Prevention of cardiovascular disease remains an important public health issue, with well-documented associations between cardiovascular risk factors in adulthood and cardiovascular events. 1 Despite interest in risk factors in childhood and subsequent cardiovascular disease in adults, as recently reviewed, 2,3 findings from longitudinal studies that begin with the assessment of childhood risk factors have generally been restricted to associations with subclinical disease in adulthood.
The possibility of extending the findings to include associations with cardiovascular events in adults has been hampered by the lack of cohorts with complete childhood data available on anthropometric measures, blood pressure and laboratory values and with follow-up carried out until ages at which cardiovascular events they become prevalent.
The International Children’s Cardiovascular Cohort Consortium (i3C) 4,5 includes seven cohorts in Australia, Finland, and the United States, with data collected on cardiovascular risk factors from early childhood to adolescence and cardiovascular events in adults. In the current study, the authors used these data to examine the development of cardiovascular disease across the lifespan and test the hypothesis that traditional cardiovascular risk factors in childhood are associated with the subsequent development of cardiovascular events in adults.
| Methods |
> Study design and supervision
A total of 42,324 participants aged 3 to 19 years were enrolled in the seven cohorts of the i3C Consortium from the 1970s to the 1990s; Of these participants, 40,648 had identifying information for follow-up and were included in the sampling frame. 4
This study was approved by the institutional review board at each site of the seven cohorts. Written parental permission and oral consent were obtained from the participant for childhood visits, written informed consent was requested from the participant for adult in-person visits, and oral consent was obtained under waiver of consent documentation for the recent follow-up questionnaire.
The study focused on the five risk factors most frequently evaluated in childhood and adolescence: body mass index, systolic blood pressure, total cholesterol level, triglyceride level, and smoking in youth. Triglyceride levels were transformed using the natural logarithm (ln[triglycerides]). Data on cardiovascular risk factors were harmonized across the seven cohorts into a single database (114,476 visits, with 1 to 19 visits per participant).
Because separate protocols, with varying schedules for clinic visits that were conducted at different ages of participants, were used for each cohort, not every study measure was assessed in each cohort, in each participant within a cohort, or in all participants of all ages. 5
Age, sex, parent-reported race (which was updated if the participant was an adult), height, weight, and systolic blood pressure (measured by mercury sphygmomanometry) were prospectively assessed at clinic visits; Fasting plasma levels of cholesterol and serum triglycerides were measured using standard methods 6 . Education levels of parents and participants were obtained at child and adult visits.
From 2015 to 2019, i3C Consortium researchers conducted a coordinated study to locate and survey participants and search for national death rates for participants who were not located. 5 Fatal cardiovascular events in all cohorts were classified according to the causes of death coded in the International Classification of Diseases (ICD), versions 9 and 10. Finnish participants were followed for non-fatal cardiovascular events until December 31, 2017, using the Finnish national medical registry and events were classified according to the same version of the ICD that was used for the classification of deaths.
Adult participants from the US and Australia who had been successfully located reported any cardiovascular events that had occurred, and medical records were requested for adjudication of participant reports. Medical records were reviewed by a medical committee blinded to the participants’ study data, and each reported event was classified as a confirmed cardiovascular event, not a cardiovascular event, or not possible to adjudicate.
Nonfatal cardiovascular events included first instance of adjudicated myocardial infarction, stroke, transient ischemic attack, ischemic heart failure, angina pectoris, peripheral arterial disease, carotid intervention, abdominal aortic aneurysm, or coronary revascularization.
| Statistic analysis |
Because of the potential for bias from loss to follow-up, fatal cardiovascular events were analyzed separately from the composite outcome of fatal or nonfatal cardiovascular events. There were 319 fatal cardiovascular events among the 38,589 participants (95% of the sampling frame) that could be classified as alive and located, deceased with a known cause, or searched for and not found in the death indices and therefore presumed alive.
The analysis of fatal and nonfatal cardiovascular events included 779 adjudicated nonfatal events and 784 imputed nonfatal events (the median number across imputations) for individuals who were not located or who reported a cardiovascular event that could not be adjudicated. Among the 13,401 participants with adult measurements before any cardiovascular event, there were 115 fatal cardiovascular events and a mean of 524 fatal or nonfatal events (406 observed) across imputations.
