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).

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. (Funded by the National Institutes of Health.).

Prevalence Implications of the 2017 American Academy of Pediatrics Hypertension Guideline and Associations with Adult Hypertension.

OBJECTIVE: To evaluate the impact of the 2017 American Academy of Pediatrics hypertension Clinical Practice Guideline (CPG), compared with the previous guideline ("Fourth Report"), on the frequency of hypertensive blood pressure (BP) measurements in childhood and associations with hypertension in adulthood using data from the International Childhood Cardiovascular Cohort Consortium. STUDY DESIGN: Childhood BPs were categorized in normal, prehypertensive/elevated, and hypertensive (stage 1 and 2) ranges using the Fourth Report and the CPG. Participants were contacted in adulthood to assess self-reported hypertension. The associations between childhood hypertensive range BPs and self-reported adult hypertension were evaluated. RESULTS: Data were available for 34 014 youth (10.4 ± 3.1 years, 50.6% female) with 92 751 BP assessments. Compared with the Fourth Report, the CPG increased hypertensive readings from 7.6% to 13.5% and from 1.3% to 2.5% for stage 1 and 2 hypertensive range, respectively (P < .0001). Of 12 761 adults (48.8 ± 7.9 years, 43% male), 3839 (30.1%) had self-reported hypertension. The sensitivity for predicting adult hypertension among those with hypertensive range BPs at any point in childhood, as defined by the Fourth Report and the CPG, respectively, was 13.4% and 22.4% (specificity 92.3% and 85.9%, P < .001), with no significant impact on positive and negative predictive values. Associations with self-reported adult hypertension were similar and weak (c-statistic range 0.61-0.68) for hypertensive range BPs as defined by the Fourth Report and CPG. CONCLUSIONS: The CPG significantly increased the prevalence of childhood BPs in hypertensive ranges and improved the sensitivity, without an overall strengthened association, of predicting self-reported adult hypertension.

Obesity during childhood is associated with higher cancer mortality rate during adulthood: the i3C Consortium.

BACKGROUND: In high-income countries, cancer is the leading cause of death among middle-aged adults. Prospective data on the effects of childhood risk exposures on subsequent cancer mortality are scarce. METHODS: We examined whether childhood body mass index (BMI), blood pressure, glucose and lipid levels were associated with adult cancer mortality, using data from 21,012 children enrolled aged 3-19 years in seven prospective cohort studies from the U.S., Australia, and Finland that have followed participants from childhood into adulthood. Cancer mortality (cancer as a primary or secondary cause of death) was captured using registries. RESULTS: 354 cancer deaths occurred over the follow-up. In age-, sex, and cohort-adjusted analyses, childhood BMI (Hazard ratio [HR], 1.13; 95% confidence interval [CI] 1.03-1.24 per 1-SD increase) and childhood glucose (HR 1.22; 95%CI 1.01-1.47 per 1-SD increase), were associated with subsequent cancer mortality. In a multivariable analysis adjusted for age, sex, cohort, and childhood measures of fasting glucose, total cholesterol, triglycerides, and systolic blood pressure, childhood BMI remained as an independent predictor of subsequent cancer mortality (HR, 1.24; 95%CI, 1.03-1.49). The association of childhood BMI and subsequent cancer mortality persisted after adjustment for adulthood BMI (HR for childhood BMI, 1.35; 95%CI 1.12-1.63). CONCLUSIONS: Higher childhood BMI was independently associated with increased overall cancer mortality.

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 <95th percentile for BMI and <100 mg/dL for glucose. Insulin was positively associated with adult T2DM after adjustment for BMI and glucose and added to T2DM discrimination. 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.

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.

Prediction of adult class II/III obesity from childhood BMI: the i3C consortium.

