Conventional and novel cardiovascular risk factors in young Finns and their associations with structural and functional vascular changes of subclinical atherosclerosis. The Cardiovascular Risk in Young Finns Study

Background: Atherosclerosis begins in early life progressing from asymptomatic to symptomatic as we age. Although substantial progress has been made in identifying the determinants of atherosclerosis in middle to older age adults at increased cardiovascular risk, there is lack of data examining determinants and prediction of atherosclerosis in young adults. Aims: The current study was designed to investigate levels of cardiovascular risk factors in young adults, subclinical measures of atherosclerosis, and prediction of subclinical arterial changes with conventional risk factor measures and novel metabolic profiling of serum samples. Subjects and Methods: This thesis utilised data from the follow-ups performed in 2001 and 2007 in the Cardiovascular Risk in Young Finns study, a Finnish population-based prospective cohort study that examined 2,204 subjects who were aged 30-45 years in 2007. Subclinical atherosclerosis was studied using noninvasive ultrasound measurements of carotid intima-media thickness (IMT), carotid arterial distensibility (CDist) and brachial flow-mediated dilation (FMD). Measurements included conventional risk factors and metabolic profiling using highthroughput nuclear magnetic resonance (NMR) methods that provided data on 42 lipid markers and 16 circulating metabolites. Results: Trends in lipids were favourable between 2001 and 2007, whereas waist circumference, fasting glucose, and blood pressure levels increased. To study the stability of noninvasive ultrasound markers, 6-year tracking (the likelihood to maintain the original fractile over time) in 6 years was examined. IMT tracked more strongly than CDist and FMD. Cardiovascular risk scores (Framingham, SCORE, Finrisk, Reynolds and PROCAM) predicted subclinical atherosclerosis equally. Lipoprotein subclass testing did not improve the prediction of subclinical atherosclerosis over and above conventional risk factors. However, circulating metabolites improved risk stratification. Tyrosine and docosahexaenoic acid were found to be novel biomarkers of high IMT. Conclusions: Prediction of cardiovascular risk in young Finnish adults can be performed with any of the existing risk scores. The addition of metabonomics to risk stratification improves prediction of subclinical changes and enables more accurate targeting of prevention at an early stage.Perinteiset ja uudet sydän- ja verisuonitautien riskitekijät nuorilla suomalaisilla ja niiden yhteydet rakenteellisiin ja toiminnallisiin varhaisiin ateroskleroottisiin valtimomuutoksiin. Lasten Sepelvaltimotaudin Riskitekijät -projekti. Tausta: Ateroskleroosin kehittyminen alkaa varhain ja kehittyy ikaantymisen myota oireettomasta sairaudesta oireelliseksi. Vaikka ateroskleroosin mittausmenetelmat ja kohonneessa sydan- ja verisuonitautiriskissa olevien keski-ikaisten ja vanhempien ihmisten tunnistaminen ovat kehittyneet huomattavasti, nuorten aikuisten sydan- ja verisuonitautiriskin maarittamista ja varhaisen ateroskleroosin ennustamista on tutkittu vain vahan. Tavoitteet: Tutkimuksessa selvitettiin sydan- ja verisuonitautien riskitekijoiden tasoja nuorilla aikuisilla, varhaisten ateroskleroottisten muutosten mittaamista ja varhaisten valtimomuutosten ennustamista perinteisilla riskitekijoilla ja uudella menetelmalla, seeruminaytteiden metabolisella profiloinnilla. Tutkimushenkilöt ja -menetelmät: Tutkimuksessa kaytettiin Lasten Sepelvaltimotaudin Riskitekijat –projektissa vuosina 2001 ja 2007 kerattyja mittaustuloksia 2204 aikuiselta, jotka vuonna 2007 olivat 30-45-vuotiaita. Varhaista ateroskleroosia tutkittiin noninvasiivisesti ultraaanella mittaamalla kaulavaltimon intima-media-paksuus (IMT) ja distensibiliteetti (CDist) ja olkavaltimon virtausvalitteinen laajeneminen (FMD). Lisaksi mitattiin perinteiset riskitekijat ja seeruminaytteiden metabolinen profiili, joka koostui 42 lipidimarkkerista ja 16 metaboliitista. Tulokset: Vuosien 2001 ja 2007 valilla lipiditasojen kehitys oli myonteista, mutta vyotaronymparys, paastoglukoosi ja verenpaine nousivat. IMT-mittaukset olivat stabiilimpia verrattuna CDist- ja FMD-mittauksiin. Sydan- ja verisuonitautiriskilaskurit (Framingham, SCORE, Finrisk, Reynolds ja PROCAM) ennustivat varhaista ateroskleroosia yhta tarkasti. Lipoproteiinien alaluokkien maarittaminen ei parantanut varhaisen ateroskleroosin ennustamista perinteisiin riskitekijoihin verrattuna, mutta metaboliittien maarittaminen paransi riskin arviointia. Tyrosiini ja dokosaheksaeenihappo olivat uusia korkean IMT:n biomarkkereita. Johtopäätökset: Varhaisen ateroskleroosin ennustamiseen nuorilla suomalaisilla voidaan kayttaa kaikkia nykyisia riskilaskureita. Metabolinen profilointi parantaa varhaisen ateroskleroosin riskin arviointia ja mahdollistaa varhaisen ja tarkan hoidon aloittamisen.Siirretty Doriast

