Childhood predictors of adult fatty liver. The Cardiovascular Risk in Young Finns Study.

BACKGROUND & AIMS: Fatty liver is a potentially preventable cause of serious liver diseases. This longitudinal study aimed to identify childhood risk factors of fatty liver in adulthood in a population-based group of Finnish adults. METHODS: Study cohort included 2,042 individuals from the Cardiovascular Risk in Young Finns Study aged 3-18years at baseline in 1980. During the latest follow-up in 2011, the liver was scanned by ultrasound. In addition to physical and environmental factors related to fatty liver, we examined whether the genetic risk posed by a single nucleotide polymorphism in the patatin-like phospholipase domain-containing protein 3 gene (PNPLA3) (rs738409) strengthens prediction of adult fatty liver. RESULTS: Independent childhood predictors of adult fatty liver were small for gestational age, (odds ratio=1.71, 95% confidence interval=1.07-2.72), variant in PNPLA3 (1.63, 1.29-2.07 per one risk allele), variant in the transmembrane 6 superfamily 2 gene (TM6SF2) (1.57, 1.08-2.30), BMI (1.30, 1.07-1.59 per standard deviation) and insulin (1.25, 1.05-1.49 per standard deviation). Childhood blood pressure, physical activity, C-reactive protein, smoking, serum lipid levels or parental lifestyle factors did not predict fatty liver. Risk assessment based on childhood age, sex, BMI, insulin levels, birth weight, TM6SF2 and PNPLA3 was superior in predicting fatty liver compared with the approach using only age, sex, BMI and insulin levels (C statistics, 0.725 vs. 0.749; p=0.002). CONCLUSIONS: Childhood risk factors on the development of fatty liver were small for gestational age, high insulin and high BMI. Prediction of adult fatty liver was enhanced by taking into account genetic variants in PNPLA3 and TM6SF2 genes. LAY SUMMARY: The increase in pediatric obesity emphasizes the importance of identification of children and adolescents at high risk of fatty liver in adulthood. We used data from the longitudinal Cardiovascular Risk in Young Finns Study to examine the associations of childhood (3-18years) risk variables with fatty liver assessed in adulthood at the age of 34-49years. The findings suggest that a multifactorial approach with both lifestyle and genetic factors included would improve early identification of children with a high risk of adult fatty liver.

Prolonged sleep restriction induces changes in pathways involved in cholesterol metabolism and inflammatory responses.

Sleep loss and insufficient sleep are risk factors for cardiometabolic diseases, but data on how insufficient sleep contributes to these diseases are scarce. These questions were addressed using two approaches: an experimental, partial sleep restriction study (14 cases and 7 control subjects) with objective verification of sleep amount, and two independent epidemiological cohorts (altogether 2739 individuals) with questions of sleep insufficiency. In both approaches, blood transcriptome and serum metabolome were analysed. Sleep loss decreased the expression of genes encoding cholesterol transporters and increased expression in pathways involved in inflammatory responses in both paradigms. Metabolomic analyses revealed lower circulating large HDL in the population cohorts among subjects reporting insufficient sleep, while circulating LDL decreased in the experimental sleep restriction study. These findings suggest that prolonged sleep deprivation modifies inflammatory and cholesterol pathways at the level of gene expression and serum lipoproteins, inducing changes toward potentially higher risk for cardiometabolic diseases.

Repeated Blood Pressure Measurements in Childhood in Prediction of Hypertension in Adulthood.

