Incidence of stunned, hibernating and scarred myocardium in ischaemic cardiomyopathy

Purpose Different criteria to identify residual viability in chronically dysfunctioning myocardium in patients with coronary artery disease (CAD) can be derived by the combined assessment of myocardial blood flow (MBF) and glucose utilisation (MRG) using positron emission tomography (PET). The aim of this study was to evaluate, in a large number of patients, the prevalence of these different patterns by purely quantitative means.Methods One hundred and sixteen consecutive patients with ischaemic cardiomyopathy (LVEF 40%) underwent resting 2D echocardiography to assess regional contractile function (16-segment model). PET with ¹⁵O-labelled water (H₂¹⁵O) and ¹⁸F-fluorodeoxyglucose (FDG) was used to quantify MBF and MRG during hyperinsulinaemic euglycaemic clamp. Dysfunctional segments with normal MBF (0.6 ml min^–1 g^–1) were classified as stunned, and segments with reduced MBF (<0.6 ml min^–1 g^–1) as hibernating if MRG was 0.25 mol min^–1 g^–1. Segments with reduced MBF and MRG <0.20 mol min^–1 g^–1 were classified as transmural scars and segments with reduced MBF and MRG between 0.20 and 0.25 mol min^–1 g^–1 as non-transmural scars.Results Eight hundred and thirty-four (46%) segments were dysfunctional. Of these, 601 (72%) were chronically stunned, with 368 (61%) having normal MRG (0.47±0.20 mol min^–1 g^–1) and 233 (39%) reduced MRG (0.16±0.05 mol min^–1 g^–1). Seventy-four (9%) segments with reduced MBF had preserved MRG (0.40±0.18 mol min^–1 g^–1) and were classified as hibernating myocardium. In addition, 15% of segments were classified as transmural and 4% as non-transmural scar. The mean MBF was highest in stunned myocardium (0.95±0.32 ml min^–1 g^–1), intermediate in hibernating myocardium and non-transmural scars (0.47±0.09 ml min^–1 g^–1 and 0.48±0.08 ml min^–1 g^–1, respectively), and lowest in transmural scars (0.40±0.14 ml min^–1 g^–1, P<0.01). MRG was comparable in hibernating and stunned myocardium with preserved MRG (0.40±0.19 mol min^–1 g^–1 vs 0.46±0.20 mol min^–1 g^–1, NS), and lowest in stunned myocardium with reduced MRG and transmural scars.Conclusion Chronic stunning is more prevalent than expected. The degree of MRG reduction in stunned myocardium may disclose segments at higher risk of permanent damage.     

Relation of coronary vasoreactivity and coronary calcification in asymptomatic subjects with a family history of premature coronary artery disease

Electron-beam computed tomography (EBCT) allows non-invasive imaging of coronary calcification and has been promoted as a screening tool for coronary artery disease (CAD) in asymptomatic high-risk subjects. This study assessed the relation of coronary calcifications to alterations in coronary vascular reactivity by means of positron emission tomography (PET) in asymptomatic subjects with a familial history of premature CAD. Twenty-one subjects (mean age 51±10 years) underwent EBCT imaging for coronary calcifications expressed as the coronary calcium score (CCS according to Agatston) and rest/adenosine-stress nitrogen-13 ammonia PET with quantification of myocardial blood flow (MBF) and coronary flow reserve (CFR). The mean CCS was 237±256 (median 146, range 0–915). The CCS was <100 in eight subjects and >100 units in 13. As defined by age-related thresholds, 15 subjects had an increased CCS (>75th percentile). Overall mean resting and stress MBF and CFR were 71±16 ml 100 g^–1 min^–1, 218±54 ml 100 g^–1 min^–1 and 3.20±0.77, respectively. Three subjects with CCS ranging from 114 to 451 units had an abnormal CFR (<2.5). There was no relation between CCS and resting or stress MBF or CFR (r=0.17, 0.18 and 0.10, respectively). In asymptomatic subjects a pathological CCS was five times more prevalent than an abnormal CFR. The absence of any close relationship between CCS and CFR reflects the fact that quantitative myocardial perfusion imaging with PET characterises the dynamic process of vascular reactivity while EBCT is a measure of more stable calcified lesions in the arterial wall whose presence is closely related to age.     

