BMS-747 158-02: A novel PET myocardial perfusion imaging agent

Background BMS-747158-02 is a fluorine 18-labeled pyridaben derivative designed as a new myocardial perfusion imaging agent for use with positron emission tomography (PET). This study evaluated BMS-747158-02 in animal models of cardiac perfusion and compared it with established single photon emission computed tomography agents. Methods and Results In a rat biodistribution study, BMS-747158-02 (15 μCi) had substantially higher myocardial uptake than technetium 99m, sestamibi (100 μCi) at 15 minutes (3.5%±0.3% % ID/g vs 1.9%±0.1% %ID/g) and 120 minutes (3.2%±0.4% of injected dose per gram vs 1.8%±0.0% of injected dose per gram) after intravenous administration. Uptake ratios of heart to lung and liver at 60 minutes were also higher for BMS-747158-02 (12.7±1.4 and 3.7±0.2, respectively) than Tc-99m sestamibi (5.9±0.5 and 2.4±0.4, respectively). In an isolated rabbit heart model at flow rates of 1.66 to 5.06 mL · min⁻¹ · g⁻¹ wet left ventricular weight, the net BMS-747158-02 heart uptake increased proportionally (0.93±0.15 to 2.44±0.40 mL · min⁻¹ · g⁻¹) and to a greater extent than that of thallium 201 (0.76±0.02 to 1.11 ±0.02 mL · min⁻¹ · g⁻¹) or Tc-99m sestamibi (0.49±0.03 to 0.77±0.08 mL · min⁻¹ · g⁻¹). PET imaging with BMS-747158-02 showed a clear and sustained cardiac uptake in rats, rabbits, and nonhuman primates with minimal lung interference and rapid liver clearance. Myocardial perfusion deficit zones created by either permanent left coronary ligation or reperfusion after ligation in rats were both clearly identified on PET cardiac images of BMS-747158-02 and had good agreement with in vitro histology. Conclusions BMS-747158-02 exhibited high and sustained cardiac uptake that was proportional to blood flow, and it represents a new class of PET myocardial perfusion imaging agent.     

Assessment of 18F-labeled mitochondrial complex I inhibitors as PET myocardial perfusion imaging agents in rats, rabbits, and primates

Purpose  Myocardial extractions of mitochondria complex I (MC-I) inhibitors were high and well correlated with flow. This study assessed the potential of MC-I inhibitors to be developed as myocardial perfusion imaging (MPI) agents. Methods  RP1003, RP1004, and RP1005 representing three classes of MC-I inhibitor were synthesized and radio-labeled with ¹⁸F. These agents were evaluated for IC₅₀ values, tissue biodistribution, and cardiac PET imaging. ¹⁸F-RP1004 was further examined for first-pass extraction and by imaging in non-human primates (NHP) and rats following coronary ligation. Results  RP1003, RP1004, and RP1005 exhibited high MC-I inhibitory activity with IC₅₀ of 3.7, 16.7, and 14.4 nM. Heart uptakes in rats (percent injected dose per gram tissue) at 15 and 60 min after injection were 3.52 ± 0.36 and 2.68 ± 0.20 for ¹⁸F-RP1003, 2.40 ± 0.21 and 2.67 ± 0.27 for ¹⁸F-RP1004, and 2.28 ± 0.12 and 1.81 ± 0.17 for ¹⁸F-RP1005. The heart to lung and liver uptake ratios were favorable for cardiac imaging with these agents. In isolated perfused rabbit hearts, the uptake of ¹⁸F-RP1004 increased from 0.74 ± 0.19 to 1.68 ± 0.39 mL/min/g at flow rates of 1.66 to 5.06 mL/min/g. These values were higher than or similar to that of ^99mTc-sestamibi. Cardiac imaging with these agents in rats and rabbits allowed visualization of the heart with minimal lung interference and rapid liver activity clearance. Imaging with ¹⁸F-RP1004 also showed clear myocardium and marked liver activity washout in the NHP and clear detection of the perfusion-deficit area associated with left coronary artery ligation in the rat. Conclusion  MC-I inhibitors have the potential to be a new class of MPI agent.     

