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     

Blood flow, flow reserve, and glucose utilization in viable and nonviable myocardium in patients with ischemic cardiomyopathy

Purpose

The aim of the study was to determine whether glucose uptake in viable myocardium of ischemic cardiomyopathy patients depends on rest myocardial blood flow (MBF) and the residual myocardial flow reserve (MFR).

Methods

Thirty-six patients with ischemic cardiomyopathy (left ventricular ejection fraction 25?±?10 %) were studied with ¹³N-ammonia and ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Twenty age-matched normals served as controls. Regional MBF was determined at rest and during dipyridamole hyperemia and regional FDG extraction was estimated from regional FDG to ¹³N-ammonia activity ratios.

Results

Rest MBF was reduced in viable (0.42?±?0.18 ml/min per g) and nonviable regions (0.32?±?0.09 ml/min per g) relative to remote regions (0.68?±?0.23 ml/min per g, p?<?0.001) and to normals (0.63?±?0.13 ml/min per g). Dipyridamole raised MBFs in controls, remote, viable, and nonviable regions. MBFs at rest (p?<?0.05) and stress (p?<?0.05) in viable regions were significantly higher than that in nonviable regions, while MFRs did not differ significantly (p?>?0.05). Compared to MFR in remote myocardium, MFRs in viable regions were similar (1.39?±?0.56 vs 1.70?±?0.45, p?>?0.05) but were significantly lower in nonviable regions (1.23?±?0.43, p?<?0.001). Moreover, the FDG and thus glucose extraction was higher in viable than in remote (1.40?±?0.14 vs 0.90?±?0.20, p?<?0.001) and in nonviable regions (1.13?±?0.21, p?<?0.001). The extraction of FDG in viable regions was independent of rest MBF but correlated inversely with MFRs (r?=?0.424, p?<?0.05). No correlation between the FDG extraction and MFR was observed in nonviable regions.

Conclusion

As in the animal model, decreasing MFRs in viable myocardium are associated with increasing glucose extraction that likely reflects a metabolic adaptation of remodeling hibernating myocytes.     

Impaired myocardial fatty acid metabolism detected by123I-BMIPP in patients with unstable angina pectoris: Comparison with perfusion imaging by99mTc-sestamibi

The present study was undertaken to determine the potential diagnostic value of¹²³I-BMIPP scintigraphy for the detection of altered myocardial fatty acid metabolism in patients with unstable angina. Both myocardial metabolic imaging with¹²³I-BMIPP and perfusion imaging with^99mTcsestamibi were performed at rest in 28 patients with unstable angina in the pain-free state. The regional uptakes of¹²³I-BMIPP or^99mTc-sestamibi were scored semiquantitatively (0 = normal, 4 = no activity) and compared with the coronary arteriographic findings. Decreased uptakes of¹²³I-BMIPP were observed in 18 patients, and 11 patients had abnormal^99mTc-sestamibi images. Defect scores of¹²³I-BMIPP were larger than those of^99mTc-sestamibi (7.8 ± 2.1 vs. 5.2 + 1.9, p < 0.01). The sensitivity for the detection of patients with unstable angina was higher in¹²³I-BMIPP than in^99mTc-sestamibi (77% vs. 45%, p < 0.01). The site of the decreased¹²³I-BMIPP uptake corresponded to the most stenotic coronary artery lesion in all patients. Fatty acid metabolic imaging with¹²³I-BMIPP was more sensitive for detecting myocardial ischemia than perfusion imaging with^99mTc-sestamibi.¹²³I-BMIPP may be a clue to define the culprit lesion in unstable angina and be helpful to decide the best treatment and guide coronary angioplasty.     

Case Report: Unstable angina with flow-fatty acid metabolism mismatch and reverse flow-glucose metabolism mismatch patterns

A 79-year-old man with unstable angina underwent an emergency coronary angiography, and percutaneous balloon angioplasty was performed for LCX. Left ventriculography showed hypokinesis in the posterior wall, inferior and apical wall immediately after the PCI therapy. The defects on 123I-BMIPP SPECT seen in the inferior, posterior and lateral wall were more extensive than those observed on 99mTc-MIBI SPECT, and a flow-fatty acid metabolism mismatch pattern was observed. The 18F-FDG PET showed reduced uptake in the lateral segment, although 13N-NH3 PET showed normal perfusion, and a reverse flow-glucose metabolism mismatch pattern was observed. Left ventriculography showed significant improve to normal contraction on the 3-month follow up, and there was not significantly reduced uptake in 99mTc-MIBI SPECT, 123I-BMIPP SPECT, 13N-NH3 PET or 18F-FDG PET.     

