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Background: Elevated lipoprotein(a) [Lp(a)] is a common risk factor for cardiovascular disease outcomes with unknown mechanisms. We examined its potential role in identifying youths who are at increased risk of developing adult atherosclerotic cardiovascular disease (ASCVD)., Methods: Lp(a) levels measured in youth 9 to 24 years of age were linked to adult ASCVD and carotid intima-media thickness in the YFS (Cardiovascular Risk in Young Finns Study), in which 95 of the original 3596 participants (2.7%) recruited as children have been diagnosed with ASCVD at a median of 47 years of age. Results observed in YFS were replicated with the use of data for White participants from the BHS (Bogalusa Heart Study). In BHS, 587 White individuals had data on youth Lp(a) (measured at 8-17 years of age) and information on adult events, including 15 cases and 572 noncases. Analyses were performed with the use of Cox proportional hazard regression., Results: In YFS, those who had been exposed to high Lp(a) level in youth [defined as Lp(a) ≥30 mg/dL] had ≈2 times greater risk of developing adult ASCVD compared with nonexposed individuals (hazard ratio, 2.0 [95% CI, 1.4-2.6]). Youth risk factors, including Lp(a), low-density lipoprotein cholesterol, body mass index, and smoking, were all independently associated with higher risk. In BHS, in an age- and sex-adjusted model, White individuals who had been exposed to high Lp(a) had 2.5 times greater risk (95% CI, 0.9-6.8) of developing adult ASCVD compared with nonexposed individuals. When also adjusted for low-density lipoprotein cholesterol and body mass index, the risk associated with high Lp(a) remained unchanged (hazard ratio, 2.4 [95% CI, 0.8-7.3]). In a multivariable model for pooled data, individuals exposed to high Lp(a) had 2.0 times greater risk (95% CI, 1.0-3.7) of developing adult ASCVD compared with nonexposed individuals. No association was detected between youth Lp(a) and adult carotid artery thickness in either cohort or pooled data., Conclusions: Elevated Lp(a) level identified in youth is a risk factor for adult atherosclerotic cardiovascular outcomes but not for increased carotid intima-media thickness.

Aim: We aimed at identifying the shared biological processes underlying atherosclerosis-osteoporosis co/multimorbidity., Methods: We performed gene set analysis (GSA) of whole-blood transcriptomic data to identify biological processes shared by the early markers of these two diseases. Early markers of diseases, carotid intima-media thickness (CIMT) for atherosclerosis and trabecular bone mineral density (BMD) from distal radius and tibia for osteoporosis, were used to categorize the study participants into cases and controls. Participants with high CIMT (>90th percentile) were defined as cases for subclinical atherosclerosis. Study population-based T-scores for BMD were calculated and T-score ≤ -1 was used for the definition of low BMD cases i.e., early indicator of osteoporosis., Results: We did not identify any gene sets jointly associated with early markers of atherosclerosis and osteoporosis. We identified three novel and replicated 234 gene sets significantly associated with high CIMT with false discovery rate (FDR) ≤ 0.01. Only two genes, both related to the immune system, were identified to be associated with high CIMT by traditional differential gene expression analysis. However, none of the studied gene sets or individual genes were significantly associated with tibial or radial BMD. The three novel CIMT associated gene sets contained genes involved in copper homeostasis, neural crest cell migration and nicotinate and nicotinamide metabolism. The 234 replicated gene sets in this study are related to the immune system, hypoxia and apoptosis, consistent with the existing literature on atherosclerosis., Conclusions: This study identified novel biological processes associated with high CIMT but not with reduced BMD., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Osteoporosis and atherosclerosis are complex multifactorial diseases sharing common risk factors and pathophysiological mechanisms suggesting that these are comorbidities. Omics studies identifying joint molecular markers associated with these diseases are sparse., Subjects and Methods: Using liquid chromatography-tandem mass spectrometry, we quantified 437 molecular lipid species from the Young Finns Study cohort (aged 30-45 years and 57% women) and performed lipidome-wide multivariate analysis of variance (MANOVA) with early markers for both diseases. Carotid intima-media thickness for atherosclerosis measured with ultrasound and bone mineral density from distal radius and tibia for osteoporosis measured with peripheral quantitative computed tomography were used as early markers of the diseases., Results: MANOVA adjusted with age, sex and body mass index, identified eight statistically significant (adjusted p-value (p adj ) < 0.05) and 15 suggestively significant (p adj  < 0.25) molecular lipid species associated with the studied markers. Similar analysis adjusted additionally for smoking habit, physical activity and alcohol consumption identified four significant and six suggestively significant molecular lipid species. These most significant lipid classes/species jointly associated with the studied markers were glycerolipid/TAG(18:0/18:0/18:1), glycerophospholipid/PC(40:3), sphingolipid/Gb3(d18:1/22:0), and sphingolipid/Gb3(d18:1/24:0)., Conclusion: Our results support the osteoporosis-atherosclerosis comorbidity hypothesis and present potential new joint lipid biomarkers for these diseases., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

We analysed whole blood genome-wide expression data to identify gene co-expression modules shared by early traits of osteoporosis and atherosclerosis. Gene expression was profiled for the Young Finns Study participants. Bone mineral density and content were measured as early traits of osteoporosis. Carotid and bulbus intima media thickness were measured as early traits of atherosclerosis. Joint association of the modules, identified with weighted co-expression analysis, with early traits of the diseases was tested with multivariate analysis. Among the six modules significantly correlated with early traits of both the diseases, two had significant (adjusted p-values (p.adj) < 0.05) and another two had suggestively significant (p.adj < 0.25) joint association with the two diseases after adjusting for age, sex, body mass index, smoking habit, alcohol consumption, and physical activity. The three most significant member genes from the significant modules were NOSIP, GXYLT2, and TRIM63 (p.adj ≤ 0.18). Genes in the modules were enriched with biological processes that have separately been found to be involved in either bone metabolism or atherosclerosis. The gene modules and their most significant member genes identified in this study support the osteoporosis-atherosclerosis comorbidity hypothesis and can provide new joint biomarkers for both diseases and their dual prevention.

The atherogenic process begins already in childhood and progresses to symptomatic condition with age. We investigated the association of cholesterol efflux capacity (CEC) and vascular markers of subclinical atherosclerosis in healthy, young adults. CEC was determined in 2282 participants of the Young Finns study using cAMP treated 3 H-cholesterol-labeled J774 cells. The CEC was correlated to baseline and 6-year follow-up data of cardiovascular risk factors and ultrasound measurements of arterial structure and function. CEC was higher in women, correlated with total cholesterol, HDL-C, and apolipoprotein A-I, but not with LDL-C or apolipoprotein B. Compared to the lowest CEC quartile, the highest CEC quartile was significantly associated with high CRP levels and inversely associated with adiponectin. At baseline, high CEC was associated with decreased flow-mediated dilation (FMD) and carotid artery distensibility, as well as an increased Young's modulus of elasticity, indicating adverse changes in arterial structure, and function. The association reversed with follow-up FMD data, indicating the interaction of preclinical parameters over time. A higher CEC was directly associated with a lower risk of subclinical atherosclerosis at follow-up. In young and healthy subjects, CEC was associated with important lipid risk parameters at baseline, as in older patients and CAD patients, but inversely with early risk markers for subclinical atherosclerosis.