Cardiac stress-rest single-photon emission computed tomography with technetium 99m-labeled tetrofosmin: Influence of washout kinetics on regional myocardial uptake values of the rest study with a 1-day protocol

Background  The purpose of this study was to evaluate (1) the washout kinetics of^99mTc-labeled tetrofosmin, separately for myocardium with normal and reduced perfusion, and (2) its influence on quantitative analysis in a 1-day stress-rest protocol. Methods and Results  Twenty-five patients with angiographically proved coronary artery disease underwent bicycle exercise stress testing with injection of 200 MBq^99mTc-labeled tetrofosmin and first single-photon emission computed tomographic (SPECT) imaging 40 minutes after injection. A second SPECT was acquired 2.3±0.4 hours after the first one immediately before rest injection of 800 MBq^99mTc-labeled tetrofosmin. The rest (third) SPECT was acquired 15 minutes thereafter. The relative washout fraction per time (WOF_t) was calculated assuming linear washout kinetics. Thirty-three regional uptake values per study were calculated, normalized to the perfusion maximum (100%) in either the postexercise SPECT and the rest SPECT, for the latter with and without correction of remaining counts from stress injection. In regions with normal perfusion, WOF_t was 11.5%±3.5% per hour. In regions with markedly reduced perfusion (relative uptake <50%, WOF_t was 8.3%±9.9% per hour. The highest variation of the relative uptake values between rest SPECT with and without correction of remaining counts from stress injection was 5.4%±3.5% in regions with stress-induced ischemia. Conclusion  To use a 1-day protocol with a stress-rest radioactivity ratio of 1∶4 and an interval of more than 2 hours between the examinations, a correction for remaining counts from stress injection seems not to be necessary for the quantitative analysis of rest SPECT.     

Effects of food intake and anesthetic on cardiac imaging and uptake of BMS747158-02 in comparison with FDG

Background  

BMS747158-02 is an ¹⁸F-labeled agent being developed for PET myocardial perfusion imaging. This study examined impacts of feeding state and anesthetic on cardiac imaging and uptake of this agent in rats in comparison with ¹⁸F-fluorodeoxyglucose (FDG).     

Initial characterization of an 18F-labeled myocardial perfusion tracer.

PET allows for quantitative, regional myocardial perfusion imaging. The short half-lives of the perfusion tracers currently in use limit their clinical applicability. Here, the biodistribution and imaging quality of a new 18F-labeled myocardial perfusion agent (18F-BMS-747158-02) in an animal model are described. METHODS: The biodistribution of 18F-BMS-747158-02 was determined at 10 and 60 min after injection. The first-pass extraction fraction of the tracer was measured in isolated rat hearts perfused with the Langendorff method. Small-animal PET imaging was used to study tracer retention. RESULTS: The biodistribution at 10 min after injection demonstrated high myocardial uptake (3.1 percentage injected dose per gram [%ID/g]) accompanied by little activity in the lungs (0.3 %ID/g) and liver (1.0 %ID/g). The tracer showed a high and flow-independent myocardial first-pass extraction fraction, averaging 0.94 (SD = 0.04). PET imaging provided excellent delineation of myocardial structures. The heart-to-lung activity ratio increased from 4.7 to 10.2 between 1 and 15 min after tracer injection (at rest). Adenosine infusion (140 microg/kg/min) led to a significant increase in myocardial tracer retention (from 1.68 [SD = 0.23]) s(-1) to 3.21 [SD = 0.92] s(-1); P = 0.03). CONCLUSION: The observation of a high and flow-independent first-pass extraction fraction promises linearity between tracer uptake and myocardial blood flow. Sustained myocardial tracer uptake, combined with high image contrast, will allow for imaging protocols with tracer injection at peak exercise followed by delayed imaging. Thus, 18F-BMS-747158-02 is a promising new tracer for the quantitative imaging of myocardial perfusion and can be distributed to imaging laboratories without a cyclotron.     

Florbetapir f-18: a histopathologically validated Beta-amyloid positron emission tomography imaging agent

Florbetapir F-18 is a molecular imaging agent combining high affinity for β-amyloid, pharmacokinetic properties that allow positron emission tomography (PET) imaging within a convenient time after dose administration, and the wide availability of the radionuclide fluorine-18. Florbetapir F-18 is prepared by nucleophilic radiofluorination in approximately 60 minutes with a decay-corrected yield of 20%-40% and with a specific activity typically exceeding 100 Ci/mmol. The florbetapir F-18 dissociation constant (K(d)) for binding to β-amyloid in brain tissue from Alzheimer's disease (AD) patients was 3.7 ± 0.3 nmol/L, and the maximum binding capacity (B(max)) was 8800 ± 1600 fmol/mg protein. Autoradiography studies have shown that florbetapir F-18 selectively binds to β-amyloid aggregates in AD patient brain tissue, and the binding intensity is correlated with the density of β-amyloid quantified by standard neuropathologic techniques. Studies in animals revealed no safety concerns and rapid and transient normal brain uptake (6.8% injected dose/g at 2 minutes and 1.9% injected dose/g at 60 minutes in the mouse). Florbetapir F-18 has been well-tolerated in studies of more than 2000 human subjects. Biodistribution studies in humans revealed predominantly hepatobiliary excretion. The whole body effective dose was 7 mSv from a dose of 370 MBq. The pharmacokinetic of florbetapir F-18 make it possible to obtain a PET image with a brief (10 minutes) acquisition time within a convenient time window of 30-90 minutes after dose administration. Clinical studies have demonstrated a clear correlation between in vivo PET imaging with florbetapir F-18 and postmortem histopathologic quantitation of β-amyloid in the brain.     