Myocardial perfusion in type 2 diabetes with left ventricular hypertrophy: normalisation by acute angiotensin-converting enzyme inhibition

The purpose of this study was to assess whether acute angiotensin-converting enzyme (ACE) inhibition would improve myocardial perfusion and perfusion reserve in a subpopulation of normotensive patients with diabetes and left ventricular hypertrophy (LVH), both independent risk factors of coronary disease. Using positron emission tomography (PET), we investigated the response of regional myocardial perfusion to acute ACE inhibition with i.v. infusion of perindoprilat (vs saline infusion as control, minimum interval 3 days) in 12 diabetic patients with LVH. Myocardial perfusion was quantified with PET using nitrogen-13 ammonia infused at rest and during dipyridamole hyperaemia. Twelve healthy control subjects were included in the study, five of whom were also studied with perindoprilat. Mean blood pressure in normo-albuminuric, asymptomatic patients was 123±7/65±9 mmHg. Compared with controls, maximal perfusion was reduced in patients (1.8±0.6 vs 2.5±1.0 ml min^–1 g^–1; P<0.05), and perfusion reserve was also lower, at borderline significance (2.7±1.0 vs 3.6±1.3; P=0.059). During perindoprilat infusion, myocardial perfusion reserve in patients increased to 3.9±0.9 (P<0.001) due to normalisation of maximal perfusion (2.3±0.5 ml min^–1 g^–1, P<0.01). In the five control subjects both resting and hyperaemic perfusion remained unchanged during perindoprilat infusion. It is concluded that acute ACE inhibition with perindoprilat improves maximal achieved myocardial perfusion in non-hypertensive patients with diabetes and LVH.     

Quantitative analysis of myocardial glucose utilization in patients with left ventricular dysfunction by means of 18F-FDG dynamic positron tomography and three-compartment analysis

Purpose Myocardial glucose utilization (MGU) is altered in various heart diseases. The aim of this study was to quantitatively assess regional myocardial glucose utilization in patients with left ventricular (LV) dysfunction by dynamic ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG PET).Methods A total of 18 subjects were studied, including ten with LV dysfunction (seven with idiopathic dilated cardiomyopathy and three with aortic regurgitation; NYHA II in 8 and III in 2) and eight healthy normal volunteers. Patients with diabetes mellitus were excluded. A dynamic PET study was performed for 40 min following the injection of 370 MBq of FDG after 50-g glucose loading. On the basis of a three-compartment model, MGU, K₁, k₂, and k₃ were computed on a pixel by pixel basis to generate LV myocardial parametric maps. FDG standardized uptake value (SUV) was also calculated using static images obtained 40 min after FDG injection. These metabolic values were compared with myocardial flow distribution (%Flow), LVEF, LV volumes, and LV wall thickening (WT) determined by gated myocardial single-photon emission computed tomography using QGS software in eight myocardial segments.Results MGU correlated positively with LV volumes and negatively with LVEF. K₁ was significantly higher in the segments of the patients than in those of the normal volunteers (0.082±0.055 vs 0.041±0.017 ml min^–1 g^–1, p<0.05), although there was no difference in MGU between the groups. On the other hand, SUV, k₂, and k₃ did not differ significantly between the groups. Among the patients, the K₁ values were significantly higher in the areas with impaired WT (%WT<17%) (0.109±0.063 vs 0.069±0.062 ml min^–1 g^–1, p<0.05) and in the areas with flow reduction (%Flow<71%) (0.112±0.076 vs 0.071±0.046 ml min^–1 g^–1, p<0.05).Conclusion These results indicate that glucose utilization was preserved in the patients with LV dysfunction, mainly due to an increase in glucose transport, particularly in the regions with severely impaired LV function. Thus, the quantitative assessment of myocardial glucose utilization by FDG dynamic PET may provide useful information for assessing the regional myocardial metabolic status in patients with LV dysfunction.     