Hypertension may be predicted from childhood risk factors. Repeated observations of abnormal blood pressure in childhood may enhance prediction of hypertension and subclinical atherosclerosis in adulthood compared with a single observation. Participants (1927, 54% women) from the Cardiovascular Risk in Young Finns Study had systolic and diastolic blood pressure measurements performed when aged 3 to 24 years. Childhood/youth abnormal blood pressure was defined as above 90th or 95th percentile. After a 21- to 31-year follow-up, at the age of 30 to 45 years, hypertension (>140/90 mm Hg or antihypertensive medication) prevalence was found to be 19%. Carotid intima-media thickness was examined, and high-risk intima-media was defined as intima-media thickness >90th percentile or carotid plaques. Prediction of adulthood hypertension and high-risk intima-media was compared between one observation of abnormal blood pressure in childhood/youth and multiple observations by improved Pearson correlation coefficients and area under the receiver operating curve. When compared with a single measurement, 2 childhood/youth observations improved the correlation for adult systolic (r=0.44 versus 0.35, P<0.001) and diastolic (r=0.35 versus 0.17, P<0.001) blood pressure. In addition, 2 abnormal childhood/youth blood pressure observations increased the prediction of hypertension in adulthood (0.63 for 2 versus 0.60 for 1 observation, P=0.003). When compared with 2 measurements, third observation did not provide any significant improvement for correlation or prediction (P always >0.05). A higher number of childhood/youth observations of abnormal blood pressure did not enhance prediction of adult high-risk intima-media thickness. Compared with a single measurement, the prediction of adult hypertension was enhanced by 2 observations of abnormal blood pressure in childhood/youth.

Television viewing and fatty liver in early midlife. The Cardiovascular Risk in Young Finns Study.

INTRODUCTION: Both sedentary behaviour and fatty liver are associated with increased risk of obesity and non-communicable diseases, but their relationship remains unknown. We investigated the relationship of television (TV) viewing time with serum gamma-glutamyltransferase (GGT) and Fatty Liver Index (FLI), and ultrasonographically assessed liver fat. METHODS: A total of 1,367 adults of the population-based Cardiovascular Risk in Young Finns study (748 women, 619 men, aged 34-49 years) had fasting serum GGT, triglycerides, weight, height, and waist circumference, and self-reported TV time data from 2001, 2007, and 2011. Changes in GGT and FLI, and liver ultrasound images in 2011 were studied in groups with constantly low (≤ 1 h/d), moderate (1-3 h/d), or high (≥ 3 h/d) daily TV time, and in groups with ≥ 1 hour increase/decrease in daily TV time between 2001 and 2011. RESULTS: Constantly high TV time was associated with higher GGT and FLI (P < 0.02 in both), and 2.3-fold (95% CI 1.2-4.5) increased risk of fatty liver regardless of age, sex, leisure-time and occupational physical activity, energy intake, diet composition, alcohol use, sleep duration, socioeconomic status, and smoking. Adjustment for BMI partly attenuated the associations. CONCLUSIONS: High TV viewing increases fatty liver risk. It may be one mechanism linking sedentary behaviour with increased cardiometabolic disease risks.

Lifetime measures of ideal cardiovascular health and their association with subclinical atherosclerosis: The Cardiovascular Risk in Young Finns Study.

BACKGROUND: The American Heart Association recently defined 7 ideal health behaviors and factors that can be used to monitor ideal cardiovascular health (ICH) over time. These relate to smoking, physical activity, diet, body mass index (BMI), blood pressure, blood glucose and total cholesterol. Associations between repeated measures of ICH across the life-course with outcomes of subclinical atherosclerosis in adult life have not been reported. METHODS AND RESULTS: The sample comprised 1465 children and young adults aged 12 to 24 years (mean age 17.5 years) from the Cardiovascular Risk in Young Finns Study cohort. Participants were followed-up for 21 years since baseline (1986) and had complete ICH data available at baseline and follow-up. Average lifetime ICH index was associated with reduced risk of coronary artery calcification (CAC) (P=0.0004), high-risk carotid intima-media thickness (IMT) (P=0.0005) and high-risk carotid distensibility (<0.0001) in middle age. Participants with persistently low ICH status (lower than the median), as compared with persons with persistently high ICH status (higher than the median), had an increased risk of CAC (P=0.02), high-risk IMT (P=0.02), and high-risk distensibility (P<0.0001). Participants who improved their ICH status from low to high did not have a different risk of CAC (P=0.90), high-risk IMT (P=0.25), or high-risk distensibility (P=0.80) than participants who always had high ICH status. CONCLUSIONS: The results show that ICH can be lost and regained, and importantly that regaining of ICH has a beneficial effect on cardiometabolic health. Health care providers should work to improve health behaviors especially in those who have lost ICH.

