Juho Raiko

High-throughput quantification of circulating metabolites improves prediction of subclinical atherosclerosis

AIMS High-throughput metabolite quantification holds promise for cardiovascular risk assessment. Here, we evaluated whether metabolite quantification by nuclear magnetic resonance (NMR) improves prediction of subclinical atherosclerosis in comparison to conventional lipid testing. METHODS AND RESULTS Circulating lipids, lipoprotein subclasses, and small molecules were assayed by NMR for 1595 individuals aged 24-39 years from the population-based Cardiovascular Risk in Young Finns Study. Carotid intima-media thickness (IMT), a marker of subclinical atherosclerosis, was measured in 2001 and 2007. Baseline conventional risk factors and systemic metabolites were used to predict 6-year incidence of high IMT (≥ 90 th percentile) or plaque. The best prediction of high intima-media thickness was achieved when total and HDL cholesterol were replaced by NMR-determined LDL cholesterol and medium HDL, docosahexaenoic acid, and tyrosine in prediction models with risk factors from the Framingham risk score. The extended prediction model improved risk stratification beyond established risk factors alone; area under the receiver operating characteristic curve 0.764 vs. 0.737, P =0.02, and net reclassification index 17.6%, P =0.0008. Higher docosahexaenoic acid levels were associated with decreased risk for incident high IMT (odds ratio: 0.74; 95% confidence interval: 0.67-0.98; P = 0.007). Tyrosine (1.33; 1.10-1.60; P = 0.003) and glutamine (1.38; 1.13-1.68; P = 0.001) levels were associated with 6-year incident high IMT independent of lipid measures. Furthermore, these amino acids were cross-sectionally associated with carotid IMT and the presence of angiographically ascertained coronary artery disease in independent populations. CONCLUSION High-throughput metabolite quantification, with new systemic biomarkers, improved risk stratification for subclinical atherosclerosis in comparison to conventional lipids and could potentially be useful for early cardiovascular risk assessment.

Follow‐ups of the Cardiovascular Risk in Young Finns Study in 2001 and 2007: Levels and 6‐year changes in risk factors

Abstract.  Raiko JRH, Viikari JSA, Ilmanen A, Hutri‐Kähönen N, Taittonen L, Jokinen E, Pietikäinen M, Jula A, Loo B.‐M, Marniemi J, Lehtimäki T, Kähönen M, Rönnemaa T, Raitakari OT, Juonala M (University of Turku; University of Tampere and Tampere University Hospital, Tampere; University of Oulu, Oulu; Vaasa Central Hospital, Vaasa; University of Helsinki, Helsinki; and Center of Social and Health Services, Kuopio; Finland). Follow‐ups of the Cardiovascular Risk in Young Finns Study in 2001 and 2007: Levels and 6‐year changes in risk factors. J Intern Med 2010; 267: 370–384.

Brown adipose tissue triglyceride content is associated with decreased insulin sensitivity, independently of age and obesity.

The aim of the present study was to determine whether single‐voxel proton magnetic resonance spectroscopy (1H‐MRS) can non‐invasively assess triglyceride content in both supraclavicular fat depots and subcutaneous white adipose tissue (WAT) to determine whether these measurements correlate to metabolic variables. A total of 25 healthy volunteers were studied using 18F‐fluorodeoxyglucose positron emission tomography (PET) and 15O‐H2O PET perfusion during cold exposure, and 1H‐MRS at ambient temperature. Image‐guided biopsies were collected from nine volunteers. The supraclavicular triglyceride content determined by 1H‐MRS varied between 60 and 91% [mean ± standard deviation (s.d.) 77 ± 10%]. It correlated positively with body mass index, waist circumference, subcutaneous and visceral fat masses and 8‐year diabetes risk based on the Framingham risk score and inversely with HDL cholesterol and insulin sensitivity (M‐value; euglycaemic‐hyperinsulinaemic clamp). Subcutaneous WAT had a significantly higher triglyceride content, 76–95% (mean ± s.d. 87 ± 5%; p = 0.0002). In conclusion, the triglyceride content in supraclavicular fat deposits measured by 1H‐MRS may be an independent marker of whole‐body insulin sensitivity, independent of brown adipose tissue metabolic activation.

Plasminogen activator inhitor-1 associates with cardiovascular risk factors in healthy young adults in the Cardiovascular Risk in Young Finns Study