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     

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.     

Quantitative analysis of coronary endothelial function with generator-produced 82Rb PET: comparison with 15O-labelled water PET

Purpose

Endothelial dysfunction is the earliest abnormality in the development of coronary atherosclerosis. ⁸²Rb is a generator-produced positron emission tomography (PET) myocardial perfusion tracer that is becoming more widely used. We aimed to (1) develop a method for quantitative assessment of coronary endothelial function using the myocardial blood flow (MBF) response during a cold pressor test (CPT) in smokers, measured using ⁸²Rb PET, and (2) compare the results with those measured using ¹⁵O-water PET.

Methods

MBF was assessed at rest and during the CPT with ⁸²Rb and ¹⁵O-water in nine controls and ten smokers. A one-compartment model with tracer extraction correction was used to estimate MBF with both tracers. CPT response was calculated as the ratio of MBF during the CPT to MBF at rest.

Results

At rest, measurements of MBF for smokers vs controls were not different using ¹⁵O-water (0.86?±?0.18 vs 0.70?±?0.13, p?=?0.426) than they were using ⁸²Rb (0.83?±?0.23 vs 0.62?±?0.20, p?=?0.051). Both methods showed a reduced CPT response in smokers vs controls (¹⁵O-water, 1.03?±?0.21 vs 1.42?±?0.29, p?=?0.006; ⁸²Rb, 1.02?±?0.28 vs 1.70?±?0.52, p?<?0.001). There was high reliability [intraclass correlation coefficients: 0.48 (0.07, 0.75)] of MBF measurement between ⁸²Rb and ¹⁵O-water during the CPT.

Conclusion

Using a CPT, ⁸²Rb MBF measurements detected coronary endothelial dysfunctions in smokers. ⁸²Rb MBF measurements were comparable to those made using the ¹⁵O-water approach. Thus, ⁸²Rb PET may be applicable for risk assessments or evaluation of risk factor modification in subjects with coronary risk factors.     

Clinical results with β-methyl-p-(<Superscript>123</Superscript>I)iodophenylpentadecanoic acid,single-photon emission computed tomography in cardiac disease

This study was undertaken to evaluate the relationships between myocardial perfusion and metabolism. Simultaneous β-methyl-p-(¹²³I)iodophenylpentadecanoic acid (¹²³I-BMIPP) and thallium 201 myocardial single-photon emission computed tomography (SPECT) were performed in 25 patients with myocardial infarction (group A) and 16 patients with hypertrophic cardiomyopathy (group B). The severity scores of¹²³I-BMIPP and²⁰¹Tl myocardial SPECT images were evaluated semiquantitatively by segmental analysis. In Group A, dissociations between thallium- and¹²³I-BMIPP-imaged defects were frequently observed in patients with successful reperfusion compared with those with no reperfusion and those with reinfarction. In four patients with successful reperfusion, repeated¹²³I-BMIPP and²⁰¹Tl myocardial SPECT showed gradual improvement of the¹²³I-BMIPP severity score compared with the thallium severity score. In group B, dissociations between thallium- and¹²³I-BMIPP-imaged defects were also demonstrated in hypertrophic myocardium. In addition, nonhypertrophic myocardium also had decreased¹²³I-BMIPP uptake. In groups A and B,¹²³I-BMIPP severity scores correlated well with left ventricular function compared with thallium severity scores. These findings indicate that¹²³I-BMIPP is a suitable agent for the assessment of functional integrity, because left ventricular wall motion is energy dependent and¹²³I-BMIPP may reflect an aspect of myocardial energy production. This agent may be useful for the early detection and patient management of various heart diseases as an alternative to positron emission tomographic study.     

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.     

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 (rho-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%+/-135% 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%+/-23.6%, P<0.05 in protocol 1, and 85.9%+/-24.3% in protocol 2) in the ischaemic region, specifically in the endocardium (64.0%+/-28.9%, P<0.05 in protocol 1, and 75.1%+/-28.8%, 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.     

