This is a self-archived – parallel-published version of an original article. This version may differ from the original in pagination and typographic details. When using please cite the original. AUTHOR Jukka Pihlman, Joel Nuotio, Suvi Rovio, Katja Pahkala, Saku Ruohonen, Eero Jokinen, Tomi P Laitinen, David P Burgner, Nina Hutri-Kähönen, Päivi Tossavainen, Leena Taittonen, Mika Kähönen, Jorma SA Viikari, Olli T Raitakari, Costan G Magnussen, Markus Juonala TITLE Exposure to parental smoking and cardiac structure and function in adulthood: the Cardiovascular Risk in Young Finns Study YEAR 2022 DOI https://doi.org/10.1177/14034948221119611 VERSION Author’s accepted manuscript CITATION Pihlman J, Nuotio J, Rovio S, et al. Exposure to parental smoking and cardiac structure and function in adulthood: the Cardiovascular Risk in Young Finns Study. Scandinavian Journal of Public Health. 2022;0(0). doi:10.1177/14034948221119611 Exposure to Parental Smoking and Cardiac Structure and Function in Adulthood. The Cardiovascular Risk in Young Finns Study. Authors: Jukka Pihlmana, b, 1, Joel Nuotioa, b, Suvi Rovioa, b, Katja Pahkalaa, b, Saku Ruohonena, b, Eero Jokinenc, Tomi P Laitinend, David P Burgnere, f, Nina Hutri-Kähöneng, Päivi Tossavainenh, Leena Taittonenh, i, Mika Kähönenj, Jorma SA Viikarik, Olli T Raitakaria, b, l, Costan G Magnussen*a, b, m, Markus Juonala*k a Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland b Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland c Department of Paediatric Cardiology, Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland d Department of Clinical Physiology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland e Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia f Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia g Department of Pediatrics, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland h Department of Pediatrics, PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu, Oulu, Finland i Vaasa Central Hospital, Vaasa, Finland j Department of Clinical Physiology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland k Department of Medicine, University of Turku and Division of Medicine, Turku University Hospital, Turku, Finland l Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Finland m Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia * These authors contributed equally to this work as joint last authors. 1Corresponding author: Jukka Pihlman, Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku. Kiinamyllynkatu 10, 20520, Turku, Finland. E- mail address: jttpih@utu.fi. Key words: Passive smoking, secondhand smoking, parental smoking, parental smoking hygiene, echocardiography, cardiac remodeling Word count: 3,1093,210 Tables and figures: 4 tables, 2 supplement table, 1 supplement figure, 1 supplemental content Abstract Background and aims: The relationship between childhood tobacco smoke exposure and cardiac structure and function in mid-life is unclear. We investigated the association between parental smoking with cardiac structure and function in adulthood. Methods: 1,250 participants (56.5% female) from the Cardiovascular Risk in Young Finns Study who had data on parental smoking and/or serum cotinine, a biomarker of exposure to tobacco smoke, at baseline 1980 (age 3-18 years) and echocardiography performed in 2011. Parental smoking hygiene (i.e. smoking in the vicinity of children) was categorized by parental smoking and serum cotinine levels in offspring. Dimensions of left ventricle, diastolic and systolic function and cardiac remodeling were used as outcomes. Analyses were adjusted for sex, age, and covariates (BP, serum lipids, BMI, socioeconomic status, smoking (only in adulthood)) in childhood and adulthood. Results: Parental smoking was not associated with systolic function or diastolic function in adulthood. Participants exposed to parental smoking (Odds Ratio [OR] 1.90, 95%CI 1.23-2.92), hygienic parental smoking (OR 1.74, 95%CI 1.12-2.71), and non-hygienic parental smoking (OR 1.88, 95%CI 1.02-3.45) had higher odds of concentric remodeling (relative wall thickness >85th sex-specific percentile without left ventricular hypertrophy). These associations attenuated after adjustments for child and adult covariates in the non-hygienic parental smoking group. Conclusions: Exposed to parental smoking in childhood was associated with a higher likelihood of concentric remodeling and thicker left ventricular and interventricular septal wall in mid-life, which was not improved by parents who smoked hygienically. Parental smoking was not related to systolic and diastolic function in this relatively young population. 