Utility of Different Blood Pressure Measurement Components in Childhood to Predict Adult Carotid Intima-Media Thickness : The i3C Consortium Study

Childhood blood pressure (BP) levels predict adult subclinical atherosclerosis. However, the best childhood BP component for prediction has not been determined. This study comprised 5925 participants aged 3 to 18 years from 6 cohorts who were followed into adulthood (mean follow-up 25.8 +/- 6.2 years). Childhood BP was measured by using a standard mercury sphygmomanometer in all cohorts. Study-specific carotid intima-media thickness 90th percentile was used to define subclinical atherosclerosis. Per SD change in the predictor, childhood systolic BP (SBP; age- and sex-adjusted odds ratio [95% CI], 1.24 [1.13-1.37]), mean arterial pressure (1.10 [1.07-1.13]), and pulse pressure (1.15 [1.05-1.27]) were associated with increased adulthood intima-media thickness. In age- and sex-adjusted analyses, area under the receiver operating characteristic curves for SBP (C value [95% CI], 0.677 [0.657-0.704]) showed significantly improved prediction compared with diastolic BP (0.669 [0.646-0.693], P=0.006) or mean arterial pressure (0.674 [0.653-0.699], P=0.01). Pulse pressure provided a C value that was not different from SBP (0.676 [0.653-0.699], P=0.16). Combining different BP components did not improve prediction over SBP measurement alone. Based on the associations with adult carotid intima-media thickness, cut points for elevated SBP were 105 mmHg for 3- to 6-year-old boys, 108 mmHg for 3- to 6-year-old girls, 108 mmHg for 7- to 12-year-old boys, 106 mmHg for 7- to 12-year-old girls, 123 mmHg for 13- to 18-year-old boys, and 115 mmHg for 13- to 18-year-old girls. Our analyses suggest that several childhood BP measurement components are related to adulthood carotid intima-media thickness. Of these, SBP provided the best predictive ability.Peer reviewe

Childhood age and associations between childhood metabolic syndrome and adult risk for metabolic syndrome, type 2 diabetes mellitus and carotid intima media thickness: The international childhood cardiovascular cohort consortium

Background There is paucity of knowledge concerning the specific age in youth when the associations of metabolic syndrome (MetS) begin to be operative. Thus, we investigated the relation of age to the associations of childhood MetS with adult MetS, type 2 diabetes mellitus and high carotid intima‐media thickness.Methods and Results Five thousand eight‐hundred three participants were analyzed in 4 cohort studies (Cardiovascular Risk in Young Finns, Bogalusa Heart Study, Princeton Lipid Research Study, Insulin Study). International cutoffs and previously used 75th percentile cutoffs were used for children to define MetS and its components. Mean follow‐up period was 22.3 years. Logistic regression was used to calculate risk ratios and 95% confidence intervals. Childhood MetS and overweight were associated with over 2.4‐fold risk for adult MetS from the age of 5 years onward. Risk for type 2 diabetes mellitus was increased from the age of 8 (risk ratio, 2.6–4.1; 95% confidence interval, 1.35–6.76 and 1.12–7.24, respectively) onward for the 2 childhood MetS criteria based on international cut‐off values and for childhood overweight. Risk for high carotid intima‐media thickness was significant at ages 11 to 18 years in relation to childhood MetS or overweight (risk ratio, 2.44–4.22; 95% confidence interval, 1.55–3.55 and 2.55–5.66, respectively). Continuous childhood MetS score was associated with adult MetS from the age of 5, with type 2 diabetes mellitus from the age of 14 and with high carotid intima‐media thickness from the age of 11 years onward.Conclusions Adult MetS was predicted by MetS in childhood beginning at age 5. However, adult type 2 diabetes mellitus and subclinical atherosclerosis were not predicted by childhood data until after age 8. Body mass index measurement alone at the same age points provided similar findings.</p

Childhood BMI and Fasting Glucose and Insulin Predict Adult Type 2 Diabetes: The International Childhood Cardiovascular Cohort (i3C) Consortium