BACKGROUND AND OBJECTIVES: Adult class II/III obesity (BMI ≥ 35 kg/m2) has significant adverse health outcomes. Early prevention and treatment are critical, but prospective childhood risk estimates are lacking. This study aimed to define the prospective risk of adult class II/III obesity, using childhood BMI. METHODS: Children ages 3-19 years enrolled in cohorts of the International Childhood Cardiovascular Cohort (i3C) consortium with measured BMI assessments in childhood and adulthood were included. Prospective risk of adult class II/III obesity was modeled based on childhood age, sex, race, and BMI. RESULTS: A total of 12,142 individuals (44% male, 85% white) were assessed at median age 14 [Interquartile range, IQR: 11, 16] and 33 [28, 39] years. Class II/III adult obesity developed in 6% of children with normal weight; 29% of children with overweight; 56% of children with obesity; and 80% of children with severe obesity. However, 38% of the 1440 adults with class II/III obesity (553/1440) were normal weight as children. Prospective risk of adult class II/III obesity varied by age, sex, and race within childhood weight status classifications, and is notably higher for girls, black participants, and those in the United States. The risk of class II/III obesity increased with older adult age. CONCLUSIONS: Children with obesity or severe obesity have a substantial risk of adult class II/III obesity, and observed prospective risk estimates are now presented by age, sex, race, and childhood BMI. Clinical monitoring of children's BMI for adult class II/III obesity risk may be especially important for females and black Americans.

Long-Term Burden of Increased Body Mass Index from Childhood on Adult Dyslipidemia: The i3C Consortium Study.

Background: Data are limited regarding the association of cumulative burden and trajectory of body mass index (BMI) from early life with adult lipid disorders. Methods: The study cohort consisted of 5195 adults who had BMI repeatedly measured 4 to 21 times from childhood and had blood lipid measurements of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) and information on lipid-lowering medications in the last adult survey. The area under the curve (AUC) was calculated as a measure of long-term burden (total AUC) and trends (incremental AUC) of BMI. Results: Participants with dyslipidemia, high LDL-C, low HDL-C and high TG had consistently and significantly higher BMI levels from childhood to adulthood compared to those with normal lipid levels. After adjusting for age, race, sex, and cohort, increased risk of adult dyslipidemia was significantly associated with higher values of childhood BMI, adulthood BMI, total AUC and incremental AUC, with odds ratio (95% confidence interval) = 1.22 (1.15-1.29), 1.85 (1.74-1.97), 1.61 (1.52-1.71), and 1.59 (1.50-1.69), respectively, and p < 0.001 for all. The association patterns were similar in most race-sex subgroups. Conclusions: Adults with dyslipidemia versus normal lipid levels have consistently higher levels and distinct life-course trajectories of BMI, suggesting that the impact of excessive body weight on dyslipidemia originates in early life.

Predicting overweight and obesity in young adulthood from childhood body-mass index: comparison of cutoffs derived from longitudinal and cross-sectional data.

BACKGROUND: Historically, cutoff points for childhood and adolescent overweight and obesity have been based on population-specific percentiles derived from cross-sectional data. To obtain cutoff points that might better predict overweight and obesity in young adulthood, we examined the association between childhood body-mass index (BMI) and young adulthood BMI status in a longitudinal cohort. METHODS: In this study, we used data from the International Childhood Cardiovascular Cohort (i3C) Consortium (which included seven childhood cohorts from the USA, Australia, and Finland) to establish childhood overweight and obesity cutoff points that best predict BMI status at the age of 18 years. We included 3779 children who were followed up from 1970 onwards, and had at least one childhood BMI measurement between ages 6 years and 17 years and a BMI measurement specifically at age 18 years. We used logistic regression to assess the association between BMI in childhood and young adulthood obesity. We used the area under the receiver operating characteristic curve (AUROC) to assess the ability of fitted models to discriminate between different BMI status groups in young adulthood. The cutoff points were then compared with those defined by the International Obesity Task Force (IOTF), which used cross-sectional data, and tested for sensitivity and specificity in a separate, independent, longitudinal sample (from the Special Turku Coronary Risk Factor Intervention Project [STRIP] study) with BMI measurements available from both childhood and adulthood. FINDINGS: The cutoff points derived from the longitudinal i3C Consortium data were lower than the IOTF cutoff points. Consequently, a larger proportion of participants in the STRIP study was classified as overweight or obese when using the i3C cutoff points than when using the IOTF cutoff points. Especially for obesity, i3C cutoff points were significantly better at identifying those who would become obese later in life. In the independent sample, the AUROC values for overweight ranged from 0·75 (95% CI 0·70-0·80) to 0·88 (0·84-0·93) for the i3C cutoff points, and the corresponding values for the IOTF cutoff points ranged from 0·69 (0·62-0·75) to 0·87 (0·82-0·92). For obesity, the AUROC values ranged from 0·84 (0·75-0·93) to 0·90 (0·82-0·98) for the i3C cutoff points and 0·57 (0·49-0·66) to 0·76 (0·65-0·88) for IOTF cutoff points. INTERPRETATION: The childhood BMI cutoff points obtained from the i3C Consortium longitudinal data can better predict risk of overweight and obesity in young adulthood than can standards that are currently used based on cross-sectional data. Such cutoff points should help to more accurately identify children at risk of adult overweight or obesity. FUNDING: None.

