The relation between cardiac 123I-mIBG scintigraphy and functional response 1 year after CRT implantation.

AIMS: Cardiac resynchronization therapy (CRT) is a disease-modifying therapy in patients with chronic heart failure (CHF). Current guidelines ascribe CRT eligibility on three parameters only: left ventricular ejection fraction (LVEF), QRS duration, and New York Heart Association (NYHA) functional class. However, one-third of CHF patients does not benefit from CRT. This study evaluated whether 123I-meta-iodobenzylguanidine (123I-mIBG) assessed cardiac sympathetic activity could optimize CRT patient selection. METHODS AND RESULTS: A total of 78 stable CHF subjects (age 66.8 ± 9.6 years, 73% male, LVEF 25.2 ± 6.7%, QRS duration 153 ± 23 ms, NYHA 2.2 ± 0.7) referred for CRT implantation were enrolled. Subjects underwent 123I-mIBG scintigraphy prior to implantation. Early and late heart-to-mediastinum (H/M) ratio and 123I-mIBG washout were calculated. CRT response was defined as either an increase of LVEF to >35%, any improvement in LVEF of >10%, QRS shortening to <150 ms, or improvement in NYHA class of >1 class. In 33 patients LVEF increased to >35%, QRS decreased <150 ms in 36 patients, and NYHA class decreased in 33 patients. Late H/M ratio and hypertension were independent predictors of LVEF improvement to >35% (P = 0.0014 and P = 0.0149, respectively). In addition, early H/M ratio, LVEF, and absence of diabetes mellitus (DM) were independent predictors for LVEF improvement by >10%. No independent predictors were found for QRS shortening to <150 ms or improvement in NYHA class. CONCLUSION: Early and late H/M ratio were independent predictors of CRT response when improvement of LVEF was used as measure of response. Therefore, cardiac 123I-mIBG scintigraphy may be used as a tool to optimize selection of subjects that might benefit from CRT.

Suppression of myocardial glucose metabolism in FDG PET/CT: impact of dose variation in heparin bolus pre-administration.

INTRODUCTION: Adequate suppression of physiologic myocardial glucose uptake is important to ensure the interpretability and diagnostic reliability of [18F]fluorodeoxyglucose (FDG) PET/CT studies performed in the context of cardiac inflammation and infection. This study describes our experience with 4 preparatory protocols used in our institution. METHODS: FDG PET/CT scans were performed according to 4 preparatory protocols (716 scans total), i.e. 6-h fast (group 1), low-carbohydrate diet plus 12-h fast (group 2), low-carbohydrate diet plus 12-h fast plus intravenous heparin pre-administration (15 IU/kg) (group 3), and low-carbohydrate diet plus 12-h fast plus intravenous heparin pre-administration (50 IU/kg) (group 4). Consecutive scans were retrospectively included from time frames during which the particular protocol was used. FDG uptake in normal myocardium was scored on a scale ranging from 0 (uptake less than that in the left ventricular blood pool) to 4 (diffuse uptake greater than that in the liver). Complete suppression was defined as uptake less than or equal to the blood pool (scores 0-1). RESULTS: Complete suppression was accomplished in 27% in group 1, 68% in group 2, 69% in group 3 and 81% in group 4. Complete suppression was significantly lower in group 1 compared with all other groups (P < 0.0001 for all comparisons) and significantly higher in group 4 compared with group 2 (P = 0.005) and group 3 (P = 0.007). Groups 2 and 3 did not differ significantly (P = 0.92). CONCLUSION: A total of 50 IU/kg single-dose heparin administration before FDG PET/CT in addition to a low-carbohydrate diet and prolonged fast significantly outperformed protocols with no or lower dose (15 IU/kg) heparin in completely suppressing myocardial glucose metabolism.

Differential metabolic effects of oral butyrate treatment in lean versus metabolic syndrome subjects.