Background: Studies have shown that osteoporosis and atherosclerosis are comorbid conditions sharing common risk factors and pathophysiological mechanisms. Understanding these is crucial in order to develop shared methods for risk stratification, prevention, diagnosis and treatment. The aim of this study was to apply a system-level bioinformatics approach to lipidome-wide data in order to pinpoint the lipidomic architecture jointly associated with surrogate markers of these complex comorbid diseases., Subjects and Methods: The study was based on the Cardiovascular Risk in Young Finns Study cohort from the 2007 follow-up (n = 1494, aged 30-45 years, women: 57%). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to analyse the serum lipidome, involving 437 molecular lipid species. The subclinical osteoporotic markers included indices of bone mineral density and content, measured using peripheral quantitative computer tomography from the distal and shaft sites of both the tibia and the radius. The subclinical atherosclerotic markers included carotid and bulbus intima media thickness measured with high-resolution ultrasound. Weighted co-expression network analysis was performed to identify networks of densely interconnected lipid species (i.e. lipid modules) associated with subclinical markers of both osteoporosis and atherosclerosis. The levels of lipid species (lipid profiles) of each of the lipid modules were summarized by the first principal component termed as module eigenlipid. Then, Pearson's correlation (r) was calculated between the module eigenlipids and the markers. Lipid modules that were significantly and jointly correlated with subclinical markers of both osteoporosis and atherosclerosis were considered to be related to the comorbidities. The hypothesis that the eigenlipids and profiles of the constituent lipid species in the modules have joint effects on the markers was tested with multivariate analysis of variance (MANOVA)., Results: Among twelve studied molecular lipid modules, we identified one module with 105 lipid species significantly and jointly associated with both subclinical markers of both osteoporosis (r = 0.24, p-value = 2 × 10 - ) and atherosclerosis (r = 0.16, p-value = 2 × 10 20 ). The majority of the lipid species in this module belonged to the glycerolipid (n = 60), glycerophospholipid (n = 13) and sphingolipid (n = 29) classes. The module was also enriched with ceramides (n = 20), confirming their significance in cardiovascular outcomes and suggesting their joint role in the comorbidities. The top three of the 37 statistically significant (adjusted p-value < 0.05) lipid species jointly associated with subclinical markers of both osteoporosis and atherosclerosis within the module were all triacylglycerols (TAGs) - TAG(18:0/18:0/18:1) with an adjusted p-value of 8.6 × 10 - 10 ). The majority of the lipid species in this module belonged to the glycerolipid (n = 60), glycerophospholipid (n = 13) and sphingolipid (n = 29) classes. The module was also enriched with ceramides (n = 20), confirming their significance in cardiovascular outcomes and suggesting their joint role in the comorbidities. The top three of the 37 statistically significant (adjusted p-value < 0.05) lipid species jointly associated with subclinical markers of both osteoporosis and atherosclerosis within the module were all triacylglycerols (TAGs) - TAG(18:0/18:0/18:1) with an adjusted p-value of 8.6 × 10 - 8 , TAG(18:0/18:1/18:1) with an adjusted p-value of 3.7 × 10 - 6 , and TAG(16:0/18:0/18:1) with an adjusted p-value of 8.5 × 10 - 6 ., Conclusion: This study identified a novel lipid module associated with both surrogate markers of both subclinical osteoporosis and subclinical atherosclerosis. Alterations in the metabolism of the identified lipid module and, more specifically, the TAG related molecular lipids within the module may provide potential new biomarkers for testing the comorbidities, opening avenues for the emergence of dual-purpose prevention measures., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background The child-oriented dietary intervention given in the prospective Special Turku Coronary Risk Factor Intervention Project (STRIP) has decreased the intake of saturated fat and lowered serum cholesterol concentration in children from infancy until early adulthood. In this study, we investigated whether the uniquely long-term child-oriented intervention has affected also secondarily parental diet and cardio-metabolic risk factors. Methods The STRIP study is a longitudinal, randomized infancy-onset atherosclerosis prevention trial continued from the child's age of 8 months to 20 years. The main aim was to modify the child's diet towards reduced intake of saturated fat. Parental dietary intake assessed by a one-day food record and cardio-metabolic risk factors were analysed between the child's ages of 9-19 years. Results Saturated fat intake of parents in the intervention group was lower [mothers: 12.0 versus 13.9 daily energy (E%), p < 0.0001; fathers: 12.5 versus 13.9 E%, p < 0.0001] and polyunsaturated fat intake was higher (mothers: 6.1 versus 5.4 E%, p < 0.0001; fathers: 6.3 versus 5.9 E%, p = 0.0003) compared with the control parents. Maternal total and low-density lipoprotein cholesterol concentrations were lower in the intervention compared with the control group (mean ± SE 5.02 ± 0.04 versus 5.14 ± 0.04 mmol/l, p = 0.04 and 3.19 ± 0.04 versus 3.30 ± 0.03 mmol/l, p = 0.03, respectively). Paternal cholesterol values did not differ between the intervention and control groups. Other cardio-metabolic risk factors were similar in the study groups. Conclusions Child-oriented dietary intervention shifted the dietary fat intakes of parents closer to the recommendations and tended to decrease total and low-density lipoprotein cholesterol in the intervention mothers. Dietary intervention directed to children benefits also parents.

Upstream transcription factor 1 (USF1) allelic variants significantly influence future risk of cardiovascular disease and overall mortality in females. We investigated sex-specific effects of USF1 gene allelic variants on serum indices of lipoprotein metabolism, early markers of asymptomatic atherosclerosis and their changes during six years of follow-up. In addition, we investigated the cis-regulatory role of these USF1 variants in artery wall tissues in Caucasians. In the Cardiovascular Risk in Young Finns Study, 1,608 participants (56% women, aged 31.9 ± 4.9) with lipids and cIMT data were included. For functional study, whole genome mRNA expression profiling was performed in 91 histologically classified atherosclerotic samples. In females, serum total, LDL cholesterol and apoB levels increased gradually according to USF1 rs2516839 genotypes TT < CT < CC and rs1556259 AA < AG < GG as well as according to USF1 H3 (GCCCGG) copy number 0 < 1 < 2. Furthermore, the carriers of minor alleles of rs2516839 (C) and rs1556259 (G) of USF1 gene had decreased USF1 expression in atherosclerotic plaques (P = 0.028 and 0.08, respectively) as compared to non-carriers. The genetic variation in USF1 influence USF1 transcript expression in advanced atherosclerosis and regulates levels and metabolism of circulating apoB and apoB-containing lipoprotein particles in sex-dependent manner, but is not a major determinant of early markers of atherosclerosis.

Scavenging and reverse transport of atherogenic oxidized lipids by high-density lipoprotein (HDL) was recently suggested to contribute to atheroprotection. We investigated the associations of oxidized HDL lipids (oxHDLlipids) with known risk factors for atherosclerosis in a population-based cross-sectional study of 1395 Finnish adults ages 24-39 years (54.9% women). Analysis of oxidized lipids in isolated HDL and LDL (oxLDLlipids) was based on the determination of conjugated dienes. Oxidized LDL was measured also with a method based on antibodies against oxidized Apo-B (oxLDLprot). Serum lipids and risk factors were measured. In multivariable models, oxHDLlipids were associated inversely with age (partial R(2)=2.9% in men, 0.8% in women) and directly with oxLDLlipids (partial R(2)=3.4% in men, 4.2% in women) after adjustment for Apo-A1 (partial R(2)=9.6% in men, 25.2% in women). In men, oxHDLlipids were also associated inversely with insulin (partial R(2)=1.1%). In women, oxHDLlipids were additionally inversely associated with waist circumference (partial R(2)=1.8%) and daily smoking (partial R(2)=0.7%) and directly with C-reactive protein (CRP; partial R(2)=0.5%) and alcohol use (partial R(2)=0.5%). We conclude that an elevated risk profile characterized primarily by advanced age is associated with lower oxHDLlipid levels in a population of young Finnish men and women. Higher levels of oxHDLlipids are additionally associated with higher oxLDLlipid levels. In men, higher insulin levels are also associated with lower oxHDLlipid levels. In women, increased waist circumference and daily smoking are also associated with lower oxHDLlipid levels, and higher CRP levels and alcohol use are associated with higher oxHDLlipid levels., (© 2013 Elsevier Inc. All rights reserved.)