Due to age-related developmental changes, childhood risk factors at each visit were normalized to z scores within the i3C Consortium, which were calculated using the mean values (with standard deviations) of the study variables, stratified by age and sex. The resulting i3C-derived z scores were then averaged for each participant across their childhood and adolescent measurements (obtained at ages 3 to 19 years) to obtain a single mean childhood risk z score per person.
Classification of young smokers was based on participants’ reports during childhood, 7 in addition to adult recall of the date of smoking initiation, and was analyzed as a dichotomous variable (yes vs. no). The a priori combined risk z score was calculated as the unweighted mean of the z scores of the four childhood risk factors plus youth smoking, which was included in the calculation either as 2 (a high risk value in terms of z-score units) for smoker or 0 (medium risk) for non-smoker.
The use of this combined risk z score addresses the hypothesis that all five risk factors predict future events, without estimation of risk factor weights. Individual risk factors and combined risk z scores were analyzed as continuous measures. Additionally, they examined childhood risk factors using thresholds for standard clinical categories, 8-10 dividing the clinically normal category into low-normal and high-normal groups. Adult combined risk z scores were calculated with the same algebraic procedures and risk factors as those used for childhood combined risk z scores.
All primary analyzes were performed after multiple imputation of missing values for means of chained equations with fully conditional specification (10 replications) in PC-SAS software (version 9.4, SAS Institute); data were assumed to be missing at random. 11 Imputation was performed in three phases using subsampling methods. 12
In phase 1, multiple imputation was applied for missing data on childhood risk factors and events among 38,589 participants; in phase 2, for non-fatal events that could not be adjudicated among 1360 participants who reported a non-fatal event; and in phase 3, for missing ages in which the imputed event occurred among 779 adjudicated events and a mean of 784 imputed events.
All proportional hazards regression analyzes were performed using adulthood as the time axis and noncardiovascular mortality as a competing risk 13 and adjusted for sex, race, cohort indicator, mean childhood age, and the mean calendar year of childhood measurement and parental education level. The length of the 95% confidence intervals was not adjusted for multiple comparisons.
The appropriateness of the linearity assumption was visualized by using restricted cubic splines and examining categories of z-score units of 0.5 with open categories at the upper and lower end. The proportionality assumption was evaluated with the addition of the interaction term between the risk factor and age transformed by the natural logarithm (risk factor*ln[age]). When risks varied by participant age during follow-up, they presented hazard ratios for events in participants younger than the median age of 47.7 years or 47.7 years of age or older.
Interactions with sex, race, and age group of the childhood measurement (3 to 11 years vs. 12 to 19 years) were estimated. They examined the predictive power of the childhood combined risk z score, taking into account adult risk factors using three analytical models, one in which the adult combined risk z score was considered alone, one in which the childhood combined risk z score was matched to the adult combined risk z score, and another in which the childhood combined risk z score was matched to the change in the combined risk z score between childhood and adulthood.
| Results |
> Participants
A total of 38,589 participants were included in the total sample; 19,168 (49.7%) were male, 5792 (15.0%) were black, and the mean (±SD) age at which the participant was seen during childhood was 11.8±3.1 years. The mean age of the participants at the time of their cardiovascular event was 47.0±8.0 years. Participants with cardiovascular events were older, more likely to be male, and had a lower level of parental and personal education than those without cardiovascular events.
Correlations between childhood risk factors ranged from −0.002 to 0.35, and within-person correlations across childhood, adolescence, and adulthood ranged from 0.40 to 0.84. The mean combined risk z score was 0.16 ± 0.49.
> Cardiovascular events in adults
Hazard ratios for a fatal cardiovascular event in adulthood with respect to risk factor z scores ranged from 1.30 (95% confidence interval [CI], 1.14 to 1.47) per unit increase in z score for total cholesterol level at 1.61 (95% CI, 1.21 to 2.13) for young smokers (yes vs. no).
The hazard ratio of a fatal cardiovascular event in adulthood with respect to the combined risk z score was 2.71 (95% CI, 2.23 to 3.29) per unit increase, and the hazard ratio risk for a fatal or nonfatal cardiovascular event in adulthood was 2.75 (95% CI, 2.48 to 3.06) per unit increase.