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.     

Serial changes in BMIPP uptake in relation to thallium uptake in the rat myocardium after ischaemia

Several clinical studies have shown that iodine-123 labelled 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) uptake is often lower than the uptake of perfusion tracers in patients with ischaemic heart disease. However, BMIPP accumulation may not decrease during the acute phase of a stunned myocardium in patients with acute coronary syndrome. We evaluated serial changes in BMIPP and perfusion tracer uptake in the myocardium after ischaemia. We performed a 20-min left coronary artery occlusion followed by reperfusion in male Wister rats. One hour after the reperfusion, echocardiography was performed. Intravenous injection of iodine-125 labelled BMIPP and thallium-201 was performed 1 day (acute group) and 5 days (subacute group) after the operation. To determine the myocardial distribution of ¹²⁵I-BMIPP and ²⁰¹Tl, dual-tracer autoradiography was conducted. We identified regions of interest in the anterolateral wall as an area at risk and in the inferoseptum as a remote control area. The anterolateral wall/inferoseptum ratio (A/I ratio) was calculated to compare the distributions of ¹²⁵I-BMIPP and ²⁰¹Tl. Coronary occlusion induced hypokinesia in the anterolateral region 1 h after the reperfusion. The A/I ratio of ¹²⁵I-BMIPP was significantly higher than that of ²⁰¹Tl in the acute group (1.01±0.15 vs 0.80±0.23, P<0.001). On the other hand, there was no significant difference between the A/I ratios of ¹²⁵I-BMIPP and ²⁰¹Tl in the subacute group (0.88±0.18 vs 0.85±0.18). Two rats showed a significantly lower A/I ratio of ¹²⁵I-BMIPP than ²⁰¹Tl in the subacute phase. These data suggest that BMIPP uptake is preserved despite a decrease in perfusion in the acute phase after ischaemia. In the subacute phase, on the other hand, BMIPP uptake is similar to or even lower than thallium uptake. Since BMIPP uptake may change with time after ischaemia, careful interpretation of BMIPP uptake after ischaemia is required in a clinical setting.     

Two phase imaging of<Superscript>99m</Superscript>Tc-SESTAMIBI and<Superscript>123</Superscript>I-BMIPP for patients with angina pectoris

We saw three cases of angina pectoris in which 99mTc-SESTAMIBI delayed images at rest were useful in diagnosing ischemia risk areas. These findings indicated that delayed 99mTc-SESTAMIBI images may be more sensitive to slight ischemia than 123I-BMIPP images, and suggested that imaging with 99mTc-SESTAMIBI twice at rest may be more effective. The addition of 123I-BMIPP SPECT was considered to be useful in making an evaluation of the severity of ischemia.     

First validation of myocardial flow reserve assessed by dynamic <Superscript>99m</Superscript>Tc-sestamibi CZT-SPECT camera: head to head comparison with <Superscript>15</Superscript>O-water PET and fractional flow reserve in patients with suspected coronary artery disease. The WATERDAY study

Purpose

We assessed the feasibility of myocardial blood flow (MBF) and flow reserve (MFR) estimation using dynamic SPECT with a novel CZT camera in patients with stable CAD, in comparison with ¹⁵O–water PET and fractional flow reserve (FFR).

Methods

Thirty patients were prospectively included and underwent FFR measurements in the main coronary arteries (LAD, LCx, RCA). A stenosis ≥50% was considered obstructive and a FFR abnormal if ≤0.8. All patients underwent a dynamic rest/stress ^99mTc-sestamibi CZT-SPECT and ¹⁵O–water PET for MBF and MFR calculation. Net retention kinetic modeling was applied to SPECT data to estimate global uptake values, and MBF was derived using Leppo correction. Ischemia by PET and CZT-SPECT was considered present if MFR was lower than 2 and 2.1, respectively.

Results

CZT-SPECT yielded higher stress and rest MBF compared to PET for global and LAD and LCx territories, but not in RCA territory. MFR was similar in global and each vessel territory for both modalities. The sensitivity, specificity, accuracy, positive and negative predictive value of CZT-SPECT were, respectively, 83.3, 95.8, 93.3, 100 and 85.7% for the detection of ischemia and 58.3, 84.6, 81.1, 36.8 and 93% for the detection of hemodynamically significant stenosis (FFR?≤?0.8).

