Current Opinion in Lipidology:
NUTRITION AND METABOLISM: Edited by Paul Nestel and Ronald P. Mensink
Main findings from the prospective Cardiovascular Risk in Young Finns Study
Juonala, Markusa,b; Viikari, Jorma S.A.b; Raitakari, Olli T.a,c
aUniversity of Turku and Turku University Hospital, Cardiovascular Research Center
bDepartments of Medicine
cDepartment of Clinical Physiology, Turku, Finland
Correspondence to Markus Juonala, Department of Medicine, Turku University Hospital, Kiinamyllynkatu 4-8, 20520 Turku, Finland. Tel: +358 2 313 0503; e-mail: firstname.lastname@example.org
Purpose of review: To provide a comprehensive overview on the main findings from the Cardiovascular Risk in Young Finns Study. This prospective multicenter study initiated in 1980 (N = 3596, baseline age 3–18 years) has followed up study participants over 30 years to investigate childhood risk factors for cardiometabolic outcomes in adulthood.
Recent findings: Childhood BMI, socioeconomic status, parental risk factor status, as well as genetic polymorphisms are independent predictors of adult obesity, hypertension, and dyslipidemia. Results from the Young Finns Study and other follow-up studies have shown that conventional childhood risk factors, such as dyslipidemia, obesity, elevated blood pressure and smoking, are predictive of subclinical atherosclerosis in young adults. Recent findings suggest that childhood lifestyle (diet, physical activity) is associated with subclinical atherosclerosis and its progression in adulthood. Concerning the timing of risk factor measurements, they seem to be predictive of adult atherosclerosis from the age of 9 onwards. From a clinical point of view, a recent observation suggesting that the adverse cardiometabolic effects of childhood overweight/obesity are reversed among those who become nonobese adults, provides optimism during the days of obesity epidemic.
Summary: Current data suggest that childhood risk factors are associated with higher risk of subclinical atherosclerosis in adulthood. Future studies among aging cohorts followed since childhood will provide data on their influence on clinical cardiovascular outcomes.
In Finland, coronary heart disease (CHD) incidence was very high in the 1960s and 1970s . In line, the Seven Countries Study showed that the level of serum cholesterol in Finns was also the highest among the investigated countries in the 1960s . With reference to the studies indicating that atherosclerosis starts early and in accord with the WHO Recommendation of 1978 , a program was launched in Finland in the late 1970s to study cardiovascular risk in the youth.
The Cardiovascular Risk in Young Finns Study was designed as a collaborative effort between five universities with medical schools and several other institutions in Finland. The main aim was to study the levels of CHD risk factors and their determinants in children and adolescents of various ages in different parts of the country. Two pilot studies were carried out in 1978 (N = 264, age 8 years) and in 1979 (N = 634, aged 3, 12, and 17 years) [4,5]. The first large-scale cross-sectional study was performed in 1980. This baseline study included 3596 children and adolescents aged 3, 6, 9, 12, 15, and 18 years . Thereafter this cohort has been followed up with 3–9-year intervals. The study participants are now in middle age, and at the moment, the main aim is to investigate the effects of childhood, environmental, physical, and genetic factors on the later risk of cardiometabolic disease. Since 2007, Young Finns Study group has been actively participating in a collaborative effort between several longitudinal cohort studies initiated in childhood. This International Childhood Cardiovascular Cohort (i3C) Consortium enables the pooling of data to increase power, most importantly for the follow-up of clinical cardiovascular events in adulthood .
The Cardiovascular Risk in Young Finns Study has been carried out in all five Finnish university cities with medical schools (Helsinki, Kuopio, Oulu, Tampere, and Turku) and their rural surroundings. The first cross-sectional study was conducted in 1980 . Altogether, 4320 children and adolescents aged 3, 6, 9, 12, 15, and 18 years were randomly chosen from the population register of these areas to produce a representative sample of Finnish children. In practice, girls and boys of each age cohort in each study community were separately placed in random order on the basis of the unique personal identification number. The final sample was designed to apply the following two considerations: children and adolescents from different parts (east and west) of Finland with varying CHD risk in adults should be studied; their socioeconomic background and living conditions should vary, so as to represent reasonably well all Finnish children and adolescents and allow comparisons of urban and rural and different socioeconomic groups.
