Håkan Ahlström

MR-IMPACT: comparison of perfusion-cardiac magnetic resonance with single-photon emission computed tomography for the detection of coronary artery disease in a multicentre, multivendor, randomized trial.

AIMS To determine in a multicentre, multivendor trial the diagnostic performance for perfusion-cardiac magnetic resonance (perfusion-CMR) in comparison with coronary X-ray angiography (CXA) and single-photon emission computed tomography (SPECT). METHODS AND RESULTS Of 241 eligible patients from 18 centres, 234 were randomly dosed with 0.01, 0.025, 0.05, 0.075, or 0.1 mmol/kg Gd-DTPA-BMA (Omniscantrade mark, GE-Healthcare) per stress (0.42 mg/kg adenosine) and rest perfusion study. Coronary artery disease (CAD) was defined as diameter stenosis > or =50% on quantitative CXA. Five CMR and eight SPECT studies (of 225 complete studies) were excluded from analyses due to inadequate quality (three blinded readers scored per modality). The comparison of CMR vs. SPECT was based on receiver operating characteristic (ROC) analysis. Perfusion-CMR at the optimal CM dose (0.1 mmol/kg) had similar performance as SPECT, if only the SPECT studies of the 42 patients with this dose were considered [area under ROC curve (AUC): 0.86 +/- 0.06 vs. 0.75 +/- 0.09 for SPECT, P = 0.12]; however, diagnostic performance of perfusion-CMR was better vs. the entire SPECT population (AUC: 0.67 +/- 0.05, n = 212, P = 0.013). CONCLUSIONS In this multicentre, multivendor trial, ROC analyses suggest perfusion-CMR as a valuable alternative to SPECT for CAD detection showing equal performance in the head-to-head comparison. Comparing perfusion-CMR with the entire SPECT population suggests CMR superiority over SPECT, which warrants further evaluation in larger trials.

Positron emission tomography studies in patients with locally advanced and/or metastatic breast cancer: a method for early therapy evaluation?

PURPOSE To investigate if sequential positron emission tomographic (PET) scans with the glucose analog 18F-2-fluoro-2-deoxy-D-glucose (18FDG) and/or L-methyl-11C-methionine (11C-methionine) in patients with breast cancer could provide early information on the efficacy of polychemotherapy. PATIENTS AND METHODS Sixteen patients with breast cancer (11 with locally advanced tumors, three with recurrent disease in the contralateral breast, two of them with distant and regional metastases, and two with distant metastases) underwent a baseline and two follow-up PET scans after the first and third/fourth polychemotherapy course. Tumor response was determined clinically/radiographically after three/four polychemotherapy courses. RESULTS Five patients were investigated with 18FDG, seven with both 11C-methionine and 18FDG, and four with only 11C-methionine before polychemotherapy. 11C-methionine presented a more distinct visualization of primary/contralateral breast cancers in five of seven patients when compared with 18FDG. Twelve of 16 patients demonstrated a response using conventional methods after the third/fourth course of polychemotherapy. Eight of these 12 clinical responders had a significant decrease in tracer uptake at the first PET scan performed 6 to 13 days after the first polychemotherapy course, and these reductions were further augmented after the third/fourth course and corresponded to the conventional therapy evaluation (clinical examination, computed tomography [CT], ultrasonography, and mammography). CONCLUSION Our data indicate that PET may be of clinical value in predicting response to chemotherapy in patients with locally advanced breast cancer and/or metastatic disease earlier than any other method used.

Effects of n−6 PUFAs compared with SFAs on liver fat, lipoproteins, and inflammation in abdominal obesity: a randomized controlled trial