Aims: The role of neuropeptide Y (NPY) and its gene polymorphisms in the development of atherosclerosis has become increasingly evident. In asthma, NPY has been shown to be involved as immunomodulator. In this study, we investigated the role of two functional NPY polymorphisms, NPY-Leu7Pro (rs16139) and NPY-399C/T (rs16147) and obesity for the development of asthma as well as atherosclerosis in asthmatic and non-asthmatic subjects. Also, we measured heart rate variability (HRV) and NPY in serum since these might contribute through these polymorphisms to both diseases., Methods and Results: Thousand hundred and seventy six Finnish young adults were genotyped and three groups (G1-G3) were formed based on the observed diplotypes. The NPY-Pro7 allele always co-existed with the NPY-399T allele indicating complete linkage disequilibrium. Here we show that overweight (BMI≥25kg/m2) was associated with 2.5-fold increased risk for asthma in subjects with the NPY-399T allele without NPY-Pro7 allele (G2, n=716). Overweight was also associated with increased atherosclerosis determined by carotid intima media thickness (cIMT), but asthma seemed to be more significant determinant than overweight in determing cIMT having a decreasing effect. NPY concentration in serum was diplotype-driven (G1=792.2(29.5), G2=849.0(18.9), G3=873.9(45.2) pg/ml) and correlated positively with cIMT in the group having NPY-Pro7 allele (G3, n=142). However, the subjects with asthma had a negative NPY-cIMT relationship. Total HRV was increased in asthma and correlated negatively with cIMT irrespective of the NPY genotype., Conclusions: Overweight together with the NPY-399T allele without NPY-Pro7 allele was associated with increased risk for asthma. Atherosclerosis was decreased in subjects with asthma depending on the NPY genotype. The results reveal novel insights into the genetics and biology of the relationship of atherosclerosis and asthma., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: To assess how multidimensional personality-trait theories, such as the Psychobiological Model of Temperament and Character, and the Five-factor Model of Personality, are associated with subclinical atherosclerosis as indicated by carotid intima-media thickness (IMT). The analysis was designed to tolerate non-linear development in which the same personality profiles can have multiple final outcomes and different antecedent profiles can have the same final outcome., Methods: 605 men and 844 women (average age 31.6year, s.d.=5.0, range=24-39) provided data on IMT and traits of the psychobiological model, 725 men and 1011 women were assessed for IMT and the five-factor model (age 37.7year, s.d.=5.0, range=30-45). Robust multidimensional Hotelling's T(2) statistic was used to detect personality differences between participants with high IMT and others. Model-based clustering method further explored the effect., Results: Those with a high level of subclinical atherosclerosis within the sample (highest IMT-decile) had a combined higher persistence (i.e., were perseverative or perfectionistic), more disorganized (schizotypal) character, and more antisocial temperamental configuration than others (P=0.019). No effect was found for the five-factor model (P=0.978). Traditional methods that did not account for multidimensionality and nonlinearity did not detect an association., Conclusion: Psychological well-being may have positive effects on health that reduce atherosclerosis in the population as a whole. Increased subclinical atherosclerosis was associated with a profile that combines known risk factors, such as cynical distrust and hostile tendencies. More frequent use of statistical procedures that can cope with non-linear interactions in complex psychobiological systems may facilitate scientific advances in health promotion., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background and Objective: As atherosclerosis is a lifelong process, prevention of exposure to its risk factors should start at an early age. Our aim was to study the influences of repeated low saturated fat dietary counseling on dietary intakes and lipoprotein measures from infancy to adulthood., Methods: Dietary intakes (food records) and serum lipid profile were studied annually from 7 months to 19 years of age in an atherosclerosis prevention study (Special Turku Coronary Risk Factor Intervention Project), comprising 540 children in the intervention group and 522 children in the control group. Serum total and high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were measured and used to estimate very low-density lipoprotein-TG, intermediate-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and HDL(2)-C, as well as apolipoproteins A-1 and B., Results: Compared with controls, the intervention children had a lower saturated fat intake (mean daily difference [95% confidence interval] between groups: -2.1 [-2.3, -1.9] percentage of total energy intake in boys; -1.9 [-2.1, -1.7] percentage of total energy intake in girls, both P < .001) and LDL-C concentration (difference [95% confidence interval] between groups: -0.18 [-0.26, -0.10] mmol/L, P < .001 in boys; -0.10 [-0.19, -0.01] mmol/L, P = .037 in girls), whereas HDL-C and apolipoprotein A-1 did not differ between the study groups. In boys, total cholesterol and intermediate-density lipoprotein cholesterol, very low-density lipoprotein-TG, apolipoprotein B, and TG concentrations were also lower in the intervention than in the control group, whereas no differences were found in girls., Conclusions: Repeated dietary counseling is effective in decreasing saturated fat intake and serum LDL-C values from infancy until 19 years of age in both genders. In boys, significant intervention effects are evident in various lipoprotein measures, indicating a more favorable lipid profile in the counseling group.

Objective: Vascular adhesion protein-1 is an endothelial enzyme that regulates leukocyte traffic and contributes to vascular damage in animal models. The relations of soluble vascular adhesion protein-1 (sVAP-1) with cardiovascular risk factors and markers of subclinical atherosclerosis at a population level have not been studied., Methods and Results: We developed a new high-throughput method and measured sVAP-1 activities in serum of 2183 persons (The Cardiovascular Risk in Young Finns Study). In women, sVAP-1 activity correlated indirectly with body mass index (r=-0.15, P<0.0001), triglycerides (r=-0.13, P<0.0001), C-reactive protein (r=-0.23; P<0.0001), and brachial artery flow-mediated vasodilatation (r=-0.076, P=0.0089) and directly with carotid plaques (r=0.066, P=0.023). None of these correlations was significant in men. In women, all these univariate correlations remained significant after adjustment for body mass index, and direct correlations with LDL-cholesterol (r=0.094, P=0.0014) and carotid intima-media thickness (r=0.075, P=0.010) became evident. In men, sVAP-1 activity associated directly with glucose (r=0.074, P=0.020), intima-media thickness (r=0.072, P=0.025), metabolic syndrome (P=0.016), and type 1 (P=0.0002) and type 2 (P<0.0001) diabetes. In multivariable analyses, sVAP-1 activity was an independent determinant of carotid intima-media thickness (P=0.0072) and plaques [odds ratio 1.71 (95% confidence interval 1.07-2.72, P=0.025] in women, but not in men., Conclusions: sVAP-1 activity correlates directly with intima-media thickness and carotid plaques in general population and may play a role in the pathophysiology of preclinical atherosclerosis.

Association testing of multiple correlated phenotypes offers better power than univariate analysis of single traits. We analyzed 6,600 individuals from two population-based cohorts with both genome-wide SNP data and serum metabolomic profiles. From the observed correlation structure of 130 metabolites measured by nuclear magnetic resonance, we identified 11 metabolic networks and performed a multivariate genome-wide association analysis. We identified 34 genomic loci at genome-wide significance, of which 7 are novel. In comparison to univariate tests, multivariate association analysis identified nearly twice as many significant associations in total. Multi-tissue gene expression studies identified variants in our top loci, SERPINA1 and AQP9, as eQTLs and showed that SERPINA1 and AQP9 expression in human blood was associated with metabolites from their corresponding metabolic networks. Finally, liver expression of AQP9 was associated with atherosclerotic lesion area in mice, and in human arterial tissue both SERPINA1 and AQP9 were shown to be upregulated (6.3-fold and 4.6-fold, respectively) in atherosclerotic plaques. Our study illustrates the power of multi-phenotype GWAS and highlights candidate genes for atherosclerosis., Competing Interests: The authors have declared that no competing interests exist.

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10(-8)). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.

Background: The role of atherosclerosis in carpal tunnel syndrome (CTS) has not previously been addressed in population studies. The aim of this study was to investigate the associations of cardiovascular risk factors, carotid artery intima-media thickness (IMT), and clinical atherosclerotic diseases with CTS., Methods: In this cross sectional study, the target population consisted of subjects aged 30 or over who had participated in the national Finnish Health Survey in 2000-2001. Of the 7977 eligible subjects, 6254 (78.4%) were included in our study. Carotid IMT was measured in a sub-sample of subjects aged 45 to 74 (N=1353)., Results: Obesity (adjusted odds ratio (OR) 2.4, 95% confidence interval (CI) 1.1-5.4), high LDL cholesterol (OR 3.8, 95% CI 1.6-9.1 for >190 vs. <129 mg/dL), high triglycerides (OR 2.7, 95% CI 1.2-6.1 for >200 vs. <150 mg/dL), hypertension (OR 3.4, 95% CI 1.6-7.4) and cardiac arrhythmia (OR 10.2, 95% CI 2.7-38.4) were associated with CTS in subjects aged 30-44. In the age group of 60 years or over, coronary artery disease (OR 1.9, 95% CI 1.1-3.5), valvular heart disease (OR 2.3, 95% CI 1.0-5.0) and carotid IMT (1.4, 95% CI 0.9-2.1 for each 0.23 mm increase) were associated with CTS. Carotid IMT was associated with CTS only in subjects with hypertension or clinical atherosclerotic vascular disease, or in those who were exposed to physical workload factors., Conclusions: Our findings suggest an association between CTS and cardiovascular risk factors in young people, and carotid IMT and clinical atherosclerotic vascular disease in older people. CTS may either be a manifestation of atherosclerosis, or both conditions may share similar risk factors.

