Persistent Hyperglycemia and Insulin Resistance With the Risk of Worsening Cardiac Damage in Adolescents: A 7-Year Longitudinal Study of the ALSPAC Birth Cohort Free

Insulin resistance (IR) and dysglycemia are precursors of young-onset type 2 diabetes and have been associated with cardiac and vascular alterations in the presence of young-onset type 2 diabetes (1–5). We recently observed that fat mass in mid-adolescence may be unidirectionally associated with later IR whereas in late adolescence and young adulthood, fat mass and IR are likely bidirectionally reinforcing, with three-fourths of the vicious pathologic cycle driven by fat mass and one-fourth by IR (6). Despite the increasing incidence of young-onset type 2 diabetes globally (3,4), the U.S. Preventive Services Task Force deemed there was insufficient evidence to assess the benefits of screening for type 2 diabetes in children and adolescents and requested further evidence on cardiovascular outcomes in the young population (7).

A key evidence point is whether IR- and dysglycemia-induced cardiac remodeling exist in apparently healthy adolescents. This point remains unexamined due to the scarcity of large-scale and long-term studies with repeated echocardiography assessments (5,8). Other competing risk factors for premature cardiac remodeling in apparently healthy youth are elevated lipid levels, blood pressure, obesity, tobacco smoking, and sedentary behavior, which could co-occur with glycemic traits (9–12). Therefore, longitudinal data to examine discordant changes in glycemic versus coexisting factors on changes in subclinical cardiac structure are critically necessary to determine the precursors of atherosclerotic cardiovascular events (13,14).

Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort (England, U.K.), this study examined 1) the longitudinal associations of persistent hyperglycemia and increased IR with the risk of changes in cardiac structure and function and premature progressive cardiac damage from ages 17–24 years, and 2) the mediating roles of lipids, high-sensitivity C-reactive protein (hsCRP), systolic blood pressure, total body fat mass, and lean mass in the associations of dysglycemia and IR with cardiac changes.

Details of the ALSPAC birth cohort have been published (15–17). Data from the ALSPAC birth cohort are used to investigate factors that influence childhood development and growth. Altogether, 14,541 pregnancies of women residing in Avon, southwestern England, U.K., who had a total of 14,676 fetuses were enrolled between 1 April 1991 and 31 December 1992. Of these, 13,988 children were alive at 1 year of age. From age 7 years, an attempt was made to bolster the initial sample with eligible cases who did not join the study originally. The phases of enrolment are described in more detail in the cohort profile report and its update (15,16). The total sample size from the age of 7 years, therefore, is 15,447 pregnancies, resulting in 15,658 fetuses, of which 14,901 children were alive at 1 year of age. Annual face-to-face clinics commenced from the age of 7 years and are ongoing. Altogether, 2,079 participants had cardiac structural measures at the age 17-year clinic visit and 1,957 participants had cardiac measures at 24 years (Supplementary Fig. 1).

For the present analysis, 1,595 participants who had complete cardiac and blood sample measures at age 24 years were included, approximating 82% of participants with cardiac measures at the age 24-year clinic visit. The characteristics of the included 1,595 participants were similar those of the excluded 363 participants (19%) (Supplementary Table 1).

Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. Informed consent for the use of data collected via questionnaires and clinics was obtained from participants, following the recommendations of the ALSPAC Ethics and Law Committee at the time. Study data at 24 years were collected and managed using REDCap electronic data capture tools (18).