BACKGROUND Replacing SFAs with vegetable PUFAs has cardiometabolic benefits, but the effects on liver fat are unknown. Increased dietary n-6 PUFAs have, however, also been proposed to promote inflammation-a yet unproven theory. OBJECTIVE We investigated the effects of PUFAs on liver fat, systemic inflammation, and metabolic disorders. DESIGN We randomly assigned 67 abdominally obese subjects (15% had type 2 diabetes) to a 10-wk isocaloric diet high in vegetable n-6 PUFA (PUFA diet) or SFA mainly from butter (SFA diet), without altering the macronutrient intake. Liver fat was assessed by MRI and magnetic resonance proton (1H) spectroscopy (MRS). Proprotein convertase subtilisin/kexin type-9 (PCSK9, a hepatic LDL-receptor regulator), inflammation, and adipose tissue expression of inflammatory and lipogenic genes were determined. RESULTS A total of 61 subjects completed the study. Body weight modestly increased but was not different between groups. Liver fat was lower during the PUFA diet than during the SFA diet [between-group difference in relative change from baseline; 16% (MRI; P < 0.001), 34% (MRS; P = 0.02)]. PCSK9 (P = 0.001), TNF receptor-2 (P < 0.01), and IL-1 receptor antagonist (P = 0.02) concentrations were lower during the PUFA diet, whereas insulin (P = 0.06) tended to be higher during the SFA diet. In compliant subjects (defined as change in serum linoleic acid), insulin, total/HDL-cholesterol ratio, LDL cholesterol, and triglycerides were lower during the PUFA diet than during the SFA diet (P < 0.05). Adipose tissue gene expression was unchanged. CONCLUSIONS Compared with SFA intake, n-6 PUFAs reduce liver fat and modestly improve metabolic status, without weight loss. A high n-6 PUFA intake does not cause any signs of inflammation or oxidative stress. Downregulation of PCSK9 could be a novel mechanism behind the cholesterol-lowering effects of PUFAs. This trial was registered at clinicaltrials.gov as NCT01038102.

MR-IMPACT II: Magnetic Resonance Imaging for Myocardial Perfusion Assessment in Coronary artery disease Trial: perfusion-cardiac magnetic resonance vs. single-photon emission computed tomography for the detection of coronary artery disease: a comparative multicentre, multivendor trial

AIMS Perfusion-cardiac magnetic resonance (CMR) has emerged as a potential alternative to single-photon emission computed tomography (SPECT) to assess myocardial ischaemia non-invasively. The goal was to compare the diagnostic performance of perfusion-CMR and SPECT for the detection of coronary artery disease (CAD) using conventional X-ray coronary angiography (CXA) as the reference standard. METHODS AND RESULTS In this multivendor trial, 533 patients, eligible for CXA or SPECT, were enrolled in 33 centres (USA and Europe) with 515 patients receiving MR contrast medium. Single-photon emission computed tomography and CXA were performed within 4 weeks before or after CMR in all patients. The prevalence of CAD in the sample was 49%. Drop-out rates for CMR and SPECT were 5.6 and 3.7%, respectively (P = 0.21). The primary endpoint was non-inferiority of CMR vs. SPECT for both sensitivity and specificity for the detection of CAD. Readers were blinded vs. clinical data, CXA, and imaging results. As a secondary endpoint, the safety profile of the CMR examination was evaluated. For CMR and SPECT, the sensitivity scores were 0.67 and 0.59, respectively, with the lower confidence level for the difference of +0.02, indicating superiority of CMR over SPECT. The specificity scores for CMR and SPECT were 0.61 and 0.72, respectively (lower confidence level for the difference: -0.17), indicating inferiority of CMR vs. SPECT. No severe adverse events occurred in the 515 patients. CONCLUSION In this large multicentre, multivendor study, the sensitivity of perfusion-CMR to detect CAD was superior to SPECT, while its specificity was inferior to SPECT. Cardiac magnetic resonance is a safe alternative to SPECT to detect perfusion deficits in CAD.

Relationship between circulating FGF23 and total body atherosclerosis in the community