OBJECTIVE To examine childhood BMI, fasting glucose, and insulin in relation to incident adult type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS We used data from the International Childhood Cardiovascular Cohort (i3C) Consortium. Data included childhood (age 3-19 years) measurements obtained during the 1970s-1990s; a health questionnaire, including self-report of adult T2DM (occurrence age, medication use) obtained at mean age 40 years; and a medical diagnosis registry (Finland). RESULTS The sample included 6,738 participants. Of these, 436 (6.5%) reported onset of T2DM between ages 20 and 59 (mean 40.8) years, and 86% of them reported use of a confirmed antidiabetic medication. BMI and glucose (age and sex standardized) were associated with incident T2DM after adjustment for cohort, country, sex, race, age, and calendar year of measurement. Increasing levels of childhood BMI and glucose were related to an incrementally increased risk of T2DM beginning at age 30 years, beginning at cut points CONCLUSIONS Childhood BMI and glucose are predictors of adult T2DM at levels previously considered to be within the normal range. These easy-to-apply measurements are appealing from a clinical perspective. Fasting insulin has the potential to be an additional predictor.</div

Body-mass index trajectories from childhood to mid-adulthood and their sociodemographic predictors: Evidence from the International Childhood Cardiovascular Cohort (i3C) Consortium

BackgroundUnderstanding lifecourse trajectories of body-mass index (BMI) is important for identifying groups at high risk of poor health and potential target points for intervention. This study aimed to describe BMI trajectories from childhood to mid-adulthood in four population-based cohorts established in the 1970s and 1980s and to identify childhood sociodemographic factors related to trajectory membership.MethodsBetween Dec 17, 1970 and Dec 15, 1994, data were collected at the first visit from 9830 participants from the International Childhood Cardiovascular Cohort (i3C) Consortium, which includes participants from Australia (1985), Finland (1980) and the USA (1970–1994). Participants had at least three measures of height and weight, including one in childhood (6–18 years) and one in adulthood (>18 years), and were aged 30–49 years at last measurement. Latent Class Growth Mixture Modelling was used to identify lifecourse BMI trajectory groups and log multinomial regression models were fit to identify their childhood sociodemographic predictors.FindingsFive consistent BMI trajectory groups were identified amongst the four cohorts: persistently low (35.9–58.6%), improving from high (0.7–4.8%), progressing to moderate (9.3–43.7%), progressing to high (1.1–6.0%), and progressing to very high (0.7–1.3%). An additional three BMI trajectory groups were identified in some, but not all, cohorts: adult onset high (three cohorts; 1.8–20.7%), progressing to moderate-high (two cohorts; 5.2–13.8%), and relapsing yo-yoers (alternating upward and downward; one cohort; 1.3%). In pooled analyses, each predictor variable in childhood, including age, gender, parental education and race, was associated with increased likelihood of belonging to the most (e.g., improving from high) and least (e.g., progressing to very high) favourable BMI trajectory groups, suggesting a U-shaped (or inverse U-shaped) pattern of association.InterpretationFive consistent BMI trajectory groups were identified across four cohorts from Australia, Finland, and the USA, mainly across two eras of birth. While most participants remained on a persistently low trajectory (50%), many demonstrated worsening BMI trajectories (47%), with only few demonstrating improving trajectories (FundingThis study was supported by funding from the National Institutes of Health, National Heart, Lung and Blood Institute (grant number R01 HL121230).</p

Body-mass index trajectories from childhood to mid-adulthood and their sociodemographic predictors : Evidence from the International Childhood Cardiovascular Cohort (i3C) Consortium

Background: Understanding lifecourse trajectories of body-mass index (BMI) is important for identifying groups at high risk of poor health and potential target points for intervention. This study aimed to describe BMI trajectories from childhood to mid-adulthood in four population-based cohorts established in the 1970s and 1980s and to identify childhood sociodemographic factors related to trajectory membership. Methods: Between Dec 17, 1970 and Dec 15, 1994, data were collected at the first visit from 9830 participants from the International Childhood Cardiovascular Cohort (i3C) Consortium, which includes participants from Australia (1985), Finland (1980) and the USA (1970–1994). Participants had at least three measures of height and weight, including one in childhood (6–18 years) and one in adulthood (>18 years), and were aged 30–49 years at last measurement. Latent Class Growth Mixture Modelling was used to identify lifecourse BMI trajectory groups and log multinomial regression models were fit to identify their childhood sociodemographic predictors. Findings: Five consistent BMI trajectory groups were identified amongst the four cohorts: persistently low (35.9–58.6%), improving from high (0.7–4.8%), progressing to moderate (9.3–43.7%), progressing to high (1.1–6.0%), and progressing to very high (0.7–1.3%). An additional three BMI trajectory groups were identified in some, but not all, cohorts: adult onset high (three cohorts; 1.8–20.7%), progressing to moderate-high (two cohorts; 5.2–13.8%), and relapsing yo-yoers (alternating upward and downward; one cohort; 1.3%). In pooled analyses, each predictor variable in childhood, including age, gender, parental education and race, was associated with increased likelihood of belonging to the most (e.g., improving from high) and least (e.g., progressing to very high) favourable BMI trajectory groups, suggesting a U-shaped (or inverse U-shaped) pattern of association. Interpretation: Five consistent BMI trajectory groups were identified across four cohorts from Australia, Finland, and the USA, mainly across two eras of birth. While most participants remained on a persistently low trajectory (50%), many demonstrated worsening BMI trajectories (47%), with only few demonstrating improving trajectories (<5%). Age, gender, parental education, and race appear to be important predictors of BMI trajectory group membership and need consideration in preventive and management strategies. Funding: This study was supported by funding from the National Institutes of Health, National Heart, Lung and Blood Institute (grant number R01 HL121230).publishedVersionPeer reviewe

Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene

Journal ArticleDecreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 "A" allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoproterenol- stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity

Childhood/Adolescent Smoking and Adult Smoking and Cessation: The International Childhood Cardiovascular Cohort (i3C) Consortium

BACKGROUND: Despite declining US adolescent smoking prevalence from 40% among 12th graders in 1995 to around 10% in 2018, adolescent smoking is still a significant problem. Using the International Childhood Cardiovascular Cohort (i3C) Consortium, which includes 7 international cohorts recruited in childhood and followed into adulthood, the present study was designed to confirm the important relation between adolescent smoking and daily adult smoking and present new data on adult smoking into the forties and comparison of smoking in the United States, Finland, and Australia. METHODS AND RESULTS: Childhood smoking experience during ages 6 to 19 in the 1970s and 1980s was classifiable in 6687 i3C participants who also provided smoking status in their twenties and forties through 2011-2018. Prevalence of daily smoking in their twenties was directly related to degree of smoking during adolescence and inversely related to the age at which that smoking experience occurred (P trend, < 0.001). Similar patterns were observed for prediction of smoking during age forties. Among the 2465 smokers in their twenties, cessation by their forties was generally inverse to degree of smoking in ages 6 to 19 (P trend, <0.001). Prevalence of smoking during adolescence and adulthood was similar among US, Finnish, and Australian participants. CONCLUSIONS: These long--term follow--up data show that smoking intensity increased throughout adolescence. Prevalence of adult smoking and cessation by the forties were both correlated with levels of childhood smoking intensity. These data lend support to preventive strategies designed to reduce, delay, or eliminate any youth access to cigarettes

Non-HDL Cholesterol Levels in Childhood and Carotid Intima-Media Thickness in Adulthood

BACKGROUND: Elevated non–high-density lipoprotein cholesterol (HDL-C) levels are used to identify children at increased cardiovascular risk, but the use of non–HDL-C in childhood to predict atherosclerosis is unclear. We examined whether the National Heart, Lung, and Blood Institute classification of youth non–HDL-C status predicts high common carotid artery intima-media thickness in adulthood.METHODS: We analyzed data from 4 prospective cohorts among 4582 children aged 3 to 19 years who were remeasured as adults (mean follow-up of 26 years). Non–HDL-C status in youth and adulthood was classified according to cut points of the National Heart, Lung, and Blood Institute and the National Cholesterol Education Program Adult Treatment Panel III. High carotid intima-media thickness (cIMT) in adulthood was defined as at or above the study visit-, age-, sex-, race-, and cohort-specific 90th percentile of intima-media thickness.RESULTS: In a log-binomial regression analysis adjusted with age at baseline, sex, cohort, length of follow-up, baseline BMI, and systolic blood pressure, children with dyslipidemic non–HDL-C were at increased risk of high cIMT in adulthood (relative risk [RR], 1.29; 95% confidence interval [CI], 1.07–1.55). Compared with the persistent normal group, the persistent dyslipidemia group (RR, 1.80; 95% CI, 1.37–2.37) and incident dyslipidemia (normal to dyslipidemia) groups (RR, 1.45; 95% CI, 1.07–1.96) had increased risk of high cIMT in adulthood, but the risk was attenuated for the resolution (dyslipidemia to normal) group (RR, 1.17; 95% CI, 0.97–1.41).CONCLUSIONS: Dyslipidemic non–HDL-C levels predict youth at risk for developing high cIMT in adulthood. Those who resolve their non–HDL-C dyslipidemia by adulthood have normalized risk of developing high cIMT in adulthood.</div