Anthropometry (height and weight) of participants at ages 17 and 24 years was assessed by observing standard protocols, and BMI was computed as weight in kilograms per height in meters squared. Overweight/obesity was categorized as BMI >24.99 kg/m². Heart rate and systolic and diastolic blood pressures were measured at ages 17 and 24 years using an Omron 705-IT monitor, as previously detailed (17,19). Fasting blood samples at ages 17 and 24 years were collected, spun, and frozen at –80°C, and later assayed for glucose and insulin, as detailed previously (17,19–21). Fasting insulin was measured using an ultrasensitive, automated microparticle enzyme immunoassay (Mercodia), which does not cross-react with proinsulin; the sensitivity of the immunoassay was 0.07 mU/L (8,19). Participants with fasting glucose levels >5.6 mmol/L and fasting insulin levels >11.78 mU/L (∼85th percentile) were categorized as at risk for hyperglycemia and hyperinsulinemia (8,19,22). We also applied a glucose cut point of 6.1 mmol/L to reduce misclassifications, because >70% of adolescents in our cohort who were classified has having prediabetes at age 15 years when the population glucose concentration was high returned to normoglycemia by age 17 years (8). Nearly 98% of our adolescents at age 15 years had attained puberty, and all adolescents attained puberty by age 17 years (8). The HOMA-IR was calculated as (fasting insulin × fasting glucose/22.5) (23). The >75th percentile of HOMA-IR was categorized as high or elevated IR. Persistent hyperglycemia, hyperinsulinemia, and high IR were described as having values above the cut points at both time periods (adolescence and young adulthood).

Fasting plasma triglyceride, HDL cholesterol (HDL-c), LDL cholesterol (LDL-c), and hsCRP levels were assessed at both the 17- and 24-year clinic visits, in line with standard protocols (17,19,20). Total fat mass and lean mass were assessed using a DEXA scanner (GE Medical Systems, Madison, WI) at 17-year and 24-year clinic visits. Questionnaires to assess smoking behavior were administered at the 17-year and 24-year clinic visits. A specific question regarding whether participants smoked in the past 30 days was used as an indicator of current smoking status (11). At the 17-year clinic visit, participants were briefly asked about their personal and family (mother, father, and siblings) medical history, such as a history of hypertension, diabetes, high cholesterol, and vascular disease. The participant’s mother’s socioeconomic status was grouped according to the 1991 British Office of Population and Census Statistics classification (19,24). Sedentary time, light physical activity, and moderate to vigorous physical activity were assessed with waist-worn ActiGraph accelerometer devices for seven consecutive days at the 15-year clinic visits and four consecutive days at the age 24 years clinic visits, with valid wear days including at least two weekdays and one weekend day (8,19,24–26).

At mean (SD) age 17.7 (0.4) years clinic visit, echocardiography was performed according to American Society of Echocardiography guidelines (13) by one of two experienced echocardiographers using an HDI 5000 ultrasound machine (Phillips Healthcare, Amsterdam, the Netherlands) equipped with a P4‐2 Phased Array ultrasound transducer. At mean (SD) age 24.4 (0.6) years clinic visit, echocardiography was performed by two experienced echocardiographers using a Philips EPIQ 7G Ultrasound System equipped with a X5-1 transducer. The Philips Q-station was used for the M-mode, two-dimensional, and Doppler echo analyses, and TomTec software was used for the three-dimensional echo analyses. Measures of cardiac structure were left ventricular mass index for height raised to the power of 2.7 (LVMI^2.7) and relative wall thickness (RWT) computed from septal wall thickness, posterior wall thickness, and LV diastolic diameter (LVDD). Measures of cardiac function were LVD function (LVDF) early (E) to atrial (A) wave ratio and LV filling pressure (LVFP) E/é wave ratio (the ratio of the velocities of early diastolic mitral inflow [the E-wave] to early diastolic mitral annual tissue [e′-wave]) (14,27). Pulsed Doppler examination of transmitral flow was recorded from the apical four-chamber view. For LV measurements, the sample volume was positioned between the mitral annulus and the tips of the mitral leaflets, with the position adjusted to maintain the sample volume at an angle as near parallel to transmitral flow as possible with the participant in passive end-expiration (13). The peak flow velocity of the E and A waves were measured from the three consecutive cardiac cycles displaying the highest measurable velocity profiles (13). A similar measurement (e′) was conducted at the tricuspid valve. Tissue Doppler echocardiography was performed in the four-chamber view on the lateral, inferior, and septal LV walls to obtain myocardial wall velocities. Data were acquired with the beam parallel to the wall of interest and with optimal settings to ensure no over-gain of the low-velocity signals. A 5-mm sample volume was placed at the level of the mitral valve annulus and a loop of 8–10 cardiac cycles was recorded. The reproducibility of echocardiographic examinations was assessed by recalling 30 participants and repeating their measurements. The intraclass correlation of repeated measurements ranged from 0.75 to 0.93 (intraobserver) and 0.78 to 0.93 (interobserver) (27). LV hypertrophy was defined as LVMI^2.7 ≥51 g/m^2.7 because that predicts hard cardiovascular events, increased RWT was defined as ≥0.44, LVDD as E/A <1.5, and increased LVFP (hiLVFP) as E/e′ ≥8 (14).