The hazard ratio with respect to the combined risk z score showed some attenuation for fatal or nonfatal events in older adults. None of the interaction terms of child age group (3–11 years vs. 12–19 years), race, or sex stood out. Childhood risk score was also positively associated with total mortality.
Study measures in adulthood were assessed in participants at a mean age of 31.0±5.6 years. In analyzes involving participants who had data on study measures in both childhood and adulthood, the adult combined risk z score was associated with adult cardiovascular events, both alone and when paired with the z of combined childhood risk.
The childhood combined risk z score, when combined with the adult combined risk z score, was attenuated and remained independently associated only with fatal or nonfatal cardiovascular events. In the analysis including the childhood combined risk z score and the change in the combined risk z score from childhood to adulthood, both predictors were associated with fatal cardiovascular events and with fatal or nonfatal cardiovascular events, with the relationship lower risk for predicting events at older adult ages than at younger adult ages. Between 30% and 50% of participants in each quartile of the childhood combined risk z score remained in the same quartile of the combined risk z score in adulthood.
> Risk factor categories and thresholds
Using “no” (for young smokers), low normal (for body mass index and systolic blood pressure), and acceptable low (for triglyceride level and total cholesterol level) as references in the standard clinical categories currently used For risk factors, the gradient of the risk ratio of cardiovascular events, whether single fatal or fatal or nonfatal, was evident across clinical categories for each risk factor.
An increased risk was observed not only among participants in the highest risk factor level category but also — in the analysis of fatal or nonfatal events — among those in the high-normal or high-acceptable mass index categories. body, systolic blood pressure, and triglyceride level.
The risk gradient across the combined risk z score categories was steeper than the risk gradient across the categories of any of the individual risk factors; Among participants with a combined risk z score of 0 or greater (23,103 of 38,589 [59.9%]), the risk of adult cardiovascular events was 2 to 9 times greater than the risk among those in the z score category lower (a z score of less than -0.5), and the risk increases with age in life table analysis. Several sensitivity analyzes were performed to assess the effect of loss to follow-up, reasonableness of imputation results, and differences between cohorts, which did not materially change the findings.
| Discussion |
The current study, with its large sample and use of prospective data on five traditional cardiovascular risk factors (body mass index, total cholesterol level, triglyceride level, systolic blood pressure, and youth smoking) from childhood to adulthood, showed broad associations between the levels of these childhood risk factors, individually and in combination, and the development of cardiovascular incidents in adults beginning as early as 40 years of age.
Cardiovascular events in children are rare, 14 but autopsies have shown widespread histological atherosclerotic lesions of the aorta and coronary arteries in young people that were associated with dyslipidemia, arterial hypertension, and smoking. 15,16
Data from the Coronary Artery Risk Development in Young Adults (CARDIA) study have demonstrated a relationship between the Framingham risk score and cardiovascular events among young adults followed for 20 years, 17 but studies relating risk factors are lacking. of childhood with those of adults.
Traditional cardiovascular risk factors have been evaluated in childhood due to their presumed association with the occurrence of cardiovascular events in adults. 2 Each risk factor was related to cardiovascular events in adults in this study, and combining the risk factors into a mean risk score, similar in concept to the Framingham score, resulted in a stronger association than any one risk factor. individual; Among 38,589 participants, 59.9% who had a combined risk z score of 0 or greater, corresponding to the risk factor level of an average child, had an increased risk of cardiovascular events, compared with those who had the z in the lowest category (a z score of less than -0.5).
Risk factors during childhood (3 to 11 years) and adolescence (12 to 19 years) were similarly related to adult cardiovascular events, as they were risk factors across sex and racial groups. Hazard ratios for fatal or nonfatal events with respect to the childhood combined risk z score decreased with increasing adulthood.