BACKGROUND: Gut microbiota-derived short-chain fatty acids (SCFAs) have been associated with beneficial metabolic effects. However, the direct effect of oral butyrate on metabolic parameters in humans has never been studied. In this first in men pilot study, we thus treated both lean and metabolic syndrome male subjects with oral sodium butyrate and investigated the effect on metabolism. METHODS: Healthy lean males (n = 9) and metabolic syndrome males (n = 10) were treated with oral 4 g of sodium butyrate daily for 4 weeks. Before and after treatment, insulin sensitivity was determined by a two-step hyperinsulinemic euglycemic clamp using [6,6-2H2]-glucose. Brown adipose tissue (BAT) uptake of glucose was visualized using 18F-FDG PET-CT. Fecal SCFA and bile acid concentrations as well as microbiota composition were determined before and after treatment. RESULTS: Oral butyrate had no effect on plasma and fecal butyrate levels after treatment, but did alter other SCFAs in both plasma and feces. Moreover, only in healthy lean subjects a significant improvement was observed in both peripheral (median Rd: from 71 to 82 µmol/kg min, p < 0.05) and hepatic insulin sensitivity (EGP suppression from 75 to 82% p < 0.05). Although BAT activity was significantly higher at baseline in lean (SUVmax: 12.4 ± 1.8) compared with metabolic syndrome subjects (SUVmax: 0.3 ± 0.8, p < 0.01), no significant effect following butyrate treatment on BAT was observed in either group (SUVmax lean to 13.3 ± 2.4 versus metabolic syndrome subjects to 1.2 ± 4.1). CONCLUSIONS: Oral butyrate treatment beneficially affects glucose metabolism in lean but not metabolic syndrome subjects, presumably due to an altered SCFA handling in insulin-resistant subjects. Although preliminary, these first in men findings argue against oral butyrate supplementation as treatment for glucose regulation in human subjects with type 2 diabetes mellitus.

Dual-time-point FDG PET/CT imaging in prosthetic heart valve endocarditis.

PURPOSE: FDG PET/CT has been of increasing interest in the diagnostic workup of prosthetic heart valve endocarditis (PVE). Some reports advocate later imaging time points to improve the diagnostic accuracy for PVE. In this study, we compared standard and late FDG PET/CT images in patients with a clinical suspicion of PVE. MATERIALS AND METHODS: Fourteen scans in 13 patients referred for FDG PET/CT for suspicion of PVE performed at standard (60 min post injection) and late (150 min post injection) time points were scored based on visual interpretation and semi-quantitatively with SUVmax and target-to-background ratio (TBR, defined as [SUVmax valve/SUVmean blood pool]). Final diagnosis was based on surgical findings in all cases of infection (n = 6) and unremarkable follow-up in all others (n = 8). RESULTS: Late images were more prone to false positive interpretation for both visual and semi-quantitative analyses. Visual analysis of the standard images yielded 1 false negative and 1 false positive result. On the late images, no scans were false negative but 5 scans were false positive. CONCLUSION: Late FDG PET/CT imaging for PVE seems prone to false positive results. Therefore, late imaging should be interpreted with caution.

Bromocriptine and insulin sensitivity in lean and obese subjects.

Bromocriptine is a glucose-lowering drug, which was shown to be effective in obese subjects with insulin resistance. It is usually administered in the morning. The exact working mechanism of bromocriptine still has to be elucidated. Therefore, in this open-label randomized prospective cross-over mechanistic study, we assessed whether the timing of bromocriptine administration (morning vs evening) results in different effects and whether these effects differ between lean and obese subjects. We studied the effect of bromocriptine on insulin sensitivity in 8 lean and 8 overweight subjects using an oral glucose tolerance test. The subjects used bromocriptine in randomized cross-over order for 2 weeks in the morning and 2 weeks in the evening. We found that in lean subjects, bromocriptine administration in the evening resulted in a significantly higher post-prandial insulin sensitivity as compared with the pre-exposure visit (glucose area under the curve (AUC) 742 mmol/L * 120 min (695-818) vs 641 (504-750), P = 0.036, AUC for insulin did not change, P = 0.575). In obese subjects, both morning and evening administration of bromocriptine resulted in a significantly higher insulin sensitivity: morning administration in obese: insulin AUC (55,900 mmol/L * 120 min (43,236-96,831) vs 36,448 (25,213-57,711), P = 0.012) and glucose AUC P = 0.069; evening administration in obese: glucose AUC (735 mmol/L * 120 min (614-988) vs 644 (568-829), P = 0.017) and insulin AUC, P = 0.208. In conclusion, bromocriptine increases insulin sensitivity in both lean and obese subjects. In lean subjects, this effect only occurred when bromocriptine was administrated in the evening, whereas in the obese, insulin sensitivity increased independent of the timing of bromocriptine administration.