Conclusions

Dynamic ^99mTc-sestamibi CZT-SPECT was technically feasible and provided similar MFR compared to ¹⁵O–water PET and high diagnostic value for detecting impaired MFR and abnormal FFR in patients with stable CAD.

     

Quantitative assessment of regional myocardial blood flow using oxygen-15-labelled water and positron emission tomography: a multicentre evaluation in Japan

Recently, a method has been proposed for the quantitative measurement of regional myocardial blood flow (MBF) using oxygen-15-labelled water and positron emission tomography (PET). A multicentre project was organized with the intention of evaluating the accuracy of this method, particularly as a multicentre clinical investigative tool. Each of seven institutions performed PET studies on more than five normal volunteers following a specified protocol. The PET study included a transmission scan, a ¹⁵O-carbon monoxide static scan and a ¹⁵O-water dynamic scan, thereby yielding MBF values which should have been independent of the spatial resolution of the PET scanner employed. Fifty-three subjects (aged 20–63 years, mean±SD 36±12 years) were studied at rest, and 31 of these subjects were also studied after dipyridamole in five institutions. Inter-institution consistency and intra-subject variation in MBF values were then evaluated. MBF averaged for all subjects was 0.93±0.34 ml min^–1 g^–1 at rest and 3.40±1.73 ml min^–1 g^–1 after the administration of dipyridamole, and the flow reserve (defined as the ratio of the two MBF values) was 3.82±2.12; these values are consistent with previous reports. Resting MBF values were significantly correlated with the heart rate–blood pressure product (RPP) (y=0.31+6.56E^-5 x, P<0.010), and RPP was in resting MBF observed in all institutions was well explained by the age-dependent RPP. No significant difference was observed in resting MBF among the institutions. Except in one institution, no significant difference was seen in dipyridamole MBF or myocardial flow reserve. No significant difference was found among the myocardial segments. Regional variation was reasonably small in five institutions, but was not acceptable in two institutions, which was attributed to the scanner performance. These observations suggest that the ¹⁵O-water PET technique is useful for a multicentre clinical study if the PET scanner can provide time-activity data with good count statistics. Received 25 April and in revised form 30 August 1999     

Kinetics of radioiodinated species in subcellular fractions from rat hearts following administration of iodine-123-labelled 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (123I-BMIPP)

It is recognized that iodine-123-labelled 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (¹²³IBMIPP) slowly washes out of the myocardium. The mechanism for the washout was investigated in normal rat hearts by analyses of the subcellular distribution and lipid classes based on the BMIPP metabolism. Rat hearts were excised at 1–120 min after intravenous injection of¹²³I-BMIPP. After counting the radioactivity, the hearts were digested with Nagarse and homogenized, and then fractionated into the cytosolic, mitochondrial, microsomal and crude nuclear fractions by centrifugations. The radioactivity of each fraction was counted, and the lipid classes were analysed by radio-thin-layer chromatographic and high-performance liquid chromatographic methods. The heart uptake of 1231-BMIPP was maximal at 5 min (6.81%±0.36% ID/g), and 41% of the radioactivity disappeared within 120 min. The myocardial radioactivity was immediately distributed into the cytosolic, mitochondrial, microsomal and crude nuclear fractions. The distribution (%) of each fraction was almost identical from 5 min through 120 min. The cytosolic fraction was always the major site of radioactivity deposition (60%), and the time-activity curve of the cytosolic fraction paralleled that of the whole heart throughout the 120-min study period. In the cytosolic fraction, most of the radioactivity was incorporated into the triglyceride class, and the rest was present in the free fatty acid, phospholipid (phosphatidylcholine) and diglyceride classes. In the mitochondrial fraction, the radioactivity was mostly incorporated into the phospholipid class (phosphatidylethanolamine), followed by free fatty acids. The final metabolite of¹²³I-BMIPP,¹²³I-p-iodophenylacetic acid (¹²³I-PIPA), initially appeared in the mitochondrial fraction as early as 1 min, and subsequently in the cytosolic fraction at 5 min. Another intermediary metabolite,¹²³I-p-iodophenyldodecanoic acid (¹²³I-PIPC₁₂), was found only in the mitochondrial fraction after 5 min. In conclusion, the slow washout kinetics of¹²³I-BMIPP from the myocardium mainly reflects the turnover rate of the triglyceride pool in the cytosol. The BMIPP metabolism, i.e. initial -oxidation followed by subsequent cycles of -oxidation, was confirmed in vivo. The participation of the mitochondria in the metabolism was also proven.     

