Cardiovascular Risk Factors in Childhood and Left Ventricular Diastolic Function in Adulthood Jarkko S. Heiskanen, MD,a,b Saku Ruohonen, PhD,a,b,c Suvi P. Rovio, PhD,a,b Katja Pahkala, PhD,a,b Ville Kytö, MD, PhD,a,b,d Mika Kähönen, MD, PhD,e Terho Lehtimäki, MD, PhD,f Jorma S.A. Viikari, MD, PhD,g Markus Juonala, MD, PhD,g Tomi Laitinen, MD, PhD,h Päivi Tossavainen, MD, PhD,i Eero Jokinen, MD, PhD,j Nina Hutri-Kähönen, MD, PhD,k Olli T. Raitakari, MD, PhDa,b,l

BACKGROUND AND OBJECTIVES: Cardiovascular risk factors, such as obesity, blood pressure, and abstract physical inactivity, have been identified as modifiable determinants of left ventricular (LV) diastolic function in adulthood. However, the links between childhood cardiovascular risk factor burden and adulthood LV diastolic function are unknown. To address this lack of knowledge, we aimed to identify childhood risk factors associated with LV diastolic function in the participants of the Cardiovascular Risk in Young Finns Study. METHODS: Study participants (N = 1871; 45.9% men; aged 34–49 years) were examined repeatedly between the years 1980 and 2011. We determined the cumulative risk exposure in childhood (age 6–18 years) as the area under the curve for systolic blood pressure, adiposity (defined by using skinfold and waist circumference measurements), physical activity, serum insulin, triglycerides, total cholesterol, and high- and low-density lipoprotein cholesterols. Adulthood LV diastolic function was defined by using E/é ratio. RESULTS: Elevated systolic blood pressure and increased adiposity in childhood were associated with worse adulthood LV diastolic function, whereas higher physical activity level in childhood was associated with better adulthood LV diastolic function (P , .001 for all). The associations of childhood adiposity and physical activity with adulthood LV diastolic function remained significant (both P , .05) but were diluted when the analyses were adjusted for adulthood systolic blood pressure, adiposity, and physical activity. The association between childhood systolic blood pressure and adult LV diastolic function was diluted to nonsignificant (P = .56). CONCLUSIONS: Adiposity status and the level of physical activity in childhood are independently associated with LV diastolic function in adulthood.

WHAT’S KNOWN ON THIS SUBJECT: In adults, decreased left ventricular (LV) aResearch Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; bCentre diastolic function is associated with several known cardiovascular risk for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland; cOrion Pharma, d e factors such as overweight, hypertension, and physical inactivity. However, Turku, Finland; Heart Center, Turku University Hospital, Turku, Finland; Department of Clinical Physiology, the link between childhood cardiovascular risk factor burden and Tampere University Hospital and Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; adulthood LV diastolic function is unknown. fDepartment of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; gDepartment of Medicine, WHAT THIS STUDY ADDS: This study reveals that lower LV diastolic function University of Turku and Division of Medicine, Turku University Hospital, Turku, Finland; hDepartment of Clinical in adulthood is associated with an increased burden of adiposity and Physiology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland; iDepartment of decreased physical activity in childhood, supporting the benefits of avoiding Pediatrics, PEDEGO Research Unit and Medical Research Center Oulu, Oulu University Hospital and University of high adiposity and adopting a physically active lifestyle from childhood. Oulu, Oulu, Finland; jDepartment of Paediatric Cardiology, Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland; kDepartment of Paediatrics, Tampere University Hospital and Faculty of Medicine and To cite: Heiskanen JS, Ruohonen S, Rovio SP, et al. l Health Technology, Tampere University, Tampere, Finland; and Department of Clinical Physiology and Nuclear Cardiovascular Risk Factors in Childhood and Left Medicine, Turku University Hospital, Turku, Finland Ventricular Diastolic Function in Adulthood. Pediatrics. 2021;147(3):e2020016691