Cardiac sympathetic activity in chronic heart failure: cardiac 123I-mIBG scintigraphy to improve patient selection for ICD implantation.

Heart failure is a life-threatening disease with a growing incidence in the Netherlands. This growing incidence is related to increased life expectancy, improvement of survival after myocardial infarction and better treatment options for heart failure. As a consequence, the costs related to heart failure care will increase. Despite huge improvements in treatment, the prognosis remains unfavourable with high one-year mortality rates. The introduction of implantable devices such as implantable cardioverter defibrillators (ICD) and cardiac resynchronisation therapy (CRT) has improved the overall survival of patients with chronic heart failure. However, after ICD implantation for primary prevention in heart failure a high percentage of patients never have appropriate ICD discharges. In addition 25-50 % of CRT patients have no therapeutic effect. Moreover, both ICDs and CRTs are associated with malfunction and complications (e. g. inappropriate shocks, infection). Last but not least is the relatively high cost of these devices. Therefore, it is essential, not only from a clinical but also from a socioeconomic point of view, to optimise the current selection criteria for ICD and CRT. This review focusses on the role of cardiac sympathetic hyperactivity in optimising ICD selection criteria. Cardiac sympathetic hyperactivity is related to fatal arrhythmias and can be non-invasively assessed with 123I-meta-iodobenzylguanide (123I-mIBG) scintigraphy. We conclude that cardiac sympathetic activity assessed with 123I-mIBG scintigraphy is a promising tool to better identify patients who will benefit from ICD implantation.

Role of the autonomic nervous system in activation of human brown adipose tissue: A review of the literature.

Brown adipose tissue (BAT) is able to convert calories into heat rather than storing them. Therefore, activated BAT could be a potential target in the battle against obesity and type 2 diabetes. This review focuses on the role of the autonomic nervous system in the activation of human BAT. Although the number of studies focusing on BAT in humans is limited, involvement of the sympathetic nervous system (SNS) in BAT activation is evident. Metabolic BAT activity can be visualized with (18)F-fluorodeoxyglucose, whereas sympathetic activation of BAT can be visualized with nuclear-medicine techniques using different radiopharmaceuticals. Also, interruption of the sympathetic nerves leading to BAT activation diminishes sympathetic stimulation, resulting in reduced metabolic BAT activity. Furthermore, both ß- and α-adrenoceptors might be important in the stimulation process of BAT, as pretreatment with propranolol or α-adrenoceptor blockade also diminishes BAT activity. In contrast, high catecholamine levels are known to activate and recruit BAT. There are several interventional studies in which BAT was successfully inhibited, whereas only one interventional study aiming to activate BAT resulted in the intended outcome. Most studies have focused on the SNS for activating BAT, although the parasympathetic nervous system might also be a target of interest. To better define the possible role of BAT in strategies to combat the obesity epidemic, it seems likely that future studies focusing on both histology and imaging are essential for identifying the factors and receptors critical for activation of human BAT.

¹8F-FDG PET/CT in inflammation of unknown origin: a cost-effectiveness pilot-study.