Oxidative metabolism in the myocardium in normal subjects during dobutamine infusion

To assess the biventricular response of the clearance rate of carbon-11 acetate as an index of myocardial oxidative metabolism to increase in work-load, dynamic positron emission tomography was performed at rest and during dobutamine infusion in 14 normal subjects. The clearance rate constant (K_mono) of the left ventricular (LV) myocardium increased during dobutamine infusion (0.112±0.020 min^–1 vs 0.065±0.015 min^–1 at rest) (P<0.001) in proportion to the increase in the pressure-rate product. K_mono in the right ventricular (RV) myocardium also increased (0.080±0.018 min^–1 vs 0.034±0.013 min^–1 at rest) (P<0.001), with an excellent correlation with the LV K_mono (r=0.920). The fact that the increase in RV Kmono during dobutamine infusion was greater (158%±81%) than that in LV Kmono (79%±39%) (P < 0.005) indicates a greater increase in oxidative metabolism in the RV in response to inotropic stimulation in normal subjects. Correspondence to: N. Tamaki     

Coronary vasomotion in patients with syndrome X: evaluation with positron emission tomography and parametric myocardial perfusion imaging

The aim of this study was to elucidate further the causative mechanism of abnormal coronary vasomotion in patients with syndrome X. In patients with syndrome X, defined as angina pectoris and documented myocardial ischaemia during stress testing with normal findings at coronary angiography, abnormal coronary vasomotion of either the micro- or the macrocirculation has been suggested as the causative mechanism. Accordingly, we evaluated endothelial function, vasodilator reserve, and perfusion heterogeneity in these patients. Twenty-five patients with syndrome X (definitely normal coronary arteriogram, group A), 15 patients with minimal coronary artery disease (group B) and 21 healthy volunteers underwent [¹³N]ammonia positron emission tomography at rest, during cold pressor stimulation (endothelial function) and during dipyridamole stress testing (vasodilator reserve). Heterogeneity of myocardial perfusion was analysed by parametric polar mapping using a 480-segment model. In both patient groups, resting perfusion was increased compared to the normal subjects: group A, 127±31 ml·min^–1·100 g^–1; group B, 124±30 ml·min^–1·100 g^–1 normal subjects, 105±21 ml·min^–1·100 g^–1 (groups A and B vs normals,P<0.05). These differences were abolished after correction for rate-pressure product. During cold pressor stimulation, the perfusion responses (ratio of cold pressor perfusion to resting perfusion) were similar among the patients and the control subjects (group A, 1.20±0.23; group B, 1.24±0.22; normal subjects, 1.23±0.14). Likewise, during dipyridamole stress testing, perfusion responses were similar among the three groups (group A, 2.71±0.67; group B, 2.77±1.29; normal subjects, 2.91±1.04). In group A the heterogeneity of resting perfusion, expressed as coefficient of variation, was significantly different from the volunteers (20.1±4.5 vs 17.0±3.0,P<0.05). In group B (coefficient of variation 19.4±3.9) the difference from normal volunteers was not significant. In this study, patients with syndrome X and patients with minimal coronary artery disease showed normal perfusion responses during cold pressor stimulation and dipyridamole stress testing. Our findings therefore suggest that endothelial dysfunction and impaired vasodilator reserve are of no major pathophysiological relevance in patients with syndrome X. Rather, other mechanisms such as increased sympathetic tone and focal release of vasoactive substances may play a role in the pathogenesis of syndrome X.     

Validation of myocardial blood flow estimation with nitrogen-13 ammonia PET by the argon inert gas technique in humans

We simultaneously determined global myocardial blood flow (MBF) by the argon inert gas technique and by nitrogen-13 ammonia positron emission tomography (PET) to validate PET-derived MBF values in humans. A total of 19 patients were investigated at rest (n=19) and during adenosine-induced hyperaemia (n=16). Regional coronary artery stenoses were ruled out by angiography. The argon inert gas method uses the difference of arterial and coronary sinus argon concentrations during inhalation of a mixture of 75% argon and 25% oxygen to estimate global MBF. It can be considered as valid as the microspheres technique, which, however, cannot be applied in humans. Dynamic PET was performed after injection of 0.8ǂ.2 GBq ¹³N-ammonia and MBF was calculated applying a two-tissue compartment model. MBF values derived from the argon method at rest and during the hyperaemic state were 1.03ǂ.24 ml min^-1 g^-1 and 2.64ǃ.02 ml min^-1 g^-1, respectively. MBF values derived from ammonia PET at rest and during hyperaemia were 0.95ǂ.23 ml min^-1 g^-1 and 2.44ǂ.81 ml min^-1 g^-1, respectively. The correlation between the two methods was close (y=0.92x+0.14, r=0.96; P<0.0001). No indication was found for limited extraction of ammonia in the myocardium. The high concordance of global MBF values derived with argon and ammonia indicates that the implicit correction of spillover and recovery effects, incorporated in the model by including an effective blood volume parameter, works correctly quantitatively. Our data provide the previously missing human validation of MBF measurements from ¹³N-ammonia PET.     

