Cumulative muscle mass and blood pressure but not fat mass drives arterial stiffness and carotid intima-media thickness progression in the young population and is unrelated to vascular organ damage

Carotid intima-media thickness (cIMT) and carotid-femoral pulse wave velocity (cfPWV) are key markers of subclinical atherosclerosis and arteriosclerosis linked to future cardiovascular morbidity and mortality. While body mass index (BMI) has been associated with higher cfPWV and cIMT, BMI conflates fat and lean mass and may misrepresent true body composition effects. Emerging evidence, including Mendelian randomization, suggests BMI may not causally influence cfPWV or cIMT in adolescence, motivating analyses that use dual-energy X-ray absorptiometry (DEXA) to distinguish fat and lean mass. Additionally, cumulative BP exposure in early adulthood predicts later cardiovascular events, but data from childhood are limited. This study investigated whether cumulative exposures from ages 9–24 years to total and trunk fat mass, lean mass, BMI, and BP are associated with cfPWV and cIMT levels at 24 years and with their progression from 17 to 24 years, using the ALSPAC cohort. The overarching hypothesis was that cumulative lean mass and blood pressure, rather than fat mass, drive adverse vascular remodeling in youth.

Prior studies show that higher BMI is associated with increased arterial stiffness and cIMT across the life course, but BMI does not differentiate fat from lean mass, potentially obscuring true relationships. Mendelian randomization has reported no causal role for BMI in cfPWV and cIMT at age 17, suggesting confounding or mediation by other body composition components. DEXA-based assessments more accurately capture cardiovascular risk than anthropometry. Persistent elevated BP from ages 18–39 increases cardiovascular event risk, underscoring the importance of cumulative BP exposure, though childhood data are scarce. These gaps justify evaluating cumulative, DEXA-derived fat and lean mass and BP from childhood in relation to vascular aging markers.

Design and cohort: Prospective analyses within the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK birth cohort. A total of 15,454 pregnancies were enrolled (1991–1992). Clinic assessments occurred at ages 9, 17, and 24 years. For cross-sectional analyses at age 24, 1799 participants had complete data on body composition, BP, cfPWV, and cIMT. For longitudinal analyses, 3863 had complete cfPWV and cIMT at age 17; 1852 had complete cfPWV and cIMT at age 24. Exposures: Body composition by DEXA at ages 9 and 17 (GE Lunar, GE Medical Systems) and at age 24 (Lunar Prodigy, software v15). Repeatability for body fat mass in a subsample had a repeatability coefficient of 0.5 kg. Calculated indices included BMI (kg/m²), total and trunk fat mass indices (FMI: fat mass/height²), and lean mass index (LMI: lean mass/height²). BMI at 17 and 24 years was categorized as normal (<24.99 kg/m²) vs overweight/obese (≥25 kg/m²). Blood pressure: measured at 9 and 17 years using standard protocols and at 24 years using Omron M6; systolic and diastolic BP considered both continuous and categorized (normotensive <120 mmHg systolic vs elevated ≥120 mmHg). Anti-hypertensive use was rare at 17 years (<10 participants); medication data were unavailable at 24 years. Outcomes: cfPWV measured at 17 and 24 years using Vicorder; cIMT measured by ultrasound (Vivid7 with 12–13.5 MHz linear transducers). cIMT was the mean of the average right and left common carotid artery measurements. Age- and sex-specific 90th percentiles were used to define high-risk cfPWV and cIMT in some analyses. Covariates: Cardiometabolic factors included systolic BP, LDL-C, hsCRP at 9, 17, 24 years; fasting glucose at 17, 24 years; and fat or lean mass at respective ages, depending on the exposure. Lifestyle and other factors included smoking at 17 and 24 years, physical activity at 24 years (ActiGraph GT3X+ over four days with established cutoffs), and family history of hypertension, diabetes, high cholesterol, and vascular disease. Heart rate was not adjusted due to collinearity with systolic BP (r=0.87); height was not adjusted due to collinearity with lean mass (r=0.95). Multiple imputation was used; imputed results are primary, with non-imputed sensitivity analyses reported in supplements. Statistical analysis: Cross-sectional associations at age 24 were assessed using multiple linear regression, with generalized linear models and Sidak correction for multiple comparisons; ANOVA tested linear trends. Cumulative exposure analyses from ages 9–24 used linear mixed-effect models with exposures categorized into age- and population-specific tertiles (low, moderate, high). Two main adjustment models: Model 1 adjusted for sex, baseline age, time between 9 and 24 years, cardiometabolic factors across visits, and relevant body composition measures; Model 2 additionally adjusted for lifestyle factors (physical activity, smoking, family history). Sensitivity analyses included BMI category stratification and additional adjustments (insulin, diet, socioeconomic status, ethnicity). Additional analyses examined the effect of cumulative exposures on cfPWV and cIMT at age 24, and explored the role of vascular organ damage (≥90th percentile cfPWV or cIMT) in progression models.

