Does arterial stiffness progression temporally precede higher low-grade inflammation in adolescents? Causal longitudinal evidence using auto-regressive cross-lagged structural equation models
Authors: Agbaje A O , Barmi S , Sansum K M , Baynard T , Barker A R , Tuomainen T P 
Published: October 2022

Abstract

Background
Arterial stiffness, a precursor of arteriosclerosis, measured using carotid-femoral pulse wave velocity (cfPWV) is a strong predictor of cardiovascular morbidity and mortality in adults. Emerging evidence among adolescents, young adults, and middle-aged adults suggest that arterial stiffness may predict the risk of hypertension, obesity, insulin resistance, and the onset of type 2 diabetes and could be a causal risk factor for these diseases. However, it is unknown whether higher arterial stiffness temporally precedes elevated inflammation in the young population or if there is a bi-directional relationship. This evidence is crucial to developing interventions for attenuating arterial stiffness in early life.

Purpose
To examine the temporal causal longitudinal associations between repeated measures of cfPWV and high sensitivity C-reactive protein (hsCRP).

Methods
We studied 3862 adolescents, aged 17.7 years, followed-up for 7 years, from Avon Longitudinal Study of Parents and Children, birth cohort, UK. Fasting plasma hsCRP was assessed at 17.7 and 24.5-year clinic visits. In the same clinic visits, cfPWV was computed from pressure waveforms obtained using the Vicorder device (Skidmore Medical, Bristol, UK), 5 minutes after participants rested in a semi-prone position, with 2 blood pressure measurement channels and 2 Velcro pressure sensor cuffs applied over each of the carotid and femoral arteries. The assessment was repeated until three readings that were within 0.5 m/s of each other were recorded. We conducted autoregressive cross-lagged structural equation model path analyses to untangle temporal associations. We adjusted for sex, time in years between ages 17.7 and 24.5 years, age, low-density lipoprotein cholesterol, insulin, triglyceride, high-density lipoprotein cholesterol, fasting blood glucose, systolic blood pressure, heart rate, dual-energy Xray absorptiometry measured total fat mass and lean mass, ActiGraph measured moderate to vigorous physical activity at 15.5 years, smoking status, and family history of cardiovascular and metabolic diseases.

Results
Among 3862 adolescents (55.5% female), median (IQR) hsCRP at 17.7 and 24.5 years were 0.56 (0.98) mg/L and 0.84 (1.62) mg/L, respectively. The median (IQR) cfPWV at 17.7 and 24.5 years were 5.79 (0.66) m/s and 6.12 (1.12) m/s, respectively. Higher hsCRP at age 17.7 years was associated with higher cfPWV [Standardized β = 0.058, standard error = 0.004, p=0.037] at age 24.5 years. However, higher cfPWV at age 17.7 years was not associated with higher hsCRP [β = 0.023, standard error = 0.243, p=0.341] at 24.5 years.

Conclusion
We observed that elevated low-grade inflammation in adolescence may temporally cause higher arterial stiffness 7 years later, but not vice versa. Clinical and public health interventions targeted at reducing low-grade inflammation to regress the development of arteriosclerotic cardiovascular disease before mid-adulthood are needed.

Funding Acknowledgement
Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Finnish Cultural Foundation