PURPOSE: Patients with increased inflammatory parameters, nonspecific signs and symptoms without fever and without a diagnosis after a variety of diagnostic procedures are a diagnostic dilemma and are referred to as having inflammation of unknown origin (IUO). The objective of this pilot study was to compare the cost-effectiveness of a diagnostic work-up/strategy with and without (18)F-FDG PET/CT in patients with IUO using a published dataset as a reference. METHODS: IUO patients without (18)F-FDG PET/CT (group A, 46 patients) and IUO patients referred for (18)F-FDG PET/CT (group B, 46 patients) were selected. IUO was defined as the combination of nonspecific signs and symptoms and a prolonged erythrocyte sedimentation rate (ESR), defined as ≥age/2 in men and ≥(age + 10)/2 in women (ESR in millimetres per hour and age in years), and/or C-reactive protein (CRP) ≥15 mg/l. The costs of all tests and procedures and the number of hospitalization days in each patient to reach a diagnosis were calculated using current Dutch tariffs. RESULTS: In group A a diagnosis was reached in 14 of the 46 patients. The mean cost per patient of all the diagnostic procedures was 2,051, and including the cost of hospitalization was 12,614. In group B a diagnosis was reached in 32 of the 46 patients. The mean cost per patient of all the diagnostic procedures was 1,821, significantly lower than in group A (p < 0.0002), and including the cost of hospitalization was 5,298. CONCLUSION: In IUO (18)F-FDG PET/CT has the potential to become a cost-effective routine imaging technique indicating the direction for further diagnostic decisions thereby allowing unnecessary, invasive and expensive diagnostic investigations to be avoided and possibly the duration of hospitalization to be reduced. However, a prospective multicentre "bottom-up microcosting" cost-effectiveness study is warranted before these preliminary data can be extrapolated to clinical practice.

The role of 18F-FDG PET/CT in large-vessel vasculitis: appropriateness of current classification criteria?

Patients with clinical suspicion of large-vessel vasculitis (LVV) may present with nonspecific signs and symptoms and increased inflammatory parameters and may remain without diagnosis after routine diagnostic procedures. Both the nonspecificity of the radiopharmaceutical (18)F-FDG and the synergy of integrating functional and anatomical images with PET/CT offer substantial benefit in the diagnostic work-up of patients with clinical suspicion for LVV. A negative temporal artery biopsy, an ultrasonography without an arterial halo, or a MRI without aortic wall thickening or oedema do not exclude the presence of LVV and should therefore not exclude the use of (18)F-FDG PET/CT when LVV is clinically suspected. This overview further discusses the notion that there is substantial underdiagnosis of LVV. Late diagnosis of LVV may lead to surgery or angioplasty in occlusive forms and is often accompanied by serious aortic complications and a fatal outcome. In contrast to the American College of Rheumatology 1990 criteria for vasculitis, based on late LVV effects like arterial stenosis and/or occlusion, (18)F-FDG PET/CT sheds new light on the classification of giant cell arteritis (GCA) and Takayasu arteritis (TA). The combination of these observations makes the role of (18)F-FDG PET/CT in the assessment of patients suspected for having LVV promising.

Cardiac sympathetic innervation and cardiac resynchronization therapy.

Cardiac resynchronization therapy (CRT) is a disease modifying, device-driven treatment that can reduce morbidity and mortality in patients with heart failure. According to the current guidelines, the indication for CRT is only based on QRS duration and functional class of heart failure. However, a substantial amount of patients do not respond to therapy. In addition, CRT is accompanied by significant cost and potential morbidity. It is therefore vital to improve patient selection for CRT to improve patient outcome and minimize therapy-related complications. In this regard, cardiac sympathetic innervation may be of interest. This review addresses the currently available literature, 9 studies with a total number of 225 patients, on CRT and cardiac innervation scintigraphy with (123)I-metaiodobenzylguanidine.

Cold-induced activity of brown adipose tissue in young lean men of South-Asian and European origin.