Basal and hyperaemic myocardial blood flow in regionally denervated canine hearts: an in vivo study with positron emission tomography

Purpose Positron emission tomography (PET) studies in patients with diabetic autonomic neuropathy (DAN) have demonstrated the impact of this disease on cardiac sympathetic innervation and myocardial blood flow (MBF). To investigate the effects of selective partial sympathetic denervation of the left ventricle (LV) on baseline and hyperaemic MBF, we measured myocardial presynaptic catecholamine re-uptake (uptake-1), β-adrenoceptor (β-AR) density and MBF non-invasively by means of PET in a canine model of regional sympathetic denervation. Methods In 11 anaesthetised dogs, the sympathetic nerves of the free wall and septum of the LV were removed by means of dissection and phenol painting. Three weeks later, the animals were studied with PET. MBF was measured at baseline and following i.v. adenosine (140 μg kg⁻¹ min⁻¹) and dobutamine (20 μg kg⁻¹ min⁻¹) using¹⁵O-labelled water. Sympathetic denervation was confirmed by an 80±12% decrease in the volume of distribution (V_d) of [¹¹C]hydroxyephedrine (HED) compared with innervated regions. Myocardial β-AR density was measured using [¹¹C]CGP12177. Results Innervated and denervated regions showed no differences in MBF at baseline and during adenosine or dobutamine. [¹¹C]HED V_dwas inversely correlated with MBF in both regions at baseline, and the correlation was lost during hyperaemia in denervated regions. However, for any given value of MBF, [¹¹C]HED V_dwas significantly lower in the denervated regions. β-AR density was comparable in denervated and innervated regions (17.9±4.2 vs 18.4±3.3 pmol g⁻¹;p=NS). Conclusion In this experimental model, selective, regional sympathetic denervation of the LV, which results in a profound reduction in [¹¹C]HED V_d, did not affect baseline or hyperaemic MBF. In addition, we demonstrated that, under baseline conditions, there was a significant inverse correlation between [¹¹C]HED V_dand MBF in both denervated and innervated regions.     

Myocardial blood flow and perfusion reserve in infarcted patients with stress-induced normalization of previously negative T waves: A positron emission tomography study

Background  The clinical correlations between stress-induced normalization of previously negative T waves (NTW) and regional myocardial blood flow (MBF) regulation and tissue viability remain debatable. Methods and Results  To confirm these correlations, 14 patients with previous anterior myocardial infarction (13 Q waves) and NTW on baseline electrocardiographic precordial leads and 10 healthy subjects were studied by means of positron emission tomography (PET). The MBF values were obtained in the anterior infarcted myocardial regions in either resting condition or during dipyridamole infusion, using N-13 ammonia as a flow tracer. Seven subjects had normalization of NTW (Group 1) and 7 had persistent NTW (Group 2) during dipyridamole infusion. The resting MBF values were similar for both Group 1 and Group 2 (0.43±0.13 versus 0.51±0.15 mL·min⁻¹.g⁻¹, respectively; P=not significant) and were significantly lower than in the anterior myocardial regions of healthy subjects (1.03±0.23 mL·min⁻¹.g⁻¹, P<.001). After administration of dipyridamole, the MBF was significantly higher in Group 1 than in Group 2 (0.88±0.37 versus 0.55±0.17 mL·min⁻¹.g⁻¹, respectively; P<.05) and markedly lower than in healthy subjects (3.78±0.64 mL·min⁻¹.g⁻¹, respectively; P<.05) and markedly lower than in healthy subjects (3.78±0.64 mL·min⁻¹.g⁻¹, P<.001). Coronary reserves (dipyridamole/resting MBF) were 2.03±0.40 and 1.14±0.44 in Group 1 and Group 2, respectively (P<.002). Conclusion  Despite similar values of resting perfusion, infarcted dysfunctional areas with or without NTW during stress may present different regional MBF responses; normalization of NTW demonstrates higher coronary flow reserve than persistent NTW, suggesting a better preserved coronary microcirculatory function in the former, indicative of the presence of myocardial viability. Presented in part at the 3rd International Congress on Nuclear Cardiology, Florence, April 1997.     