Adult dyslipidemia prediction is improved by repeated measurements in childhood and young adulthood. The Cardiovascular Risk in Young Finns Study.

BACKGROUND: Prediction of adult dyslipidemia has been suggested to improve with multiple measurements in childhood or young adulthood, but there is paucity of specific data from longitudinal studies. METHODS AND RESULTS: The sample comprised 1912 subjects (54% women) from the Cardiovascular Risk in Young Finns Study who had fasting lipid and lipoprotein measurements collected at three time-points in childhood/young adulthood and had at least one follow-up in later adulthood. Childhood/young adult dyslipidemia was defined as total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C) or triglycerides (TG) in the highest quintile, or high-density lipoprotein cholesterol (HDL-C) in the lowest quintile. Adult dyslipidemia was defined according to European cut-points (TC > 5.0 mmol/L, LDL-C >3 mmol/L, Non-HDL-C >3.8 mmol/L, HDL-C <1.0 mmol/L (in men)/<1.2 mmol/L (in women) and TG > 1.7 mmol/L). With the exception of triglycerides, Pearson correlation coefficients for predicting adult levels significantly improved when two lipid or lipoprotein measurements in childhood/young adulthood were compared with one measurement (all P < 0.01). For triglycerides, there was significant improvement only when three measurements were considered (P = 0.004). Two measurements significantly improved prediction of dyslipidemia levels in adulthood for non-HDL-C, LDL-C, HDL-C and TG compared with one measurement (P < 0.05 for improved area-under the receiver-operating characteristic curve). Risk of dyslipidemia in adulthood grew according to the number of times a person had been at risk in childhood. CONCLUSIONS: Based on these results, it seems that compared to a single measurement two lipid measures in childhood/early adulthood significantly improve prediction of adult dyslipidemia. A lack of dyslipidemia in childhood does not strongly exclude later development of dyslipidemia. Multiple measurements increase the prediction accuracy, but the incremental prognostic/diagnostic accuracy of especially third measurement is modest.

Prevalence and determinants of fatty liver in normal-weight and overweight young adults. The Cardiovascular Risk in Young Finns Study.

BACKGROUND AND AIMS: Fatty liver may have different determinants in normal-weight and in obese individuals. We measured factors associated with fatty liver in 863 normal-weight (BMI < 25) and 1135 overweight/obese (BMI ≥ 25) young and middle-aged adults (45% male, age 34-49 years) in the population-based Cardiovascular Risk in Young Finns Study. METHODS AND RESULTS: The prevalence of fatty liver detected with ultrasound was 29% in overweight/obese and 5% in normal-weight participants. In overweight/obese, the independent correlates were waist circumference (odds ratio for 1 standard deviation increase = 3.78), alanine transaminase (2.11), BMI (2.00), male sex (1.74), triglycerides (1.44), systolic blood pressure (1.31), fasting insulin (1.23), and physical activity (0.76). In normal weight, the independent correlates included alanine transaminase (3.05), smoking (2.56), systolic blood pressure (1.54), and alcohol intake (1.41). In normal-weight participants, the associations with fatty liver were stronger for alcohol intake and smoking, and weaker for triglycerides, than in overweight/obese participants (P for interaction < 0.05). CONCLUSION: Prevalence of fatty liver was 29% in overweight/obese and 5% in normal-weight adults. Differences in factors associated with fatty liver were seen between these two groups: alcohol intake and smoking were more strongly and triglycerides more weakly associated in normal-weight than in overweight/obese participants.

Interactions between genetic variants and dietary lipid composition: effects on circulating LDL cholesterol in children.