After the first cross-sectional study in 1980, follow-up studies have been conducted 3–9 years apart (Fig. 1). In adulthood, field studies have been conducted in 2001, 2007, and 2010–2012. The participation rates in follow-up studies have been satisfactory. In childhood, in 1983 and 1986, a total of 2991 (83.2%) and 2799 (78.3%) individuals participated. In 2001, 2283 individuals (63.5%) of the original cohort participated in clinical examinations, and 2620 (72.9%) individuals returned questionnaires. In 2007, a total of 2204 individuals participated and in 2010–2012, there were 2063 participants. So far, 76 participants have deceased, two of them due to cardiovascular disease. We have examined the representativeness of the remaining cohort on several occasions. Early in the study, those lost during the follow-up tended to be older, more often men, and more often smokers [8,9]. Detailed analyses of nonparticipants were done in adult follow-ups. Interestingly, the participation has been dynamic, so that many patients lost to follow-up early in the study have actually returned to the study later on . When we tested the representativeness of the participants in adult follow-up by comparing their baseline characteristics with those of the nonparticipants [10,11], we found that the participants were more often women and older than nonparticipants. Otherwise, comparing nonparticipants and participants using age-adjusted analysis, there were no significant differences in either men or women in total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, blood pressure (BP), physical activity, or parents’ education [10,11]. In 2007, BMI was higher in female nonparticipants than in participants .
The main study variables are shown in Table 1. In the first cross-sectional study in 1980, a comprehensive data collection was performed using questionnaires, physical measurements, and blood tests, including general health status, serum lipids, insulin, obesity indices, BP, lifestyle factors, smoking status, alcohol use, food consumption, dietary intakes, food behavior, physical activity, psychological and behavioral factors, and socioeconomic status. In the follow-ups, serial information concerning these risk factors has been gathered. In addition, several novel risk factors, including C-reactive protein (CRP), homocysteine, asymmetric dimethlyarginine, adiponectin, leptin, and a comprehensive set of metabonomic variables have been analyzed. In addition, heart rate variability measurements to study autonomic nervous system function have been collected in adulthood.
To assess subclinical atherosclerosis, carotid artery intima–media thickness (IMT), carotid elasticity, and brachial flow-mediated dilatation (FMD) were measured in the 21-year and 27-year follow-ups in 2001 and 2007 [11–13]. These noninvasive vascular markers were chosen because they can be measured quickly and with relative ease in large population studies. During the latest follow-up in 2010–2012, cardiac ultrasound examinations were performed to study especially left ventricular mass, and liver ultrasound measures to assess fat content. In addition, cognitive testing was done.
In adult follow-ups, genomic DNA was extracted from peripheral blood leukocytes. Genome-wide single-nucleotide polymorphisms (SNPs) data were obtained with a custom-built Illumina BeadChip Human670K.
By far, the main issues addressed in the Young Finns Study have considered the associations between child and adult risk factors and the effect of childhood factors on subclinical markers of atherosclerosis.
The associations of child and adult risk factors
Important for strategies of primary prevention among children and adolescents is the question whether risk factors measured at one time point are predictive of risk factor values years later. Interestingly, concerning lipid measurements, in a subcohort of 57 individuals, the greatest relative decrease in correlations took place during the determination periods of 2 and 7 days, whereafter the decline was much slower . In the 12-year follow-up between 1980 and 1992, significant tracking was found for each of the serum lipid variables . The range of 12-year correlation was 0.48–0.58 for serum cholesterol levels and 0.33–0.37 for triglycerides. Twenty-seven-year correlations were of comparable level : 0.51–0.56 for cholesterol levels, 0.46 for BMI, and 0.27 for SBP and triglycerides. In addition, elevated childhood risk factors were strongly associated with respective adult abnormalities. Children with overweight/obesity had 6–14 times increased risk of adult obesity, and those with elevated childhood LDL-cholesterol levels had over four times increased risk of adult hypercholesterolemia. Our studies have also shown that lifestyle adopted in childhood is clearly predictive of diet and physical activity in adulthood [17,18]. Dietary patterns are established already in childhood, persist into adulthood, and are significantly associated with CHD risk factors [19,20].
