Risk factors for cardiovascular disease and type 2 diabetes retained from childhood to adulthood predict adult outcomes: the Princeton LRC Follow-up Study

Recently, an expert panel recommended screening all American children for risk factors for cardiovascular disease (CVD) [1], not just children of parents with known CVD or high risk factors. Pediatric risk factors for atherosclerosis have been shown to associate with young adult atherosclerotic lesions [2], carotid intima-media thickening (CIMT) [3–7], and cardiovascular disease (CVD) events [8]. Moreover, adolescent CVD risk factor status predicts increased adult CIMT, independent of adult risk factors [9, 10], and children with metabolic syndrome (MetS) have 2–3 times greater risk of high CIMT and type 2 diabetes mellitus (T2DM) as adults versus children free of MetS [11]. Obese children who remained obese as adults have increased type 2 diabetes (T2DM), hypertension, dyslipidemia, and increased CIMT, but risks for these outcomes are attenuated in obese children who became non-obese adults, with outcomes similar to those non-obese in both childhood and adulthood [12].

It is not well understood whether childhood risk factors cause adult CVD directly, independent of adult risk factors, or only in those individuals whose risk factors tracked into adulthood, thereby increasing the length of exposure to high risk factors [10, 13]. The best predictor of high blood pressure (HBP) in adulthood has been reported to be adult obesity or change in obesity; pediatric obesity does not predict adult HBP when adult obesity is in the model [13]. However, HBP is itself a risk factor, not a CVD event. Positive associations between childhood BMI and adult CIMT are generally attenuated once adjusted for adult BMI [14]. Child-adult relationships may be dependent on tracking of BMI from childhood to adulthood [14], since risk of events increases with the length of exposure [15, 16]. There is a stepwise increase in the incidence of T2DM with the duration of obesity [15].

In the current study, our specific aim was to assess whether risk factors for CVD and T2DM retained from childhood to adulthood predict CVD and T2DM in young adulthood or whether childhood risk factors are attenuated [12] by changes in risk factors from childhood to young adulthood.

We used data from the NHLBI Princeton Follow-up Study (PFS, 1999–2003), a 22–30 year follow-up of black and white former schoolchildren first studied in the NHLBI Lipid Research Clinics (LRC, 1973–1976) [8, 17]. PFS collected data following a protocol approved by the Children’s Hospital Institutional Review Board, with signed informed consent [17].

Pediatric and adult CVD risk factor measures 26 years later were highly correlated, Table 1. Twenty-six of the 770 subjects (3.4%) were taking cholesterol-lowering medications at their PFS visit, Table 1. Excluding their LDLC values from the analyses of correlations between LRC and PFS did not appreciably affect the correlation coefficients, Table 1. After adjusting for BMI at mean ages 12 and 38, age 12 and age 38 risk factors remained closely correlated, Table 1.

High TG in childhood retained into adulthood characterized the 19 subjects who had CVD in adulthood, while normal TG at both visits characterized the 751 subjects free of CVD at the PFS visit, Figure 1. There were 55 subjects with high TG at both visits, of whom 8 (14.6%) had CVD compared to 5 of 490 with normal TG at both visits (1%) for a risk ratio of 14.6 to 1, Figure 1, Table 2. The incidence of CVD was 1.9% in subjects with high TG at LRC but normal TG at PFS, and 2.9% in subjects with normal TG at LRC but high TG at PFS. Thus, there was a linear trend for CVD across the four TG classification groups (p < .0001), Table 2.

Normal BMI in childhood retained into adulthood characterized the 751 subjects free of CVD at the PFS visit, while high BMI in childhood retained into adulthood characterized the 19 subjects who had adult CVD, Figure 2. There were 113 subjects with high BMI at both visits, of whom 7 (6.2%) had CVD and 427 with normal BMI at both visits of whom 4 had CVD (0.9%) for a risk ratio of 6.9 to 1. The incidence of CVD was 2.5% in subjects with high BMI at LRC but normal BMI at PFS, and 4.0% in subjects with normal BMI at LRC but high TG at PFS. Thus, there was a linear trend for CVD across the four BMI classification groups (p = .0005), 2.

High blood pressure retained from childhood to adulthood was much more common in the 29 subjects who had adult T2DM (28%) than in the 417 free of adult T2DM (5%), while normal childhood blood pressure retained into adulthood characterized the 417 subjects free of T2DM at the PFS visit (65%), Figure 3. The incidence of T2DM was 28.6% in subjects with high BP at LRC and PFS compared to 3.6% in subjects with normal BP at both LRC and PFS, for a relative risk of 8 to 1. The one of 22 subjects with high BP at LRC but normal BP at PFS did have T2DM so the incidence rate was 4.6%. In subjects with normal BP at LRC but high BP at PFS the incidence of T2DM was 8.6%. Thus, there was a linear trend for T2DM across the four BP classification groups (p < .0001), Table 2.