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 147, number 3, March 2021:e2020016691 ARTICLE The prevalence of overweight and risk factor burden and adulthood LV and study protocol has been reported low levels of physical activity are diastolic function are unknown. To earlier.11 The study protocol has been rising across Western countries, with address this lack of knowledge, we approved by the ethics committee of an increased need for active aimed to identify childhood risk the University of Turku and Turku prevention.1,2 Cardiovascular risk factors associated with LV diastolic University Central Hospital, and burden accumulated across the function in the 34- to 49-year-old informed consent was obtained from lifetime contributes to cardiovascular participants of the Cardiovascular all participants. All authors had full disease outcomes that are the leading Risk in Young Finns Study (YFS). The access to the data. causes of death globally.3 The longitudinal study design with decrease in left ventricular (LV) repeated risk factor measurements Echocardiographic Measurements diastolic function is an early beginning from childhood allows us Echocardiography was performed in functional alteration of the heart. We the unique assessment of cumulative 2011 for 1994 participants according have previously shown that higher risk factor burden from childhood. to the joint American and European waist circumference, systolic blood 9,12 guidelines. After excluding the pressure, and smoking are associated participants with severe with lower LV diastolic function in METHODS cardiovascular diseases (including adults.4 Adverse effects of childhood stroke, myocardial infarction, atrial obesity on adulthood LV mass has Study Population fibrillation, unstable angina pectoris, been previously shown in the The YFS is an ongoing multicenter, cardiomyopathies, and regurgitation Bogalusa Heart Study.5 Additionally, longitudinal, population-based study or stenosis of the mitral or aortic obese children have been reported to on cardiovascular risk factors from valve), type 1 diabetes, or missing have worse LV diastolic function childhood to adulthood, representing echocardiographic measurements, the compared with normal-weight the general Finnish population. The study population of the current study children.6 Conversely, achieving ideal baseline study was conducted in consisted of 1871 participants (859 cardiovascular health, defined by the 1980 and included 3596 children and men and 1012 women; mean age 41.8 American Heart Association, in adolescents (49.0% males aged 3, 6, 6 5.0 years). childhood has been associated with 9, 12, 15, and 18 years). Extensive better LV diastolic function in data on cardiovascular risk factors Trained ultrasound technicians adulthood.7 were recorded at the baseline in performed the echocardiographic 1980, and all follow-up studies were examinations at 5 YFS study centers. Heart failure with preserved ejection conducted in 1983, 1986, 1989, 2001, All ultrasound technicians were fraction is a clinical syndrome 2007, and 2011.11 Population trained by a cardiac imaging characterized by symptoms of heart characteristics from the year 2011 specialist. Transthoracic failure without a decrease of LV are presented in Table 1. Detailed echocardiography was performed systolic function.8 Instead, LV information on the YFS population with Acuson Sequoia 512 (Mountain diastolic function is decreased, including slow LV filling and TABLE 1 Population Characteristics (the Follow-up Year 2011) 9 increased diastolic LV stiffness. Women (n = 1012) Men (n = 859) Currently, there is no evidence-based Meana SD Meana SD medicine that improves the prognosis of the condition. Moreover, LV E/é ratio 5.0 1.0 4.6 0.9 Age, y 41.9 5.0 41.7 5.0 diastolic function is already Systolic blood pressure, mm Hg 115.3 13.6 122.9 13.4 considerably decreased when the Height, cm 166.1 6.0 179.8 6.6 symptoms of heart failure appear. Waist circumference, cm 87.0 13.5 96.4 12.0 Therefore, it is important to Weight, kg 71.4 14.8 86.9 15.2 understand the role of risk burden BMI 25.9 5.2 26.8 4.2 Serum total cholesterol, mmol/L 5.1 0.9 5.3 1.0 acquired during the life course to be Triglycerides, mmol/L 1.1 1.2 1.6 1.1 able to provide effective prevention. HDL-C, mmol/L 1.4 0.3 1.2 0.3 In adult populations, overweight, LDL-C, mmol/L 3.1 0.8 3.4 0.9 insulin resistance, and elevated Insulin, mU/I 8.8 10.8 10.1 9.6 systolic blood pressure are well- Physical activity (index score 5–15) 9.2 1.9 8.9 1.9 Overweight, % 30.5 — 44.4 — known modifiable risk factors for Obese, % 18.8 — 19.9 — heart failure with preserved ejection Overweight or obese, % 49.3 — 64.3 — fraction.10 However, the links Overweight defined as BMI between 25 and 30; obese defined as BMI $30. —, not applicable. between childhood cardiovascular a Parameters with "%" indicate percentage rather than mean.