Clearance of thallium-201 from the peripheral blood: Comparison of immediate and standard thallium-201 reinjection

As several reinjection procedures have shown encouraging results in terms of imaging, we investigated whether the kinetics of thallium-201 would differ between the standard stress-redistribution-reinjection approach and the stress-immediate reinjection approach. In 53 consecutive patients with undiagnosed chest pain, 75 MBq (2 mCi)²⁰¹Tl was injected at maximal exercise. In 26 of these patients (group I), 37 MBq (1 mCi)²⁰¹Tl was reinjected immediately after completing the exercise images (the immediate reinjection procedure) and in 27 patients (group II), 37 MBq (1 mCi)²⁰¹Tl was reinjected after completing 3-h redistribution images (the standard reinjection procedure). Mean peak²⁰¹Tl blood activity after exercise was 17.7±12.5 kBq/ml (4.8±3.4 mCi/ml) for group I versus 16.4±9.2 kBq/ml (4.4±2.5 mCi/ml) for group II (NS). The relative increase in²⁰¹Tl blood activity after reinjection of half the initial dose [37 MBq (1 mCi)] exceeded 50% of the initial peak in both groups. The relative amount of²⁰¹Tl delivered to the myocardium was assessed by the area under the curve after both exercise and reinjection, and was 117%±72% for group I and 112%±73% for group II (NS). Blood clearance of²⁰¹Tl was at least biexponential. Mean early decay constants (₁) after exercise and reinjection were 0.30±0.18 min^–1 and 0.22±0.046 min^–1 respectively for group I (T _1/2 2.3 min and 3.2 min respectively, NS), and 0.30±0.12 min^–1 and 0.24±0.07 min^–1 respectively for group II (T _1/2 2.3 min and 2.9 min respectively, NS). For both procedures no significant differences were found between ₁ after exercise and ₁ after injection. The mean late clearance (₂) from the blood was 0.032±0.056 min^–1 and 0.012±0.012 min^–1 respectively for group I (T _1/2 21.6 min and 57.7 min respectively, NS), and 0.036±0.030 min^–1 and 0.014±0.014 min^–1 respectively for group II (T _1/2 19.3 min and 49.5 min respectively, NS). Also, no significant differences were found between ₂ after exercise for both groups and between ₂ after reinjection for both groups. We conclude that reinjection of 37 MBq (1 mCi)²⁰¹Tl (half the initial dose) results in a relative increase in the initial peak and a relative increase in the amount of²⁰¹Tl delivered to the myocardium of more than 50% for both the standard and the immediate reinjection procedure. The clearance of²⁰¹Tl from the blood was not influenced by exercise or by the time of reinjection. Based on²⁰¹Tl kinetics as measured in the peripheral blood, there is no reason to postpone reinjection until 3–4 h following exercise.     

Evaluation of iterative reconstruction (OSEM) versus filtered back-projection for the assessment of myocardial glucose uptake and myocardial perfusion using dynamic PET

Purpose Iterative reconstruction methods based on ordered-subset expectation maximisation (OSEM) has replaced filtered backprojection (FBP) in many clinical settings owing to the superior image quality. Whether OSEM is as accurate as FBP in quantitative positron emission tomography (PET) is uncertain. We compared the accuracy of OSEM and FBP for regional myocardial ¹⁸F-FDG uptake and ¹³NH₃ perfusion measurements in cardiac PET. Methods Ten healthy volunteers were studied. Five underwent dynamic ¹⁸F-FDG PET during hyperinsulinaemic–euglycaemic clamp, and five underwent ¹³NH₃ perfusion measurement during rest and adenosine-induced hyperaemia. Images were reconstructed using FBP and OSEM ± an 8-mm Gaussian post-reconstruction filter. Results Filtered and unfiltered images showed agreement between the reconstruction methods within ±2SD in Bland-Altman plots of K _i values. The use of a Gaussian filter resulted in a systematic underestimation of K _i in the filtered images of 11%. The mean deviation between the reconstruction methods for both unfiltered and filtered images was 1.3%. Agreement within ±2SD between the methods was demonstrated for perfusion rate constants up to 2.5 min⁻¹, corresponding to a perfusion of 3.4 ml g⁻¹ min⁻¹. The mean deviation between the two methods for unfiltered data was 2.7%, and for filtered data, 5.3%. Conclusion The ¹⁸F-FDG uptake rate constants showed excellent agreement between the two reconstruction methods. In the perfusion range up to 3.4 ml g⁻¹ min⁻¹, agreement between ¹³NH₃ perfusion obtained with OSEM and FBP was acceptable. The use of OSEM for measurement of perfusion values higher than 3.4 ml g⁻¹ min⁻¹ requires further evaluation.     