1 Introduction Cardiovascular disease (CVD) is the main cause of death globally and the majority of these deaths are preventable1. Tobacco smoke is an important modifiable risk factor for CVD and atherosclerosis. Both active smoking and exposure to environmental tobacco smoke (or passive smoking) are associated with CVD2 and with adverse changes in cardiac structure and left ventricle (LV) diastolic function which has been shown to associate with an increased incidence of heart failure3. Although implementation of strict tobacco policies have reduced smoking and exposure to secondhand tobacco smoke, there is increasing evidence that children exposed to parental smoking suffer long-term detrimental effects to their vascular health, independent of individual smoking habits and exposure to passive smoking later in life4,5. Exposure to parental smoking in childhood might increase the harmful effects of subsequent active smoking6. Furthermore, non-hygienic parental smoking (i.e. smoking in the presence of children) in childhood has been shown to increase the risk of carotid atherosclerotic plaque later in adulthood7. Moreover, acute and chronic exposure to passive smoking is known to impair LV systolic and diastolic function3. These dysfunctions may result from cardiac remodeling which is defined as molecular, cellular and/or interstitial changes that appear clinically as alterations in size, mass, geometry and function of the heart after injury8. Incidentally, 4-tiered (normal geometry, concentric remodeling, eccentric hypertrophy, and concentric hypertrophy) classification of LV remodeling by relative LV wall thickness and LV mass can be used to assess risk for cardiovascular events in high risk patients9. However, the relationship between exposure to tobacco smoke and structure and function of the heart is not well understood. The main aim of this study was to determine the association between parental smoking in childhood and cardiac structure and function in adulthood and whether hygienic smoking modifies this effect. We used data from the Cardiovascular Risk in Young Finns Study, a population-based sample of individuals followed from childhood to adulthood for up to 31 years. We hypothesized that exposure to parental smoking in childhood/adolescence, especially those exposed to poor parental smoking hygiene, have worse cardiac structure and function in adulthood than those not exposed to parental smoking. 2 Methods The Cardiovascular Risk in Young Finns Study is an ongoing longitudinal population-based study of cardiovascular risk factors from childhood to adulthood, conducted in five university hospitals in Finland (Helsinki, Kuopio, Oulu, Tampere, and Turku) and their rural surrounds. The baseline study was conducted in 1980 when 3,596 randomly selected children and adolescents aged 3, 6, 9, 12, 15 and 18 years participated. Since 1980 the cohort has been regularly followed-up in 3 to 9-year intervals. A detailed description of the cohort has been published previously10. Participants or their parents provided written informed consent and the study was approved by local ethics committees. Participants who had a) full data on parental smoking from 1980 or 1983 and serum cotinine levels from 1980 (n=1,678), and b) echocardiography performed in 2011 (n=1,491) were included in this study (n=1,250). Supplement Figure 1 provides a flow chart of the participants and non-participants. Information on parental smoking was collected from self-report questionnaires in 1980 and 1983. Parents who indicated that they or their partner had ever smoked daily for at least 1 year were classified as “at least one smoking parent” in 1980 or 1983 shown to associate with measured serum cotinine in child offspring7. Fasting serum samples of the participants were collected in 1980 and stored at -20 °C without thawing and analyzed in 2014. A total of 1,999 participants had cotinine analyzed from childhood/adolescence. Serum cotinine concentration was quantified using two methods (described in supplemental content). For statistical analyses, participants were divided into 1) low (0-0.99ng/mL, n=1,448) and 2) elevated (≥1.00-<3ng/mL, n=232) serum cotinine groups11. We generated a variable of parental smoking hygiene that combined self-reports of parental smoking data from the baseline survey in 1980 with serum cotinine measurements10. Parental smoking hygiene was categorized as: 1) no parental smoking (children with non-smoking parents and low serum cotinine levels (29.4 %)); 2) hygienic parental smoking (children with at least one smoking parent and low serum cotinine levels (58.2%)); and 3) non-hygienic parental smoking (children with at least one smoking parent and a serum cotinine level ≥1 and < 3 ng/mL (12,4 %)) 11 27 participants were excluded from analyses because they had measurable cotinine levels without self-reported parental smoking and 3 participants were excluded because they were missing information on parental smoking (supplement figure 1). Participants with cotinine levels of ≥3ng/ml were excluded from the analyses as they were assumed to be active smokers12. Covariates included questionnaire and anthropometric measures. Questionnaire measures gathered at baseline included childhood physical activity