Downloaded from www.aappublications.org/news by guest on September 26, 2021 2 HEISKANEN et al View, CA) ultrasonography by using skinfold measurements in triplicate adulthood LV diastolic function in the a 3.5-MHz scanning frequency from the nondominant arm by using previous model (ie, adiposity, physical phased-array transducer. Analysis of a Harpenden skinfold caliper.20 Using activity, and systolic blood pressure) the echo images was done by one these adiposity measures, an area were entered into the same statistical observer blinded to the clinical under the curve (AUC) variable was model (childhood model). Third, details with the CommPACS 10.7.8 created for childhood adiposity a multivariable linear model (MediMatic Solutions, Genova, Italy) (standardized mean = 100; SD = 15). (combined model) was created analysis program.13 In the adulthood follow-up studies in adjusting the childhood model 2001, 2007, and 2011, waist additionally for corresponding E/é ratio is a noninvasive circumference (centimeters) was adulthood parameters (ie, adulthood measurement representing LV filling 9 used to indicate adiposity. Data on adiposity, physical activity, and pressure in early diastole. Pulsed- leisure-time physical activity were systolic blood pressure). wave Doppler imaging was used to collected by using a validated self- To study the associations of measure E. Pulsed-wave tissue report questionnaire from childhood cardiovascular risk factor Doppler imaging was used to participants aged 9 to 18 years clustering on adulthood LV diastolic measure é; E wave describes the (Supplemental Information).21 The fl function, we calculated a childhood mitral blood ow during the early questionnaire was administered in fi risk score using those childhood risk lling of the LV, and é measures connection with the medical factors that associated significantly mitral annular early diastolic velocity. examination. For participants aged with LV diastolic function in the In this study, E/é ratio (mean 4.8; 6 years, physical activity was – multivariable models. The factors range 2.2 9.0) was calculated by collected by using parents’ ratings included in the score were (1) using the average of lateral and septal (Supplemental Information).21 values of é velocity.9 High E/é ratio childhood adiposity, (2) physical reflects low LV diastolic function and To describe the long-term burden of activity, and (3) systolic blood has been associated with all-cause the risk factors, we estimated pressure. First, for all 3 risk factors, mortality in several disease participant-specific curves for age the participants were categorized into states.14,15 The complete window between 6 and 18 years, those having the risk factor (1 point) methodology of the cardiac imaging systolic blood pressure, adiposity, and those without the risk factor (0 and the off-line analysis of the cardiac physical activity, insulin, triglycerides, points). Having a risk factor was measurements in the YFS have been total cholesterol, HDL-C, and LDL-C defined as having the AUC value published earlier.13 by mixed-model regression splines.22 within the highest quartile for For more detailed information on the adiposity and systolic blood pressure Clinical Measurements and methodology, please see the and in the lowest quartile for physical Questionnaires Supplemental Information. activity. The risk score was then calculated by summing all 3 risk Standard methods were used to factors (range 0–3), resulting in 4 measure blood pressure, fasting Statistical Analysis groups: 0 risk factors (n = 870), 1 risk serum glucose, total cholesterol, and The distributions of the study factor (n = 652), 2 risk factors (n = high-density lipoprotein cholesterol variables were confirmed by visual 296), and 3 risk factors (n = 53). (HDL-C) concentrations throughout evaluation and the Kolmogorov- Finally, the mean E/é ratio was the study.16 Low-density lipoprotein Smirnov test. Unmodifiable calculated for each group by using cholesterol (LDL-C) was calculated parameters with a strong association least-squares means (The R Package according to Friedewald et al.17 In with LV diastolic function, namely, lsmeans)23 adjusting the analyses 1980, 1983, and 