Background: Lipoprotein(a) [Lp(a)] is an established risk factor for coronary disease and stroke, but mechanisms underlying this association are unknown. We examined the association of Lp(a) with early atherosclerosis by using conventional epidemiologic analysis and a Mendelian randomization analysis. The latter utilized genetic variants that are associated with Lp(a) to estimate causal effect., Methods: A prospective population-based cohort study of 939 men and 1141 women was conducted. Lp(a) was measured repeatedly at mean ages 17 and 38 years. Measurements of carotid intima-media thickness (IMT) and brachial flow-mediated dilation (FMD) at mean ages 32 and 38 years were used to determine the level and 6-year progression of subclinical atherosclerosis. Lp(a)-related genetic variant, rs783147, was identified by a genome wide association analysis (P = 3.1 × 10⁻⁵⁸), and a genetic score was constructed based on 10 Lp(a)-related variants. Mendelian randomization test was performed using a two-stage instrumental variables analysis., Results: rs783147 and the genetic score were strong instruments for nonconfounded Lp(a) levels (F-statistics 269.6 and 446.0 in the first-stage instrumental variable analysis). However, Lp(a) levels were not associated with the levels of or change in IMT or FMD in any of the conventional and instrumental variables tests. The null finding was observed both with rs783147 and the genetic score as instruments and remained unchanged after adjustment for clinical characteristics, such as age, sex, HDL and LDL cholesterol, ApoB, systolic and diastolic blood pressure, diabetes and smoking., Conclusions: Data from conventional and Mendelian randomization analyses provide no support for early atherogenic effects of increased Lp(a) levels.

Background and Aim: Interleukin-18 (IL-18) is a pro-atherosclerotic cytokine. We wanted to evaluate whether IL-18 gene polymorphism associates independently of risk factors, with early subclinical markers of atherosclerosis (intima-media thickness (IMT), coronary artery compliance (CAC), and flow-mediated dilatation (FMD)) in a population of young healthy Caucasian adults., Methods: This study was based on the on-going Cardiovascular Risk in Young Finns Study consisting of 2260 young adults, mean age being 31.7 (range 24-39 years) (1247 women and 1013 men)., Results: Five studied tagSNPs formed six major haplotypes, which accounted for 99.9% of all variation of the IL-18 gene. According to adjusted analysis of variance, the IL-18 gene polymorphism did not associate with subclinical atherosclerosis in the whole study population. However, one major haplotype associated differently among men and women with IMT (P = 0.011). Male carriers of a major CCTgT haplotype (n = 441) seemed to have a lower IMT when compared to the non-carriers (-0.016 mm, 95% confidence interval (CI) -0.028 to -0.004, P = 0.014). Among women no significant associations were observed., Conclusions: Among all study subjects, the polymorphism of the IL-18 gene is not associated with subclinical markers of atherosclerosis. However, among men one major IL-18 haplotype seemed to associate with substantially lower IMT values.

Background: Exposure to tobacco smoke is associated with markers of preclinical atherosclerosis in adults, but its effect on arterial structure in adolescents is unknown., Methods and Results: Healthy 13-year-old adolescents from the atherosclerosis prevention trial STRIP were studied. Maximum carotid and aortic intima-media thickness and brachial artery flow-mediated dilation were measured in 494 adolescents using high-resolution ultrasound. Serum lipid, lipoprotein, and apolipoprotein (Apo) A-I and B concentrations were determined using standard methods. Exposure to tobacco smoke was measured annually between ages 8 and 13 years using serum cotinine concentrations, analyzed with gas chromatography. To define longitudinal exposure, cotinine values of children having serum cotinine measured 2 to 6 times during follow-up were averaged and divided into tertiles (exposure groups): low (n=160), intermediate (n=171), and high (n=163). Adolescents with higher longitudinal exposure to tobacco smoke had increased carotid intima-media thickness (exposure groups [mean+/-SD]: low, 0.502+/-0.079 mm; intermediate, 0.525+/-0.070 mm; high, 0.535+/-0.066 mm; P<0.001) and increased aortic intima-media thickness (exposure groups: low, 0.527+/-0.113 mm; intermediate, 0.563+/-0.139 mm; high, 0.567+/-0.126 mm; P=0.008). The flow-mediated dilation decreased when cotinine level increased (exposure groups: low, 10.43+/-4.34%; intermediate, 9.78+/-4.38%; high, 8.82+/-4.14%; P=0.004). Moreover, ApoB (P=0.014) and ApoB/ApoA-I ratio (P=0.045) increased with increase in cotinine level. The associations between tobacco smoke exposure and ultrasound variables were unchanged after adjusting for traditional atherosclerosis risk factors and for ApoB., Conclusions: Frequent exposure to tobacco smoke is independently associated with arterial changes of preclinical atherosclerosis and increased ApoB levels among healthy adolescents. Clinical Trial Registration- clinicaltrials.gov. Identifier: NCT00223600.

Objective: Inflammatory factors modify the risk of coronary heart disease. Pleiotropic cytokine interleukin-10 (IL-10) has been suggested as modifying risk for atherosclerosis. Promoter region genetic polymorphism of IL-10 gene (IL10) is known to be associated with the variation of IL-10 production. We investigated whether single-base exchange polymorphisms -1082 G>A (rs1800896), -819 C>T (rs1800871) and -592 C>A (rs1800872) at IL10 gene are associated with risk factors and early markers of atherosclerosis in young subjects., Methods and Results: As a part of the Cardiovascular Risk in Young Finns Study, we determined carotid artery compliance (CAC), stiffness index (SI) and Young's elastic modulus (YEM), intima media thickness (IMT), IL10 genotype and atherosclerosis risk parameters for 2260 subjects aged 24-39 years. In male subjects CAC was lower in carriers of IL-10 high- to intermediate-producer haplotype -1082 G; -819 C; -592 C (GCC+, 1.96+/-0.67) than in noncarriers (GCC-, 2.10+/-0.62, %/10 mmHg, mean+/-SD, p=0.0010). An inverse association was observed in SI (GCC+, 5.76+/-2.12 and GCC-, 5.26+/-1.46, p=0.0034) and YEM (GCC+, 347+/-165 and GCC-, 305+/-110, mm Hg.mm, p=0.0005). Associations remained significant when adjusted to age, BMI, smoking and serum lipids as well as fasting glucose and insulin levels. The genetic effect size for these parameters was not significant in women., Conclusions: IL10 promoter region high- to intermediate-producer haplotype GCC associates with decreased arterial elasticity in men. These results are in disconcordance with the supposed antiatheromatous properties of IL-10., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

Background: Serum amyloid A (SAA) is a sensitive marker of inflammation and its elevation has been implicated in obesity and in cardiovascular disease, yet data on its regulation in young adults or on its role in early atherosclerosis is scarce. We investigated which factors explain the variation in SAA and analysed whether SAA could be associated with preclinical atherosclerosis., Methods: Serum amyloid A levels were measured in participants of the Cardiovascular Risk in Young Finns Study (n = 2280, n = 1254 women, n = 1026 men). Correlates and determinants of SAA were analysed and the effect of SAA on subclinical atherosclerosis, measured as intima-media thickness (IMT) and carotid artery compliance, was evaluated with risk-factor adjusted models., Results: Serum amyloid A correlated directly and independently of BMI with C-reactive protein (CRP), waist circumference and leptin in both sexes, with total cholesterol, LDL cholesterol and ApolipoproteinA1 (ApoA1) in women and with triglycerides, insulin levels and insulin resistance in men. Use of combined oral contraceptives and intrauterine device was also associated with SAA levels. Determinants for SAA included CRP, leptin and ApoA1 in women, and CRP, leptin and HDL cholesterol in men. SAA levels correlated with carotid compliance in both sexes and with IMT in men, yet SAA had no independent effect on IMT or carotid compliance in multivariable analysis., Conclusions: Serum amyloid A was associated with several metabolic risk factors but was not an independent predictor of IMT or carotid artery compliance. Further longitudinal studies will show whether SAA holds a prognostic value as a risk marker, analogously to CRP.