AIMS/HYPOTHESIS: South Asians have a disproportionately high risk of developing abdominal obesity, insulin resistance and type 2 diabetes. Brown adipose tissue (BAT) has been identified as a possible target to fight obesity and protect against metabolic disturbance. We explored whether lower BAT activity in South Asians compared with Europids may contribute to the high risk of metabolic disturbance. METHODS: We studied 20 healthy men (ten Europids/ten South Asians, BMI 19-25 kg/m(2), age 18-32 years). Following 2 h of cold exposure (16-18°C) after an overnight fast, (18)F-fluorodeoxyglucose ((18)F-FDG) positron-emission tomography-computed tomography (CT) and (123)I-metaiodobenzylguanidine ((123)I-MIBG) single-photon emission computed tomography-CT were performed to visualise metabolic BAT activity and sympathetic stimulation of BAT. Metabolic BAT activity was defined as maximal standardised uptake value (SUV(max)) of (18)F-FDG, and sympathetic stimulation of BAT as semiquantitative uptake value (SQUV) of (123)I-MIBG. We performed hyperinsulinaemic-euglycaemic clamps to assess insulin sensitivity. Spearman's correlations for SUV(max) of (18)F-FDG and both SQUV of (123)I-MIBG and insulin sensitivity were determined. RESULTS: The median (interquartile range) SUV(max) of (18)F-FDG in South Asians (7.5 [2.2-10.6] g/ml) was not different from the median SUV(max) obtained in Europids (4.5 [2.2-8.4] g/ml; p = 0.59). There was no correlation between BAT activity and insulin sensitivity. Correlations between SQUV of (123)I-MIBG and SUV(max) of (18)F-FDG were positive, both in the total population (ρ = 0.80, p < 0.001) and after stratification by ethnicity (Europids, ρ = 0.65, p = 0.04; South Asians, ρ = 0.83, p = 0.01). CONCLUSIONS/INTERPRETATION: This is the first study to prospectively investigate ethnic differences in metabolic BAT activity during cold exposure. We did not find differences in BAT activity between South Asians and Europids. Therefore, it seems unlikely that BAT plays an important role in the development of unfavourable metabolic profiles in South Asians.

Early recognition of aortitis of the aorta ascendens with ¹8F-FDG PET/CT: syphilitic?

We present the case of a 42-year-old woman known with a human leukocyte antigen B27 positive ankylosing spondylitis. Despite treatment with a tumor necrosis factor blocking agent, the patient was not pain free and inflammation markers remained elevated. An (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) was performed in an attempt to exclude possible other inflammatory processes. The (18)F-FDG PET/CT revealed increased metabolic activity in the ascending aortic wall, which appeared unexpectedly related to late syphilis. Based on this case and existing literature on this subject, we come to the conclusion that (18)F-FDG PET/CT can help in an early establishment of syphilitic aortitis before the possible life-threatening sequelae of syphilitic aortitis occur.

The role of molecular imaging in the differential diagnosis of parkinsonism.

This review focuses on the possibilities to use scintigraphic techniques to help differentiate neurodegenerative brain diseases associated with parkinsonian features. In particular, the findings of dopaminergic imaging, FDG PET imaging, and cardiac sympathetic imaging are described. Considerable overlap in individual data on striatal postsynaptic D2/3 binding and presynaptic DAT binding/DOPA uptake exists between different parkinsonian syndromes, which may hamper its role as the sole imaging technique to differentiate PD from other parkinsonian syndromes. The results of recent studies suggested, however, that the combination of pre- and postsynaptic dopaminergic imaging may gain further insight in the pathophysiological mechanisms in patients with parkinsonian features. Also, most of the commonly used DAT tracers bind not only to striatal DATs, but to serotonin transporters in extrastriatal brain areas as well. Preliminary studies suggest that this additional information may be helpful to increase the accuracy to differentiate between patients with parkinsonian features. Finally, both brain [18F]FDG PET and cardiac sympathetic imaging are very promising tools to differentiate different parkinsonian syndromes from each other in routine clinical studies.

A Rationale for the Use of F18-FDG PET/CT in Fever and Inflammation of Unknown Origin.

This review focuses on the diagnostic value of hybrid F18-FDG Positron Emission Tomography/Computerized tomography (PET/CT) in fever of unknown origin (FUO) and inflammation of unknown origin (IUO). Due to the wide range of possible causes both FUO and IUO remain a clinical challenge for both patients and physicians. In addition, the aetiology of IUO shows the same variation in diseases as the FUO spectrum and probably requires the same diagnostic approach as FUO. There are numerous historically used diagnostic approaches incorporating invasive and non-invasive, and imaging techniques, all with relative high specificity but limited sensitivity. This hampers the generalization of these diagnostic approaches. However, recently published reports show that F18-FDG PET/CT in FUO and IUO has a high sensitivity and a relative non-specificity for malignancy, infection and inflammation. This makes F18-FDG PET/CT an ideal diagnostic tool to start the diagnostic process and to guide subsequent focused diagnostic approaches with higher specificity. In addition, F18-FDG PET/CT has a relative high negative predictive value. Therefore F18 FDG PET/CT should be incorporated in the routine diagnostic work-up of patients with FUO and IUO, preferably at an early stage in the diagnostic process.