The participants’ descriptive characteristics were summarized as means and SDs, medians and interquartile ranges, or frequencies and percentages. Change in variables over time was tested with a paired t test for normally distributed continuous variables, Wilcoxon signed-rank test for skewed continuous variables, and McNemar change tests for categorical variables.

The separate associations of the 7-year changes in glucose, insulin, and HOMA-IR values with each of the progressive changes in LVMI^2.7, RWT, LVDF, and LVFP were examined using generalized linear mixed-effect models for repeated measures. Model 1 was unadjusted. Model 2 was adjusted for sex and other time-varying covariates measured at both baseline and follow-up such as age; hsCRP; heart rate; systolic blood pressure; fat mass; lean mass; smoking status; family history of hypertension, diabetes, high cholesterol, or vascular disease; socioeconomic status; sedentary time; light physical activity; moderate to vigorous physical activity; LDL-c, HDL-c, triglyceride, glucose, or insulin levels, depending on the predictor. When HOMA-IR was the predictor, there were no further adjustments for glucose and insulin. The persistence of altered metabolic status from adolescence through young adulthood predicting the odds of cardiac damage progression was examined with fully adjusted, generalized, linear mixed-effect models with logit links. Sex-based analyses are presented in Supplementary Table 2 and Supplementary Fig. 2.

Mediating path analyses using structural equation models separately examined the mediating role of each change in LDL-c, triglyceride, hsCRP, systolic blood pressure, total body fat mass, and lean mass on the longitudinal associations of each change in glucose and HOMA-IR with the progression in LVMI^2.7. The mediation analysis was conducted in line with the Guideline for Reporting Mediation Analyses of Randomized Trials and Observational Studies (AGReMA) (28). The examined mediation mechanism between metabolic and cardiac indices is partly based on previous studies in which worsening cardiometabolic profiles were associated with cardiac diseases (10,14,29). Analyses were adjusted for sex, family history of hypertension, diabetes, high cholesterol, or vascular disease; socioeconomic status; and time-varying covariates measured at both baseline and follow-up, such as age; heart rate; smoking status; sedentary time; light physical activity; moderate to vigorous physical activity; HDL-c, LDL-c, and triglyceride levels; fat mass; lean mass; and hsCRP level; in addition to insulin, depending on the predictor or mediator.

The path models had three equations per regression analysis: the longitudinal associations of change in glucose or HOMA-IR with change in LDL-c, triglyceride, and hsCRP levels, systolic blood pressure, and total body fat mass or lean mass (Eq. 1); the longitudinal associations of change in LDL-c, triglyceride, and hsCRP levels, systolic blood pressure, and total body fat mass or lean mass with LVMI^2.7 (Eq. 2); and the longitudinal associations of change in glucose or HOMA-IR with change in LVMI^2.7 (Eq. 3; total effect). Equation 3′ (direct effect) accounted for the mediating role of change in LDL-c, triglyceride, and hsCRP levels; systolic blood pressure; total body fat mass; or lean mass on the longitudinal associations of change in glucose or HOMA-IR with changes in LVMI^2.7. The proportion of mediating or suppressing roles was estimated as the ratio of the difference between Eq. 3 and Eq. 3′ or the multiplication of Eqs. 1 and 2 divided by Eq. 3 and expressed as a percentage.