The common C-480T polymorphism (rs1800588) of the hepatic lipase gene (LIPC) has been associated with high-density lipoprotein (HDL) cholesterol, atherosclerosis, and coronary artery disease. In this study, we examined whether the polymorphism is associated with serum lipid and lipoprotein concentrations, as well as with subclinical atherosclerosis in Young Finns. The participants comprised 2041 men and women (aged 24-39 years) enrolled in the Cardiovascular Risk in Young Finns Study with complete data concerning the rs1800588 polymorphism and serum lipids concentration. All participants underwent an ultrasound examination for brachial artery flow-mediated vasodilatation (FMD) and carotid artery intima-media thickness (IMT) measurement. The marker of arterial elasticity, carotid artery compliance (CAC), was also calculated by means of ultrasound and concomitant brachial blood pressure measurements. In all subjects, serum total cholesterol (p < 0.001), HDL cholesterol (p = 0.006), apolipoprotein AI (apoAI, p < 0.001), and triglyceride (p = 0.009) concentrations increased according to rs1800588 genotype in the order CC, CT, and TT. The same order applied only to apoAI after adjustment for age, body mass index, systolic and diastolic blood pressure, smoking, alcohol consumption, physical activity, diabetes, hypertension, contraceptive hormone use in women, and concentrations of glucose, insulin and C-reactive protein in men and women separately (p = 0.007 and p = 0.003, respectively). The polymorphism was also associated with HDL cholesterol, total cholesterol, and triglyceride levels in women (adjusted p = 0.004, p = 0.007 and 0.02, respectively), but not in men (p was not significant for all). No significant association between the rs1800588 and brachial FMD, carotid IMT, or CAC was found among the entire study population or among women or men separately, with or without adjustment for the above-mentioned factors. The rs1800588 is associated with serum lipid and apolipoprotein concentrations, especially in women, but does not seem to be a determinant of brachial artery FMD, carotid IMT, or CAC in young healthy adults.

Early identification of common familial dyslipidemias may prevent premature atherosclerotic disease. This study estimated the diagnostic values of few early childhood repeatedly deviant lipid samples by the knowledge of the parent's dyslipidemia. The first 7 years of age data of 353 children with their parents were evaluated from atherosclerosis risk-factor intervention study controls. Parents' low high-density-lipoprotein-cholesterol concentration (hypo-HDL-C), and high total cholesterol concentration-HDL-C (hyper-non-HDL-C) were defined. True hypo-HDL-C and hyper-non-HDL-C children were defined when their respective individual longitudinal means were beyond the appropriate lipid quintiles. Sensitivities, specificities, positive and negative predictive values of the early lipid samples were estimated with individual standard deviation models and bootstrap confidence. Hypo-HDL-C children proportions were 15.3% of all, and 20.9% of the children from the hypo-HDL-C parents (p=0.26). Hyper-non-HDL-C children were 16.7% of all and 31.8% of the children from the hyper-non-HDL-C parents (p=0.008). One early non-HDL-C sample in the highest quintile predicted 56% of the hyper-non-HDL-C children from healthy parents, but 83% of the hyper-non-HDL-C children from the hyper-non-HDL-C parents. Mean of three samples improved the latter prediction to 91%. This showed that if hypercholesterolemic parent's child expressed repeatedly hyper-non-HDL-C, it predicts true dyslipidemia of the child.

Background and Design: The purpose of this randomized controlled cross-over study was to determine the acute effects of high doses of alcoholic beverages on circulating markers related to atherosclerosis and fibrinolysis., Methods: Twenty-two healthy men consumed a high dose (8.1+/-0.9 dl) of alcohol-containing red wine and dealcoholized red wine, and an equal ethanol dose of cognac (2.4+/-0.3 dl). Blood samples were taken before and shortly after interventions., Results: Red wine, unlike dealcoholized red wine and cognac, increased tissue plasminogen activator inhibitor-1 levels significantly, indicating an acute inhibition of fibrinolysis after a high dose., Conclusion: Findings may explain the increased risk of cardiovascular mortality among binge drinkers.

Objective: Inflammatory factors modify the risk of coronary heart disease. Promoter region genetic polymorphism of inflammatory cytokine interleukin-6 (IL6 -174 G>C) is associated with the variation of IL-6 production. We investigated whether IL6 -174 G>C associates with the risk factors of atherosclerosis and carotid artery compliance (CAC) in young subjects., Methods and Results: As part of the Cardiovascular Risk in Young Finns Study, we performed carotid artery ultrasound examinations, IL6 -174 G>C genotyping and coronary heart disease risk factor determination for 2228 subjects aged 24-39 years. In men CAC was higher for IL6 -174 GG (2.10+/-0.65) than for GC (2.00+/-0.68) or CC (1.95+/-0.63, %/10mmHg, mean+/-S.D., p=0.0221). A similar association was observed for HDL cholesterol (GG 1.22+/-0.29, GC 1.15+/-0.27 and CC 1.14+/-0.28mmol/L, p=0.0015) and apolipoprotein A1 (apoA1) (GG 1.44+/-0.21, GC 1.40+/-0.20, CC 1.38+/-0.21mmol/L, p=0.0118). The opposite genotype effect was present in systolic (GG 127+/-13.1, GC 129+/-13.1, CC 130+/-14.3mmHg, p=0.0382) and diastolic blood pressure (GG 73.8+/-9.14, GC 75.1+/-8.68, CC 75.9+/-9.70mmHg, p=0.0374). The genetic effect size for these parameters was not significant in women., Conclusions: IL6 -174 allele G homozygozity associates with beneficial profile of early predictors of atherosclerosis such as high CAC, HDL-C and apoA1 as well as low systolic and diastolic blood pressure in men.

Atherosclerosis is characterized by a prominent inflammatory component and C-reactive protein (CRP) has been implicated to modulate the complement activity in atherosclerotic arteries via complement factor H (CFH) binding. In this study, we examined whether the gene-gene interactions between CRP haplotypes and CFH Tyr402His functional polymorphism exerted an effect on early atherosclerosis. Single nucleotide polymorphisms (SNPs) in CFH (Tyr402His) and CRP (-717A>G, -286C >T>A, +1059G>C, +1444C>T and +1846G>A) were genotyped in the participants of the Cardiovascular Risk in Young Finns Study (n=1698, aged 24-39 years). The CRP SNPs were further constructed into haplotypes and their interactive effects with the CFH Tyr402His polymorphism on the early atherogenic vascular changes [i.e. carotid artery compliance (CAC) and intima-media thickness (IMT)] were examined. After risk factor adjustment, a significant gene-gene interaction (P=0.007) on CAC was observed between CRP haplotype ATGTG and CFH Tyr402His polymorphism in males. Furthermore, logistic regression analysis verified the risk-modifying interactive effect on CAC between these loci (OR 3.70, 95% CI 1.37-10.02, P=0.010). No effects on CAC were observed in females and no effects on IMT were detected in either sex. We conclude that the combined presence of CRP haplotype ATGTG and CFH 402His allele may be disadvantageous to carotid artery elasticity in males.

Individuals suffering from ATH (adult-type hypolactasia), defined by the LCT (gene encoding lactase-phlorizin hydrolase) C/C(-13910) genotype (rs4988235), use less milk and dairy products and may have higher plasma HDL (high-density lipoprotein) and lower triacylglycerol (triglyceride) concentrations than their counterparts without ATH. To investigate the effects of ATH status on the early markers of atherosclerosis, we examined its association with CIMT (carotid intima-media thickness), CAC (carotid artery compliance) and brachial artery FMD (flow-mediated dilation) in a young population-based cohort of otherwise healthy individuals. As part of the Cardiovascular Risk in Young Finns Study, we performed CIMT, CAC and FMD analyses, LCT C/T(-13910) genotyping and risk factor determination in 2109 young subjects 24-39 years of age (45% males) at the time of the examination. The consumption of both milk and dairy products was lowest and the consumption of alcohol highest in subjects with the C/C(-13910) genotype (P<0.001 for all) in comparison with subjects without ATH (TT+CT). In multivariate analysis, no significant association between ATH status and CIMT, CAC or brachial artery FMD was found after adjustment for the use of alcohol, dairy products and all other major risk factors of coronary artery disease. In otherwise similar statistical analysis, the results remained non-significant when females and males were analysed in their own groups. In conclusion, the finding does not support the involvement of ATH in the pathogenesis of early atherosclerosis.

Background: Children with persistent Chlamydia pneumoniae infection may be at increased risk for atherosclerosis. The impact of antimicrobial therapy for primary prevention of atherosclerotic cardiovascular disease is unsolved., Objective: The purpose of this study was to determine whether treatment with antimicrobial agents effective against C pneumoniae during childhood, regardless of indication, has a favorable influence on the arterial wall-thickness in children by the time they reach adolescence., Subjects and Methods: The association of macrolide, tetracycline, quinolone, and rifamycin use (number of exposure events) between ages 5 and 13 years with carotid and aortic intima-media thickness at age 13 years was investigated among 508 healthy children. Information about the use of medications was obtained from the Finnish prescription register. Arterial intima-media thickness was measured with a high-resolution ultrasound., Results: Mean aortic intima-media thickness showed a significant direct association with the number of antichlamydial antimicrobial exposure events also after controlling for established atherosclerotic risk factors. Elevated C-reactive protein level had an additional effect on aortic intima-media thickness in a multivariable model. Carotid intima-media thickness was not associated with the number of preceding antichlamydial treatments., Conclusions: Recurrent antichlamydial treatments in childhood have no favorable influence on early vascular changes but are associated with increased intima-media thickness in the abdominal aorta. These findings suggest that the use of antimicrobial agents does not offer protection against the potential atherogenicity of repeated infectious insults.