Relation of Blood Pressure in Childhood to Self-Reported Hypertension in Adulthood.

Blood pressure (BP) tracking (maintaining a BP percentile) across life is not well defined but is important in predicting which children will become hypertensive adults. We computed BP tracking in subjects with BP measured in childhood and adulthood and performed logistic regression to determine the ability of childhood BP to predict adult hypertension (N=5035, 46.7 years, 74.2% white, 17.7% black; 39.6% male). Prevalence of hypertension was 29%. Correlations between systolic BP for child and adolescent were r=0.48; for adolescent and young adult were r=0.40, and for child and young adult were r=0.24 (all P<0.0001). Participants self-reporting adult hypertension were less likely to be white (38.7% black, 27.6% white, 20.9% other; P<0.0001) and female (26.4% females, 32.9% male, P<0.0001). Participants with adult hypertension were more likely to have higher BP and adiposity by age 10 years and abnormal lipids and glucose by age 16 years. There was a graded increase in the frequency of self-reported adult hypertension across the BP change groups, even within the persistently normotensive group (X2<0.0001) from 19% in children with a systolic BP% persistently below the median to 80% for individuals with elevated BP in both childhood and adolescence. Although our precision to predict which individual child is at risk of adult BP-related cardiovascular disease is weak, an increase in systolic BP and body mass index percentile from childhood to adolescence should signal a need for lifestyle intervention to prevent future sustained hypertension-related cardiovascular disease.

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.

Periprocedural Stroke and Myocardial Infarction as Risks for Long-Term Mortality in CREST.

BACKGROUND: The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) previously reported increased mortality in patients who sustained a periprocedural stroke or cardiac event (myocardial infarction [MI] or biomarker only) in follow-up to 4 years. We now extend these observations to 10 years. METHODS AND RESULTS: CREST is a randomized controlled trial designed to compare the outcomes of carotid stenting versus carotid endarterectomy. Proportional hazards models were used to assess the association between mortality and periprocedural stroke, MI, or biomarker-only events. For 10-year follow-up, patients with periprocedural stroke were at 1.74× the risk of death compared with those without stroke (adjusted hazard ratio [HR]=1.74; 95% CI, 1.21-2.50; P<0.003). This increased risk was driven by increased early (between 0 and 90 days) mortality (adjusted HR=14.41; 95% CI, 5.33-38.94; P<0.0001), with no significant increase in late (between 91 days and 10 years) mortality (adjusted HR=1.40; 95% CI, 0.93-2.10; P=0.11). Patients with a protocol MI were at 3.61× increased risk of death compared with those without MI (adjusted HR=3.61; 95% CI, 2.28-5.73; P<0.0001), with an increased hazard both early (adjusted HR=8.20; 95% CI, 1.86-36.2; P=0.006) and late (adjusted HR=3.40; 95% CI, 2.09-5.53; P<0.0001). Patients with a biomarker-only event were at 2.04× increased risk overall (adjusted HR=2.04; 95% CI, 1.09-3.84; P=0.03) than those without MI, with an increased early hazard (adjusted HR=8.44; 95% CI, 1.09-65.5; P=0.04) and a suggestive but nonsignificant association toward higher 91-day to 10-year risk (1.88; 95% CI, 0.97-3.64; P=0.062) contributing to the increased risk. CONCLUSIONS: In the CREST trial, patients with periprocedural events demonstrate a substantial increase in future mortality to 10 years. For stroke, this risk is largely confined to an early time frame while periprocedural MI or biomarker-only events confer a continuous increased mortality for 10 years. Strategies to reduce periprocedural events and to optimize the evaluation and management of patients with cardiac events should be considered in efforts to reduce not only early but also long-term mortality. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00004732.

A comprehensive evaluation of the genetic architecture of sudden cardiac arrest.

Aims: Sudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA. Methods and results: We carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk. Conclusions: Our findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community.