index, fruit and vegetable consumption and parent self-report of family annual income, which was considered as an indicator of socio-economic status (SES) and categorized as: 1) very low (<18,000 euros/year), 2) low (18,000–28,000 euros/year), 3) intermediate (28,001–38,000 euros/year), and 4) high (>38,000euros/year) income groups 11. In case of missing information in 1980, data from the first follow-up in 1983 was used. Adolescent smoking status was defined from baseline (1980) or the first follow-up (1983). Participants aged below 12 years were considered non-smokers. Physical activity index was calculated at baseline and due to separate questionnaires used for children (3-6 years of age) and older children (9-18 years of age) the values were standardized as previously described13,14. Participants’ household annual income in the year 2011 was considered as an indicator of adulthood SES and was categorized as: 1) low (<21,680 euros/year), 2) intermediate (21,680–48,770 euros/year), and 3) high (>48,770 euros/year) income groups. In case of missing information in 2011, data from the previous follow-up in 2007 were used. Adult participants current daily smoking status was gathered at the year 2011 follow-up. At baseline and all follow-up visits, weight was measured without shoes in light clothes with a digital Seca weighing scale to nearest kilogram (kg). A Seca stadiometer was used for height measurements and BMI was calculated as weight (kg) divided by height in meters squared (m2). Baseline (1980) measurement was used as the primary indicator of childhood/adolescent BMI. In case of missing information, data from year 1983 follow-up was used. For Adulthood BMI data was derived from the latest follow-up study (2011). In case of missing information, data from the 2007 follow-up was used. Fasting lipids were measured in the same laboratory at each follow-up with standard methods for serum total cholesterol, high-density lipoprotein (HDL)-cholesterol, and triglycerides. Low- density lipoprotein (LDL)-cholesterol was calculated using the Friedewald equation. Brachial artery blood pressure was measured at baseline using an ultrasound device (Arteriosonde 1020, Roche) among participants aged 3 years, and using a standard mercury sphygmomanometer for participants aged ≥6 years at baseline. In case of missing information, data from the 1983 follow-up was used. Adult blood pressure measurements were collected in the 2011 follow-up using a random-zero sphygmomanometer (Hawksley & Sons Ltd, Lancin, UK). All measurements were taken using a standardized method repeated 3 times on the right arm after the participant had been seated for 5 minutes with the average of the 3 measurements used. Echocardiographic examinations were performed in 2011 according to American and European guidelines15,16. Transthoracic echocardiography was performed using a 3.5 MHz scanning frequency phased-array transducer (Sequoia 512, Acuson, CA, USA). Studies were saved in digital images which were all analyzed using the ComPACS 10.7.8 (MediMatic Solutions, Genova, Italy) analysis program by one reader blinded to subjects’ details17. LV mass was calculated as previously described18 and indexed LV mass was attained according to subject’s participant height using the allometric power of 2.7 (indexed LV mass=LV mass/height2.7) since this indexation has been shown to perform better among those with obesity19. Relative wall thickness was calculated and LV geometry groups were defined using sex-specific cut-off points18. Concentric remodeling was defined as high relative wall thickness (>85 percentile point) without LV hypertrophy. Eccentric hypertrophy was defined as LV hypertrophy without high relative wall thickness. Concentric hypertrophy was defined as LV hypertrophy with relative wall thickness. The intraclass correlation coefficients with the 5th and 95th percentile confidence intervals and coefficient of variance have been reported earlier along with the complete methodology for cardiac imaging and image analysis in the Young Finns Study17. Interventricular septal wall thickness and LV posterior wall thickness were measured from parasternal long-axis view in M-mode at end-diastole. LV diameter was measured from parasternal long-axis view in M-mode at end-diastole. LV ejection fraction and ratios of E/e’ and EA were calculated according to American and European guidelines15,16. Left atrium volume index was calculated in four-chamber apical view at end-systole and divided by body surface area using Du Bois formula (BSA = 0.007184 × weight0.425 × height0.725). Baseline characteristics of the study population are reported as mean (SD) or median (25th and 75th percentiles, if skewed distributions) for continuous variables or as proportions for categorical variables. For confirmation of participants’ parental smoking exposure, we combined cotinine levels to questionnaire data for parental smoking hygiene variable. The relationship between