Associations Between Brain Gray Matter Volumes and Adipose Tissue Metabolism in Healthy Adults

Objective Gray matter (GM) volume in different brain loci has been shown to vary in obesity and diabetes, and elevated fasting plasma nonesterified fatty acid (NEFA) levels have been suggested as one potential mechanism. The hypothesis presented in this study is that brown adipose tissue (BAT) activity may correlate with GM volume in areas negatively associated with obesity and diabetes.Methods A total of 36 healthy patients (M/F: 12/24, age 39.7 +/- 9.4 years, BMI 27.5 +/- 5.6 kg/m(2)) were imaged with positron emission tomography using fatty acid analog [F-18]FTHA to measure NEFA uptake and with [O-15]H2O to measure perfusion during cold exposure, at room temperature during fasting, or during a postprandial state. A 2-hour hyperinsulinemic euglycemic clamp was performed to measure whole-body insulin sensitivity (M value, mean 7.6 +/- 3.9 mg/kg/min). T1-weighted magnetic resonance imaging at 1.5 T was performed on all patients.Results BAT NEFA uptake was associated directly with GM volume in anterior cerebellum and occipital lobe (P <= 0.04) when adjusted for age, gender, and intra-abdominal fat volume and with anterior cerebellum, limbic lobe, and temporal lobe GM volumes when adjusted for M value.Conclusions BAT NEFA metabolism may participate in protection from cognitive degeneration associated with cardiometabolic risk factors, such as central obesity and insulin resistance. Potential causal relationships between BAT activity and GM volumes remain to be examined

Changes in electrocardiogram parameters during acute nonshivering cold exposure and associations with brown adipose tissue activity, plasma catecholamine levels, and brachial blood pressure in healthy adults

Background: Sympathetic activity causes changes in electrocardiogram (ECG) during cold exposure and the changes have been studied mostly during hypothermia and less during mild acute nonshivering cold exposure. Cold-induced sympathetic activity also activates brown adipose tissue (BAT) and increases arterial blood pressure (BP) and plasma catecholamine levels. We examined changes in ECG parameters during acute nonshivering cold exposure and their associations with markers of sympathetic activity during cold exposure: brachial blood pressure (BP), plasma catecholamine levels, and BAT activity measured by positron emission tomography (PET).Methods and results: Healthy subjects (M/F = 13/24, aged 20-55 years) were imaged with [O-15]H2O (perfusion, N = 37) and [F-18]FTHA to measure plasma nonesterified fatty acid uptake (NEFA uptake, N = 37) during 2-h nonshivering cold exposure. 12-lead ECG (N = 37), plasma catecholamine levels (N = 17), and brachial BP (N = 31) were measured at rest in room temperature (RT) and re-measured after a 2-h nonshivering cold exposure. There were significant differences between RT and cold exposure in P axis (35.6 +/- 26.4 vs. 50.8 +/- 22.7 degrees, p = 0.005), PR interval (177.7 +/- 24.6 ms vs.163.0 +/- 28.7 ms, p = 0.001), QRS axis (42.1 +/- 31.3 vs. 56.9 +/- 24.1, p = 0.003), and QT (411.7 +/- 25.5 ms vs. 434.5 +/- 39.3 ms, p = 0.001). There was no significant change in HR, QRS duration, QTc, JTc, and T axis during cold exposure. Systolic BP (127.2 +/- 15.7 vs. 131.8 +/- 17.9 mmHg, p = 0.008), diastolic BP (81.7 +/- 12.0 vs. 85.4 +/- 13.0 mmHg, p = 0.02), and plasma noradrenaline level increased during cold exposure (1.97 +/- 0.61 vs. 5.07 +/- 1.32 mu mol/L, p = 0.001). Cold-induced changes in ECG parameters did not correlate with changes in BAT activity, brachial BP, plasma catecholamines, or skin temperature.Conclusions: During short-term nonshivering cold exposure, there were increases in P axis, PR interval, QRS axis, and QT compared to RT in healthy adults. Cold-induced changes in ECG parameters did not correlate with BAT activity, brachial BP, or plasma catecholamine levels which were used as markers of cold-induced sympathetic activity