The Young Finns data have allowed comprehensive analyses of childhood predictors of adult cardiovascular risk factors. It has been observed that in addition to BMI, childhood levels of CRP, family income (inverse association), mother's BMI, and polymorphisms near genes TFAP2B, LRRN6C, and FLJ35579 are independently associated with the risk of adult obesity [21▪]. Moreover, a risk assessment based on childhood BMI, mother's BMI, and family income was superior in predicting obesity compared with the approach using data only on BMI. Childhood BP, parental hypertension, childhood overweight/obesity, low parental occupational status, and a genetic risk score based on 29 newly identified SNPs for elevated BP predicted adult hypertension [22▪]. For lipids, a risk score based on previously identified loci for high triglycerides improved the risk discrimination over childhood lipid measurement for adult hypertriglyceridemia . Concerning the clustering of adult risk factors, it has been found that high levels of BMI, triglycerides, and insulin, low frequency of vegetable consumption, family history of hypertension, and family history of type 2 diabetes predict the occurrence of metabolic syndrome in adulthood [24,25▪]. In childhood, several risk habits, such as aggressiveness, past unemployment, and a low sense of responsibility also clustered and were associated with several metabolic risk factors . Suggesting the importance of dietary fatty acid intake, serum cholesterol ester fraction in childhood is independently associated with adulthood BP .
Regarding risk factor trends over time, we observed a rapid decrease in total cholesterol levels between 1980 and 1986, whereas the decrease was slower between 1986 and 2001 . At the same time, a clear increase in BMI and triglycerides levels, and a decrease in HDL-cholesterol and BP levels were observed. Between 2001 and 2007 LDL-cholesterol levels decreased, whereas waist circumference, glucose, and BP levels increased .
Childhood risk factors and subclinical atherosclerosis in adulthood
At present, there are no prospective long-term data available that could be used to test the hypothesis that exposure to risk factors in childhood influence cardiovascular morbidity or mortality. Therefore, within the Young Finns Study, ultrasound measures of carotid and brachial arteries have been used as surrogate measures of atherosclerosis. In line with other longitudinal studies, such as Bogalusa Heart Study  and Muscatine Study , we have observed that several conventional cardiovascular risk factors measured in childhood are predictive of subclinical atherosclerosis later in life. Childhood cholesterol and apolipoprotein levels have been associated with increased carotid IMT, decreased carotid elasticity, and impaired brachial endothelial function in adulthood [12,31,32]. Childhood BP and adiposity measures predict high IMT and low elasticity, and among 12–18-year olds, BP levels were also associated with lower brachial FMD values [12,31,33,34▪▪]. In a collaborative effort between Young Finns and the Bogalusa Heart Study, pediatric metabolic syndrome was predictive of adult IMT but did not provide any additional information when compared with using only data on childhood BMI levels . Adolescent smoking has been associated with increased carotid IMT . Concerning clinical aspects, one important question concerning childhood risk factor measurements is the effect of age. This issue was studied within the i3C consortium . The results suggest that the child's overall risk factor profile is predictive of adult atherosclerosis from the age of 9 onwards. However, BMI levels were informative already at the age of 3 years.
