Vera Mikkilä

Longitudinal changes in diet from childhood into adulthood with respect to risk of cardiovascular diseases: The Cardiovascular Risk in Young Finns Study

Objective: To assess nutrient intakes relevant in the prevention of cardiovascular diseases (CVD) among young adults in Finland and to find past and present determinants of quality of diet.Design: Prospective study, 21 years of follow-up.Setting: The Cardiovascular Risk in Young Finns Study, Finland.Subjects: At baseline in 1980: 3569 children aged 3–18 y participated (83% of those invited), and every second of them (1780) were selected to the dietary study. At follow-ups in 1986 and 2001: 1200 and 1037 of the original sample, respectively, participated.Methods: Food consumption was assessed using 48-h dietary recall. Intakes in 2001 were compared with those obtained in 1980 and 1986. Nutrients selected for further examination were those implicated in the risk of CVD: saturated, monounsaturated, polyunsaturated and n-3 fatty acids, fibre and salt. An index describing the quality of adulthood diet was constructed. Multivariate logistic regression was used to identify independent childhood and adulthood determinants of the quality index.Results: The average intakes showed substantial changes since 1980. Intakes of fat and saturated fat had decreased, while the consumption of vegetables and fruit had increased. However, a great disparity was present between the recommended levels and actual intakes for many of the nutrients, particularly salt, saturated fat and fibre. Intake of fat and consumption of vegetables in childhood and physical activity in adulthood were important health behavioural determinants of the cardiovascular quality of the adult diet. Socio-demographic factors, including education of the subject and their parents, had no significant associations with diet.Conclusions: While intakes of energy and nutrients have changed favourably in Finnish young adults between 1980 and 2001 with regard to the risk of CVD, they are still far from recommended levels. Childhood diet is a significant determinant of adult diet even after 21 y.Sponsorship: This study was supported by the Academy of Finland (grant 77841) and Juho Vainio Foundation.

Metabolite Profiling and Cardiovascular Event Risk A Prospective Study of 3 Population-Based Cohorts

Background— High-throughput profiling of circulating metabolites may improve cardiovascular risk prediction over established risk factors. Methods and Results— We applied quantitative nuclear magnetic resonance metabolomics to identify the biomarkers for incident cardiovascular disease during long-term follow-up. Biomarker discovery was conducted in the National Finnish FINRISK study (n=7256; 800 events). Replication and incremental risk prediction was assessed in the Southall and Brent Revisited (SABRE) study (n=2622; 573 events) and British Women’s Health and Heart Study (n=3563; 368 events). In targeted analyses of 68 lipids and metabolites, 33 measures were associated with incident cardiovascular events at P<0.0007 after adjusting for age, sex, blood pressure, smoking, diabetes mellitus, and medication. When further adjusting for routine lipids, 4 metabolites were associated with future cardiovascular events in meta-analyses: higher serum phenylalanine (hazard ratio per standard deviation, 1.18; 95% confidence interval, 1.12–1.24; P=4×10–10) and monounsaturated fatty acid levels (1.17; 1.11–1.24; P=1×10–8) were associated with increased cardiovascular risk, while higher omega-6 fatty acids (0.89; 0.84–0.94; P=6×10–5) and docosahexaenoic acid levels (0.90; 0.86–0.95; P=5×10–5) were associated with lower risk. A risk score incorporating these 4 biomarkers was derived in FINRISK. Risk prediction estimates were more accurate in the 2 validation cohorts (relative integrated discrimination improvement, 8.8% and 4.3%), albeit discrimination was not enhanced. Risk classification was particularly improved for persons in the 5% to 10% risk range (net reclassification, 27.1% and 15.5%). Biomarker associations were further corroborated with mass spectrometry in FINRISK (n=671) and the Framingham Offspring Study (n=2289). Conclusions— Metabolite profiling in large prospective cohorts identified phenylalanine, monounsaturated fatty acids, and polyunsaturated fatty acids as biomarkers for cardiovascular risk. This study substantiates the value of high-throughput metabolomics for biomarker discovery and improved risk assessment.Background— High-throughput profiling of circulating metabolites may improve cardiovascular risk prediction over established risk factors. Methods and Results— We applied quantitative nuclear magnetic resonance metabolomics to identify the biomarkers for incident cardiovascular disease during long-term follow-up. Biomarker discovery was conducted in the National Finnish FINRISK study (n=7256; 800 events). Replication and incremental risk prediction was assessed in the Southall and Brent Revisited (SABRE) study (n=2622; 573 events) and British Women’s Health and Heart Study (n=3563; 368 events). In targeted analyses of 68 lipids and metabolites, 33 measures were associated with incident cardiovascular events at P <0.0007 after adjusting for age, sex, blood pressure, smoking, diabetes mellitus, and medication. When further adjusting for routine lipids, 4 metabolites were associated with future cardiovascular events in meta-analyses: higher serum phenylalanine (hazard ratio per standard deviation, 1.18; 95% confidence interval, 1.12–1.24; P =4×10–10) and monounsaturated fatty acid levels (1.17; 1.11–1.24; P =1×10–8) were associated with increased cardiovascular risk, while higher omega-6 fatty acids (0.89; 0.84–0.94; P =6×10–5) and docosahexaenoic acid levels (0.90; 0.86–0.95; P =5×10–5) were associated with lower risk. A risk score incorporating these 4 biomarkers was derived in FINRISK. Risk prediction estimates were more accurate in the 2 validation cohorts (relative integrated discrimination improvement, 8.8% and 4.3%), albeit discrimination was not enhanced. Risk classification was particularly improved for persons in the 5% to 10% risk range (net reclassification, 27.1% and 15.5%). Biomarker associations were further corroborated with mass spectrometry in FINRISK (n=671) and the Framingham Offspring Study (n=2289). Conclusions— Metabolite profiling in large prospective cohorts identified phenylalanine, monounsaturated fatty acids, and polyunsaturated fatty acids as biomarkers for cardiovascular risk. This study substantiates the value of high-throughput metabolomics for biomarker discovery and improved risk assessment. # CLINICAL PERSPECTIVE {#article-title-51}