parental smoking and serum cotinine measurement with continuous outcome variables was assessed using least squares means in generalized linear model adjusted with Tukey-Kramer approximation and for categorical outcome variables using logistic regression. Two models were created for the analyses; model 1 adjusted for sex and age, model 2 included model 1 covariates and additionally adjusted for childhood risk factors (systolic blood pressure, HDL- cholesterol, LDL-cholesterol, triglycerides, BMI, and family SES) and adult risk factors (BMI, systolic and diastolic blood pressure, HDL-cholesterol, LDL-cholesterol and triglycerides, participants own SES and own smoking status). We performed sensitivity analyses that excluded participants who reported they were current smokers in adolescence and that additionally adjusted for daily fruit and vegetable consumption and physical activity index in addition to those covariates included in model 2. We also conducted sensitivity analyses categorizing subgroups by age: 1) ≤6 years of age at baseline; 2) 15-18 years of age in baseline. Moreover, we analysed the data adjusted for age, sex, and adulthood alcohol intake (result are shown in supplemental content). To assess the degree of multicollinearity in the multivariable analyses, we investigated variance inflation factors and found no highly collinear relationships (variance inflation factor always <2.9). All statistical analyses were performed using SAS version 9.4 and statistical significance was inferred at a two-tailed Р- value <0.05. 3 Results Baseline characteristics of participants are show in Table 1. The total number of participants was 1,987 (54.2 % female) who had serum cotinine levels and parental smoking data available in childhood. Of these, 1,491 had at least one echocardiography measurement available. The mean age of participants was 42.2 years at the 2011 follow-up. Associations between parental smoking with cardiac outcomes are shown in Table 2. We observed associations between parental smoking status with interventricular septal wall thickness (adjusted means, (95%CI): 7.29 (7.20-7.37) among participants with non-smoking parents vs. 7.39 (7.34-7.45) among participants with smoking parents, p=0.04) and LV posterior wall thickness (adjusted means + (95%CI): 7.22 (7.15-7.30) vs. 7.32 (7.26-7.37), p=0.045), but these were attenuated when further adjusted for childhood and adulthood covariates (adjusted means + (95%CI): 7.40 (7.29-7.51) vs. 7.48 (7.39-7.57), p=0.13 and 7.32 (7.22-7.42) vs. 7.37 (7.29-7.45), p=0.27, respectively). We observed no significant differences in the other echocardiography outcomes examined. Associations between parental smoking hygiene and cardiac outcomes are shown in Table 3. We observed no significant differences in adult echocardiography variables according to parental smoking hygiene (all p>0.10). Odds ratios between parental smoking, childhood serum cotinine levels, and parental smoking hygiene with cardiac remodeling are shown in Table 4. In analyses adjusted for age and sex, participants exposed to parental smoking (OR 1.90, 95%CI 1.23-2.92), hygienic parental smoking (OR 1.74, 95%CI 1.12-2.71), and non-hygienic parental smoking (OR 1.88, 95%CI 1.02-3.45) had higher odds of concentric remodeling. The association between parental smoking and concentric remodeling persisted with adjustment for child and adult covariates (OR 1.72, 95%CI 1.09-2.70). association between hygienic parental smoking and concentric remodeling remained following adjustment for childhood and adulthood risk factors (OR 1.61, 95%CI 1.01-2.56) whereas the association between non-hygienic parental smoking and concentric remodeling became non-significant diluted when adjusted for child and adult covariates. The association between hygienic parental smoking and concentric hypertrophy was not statistically significant. The evidence for associations between non-hygienic parental smoking and concentric hypertrophy were limited (n=2) in analyses adjusted for sex and age (OR 5.17, 95%CI 0.93- 28.95) but additional adjustments for risk factors attenuated the association. We observed no other associations between parental smoking or parental smoking hygiene and concentric or eccentric hypertrophy. The association between childhood serum cotinine levels and cardiac outcomes are shown in supplement table 1. We observed no significant differences in adult echocardiography variables according to childhood serum cotinine level. In sensitivity analyses, active smokers in adolescence were excluded and additional adjustments were made for daily fruit and vegetable consumption and childhood physical activity index with the results remaining essentially similar except the association between non-hygienic parental smoking and concentric remodeling (OR 1.78, 95%CI 0.92-3.45) and concentric hypertrophy was diluted. We also conducted sensitivity analyses categorizing subgroups by age: 1) ≤6 years of age at baseline; 2) 15-18 years of age in baseline. The overall results in the fully adjusted models were consistent with those shown for the main results. Finally, we analysed the data adjusted for age, sex, and adulthood risk factors and these results are in line with our reported results and did not change the results. 