AIMS Hypofibrinolysis displayed by elevated serum plasminogen activator inhibitor 1 (PAI-1) level has been associated with cardiovascular disease (CVD) and its risk factors such as obesity and insulin resistance. However, no studies have examined associations between PAI-1 and CVD risk factors in healthy subjects. We examined associations between serum PAI-1, ultrasound markers of atherosclerosis and CVD risk factors and whether PAI-1 improves prediction of atherosclerosis over known risk factors in a cohort of asymptomatic adults. METHODS We analyzed PAI-1 and CVD risk factors and assessed carotid intima-media thickness (cIMT), distensibility (CDist) and the presence of a carotid atherosclerotic plaque and flow-mediated dilation (FMD) ultrasonographically for 2202 adults (993 men and 1,209 women, aged 30-45 years) participating in the ongoing longitudinal cohort study, The Cardiovascular Risk in Young Finns Study. High cIMT was defined as >90th percentile and/or carotid plaque and low CDist and low FMD as <20th percentile. RESULTS In bivariate analyses, PAI-1 correlated directly with cIMT and the risk factors: blood pressure, BMI, waist and hip circumference, alcohol use, total and LDL-cholesterol, triglycerides, glomerular filtration rate, high-sensitivity CRP and glucose (all P<0.005). PAI-1 was higher in men and increased with age. Inverse correlation was observed with CDist, HDL-cholesterol and adiponectin in both sexes, with testosterone and sex hormone binding globulin in men and with creatinine and oral contraceptive use in women (P<0.005). Independent direct associations were observed between PAI-1 and waist circumference, serum triglycerides, insulin, alcohol use and age and inverse with serum creatinine, HDL-cholesterol and adiponectin. PAI-1 did not improve estimation of high cIMT, low CDist and low FMD over conventional risk factors (P for difference in area under curve ≥ 0.37). CONCLUSION PAI-1 was independently associated with several known CVD risk factors, especially obesity markers, in both men and women. However, addition of PAI-1 to known risk factors did not improve cross-sectional prediction of high cIMT, low CDist and low FMD suggesting that PAI-1 is not a clinically important biomarker in early atherosclerosis.

Cardiovascular risk scores in the prediction of subclinical atherosclerosis in young adults: evidence from the cardiovascular risk in a young Finns study:

Aim To study the utility of risk scores in the prediction of subclinical atherosclerosis in young adults. Methods and results Participants were 2204 healthy Finnish adults aged 24–39 years in 2001 from a population-based follow-up study Cardiovascular Risk in Young Finns. We examined the performance of the Framingham, Reynolds, Systematic Coronary Risk Evaluation (SCORE), PROCAM, and Finrisk cardiovascular risk scores to predict subclinical atherosclerosis, that is carotid artery intima-media thickness (IMT) and plaque, carotid artery distensibility (CDist), and brachial artery flow-mediated dilatation (FMD) 6 years later. In a 6-year prediction of high IMT (highest decile or plaque), areas under the receiver operating characteristic curves (AUC) for baseline Finrisk (0.733), SCORE (0.726), PROCAM (0.712), and Reynolds (0.729) risk scores were similar as for Framingham risk score (0.728, P always ≥ 0.15). All risk scores had a similar discrimination in predicting low CDist (lowest decile) (0.652, 0.642, 0.639, 0.658, 0.652 respectively, P always ≥ 0.41). In the prediction of low FMD (lowest decile), Finrisk, PROCAM, Reynolds, and Framingham scores had similar AUCs (0.578, 0.594, 0.582, 0.568, P always ≥ 0.08) and SCORE discriminated slightly better (AUC = 0.596, P<0.05). The prediction of subclinical outcomes was consistent when estimated from other statistical measures of discrimination, reclassification, and calibration. Conclusion Cardiovascular disease risk scores had equal value in predicting subclinical atherosclerosis measured by IMT and CDist in young adults. SCORE was more accurate in predicting low FMD than Framingham risk score.

Human Brown Adipose Tissue Temperature and Fat Fraction Are Related to Its Metabolic Activity

Background and Aim The metabolic activity of human brown adipose tissue (BAT) has been previously examined using positron emission tomography (PET). The aim of this study was to use proton magnetic resonance spectroscopy (1H MRS) to investigate whether the temperature and the fat fraction (FF) of BAT and white adipose tissue (WAT) are associated with BAT metabolic activity determined by deoxy-2-18F-fluoro-d-glucose (18F-FDG)-PET. Materials and Methods Ten healthy subjects (four women, six men; 25 to 45 years of age) were studied using PET-magnetic resonance imaging during acute cold exposure and at ambient room temperature. BAT and subcutaneous WAT 1H MRS were measured. The tissue temperature and the FF were derived from the spectra. Tissue metabolic activity was studied through glucose uptake using dynamic FDG PET scanning during cold exposure. A 2-hour hyperinsulinemic euglycemic clamp was performed on eight subjects. Results The metabolic activity of BAT associated directly with the heat production capacity and inversely with the FF of the tissue. In addition, the lipid-burning capacity of BAT associated with whole-body insulin sensitivity. During cold exposure, the FF of BAT was lower than at room temperature, and cold-induced FF of BAT associated inversely with high-density lipoprotein and directly with low-density lipoprotein cholesterol. Conclusion Both 1H MRS-derived temperature and FF are promising methods to study BAT activity noninvasively. The association between the lipid-burning capacity of BAT and whole-body insulin sensitivity emphasizes the role of BAT in glucose handling. Furthermore, the relation of FF to high-density lipoprotein and low-density lipoprotein cholesterol suggests that BAT has a role in lipid clearance, thus protecting tissues from excess lipid load.