BACKGROUND Fibroblast growth factor-23 (FGF23) is a regulator of mineral metabolism and has been suggested to play a role in vascular calcification in chronic kidney disease (CKD). Data on the association between FGF23 and atherosclerosis, both in CKD and in the community, is limited. METHODS The total body atherosclerosis score (AS) was determined by a magnetic resonance imaging-based angiography in 306 elderly men and women, representing a subsample of the community-based PIVUS cohort. Subjects were divided into three categories based on AS: AS = 0, low AS and high AS. Serum FGF23 was measured using a two-site monoclonal antibody ELISA. RESULTS In continuous and multi-category regression models, higher FGF23 was associated with a significant increase in the odds of having a high AS (OR 1.43, CI 1.06-1.92 to OR 3.01, CI 1.52-5.99). This association was stronger in individuals with eGFR <60 mL/min/1.73 m(2) (n = 27), reaching a nearly 6-fold increase in the odds for a high AS in the upper FGF23 tertile (OR 5.64, CI 2.78-11.5). We found weaker support for a relationship between FGF23 and the presence of atherosclerosis as subjects in the highest FGF23 tertile had an increased risk for an AS > 0 in crude models (OR 1.93, CI 1.05-3.55), but this was not statistically significant in adjusted (OR 1.42, CI 0.74-1.72) models. CONCLUSIONS We provide novel evidence supporting an association between serum FGF23 and total body atherosclerosis in the community. Additional studies are warranted to determine the prospective relationship between FGF23 and atherosclerosis, and whether FGF23 is a modifiable cardiovascular risk factor.

Prevalence and pathophysiological mechanisms of elevated cardiac troponin I levels in a population-based sample of elderly subjects

AIMS To evaluate the prevalence of cardiac troponin I (cTnI) elevation in an elderly community population and the association of cTnI levels with cardiovascular risk factors, vascular inflammation, atherosclerosis, cardiac performance, and areas indicative of infarcted myocardium identified by cardiac magnetic resonance imaging. METHODS AND RESULTS cTnI elevation defined as cTnI levels >0.01 microg/L (Access AccuTnI, Beckman Coulter) was found in 21.8% of the study participants (n = 1005). cTnI > 0.01 microg/L was associated with cardiovascular high-risk features, the burden of atherosclerosis in the carotid arteries, left-ventricular mass, and impaired left-ventricular systolic function. No associations were found between cTnI and inflammatory activity, diastolic dysfunction, or myocardial scars. Male gender (OR 1.6; 95% CI 1.1-2.4), ischaemic ECG changes (OR 1.7; 95% CI 1.1-2.7), and NT-pro-brain natriuretic peptide levels (OR 1.4; 95% CI 1.1-1.7) independently predicted cTnI > 0.01 microg/L. cTnI > 0.01 microg/L correlated also to an increased cardiovascular risk according to the Framingham risk score. CONCLUSION cTnI > 0.01 microg/L is relatively common in elderly subjects and is associated with cardiovascular high-risk features and impaired cardiac performance. Cardiac troponin determined by a highly sensitive assay might thus serve as an instrument for the identification of subjects at high cardiovascular risk in general populations.

Positron emission tomography with 5-hydroxytryprophan in neuroendocrine tumors.

PURPOSE Carcinoid tumors, especially those of midgut origin, produce serotonin via the precursors tryptophan and 5-hydroxytryptophan (5-HTP). We have evaluated the usefulness of positron emission tomography (PET) with carbon-11-labeled 5-HTP in the diagnosis and treatment follow-up evaluation of patients with neuroendocrine tumors. PATIENTS AND METHODS PET using 11C-labeled 5-HTP was compared with computed tomography (CT) in 18 patients (14 midgut, one foregut, one hindgut carcinoid, and two endocrine pancreatic tumors [EPT]). In addition, 10 of 18 patients were monitored with PET examinations during treatment. RESULTS All 18 patients, including two with normal urinary 5-hydroxyindole acetic acid (U-5-HIAA), had increased uptake of 11C-labeled 5-HTP in tumorous tissue as compared with normal tissue. Liver metastases, as well as lymph node, pleural, and skeletal metastases, showed enhanced 5-HTP uptake and PET could detect more lesions than CT in 10 patients and equal numbers in the others. Tumor visibility was better for PET than for CT due to the high and selective uptake of 5-HTP with a high tumor-to-background ratio. Binding studies indicated an irreversible trapping of 5-HTP in the tumors. Linear regression analyses showed a clear correlation (r = .907) between changes in U-5-HIAA and changes in the transport rate constant for 5-HTP during treatment. CONCLUSION PET with 11C-labeled 5-HTP demonstrated high uptake in neuroendocrine gastrointestinal tumors and thereby allowed improved visualization compared with CT. The in vivo data on regional tumor metabolism, as expressed in 11C-5-HTP uptake and transport rate, provided additional information over conventional radiologic techniques. The close correlation between the changes in 11C-5-HTP transport rate and U-HIAA during medical treatment indicates the potential of 11C-5-HTP-PET as a means to monitor therapy.

