Cardiometabolic Changes in Early Life Favor Girls

Sex differences in adult heart disease may be related to diverging trajectories in cardiometabolic disease factors beginning as early as childhood, a metabolomics study showed.

With granular and high-resolution cardiovascular phenotyping, the difference between males and females was apparent between ages 7 to 25:

• Very-low-density lipoprotein (VLDL) particles fell disproportionately over time in girls, who wound up having lower VLDL as young women compared with men
• High-density lipoprotein (HDL) particles increased disproportionately in girls, who wound up having higher HDL as young women
• Low-density lipoprotein (LDL) particles stayed relatively higher from girlhood to young womanhood compared with males

Girls started out with lower HDL cholesterol and higher levels of other types of cholesterol compared with boys at age 7. By age 25, women had higher esterified, free, total, and HDL cholesterol, as well as lower VLDL and remnant cholesterol, while levels of LDL cholesterol were no different between the sexes, according to Linda O'Keeffe, PhD, an epidemiologist at University College Cork in Ireland, and colleagues.

"Overall, our findings suggest that childhood and adolescence are important periods for the emergence of sex differences in atherogenic lipids (apolipoprotein B containing VLDL and LDL traits) and predictive biomarkers (glucose and HDL) for cardiometabolic diseases, mostly to the detriment of males," they wrote in Heart.

It is well-established that heart disease risk is higher in men until mid-life, after which there is a catch-up in older women.

This study added granular data to the evidence for an early divergence in cardiometabolic risk factors between men and women. O'Keeffe's group had previously shown distinct patterns of change in conventional cardiometabolic risk factors through the first decades of life, with change for some risk factors coinciding with the sensitive period of puberty, and sex differences in circulating lipids that began at birth and widened further by age 18.

The present study may support a prevention-focused clinical approach that includes the regular measurement of lipid levels from birth through early childhood and adolescence, noted Carolina Downie and Xinruo Zhang, both predoctoral researchers at the University of North Carolina at Chapel Hill, in an accompanying editorial.

"Given that population-level differences in cardiovascular outcomes between men and women reflect both mechanisms influenced by biological sex (e.g., hormonal regulations, genetic heterogeneity) and socially constructed gender-related patient and clinician behaviors, assessing how sex-specific trajectories in cardiometabolic molecular traits are mediated by other downstream factors will be necessary," the duo wrote.

O'Keeffe and team acknowledged that longitudinal mediation studies are required to investigate the effects of adiposity, puberty timing, and other health behaviors. Moreover, long-term work is required to study the association between early-life trajectories of cardiometabolic risk factors and late-life atherosclerotic risk, they said.

According to the U.S. Preventive Services Task Force, there is insufficient evidence for universal screening for heterozygous familial hypercholesterolemia and multifactorial dyslipidemia in children and adolescents.

This prospective cohort study assessed sex-specific trajectories of 148 metabolic traits on a targeted metabolomics platform. This involved nuclear magnetic resonance (NMR) spectroscopy performed on EDTA plasma samples to quantify concentrations of cholesterol, triglycerides, and other lipid content in lipoprotein subclass particles, apolipoproteins, fatty acids, glucose, and inflammatory glycoprotein acetyls.

The researchers included over 7,000 participants in the Avon Longitudinal Study of Parents and Children birth cohort study who had various repeat measures at 7, 15, 18, and 25 years. This cohort was roughly split between the sexes and fairly homogenous, being mostly of white ethnicity and relatively socially advantaged.

Limitations to the study included infrequent NMR measures and potential bias from excluding people who did not attend an NMR clinic.

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