Comparison of myocardial blood flow induced by adenosine triphosphate and dipyridamole in patients with coronary artery disease

Myocardial perfusion imaging with adenosine triphosphate (ATP) has been used increasingly to diagnose coronary artery disease (CAD) and assess risk for this disease. This study compared absolute myocardial blood flow (MBF) and myocardial flow reserve index (MFR) with ATP and dipyridamole (DIP) in patients with CAD. MBF was quantified by 15O-H2O PET in 21 patients with CAD (17 male, 4 female), aged 55 to 81 years. MBF was measured at rest, during intravenous injection of ATP (0.16 mg/kg/min), and again after DIP infusion (0.56 mg/kg). Regions of interest were drawn in nonischemic and ischemic segments based on findings from thallium-201 (201T1) scintigraphy and coronary angiography (CAG). Absolute MBF values and indexes of MFR were calculated in nonischemic and ischemic segments. Intravenous injection of ATP and DIP significantly increased MBF in nonischemic (2.4 +/- 0.9 and 2.1 +/- 0.8 ml/g/min, respectively; p < 0.01, for both) and in ischemic segments (1.3 +/- 0.4 and 1.5 +/- 0.4 ml/g/min, respectively; p < 0.01, for both). There was a significant difference in MBF values between ATP and DIP in nonischemic segments (p < 0.05), which was not observed in ischemic segments. In nonischemic segments, ATP produced higher MFR than DIP (2.1 +/- 0.8 and 1.8 +/- 0.7, respectively; p < 0.05), while no significant difference was observed in ischemic segments (1.5 +/- 0.6 and 1.7 +/- 0.3, respectively). ATP produced a greater hyperemia than DIP between the ischemic and nonischemic myocardium in patients with CAD. ATP is as effective as DIP for the diagnosis of CAD.     

A patient with type I CD36 deficiency whose myocardium accumulated123I-BMIPP after 4 years

A 73-year-old man with aortic regurgitation was examined by 123I-alpha-methyl-p-iodophenylpentadecanoic acid (BMIPP) myocardial single photon emission computed tomography (SPECT) in 1995. Myocardial accumulation was not evident on either the early or the delayed image obtained 15 minutes and 3 hours, respectively, after injecting 123I-BMIPP. Flow cytometric analysis of CD36 expression in monocytes and platelets identified a type I CD36 deficiency. The patient was hospitalized for severe heart failure in 1999. Upon admission, the cardiothoracic ratio on chest X-rays was 73%, and the left ventricular end-diastolic diameter on echocardiograms was enlarged to 77 mm. On the second day, we performed 123I-BMIPP myocardial SPECT. Myocardial accumulation was evident in the delayed, but not in the early image. We repeated 123I-BMIPP myocardial SPECT on the 10th day after admission. Myocardial accumulation was evident on both early and delayed images. 99mTc-tetrofosmin myocardial SPECT was immediately performed after 123I-BMIPP myocardial SPECT to distinguish myocardial from pooling images in the left ventricle, but, because the images from both 99Tc-tetrofosmin and 123I-BMIPP myocardial SPECT were idential, we considered that the 123I-BMIPP myocardial SPECT images reflected the actual myocardial condition. The CD36 molecule transports long-chain fatty acid (LCFA) on the myocardial membrane, but 123I-BMIPP scintigraphy does not show any myocardial accumulation in patients with type I CD36 deficiency, indicating that myocardial LCFA uptake occurs through CD36 on the human myocardial membrane. Even though our patient had type I CD36 deficiency, BMIPP was uptaken by the myocardium during heart failure, suggesting a variant pathway on the human myocardial membrane for LCFA uptake.     