We investigated the associations of anger and cynicism with carotid artery intima-media thickness (IMT) and whether these associations were moderated by childhood or adulthood socioeconomic status (SES). The participants were 647 men and 893 women derived from the population-based Cardiovascular Risk in Young Finns Study. Childhood SES was measured in 1980 when the participants were aged 3-18. In 2001, adulthood SES, anger, cynicism, and IMT were measured. There were no associations between anger or cynicism and IMT in the entire population, but anger was associated with thicker IMT in participants who had experienced low SES in childhood. This association persisted after adjustment for a host of cardiovascular risk factors. It is concluded that the ill health-effects of psychological factors such as anger may be more pronounced in individuals who have been exposed to adverse socioeconomic circumstances early in life.

Objective: To study whether the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism or serum homocysteine concentration is associated with carotid artery intima media thickness (IMT), carotid artery compliance (CAC) or brachial artery flow mediated dilatation (FMD) in a healthy Finnish adult population., Methods: Cross-sectional data obtained in 2001 for the Cardiovascular Risk in Young Finns Study were used. Carotid artery IMT, CAC and brachial FMD were measured by ultrasound and serum homocysteine concentrations using a commercial immunoassay kit. We studied 1,440 subjects (aged 24-39 years). Genotyping was performed using the 5' nuclease TaqMan assay., Results: Homocysteine values differed between genotypes in women and men (ANOVA, p<0.001 for both sex groups): the genotype raised values in the order of CC, CT, TT. There was a significant difference in CAC values between the MTHFR genotypes in men (ANOVA, p = 0.008), and the CC genotype had the lowest values. In multivariate linear regression analysis adjusted for other major coronary risk factors (e.g. age, smoking, body mass index, systolic blood pressure, C-reactive protein), the association remained significant (R (2) = 25.8 %, beta = 0.091; p = 0.02). Homocysteine level was directly associated with CAC in the whole population (R (2) = 18.0 %, beta = 0.012; p = 0.014) and in women (R (2) = 9.3%, beta = 0.02; p = 0.013), but not in men (R (2) = 15.2 %, beta = 0.004; p = 0.444). We found no association between homocysteine level or the MTHFR polymorphism and carotid IMT or brachial artery FMD., Conclusions: The findings suggest that the MTHFR polymorphism does not influence IMT or FMD, but that the T allele may have an effect on CAC in men.

Background: Carotid artery intima-media thickness (IMT), which is measured by ultrasound, is used in the assessment of early atherosclerotic changes, and has been associated with apolipoprotein E (APOE) polymorphism in many studies comprising elderly subjects. However, results are still inconclusive and data relating to young adults are missing. Whether common APOE polymorphism is related to carotid IMT was studied in a population of young adults. Also brachial flow-mediated dilatation (FMD) and carotid artery compliance (CAC) were determined to clarify their relation to this genetic factor., Methods and Results: A total of 1,188 young adults (aged 24-39 years) participating in the Cardiovascular Risk in Young Finns Study with complete data of common APOE polymorphism underwent a carotid and brachial ultrasound. Patients' lipid levels and blood pressure were also examined. There was no significant association between the APOE phenotypes and carotid IMT, brachial FMD or CAC either in young men or in young women. The results were similar for systolic and diastolic blood pressure. In the same population, the well-known association between APOE phenotypes and lipids was seen., Conclusions: Common APOE polymorphism does not seem to be an independent genetic determinant of carotid IMT, brachial FMD or CAC.

Background: Atherosclerosis development might be delayed or prevented by dietary measures. The aims of the present study were to evaluate the effect of low-saturated-fat, low-cholesterol dietary counseling on fat intakes, growth, serum cholesterol values, and pubertal development in children and adolescents., Methods and Results: In the randomized prospective Special Turku Coronary Risk Factor Intervention Project (STRIP), a low-saturated-fat, low-cholesterol diet was introduced to intervention infants (n=540) at 7 months of age, and control children (n=522) received an unrestricted diet. Dietary intakes, serum cholesterol values, somatic growth, and development were followed up throughout childhood and adolescence. Saturated fat intakes, serum total cholesterol, and low-density lipoprotein cholesterol values were lower (P<0.001) in the intervention than in control children during the 14 years, whereas high-density lipoprotein cholesterol values in the 2 study groups showed no difference. Boys had lower total and low-density lipoprotein cholesterol concentrations than girls throughout childhood (P<0.001), and the intervention effect on serum cholesterol concentration was larger in boys than girls. The 2 study groups showed no difference in growth, body mass index, pubertal development, or age at menarche (median, 13.0 and 12.8 years in the intervention and control girls, respectively; P=0.52). The cholesterol values decreased as puberty progressed. Mean concentrations of total and high-density lipoprotein cholesterol decreased from approximately 4.5 and approximately 1.4 mmol/L, respectively, in Tanner stage 1 (prepubertal) boys to approximately 3.9 and approximately 1.1 mmol/L in Tanner stage 4 (late pubertal) boys., Conclusions: Repeated dietary counseling remains effective in decreasing saturated fat and cholesterol intake and serum cholesterol values at least until 14 years of age. Puberty markedly influences serum cholesterol concentrations.

Background: The present study was designed to investigate the effects of apoB XbaI and apoA-I/C-III/A-IV SstI polymorphisms to carotid artery intima-media thickness (IMT), carotid artery compliance (CAC) and brachial artery flow-mediated vasodilatation (FMD)., Methods and Results: As part of the Cardiovascular Risk in Young Finns Study, the carotid IMT, CAC and brachial FMD of 2,265 subjects (mean age +/- SD 32 +/-5 years) were measured with ultrasonography, and genotyping of the apolipoprotein polymorphisms was performed. The frequencies of the genotypes did not differ between the groups with high (above median 0.57 mm) and low (below median) IMT, CAC or FMD. The average carotid IMT differed between the 3 apoB XbaI genotypes (ANOVA, p=0.04), but not between the apoA-I/C-III/A-IV SstI genotypes (ANOVA, p=0.53). The relationship between the polymorphisms and carotid IMT was not significant in any of the covariate-adjusted logistic and linear regression analyses. CAC and FMD were not influenced by either of the polymorphisms in ANOVA and regression analyses., Conclusions: The polymorphisms apoA-I/C-III/A-IV SstI and apoB XbaI do not seem to affect carotid artery characteristics or brachial artery FMD in young adulthood.

Indoleamine 2,3 dioxygenase (IDO), an enzyme involved in the catabolism of tryptophan, suppresses T cell activity and is up-regulated by various inflammatory stimuli. The ratio of kynurenine, the main metabolite of tryptophan, to tryptophan (kyn/trp) reflects IDO activity. We calculated IDO activity and measured carotid intima-media thickness (IMT), a presymptomatic predictor of atherosclerosis, in 986 young adults (544 female, 442 male) for whom data on levels of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride, high sensitive C-reactive protein (CRP), body mass index (BMI), waist circumference, waist-to-hip ratio, systolic and diastolic blood pressure and smoking habits were available. IDO activity correlated significantly with IMT in female subjects, but not in males. In a multivariate linear regression model, IDO did not correlate independently with IMT in female subjects. However, IDO activity correlated significantly with several risk factors for atherosclerosis in females, i.e. with age, LDL-C, BMI, weakly with CRP and inversely with HDL-C and triglyceride. In males IDO activity correlated significantly with CRP and inversely with HDL-C. In conclusion, our results suggest that the IDO enzyme is involved in the immune regulation of early atherosclerosis, particularly in young female adults, and could constitute a novel marker of immune activation in early atherosclerosis in females.

There is a growing body of evidence attesting the significance of inflammation in the pathogenesis of atherosclerosis. Protein tyrosine phosphate PTPN22 C/T single nucleotide polymorphism (SNP) at + 1858 has been identified recently as a susceptibility factor for various inflammatory autoimmune diseases. We hypothesized that data on the genetic polymorphism of the PTPN22 enzyme associated with an increased risk of autoimmunity could also provide insight into the possible role of autoimmunity in the pathogenesis of atherosclerosis. Therefore we analysed the PTPN22 + 1858 C/T polymorphism in a population of young Finnish adults (n = 2268) for whom data on carotid artery intima-media thickness (IMT), a presymptomatic predictor of atherosclerosis, and risk factors for atherosclerosis were available. In males carriage of the T allele of PTPN22 + 1858 was associated significantly with IMT in univariate and multivariate analyses, while in females it was associated with several risk factors for atherosclerosis (BMI, waist circumference, waist-to-hip ratio, serum concentrations of C-reactive protein and triglycerides) but not with IMT. Our results indicate that the genetic polymorphism of PTPN22 + 1858 known to predispose to autoimmunity also enhances the development of atherosclerosis and thereby links the genetics of autoimmunity and atherosclerosis.