A mediating or indirect role is confirmed when there are statistically significant associations between the predictor and mediator, the predictor and outcome, the mediator and outcome, and when the longitudinal association between the predictor and outcome variable was attenuated upon inclusion of the mediator (30). However, when the magnitude of the longitudinal association between the predictor and outcome is increased upon inclusion of a third variable, a suppression is confirmed (30). This means that suppression occurs when the mediational path has an opposite effect (i.e., instead of a decrease in the point estimate of the direct effect between an exposure and an outcome in relation to the total effect, there is an increase in the direct effect above the total effect’s point estimate) (30). We considered a statistically significant mediation or suppression of <1% as minimal, and of ≥1% as partial. Path analyses were conducted with 1,000 bootstrapped samples (31). We additionally conducted sex-based mediation analyses of the role of fat mass in the relationships between HOMA-IR and LVMI^2.7.

Differences and associations with a two-sided P value <0.05 were considered statistically significant, with interpretations aided with effect estimates and their CIs or SEs. Analyses involving 20% of a sample of 10,000 children in the ALSPAC at 0.8 statistical power, 0.05 α, and two-sided P value would show a minimum detectable effect size of 0.062 SDs if they had relevant exposure for a normally distributed quantitative variable (32). Missing data were handled with 20 cycles of multiple imputations, because it has >98% efficiency in simulating real data in our cohort (17,19,24). Multiple comparisons were adjusted for using sequential Sidak correction. All statistical analyses were performed using SPSS statistics software, version 29.0 (IBM Corp, Armonk, NY) and mediation analyses was performed with IBM AMOS, version 29.

The informed consent obtained from ALSPAC participants does not allow the data to be made freely available through any third-party–maintained public repository. However, data used for this submission can be made available on request to the ALSPAC executive. The ALSPAC data management plan describes in detail the policy regarding data sharing, which is through a system of managed open access. Full instructions for applying for data access are given at https://www.bristol.ac.uk/alspac/researchers/access/. The ALSPAC study website contains details of all the data that are available (https://www.bristol.ac.uk/alspac/researchers/our-data/).

Among 1,595 adolescents (mean [SD] age, 17.74 [0.38] years; 955 [59.8%] female participants]) glucose, insulin, and HOMA-IR levels increased in the total cohort and in both male and female participants. The prevalence of hyperglycemia increased fivefold during growth from age 17 through 24 years irrespective of the glucose cut points (Table 1). The prevalence of LV hypertrophy increased threefold in the total cohort from 2.4 to 7.1%, and in both sexes (Table 1 and Supplementary Table 2). The prevalence of LVDD increased in the total cohort from 9.2 to 15.8%, and in both sexes over a period of 7 years (Table 1 and Supplementary Table 2). The mean (SD) BMI for the total cohort at baseline was 21.5 (3.82) kg/m² and 23.1 (4.6) kg/m² at follow-up. Approximately 96% of the cohort are White. Other characteristics are described in Table 1 and Supplementary Table 2.

In fully adjusted whole-cohort (Table 2) and sex-specific analyses (Supplementary Table 3) from ages 17 to 24 years, increasing glucose concentration was significantly associated with increasing LVMI^2.7 and RWT. Although increased glucose concentration was associated with decreased LVFP in the whole cohort and male participants, it was associated with decreased LVDF in female participants but increased LVDF in male participants (Table 2 and Supplementary Table 3). Increased insulin concentration in the whole cohort was significantly associated with increased LVFP (Table 2). Increased HOMA-IR was associated with increased LVMI^2.7 and RWT (Table 2).