Utility of Different Blood Pressure Measurement Components in Childhood to Predict Adult Carotid Intima-Media Thickness

Childhood blood pressure (BP) levels predict adult subclinical atherosclerosis. However, the best childhood BP component for prediction has not been determined. This study comprised 5925 participants aged 3 to 18 years from 6 cohorts who were followed into adulthood (mean follow-up 25.8±6.2 years). Childhood BP was measured by using a standard mercury sphygmomanometer in all cohorts. Study-specific carotid intima-media thickness ≥90th percentile was used to define subclinical atherosclerosis. Per SD change in the predictor, childhood systolic BP (SBP; age- and sex-adjusted odds ratio [95% CI], 1.24 [1.13–1.37]), mean arterial pressure (1.10 [1.07–1.13]), and pulse pressure (1.15 [1.05–1.27]) were associated with increased adulthood intima-media thickness. In age- and sex-adjusted analyses, area under the receiver operating characteristic curves for SBP (C value [95% CI], 0.677 [0.657–0.704]) showed significantly improved prediction compared with diastolic BP (0.669 [0.646–0.693], P=0.006) or mean arterial pressure (0.674 [0.653–0.699], P=0.01). Pulse pressure provided a C value that was not different from SBP (0.676 [0.653–0.699], P=0.16). Combining different BP components did not improve prediction over SBP measurement alone. Based on the associations with adult carotid intima-media thickness, cut points for elevated SBP were 105 mm Hg for 3- to 6-year-old boys, 108 mm Hg for 3- to 6-year-old girls, 108 mm Hg for 7- to 12-year-old boys, 106 mm Hg for 7- to 12-year-old girls, 123 mm Hg for 13- to 18-year-old boys, and 115 mm Hg for 13- to 18-year-old girls. Our analyses suggest that several childhood BP measurement components are related to adulthood carotid intima-media thickness. Of these, SBP provided the best predictive ability.</p

Childhood Cardiovascular Risk Factors and Adult Cardiovascular Events

BACKGROUND Childhood cardiovascular risk factors predict subclinical adult cardiovascular disease, but links to clinical events are unclear. METHODS In a prospective cohort study involving participants in the International Childhood Cardiovascular Cohort (i3C) Consortium, we evaluated whether childhood risk factors (at the ages of 3 to 19 years) were associated with cardiovascular events in adulthood after a mean follow-up of 35 years. Body-mass index, systolic blood pressure, total cholesterol level, triglyceride level, and youth smoking were analyzed with the use of i3C-derived age- and sex-specific z scores and with a combined-risk z score that was calculated as the unweighted mean of the five risk z scores. An algebraically comparable adult combined-risk z score (before any cardiovascular event) was analyzed jointly with the childhood risk factors. Study outcomes were fatal cardiovascular events and fatal or nonfatal cardiovascular events, and analyses were performed after multiple imputation with the use of proportional-hazards regression. RESULTS In the analysis of 319 fatal cardiovascular events that occurred among 38,589 participants (49.7% male and 15.0% Black; mean [±SD] age at childhood visits, 11.8±3.1 years), the hazard ratios for a fatal cardiovascular event in adulthood ranged from 1.30 (95% confidence interval [CI], 1.14 to 1.47) per unit increase in the z score for total cholesterol level to 1.61 (95% CI, 1.21 to 2.13) for youth smoking (yes vs. no). The hazard ratio for a fatal cardiovascular event with respect to the combined-risk z score was 2.71 (95% CI, 2.23 to 3.29) per unit increase. The hazard ratios and their 95% confidence intervals in the analyses of fatal cardiovascular events were similar to those in the analyses of 779 fatal or nonfatal cardiovascular events that occurred among 20,656 participants who could be evaluated for this outcome. In the analysis of 115 fatal cardiovascular events that occurred in a subgroup of 13,401 participants (31.0±5.6 years of age at the adult measurement) who had data on adult risk factors, the adjusted hazard ratio with respect to the childhood combined-risk z score was 3.54 (95% CI, 2.57 to 4.87) per unit increase, and the mutually adjusted hazard ratio with respect to the change in the combined-risk z score from childhood to adulthood was 2.88 (95% CI, 2.06 to 4.05) per unit increase. The results were similar in the analysis of 524 fatal or nonfatal cardiovascular events. CONCLUSIONS In this prospective cohort study, childhood risk factors and the change in the combined-risk z score between childhood and adulthood were associated with cardiovascular events in midlife.publishedVersionPeer reviewe