Increased atherogenicity of LDL and impaired HDL function in children with FH

Children with FH display changes in LDL and HDL function: a cross-sectional study

Presented at EAS 2021 by Jacob Christensen, PhD (Oslo, Norway)

Introduction and methods

The function of lipoproteins is emerging as an important risk factor in the progression of ASCVD. The intrinsic property of LDL to aggregate upon modification, for instance, is associated with ASCVD. Also, HDL function, which can be quantified by measuring cholesterol efflux capacity, is associated with risk for ASCVD. However, whether children with familiar hypercholesterolemia (FH) have altered lipoprotein particle functions is unknown.

This study assessed LDL and HDL function and activity of four enzymes that are involved in lipoprotein metabolism in plasma samples from children with FH (13±4 years; n=47) and healthy children (10±2 years, n=56).

LDL function was determined by measuring the susceptibility of LDL to form aggregates by induction with human recombinant sphingomyolinase. HDL function was assessed with a HDL-apoA-I exchange (HAE) assay. This assay uses electron paramagnetic resonance spectroscopy which captures the conformational changes that apoA-I undergoes upon direct association or dissociation with HDL particles and correlates with cholesterol efflux capacity. Also, enzyme activity of LCAT, CETP, PLTP, and PON1 was analyzed. The potential biological mechanism behind variations in lipoprotein function was further explored using a nuclear magnetic resonance based metabolomics profiling approach.

Main results

• The FH group had elevated levels of total cholesterol and LDL-c compared to the group with healthy children (total-c: 5.4±2 mmol/L vs. 4.0±0.8 mmol/L, P<0.001; and LDL-c: 3.6±1.8 mmol/L vs. 2.1±0.9 mmol/L, P<0.001). Both groups had an HDL-c concentration of 1.5±0.3 mmol/L.

• Children with FH had increased LDL aggregation compared to healthy children (P<0.001). LDL aggregation was still significantly higher when adjusted for apoB levels (P<0.01).

• The cholesterol efflux capacity was significantly lower in children with FH compared to healthy children (P<0.001). Similar data were obtained after correction for apoA-I levels.

• The enzyme activity of LCAT, CETP, PLTP, and PON1 was similar between FH and healthy children.

• After further adjustments for sex, age, and BMI, the susceptibility of LDL to form aggregates was still significantly increased (P<0.01) and the cholesterol efflux capacity was still significantly reduced (P<0.001) in children with HF compared to healthy subjects.

• The metabolomics assay revealed a positive association of LDL aggregation with LDL subclasses, ApoB, and LDL particle diameter and when corrected for apoB, a negative association with VLDL particles, smallest HDL (S-HDL and M-HDL) particles, and VLDL size was observed. The profile of association between cholesterol efflux capacity and metabolites was a mirror image of the LDL aggregation association data, albeit with minor differences.

• There was an inverse relationship between the regression coefficients for LDL aggregation and cholesterol efflux capacity using data of all metabolic biomarkers (R² = 0.77, P<0.001).

Conclusion

Children with FH had LDL particles with an increased atherogenicity and impaired function of HDL compared to healthy children.

Christensen suggested at the end that alterations in LDL receptor function, plasma LDL concentrations, and the cumulative cholesterol burden in FH may jointly be the overarching drivers and common denominators linking these metrics in a biologically relevant context.

-Our reporting is based upon the information provided at the EAS 2021 congress-