In a fully adjusted model, persistent hyperglycemia of >5.6 mmol/L (odds ratio [OR] 1.46 [95% CI 1.35–1.57]; P < 0.001) and >6.1 mmol/L (OR, 3.10; 95% CI, 1.19–8.08; P = 0.021), were separately associated with higher odds of LV hypertrophy progression over 7 years (Table 2). Persistent hyperglycemia of >5.6 mmol/L was associated with worsening high RWT, LVDD, and high LVFP over 7 years (Table 2). There were no statistically significant relationships of persistent insulinemia with LV hypertrophy, high RWT, and LVDD, except for high LVFP (Table 2). Persistently high IR was significantly associated with worsening LV hypertrophy, high RWT, and LVDD.

Increased fat mass significantly mediated the associations of increased HOMA-IR with increased LVMI^2.7 (62.3% mediation effect) (Table 3 and Fig. 1). Increased LDL-c partly mediated the associations of the increased glucose with increased LVMI^2.7 (6.3% mediation effect), but increased hsCRP suppressed the association by the same amount (Table 3). Increased triglyceride levels and systolic blood pressure partly mediated the associations of increased HOMA-IR with increased LVMI^2.7 (11.8–18.6% mediation effect) (Table 3).

Among male participants, increased total fat mass significantly suppressed the associations of increased HOMA-IR with increased LVMI^2.7 (178% suppression effect) (Supplementary Fig. 2). The total effect standardized β of 0.069 (95% CI 0.016–0.120; P = 0.008) and the indirect effect of β = 0.123 (95% CI 0.098–0.150; P = 0.002) were statistically significant (Supplementary Fig. 2). Among female participants, increased total fat mass significantly mediated the associations of increased HOMA-IR with increased LVMI^2.7 (94.5% mediation effect) (Supplementary Fig. 2). The total effect standardized β of 0.153 (95% CI 0.107–0.199; P = 0.003) and the indirect effect β of 0.145 (95% CI 0.114–0.175; P = 0.003) were statistically significant (Supplementary Fig. 2).

In a large adolescent population, persistent hyperglycemia was associated with threefold higher odds of progressive cardiac structural damage, whereas increased glucose levels and IR were associated with worsening cardiac remodeling and diastolic dysfunction indices. The relationship between increased glucose and worse cardiac structural change was consistent across sexes. Increased triglyceride levels, systolic blood pressure, and fat mass partly mediated the relationship of IR with increased cardiac mass. Given previous literature on pediatric obesity, elevated blood pressure, and dyslipidemia as predictors of LV remodeling, these findings add worsening hyperglycemia and IR as predictors of structural and functional cardiac alterations necessitating primordial and primary preventive approaches to mitigating these changes in the young population (1–5).

In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, which included 411 young adults with type 2 diabetes, mean age of 23 years, and who were followed up for 5 years, the prevalence of LV hypertrophy was 15.8%, which was twice as high as in the present study follow-up age of 24 years (2). Unfortunately, treatment failed to reverse the cardiac organ injury observed in the TODAY study, which worsened (2). After 10 years follow-up of the TODAY study, 17 major cardiovascular events occurred and one death due to myocardial infarction, consistent with previous literature indicating LV hypertrophy predicts future atherosclerotic cardiovascular diseases (33). In our cohort, increased glucose level and IR were both associated with increased LVM and RWT, in addition to hyperglycemia-induced increased odds for LV hypertrophy suggesting the likelihood of concentric hypertrophy (34). These findings in an apparently healthy cohort extend the evidence already documented in adolescents and young adults diagnosed with young-onset type 2 diabetes (1–5). In adult studies such as the Coronary Artery Risk Development in Young Adults (CARDIA) and Framingham Heart studies, long-standing adult-onset type 2 diabetes has been longitudinally associated with adverse cardiac remodeling (35,36). The consistent effect of elevated glucose levels on cardiac structure and functional indices in youth extends previously reported evidence among 95,783 adults in whom progressively increased glucose levels were associated with cardiovascular risk, including fatal or nonfatal cardiovascular outcomes (e.g., sudden death, stroke, or acute myocardial infarction) during a 12.4-year follow-up period (37). In the adult study, fasting and 2-h glucose levels of 6.1 mmol/L and 7.8 mmol/L were associated with cardiovascular event risk of 1.33 (95% CI 1.06–1.67) and 1.58 (95% CI 1.19–2.10), respectively (37). In the present study, the odds of persistent hyperglycemia-associated worsening LV hypertrophy was twofold higher when the ≥6.1 mmol/L hyperglycemia cut point (OR = 3.01) was the predictor, compared with the ≥5.6 mmol/L cut point (OR = 1.45). These findings may indicate one of the earliest and covert, yet deleterious, consequences of uncontrolled high glucose concentration on the cardiovascular system of young people.