Effect of spinal cord stimulation on cardiac adrenergic nerve function in patients with cardiac syndrome X

Background. In patients with cardiac syndrome X (CSX) who present with refractory angina episodes, spinal cord stimulation (SCS) has beneficial effects. The mechanisms of SCS, however, remain speculative. We assessed the effects of SCS on cardiac sympathetic function in these patients. Methods and Results. We studied 11 CSX patients treated by SCS for refractory angina (mean age, 60±9 years; 5 men and 6 women), both during SCS therapy (SCS-ON) and after withdrawal of SCS therapy (SCS-OFF), using a randomized crossover design. Planar and single photon emission computed tomography iodine 123 metaiodobenzylguanidine (MIBG) myocardial scintigraphy and technetium 99m sestamibi (MIBI) bicycle exercise stress testing were performed at the end of each period. Compared with 10 healthy control subjects, CSX patients showed a lower heart-mediastinum ratio for MIBG uptake (2.19±0.3 vs 1.69±0.3,P=.001) and a higher cardiac MIBG uptake score (4.0±2.5 vs 19.7±27,P=.08). There were no differences in CSX patients during the SCS-ON and SCS-OFF phases of the study in heart-mediastinum ratio (1.74±0.3 vs 1.69±0.3,P=.13), cardiac washout rate of MIBG (42.9%±14% vs 43.3%±14%,P=.08), or MIBG defect score (18.7±25 vs 19.7±27,P=.22). Reversible perfusion defects during the SCS-OFF phase were detected in 8 patients; an improvement in perfusion defects was observed in 2 patients (25%) during the SCS-ON phase. Conclusions. Our data confirm the presence of abnormal cardiac adrenergic nerve function in CSX patients. SCS was unable to result in significant improvement of cardiac MIBG uptake abnormalities, suggesting that its therapeutic effects are unlikely to be mediated by modulation of cardiac adrenergic nerve activity.     

Uptake of F-18 FDG and ultrasound analysis of carotid plaque

Objectives

To elucidate the relation between the echolucent plaque on carotid ultrasound and acute inflammation on F-18 FDG carotid PET/CT.

Methods

Thirty nine patients (M:F ratio = 23:16, mean age = 63 ± 11 years) that underwent coronary angiography and carotid ultrasound were divided into three groups—echolucent plaque (n = 22), calcified (n = 10), and no plaque(n = 7). All the patients underwent F-18 FDG carotid PET/CT. The mean standardized uptake values (SUV), namely target to background ratio (TBR) on 180 minutes delayed F-18 FDG carotid PET/CT images were compared with levels of serum inflammatory markers and lipid profiles, and in terms of the presence of carotid plaque on carotid US.

Results

180 minutes TBR of carotid arterial wall at echolucent plaque, calcified plaque, and no plaque were 1.40 ± 0.05, 1.23 ± 0.03, 1.17 ± 0.03 in both carotid artery. TBR of carotid arterial walls for echolucent plaque were significantly larger than TBR for calcified, and no plaque respectively at the both side of carotid artery (P < .05). Serum HDL levels were found to be inversely correlated with F-18 FDG uptake at both carotid arteries (r = ?0.43, P = .005) on 180 minutes delayed phase images. Also serum hs-CRP levels were found to be correlated with F-18 FDG TBR values of right carotid arteries (r = 0.41, P = .04).

Conclusions

Our results show that F-18 FDG carotid PET/CT can depict metabolically active atherosclerotic plaques, and suggest that F-18 FDG carotid PET/CT can be used as a noninvasive imaging modality for functional evaluation of atherosclerosis.     

