserve in patients with chronic stable angina

Purpose Long-chain fatty acid (LCFA) is the main energy source for normal myocardium at rest, but in ischemic myocardium, the main energy substrate shifts from LCFA to glucose. ¹²³I-BMIPP is a radiolabeled LCFA analog. In chronic stable angina without previous infarction, we suppose that reduced ¹²³I-BMIPP uptake is related to the substrate shift in myocardium with decreased myocardial flow reserve (MFR). The purpose of this study was to relate ¹²³I-BMIPP uptake to rest myocardial blood flow (MBF), hyperemic MBF, and MFR assessed with ¹⁵O-water positron emission tomography (PET).Methods We enrolled 21 patients with chronic stable angina without previous infarction, all of whom underwent ¹²³I-BMIPP single-photon emission computed tomography (SPECT) and ¹⁵O-water PET. The left ventricle was divided into 13 segments. In each segment, rest MBF and hyperemic MBF were measured by PET. ¹²³I-BMIPP uptake was evaluated as follows: score 0=normal, 1=slightly decreased uptake, 2=moderately decreased uptake, 3=severely decreased uptake, and 4=complete defect. ¹²³I-BMIPP uptake was compared with rest MBF, hyperemic MBF, and MFR.Results The numbers of segments with ¹²³I-BMIPP scores 0, 1, 2, 3, and 4 were 178, 40, 25, 24, and 0, respectively. The rest MBFs for scores 0, 1, 2, and 3 were 0.93±0.25, 0.86±0.21, 0.97±0.30, and 0.99±0.37 ml/min/g, respectively. The hyperemic MBFs for scores 0, 1, 2, and 3 were 2.76±1.29, 1.84±0.74, 1.37±0.39, and 1.08±0.40 ml/min/g, respectively. The MFRs for scores 0, 1, 2, and 3 were 3.01±1.38, 2.20±0.95, 1.44±0.22, and 1.10±0.26, respectively. As ¹²³I-BMIPP uptake declined, hyperemic MBF and MFR decreased.Conclusion In chronic stable angina without previous infarction, reduced ¹²³I-BMIPP uptake implies decreased MFR.