Youth-onset type 2 diabetes has a more extreme metabolic phenotype than does adult-onset type 2 diabetes, with greater IR and deterioration of β-cell function (5). Dietary intervention and light physical activity from childhood may be able to reverse metabolic alterations, thereby primordially preventing premature cardiac structural damage (5,21,38). Although hyperglycemia seems to worsen cardiac structure in both sexes, it appears that cardiac function response is sex differential. Each unit increase in glucose was associated with a fivefold larger effect estimate of increased LVM in female participants compared with male participants. Evidence in adults suggests that women with type 2 diabetes have a greater relative risk of cardiovascular disease than men (39). Worsening glycemia was associated with improved LVFP in men but worse LVDF in women. The alterations of these cardiac functional parameters are precursors of heart failure with preserved ejection fraction in adults (14). Moreover, an aggressive hyperglycemia-induced cardiac structural and functional damage in women relative to men might have begun several decades before a clinical diagnosis of type 2 diabetes, likely in the mid-40s age range (39). In addition, higher blood glucose levels could also be a marker for IR or metabolic syndrome (23).

The long-term persistence of hyperglycemic stress on cardiomyocytes even after blood glucose normalization triggers mitochondrial dysfunction and endoplasmic reticulum stress–induced inflammation (29). This promotes reactive oxygen species and increases the risk of cellular damage (29). Persistent hyperglycemia results in advanced glycation end-product generation, which accumulates in the vessel wall, compromising the structural integrity of the extracellular matrix, inducing endothelium damage, and nitric oxide reduction (29). Hyperglycemia promotes increased inflammation, leading to increased IR and β-cell dysfunction, perpetuating a vicious cycle of hyperglycemia and subsequent IR (29). In the presence of hyperglycemia and IR, cardiac metabolic flexibility is lost, resulting in reduced use of free fatty acids, and in intramyocardial lipid accumulation. This may contribute to cardiomyocyte enlargement with consequent hypertrophy, along with metabolic alterations through impaired mitochondrial function that lead to contractile dysfunction (29). In the present study, we observed that the pathway through which IR exerts its influence on cardiac structure is mainly through increased fat mass, but we also observed important sex differences. Among female participants, 95% of the longitudinal association of IR with cardiac mass was explained by increased fat mass. On the contrary, fat mass suppressed the association of IR with increased cardiac mass in male participants, which also is referred to as inconsistent mediation. In the cohort, female participants have more fat mass relative to male participants, but the effect of fat mass on cardiac indices seems significant despite having an average BMI in both male and female participants at baseline and follow-up within the normal healthy BMI range (6,24,40). Obesity in youth is known to be a hypervolemic and hyperdynamic state, which could induce LV remodeling and induce dysglycemia (39). The vicious cycle of increased fat mass and IR appears to begin in adolescence, and the findings of the present study indicate metabolic-induced cardiac alterations might have been concurrently initiated (6). Triglycerides also had an approximately 20% mediating effect on the relationship of IR with increased cardiac mass, which may indicate the role of diet; however, triglyceride levels also may be a risk factor for increased IR (38). This evidence collectively supports the need for primordial and primary prevention of hyperglycemia, IR, and excess fat mass in the young population to decrease the risk of young-onset type 2 diabetes and cardiovascular disease sequelae (5,21,24,26).