Comparison of reprojected bone SPECT/CT and planar bone scintigraphy for the detection of bone metastases in breast and prostate cancer

Objective The aim of this study was to compare reprojected bone SPECT/CT (RBS) against planar bone scintigraphy (BS) in the detection of bone metastases in breast and prostate cancer patients. Methods Twenty-six breast and 105 prostate cancer patients with high risk for bone metastases underwent Tc-99m-HMDP BS and whole-body SPECT/CT, 1.5-T whole-body diffusion-weighted MRI and F-18-NaF or F-18-PSMA-1007 PET/CT within two prospective clinical trials (NCT01339780 and NCT03537391). Consensus reading of all imaging modalities and follow-up data were used to define the reference standard diagnosis. The SPECT/CT data were reprojected into anterior and posterior views to produce RBS images. Both BS and RBS images were independently double read by two pairs of experienced nuclear medicine physicians. The findings were validated against the reference standard diagnosis and compared between BS and RBS on the patient, region and lesion levels. Results All metastatic patients detected by BS were also detected by RBS. In addition, three metastatic patients were missed by BS but detected by RBS. The average patient-level sensitivity of two readers for metastases was 75% for BS and 87% for RBS, and the corresponding specificity was 79% for BS and 39% for RBS. The average region-level sensitivity of two readers was 64% for BS and 69% for RBS, and the corresponding specificity was 96% for BS and 87% for RBS. Conclusion Whole-body bone SPECT/CT can be reprojected into more familiar anterior and posterior planar images with excellent sensitivity for bone metastases, making additional acquisition of planar BS unnecessary.Peer reviewe

Human Brown Fat Radiodensity Indicates Underlying Tissue Composition and Systemic Metabolic Health

Context: Metabolic imaging studying brown adipose tissue (BAT) physiology has increased, in which computed tomography (CT) is commonly used as an anatomical reference for metabolic positron emission tomography (PET) imaging. However, the capacity of CT to provide metabolic information has been underexploited.Objective: To evaluate whether CT radiodensity of BAT could noninvasively estimate underlying tissue morphology, regarding amount of stored triglycerides. Furthermore, could the alteration in tissue characteristics due to cold stimulus, as a marker for active BAT, be detected with radiodensity? Can BAT be differentiated from white adipose tissue (WAT) solely using CT-based measurements?Design, Setting, and Participants: A cross-sectional study evaluating 66 healthy human subjects with CT, PET, and H-1-magnetic resonance spectroscopy (H-1-MRS).Main Outcome Measures: BAT radiodensity was measured with CT. BAT-stored triglyceride content was measured with H-1-MRS. Arterial blood volume in BAT, as a marker of tissue vascularity, was measured with [O-15]H2O, along with glucose or fatty acid uptake using [F-18]2-fluoro-2-deoxy-D-glucose or 14(R,S)-[F-18]fluoro-6-thia-heptadecanoic acid PET imaging, respectively.Results: BAT radiodensity was found to be correlating with tissue-retained blood and triglyceride content. Cold stimulus induced an increase in BAT radiodensity. Active BAT depots had higher radiodensity than both nonactive BAT and WAT. BAT radiodensity associated with systemic metabolic health parameters.Conclusion: BAT radiodensity can be used as a marker of underlying tissue morphology. Active BAT can be identified using CT, exploiting tissue composition information. Moreover, BAT radiodensity provides an insight into whole-body systemic metabolic health