Context: Recent data indicate a marked increase in the prevalence of obesity among school-aged children. Thus, efficacious programmes that prevent overweight development in children are urgently needed., Objective: To evaluate the impact of repeatedly given, individualised dietary and lifestyle counselling on the prevalence of overweight during the first 10 years of life., Design and Participants: This study was a part of the Special Turku Coronary Risk Factor Intervention Project for Children (STRIP), which is a prospective, randomised trial aimed at reducing the exposure of the intervention children to the known risk factors of atherosclerosis. At the child's age of 7 months, 1062 children were assigned to an intervention group (n=540) or to a control group (n=522). The intervention children received individualised counselling focused on healthy diet and physical activity biannually. Height and weight of the children were measured at least once a year., Main Outcome Measure: Prevalence of overweight and obesity among the intervention and control children by sex and age. Children were classified as overweight or obese if their weight for height was >20% or > or =40% above the mean weight for height of healthy Finnish children, respectively., Results: After the age of 2 years, there were continuously fewer overweight girls in the intervention group than in the control group. At the age of 10 years, 10.2% of the intervention girls and 18.8% of the control girls were overweight (P=0.0439), whereas 11.6% of the intervention boys and 12.1% of the control boys were overweight (P approximately 1.00). Only three children in the intervention group were obese at some age point, whereas 14 control children were classified as obese at some age point., Conclusion: Individualised dietary and lifestyle counselling given twice a year since infancy decreases prevalence of overweight in school-aged girls even without any primary energy restrictions.

Aims: Eastern Finns have higher risk of coronary heart disease (CHD) and carotid intima-media thickness than western Finns although current differences in CHD risk factors are minimal. Left ventricular (LV) mass and diastolic function predict future cardiovascular events but their east–west differences are unknown. We examined the association of eastern/western baseline origin with LV mass and diastolic function. Methods : The study population included 2045 subjects of the Cardiovascular Risk in Young Finns Study with data from the baseline survey (1980) and the latest follow-up (2011) when echocardiography was performed at the age of 34–49 years. Results: Subjects with eastern baseline origin had in 2011 higher LV mass (139±1.0 vs. 135±1.0 g, p=0.006) and E/e′-ratio indicating weaker LV diastolic function (4.86±0.03 vs. 4.74±0.03, p=0.02) than western subjects. Results were independent of age, sex, area of examination and CHD risk factors such as blood pressure and BMI (LV mass indexed with height: p<0.0001; E/e′-ratio: p=0.01). LV end-diastolic volume was higher among subjects with eastern baseline origin (135±0.9 vs. 131±0.9 ml, p=0.0011) but left atrial end-systolic volume, also indicating LV diastolic function, was not different between eastern and western subjects (43.4±0.5 vs. 44.0±0.5 ml, p=0.45). Most of the subjects were well within the normal limits of these echocardiographic measurements. Conclusions: In our healthy middle-aged population, geographic origin in eastern Finland associated with higher LV mass compared to western Finland. Higher E/e′-ratio suggests that subjects with eastern baseline origin might have higher prevalence of diastolic dysfunction in the future than western subjects. [ABSTRACT FROM AUTHOR]

The intake of polyunsaturated fatty acids (PUFAs) is generally linked with a reduced cardiovascular disease (CVD) risk, but an elevated n6PUFA intake, without simultaneous n3PUFA supply, may elevate the risk. PUFAs are suspected as being easily oxidized and have a potential role in lipoprotein oxidation and inflammation. Saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs) are resistant to oxidation. However, in a Western diet, their most important source is red meat, a food stuff rich in heme iron which can catalyze oxidative reactions. Therefore, different serum fatty acid (FA) proportions (free + esterified) were correlated with the status of low-density lipoprotein (LDL) oxidation in vivo (conjugated dienes = oxLDLlipids and antibody-based oxidized proteins = oxLDLprot) and inflammation (serum CRP) in 2196 Finnish subjects (age: 24-39 years) using CVD risk factor-adjusted linear regression models. High n6PUFA, PUFA/SFA and n6/n3 ratios, and low SFA and MUFA were all associated with reduced levels of oxLDLlipids, oxLDLprot, and CRP. These findings at the population level suggest that PUFAs are negatively and SFAs and MUFAs positively related with LDL oxidation and inflammation; these conclusions are in line with previous observations linking PUFAs, particularly n6PUFAs, with lower CVD risk, and SFAs with increased risk. [ABSTRACT FROM AUTHOR]

Summary Human cytomegalovirus (CMV) infection is associated with a higher risk of cardiovascular disease in immunocompromised organ transplant patients. It has been linked with the pathogenesis of elevated arterial blood pressure. However, controversy exists as to whether CMV infection is associated with endothelial function, and little is known about its role as a potential risk factor for early atherosclerosis development at a young age. We aimed to discover if CMV antibody titres are associated with early vascular changes (carotid intima-media thickness, carotid artery distensibility and brachial artery flow-mediated dilation), blood pressure elevation or other traditional cardiovascular risk factors. CMV antibody titres were measured in 1074 women and 857 men (aged 24-39 years) taking part in the Cardiovascular Risk in Young Finns study. CMV antibody titres were significantly higher in women compared to men. In men, high CMV antibody titres were associated directly with age ( P < 0·001) and systolic ( P = 0·053) and diastolic ( P = 0·002) blood pressure elevation, and associated inversely with flow-mediated dilation ( P = 0·014). In women, CMV antibody titres did not associate with any of the analysed parameters. In a multivariate regression model, which included traditional atherosclerotic risk factors, CMV antibody titres were independent determinants for systolic ( P = 0·029) and diastolic ( P = 0·004) blood pressure elevation and flow-mediated dilation ( P = 0·014) in men. High CMV antibody titres are associated independently with blood pressure and brachial artery flow-mediated dilation in young men. This association supports the hypothesis that common CMV infection and/or an immune response to CMV may lead to impaired vascular function at a young age. [ABSTRACT FROM AUTHOR]

Background/Objectives:Dietary habits have a major role in obesity, type 2 diabetes and atherosclerotic cardiovascular diseases. In this study, we compared the effects of sea buckthorn (SB) and its fractions, and bilberries (BBs) on associated variables of metabolic diseases on overweight and obese women.Subjects/Methods:In total, 110 female volunteers were recruited, and they followed four different berry diets (BB, SB, SB phenolic extract (SBe) and SB oil (SBo)) in a randomized order for 33-35 days. Each intervention was followed by a wash-out period of 30-39 days. Blood samples were drawn and physical measurements were performed after each period. Eighty volunteers completed the study.Results:There was statistically significant decrease in waist circumference after BB (Δ, −1.2 cm; P=0.041) and SB (Δ, −1.1 cm; P=0.008) periods and also a small decrease in weight after BB diet (Δ, −0.2 kg; P=0.028). Vascular cell adhesion molecule decreased after BB (Δ, −49.8 ng/ml; P=0.002) and SBo (Δ, −66.1 ng/ml; P=0.001) periods, and in intercellular adhesion molecule (ICAM) after SBe diet (Δ, −6.1 ng/ml; P=0.028).Conclusions:Based on the results, it can be stated that different berries and berry fractions have various but slightly positive effects on the associated variables of metabolic diseases. [ABSTRACT FROM AUTHOR]