Advances in PET myocardial perfusion imaging: F-18 labeled tracers

Coronary artery disease and its related cardiac disorders represent the most common cause of death in the USA and Western world. Despite advancements in treatment and accompanying improvements in outcome with current diagnostic and therapeutic modalities, it is the correct assignment of these diagnostic techniques and treatment options which are crucial. From a diagnostic standpoint, SPECT myocardial perfusion imaging (MPI) using traditional radiotracers like thallium-201 chloride, Tc-99m sestamibi or Tc-99m tetrofosmin is the most utilized imaging technique. However, PET MPI using N-13 ammonia, rubidium-82 chloride or O-15 water is increasing in availability and usage as a result of the growing number of medical centers with new-generation PET/CT systems taking advantage of the superior imaging properties of PET over SPECT. The routine clinical use of PET MPI is still limited, in part because of the short half-life of conventional PET MPI tracers. The disadvantages of these conventional PET tracers include expensive onsite production and inconvenient on-scanner tracer administration making them unsuitable for physical exercise stress imaging. Recently, two F-18 labeled radiotracers with longer radioactive half-lives than conventional PET imaging agents have been introduced. These are flurpiridaz F 18 (formerly known as F-18 BMS747158-02) and F-18 fluorobenzyltriphenylphosphonium. These longer half-life F-18 labeled perfusion tracers can overcome the production and protocol limitations of currently used radiotracers for PET MPI.     

Noninvasive determination of myocardial blood flow, oxygen consumption and efficiency in normal humans by carbon-11 acetate positron emission tomography imaging

The aims of this study were: (1) to measure noninvasively and near simultaneously myocardial blood flow, oxygen consumption, and contractile function and (2) to analyze myocardial energy expenditure and efficiency at rest and during dobutamine stress in normal humans. Dynamic and gated carbon-11 acetate positron emission tomography (PET) imaging was performed in 11 normal subjects. The initial uptake of ¹¹C-acetate was measured to estimate myocardial blood flow. Oxygen consumption was derived from the monoexponential slope of the ¹¹C-clearance curve recorded during myocardial washout. ECG-gated systolic and diastolic images were acquired during the peak myocardial ¹¹C activity to measure left ventricular radius, myocardial wall thickness, and long axis length. Myocardial oxygen consumption and parameters of cardiac geometry were used to determine myocardial energetics and cardiac efficiency by tension-area area analysis. Myocardial blood flow averaged 0.8±0.06 ml min^–1 g^–1 at rest and 1.48±0.15 ml min^–1 g^–1 during dobutamine stress. Oxygen delivery and consumption were 151±13 and 88±15 μl O₂ min^–1 g^–1 at rest and increased to 291±31 and 216±31 μl O₂ min^–1 g^–1, respectively, during pharmacological stress (P<0.001). Oxygen extraction increased from 59%±8% at rest to 76%±9% during stress (P<0.001). Mechanical efficiency was 29%±6% at rest and 32%±6% during dobutamine stress (P=NS) while external work efficiency was 16%±6% at rest and increased to 21%±4% (P<0.01) during dobutamine stress. Stepwise linear regression analysis identified rate-pressure product and external cardiac work as major correlates of oxygen consumption. In summary, rapid dynamic and gated PET ¹¹C acetate imaging provides the unique capability to study noninvasively determinants of myocardial energy delivery, expenditure, and efficiency. Received: 15 March and in revised form 28 May 1999     

18F-FDG-PET of musculoskeletal tumors: a correlation with the expression of glucose transporter 1 and hexokinase II

Objective  It remains controversial whether positron emission tomography (PET) with 2-deoxy-2-[F-18]fluoro-d-glucose (F-18-FDG) can differentiate between benign and malignant musculoskeletal tumors. To uncover the mechanism of F-18-FDG accumulations, we analyzed the correlation between the F-18-FDG accumulation and the expression of glucose transporter 1 (Glut-1) and hexokinase II (HK-II) in benign and malignant musculoskeletal tumors. Methods  The maximum standardized uptake values (SUV_max) of F-18-FDG in 24 benign and 26 malignant musculoskeletal tumors were compared with the histologic malignancies, and the expression of Glut-1 and HK-II was analyzed by immunohistochemistry. Results  The SUV_max for malignant tumors (6.33 ± 4.79) was significantly higher than those with benign tumors (3.47 ± 3.12, P < 0.01). The expression of Glut-1 was high in 12 patients (all malignant) and low in 38 patients (24 benign and 14 malignant), and the expression of HK-II was high in 36 patients (11 benign and 25 malignant) and low in 14 patients (13 benign and 1 malignant). Cases with high expression of Glut-1 and HK-II at immunohistochemistry showed a higher SUV_max than those with low expression (Glut-1 8.03 ± 5.10 and 3.98 ± 3.53, P < 0.01; HK-II 5.73 ± 4.49 and 2.99 ± 3.02, P < 0.01). No significant dividing threshold of the SUV_max of F-18 FDG was found for the differential diagnosis between benign and malignant tumors or for the expression of Glut-1 and HK-II. Conclusions  The limited capability of F-18 FDG-PET in the differential diagnosis of musculoskeletal tumors is owing partly to the various levels of Glut-1 and HK-II expression in individual tumors.     