4 Discussion We hypothesized that parental smoking would be associated with adverse structural and functional cardiac changes, but we found no strong evidence of this. However, we observed an association between parental smoking in childhood with interventricular septal and LV posterior wall thickness in adulthood. Furthermore, parental smoking and smoking hygiene status were associated with concentric remodeling in adults. To our knowledge this is the only longitudinal prospective study examining the association between exposure to parental smoking in childhood with the use of an objectively measured biomarker (serum cotinine) and echocardiography measurements performed in adulthood. While increased LV mass, a predecessor to cardiac remodeling, has been shown to associate with smoking in mid-life20 and to exposure to secondhand smoke in rabbits21, our results do not confirm this association. However, parental smoking was associated with increased thickness of interventricular septal and LV posterior walls, which may be predictive of future LV hypertrophy. As our participants are relatively young, the association to LV hypertrophy and function might become evident as they age. In line with previous studies, after adjusting for SES the association diluted22. In addition, it is known that exposure to secondhand smoking in childhood can result in higher blood pressure23, increased arterial stiffness24, flow- mediated dilation impairment4, and endothelial dysfunction, among others25. Combined, these factors might cause cardiac remodeling later in life by pressure overload26. Previous studies have found LV remodeling and higher age to associate with worse LV diastolic function which is often the first stage of heart failure27. Also, cardiovascular morbidity is higher among patients with concentric remodeling than in patients with normal geometry28. In our study, concentric remodeling (ie. high relative wall thickness without LV hypertrophy) was associated with exposure to parental smoking and parental smoking hygiene. Although both active smoking and exposure to chronic secondhand smoking in childhood have been linked with decreased LV diastolic function in Hispanics/Latinos3, we found no association regarding parental smoking, serum cotinine levels or parental smoking hygiene status in our cohort. Potentially, this difference is due to younger age of our participants (42 years vs. 56 years of age). While smoking is associated with higher risk of heart failure, a recent study found chronic exposure to secondhand smoking in childhood paradoxically increased LV ejection fraction3. Nevertheless, in our relatively young cohort, we found no association between parental smoking and LV ejection fraction or cardiac output. The main strength of this study is its large study population and comprehensive data of lifestyle, biochemistry, and anthropometric measurements as well as socioeconomic information starting from childhood with over 30 years of follow-up. An apparent limitation of observational studies is that they are not able to establish causality, however it would be impossible to achieve a life-long trial on CVD progression in humans. Additional limitations include lack of data on prenatal parental smoking exposure which has been shown to have long-lasting adverse effects to cardiovascular health. Furthermore, we were not able to evaluate change in the smoking hygiene over time. As some of the parents stopped regular smoking during the offspring’s childhood. This could have diluted our findings. Moreover, young adults in the 1980s might have had been exposed to secondhand smoke outside of their family unit. However, we tried to minimize the effect of this by using cotinine levels in our study and excluded participants who had inconsistency between questionnaire data and cotinine levels. Therefore, the contrast between the results for serum cotinine and queried parental smoking suggests underestimation of smoking among the parents. In addition, we were not able to consider snus use in childhood as a potential confounder as data were not collected. Nevertheless, use of snus in youth in the 1980s was rare in Finland and has become more common among males only during the 1990s – though the rates remained relatively low (daily use of snus ~3 % in boys aged 16-18 years and <1 % in girls and women)29. Thus, use of snus is not likely to largely impact our results. In addition, individual variability in the rate of elimination of nicotine and cotinine could not be evaluated from our data and should be considered when interpreting our results. Non-participation at follow-up is inevitable in longitudinal