The role of the inflammatory mediator C-reactive protein (CRP) in atherosclerosis is recognized although its specific functions are not entirely clear. CRP binds to the Fcγ receptor2A (FcγR2A) and its polymorphism, FCGR2A (Arg131His), strongly influences the binding. We wanted to evaluate the CRP-mediated proatherogenic process on early atherosclerosis and investigated whether CRP and FCGR2A show an interactive effect on carotid intima-media thickness (IMT). Polymorphisms of FCGR2A (Arg131His) and CRP (–717A > G, –286C > T > A, +1059G > C, +1444C > T and +1846G > A) were genotyped and their effects on IMT were analyzed in 2260 young adults participating in the Cardiovascular Risk in Young Finns Study. CRP haplotypes were constructed based on the CRP polymorphisms. The FCGR2A(Arg131His) polymorphism did not have an independent effect on IMT but a significant gene-gene interaction, epistasis, between FCGR2A and CRP genetics on IMT was found. The epistatic effect was seen in men at haplotype and genotypic level; both CRP haplotype GCGCG (–717, –286, +1059, +1444 and +1846) and CRP–717A > G polymorphism interacted with FCGR2A(Arg131His) on IMT. After adjustment with classical risk factors the P-values for interaction were P = 0.013 and P = 0.010, respectively. No associations were observed in women. In conclusion, this study showed that the effect of CRP genetics on early atherosclerotic changes is modulated by the FCGR2A genetics. [ABSTRACT FROM AUTHOR]

Objectives. The prevalence of the metabolic syndrome is increasing worldwide. We studied its prevalence in Finnish young adults. Three definitions were applied: National Cholesterol Education Program (NCEP), European Group for the Study of Insulin Resistance (EGIR) and International Diabetes Federation (IDF) criteria. We also investigated the secular trend in the metabolic syndrome amongst 24-year-old adults from 1986 to 2001. Design. Population-based follow-up study. Subjects. 2182 healthy young adults (1007 men; 1175 women) aged 24–39 years. Main outcome measures. Metabolic syndrome and its components. Results. The prevalence of the metabolic syndrome was 13.0% with NCEP criteria, 9.8% with EGIR criteria and 14.3% with IDF criteria. With NCEP and IDF criteria, the prevalence increased with age in both sexes, but more dramatically in men. There was over sixfold increase in the metabolic syndrome from 4.0% to 25.2% ( P < 0.0001) in men between ages 24 and 39 years using the IDF criteria. Increases in obesity and serum triglycerides accounted much for the increase in the prevalence by age. The significant secular trend was seen between years 1986 and 2001 in 24-year-old subjects. The prevalence of the metabolic syndrome increased significantly from 1.0% to 7.5% ( P < 0.0001) in 15 years. Conclusions. There is a substantial increase in the prevalence of the metabolic syndrome in healthy young adults between ages 24 and 39 driven mostly by the increase in obesity. The prevalence of the metabolic syndrome is higher amongst Finnish young adult men compared with women. The secular trend between 1986 and 2001 suggest a dramatic increase in the prevalence of the metabolic syndrome in 24-year-old young adults. Condensed abstract The prevalence of the metabolic syndrome may be increasing in young people. We studied the prevalence of the metabolic syndrome in 2182 young Finnish adults aged 24–39 years using NCEP, EGIR and IDF criteria. The prevalence of the metabolic syndrome was higher amongst Finnish men than women and increased dramatically with age. There was also a dramatic increase in the prevalence of the metabolic syndrome in 24-year-old adults between 1986 and 2001. [ABSTRACT FROM AUTHOR]

Objective:To assess prospectively the consumption of fruit and vegetables and its' correlation to the parental consumption in boys and girls taking part in an atherosclerosis prevention study (Special Turku Coronary Risk Factor Intervention Project for Children (STRIP) study).Hypothesis:Nutrition counselling focused on cardiovascular health effects vegetable and fruit consumption.Design:A prospective, randomised, clinical trial.Subjects:Children were recruited to the STRIP study between 1989 and 1992. At the age of 7 months, children were randomised to the intervention (n=540) or the control group (n=522) and were followed up until the age of 11 years.Intervention:Families in the intervention group have, since randomisation, received biannual individualised dietary counselling aimed at reduction of cardiovascular risk factors, especially saturated fat intake. Food records were used to assess fruit and vegetable consumption of children and parents.Results:The percentage of total energy intake provided by fruit and vegetables decreased when the children grew older (P for age <0.001). The 1- to 10-year-old intervention boys consumed more vegetables (mean difference 3.18 g/day; CI 1.48–4.86; P<0.001) and fruit (mean difference 10.1 g/day; CI 5.28–14.94; P<0.001) than did the control. Mother's consumption correlated with the consumption of their daughters and sons, whereas father's consumption correlated only with the consumption of their sons.Conclusions:Finnish children taking part in the atherosclerosis prevention study had a remarkably low fruit and vegetable consumption, which furthermore decreased with age. The children's consumption correlated with the parental consumption, except between boys and mothers. A slight intervention effect was present only among boys.European Journal of Clinical Nutrition (2006) 60, 172–180. doi:10.1038/sj.ejcn.1602283; published online 12 October 2005 [ABSTRACT FROM AUTHOR]

This review covers two ongoing studies in Finland: the Cardiovascular Risk in Young Finns study, which started in 1978, and the Special Turku Coronary Risk Factor Intervention Project for Children (STRIP), which started in 1989. In the cross-sectional Cardiovascular Risk in Young Finns study, cardiovascular risk factors were first assessed in 1980 in 3596 children and adolescents covering ages between 3 and 18 y at 3-y intervals. The latest follow-up examination was performed in 2001, when risk factors and early markers of atherosclerosis in carotid and brachial arteries were examined in 2264 subjects from the original cohorts, now covering ages from 24 to 39 y. The results clearly show that an individual's coronary heart disease (CHD) risk factor profile is regulated by early lifestyle-related factors and that exposure to risk factors in childhood induces changes in arteries that contribute to the development of atherosclerosis in adulthood. In the STRIP study, 1062 infants were randomized into an intervention group ( n = 540; low-saturated-fat, low-cholesterol diet) or a control group ( n = 522) at 7 mo of age. Fat, saturated fat and cholesterol intakes have been lower, while the polyunsaturated to saturated fat ratio has been higher in the intervention children than in the control children throughout the ongoing trial. During the first 7 y of life, serum cholesterol concentration was 0.2-0.3 mmol/l lower in the intervention boys than in the control boys, but the difference was negligible in girls. Neurological development of the intervention children at age 5 y was at least as good as that of the control children. Counselling had no effect on children's growth. [ABSTRACT FROM AUTHOR]

Unlabelled: Overweight and obesity are increasing in Swedish boys and girls aged 7-16 y. The fitness of 16-y-old Swedish boys in 2001 was approximately 10% worse than in 1987.Conclusion: It is important to start the prevention of atherosclerosis and type 2 diabetes early. The number of children with physical inactivity and obesity should be as low as possible. [ABSTRACT FROM AUTHOR]

Abstract Background The role of atherosclerosis in carpal tunnel syndrome (CTS) has not previously been addressed in population studies. The aim of this study was to investigate the associations of cardiovascular risk factors, carotid artery intima-media thickness (IMT), and clinical atherosclerotic diseases with CTS. Methods In this cross sectional study, the target population consisted of subjects aged 30 or over who had participated in the national Finnish Health Survey in 2000-2001. Of the 7977 eligible subjects, 6254 (78.4%) were included in our study. Carotid IMT was measured in a sub-sample of subjects aged 45 to 74 (N = 1353). Results Obesity (adjusted odds ratio (OR) 2.4, 95% confidence interval (CI) 1.1-5.4), high LDL cholesterol (OR 3.8, 95% CI 1.6-9.1 for >190 vs. 200 vs. Conclusions Our findings suggest an association between CTS and cardiovascular risk factors in young people, and carotid IMT and clinical atherosclerotic vascular disease in older people. CTS may either be a manifestation of atherosclerosis, or both conditions may share similar risk factors.

Objective To determine associations of systemic metabolites with subclinical atherosclerosis. Methods 4407 serum samples were measured by nuclear magnetic resonance (NMR) spectroscopy from the Cardiovascular Risk in Young Finns Study, and carotid intima-media thickness (IMT) was assessed by ultrasound. Numerous lipoprotein lipids subclasses as well as low-molecular-weight metabolites were quantified from the NMR data. Results In these young adults (aged 24-45 years) data-driven analysis using self-organising maps showed distinct metabolic phenotypes associated with elevated IMT. The phenotypes were characterised by varying combinations of metabolic disturbances including elevated very-low-density lipoprotin (VLDL) and LDL subclasses, but also several low-molecular-weight metabolites. Results for 6-year incidence of high carotid IMT and IMT progression as shown by discrimination and reclassification will also be discussed. Conclusion The study showed different metabolic phenotypes inherently associated with subclinical atherosclerosis. Prediction of subclinical atherosclerosis was improved by comprehensive metabolic profiling. The findings substantiate developments towards the use of multi-metabolic risk phenotypes in cardiovascular risk assessment. [ABSTRACT FROM AUTHOR]