Non-High-Density Lipoprotein Cholesterol Levels From Childhood to Adulthood and Cardiovascular Disease Events

Abstract

Importance: Elevated non-high-density lipoprotein cholesterol (non-HDL-C; a recommended measure of lipid-related cardiovascular risk) is common in children and increases risk of adult cardiovascular disease (CVD). Whether resolution of elevated childhood non-HDL-C levels by adulthood is associated with reduced risk of clinical CVD events is unknown.

Objective: To examine the associations of non-HDL-C status between childhood and adulthood with incident CVD events.

Design, setting, and participants: Individual participant data from 6 prospective cohorts of children (mean age at baseline, 10.7 years) in the US and Finland. Recruitment took place between 1970 and 1996, with a final follow-up in 2019.

Exposures: Child (age 3-19 years) and adult (age 20-40 years) non-HDL-C age- and sex-specific z scores and categories according to clinical guideline-recommended cutoffs for dyslipidemia.

Main outcomes and measures: Incident fatal and nonfatal CVD events adjudicated by medical records.

Results: Over a mean length of follow-up of 8.9 years after age 40 years, 147 CVD events occurred among 5121 participants (60% women; 15% Black). Both childhood and adult non-HDL-C levels were associated with increased risk of CVD events (hazard ratio [HR], 1.42 [95% CI, 1.18-1.70] and HR, 1.50 [95% CI, 1.26-1.78] for a 1-unit increase in z score, respectively), but the association for childhood non-HDL-C was reduced when adjusted for adult levels (HR, 1.12 [95% CI, 0.89-1.41]). A complementary analysis showed that both childhood non-HDL-C levels and the change between childhood and adulthood were independently associated with the outcome, suggesting that from a preventive perspective, both childhood non-HDL-C levels and the change into adulthood are informative. Compared with those whose non-HDL-C levels remained within the guideline-recommended range in childhood and adulthood, participants who had incident non-HDL-C dyslipidemia from childhood to adulthood and those with persistent dyslipidemia had increased risks of CVD events (HR, 2.17 [95% CI, 1.00-4.69] and HR, 5.17 [95% CI, 2.80-9.56], respectively). Individuals who had dyslipidemic non-HDL-C in childhood but whose non-HDL-C levels were within the guideline-recommended range in adulthood did not have a significantly increased risk (HR, 1.13 [95% CI, 0.50-2.56]).

Conclusions and relevance: Individuals with persistent non-HDL-C dyslipidemia from childhood to adulthood had an increased risk of CVD events, but those in whom dyslipidemic non-HDL-C levels resolve by adulthood have similar risk to individuals who were never dyslipidemic. These findings suggest that interventions to prevent and reduce elevated childhood non-HDL-C levels may help prevent premature CVD.

Figure 1.. Study Cohort Determination

CVD indicates cardiovascular disease; i3C, International Childhood Cardiovascular Cohort; and non–HDL-C, non–high-density lipoprotein cholesterol. ^aDates of first visits ranged from 1970 to 2007 (in the Minnesota Childhood Cardiovascular Cohorts, 1 set of participants was first recruited in 1995-1996, but 438 siblings of participants had their first study visits between 1997 and 2007). ^bExclusion of lipid (or HDL-C) testing in the original study protocols of 2 cohorts in the i3C Consortium is the primary reason for no childhood non–HDL-C measurements. Of the 16 052 participants without childhood non–HDL-C measurements, 14 409 (90%) were from the Childhood Determinants of Adult Health Study (CDAH) and the Muscatine Study. In CDAH, due to predetermined criteria based on age and logistical constraints, only 21% of participants (1738/8426) had blood samples collected at the only childhood visit in 1985. The Muscatine cohort began in 1970, and the absence of HDL-C measurement prior to 1974 resulted in a reduced subset of children eligible for inclusion (2121/9842) in the current analysis based on the need for HDL-C to calculate non–HDL-C. ^cAge at end of follow-up indicates age at time of event, at time of non–CVD death, or at end of follow-up, whichever occurred first. ^dSee Table for participant groups by change in non–HDL-C status from childhood to adulthood. There were 7 combined cohorts, with the Australian cohort (Childhood Determinants of Adult Health) ultimately entirely excluded from analysis. ^eIncident CVD included the first occurrence of adjudicated myocardial infarction, stroke, transient ischemic attack, ischemic heart failure, angina, peripheral artery disease, carotid intervention, abdominal aortic aneurysm, or coronary revascularization, as well as CVD deaths. Adjudication of deidentified medical records for CVD events was conducted by 2 physicians blinded to participant identity, with disagreements settled by the adjudication committee (eAppendix in Supplement 1).