The International Childhood Cardiovascular Cohort (i3C) consortium outcomes study of childhood cardiovascular risk factors and adult cardiovascular morbidity and mortality: Design and recruitment.

Although it is widely thought that childhood levels of cardiovascular (CV) risk factors are related to adult CV disease, longitudinal data directly linking the two are lacking. This paper describes the design and organization of the International Childhood Cardiovascular Cohort Consortium Outcomes Study (i3C Outcomes), the first longitudinal cohort study designed to locate adults with detailed, repeated, childhood biological, physical, and socioeconomic measurements and a harmonized database. I3C Outcomes uses a Heart Health Survey (HHS) to obtain information on adult CV endpoints, using mail, email, telephone, and clinic visits in the United States (U.S.) and Australia and a national health database in Finland. Microsoft Access, REsearch Data Capture (REDCap) (U.S.), LimeSurvey (Australia), and Medidata™ Rave data systems are used to collect, transfer and organize data. Self-reported CV events are adjudicated via hospital and doctor-released medical records. After the first two study years, participants (N = 10,968) were more likely to be female (56% vs. 48%), non-Hispanic white (90% vs. 80%), and older (10.4 ±â€¯3.8 years vs. 9.4 ±â€¯3.3 years) at their initial childhood study visit than the currently non-recruited cohort members. Over 48% of cohort members seen during both adulthood and childhood have been found and recruited, to date, vs. 5% of those not seen since childhood. Self-reported prevalences were 0.7% Type 1 Diabetes, 7.5% Type 2 Diabetes, 33% hypertension, and 12.8% CV event. 32% of CV events were judged to be true. I3C Outcomes is uniquely able to establish evidence-based guidelines for child health care and to clarify relations to adult CV disease.

Impact of Lipid Measurements in Youth in Addition to Conventional Clinic-Based Risk Factors on Predicting Preclinical Atherosclerosis in Adulthood: International Childhood Cardiovascular Cohort Consortium.

BACKGROUND: Data suggest that the prediction of adult cardiovascular disease using a model comprised entirely of adult nonlaboratory-based risk factors is equivalent to an approach that additionally incorporates adult lipid measures. We assessed and compared the utility of a risk model based solely on nonlaboratory risk factors in adolescence versus a lipid model based on nonlaboratory risk factors plus lipids for predicting high-risk carotid intima-media thickness (cIMT) in adulthood. METHODS: The study comprised 2893 participants 12 to 18 years of age from 4 longitudinal cohort studies from the United States (Bogalusa Heart Study and the Insulin Study), Australia (Childhood Determinants of Adult Health Study), and Finland (The Cardiovascular Risk in Young Finns Study) and followed into adulthood when cIMT was measured (mean follow-up, 23.4 years). Overweight status was defined according to the Cole classification. Hypertension was defined according to the Fourth Report on High Blood Pressure in Children and Adolescents from the National High Blood Pressure Education Program. High-risk plasma lipid levels were defined according to the National Cholesterol Education Program Expert Panel on Cholesterol Levels in Children. High cIMT was defined as a study-specific value ≥90th percentile. Age and sex were included in each model. RESULTS: In univariate models, all risk factors except for borderline high and high triglycerides in adolescence were associated with high cIMT in adulthood. In multivariable models (relative risk [95% confidence interval]), male sex (2.7 [2.0-2.6]), prehypertension (1.4 [1.0-1.9]), hypertension (1.9 [1.3-2.9]), overweight (2.0 [1.4-2.9]), obesity (3.7 [2.0-7.0]), borderline high low-density lipoprotein cholesterol (1.6 [1.2-2.2]), high low-density lipoprotein cholesterol (1.6 [1.1-2.1]), and borderline low high-density lipoprotein cholesterol (1.4 [1.0-1.8]) remained significant predictors of high cIMT (P<0.05). The addition of lipids into the nonlaboratory risk model slightly but significantly improved discrimination in predicting high cIMT compared with nonlaboratory-based risk factors only (C statistics for laboratory-based model 0.717 [95% confidence interval, 0.685-0.748] and for nonlaboratory 0.698 [95% confidence interval, 0.667-0.731]; P=0.02). CONCLUSIONS: Nonlaboratory-based risk factors and lipids measured in adolescence independently predicted preclinical atherosclerosis in young adulthood. The addition of lipid measurements to traditional clinic-based risk factor assessment provided a statistically significant but clinically modest improvement on adolescent prediction of high cIMT in adulthood.