High TG retained from childhood to adulthood was much more common in subjects who developed T2DM as adults (31%) than in those free of T2DM (6%), Figure 4. The incidence of T2DM was 27.3% in subjects with high TG at LRC and PFS compared to 3.8% in subjects with normal TG at both LRC and PFS, for a relative risk of 7.1. No person with high TG at LRC but normal TG at PFS had T2DM, incidence rate = 0.0%. In subjects with normal TG at LRC but high TG at PFS the incidence of T2DM was 9.6%. Thus, there was a linear trend for T2DM across the four TG change classification groups (p < .0001), Table 2.

Adult T2DM (29 yes, 417 no) was associated with BP and TG high in childhood and retained into adulthood (p = .0006, .003), with childhood glucose (p = .006), with adult age (p = .002), and with black race (p = .04), Table 3.

Adult IFG (88 yes, 617 no) was positively associated with adult BP and TG (high vs not high), p < .0001, p = .0009, respectively, and with cigarette smoking, p = .018, Table 3.

Neither pediatric nor young adult LDLC was associated with young adult CVD, p > .05.

In the current study, risk factors for CVD retained from childhood to adulthood predicted CVD in young adulthood. Risk for CVD was attenuated when childhood risk factors were not maintained into adulthood, congruent with the report by Juonala et al. [12]. Children who had high TG and retained high TG as adults had increased CVD events. Children who had normal BMI and retained normal BMI as adults had reduced CVD events. Children who had high childhood BP and TG and retained these into adulthood were more likely to have adult T2DM, children with childhood risk factors not retained were not associated with increased adult T2DM, congruent with the report by Juonala et al. [12].

In contrast to CVD and T2DM, adult IFG was associated with adult high BP, TG, and cigarette smoking, and was not associated with retention of risk factors from childhood to adulthood.

Our finding of a significant association of high TG retained from childhood to adulthood with young adult CVD is consistent with pediatric [8] and adult studies where non-fasting [23–25] and fasting TG [26–29] are independent risk factors for CVD and for ischemic stroke [30]. The association of TG high from childhood through young adulthood with adult CVD may, speculatively, reflect the presence of pediatric metabolic syndrome, a known predictor of adult CVD [18]. Moreover, TG levels in adolescent males have been related to coronary artery calcification 15 to 20 years later in young adults [31]. Coronary artery streaks in 6 to 30 year olds are significantly correlated with antecedent TG and very low density lipoprotein cholesterol [32, 33]. In a post-mortem study of 15 to 34 year old men, the percentage of the right coronary arterial intima involved with atherosclerosis correlated with a combination of LDL and VLDL cholesterol levels, and was inversely associated with HDL cholesterol [34].

Normal childhood BMI retained to adulthood was a significant negative risk factor for adult CVD. The association of normal BMI retained from childhood to adulthood with low young adult CVD events is consistent with the report by Chen et al. [35] where clustering of bottom quartile BMI, HOMA IR, SBP, and the ratio of total/HDL cholesterol was associated with decreasing mean values of carotid intima-media thickness in adulthood.

High childhood BP and TG, two components of the metabolic syndrome complex, retained into adulthood were associated with adult T2DM, findings broadly in agreement with those of Everhart et al. [15] and Lee et al. [16], which suggested that the duration of the risk factor presence from childhood to young adulthood and the cumulative exposure to risk factors predict adult outcomes.

Our finding of an association of glucose levels in childhood with the development of T2DM in adulthood is consistent with a recent report from the Bogalusa Heart Study that fasting plasma glucose in childhood is a predictor of T2DM in young adulthood even when the pediatric glucose is within the normal range [36]. Moreover, childhood insulin response during an oral glucose challenge predicts adult acute insulin response [37].

Given the significant tracking of risk factors for CVD and T2DM as observed in the current and previous studies [11, 38–40], failure to act on such childhood risk factors high TG, high BP, and obesity [12, 16] means the underlying pathology may continue into young adulthood, increasing the likelihood of an adverse outcome [10, 41]. These findings emphasize the importance of risk factor screening in childhood [1]. Lifestyle [1] and pharmacologic intervention [1, 42, 43] in childhood-adolescence might prevent development of CVD or T2DM in young adulthood.

A weakness in the current study is the absence of knowledge concerning when (at what age) participants with normal factors in childhood developed abnormal risk factors and when participants with abnormal factors in childhood developed normal risk factors. Thus, it was not possible to evaluate more precisely the length of time the at-risk state existed.

In the current study, neither pediatric nor young adult LDLC was associated with young adult CVD, perhaps attributable to treatment of high LDLC in 26 of 770 (3. 4%) young adults at PFS, or to the fact that with only 19 CVD endpoints by mean age 38, the study may not have had adequate power to declare an LDLC effect significant. Treatment to lower LDLC might, speculatively, also have reduced the power of LDLC to predict CVD.

Conventionally, parental history of CVD serves as an indication for screening for lipid abnormalities in children [44, 45]. After detailed review of basing childhood screening on parental history, the recent Expert Panel statement [1] called for universal risk factor screening in children [1]. Identification of CVD risk factors in a child can directly facilitate primary prevention [1] in the child through young adulthood, and also focus diagnostic attention on the potentially high-risk parent.

Risk factors for CVD and T2DM retained from childhood to adulthood predict CVD and T2DM in young adulthood and support universal childhood screening.