Quantification of myocardial blood flow with <Superscript>82</Superscript>Rb positron emission tomography: clinical validation with <Superscript>15</Superscript>O-water

Purpose

Quantification of myocardial blood flow (MBF) with generator-produced ⁸²Rb is an attractive alternative for centres without an on-site cyclotron. Our aim was to validate ⁸²Rb-measured MBF in relation to that measured using ¹⁵O-water, as a tracer 100% of which can be extracted from the circulation even at high flow rates, in healthy control subject and patients with mild coronary artery disease (CAD).

Methods

MBF was measured at rest and during adenosine-induced hyperaemia with ⁸²Rb and ¹⁵O-water PET in 33 participants (22 control subjects, aged 30?±?13 years; 11 CAD patients without transmural infarction, aged 60?±?13 years). A one-tissue compartment ⁸²Rb model with ventricular spillover correction was used. The ⁸²Rb flow-dependent extraction rate was derived from ¹⁵O-water measurements in a subset of 11 control subjects. Myocardial flow reserve (MFR) was defined as the hyperaemic/rest MBF. Pearson’s correlation r, Bland-Altman 95% limits of agreement (LoA), and Lin’s concordance correlation ρ _c (measuring both precision and accuracy) were used.

Results

Over the entire MBF range (0.66–4.7 ml/min/g), concordance was excellent for MBF (r?=?0.90, [⁸²Rb–¹⁵O-water] mean difference?±?SD?=?0.04?±?0.66 ml/min/g, LoA?=??1.26 to 1.33 ml/min/g, ρ _c?=?0.88) and MFR (range 1.79–5.81, r?=?0.83, mean difference?=?0.14?±?0.58, LoA?=??0.99 to 1.28, ρ _c?=?0.82). Hyperaemic MBF was reduced in CAD patients compared with the subset of 11 control subjects (2.53?±?0.74 vs. 3.62?±?0.68 ml/min/g, p?=?0.002, for ¹⁵O-water; 2.53?±?1.01 vs. 3.82?±?1.21 ml/min/g, p?=?0.013, for ⁸²Rb) and this was paralleled by a lower MFR (2.65?±?0.62 vs. 3.79?±?0.98, p?=?0.004, for ¹⁵O-water; 2.85?±?0.91 vs. 3.88?±?0.91, p?=?0.012, for ⁸²Rb). Myocardial perfusion was homogeneous in 1,114 of 1,122 segments (99.3%) and there were no differences in MBF among the coronary artery territories (p?>?0.31).

Conclusion

Quantification of MBF with ⁸²Rb with a newly derived correction for the nonlinear extraction function was validated against MBF measured using ¹⁵O-water in control subjects and patients with mild CAD, where it was found to be accurate at high flow rates. ⁸²Rb-derived MBF estimates seem robust for clinical research, advancing a step further towards its implementation in clinical routine.

     

Effects of patient movement on measurements of myocardial blood flow and viability in resting 15O-water PET studies

Background

Patient movement has been considered an important source of errors in cardiac PET. This study was aimed at evaluating the effects of such movement on myocardial blood flow (MBF) and perfusable tissue fraction (PTF) measurements in intravenous ¹⁵O-water PET.

Methods

Nineteen ¹⁵O-water scans were performed on ten healthy volunteers and three patients with severe cardiac dysfunction under resting conditions. Motions of subjects during scans were estimated by monitoring locations of markers on their chests using an optical motion-tracking device. Each sinogram of the dynamic emission frames was corrected for subject motion. Variation of regional MBF and PTF with and without the motion corrections was evaluated.

Results

In nine scans, motions during ¹⁵O-water scan (inter-frame (IF) motion) and misalignments relative to the transmission scan (inter-scan (IS) motion) larger than the spatial resolution of the PET scanner (4.0 mm) were both detected by the optical motion-tracking device. After correction for IF motions, MBF values changed from 0.845 ± 0.366 to 0.780 ± 0.360 mL/minute/g (P < .05). In four scans with only IS motion detected, PTF values changed significantly from 0.465 ± 0.118 to 0.504 ± 0.087 g/mL (P< .05), but no significant change was found in MBF values.

Conclusions

This study demonstrates that IF motion during ¹⁵O-water scan at rest can be source of error in MBF measurement. Furthermore, estimated MBF is less sensitive than PTF values to misalignment between transmission and ¹⁵O-water emission scans.