1986, serum insulin age, sex, and adulthood height,4 as according to the combined model. was measured with a modification of well as the study site, were used as the immunoassay method of Herbert covariates in all statistical models. We used all available data in the et al.18 The concentration of serum First, multivariable linear models analyses; therefore, the number of insulin was determined with an were conducted separately for each participants varies between the immunoassay in years 2001, 2007, childhood cardiovascular risk factor. models. Variance inflation factors and 2011.19 At all follow-ups, the Variables were standardized (mean were used to detect multicollinearity participants’ weight (kilograms) and 0 and SD 1) to ensure the in multivariable models (no height (centimeters) were measured. comparability of the point estimates significant multicollinearities were In the follow-up studies conducted in among the studied risk factors and to found). P values #.05 were 1980, 1983, and 1986, childhood visualize the results as a forest plot. considered statistically significant in adiposity was measured by using Second, all childhood variables all analyses. Data were analyzed by subscapular, biceps, and triceps revealing significant associations with using the R statistical package,

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 147, number 3, March 2021 3 version 3.3.2. (R Foundation for TABLE 2 Associations Between LV Diastolic Function (E/é Ratio) and Childhood Risk Factors Statistical Computing, Vienna, Childhood Model Combined Model Austria) (http://www.R-project.org/). Estimate SE P Estimate SE P Female sex 0.084 0.066 .202 20.217 0.072 .003 Age, y 0.093 0.022 ,.001 0.084 0.023 ,.001 RESULTS Height in adulthood, cm 20.140 0.031 ,.001 20.137 0.032 ,.001 Cumulative systolic blood pressure in childhood 0.100 0.022 ,.001 0.015 0.025 .557 Childhood Risk Factors and Cumulative physical activity in childhood 20.061 0.023 .007 20.053 0.024 .029 Adulthood LV Diastolic Function Cumulative adiposity in childhood 0.091 0.025 ,.001 0.075 0.028 .007 Systolic blood pressure in adulthood, mm Hg ———0.180 0.025 ,.001 The high cumulative burden of Physical activity in adulthood (index score 5–15) ———0.018 0.022 .410 childhood adiposity and systolic Adiposity in adulthood, cm ———0.039 0.028 .166 blood pressure were associated with Both models were additionally adjusted for study center. Childhood cumulative parameters were calculated as AUC worse adulthood LV diastolic variables from estimated participant-specific curves (age window 6–18 y). Explanatory variables were standardized function. The high cumulative (mean 0 and SD 1). —, not applicable. childhood physical activity exposure was associated with a better serum insulin, triglycerides, total including systolic blood pressure, adulthood LV diastolic function cholesterol, HDL-C, or LDL-C with physical activity, and adiposity (Fig 1). The results remained similar adult LV diastolic function (Fig 1). measurements from both childhood when all 3 childhood risk factors and adulthood (Table 2, combined were entered simultaneously in To study whether the associations of model). Childhood adiposity was a multivariable linear model (Table 2, childhood risk factors remained found to have an association with childhood model). No significant significant after controlling for the worse adulthood LV diastolic function associations were found for the counterpart adulthood risk factors, independent of adulthood adiposity. cumulative childhood burden of we conducted a multivariable model The adjustment with the counterpart

E/é Ratio Systolic blood pressure Adiposity Physical activity Insulin Triglycerides Total cholesterol HDL-C LDL-C –0.2 –0.1 0.0 0.1 0.2 Estimate (95% CI) FIGURE 1 Standardized b-estimates for the associations between each separate childhood (age 6–18 years) cumulative cardiovascular risk factor and adulthood E/ é ratio. Linear regression analyses were conducted separately for each cardiovascular risk factor adjusting for age, sex, study center (in the year 2011), and adulthood height. Standardized cardiovascular risk factor variables (mean 0 and SD 1) are shown. Error bars denote 95% confidence intervals (CIs).