Phase analysis by gated F-18 FDG PET/CT for left ventricular dyssynchrony assessment: a comparison with gated Tc-99m sestamibi SPECT

Purpose

To investigate the value of gated F-18 FDG PET/CT on left ventricular (LV) dyssynchrony assessment in comparison with gated Tc-99m sestamibi SPECT in patients with coronary artery disease (CAD).

Methods

The data of 100 consecutive CAD patients who underwent both gated myocardial Tc-99m sestamibi SPECT and F-18 FDG PET/CT imaging were analyzed. Phase standard deviation (SD) and histogram bandwidth (BW) were derived from phase analysis using Cedars software package. The correlation and agreement of SD and BW between Tc-99m sestamibi SPECT and F-18 FDG PET/CT were examined. Myocardial viability and the site of latest activation assessed by the two imaging methods were compared as well.

Results

A moderate correlation for SD (r = 0.58, p < 0.0001) and BW (r = 0.60, p < 0.0001) was found between gated SPECT and gated F-18 FDG PET/CT. Bland–Altman analysis revealed an overestimation of SD and BW (6.4° ± 14.3° and 22.0° ± 46.8°) by gated F-18 FDG PET/CT. Multivariate logistic regression analysis identified that significant LV remodeling on SPECT imaging, LV functional parameters and F-18 FDG uptake ratio of myocardium to blood pool (SUV_M/B) were associated with the overestimation. Myocardial SPECT and F-18 FDG PET/CT had a 67.1 % identity in determining the latest activation site and 5.2 % more viable myocardium was detected by F-18 FDG PET/CT than SPECT.

Conclusion

Gated F-18 FDG PET/CT moderately correlated with gated Tc-99m sestamibi SPECT in assessing LV dyssynchrony. Gated F-18 FDG PET/CT phase analysis should be cautiously applied in CAD patients with significant LV remodeling on SPECT imaging, severe LV functional impairment or poor myocardial F-18 FDG uptake.     

Regional alterations in myocardial sympathetic innervation in patients with transient left-ventricular apical ballooning (Tako-Tsubo cardiomyopathy)

Background  Excess sympathetic nervous activity was proposed to play a crucial role in the pathogenesis of transient left-ventricular apical ballooning (TLVAB, also known as Tako-Tsubo cardiomyopathy). This study was conducted to assess presynaptic adrenergic alterations in the dysfunctional myocardium of patients with TLVAB. Methods and Results  Ten consecutive patients undergoing coronary angiography for acute coronary syndrome who fulfilled the proposed Mayo Clinic criteria for the diagnosis of TLVAB were investigated. Myocardial iodine-123 metaiodobenzylguanidine (¹²³I-MIBG) studies (planar and single-photon emission computed tomography [SPECT]) were performed to evaluate adrenergic innervation. Concomitantly, myocardial perfusion was assessed by means of technetium-99m methoxyisobutylisonitrile (^99mTc-MIBI) SPECT. In all patients, angiography revealed typical ballooning of the left-ventricular (LV) apex and hyperkinesis of the basal LV segments (overall ejection fraction, 41%±5% [mean±SEM]). Planar ¹²³I-MIBG scans revealed decreased heart-to-mediastinum ratios at early (20 minutes) and delayed (4 hours) images (2.1±0.1 and 1.9±0.1, respectively). The cardiac washout rate of ¹²³I-MIBG on the late images was increased to 34%±3%. The ¹²³I-MIBG uptake on SPECT scans was obviously reduced in the akinetic LV apex (defect score, 3.30±0.34), whereas ^99mTc-MIBI SPECT indicated normal or only mildly reduced perfusion within this region (defect score, 0.89±0.35). Conclusions  Our study indicates a functional alteration in presynaptic sympathetic neurotransmission in patients with TLVAB, and suggests a pathophysiologic explanation of the impairment of LV function.     

Comparing amyloid-β deposition,neuroinflammation, glucose metabolism,and mitochondrial complex I activity in brain: a PET study in aged monkeys

Purpose

The aim of the present study was to compare amyloid-β (Aβ) deposition, translocator protein (TSPO) activity, regional cerebral metabolic rate of glucose (rCMRglc), and mitochondrial complex I (MC-I) activity in the brain of aged monkeys.