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     

Demonstration of disturbed free fatty acid metabolism of myocardium in patients with non-insulin-dependent diabetes mellitus as measured with iodine-123-heptadecanoic acid

Myocardial free fatty acid metabolism and left ventricular function were evaluated in 15 middle-aged patients with non-insulin-dependent diabetes mellitus (NIDDM) and in 8 healthy control subjects. The study subjects had no evidence of coronary heart disease on the basis of clinical history, exercise ECG or myocardial perfusion scintigraphy. During peak exercise, iodine-123 hepatadecanoic acid (HDA) was intravenously injected. Myocardial activity distribution of ¹²³I-HDA was measured 10, 30, and 50 min after exercise using single-photon emission tomography (SPET); and then further corrected by free ¹²³I-iodine. Venous blood samples were drawn for detecting the plasma activity of ¹²³I. The net extraction of ¹²³I-HDA into the myocardium was obtained by dividing the corrected tissue ¹²³I concentration by the integral of the plasma time activity curve. The net extraction was 0.40 ± 0.06 min^–1 (mean ± SD) patients with NIDDM and 0.38 ± 0.06 min^–1 in control subjects (P>0.1), respectively. The faster elimination rate of ¹²³I-HDA was found in patients with NIDDM (0.029±0.008 min^–1) than in control subjects (0.022±0.004 min^–1; P<0.01). There was no statistically significant difference in left ventricular ejection fraction (LVEF) at rest between patients with NIDDM (53±9%) and control subjects (56±2%), whereas the increase of LVEF during exercise remained lower in patients with NIDDM (3.4±8.2%) than in control subjects (11.8±5.8%; P<0.025). A significant correlation (r=0.64; P < 0.01) was found between the net extraction of ¹²³I-HDA and the change of LVEF, as well as with exercise load (r=0.68; P<0.01). In conclusion, evidence of an increased fatty acid utilization and triglyceride synthesis rate was observed in the diabetic myocardium. Offprint requests to: J.T. Kuikka     

Myocardial glucose utilisation in type II diabetes mellitus patients treated with sulphonylurea drugs

Purpose Chronic sulphonylurea treatment maintains improved glycaemic control through mechanisms other than enhancement of insulin secretion and may act on various organs. The aim of this study was to investigate whether the chronic use of sulphonylurea drugs influences PET measurement of myocardial glucose utilisation (MGU) in type II diabetes mellitus.Methods Forty-two patients with type II diabetes mellitus and 17 control subjects underwent dynamic ¹⁸F-FDG PET to measure MGU during hyperinsulinaemic euglycaemic clamping. Twenty-one patients had been taking sulphonylurea drugs for more than 1 year (SU group), and the other 21 patients were drug naive (non-SU group). The haemoglobin A1c levels in the two patient groups were similar. Glucose disposal rate (GDR) was also determined as a marker of whole-body insulin resistance.Results GDR in the SU group (9.01±2.53 mg min⁻¹ kg⁻¹) was significantly higher than that in the non-SU group (4.10±2.47, p<0.01) and was similar to that in the controls (9.76±2.97). MGU in the SU group (7.66±3.02 mg min⁻¹ 100 g⁻¹) was significantly higher than that in the non-SU group (5.53±2.05, p<0.01) and was similar to that in the controls (7.49±2.74).Conclusion Chronic sulphonylurea treatment influences MGU independent of the degree of glycaemic control. The effect of medication should be kept in mind when measuring and interpreting MGU in patients with type II diabetes mellitus.     

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.