studies. However, participation rates have been reasonably high, and participation has been dynamic, so that many participants lost to follow-up early in the study have returned at subsequent follow-ups30. Thus, the study population is likely representative of the original population10,31. Moreover, we understand that additional adjustments for Model 2 might have included factors which were perhaps mediating at least part of the association between the exposure and the outcome. In line, we have previously reported baseline risk factor levels to be essentially similar among participants and nonparticipants at subsequent follow‐ups32. Furthermore, it is not possible to study the associations of parental smoking exposure on CVD as it develops gradually over decades and participants of YFS are in their early midlife. Hence, none of the participants meet the clinical criteria of concentric hypertrophy. However, the cut-offs used allowed us to investigate associations between parental smoking and cardiac remodeling. We acknowledge that strict measures have been implemented on tobacco control in most developed countries since our cohort commenced in 1980 that has led to a substantial decline in daily smokers that might limit the generalizability of our findings. Public awareness of the adverse effects of secondhand smoking has subsequently increase but remains a problem in disadvantaged groups and those in low- and middle-income countries. Finally, our participants were an ethnically homogenous group of white Caucasians, which limits the generalizability of our results. In conclusion, we found that exposure to parental smoking in childhood is associated with higher odds of concentric remodeling in later life and may also influence left ventricular wall diameters. Although these findings need to be replicated in other independent cohorts, we found exposure to parental smoking was not associated with higher likelihood of systolic or diastolic dysfunction in this relatively young study population. Conflict of interest The authors declared they do not have anything to disclose regarding no conflict of interest with respect to this manuscript. Financial support The Young Finns Study has been financially supported by the Academy of Finland: grants 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gondi), and 41071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001); Juho Vainion Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; The Sigrid Julius Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jansson Foundation; Signe and Ane Gyllenberg Foundation; Diabetes Research Foundation of Finnish Diabetes Association; and EU Horizon 2020 (grant 755320 for TAXINOMISIS); and European Research Council (grant 742927 for MULTIEPIGEN project); Tampere University Hospital Supporting Foundation. CGM is supported by a National Heart Foundation of Australia Future Leader Fellowship (100849). Author contributions MD J. Pihlman had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Jukka Pihlman, MD: conceptualization, investigation, formal analysis, software, data curation, validation, methodology, writing - original draft, writing - review and editing, visualization Joel Nuotio, MD, PhD: conceptualization, writing - review and editing, supervision Suvi Rovio, PhD: conceptualization, writing - review and editing. Katja Pahkala, PhD: conceptualization, writing - review and editing, funding acquisition, project administration Saku Ruohonen, MD: conceptualization, writing - review and editing. Euro Jokinen, MD: conceptualization, writing - review and editing, funding acquisition, project administration Tomi P Laitinen, MD: conceptualization, writing - review and editing, funding acquisition, project administration David P Burgner, MD: conceptualization, writing - review and editing. Nina Hutri-Kähönen, MD: conceptualization, writing - review and editing, funding acquisition, project administration Paiva Tsakane, MD: conceptualization, writing - review and editing, funding acquisition, project administration Leena Taittonen, MD: conceptualization, writing - review and editing, funding acquisition, project administration Mika Kähönen, MD: conceptualization, writing - review and editing, funding acquisition, project administration Jorma SA Viikari, MD: conceptualization, validation, writing - review and editing, funding acquisition, project administration Olli T Raitakari, MD: conceptualization, validation, writing - review and editing, funding acquisition, project administration Costan G Magnussen, MD: conceptualization, writing - review and editing, supervision Markus Juonala, MD: conceptualization, methodology, validation, writing - review and editing, supervision, funding acquisition, project administration Acknowledgements The authors wish to thank Noora Kartiosuo, MSc, from the Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, for statistical advice. 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