- Sample: 3863 with complete cfPWV and cIMT at 17 years; 1852 at 24 years; 1799 with complete body composition, BP, and vascular measures at 24. Females had higher fat mass and lower lean mass than males at all ages; females had lower systolic BP, cfPWV, and cIMT at 17 and 24 years. - Cross-sectional (age 24): Lean mass and systolic and diastolic BP were positively associated with cfPWV after multivariable adjustment; BMI was negatively associated with cfPWV. Lean mass, LMI, and systolic BP were positively associated with cIMT; BMI was negatively associated with cIMT. Total and trunk fat mass quartiles showed no linear-trend associations with cfPWV or cIMT. - Cumulative exposure effects on cfPWV and cIMT at age 24: Accumulated high exposures from ages 9–24 to total fat mass, BMI, lean mass, systolic BP, and diastolic BP were associated with faster cfPWV at age 24. Cumulative high exposures to lean mass, LMI, BMI, and systolic BP were strongly associated with higher cIMT at age 24. - Progression from 17 to 24 years (7-year change): Cumulative high exposures to lean mass (effect estimate 0.006 m/s; 95% CI 0.001 to 0.010; p=0.022), systolic BP (0.013 m/s; 0.009 to 0.017; p<0.0001), and diastolic BP (0.023 m/s; 0.019 to 0.027; p<0.0001) were positively associated with the increase in cfPWV. Cumulative high exposures to lean mass (0.012 mm; 0.008 to 0.016; p<0.0001), BMI (0.007 mm; 0.003 to 0.011; p=0.001), and systolic BP (0.010 mm; 0.006 to 0.014; p<0.0001) were associated with thicker cIMT at 17–24 years. - Sex differences: For cfPWV progression, cumulative high lean mass showed a positive association in males (0.025 m/s; 0.015 to 0.035; p<0.0001) and an inverse association in females (-0.007 m/s; -0.013 to -0.001; p=0.017). - Fat mass: Total and trunk fat mass from childhood showed no association with cfPWV or cIMT progression. - Prevalence: Elevated systolic BP (≥120 mmHg) prevalence was 26.1% at 17 years and 32.6% at 24 years (descriptive).

Findings indicate that cumulative exposure from childhood through young adulthood to higher lean mass and higher blood pressure is linked to accelerated arterial stiffness progression and increased carotid wall thickness, whereas cumulative fat mass does not drive vascular progression. This helps clarify prior BMI-based associations: BMI’s positive associations with vascular measures may be driven by its lean mass component rather than fat mass, as fat mass itself was not associated with progression. The robust associations of systolic and diastolic BP with cfPWV progression and of systolic BP with cIMT underscore the importance of early-life BP control for preventing vascular aging. The observed sex-specific effect of lean mass on cfPWV progression suggests differing vascular adaptations to muscle mass between males and females, warranting further investigation. Overall, the results support focusing on precise body composition measures and BP trajectories in youth to understand and mitigate early vascular remodeling.

Cumulative lean (muscle) mass and blood pressure from childhood to young adulthood are key drivers of increased arterial stiffness and carotid wall thickness, while fat mass does not contribute to vascular progression in this cohort. These findings highlight the need to monitor and manage BP early in life and to consider body composition beyond BMI in cardiovascular risk assessment. Future research should elucidate mechanisms underlying sex-specific associations, explore whether vascular changes reflect adaptive remodeling versus pathology, and assess whether these early-life trajectories translate into later clinical events.

- Potential selection/attrition bias due to loss to follow-up, though excluded and included participants had similar demographics. - BP medication data were unavailable at age 24, and a small number used antihypertensives at 17, which could influence associations. - Heart rate and height were not included in models due to high collinearity with systolic BP and lean mass, respectively, which may limit adjustment for these factors. - Reliance on imputation for missing data, although sensitivity analyses with non-imputed data were broadly consistent. - Generalizability may be limited to similar populations; clinical cardiovascular events were not assessed given participant ages. - Device and protocol changes across visits (different DEXA systems, ultrasound equipment) could introduce measurement variability, though standardized protocols were used.