Downloaded from www.aappublications.org/news by guest on September 26, 2021 4 HEISKANEN et al adulthood risk factors diluted the function (P = .007). Compared with metabolism.24 Moreover, both effect estimate by ∼18%. Childhood the participants with no childhood childhood and adulthood obesity are physical activity had an association risk factors, the participants with 2 or associated with myocardium with better adulthood LV diastolic 3 childhood risk factors had a higher remodeling and alteration of LV function independent of adulthood E/é ratio denoting worse LV diastolic systolic and diastolic function.25,26 physical activity. After further function (P = .047 and P = .0066, This deterioration in LV diastolic adjustment with the counterpart respectively). function has been suggested to affect adulthood risk factors, the effect the elastic properties of the Finally, all multivariable models were estimate of childhood physical myocardium through multifactorial further adjusted for left atrial and activity was diluted by ∼13%. The mechanisms.25,27,28 Our present ventricular volume, ejection fraction, association of childhood systolic results indicate that increased and LV mass in separate models. The blood pressure with adulthood LV childhood adiposity has an inverse results of these analyses were similar diastolic function was no longer association with LV diastolic function to those of the main analyses significant when the adulthood risk in adulthood and that this link reported in Table 2 and Fig 2 (data factors were taken into account (the remains significant after controlling not shown), suggesting that the effect estimate was diluted by 85%). for adulthood risk factor profile. This results are not driven by changes in suggests that excess childhood LV volume, LV mass, or LV systolic Clustering of the Childhood Risk adiposity may have long-term function. Factors adverse influences on LV diastolic The results from the analyses for the Sensitivity Analyses function. Importantly, although childhood risk factor score, indicating childhood adiposity was associated the number of childhood risk factors, Sensitivity analyses were conducted independently with adulthood LV are shown in Fig 2. A significant trend by using (1) arithmetic means instead diastolic function, the was found between a higher number of least-squares means or (2) cutoff cardiometabolic markers closely of childhood cardiovascular risk limits of 80th/20th for the risk linked to adiposity, including factors and worse LV diastolic factors to calculate the childhood childhood insulin, triglycerides, total cardiovascular risk score indicating cholesterol, HDL-C, and LDL-C, were the childhood risk factor not. Therefore, our results suggest 6.0 accumulation. The results from the that the association between sensitivity analyses were similar to childhood adiposity and adulthood LV the main analyses (data not shown). 5.0 diastolic function is not driven by these cardiometabolic markers. DISCUSSION 4.0 Previous studies have revealed that This study reveals that the cumulative physical activity has numerous burden of adiposity, physical activity, beneficial effects on cardiovascular 3.0 and systolic blood pressure in health.29,30 Physically active E/é Ratio childhood is associated with LV individuals have fewer cardiovascular diastolic function at ages 34 to 49. 2.0 comorbidities, including diabetes Importantly, the associations of mellitus, hypertension, and childhood adiposity and physical dyslipidemia, than those with low 1.0 activity with adulthood LV diastolic physical activity levels.31 Previous function were independent of the studies have revealed that lower adulthood levels of the same risk .47a .047a .0066a cardiorespiratory fitness is a risk 0.0 fi 0123 factor. This is the rst study to factor for worse LV diastolic function Number of the Risk Factors indicate that the cumulative and heart failure with preserved cardiovascular risk factor exposure FIGURE 2 ejection fraction and may contribute Association between childhood cardiovascular already in childhood may to the prognosis of the disease.32–35 risk score and adjusted means for adulthood independently contribute to diastolic Furthermore, worse E/é ratio. The analyses were adjusted for age, LV function in adulthood. fi sex, research center, adulthood height, systolic cardiorespiratory tness in young blood pressure, physical activity, and waist Childhood obesity is known to adulthood was found to associate circumference. Study participants were divided associate with adverse changes in with higher LV diastolic filling into 4 groups on the basis of the sum of the pressures independent of risk factors in childhood (n): 0 = 870, 1 = 652, 2 cardiovascular risk factors, such as = 296, and 3 = 53. a P values compared with the serum lipoproteins, systolic and cardiovascular risk factor burden in 36 group with 0 risk factors. diastolic blood pressure, and glucose a middle-aged population. Our