In an extensively phenotyped large birth cohort (ALSPAC) with repeated measures of variables during late adolescence and early adulthood, we examined the associations of metabolic alterations on cardiac structure and function in an asymptomatic young population. Several objectively and repeatedly measured confounders were controlled for, such as fat mass, lean mass, physical activity, sedentary time, and several lifestyle factors, like smoking, family history, and socioeconomic status, which increased the internal validity of the study. Nonetheless, we may not exclude the existence of residual biases from unmeasured confounders, such as the unavailability of dietary records. The measure of insulin sensitivity and secretion using gold standard methods such as the clamp test was unavailable, given that the feasibility of these measures in large epidemiologic studies is limited. The participants were mostly White; thus, findings may not be generalizable to other ethnic groups. Last, establishing causation with observational studies is challenging and warrants further experimental studies.

Persistent hyperglycemia and increased IR were independently associated with the risk of worsening cardiac structural and functional damage in youth, with excess fat mass explaining >60% of the relationship. Hyperglycemia-induced cardiac alterations may affect female youth worse than male youth. Efforts targeted at preventing and treating adolescent obesity may help disrupt the pathogenesis of IR, young-onset type 2 diabetes, and cardiovascular alterations in later life.

Acknowledgments. The authors are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. They appreciate Jennifer Lyn Baker for her helpful suggestions during manuscript preparation.

Funding. The UK Medical Research Council and Wellcome (grant 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. The British Heart Foundation (grant CS/15/6/31468) funded blood pressure and Actigraph activity monitoring device measurement at 24 years. The Medical Research Council (grant MR/M006727/1) supported smoking data collection. A comprehensive list of grant funding is available on the ALSPAC website (https://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf); A.O.A.’s research group (UndeRstanding FITness and Cardiometabolic Health In Little Darlings: urFIT-child) has been funded by the Jenny and Antti Wihuri Foundation (grant 00180006); the North Savo regional and central Finnish Cultural Foundation (grants 65191835, 00200150, 00230190, and 00250189); Orion Research Foundation sr; Aarne Koskelo Foundation; Antti and Tyyne Soininen Foundation; Kuopio University Foundation; Paulo Foundation; Paavo Nurmi Foundation; Yrjö Jahnsson Foundation (grant 20217390); Ida Montin Foundation (grant 20230289); Fund of Eino Räsänen and Fund of Matti and Vappu Maukonen via the Faculty of Health Sciences University of Eastern Finland; Pediatric Research Foundation (grant 240417); the Finnish Foundation for Cardiovascular Research (grants 220021, 230012, and 240003); the Alfred Kordelin Foundation (grant 230082); and the 2024 European Association for the Study of Obesity-Novo Nordisk Foundation New Investigator Award for Childhood Obesity (grant NNF24SA0090437). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributions. A.O.A. 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. A.O.A. contributed to the study concept and design, data acquisition, analysis, and interpretation, statistical analysis, funding, and drafting the manuscript. A.O.A., J.P.Z., A.R.B., C.A.W., D.V., C.S., and T.-P.T. critically reviewed and revised the manuscript for important intellectual content.

Prior Presentation. An abstract from this study was presented at the European Society of Cardiology Congress, London, U.K., 1 September 2024, and published in the European Heart Journal (https://doi.org/10.1093/eurheartj/ehae6 66.2898).

Handling Editors. The journal editors responsible for overseeing the review of the manuscript were Steven E. Kahn and Kristen J. Nadeau.