BACKGROUND: Elevated serum low-density lipoprotein (LDL) cholesterol is a predictor of cardiovascular disease events, and the quality of dietary fat is known to influence serum concentrations of LDL cholesterol in children. Interindividual differences in response to diet exist, but the underlying genetic factors remain largely unknown. OBJECTIVE: We aimed to identify genetic variants that modify the variation in serum lipid response to dietary fat quality. DESIGN: We used data from 2 longitudinal Finnish cohorts designed to study risk factors for cardiovascular diseases. Large-scale genotyping was performed with Metabochip in a long-term randomized controlled dietary intervention trial, the Special Turku Coronary Risk Factor Intervention Project (STRIP), for discovery of genetic polymorphisms. The observational Cardiovascular Risk in Young Finns Study (YFS) with genome-wide genetic data was used as a replication sample for the initial findings. Dietary records were used to calculate the ratio of unsaturated to saturated fats. Interaction models and multiple follow-ups were used in the analysis. RESULTS: In the STRIP cohort, a variant within the PARK2 locus, rs9364628, showed moderate interaction with dietary fat quality and a consistent direction of effect in both scans on serum LDL-cholesterol concentration in children aged 5 and 7 y (P < 0.0084 and P < 0.0057, respectively). In the YFS cohort, we were unable to replicate the initial discovery signal, but rs12207186 within the PARK2 locus and dietary lipid quality had a stronger interaction effect on serum LDL-cholesterol concentration (P < 9.44 × 10(-5)) than did rs9364628 in children aged 6 y. CONCLUSION: This genotyping study involving 2 cohorts of healthy Finnish children indicates a possible interaction between PARK2 variants and dietary fat quality on serum LDL-cholesterol concentration. This trial was registered at clinicaltrials.gov as NCT00223600.

Exploring causality between TV viewing and weight change in young and middle-aged adults. The Cardiovascular Risk in Young Finns study.

BACKGROUND: Television viewing time (TV time) is associated with increased weight and obesity, but it is unclear whether this relation is causal. METHODS AND RESULTS: We evaluated changes in TV time, waist circumference (waist) and body mass index (BMI) in participants of the population-based Cardiovascular Risk in Young Finns study (761 women, 626 men aged 33-50 years in 2011). Waist and BMI were measured, and TV time was self-reported in 2001, 2007, and 2011. Changes in waist and BMI between 2001 and 2011 were studied a) for the whole group, b) in groups with constantly low (≤ 1 h/d), moderate (1-3 h/d), or high (≥ 3 h/d) TV time, and c) in groups with ≥ 1 hour in-/decrease in daily TV time between 2001 and 2011. BMIs in 1986 were also evaluated. We explored the causal relationship of TV time with waist and BMI by classical temporality criterion and recently introduced causal-discovery algorithms (pairwise causality measures). Both methods supported the hypothesis that TV time is causative to weight gain, and no evidence was found for reverse or bidirectional causality. Constantly low TV time was associated with less pronounced increase in waist and BMI, and waist and BMI increase was lower with decreased TV time (P<0.05). The increase in waist and BMI was at least 2-fold in the high TV time group compared to the low TV time group (P<0.05). Adjustment for age, sex, BMI/waist in 2001, physical activity, energy intake, or smoking did not change the results. CONCLUSIONS: In young and middle-aged adults, constantly high TV time is temporally antecedent to BMI and waist increase.

Cardiovascular risk factors in 2011 and secular trends since 2007: the Cardiovascular Risk in Young Finns Study.

AIMS: Cardiovascular risk factor levels in 2011 and 4-year changes between 2007 and 2011 were examined using data collected in follow-ups of the Cardiovascular Risk in Young Finns Study. METHODS: The study population comprised 2063 Finnish adults aged 34-49 years (45% male). Lipid and blood pressure levels, glucose and anthropometry were measured and life style risk factors examined with questionnaires. RESULTS: Mean total cholesterol level in 2011 was 5.19 mmol/l, low density lipoprotein (LDL)-cholesterol 3.27 mmol/l, high density lipoprotein (HDL)-cholesterol 1.33 mmol/l, and triglycerides 1.34 mmol/l. Using American Diabetes Association criteria, Type 2 diabetes (T2D) was observed in 4.1% and prediabetes (fasting glucose 5.6-6.9 mmol/l or glycated hemoglobin 5.7-6.4%) diagnosed for 33.8% of the participants. Significant changes (P < 0.05) between 2007 and 2011 included an increase in waist circumference (3.3%) in women. In both sexes, systolic (-3.0% in women, -4.0% in men) and diastolic (-3.0% in women, -3.3% in men) blood pressure and triglycerides (-3.4% in women, -6.5% in men) decreased during follow-up. CONCLUSIONS: Previously observed favorable trends in ldl-cholesterol levels have leveled off among a sample of young and middle-aged adults in finland triglyceride and blood pressure levels have decreased over one-third of the study population had prediabetes and may be at increased risk for T2D:

Childhood lifestyle and clinical determinants of adult ideal cardiovascular health: the Cardiovascular Risk in Young Finns Study, the Childhood Determinants of Adult Health Study, the Princeton Follow-Up Study.

BACKGROUND: The American Heart Association recently defined ideal cardiovascular health by simultaneous presence of seven health behaviors and factors. The concept is associated with cardiovascular disease incidence, and cardiovascular disease and all-cause mortality. To effectively promote ideal cardiovascular health already early in life, childhood factors predicting future ideal cardiovascular health should be investigated. Our aim was thus to comprehensively explore childhood determinants of adult ideal cardiovascular health in population based cohorts from three continents. METHODS: The sample comprised a total of 4409 participants aged 3-19 years at baseline from the Cardiovascular Risk in Young Finns Study (YFS; N = 1883) from Finland, Childhood Determinants of Adult Health Study (CDAH; N = 1803) from Australia and Princeton Follow-up Study (PFS; N = 723) from the United States. Participants were re-examined 19-31 years later when aged 30-48 years. RESULTS: In multivariable analyses, independent childhood predictors of adult ideal cardiovascular health were family socioeconomic status (P < 0.01; direct association) and BMI (P < 0.001; inverse association) in all cohorts. In addition, blood pressure (P = 0.007), LDL-cholesterol (P < 0.001) and parental smoking (P = 0.006) in the YFS, and own smoking (P = 0.001) in CDAH were inversely associated with future ideal cardiovascular health. CONCLUSIONS: Among several lifestyle and clinical indicators studied, higher family socioeconomic status and non-smoking (parental/own) in childhood independently predict ideal cardiovascular health in adulthood. As atherosclerotic cardiovascular diseases are rooted in childhood, our findings suggest that special attention could be paid to children who are from low socioeconomic status families, and who smoke or whose parents smoke, to prevent cardiovascular disease morbidity and mortality.

Ideal cardiovascular health in young adult populations from the United States, Finland, and Australia and its association with cIMT: the International Childhood Cardiovascular Cohort Consortium.

BACKGROUND: Goals for cardiovascular (CV) disease prevention were set by the American Heart Association in 2010 for the concept of CV health. Ideal CV health is defined by 7 CV health metrics: blood pressure, glucose, cholesterol, body mass index, and physical activity on recommended levels; nonsmoking; and a healthy diet. We studied the prevalence of ideal CV health and its associations with ultrasonographically measured carotid intima-media thickness (cIMT) cross-sectionally in 5 international populations. METHODS AND RESULTS: Prevalence of ideal CV health was assessed among 5785 young adults (age, 36.6 ± 3.2 years) comprising 335 participants from the Minneapolis Childhood Cohort Studies (Minnesota), 723 from the Princeton Follow-up Study, 981 from the Bogalusa Heart Study (BHS), 1898 from the Cardiovascular Risk in Young Finns Study (YFS), and 1848 from the Childhood Determinants of Adult Health Study (CDAH). Only 1% of the participants had all 7 ideal CV health metrics. The number of ideal CV health metrics associated inversely with cIMT in the 4 cohorts in which cIMT was available: for each additional ideal CV health metric, cIMT was 12.7 µm thinner in Minnesota (P=0.0002), 9.1 µm thinner in BHS (P=0.05), 10.4 µm thinner in YFS (P<0.0001), and 3.4 µm thinner in CDAH (P=0.03). CONCLUSIONS: The number of ideal CV health metrics was inversely associated with cIMT in the cohorts in which cIMT was available, indicating that ideal CV health metrics are associated with vascular health at the population level. Ideal CV health was rare in this large international sample of young adults, emphasizing the need for effective strategies for health promotion.