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 147, number 3, March 2021 5 findings, revealing that the childhood childhood risk factor clustering on worse LV diastolic dysfunction in the cumulative physical activity is cardiovascular health and by follow-up examination. Our study associated with better adulthood LV highlighting the role of lifestyle- population with no significant cardiac diastolic function, extend these related childhood risk factors, the diseases strengthens the significance previous observations by findings from our study underline the of these results because the demonstrating that the beneficial need for guideline-recommended possibility for bias caused by cardiac effects of childhood physical activity active prevention strategies targeted diseases is low. may carry on to adulthood. to the individuals with several Hypertension is considered a key risk cardiovascular risk factors beginning CONCLUSIONS from childhood.39 factor for LV diastolic dysfunction in This study reveals that lower levels of adults, deterring it through several The major strengths of this study adiposity and higher levels of physical potential mechanistic pathways, include the longitudinal study design activity in childhood are beneficially including pressure overload causing and the long follow-up of participants associated with LV diastolic function LV hypertrophy and alterations in the who were well phenotyped in both in adulthood. Importantly, the neurohumoral activity and childhood and adulthood. A potential clustering of cardiovascular risk fl 14,37 in ammation. In contrast, limitation of the study is a possible factors in childhood is associated childhood systolic blood pressure has selection of the study population. As with worse LV diastolic function in not been previously linked with in every longitudinal study, there is adulthood. These findings provide adulthood LV diastolic function. In a loss in the follow-up. However, novel evidence on the childhood risk our study, a higher cumulative burden detailed assessments of the factors of adulthood LV diastolic of systolic pressure in childhood was representativeness have previously function, supporting the benefits of associated with worse LV diastolic revealed no significant differences avoiding high adiposity and adopting function in adulthood. However, the between the participants and a physically active lifestyle already association diluted when adulthood nonparticipants in the age- and sex- from childhood. systolic blood pressure was taken adjusted analyses.11,16 The YFS into account, suggesting that population is racially homogeneous, ACKNOWLEDGMENTS adulthood systolic blood pressure therefore our results are Expert technical assistance in data level is a more powerful determinant generalizable to white European management and statistical analyses for the adulthood LV diastolic subjects. E/é ratio is a generally used by Johanna Ikonen, Noora Kartiosuo, function compared to childhood marker for LV diastolic function, but and Irina Lisinen is gratefully systolic blood pressure. it is not a consistent indicator of LV acknowledged. Cardiovascular risk factors tend to filling pressures in individual patients cluster already in childhood, and the in specific clinical situations.15 clustering of risk factors is thought to However, at a population level, E/é be a useful measure of cardiovascular ratio has been shown to associate ABBREVIATIONS health in children.38 Our present with an increased incidence of heart AUC: area under the curve study extends current knowledge by failure and has been used in multiple HDL-C: high-density lipoprotein revealing that the cardiovascular risk studies to predict all-cause mortality, cholesterol factor clustering (ie, an increasing cardiovascular death, and heart LDL-C: low-density lipoprotein number of risk factors) already in failure hospitalizations in several cholesterol childhood associates with lower LV diseases states.14,40 Additionally, in LV: left ventricular diastolic function in adulthood. a population-based follow-up study YFS: Cardiovascular Risk in Young Noteworthy, by broadening the by Kane et al,41 baseline E/é ratio was Finns Study outlook to the long-term effects of found to be a predictive factor for