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.

Life-time risk factors and progression of carotid atherosclerosis in young adults: the Cardiovascular Risk in Young Finns study

AIMS The aim of this study is to evaluate whether childhood risk factors are associated with a 6-year change in carotid intima-media thickness (IMT) in young adulthood independent of the current risk factors. METHODS AND RESULTS The Cardiovascular Risk in Young Finns cohort consisted of 1809 subjects who were followed-up for 27 years since baseline (1980, age 3-18 years) and having carotid IMT measured both in 2001 and 2007. Cardiovascular risk factors were assessed repeatedly since childhood. A genotype risk score was calculated using 17 newly identified genetic variants associating with cardiovascular morbidity. The number of childhood risk factors (high LDL-cholesterol, low HDL-cholesterol, high blood pressure, obesity, diabetes, smoking, low physical activity, infrequent fruit consumption) was associated with a 6-year change in adulthood IMT. In subjects with 0, 1, 2, and > or =3 childhood risk factors, IMT [mean (95% CI)) increased by 35 (28-42), 46 (40-52), 49 (41-57), and 61 (49-73) microm (P = 0.0001). This association remained significant when adjusted for adulthood risk score and genotype score (P = 0.007). Of the individual childhood variables, infrequent fruit consumption ((beta (95% CI) for 1-SD change -5(-9 to -1), P = 0.03) and low physical activity (-6(-10 to -2), P = 0.01) were associated with accelerated IMT progression after taking into account these variables assessed in adulthood. CONCLUSION These findings indicate that children with risk factors have increased atherosclerosis progression rate in adulthood, and support the idea that the prevention of atherosclerosis by means of life style could be effective when initiated in childhood.

Major dietary patterns and cardiovascular risk factors from childhood to adulthood. The Cardiovascular Risk in Young Finns Study

Studies on the impact of single nutrients on the risk of CVD have often given inconclusive results. Recent research on dietary patterns has offered promising information on the effects of diet as a whole on the risk of CVD. The Cardiovascular Risk in Young Finns Study is an ongoing, prospective cohort study with a 21-year follow-up to date. The subjects were children and adolescents at baseline (3-18 years, n 1768) and adults at the latest follow-up study (24-39 years, n 1037). We investigated the associations between two major dietary patterns and several risk factors for CVD. In longitudinal analyses with repeated measurements, using multivariate mixed linear regression models, the traditional dietary pattern (characterised by high consumption of rye, potatoes, butter, sausages, milk and coffee) was independently associated with total and LDL cholesterol concentrations, apolipoprotein B and C-reactive protein concentrations among both genders, and also with systolic blood pressure and insulin levels among women and concentrations of homocysteine among men (P < 0.05 for all). A dietary pattern reflecting more health-conscious food choices (such as high consumption of vegetables, legumes and nuts, tea, rye, cheese and other dairy products, and alcoholic beverages) was inversely, but less strongly associated with cardiovascular risk factors. Our results support earlier findings that dietary patterns have a role in the development of CVD.

Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake

Background: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants. Objective: The objective of the study was to identify common genetic variants that are associated with macronutrient intake. Design: We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 × 10−6 were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n = 7724) provided additional replication data. Results: A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (β ± SE: 0.25 ± 0.04%; P = 1.68 × 10−8) and lower fat (β ± SE: −0.21 ± 0.04%; P = 1.57 × 10−9) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI)–increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (β ± SE: 0.10 ± 0.02%; P = 9.96 × 10−10), independent of BMI (after adjustment for BMI, β ± SE: 0.08 ± 0.02%; P = 3.15 × 10−7). Conclusion: Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).

Associates of obesity and weight dissatisfaction among Finnish adolescents.

OBJECTIVE We investigated behavioural and socio-economic factors associated with obesity and weight dissatisfaction among Finnish adolescents. DESIGN A total of 60,252 Finnish adolescents aged 14 to 16 years filled in a questionnaire about their health, health behaviour and socio-economic background. Food choices were obtained by using a short food-frequency questionnaire. Obesity was defined as a weight at least 120% of the sex- and height-specific mean weight for subjects. RESULTS Of girls and boys, 54% and 66%, respectively, were satisfied with their weight. Among dissatisfied normal-weight adolescents, 81% of girls but only 48% of boys thought they were overweight. Of obese boys, 25% were satisfied with their weight. For both genders, obesity and weight dissatisfaction were associated with economic problems in the family. In girls, an association was also found with poor school performance, low educational level of parents and not having evening meals at home; and in boys, with physical inactivity and not eating school lunch. Smoking was more common among girls who were dissatisfied with their weight. Differences in food choices were small between different weight and weight satisfaction categories. CONCLUSIONS Having normal weight and being satisfied with that weight are favourable for an adolescent. Obesity and weight dissatisfaction are associated mostly with disadvantageous health behaviours and low socio-economic status. Health behaviour seems to be associated more with weight satisfaction than with actual weight.

Lifetime Fruit and Vegetable Consumption and Arterial Pulse Wave Velocity in Adulthood The Cardiovascular Risk in Young Finns Study

Background— The relationships between childhood lifestyle risk factors and adulthood pulse wave velocity (PWV) have not been reported. We studied whether childhood and adulthood lifestyle risk factors are associated with PWV assessed in adulthood. Methods and Results— The study cohort comprised 1622 subjects of the Cardiovascular Risk in Young Finns Study followed up for 27 years since baseline (1980; aged 3 to 18 years) with lifestyle risk factor data available since childhood. Arterial PWV was measured in 2007 by whole-body impedance cardiography device. Vegetable consumption in childhood was inversely associated with adulthood PWV (&bgr;=−0.06, P=0.02), and this association remained significant (&bgr;=−0.07, P=0.004) when adjusted for traditional risk factors (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, systolic blood pressure, body mass index, and smoking). Vegetable consumption was also an independent predictor of PWV in adulthood when adjusted for lifestyle or traditional risk factors (&bgr;=−0.08, P=0.002 and &bgr;=−0.07, P=0.0007, respectively). Persistently high consumption of both fruits and vegetables from childhood to adulthood was associated with lower PWV compared with persistently low consumption (P=0.03 for both). The number of lifestyle risk factors (the lowest quintile for vegetable consumption, fruit consumption, physical activity, and smoking) in childhood was directly associated with PWV in adulthood (P=0.001). This association remained significant when adjusted for the number of lifestyle risk factors in adulthood (P=0.003). Conclusions— These findings suggest that lifetime lifestyle risk factors, with low consumption of fruits and vegetables in particular, are related to arterial stiffness in young adulthood.

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 individuals 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. # Clinical Perspective {#article-title-37}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 individuals 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 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.