Methods

PET scans with ¹¹C-PIB (Aβ), ¹⁸F-BCPP-EF (MC-I), ¹¹C-DPA-713 (TSPO), and ¹⁸F-FDG (rCMRglc) were performed in aged monkeys (Macaca mulatta) in the conscious state and under isoflurane anaesthesia. ¹¹C-PIB binding to Aβ and ¹¹C-DPA-713 binding to TSPO were evaluated in terms of standard uptake values (SUV). The total volume of distribution (V _T) of ¹⁸F-BCPP-EF and rCMRglc with ¹⁸F-FDG were calculated using arterial blood sampling.

Results

Isoflurane did not affect MC-I activity measured in terms of ¹⁸F-BCPP-EF uptake in living brain. There was a significant negative correlation between ¹⁸F-BCPP-EF binding (V _T) and ¹¹C-PIB uptake (SUVR), and there was a significant positive correlation between ¹¹C-DPA-713 uptake (SUV) and ¹¹C-PIB uptake. In contrast, there was no significant correlation between rCMRglc ratio and ¹¹C-PIB uptake.

Conclusion

¹⁸F-BCPP-EF could be a potential PET probe for quantitative imaging of impaired MC-I activity that is correlated with Aβ deposition in the living brain.     

Use of iodine-123 metaiodobenzylguanidine scintigraphy to assess cardiac sympathetic denervation and the impact of hypertension in patients with non-insulin-dependent diabetes mellitus

The objectives of this clinical study using iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy were (a) to evaluate cardiac sympathetic denervation in non-insulin-dependent diabetes mellitus (NIDDM) patients with and without hypertension and (b) to investigate the relation between cardiac sympathetic denervation and prognosis in NIDDM patients. We compared clinical characteristics and MIBG data [heart to mediastinum (H/M) ratio and % washout rate (WR)] in a control group and NIDDM patients with and without hypertension. MIBG scintigraphy was performed in 11 controls and 82 NIDDM patients without overt cardiovascular disease except for hypertension (systolic blood pressure ≥140 and/or diastolic blood pressure ≥90 mmHg). After MIBG examination, blood pressure was measured regularly in all NIDDM patients. There were significant differences between 65 normotensive and 17 hypertensive NIDDM patients with respect to age (55±11 vs 63±12 years, respectively, P<0.05), prevalence of diabetic retinopathy (12% vs 35%, respectively, P<0.05) and systolic blood pressure (120±12 vs 145±16 mmHg, respectively, P<0.001). The H/M ratio in hypertensive NIDDM patients was significantly lower than in the control group (1.81±0.29 vs 2.27±0.20, respectively, P<0.01). During the follow-up period (18± 12 months), 17 NIDDM patients newly developed hypertension after MIBG examination. There were no significant differences in their clinical characteristics compared with persistently normotensive or hypertensive NIDDM patients. %WR in patients with new onset hypertension was significantly higher than in the control group (30.88%±16.87% vs 12.89%±11.94%, respectively, P<0.05). Moreover, in these patients %WR correlated with duration from the date of MIBG scintigraphy to the onset of hypertension (r=-0.512, P<0.05). Five NIDDM patients died during the follow-up period (four newly hypertensive patients and one normotensive patient). There were significant statistical differences between the control group and non-survivors in terms of age (54±11 vs 73±11 years, respectively, P<0.01), H/M ratio (2.27± 0.20 vs 1.64±0.36, respectively, P<0.01) and %WR (12.89%±11.94% vs 42.52%±22.39%, respectively, P<0.01). In conclusion, cardiac sympathetic denervation using MIBG scintigraphy observed in hypertensive NIDDM patients, and was more profound in non-survivors. MIBG scintigraphy proved useful for the evaluation of NIDDM patients with new onset hypertension, and it was found that NIDDM patients with abnormalities on MIBG scintigraphy needed to be observe carefully. Received 1 April and in revised form 27 May 1999     

Impact of exercise rehabilitation on cardiac neuronal function in heart failure: an iodine-123 metaiodobenzylguanidine scintigraphy study