Deidentified individual participant data will not be made available. Dr Heiskanen contributed to the conception and design of the work, contributed to acquisition, analysis, and interpretation of the data, and drafted the manuscript; Drs Ruohonen and Raitakari contributed to the conception and design of the work, contributed to acquisition, analysis, and interpretation of the data, and critically revised the manuscript; Drs Rovio, Pahkala, Kytö, Kähönen, Lehtimäki, Viikari, Juonala, Laitinen, Tossavainen, Jokinen, and Hutri-Kähönen contributed to the acquisition, analysis, and interpretation of data for the work and critically revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. The preliminary results of this article were presented in a poster session of the American Heart Association Scientific Sessions; November 10–12, 2018; Chicago, IL.

Downloaded from www.aappublications.org/news by guest on September 26, 2021 6 HEISKANEN et al DOI: https://doi.org/10.1542/peds.2020-016691 Accepted for publication Dec 4, 2020 Address correspondence to Jarkko S. Heiskanen, MD, Research Centre of Applied and Preventive Cardiovascular Medicine and Centre for Population Health Research, University of Turku and Turku University Hospital, Kiinamyllynkatu 10, 20520, Turku, Finland. E-mail: jsheis@utu.fi PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2021 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: The Young Finns Study has been financially supported by the Academy of Finland: grants 322098, 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), 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 Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; The Sigrid Jusélius Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; Diabetes Research Foundation of Finnish Diabetes Association; European Union Horizon 2020 (grant 755320 for TAXINOMISIS); European Research Council (grant 742927 for MULTIEPIGEN project); Tampere University Hospital Supporting Foundation; and Aarne Koskelo Foundation and Diabetes Research Foundation of Finnish Diabetes Association. The funders of this study had no role in the design and conduct of the study. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose. COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2020-025908.

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Downloaded from www.aappublications.org/news by guest on September 26, 2021 8 HEISKANEN et al Cardiovascular Risk Factors in Childhood and Left Ventricular Diastolic Function in Adulthood Jarkko S. Heiskanen, Saku Ruohonen, Suvi P. Rovio, Katja Pahkala, Ville Kytö, Mika Kähönen, Terho Lehtimäki, Jorma S.A. Viikari, Markus Juonala, Tomi Laitinen, Päivi Tossavainen, Eero Jokinen, Nina Hutri-Kähönen and Olli T. Raitakari Pediatrics originally published online February 8, 2021; originally published online February 8, 2021;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2021/02/13/peds.2 020-016691 References This article cites 40 articles, 12 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2021/02/13/peds.2 020-016691#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Epidemiology http://www.aappublications.org/cgi/collection/epidemiology_sub Preventive Medicine http://www.aappublications.org/cgi/collection/preventative_medicine _sub Cardiology http://www.aappublications.org/cgi/collection/cardiology_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 26, 2021 Cardiovascular Risk Factors in Childhood and Left Ventricular Diastolic Function in Adulthood Jarkko S. Heiskanen, Saku Ruohonen, Suvi P. Rovio, Katja Pahkala, Ville Kytö, Mika Kähönen, Terho Lehtimäki, Jorma S.A. Viikari, Markus Juonala, Tomi Laitinen, Päivi Tossavainen, Eero Jokinen, Nina Hutri-Kähönen and Olli T. Raitakari Pediatrics originally published online February 8, 2021; originally published online February 8, 2021;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/early/2021/02/13/peds.2020-016691

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