Tissue inhibitor of matrix metalloproteinases 4 (TIMP4) in a population of young adults: relations to cardiovascular risk markers and carotid artery intima-media thickness. The Cardiovascular Risk in Young Finns Study.

OBJECTIVES: The tissue inhibitor of metalloproteinases 4 (TIMP4) is present in significant amounts in human atherosclerotic coronary artery lesions, but its relations with the early pathogenesis of atherosclerotic changes have not been clarified. We studied the associations of circulating TIMP4 with pre-clinical markers of atherosclerosis and traditional cardiovascular risk factors by using longitudinal data on carotid artery intima-media (cIMT) thickness in a population-based cohort of asymptomatic young adult Finns. METHODS: Data on cIMT, plasma TIMP4, lipids, CRP, blood pressure, BMI, smoking status and daily alcohol intake were obtained from 980 24-39 year-old participants in 2001. The 6-year follow-up in cIMT measurements were performed in 2007 for 769 participants. RESULTS: Plasma TIMP4 concentrations (mean ± SD) were 2.3 ± 1.7 ng/mL in men and 2.5 ± 1.8 ng/mL in women. Age, LDL-cholesterol, BMI and systolic blood pressure were directly associated with TIMP4 concentration. In a multivariable model, the independent determinants of TIMP4 included systolic blood pressure (p = 0.008) and daily smoking (p = 0.009), both being inversely associated with TIMP4. These two baseline variables explained 1.5% of the variation in TIMP4. TIMP4 was significantly and inversely associated with cIMT measured 6 years later (beta =- 0.0135, p = 0.01) explaining 0.7% of the variability of cIMT. CONCLUSION: In young apparently healthy adults, circulating TIMP4 concentration was independently and inversely associated with cIMT, a marker of vascular structure and function.

Associations between serum uric acid and markers of subclinical atherosclerosis in young adults. The cardiovascular risk in Young Finns study.

BACKGROUND AND METHODS: Serum uric acid (SUA) is a suggested biomarker for established coronary artery disease, but the role of SUA in early phases of atherosclerosis is controversial. The relations of SUA with vascular markers of subclinical atherosclerosis, including carotid artery intima-media thickness (cIMT), carotid plaque, carotid distensibility (Cdist) and brachial flow-mediated dilatation (FMD) were examined in 1985 young adults aged 30-45 years. In addition to ordinary regression, we used Mendelian randomization techniques to infer causal associations. RESULTS: In women, the independent multivariate correlates of SUA included BMI, creatinine, alcohol use, triglycerides, glucose and adiponectin (inverse association) (Model R(2) = 0.30). In men, the correlates were BMI, creatinine, triglycerides, C-reactive protein, alcohol use, total cholesterol and adiponectin (inverse) (Model R(2) = 0.33). BMI alone explained most of the variation of SUA levels both in women and men (Partial R(2) âˆ¼ 0.2). When SUA was modeled as an explanatory variable for vascular markers, it directly associated with cIMT and inversely with Cdist in age- and sex-adjusted analysis. After further adjustments for BMI or glomerular filtration rate, these relations were reduced to non-significance. No associations were found between SUA and FMD or the presence of a carotid plaque. Mendelian randomization analyses using known genetic variants for BMI and SUA confirmed that BMI is causally linked to SUA and that BMI is a significant confounder in the association between SUA and cIMT. CONCLUSION: SUA is associated with cardiovascular risk markers in young adults, especially BMI, but we found no evidence that SUA would have an independent role in the pathophysiology of early atherosclerosis.

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.

Childhood physical, environmental, and genetic predictors of adult hypertension: the cardiovascular risk in young Finns study.