Exercise training can induce important haemodynamic and metabolic adaptations in patients with chronic heart failure due to severe left ventricular dysfunction. This study examined the impact of exercise rehabilitation on cardiac neuronal function using iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy. Fourteen patients (11 men, 3 women; mean age 48 years; range: 36–66 years) with stable chronic heart failure of NYHA class II–III and an initial resting radionuclide left ventricular ejection fraction (LVEF) <50% were enrolled in the study. Patients underwent progressive, supervised endurance training (treadmill test, Bruce protocol) during a 6-month period (60 sessions, 3 sessions per week) at a cardiac rehabilitation referral centre in order to measure exercise parameters. Planar ¹²³I-MIBG scintigraphy provided measurements of cardiac neuronal uptake (heart-mediastinum ratio activity, 4 h after intravenous injection of 185 MBq of MIBG). Radionuclide LVEF was also assessed at the outset and after 6 months of exercise training. Workload (801±428 vs 1229±245 kpm·min^–1, P = 0.001), exercise duration (504±190 vs 649±125 s, P = 0.02), and myocardial MIBG uptake (135%±19% vs 156%±25%, P = 0.02) increased significantly after rehabilitation. However, LVEF did not change significantly (23%±9% vs 21%±10%, p = NS). It is concluded that exercise rehabilitation induces improvement of cardiac neuronal function without having negative effects on cardiac contractility in patients with stable chronic heart failure. Received 23 September and in revised form 24 November 1997     

Evaluation of the relationship between [18F]FDG and P-glycoprotein expression: an experimental study

IntroductionP-glycoprotein (P-gp) is a cell-membrane-associated protein that transports a variety of drug substrates. We sought to evaluate the relationship between 2-[¹⁸F]fluoro-2-deoxy-d-glucose ([¹⁸F]FDG) and P-gp expression using breast carcinoma Bcap37/multidrug resistant (MDR1) and Bcap37 in vitro and in vivo.MethodsThe function of P-gp expressed in Bcap37/MDR1 cells was evaluated using verapamil (VER), a classical inhibitor of P-gp. The accumulation of ^99mTc-methoxyisobutylisonitrile ([^99mTc]MIBI) in vitro was measured. In vivo imaging of severe combined immune deficiency (SCID) mice implanted with Bcap37 and Bcap37/MDR1 cells was performed by scintigraphy and micro-positron emission tomography (PET).ResultsThe uptake of [^99mTc]MIBI was 0.62%±0.05% in the Bcap37/MDR1 cells and 2.02%±0.28% in the Bcap37 cells. VER significantly increased the uptake of [^99mTc]MIBI in the Bcap37/MDR1 cells (1.90%±0.09%) but not in the Bcap37 cells (2.15%±0.27%). In vivo, neither the Bcap37 nor Bcap37/MDR1 tumors grown in the SCID mice could be detected by [^99mTc]MIBI scintigraphy. Both the Bcap37 and Bcap37/MDR1 tumors were visible by micro-PET. The mean standardized uptake value (SUV) was significantly higher in the Bcap37 tumors (1.00±0.06) than in the Bcap37/MDR1 (0.67±0.11) tumors. VER significantly increased the mean SUV in the Bcap37/MDR1 tumors (1.02±0.16) but not in the Bcap37 tumors (1.09±0.22).Conclusions[¹⁸F]FDG combined with VER may be an effective noninvasive method of determining P-gp expression in tumors.     

Differentiation of myocardial ischemia and necrosis by technetium 99m glucaric acid kinetics

Background  Current clinical approaches may not always be helpful in the early differentiation of necrotic tissue from ischemic viable myocardium in patients with acute myocardial infarction. Tc-99m-glucaric acid is a carbohydrate ligand that may permit differentiation of necrosis from ischemia. However, the myocardial kinetics of Tc-99m-glucaric acid have not been well defined early after myocardial injury. The aim of this study was to evaluate the effect of necrosis in comparison to postischemic injury alone on the kinetics of Tc-99m-glucaric acid with the use of an isolated perfused rat heart model. Methods and Results  Three groups of hearts were studied: group I: control (n=6); group II: postischemia (15 minutes of no flow with complete reperfusion, n=6); and group III: necrosis (90 minutes of no flow to induce necrosis with complete reperfusion, n=6). Tc-99m-glucaric acid (1.3±0.6 mCi/L of buffer) was perfused for 30 minutes to evaluate tracer accumulation. Then tracer-free buffer was perfused for 45 minutes to evaluate clearance. The peak accumulation relative to the control group mean was significantly increased (p<0.01) in group III (necrosis) 254%±75%) compared with control (100%±10%) and compared with postischemia (108%±26%). On kinetic data analysis, the monoexponential clearance rate constant (k_c) was significantly reduced with necrosis (control: k_c=20.2±14.0×10⁻⁴ sec⁻¹; postischemia: k_c=22.3±15.2×10⁻⁴ sec⁻¹; and necrosis: k_c=1.2±0.3×10⁻⁴ sec⁻¹;p<0.05). A retention fraction was calculated from the activity after 45 minutes of clearance corrected for the peak activity for each group. The necrotic group had significant myocardial retention in comparison to control and postischemia (control: 12%±8%; postischemia: 14% ±16%; necrosis: 64%±10%;p<0.01). Conclusions  The accumulation and retention of Tc-99m-glucaric acid is markedly increased in the presence of myocardial necrosis in comparison to control and postischemic myocardial injury. In this model, Tc-99m-glucaric acid is capable of defining the presence of necrotic myocardial injury in comparison to postischemic injury alone., This agent may have potential application for the early differentiation of ischemic from necrotic myocardium in acute myocardial infarction. Supported in part by a grant from the JP Bickell Foundation of Ontario, Canada. Dr. Beanlands is a Research Scholar for the Medical Research Council of Canada. Dr. Ruddy is a Research Scholar for the Heart and Stroke Foundation of Canada. Presented in part at the 67th Scientific Sessions of the American Heart Association Meeting, 1994. Submitted for publication April 4, 1996; revision accepted Nov 27, 1996.     

