Determinants of Intima-Media Thickness in the Young The ALSPAC Study

OBJECTIVES This study characterized the determinants of carotid intima-media thickness (cIMT) in a large (n > 4,000) longitudinal cohort of healthy young people age 9 to 21 years. BACKGROUND Greater cIMT is commonly used in the young as a marker of subclinical atherosclerosis, but its evolution at this age is still poorly understood. METHODS Associations between cardiovascular risk factors and cIMT were investigated in both longitudinal (ages 9 to 17 years) and cross-sectional (ages 17 and 21 years) analyses, with the latter also related to other measures of carotid structure and stress. Additional use of ultra-high frequency ultrasound in the radial artery at age 21 years allowed investigation of the distinct layers (i.e., intima or media) that may underlie observed differences. RESULTS Fat-free mass (FFM) and systolic blood pressure were the only modi ﬁ able risk factors positively associated with cIMT (e.g., mean difference in cIMT per 1-SD increase in FFM at age 17: 0.007 mm: 95% con ﬁ dence interval [CI]: 0.004 to 0.010; p < 0.001), whereas fat mass was negatively associated with cIMT (difference: (cid:1) 0.0032; 95% CI: 0.004 to (cid:1) 0.001; p ¼ 0.001). Similar results were obtained when investigating cumulative exposure to these factors throughout adolescence. An increase in cIMT maintained circumferential wall stress in the face of increased mean arterial pressure when increases in body mass were attributable to increased FFM, but not fat mass. Risk factor (cid:1) associated differences in the radial artery occurred in the media alone, and there was little evidence of a relationship between intimal thickness and any risk factor. measures of carotid artery structure and biomechanical stress to identify potential adaptive and maladaptive changes at this age.

However, conventional cIMT is a composite measure of both intimal and medial layers and is therefore unable to determine whether changes in arterial wall thickness represent early atherosclerotic changes within the intimal layer, a remodeling response within the medial layer, or a combination of both. Although numerous studies have shown associations between well-established CV risk factors and cIMT (7), others have also reported associations with height, lean tissue mass, and vessel diameter (8)(9)(10), which suggests that physiological remodeling due to increased body size or growth may account for at least some of the changes commonly attributed to subclinical disease. These factors may be particularly relevant in the young, when cumulative exposure to CVD risk factors is low and comorbidities that increase atherosclerotic risk are largely absent.
Advances in ultra-high frequency ultrasound technology (UHFUS) now permit the individual layers of the arterial wall to be studied in detail (11)(12)(13)(14). In an extensively phenotyped longitudinal cohort of healthy young people recruited to the ALSPAC (Avon Longitudinal Study of Parents and Children) trial, we combined this novel UHFUS technology in the radial artery with both cross-sectional and longitudinal analyses of cIMT to characterize the determinants of arterial wall changes in adolescence and young adulthood, and related these changes to other measures of carotid artery structure and biomechanical stress to identify potential adaptive and maladaptive changes at this age.

METHODS
COHORT DESCRIPTION. ALSPAC is a prospective birth cohort study investigating factors that influence normal childhood development and growth. The cohort and study design have been described in detail previously (15,16), and a brief description is provided in the Supplemental Appendix. Ethical approval for all aspects of this study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committee, and conformed to the Declaration of Helsinki. If the child was younger than age 16 years, informed written consent was obtained from the parent/guardian alongside assent from the child. When age 16 years or older, participants provided their own informed written consent.
STUDY DESIGN. Using a combination of both crosssectional and longitudinal analyses from an age range spanning childhood (9 years) to young adulthood (21 years), we used 3 separate approaches to characterize determinants of IMT in a large cohort of young people free from clinical disease.
In 5,215 adolescents (mean age: 18 years) attending the ALSPAC Teen Focus 4 Clinic (ALSPAC@17), we investigated cross-sectional relationships between a range of CV risk factors (body composition, blood pressure [BP], lipids, insulin, glucose, inflammatory markers, lifestyle behaviors, and socioeconomic circumstances) and cIMT. In addition, we explored how these differences in cIMT were related to other measures of structure and stress within the carotid artery (lumen diameter, IMT/lumen ratio, and vessel circumferential wall stress).
Based on findings from the cross-sectional analysis, we next used repeat measures of body composition and BP in 4,561 participants (collected on 2 to 5 occasions between the ages of 9 and 17 years) to determine the effect of their cumulative exposure throughout adolescence on cIMT at 17 years.
Finally, further detailed phenotyping in 436 participants recalled at age 21 years allowed us to:  Determinants of Intima-Media Thickness in the Young -2 0 1 9 : ---1) assess whether increased duration of exposure to risk factors in young adulthood altered relationships seen in adolescence; and 2) use UHFUS in a subsample of these participants to investigate the contribution of intimal and medial layers to arterial changes.
Details of this cohort have been described previously (17), and a comparison of baseline characteristics between those who attended recall at age 21 years versus those who did not is shown in Supplemental Table 1.
Carotid artery structure and stress using high-frequency ultrasound. (LCGMM) analysis as previously described (23). By LCGMM, we characterized discrete patterns of FFM, FM, and systolic BP alterations from age 9 to 17 years.
One to 5 classes were tested in LCGMM models, and selection was based on log-likelihood and Bayes in-  Chiesa et al.

RESULTS
PARTICIPANT CHARACTERISTICS. Participants in ALSPAC@17 were mean age of 17.8 AE 0.4 years and were 56% female, whereas those in ALSPAC@21 were on average 20.9 AE 1.0 years of age and 66% female.
Other characteristics are shown in Table 1. were found to be negatively correlated ( Table 2).
Positive relationships were also seen for the nonmodifiable risk factors of male sex and height (  Multiple imputation was used to account for missing variables of interest.

Findings from regression models without imputation
for missing values were consistent with these results (Supplemental Table 9).  Chiesa et al. Determinants of Intima-Media Thickness in the Young -2 0 1 9 : --- Relationship between changes in body mass due to increasing fat-free mass (FFM) (pink) or fat mass (FM) (green) and carotid structure and wall stress at age 17 years. All models adjusted for age, sex, and height. The p value is for linear trend. Error bars denote 95% confidence intervals (CIs). CWS ¼ circumferential wall stress; IMT ¼ intima-media thickness.   It is important to note that our findings were derived from a young predominantly healthy population cohort and did not imply that cIMT is an  Subtle increases in intima-media thickness in a young healthy population appear predominantly medial-driven, are associated with increased fat-free mass as opposed to fat mass, and act to maintain vessel circumferential wall stress in the face of increasing blood pressure.   Determinants of Intima-Media Thickness in the Young -2 0 1 9 : ---