BACKGROUND: Hypertension is a major modifiable cardiovascular risk factor. The present longitudinal study aimed to examine the best combination of childhood physical and environmental factors to predict adult hypertension and furthermore whether newly identified genetic variants for blood pressure increase the prediction of adult hypertension. METHODS AND RESULTS: The study cohort included 2625 individuals from the Cardiovascular Risk in Young Finns Study who were followed up for 21 to 27 years since baseline (1980; age, 3-18 years). In addition to dietary factors and biomarkers related to blood pressure, we examined whether a genetic risk score based on 29 newly identified single-nucleotide polymorphisms enhances the prediction of adult hypertension. Hypertension in adulthood was defined as systolic blood pressure ≥ 130 mm Hg and/or diastolic blood pressure ≥ 85 mm Hg or medication for the condition. Independent childhood risk factors for adult hypertension included the individual's own blood pressure (P<0.0001), parental hypertension (P<0.0001), childhood overweight/obesity (P=0.005), low parental occupational status (P=0.003), and high genetic risk score (P<0.0001). Risk assessment based on childhood overweight/obesity status, parental hypertension, and parental occupational status was superior in predicting hypertension compared with the approach using only data on childhood blood pressure levels (C statistics, 0.718 versus 0.733; P=0.0007). Inclusion of both parental hypertension history and data on novel genetic variants for hypertension further improved the C statistics (0.742; P=0.015). CONCLUSIONS: Prediction of adult hypertension was enhanced by taking into account known physical and environmental childhood risk factors, family history of hypertension, and novel genetic variants. A multifactorial approach may be useful in identifying children at high risk for adult hypertension.

Ideal cardiovascular health in childhood and cardiometabolic outcomes in adulthood: the Cardiovascular Risk in Young Finns Study.

BACKGROUND: The American Heart Association (AHA) defined a new concept, cardiovascular health, and determined metrics needed to monitor it over time as part of its 2020 Impact Goal definition. Ideal cardiovascular health is defined by the presence of both ideal health behaviors and ideal health factors. The applicability of this concept to a cohort of children and its relationship with cardiometabolic outcomes in adulthood has not been reported. METHODS AND RESULTS: The sample comprised 856 participants aged 12 to 18 years (mean age 15.0 years) from the Cardiovascular Risk in Young Finns Study cohort. Participants were followed up for 21 years since baseline (1986) and had data available concerning health factors and behaviors in childhood and cardiometabolic outcomes in adulthood (2007). The number of ideal cardiovascular health metrics present in childhood was associated with reduced risk of hypertension (odds ratio [95% confidence interval] 0.66 [0.52-0.85], P<0.001), metabolic syndrome (0.66 [0.52-0.77], P<0.001), high low-density lipoprotein cholesterol (0.66 [0.52-0.85], P=0.001), and high-risk carotid artery intima-media thickness (0.75 [0.60-0.94], P=0.01) in adulthood. All analyses were age and sex adjusted, and the results were not altered after additional adjustment with socioeconomic status. CONCLUSIONS: The number of ideal cardiovascular health metrics present in childhood predicts subsequent cardiometabolic health in adulthood. Our findings suggest that pursuit of ideal cardiovascular health in childhood is important to prevent cardiometabolic outcomes in adulthood.

Genetic variants and blood pressure in a population-based cohort: the Cardiovascular Risk in Young Finns study.

Clinical relevance of a genetic predisposition to elevated blood pressure was quantified during the transition from childhood to adulthood in a population-based Finnish cohort (N=2357). Blood pressure was measured at baseline in 1980 (age 3-18 years) and in follow-ups in 1983, 1986, 2001, and 2007. Thirteen single nucleotide polymorphisms associated with blood pressure were genotyped, and 3 genetic risk scores associated with systolic and diastolic blood pressures and their combination were derived for all of the participants. Effects of the genetic risk score were 0.47 mm Hg for systolic and 0.53 mm Hg for diastolic blood pressures (both P<0.01). The combination genetic risk score was associated with diastolic blood pressure from age 9 years onward (ß=0.68 mm Hg; P=0.015). Replications in 1194 participants of the Bogalusa Heart Study showed essentially similar results. The participants in the highest quintile of the combination genetic risk score had a 1.82-fold risk of hypertension in adulthood (P<0.0001) compared with the lowest quintile, independent of a family history of premature hypertension. These findings show that genetic variants are associated with preclinical blood pressure traits in childhood; individuals with several susceptibility alleles have, on average, a 0.5-mm Hg higher blood pressure, and this trajectory continues from childhood to adulthood.