Para-[18F]fluorobenzylguanidine kinetics in a canine coronary artery occlusion model

Background

The kinetics of para-[¹⁸F]fluorobenzylguanidine ([¹⁸F]PFBG) were investigated in a canine coronary artery occlusion model.

Methods and Results

Five dogs were imaged by positron emission tomography (PET) before and after complete surgical ligation of the left anterior descending coronary artery. PET studies included a 10-minute dynamic [¹³N]NH3 perfusion scan, followed 1 hour later by 3-hour dynamic [¹⁸F]PFBG scanning. [¹⁸F]PFBG and [¹³N]NH3 images demonstrated homogeneous myocardial uptake/perfusion before infarction. One hundred eighty minutes after [¹⁸F]PFBG administration, myocardial accumulation was decreased by 60% (day, 2, 0.0065% ±0.0015% injected dose/ml) and 58% (day 16, 0.0069%±0.003% injected dose/ml) compared with a similar myocardial region of interest from the preinfarction (0.016%±0.005% injected dose/ml) study. Myocardial accumulation of [¹³N]NH3 at 9 minutes showed a 52% (day 2) and 7% (day 16) decrease compared with the preinfarction study. The accumulation of [¹⁸F]PFBG in the infarction was decreased significantly at 120 and 180 minutes on all postinfarction studies (p=0.01). In three dogs a significant decrease in the myocardial norepinephrine concentration was documented in the area of infarction (237±94 ng/gm) versus the noninfarcted (1018±48 ng/gm) myocardium (p=0.001).

Conclusions

A decreased accumulation of [¹⁸F]PFBG was observed in the area of myocardial infarct in this canine model. The magnitude of the decrease in [¹⁸F]PFBG was larger than that seen with [¹³N]NH₃ on day 16 after infarction suggesting reperfusion and persistent sympathetic neuronal dysfunction.     

Myocardial glucose metabolism in patients with hypertrophic cardiomyopathy: Assessment by F-18-FDG PET study

In an investigation of myocardial metabolic abnormalities in hypertrophic myocardium, the myocardial glucose metabolism was evaluated with F-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) in 32 patients with hypertrophie cardiomyopathy, and the results were compared with those in 9 patients with hypertensive heart disease. F-18-FDG PET study was performed in the fasting and glucose-loading states. The myocardial regional %dose uptake was calculated quantitatively. The average regional %dose uptake in the fasting state in the patients with asymmetric septal hypertrophy and dilated-phase hypertrophie cardiomyopathy was significantly higher than that in the patients with hypertensive heart disease (0.75 ± 0.34%, 0.65 ± 0.25%, and 0.43 ± 0.22%/100 g myocardium, respectively). In contrast, the average %dose uptake in the glucose-loading state in the patients with asymmetric septal hypertrophy and dilated-phase hypertrophie cardiomyopathy was not significantly different from that in patients with hypertensive heart disease (1.17 + 0.49%, 0.80 ± 0.44% and 0.99 ± 0.45%, respectively). The patients with apical hypertrophy had also low %dose uptake in the fasting state (0.38 ± 0.21%) as in the hypertensive heart disease patients, so that the characteristics of asymmetric septal hypertrophy and dilatedphase hypertrophic cardiomyopathy are considered to be high FDG uptake throughout the myocardium in the fasting state. Patients with apical hypertrophy are considered to belong to other disease categories metabolically. F-18-FDG PET study is useful in the evaluation of the pathophysiologic diagnosis of patients with hypertrophie cardiomyopathy.