Imaging of Tumor Hypoxia With F-18-EF5 PET/MRI in Cervical Cancer

Purpose of the ReportThe aim of this study was to evaluate the distribution of hypoxia using 18F-EF5 as a hypoxia tracer in cervical cancer patients with PET/MRI. We investigated the association between this 18F-EF5-PET tracer and the immunohistochemical expression of endogenous hypoxia markers: HIF1α, CAIX, and GLUT1.Patients and MethodsNine patients with biopsy-proven primary squamous cell cervix carcinoma (FIGO 2018 radiological stages IB1–IIIC2r) were imaged with dual tracers 18F-EF5 and 18F-FDG using PET/MRI (Int J Gynaecol Obstet. 2019;145:129–135). 18F-EF5 images were analyzed by calculating the tumor-to-muscle ratio to determine the hypoxic tissue (T/M ratio >1.5) and further hypoxic subvolume (HSV) and percentage hypoxic area. These 18F-EF5 hypoxic parameters were correlated with the size and localization of tumors in 18F-FDG PET/MRI and the results of hypoxia immunohistochemistry.ResultsAll primary tumors were clearly 18F-FDG and 18F-EF5 PET positive and heterogeneously hypoxic with multiple 18F-EF5–avid areas in locally advanced cancer and single areas in clinically stage I tumors. The location of hypoxia was detected mainly in the periphery of tumor. Hypoxia parameters 18F-EF5 max T/M ratio and HSV in primary tumors correlated independently with the advanced stage (P = 0.036 and P = 0.040, respectively), and HSV correlated with the tumor size (P = 0.027). The location of hypoxia in 18F-EF5 imaging was confirmed with a higher hypoxic marker expression HIF1α and CAIX in tumor fresh biopsies.ConclusionsThe 18F-EF5 imaging has promising potential in detecting areas of tumor hypoxia in cervical cancer.</p

Femoral Bone Marrow Insulin Sensitivity Is Increased by Resistance Training in Elderly Female Offspring of Overweight and Obese Mothers

Bone marrow insulin sensitivity may be an important factor for bone health in addition to bone mineral density especially in insulin resistant conditions. First we aimed to study if prenatal maternal obesity plays a role in determining bone marrow insulin sensitivity in elderly female offspring. Secondly we studied if a four-month individualized resistance training intervention increases bone marrow insulin sensitivity in elderly female offspring and whether this possible positive outcome is regulated by the offspring's mother's obesity status. 37 frail elderly females (mean age 71.9 +/- 3.1 years) of which 20 were offspring of lean/normal-weight mothers (OLM, maternal BMI = 28.1 kg/m(2)) were studied before and after a four-month individualized resistance training intervention. Nine age-and sex-matched non-frail controls (maternal BMIPeer reviewe

Femoral Bone Marrow Insulin Sensitivity Is Increased by Resistance Training in Elderly Female Offspring of Overweight and Obese Mothers

Abstract-Bone marrow insulin sensitivity may be an important factor for bone health in addition to bone mineral density especially in insulin resistant conditions. First we aimed to study if prenatal maternal obesity plays a role in determining bone marrow insulin sensitivity in elderly female offspring. Secondly we studied if a four-month individualized resistance training intervention increases bone marrow insulin sensitivity in elderly female offspring and whether this possible positive outcome is regulated by the offspring’s mother’s obesity status. 37 frail elderly females (mean age 71.9 ± 3.1 years) of which 20 were offspring of lean/normal-weight mothers (OLM, maternal BMI ≤ 26.3 kg/m2) and 17 were offspring of obese/overweight mothers (OOM, maternal BMI ≥ 28.1 kg/m2) were studied before and after a four-month individualized resistance training intervention. Nine age- and sex-matched non-frail controls (maternal BMI ≤ 26.3 kg/m2) were studied at baseline. Femoral bone marrow (FBM) and vertebral bone marrow (VBM) insulin sensitivity were measured using [18F]fluoro-2-deoxy-D-glucose positron emission tomography with computer tomography under hyperinsulinemic euglycemic clamp. We found that bone marrow insulin sensitivity was not related to maternal obesity status but FBM insulin sensitivity correlated with whole body insulin sensitivity (R = 0.487, p = 0.001). A four-month resistance training intervention increased FBM insulin sensitivity by 47% (p = 0.006) only in OOM, while VBM insulin sensitivity remained unchanged regardless of the maternal obesity status. In conclusion, FBM and VBM glucose metabolism reacts differently to a four-month resistance training intervention in elderly women according to their maternal obesity status.</p

Atlas-Based Automatic Segmentation of Brown Adipose Tissue in Upper Torso of Lean Human Subjects in CT

<p>Poster presentation in Turku XII PET Symposium</p