     

Quantitative single-photon emission tomography for tumour blood flow measurement in bronchial carcinoma

A single-photon emission tomography (SPET) technique for the absolute measurement of tumour perfusion is described. Phantom studies have shown that source-background ratios are dependent upon source size and radial position within the phantom. A means of correcting source-background count ratios for these variables has been developed and used to correct tumour-lung ratios obtained in 28 patients with bronchial carcinomas who underwent technetium-99m hexamethyl-propylene amine oxime (^99mTc-HMPAO) SPET. On SPET images, the normal lung appears as a relatively homogeneous background. The relationship between ^99mTc background concentration (kBq/ml) and counts/pixel was determined from phantom studies and the tumour ^99mTc concentration from the background ^99mTc concentration and corrected tumour-lung ratio. The total activity of the lipophilic ^99mTc-HMPAO species injected was measured. The activity reaching the systemic circulation (A _sys) was obtained by subtracting the activity trapped in the pulmonary circulation (obtained from background ^99mTc concentration and lung volume). Tumour blood flow may then be calculated from fraction of A _sys contained in the tumour provided cardiac output and extraction fraction are known. Blood flow through the central region of tumours ranged from zero to 59.0 (mean 14.1) ml min^–1 100 g^–1 and through the whole tumour from 0.6 to 68.0 (mean 20.6) ml min^–1 100 g^–1.     

Comprehensive model for simultaneous MRI determination of perfusion and permeability using a blood-pool agent in rats rhabdomyosarcoma

To present a new compartmental analysis model developed to simultaneously measure tissue perfusion and capillary permeability in a tumor using MRI and a macromolecular contrast medium. Rhadomyosarcomas were implanted subcutaneously in 20 rats and studied by 1.5-T MRI using a fast gradient echo sequence (2D fast SPGR TR/TE/ 13 ms/1.2 ms/60°) after injection of a macromolecular contrast medium. The left ventricle and tumor signal intensities were converted into concentrations and modeled using compartmental analysis, yielding tumor perfusion F, distribution volume V_distribution, volume transfer constant K^trans, rate constant of influx k_pe, and initial extraction (fraction) E. Tumor perfusion was F=43±29 ml·min^–1·100 g^–1. The permeability study allowed the measurement of k_pe=0.37±0.12 min^–1 and K^trans=0.01±0.0031 min^–1. The blood volume could be assimilated to the distribution volume (V_distribution=2.9±1.01%) since the capillary leakage was small. The simultaneous assessment of perfusion and permeability allowed quantification of the initial extraction (fraction) E=2.34±1.05%. Quantification of both tumor perfusion and capillary leakage is feasible using MRI using a macromolecular blood pool agent. The method should improve tumor characterization.     

Dual-energy perfusion-CT of pancreatic adenocarcinoma

Purpose

To evaluate the feasibility of dual-energy CT (DECT)-perfusion of pancreatic carcinomas for assessing the differences in perfusion, permeability and blood volume of healthy pancreatic tissue and histopathologically confirmed solid pancreatic carcinoma.

Materials and methods

24 patients with histologically proven pancreatic carcinoma were examined prospectively with a 64-slice dual source CT using a dynamic sequence of 34 dual-energy (DE) acquisitions every 1.5 s (80 ml of iodinated contrast material, 370 mg/ml, flow rate 5 ml/s). 80 kV_p, 140 kV_p, and weighted average (linearly blended M0.3) 120 kV_p-equivalent dual-energy perfusion image data sets were evaluated with a body-perfusion CT tool (Body-PCT, Siemens Medical Solutions, Erlangen, Germany) for estimating perfusion, permeability, and blood volume values. Color-coded parameter maps were generated.

Results

In all 24 patients dual-energy CT-perfusion was. All carcinomas could be identified in the color-coded perfusion maps. Calculated perfusion, permeability and blood volume values were significantly lower in pancreatic carcinomas compared to healthy pancreatic tissue. Weighted average 120 kV_p-equivalent perfusion-, permeability- and blood volume-values determined from DE image data were 0.27 ± 0.04 min⁻¹ vs. 0.91 ± 0.04 min⁻¹ (p < 0.0001), 0.5 ± 0.07 *0.5 min⁻¹ vs. 0.67 ± 0.05 *0.5 min⁻¹ (p = 0.06) and 0.49 ± 0.07 min⁻¹ vs. 1.28 ± 0.11 min⁻¹ (p < 0.0001). Compared with 80 and 140 kV_p the standard deviations of the kV_p120 kV_p-equivalent values were manifestly smaller.