Plasma osteopontin is not associated with vascular markers of subclinical atherosclerosis in a population of young adults without symptoms of cardiovascular disease. The Cardiovascular Risk in Young Finns Study.

OBJECTIVE: Osteopontin is used as a biomarker for measuring the severity of atherosclerosis, but the role of osteopontin in the pathogenesis of atherosclerosis is not clear. METHODS: The distribution and determinants of osteopontin were studied in a randomized cohort of 1,817 young adults (aged 30­45 years) without clinical symptoms of atherosclerosis. RESULTS: The mean ± SD osteopontin concentration was 60.7 ± 15.6 µg/mL in men and 51.7 ± 16.0 µg/mL in women. In multivariable models the correlates of osteopontin explained 6.9% (Model R² of the total variation in osteopontin in men, including CRP (ß = 3.02, p < 0.0001), SHBG (ß = 0.21, p < 0.0001), total cholesterol (ß = − 1.78, p = 0.002), age (ß = − 0.26, p = 0.02) and alcohol use (ß = 0.57, p = 0.04) and of these CRP had the greatest influence (Partial R² = 2.1%). In women, multivariable correlates of osteopontin included CRP (ß = 2.90, p < 0.0001), total cholesterol (ß = − 1.99, p = 0.002), insulin (ß = − 1.76, p = 0.001), physical activity (ß = 0.66, p = 0.03), adiponectin (ß = 0.25, p = 0.008) and diastolic blood pressure (ß = 0.14, p = 0.003). These five variables explained 6.7% (Model R²) of the total variation in osteopontin, with CRP (Partial R² = 2.7%) having the greatest influence. Osteopontin was not associated with carotid intima-media thickness, carotid elasticity, brachial endothelial function or the presence of a carotid plaque in either sex. CONCLUSION: We found no evidence of association between osteopontin levels and early vascular markers of atherosclerosis in asymptomatic young adults, suggesting that osteopontin is not implicated in the preclinical atherosclerotic changes in vascular structure and function.

A longitudinal analysis on associations of adiponectin levels with metabolic syndrome and carotid artery intima-media thickness. The Cardiovascular Risk in Young Finns Study.

OBJECTIVE: Adipose-tissue derived adiponectin has gained a lot of interest as a marker of metabolic syndrome (MetS) and cardiovascular risk. The objective of this study was to assess whether adiponectin levels in young adults predict the incidence of MetS after 6-year follow-up. To gain insight on the interrelations between MetS, adiponectin and cardiovascular risk, we also examined the associations of adiponectin and carotid atherosclerosis according to MetS status. METHODS: This analysis was part of a population-based, longitudinal cohort study conducted among 1693 Cardiovascular Risk in Young Finns Study individuals (age 31.9 ± 4.9 years in 2001) participating in follow-ups in 2001 and 2007. RESULTS: In a multivariable model adjusted for age, sex, MetS components, LDL-cholesterol, CRP, insulin, leptin, smoking and family history of coronary disease, 1-unit increase in baseline adiponectin levels was associated with reduced odds (odds ratio [OR]=0.94, 95% CI 0.89-0.99, P=0.04) of incident MetS. Of the MetS components, adiponectin levels were inversely associated with the incidence of hyperglycemia in multivariable analyses (OR=0.94 (0.90-0.99), P=0.04). When studying the adiponectin×MetS interaction on IMT, we observed a significant interaction when examining IMT in 2001 (r=-0.11 (MetS(-)) vs. r=-0.17 (MetS(+)), P for interaction 0.047) and IMT in 2007 (r=-0.12 (MetS(-)) vs. r=-0.21 (MetS(+)), P for interaction 0.005), suggesting the inverse association between adiponectin and IMT is stronger among those with MetS. CONCLUSIONS: Among young adults, high adiponectin levels were associated with decreased incidence of MetS. Moreover, our data suggest that individuals with MetS are more vulnerable to the proatherogenic effects of low adiponectin levels.