Distribution and determinants of QRS rotation of black and white persons in the general population.

BACKGROUND: The prevalence and determinants of QRS transition zones are not well established. METHODS: We examined the distributions of Normal, clockwise (CW) and counterclockwise (CCW)) QRS transition zones and their relations to disease, body size and demographics in 4624 black and white men and women free of cardiovascular disease and major ECG abnormalities enrolled in the NHANES-III survey. RESULTS: CW transition zones were least observed (6.2%) and CCW were most prevalent (60.1%) with Normal in an intermediate position (33.7%). In multivariable logistic regression analysis, the adjusted, significant predictors for CCW compared to Normal were a greater proportion of blacks and women, fewer thin people (BMI<20, thin), a greater ratio of chest depth to chest width, and an LVMass index <80g. By contrast, CW persons were older, had larger QRS/T angles, smaller ratio of chest depth to chest width, had a greater proportion of subjects with low voltage QRS, more pulmonary disease, a greater proportion with high heart rates, shorter QRS duration and were more obese (BMI≥30). CONCLUSIONS: Normal rather than being the most prevalent transition zone was intermediate in frequency between the most frequently encountered CCW and the least frequently encountered transition zone CW. Differences in the predictors of CW and CCW exist. This requires further investigation to examine how far these differences explain the differences in the published prognostic differences between CW and CCW.

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.

Antihypertensive Therapies and Left Ventricular Hypertrophy.

PURPOSE OF REVIEW: It is widely accepted that successful lowering of blood pressure (BP) in patients with hypertension leads to regression of left ventricular hypertrophy (LVH). However, whether differences exist among pharmacological BP-lowering therapies is debated. In this report, we discuss these differences in light of recent literature and the position of extant practice guidelines. RECENT FINDINGS: Studies comparing the effects of antihypertensive classes on LVH regression reached different conclusions, but the overall direction which is reflected in current society guidelines is that successful lowering of BP is more important than selection of an individual antihypertensive class. Nevertheless, some practice guidelines added statements about considering a specific antihypertensive class for its potential benefit such as angiotensin-converting enzyme inhibitors and/or excluding a class such as direct vasodilators. On the other hand, reports have been consistent about the more favorable effect of intensive BP-lowering strategy (target systolic BP < 120 mmHg) compared to standard BP lowering (target systolic BP > 140 mmHg), which is not yet discussed in the current practice guidelines. Successful lowering of BP leads to LVH regression. While reports have been inconsistent about differences among antihypertensive classes, lowering BP beyond currently recommended levels has consistently showed a greater effect on LVH regression.

The Metabolic Syndrome and Risk of Sudden Cardiac Death: The Atherosclerosis Risk in Communities Study.

BACKGROUND: Prior studies have demonstrated a link between the metabolic syndrome and increased risk of cardiovascular mortality. Whether the metabolic syndrome is associated with sudden cardiac death is uncertain. METHODS AND RESULTS: We characterized the relationship between sudden cardiac death and metabolic syndrome status among participants of the ARIC (Atherosclerosis Risk in Communities) Study (1987-2012) free of prevalent coronary heart disease or heart failure. Among 13 168 participants, 357 (2.7%) sudden cardiac deaths occurred during a median follow-up of 23.6 years. Participants with the metabolic syndrome (n=4444) had a higher cumulative incidence of sudden cardiac death than those without it (n=8724) (4.1% versus 2.3%, P<0.001). After adjustment for participant demographics and clinical factors other than components of the metabolic syndrome, the metabolic syndrome was independently associated with sudden cardiac death (hazard ratio, 1.70, 95% confidence interval, 1.37-2.12, P<0.001). This relationship was not modified by sex (interaction P=0.10) or race (interaction P=0.62) and was mediated by the metabolic syndrome criteria components. The risk of sudden cardiac death varied according to the number of metabolic syndrome components (hazard ratio 1.31 per additional component of the metabolic syndrome, 95% confidence interval, 1.19-1.44, P<0.001). Of the 5 components, elevated blood pressure, impaired fasting glucose, and low high-density lipoprotein were independently associated with sudden cardiac death. CONCLUSIONS: We observed that the metabolic syndrome was associated with a significantly increased risk of sudden cardiac death irrespective of sex or race. The risk of sudden cardiac death was proportional to the number of metabolic syndrome components.