In addition to conventional risk factors, childhood lifestyle has been shown to have an important effect on subsequent arterial health. Infrequent fruit consumption and low physical activity in childhood were associated with accelerated 6-year IMT progression in adulthood . Importantly, these associations remained significant after taking into account these variables assessed in adulthood. In addition, persistently high consumption of both fruits and vegetables from childhood to adulthood was associated with improved arterial elasticity . In line, a traditional dietary pattern, characterized by low intakes of fruits and vegetables was associated with elevated increased adulthood IMT especially in men . In January 2010, the American Heart Association released its 2020 Impact Goals . In order to improve the prevention of cardiovascular disease, a new definition of ideal cardiovascular health was published. In these criteria, there are four ideal health behaviors (nonsmoking, ideal BMI, physical activity at goal levels, and diet consistent with current guideline recommendations) and three ideal health factors (ideal levels of total cholesterol, BP, and fasting blood glucose). Using the Young Finns data from the field study in 1986 (first time glucose levels were measured), we observed that the number of ideal cardiovascular health metrics present in childhood was associated with lower risk of high carotid IMT in adulthood [40▪]. Importantly, this association was not altered after adjustment for change in the ideal cardiovascular health index between childhood and adulthood. In addition to individual's own lifestyle, it seems that also parental behaviors have long-term consequences. In joint analyses between Young Finns Study and the Childhood Determinants of Adult Health study in Australia, it was found that parental smoking during offspring's childhood was associated with impaired brachial endothelial function over 20 years later [41▪▪]. This association was independent of individual's smoking status and several other possible confounding factors in adulthood. In addition, the findings were consistent in several sensitivity analyses performed according to study cohort, sex, BMI, smoking status, and socioeconomic status. Suggesting the importance of prebirth circumstances, recent analyses from the Young Finns Study showed that preterm birth and impaired fetal growth are associated with increased carotid IMT and decreased brachial FMD .
Genetic and metabonomic risk factors
During recent years, genetic analyses and metabonomic analyses have been an active part of the Young Finns study. By far, it seems that genetic risk scores for cardiovascular disease derived from genome-wide association studies do not provide appreciable additional information over conventional risk factors in risk prediction [11,43]. However, a predictive modeling framework with machine learning-based SNP selection, improved the prediction of the extreme classes of atherosclerosis risk and progression over a 6-year period . Detailed metabolic profiling performed during adult follow-ups seems also to provide additional information for risk stratification of subclinical atherosclerosis .
Reversibility of cardiovascular risk
From a clinical point of view, it is essential to know whether the associations between childhood risk factors and adult outcomes are only due to tracking of risk factors (e.g., childhood obesity leads to adult obesity) or whether childhood circumstances have permanent deleterious effects, irrespective of later risk factor status. Concerning continuous measures of adolescent LDL-cholesterol and BP, as well as smoking, it has been observed that their associations with adult carotid IMT are independent of respective adult risk factors . In addition, clustering of these adolescent risk factors was predictive of IMT in stratified analyses among adults with a different amount of concurrent risk factors.
Instead, the effects of childhood overweight/obesity or metabolic syndrome seem to be reversible. In a collaborative analysis within the i3C consortium, the risks of several cardiometabolic outcomes were increased only among those overweight/obese children who became obese adults, whereas the risks were completely normalized among those overweight/obese children who became nonobese adults [34▪▪]. However, the risk of adult obesity and associated cardiometabolic abnormalities was strongly dependent on childhood adiposity status, as only 15% of normal-weight children became obese adults, whereas of overweight/obese children, 65% were obese at follow-up. Favorable changes in obesity status from childhood to adulthood are also associated with improved arterial elasticity in adulthood . Moreover, in the Young Finns cohort, individuals recovering from metabolic syndrome during a 6-year follow-up in young adulthood had smaller carotid IMT and higher carotid distensibility values, both absolute and 6-year change, compared with those with persistent metabolic syndrome .
The existing results from the prospective Cardiovascular Risk in Young Finns Study have shown that several childhood cardiovascular risk factors and lifestyle are associated with the risk of subclinical atherosclerosis in adulthood (Fig. 2). Recent encouraging findings suggest that obesity-associated risks can be reversed if adverse childhood adiposity status can be reversed by adulthood. In the future, with extending follow-up, the main aim is to investigate the influences of childhood factors on the risk of clinical cardiovascular events.
The Young Finns Study has been financially supported by the Academy of Finland: grants 126925, 121584, 124282, 129378, 117797, and 41071, the Social Insurance Institution of Finland, Kuopio, Tampere and Turku University Hospital Medical Funds, Juho Vainio Foundation, Paavo Nurmi Foundation, Finnish Foundation of Cardiovascular Research and Finnish Cultural Foundation, Sigrid Juselius Foundation, Emil Aaltonen Foundation and the Research foundation of Orion Corporation.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 92).
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atherosclerosis; childhood; prospective; risk factor
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