Figure 2.. Associations Between Childhood, Adult, and Childhood Plus Adult Non–HDL-C Z Scores and Adult CVD Events

CVD indicates cardiovascular disease; non–HDL-C, non–high-density lipoprotein cholesterol. Incident CVD included the first occurrence of adjudicated myocardial infarction, stroke, transient ischemic attack, ischemic heart failure, angina, peripheral artery disease, carotid intervention, abdominal aortic aneurysm, or coronary revascularization, as well as CVD deaths. There were 147 incident CVD events (5121 participants; incidence rate, 3.23 per 1000 person-years). ^aHazard ratios are reported per 1-unit increase in z scores; cohort-stratified cause-specific hazard models were used and analyses were weighted by the inverse of probability of being included in analysis and were adjusted for sex, Black race, childhood smoking, mean age at and calendar year of childhood measurement, childhood mean age- and sex-specific z scores for body mass index and systolic blood pressure, adult smoking, and change in z scores for body mass index and systolic blood pressure between childhood and adulthood. ^bVariables in parentheses are exposures of interest in each model. Childhood non–HDL-C levels at each visit were standardized as age- and sex-specific z scores within each age and sex stratum. The mean of resulting z scores across childhood measurements for each participant was then calculated to obtain a single mean z score for analysis (eAppendix in Supplement 1). The same approach was used to obtain adult non–HDL-C z scores. Change in z score was calculated by subtracting childhood mean z score from adult mean z score.

Figure 3.. Hazard Ratios and Cumulative Hazard of CVD Events According to Change in Non–HDL-C Status Between Childhood and Adulthood

CVD indicates cardiovascular disease; non–HDL-C, non–high-density lipoprotein cholesterol. See Figure 2 legend for conditions included in incident CVD events. There were 147 incident CVD events (5121 participants; incidence rate, 3.23 per 1000 person-years). The graph is truncated at age 55 years, after which only 5% of participants were followed up. ^aCohort-stratified cause-specific hazard models were used and analyses were weighted by the inverse of probability of being included in analysis and were adjusted for sex, Black race, mean age at and calendar year of childhood measurement, childhood smoking, mean age- and sex-specific z scores for body mass index and systolic blood pressure, adult smoking, and change in z scores for body mass index and systolic blood pressure between childhood and adulthood. Childhood/adult individual means of non–HDL-C for each participant were used to classify risk status. Non–HDL-C cutoffs to define dyslipidemia were 145 mg/dL in childhood and 190 mg/dL in adulthood (to convert non–HDL-C from mg/dL to mmol/L, divide values by 38.67). The 4 groups were defined as resolution (dyslipidemia in childhood, nondyslipidemia in adulthood), persistent dyslipidemia (dyslipidemia in both childhood and adulthood), incident dyslipidemia (nondyslipidemia in childhood, dyslipidemia in adulthood), and persistent normal non–HDL-C levels (nondyslipidemia in both childhood and adulthood).

Figure 4.. Hazard Ratios for Adult CVD Events According to 9 Categories of Change in Non–HDL-C Status Between Childhood and Adulthood

CVD indicates cardiovascular disease; non–HDL-C, non–high-density lipoprotein cholesterol. To convert non–HDL-C from mg/dL to mmol/L, divide values by 38.67. See Figure 2 legend for conditions included in incident CVD events. There were 147 incident CVD events (5121 participants; incidence rate, 3.23 per 1000 person-years). ^aThese groupings considered all major combinations of child and adult non–HDL-C status groups (ie, normal, elevated, and dyslipidemia at both time points). From the groupings in the Table and Figure 3, the nondyslipidemia group in childhood or adulthood was further split into normal lipid level and elevated lipid level groups, creating 3 categories for non–HDL-C status at each age period and 9 categories for change in non–HDL-C status between childhood and adulthood. Childhood and adulthood individual means of non–HDL-C levels for each participant were used to classify risk status. Non–HDL-C cutoffs of ≥120 mg/dL and ≥150 mg/dL, respectively, were used to define childhood and adulthood elevated levels, and 145 mg/dL and 190 mg/dL, respectively, to define childhood and adulthood dyslipidemia. ^bCohort-stratified cause-specific hazard models were used, and analyses were weighted by the inverse of probability of being included in analysis and adjusted for sex, Black race, mean age at and calendar year of childhood measurement, childhood smoking, mean age- and sex-specified z scores for body mass index and systolic blood pressure, adult smoking, and change in z scores for body mass index and systolic blood pressure between childhood and adulthood.