The authors evaluated cardiovascular events relative to the standard clinical categories currently used for childhood risk factors and found that children in the highest risk category (e.g., overweight or obese body mass index and levels of blood pressure prehypertensive or hypertensive) had a markedly increased risk of cardiovascular events in adulthood, as expected. However, the majority of children who were at excess risk of developing cardiovascular events in adulthood were in the medium to low combined risk z score categories. Previous longitudinal studies involving the i3C consortium also showed an association of mid-range childhood risk factor levels with the development of hypertension in adulthood 6 and diabetes in adulthood. 18
Because of the rarity of cardiovascular disease in childhood, questions remain about the merits of assessing cardiovascular risk factors in childhood rather than in adulthood, when clinical and subclinical disease are prevalent. 19 In the model including both child and adult combined risk z scores, the adult combined risk z score was a strong predictor of adult events, and the child combined risk z score was apparently attenuated. Such attenuation suggests that childhood risk factors predict events in adulthood primarily because they advance to adult values.
However, a supplementary analysis 20 showed that both the childhood combined risk z score and the change in the combined risk z score between childhood and adulthood were significant in predicting the risk of events in adults. From a prevention perspective, both childhood risk factor levels and the pathway to risk in adulthood appear to be informative.
Thus, the authors postulate that cardiovascular risk assessment should begin in childhood, and a reduction in risk factor levels between childhood and adulthood may have the potential to reduce the incidence of premature cardiovascular disease.
The authors’ study raises important questions about broader childhood strategies to reduce the risk of premature cardiovascular disease. Rather than a single focus on medical screening that identifies children with elevated levels of risk factors, the current results would suggest that an equally relevant focus on public health strategies is warranted to maintain ideal cardiovascular health in all children. twenty-one
Previous studies showed that people with lifetime genetic exposure to low levels of low-density lipoprotein cholesterol and systolic blood pressure tend to have a lower risk of cardiovascular disease, 22 and recently published results from the Special Risk Factors Intervention Project Turku Coronary Risk (STRIP) showed beneficial effects on risk factors over a 26-year period following dietary counseling that began in infancy and continued throughout childhood. 23
Furthermore, comprehensive public health education efforts in Finland over the past 40 years have led to positive lifestyle changes, a decrease in the levels of major risk factors, and dramatic reductions in cardiovascular disease-related mortality. . 24,25 In recognition of the difficulty of individual behavior change, the authors believe that these findings suggest the need for stronger public health programs for children.
Strengths of this study include the large sample, the wide age range of childhood participants, the adjudication of medical records, and a mean follow-up of children and adolescents of 35 years. Evidence that pooling data from the separate cohorts was an appropriate strategy was that the risk of cardiovascular events in adults before the age of 40 years was similarly low in all seven cohorts and that the adjusted hazard ratios with respect to each factor Risks were similar in the four oldest cohorts.
This study also has certain limitations. First, because 46.5% of the sample could not be located to determine nonfatal cardiovascular events, loss to follow-up presented a possible response bias.
The authors addressed this issue through two analytical approaches. They determined vital status and cause of death in 95% of the original participants. By limiting the initial analysis to fatal cardiovascular events in that nearly complete sample, they found the expected relationships with childhood risk factors.
They then used multiple imputation to assess the association of childhood risk factors with fatal or non-fatal cardiovascular events in adults across all participants. Regarding this final point, they relied heavily on the imputation model in evaluating the results. The primary function of multiple imputation was to reset the data on all study variables in the analysis of the distribution of the full sample, as compared to the analysis restricted to participants who were located or found to be deceased. These two approaches produced similar results; therefore, bias resulting from loss to follow-up is unlikely to have affected these findings.
Second, the generalizability of the current study was restricted by the limited number of participants from non-white groups, a factor that reflects the recruitment of the cohorts going back decades. Black participants represented 15% of the analysis sample and 21% of participants from the United States, which is a higher percentage than that of the US population.
However, the current study was not specifically powered to detect racial differences, did not include many Hispanic participants, and focused on the experience of high-income countries. Third, the authors would postulate that these unweighted values and the combined risk z score facilitate comparison of childhood and adult risk, but may not improve risk prediction over the life course.
This prospective cohort study showed that the cardiovascular risk factors of body mass index, systolic blood pressure, total cholesterol level, triglyceride level and youth smoking, particularly in combination from early childhood, were associated with cardiovascular events in adults and death from cardiovascular causes before the age of 60 years.
| Comment |
The present long-term follow-up cohort study shows that cardiovascular risk factors beginning in childhood are associated with cardiovascular events and death in adulthood. This raises the need to adopt public health policies at the population level in childhood to achieve a better quality of life and a decrease in cardiovascular events later in life.