Octreotide and interferon alfa: A new combination for the treatment of malignant carcinoid tumours

24 patients with malignant carcinoid tumours received octreotide and interferon alfa (IFN-alpha). All the patients initially received octreotide 50-100 micrograms, twice daily. When progressive symptoms or increasing biochemical markers were observed, the daily dose was raised to a median 300 micrograms. If the initial dose proved ineffective or if no improvement was seen after escalation, IFN-alpha was added (median 9 MU subcutaneously per week). After the addition of IFN-alpha, 17 of the 22 patients (77%) with elevated urinary 5-hydroxyindoleacetic acid showed a significant (> 50%) reduction. Only 1 patient progressed and 4 had continuously stable biochemical disease. No significant reduction in tumour size was noted; in 5 patients, the tumour continued to grow despite decreasing hormone levels. 18 patients had carcinoid syndrome when IFN-alpha was added in 10 (56%) symptoms ameliorated. Thus, the addition of IFN-alpha is beneficial for patients with malignant carcinoid tumours that progress and/or who do not respond to octreotide.

Overfeeding Polyunsaturated and Saturated Fat Causes Distinct Effects on Liver and Visceral Fat Accumulation in Humans

Excess ectopic fat storage is linked to type 2 diabetes. The importance of dietary fat composition for ectopic fat storage in humans is unknown. We investigated liver fat accumulation and body composition during overfeeding saturated fatty acids (SFAs) or polyunsaturated fatty acids (PUFAs). LIPOGAIN was a double-blind, parallel-group, randomized trial. Thirty-nine young and normal-weight individuals were overfed muffins high in SFAs (palm oil) or n-6 PUFAs (sunflower oil) for 7 weeks. Liver fat, visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (SAT), total adipose tissue, pancreatic fat, and lean tissue were assessed by magnetic resonance imaging. Transcriptomics were performed in SAT. Both groups gained similar weight. SFAs, however, markedly increased liver fat compared with PUFAs and caused a twofold larger increase in VAT than PUFAs. Conversely, PUFAs caused a nearly threefold larger increase in lean tissue than SFAs. Increase in liver fat directly correlated with changes in plasma SFAs and inversely with PUFAs. Genes involved in regulating energy dissipation, insulin resistance, body composition, and fat-cell differentiation in SAT were differentially regulated between diets, and associated with increased PUFAs in SAT. In conclusion, overeating SFAs promotes hepatic and visceral fat storage, whereas excess energy from PUFAs may instead promote lean tissue in healthy humans.

Clinical and Experimental Pancreatic Islet Transplantation to Striated Muscle: Establishment of a Vascular System Similar to that in Native Islets

OBJECTIVE Curing type 1 diabetes by transplanting pancreatic islets into the liver is associated with poor long-term outcome and graft failure at least partly due to inadequate graft revascularization. The aim of the current study was to evaluate striated muscle as a potential angiogenic site for islet transplantation. RESEARCH DESIGN AND METHODS The current study presents a new experimental model that is found to be applicable to clinical islet transplantation. Islets were implanted into striated muscle and intraislet vascular density and blood flow were visualized with intravital and confocal microscopy in mice and by magnetic resonance imaging in three autotransplanted pancreatectomized patients. Mice were rendered neutropenic by repeated injections of Gr-1 antibody, and diabetes was induced by alloxan treatment. RESULTS Contrary to liver-engrafted islets, islets transplanted to mouse muscle were revascularized with vessel densities and blood flow entirely comparable with those of islets within intact pancreas. Initiation of islet revascularization at the muscular site was dependent on neutrophils, and the function of islets transplanted to muscle was proven by curing diabetic mice. The experimental data were confirmed in autotransplanted patients where higher plasma volumes were measured in islets engrafted in forearm muscle compared with adjacent muscle tissue through high-resolution magnetic resonance imaging. CONCLUSIONS This study presents a novel paradigm in islet transplantation whereby recruited neutrophils are crucial for the functionally restored intraislet blood perfusion following transplantation to striated muscle under experimental and clinical situations.