Conclusion

Dual-energy CT-perfusion of the pancreas is feasible. The use of DECT improves the accuracy of CT-perfusion of the pancreas by fully exploiting the advantages of enhanced iodine contrast at 80 kV_p in combination with the noise reduction at 140 kV_p. Therefore using dual-energy perfusion data could improve the delineation of pancreatic carcinomas.     

Assessment of myocardial perfusion by dynamic O-15-labeled water PET imaging: Validation of a new fast factor analysis

Background  Factor analysis (FA) is an established method for separating myocardium from blood pool by use of oxygen 15-labeled water and positron emission tomography for analyzing myocardial blood flow (MBF). Conventional FA methods generating images from sinograms (sinoFA) are time-consuming, whereas FA can be performed on the reconstructed images (reconFA) in a fraction of time. We validated the MBF values obtained by reconFA versus sinoFA. Methods and Results  In 23 volunteers (mean age, 26.6±3.4 years) MBF was calculated from sinoFA and reconFA and blindly reanalyzed 1 month later by the same observer. Intraobserver agreement and reconFA-versus-sinoFA agreement were assessed according to Bland and Altman (BA). Reproducibility proved excellent for global sinoFA (r=0.968; P<.001; BA limits, −0.617 to 0.676 mL·min⁻¹·g⁻¹) and slightly superior for reconFA (r=0.979; P<.001; BA limits, −0.538 to 0.558 mL·min⁻¹·g⁻¹), with wider limits of agreement for segmental MBF from sinoFA (r=0.777; P<.001; BA limits, −1.676 to 1.656 mL·min⁻¹·g⁻¹) and reconFA (r=0.844; P<.001; BA limits, −1.999 to 1.992 mL·min⁻¹·g⁻¹). In addition, sinoFA and reconFA showed excellent correlation (r=0.975, P<.001) and agreement (BA limits, −0.528 to 0.648 mL·min⁻¹·g⁻¹) for global and segmental values (r=0.955; P<.001; BA limits, −1.371 to 1.491 mL·min⁻¹·g⁻¹). Conclusions  Use of reconFA allows rapid and reliable quantitative MBF assessment with O-15-labeled water. This study was supported by a grant from the Swiss National Science Foundation (professorship grant PP00A-114706).     

The uptake of 3′-deoxy-3′-[18F]fluorothymidine into L5178Y tumours in vivo is dependent on thymidine kinase 1 protein levels

Purpose The aim of this study was to investigate the role of thymidine kinase 1 (TK₁) protein in 3-deoxy-3-[¹⁸F]fluorothymidine ([¹⁸F]FLT) positron emission tomography (PET) studies.Methods We investigated the in vivo kinetics of [¹⁸F]FLT in TK₁+/– and TK₁–/– L5178Y mouse lymphoma tumours that express different levels of TK₁ protein.Results [¹⁸F]FLT-derived radioactivity, measured by a dedicated small animal PET scanner, increased within the tumours over 60 min. The area under the normalised tumour time–activity curve were significantly higher for the TK₁+/– compared with the –/– variant (0.89±0.02 vs 0.79±0.03 MBq ml^–1 min, P=0.043; n=5 for each tumour type). Ex vivo gamma counting of tissues excised at 60 min p.i. (n=8) also revealed significantly higher tumour [¹⁸F]FLT uptake for the TK₁+/– variant (6.2±0.6 vs 4.6±0.4%ID g^–1, P=0.018). The observed differences between the cell lines with respect to [¹⁸F]FLT uptake were in keeping with a 48% higher TK₁ protein in the TK₁+/– tumours versus the –/– variant (P=0.043). On average, there were no differences in ATP levels between the two tumour variants (P=1.00). A positive correlation between [¹⁸F]FLT accumulation and TK₁ protein levels (r=0.68, P=0.046) was seen. Normalisation of the data for ATP content further improved the correlation (r=0.86, P=0.003).Conclusion This study shows that in vivo [¹⁸F]FLT kinetics depend on TK₁ protein expression. ATP may be important in realising this effect. Thus, [¹⁸F]FLT-PET has the potential to yield specific information on tumour proliferation in diagnostic imaging and therapy monitoring.