Tracking of Noninvasive Ultrasound Measurements of Subclinical Atherosclerosis in Adulthood: Findings from the Cardiovascular Risk in Young Finns Study

We examined tracking of ultrasound measurements of vascular structure and function in adulthood using data collected in the 2001 and 2007 follow-ups of Cardiovascular Risk in Young Finns Study. B-mode ultrasound measures of carotid artery intima-media thickness (IMT), carotid artery distensibility (CDist) and brachial artery flow-mediated dilatation (FMD) was obtained on 1809 apparently healthy Finnish adults aged 24 to 39 years in 2001 (1014 females; 795 males). Significant 6-year tracking was observed for IMT (males, r = 0.56; females, r = 0.46), CDist (males, r = 0.35; females, r = 0.36) and FMD (males, r = 0.23; females, r = 0.20). Subjects with 10-year risk of CVD (according to the SCORE risk score) above sex-specific median had improved IMT (r = 0.44; r = 0.57, p = 0.0001) and CDist (r = 0.31; r = 0.40, p = 0.03) tracking compared with those below median. Body mass index (BMI) >or= 30 kg/m(2) decreased tracking of CDist (r = 0.36; r = 0.19, p = 0.01). In conclusion, ultrasound measurements tracked low to moderate over 6-years and was influenced by cardiovascular disease (CVD) risk factor status.

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 1H-magnetic resonance spectroscopy (1H-MRS). Main Outcome Measures BAT radiodensity was measured with CT. BAT-stored triglyceride content was measured with 1H-MRS. Arterial blood volume in BAT, as a marker of tissue vascularity, was measured with [15O]H2O, along with glucose or fatty acid uptake using [18F]2-fluoro-2-deoxy-D-glucose or 14(R,S)-[18F]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.

MR signal-fat-fraction analysis and T2*weighted imaging measure BAT reliably on humans without cold exposure

OBJECTIVE Brown adipose tissue (BAT) is compositionally distinct from white adipose tissue (WAT) in terms of triglyceride and water content. In adult humans, the most significant BAT depot is localized in the supraclavicular area. Our aim is to differentiate brown adipose tissue from white adipose tissue using fat T2* relaxation time mapping and signal-fat-fraction (SFF) analysis based on a commercially available modified 2-point-Dixon (mDixon) water-fat separation method. We hypothesize that magnetic resonance (MR) imaging can reliably measure BAT regardless of the cold-induced metabolic activation, with BAT having a significantly higher water and iron content compared to WAT. MATERIAL AND METHODS The supraclavicular area of 13 volunteers was studied on 3T PET-MRI scanner using T2* relaxation time and SFF mapping both during cold exposure and at ambient temperature; and 18F-FDG PET during cold exposure. Volumes of interest (VOIs) were defined semiautomatically in the supraclavicular fat depot, subcutaneous WAT and muscle. RESULTS The supraclavicular fat depot (assumed to contain BAT) had a significantly lower SFF and fat T2* relaxation time compared to subcutaneous WAT. Cold exposure did not significantly affect MR-based measurements. SFF and T2* values measured during cold exposure and at ambient temperature correlated inversely with the glucose uptake measured by 18F-FDG PET. CONCLUSIONS Human BAT can be reliably and safely assessed using MRI without cold activation and PET-related radiation exposure.

Bone mineral density is increased after a 16-week resistance training intervention in elderly women with decreased muscle strength

OBJECTIVE Non-pharmacological interventions are important in reducing risk for osteoporotic fractures. We investigated the effects of a 16-week individualized resistance training intervention on bone mineral density (BMD), bone turnover markers and 10-year relative risk (RR) for osteoporotic fracture. DESIGN Interventional study with a follow-up. METHODS In total, 37 elderly women (mean age 71.9 ± 3.1 years) with decreased muscle strength participated in the resistance training intervention three times per week with 60 min per session for 16 weeks under the supervision of a licensed physiotherapist. Total hip BMD with quantitative CT, bone markers (sclerostin, osteocalcin, CTX, PINP, IGF-1, 25(OH)-D) and 10-year RR for osteoporotic fracture were measured at baseline, post-intervention and at 1-year follow-up after the end of the intervention. Eleven age- and sex-matched controls did not participate in the intervention but were studied at baseline and at 1-year follow-up. RESULTS Resistance training seemed to increase total hip BMD by 6% (P = 0.005). Sclerostin (P < 0.001) and total osteocalcin (P = 0.04) increased while other bone markers remained unchanged. A 10-year RR for major osteoporotic and hip fracture remained unchanged. At follow-up total hip BMD (P < 0.001) decreased back to the baseline level with a simultaneous decrease in serum sclerostin (P = 0.045), CTX (P < 0.001) and an increase in 25(OH)-D (P < 0.001), 10-year RR for major osteoporotic (P = 0.002) and hip fracture (P = 0.01). CONCLUSIONS Our findings suggest an important role of continuous supervised resistance training for the prevention of osteoporotic fractures in elderly women with decreased muscle strength.