Enhanced status of inflammation and endothelial activation in subjects with familial hypercholesterolaemia and their related unaffected family members: a case control study

Abstract

BackgroundFamilial hypercholesterolaemia (FH) leads to premature coronary artery diseases (CAD) which pathophysiologically can be measured by inflammation, endothelial activation and oxidative stress status. However, the status of these biomarkers among related unaffected relatives of FH cases and whether FH is an independent predictor of these biomarkers have not been well established. Thus, this study aims to (1) compare the biomarkers of inflammation, endothelial activation and oxidative stress between patients with FH, their related unaffected relatives (RUC) and normolipaemic subjects (NC) (2)determine whether FH is an independent predictor of these biomarkers.MethodsOne hundred thirty-one FH patients, 68 RUC and 214 matched NC were recruited. Fasting lipid profile, biomarkers of inflammation (hsCRP), endothelial activation (sICAM-1 and E-selectin) and oxidative stress [oxidized LDL (oxLDL), malondialdehyde (MDA) and F2-isoprostanes (ISP)] were analyzed and independent predictor was determined using binary logistic regression analysis.ResultshsCRP was higher in FH and RUC compared to NC (mean ± SD = 1.53 ± 1.24 mg/L and mean ± SD = 2.54 ± 2.30 vs 1.10 ± 0.89 mg/L, p < 0.05). sICAM-1 and E-selectin were higher in FH compared to NC (mean ± SD = 947 ± 742 vs 655 ± 191 ng/mL, p < 0.001 and 175 ± 131 vs 21.6 ± 10.7 ng/mL, p < 0.001 respectively) while sICAM-1 concentration was higher in RUC compared to NC (mean ± SD = 945 ± 379 vs 655 ± 191 ng/mL, p < 0.01). Biomarkers of oxidation (ox-LDL, MDA and ISP) were elevated in FH compared to NC [mean ± SD = (48.2 ± 26.8 vs 27.3 ± 13.2 mU/L, p < 0.001), (2.57 ± 1.3 vs 1.20 ± 0.30 nmol/mL, p < 0.001) and (645 ± 396 vs 398 ± 20.5 pg/L, p < 0.001) respectively], but no significant differences were observed between RUC and NC (p > 0.05). FH was an independent predictor for sICAM-1 (p = 0.007), ox-LDL (p < 0.001) and MDA (p < 0.001) while RUC independently predicted for sICAM-1 (p < 0.001).ConclusionThe screening for FH is vital as all biomarkers associated with atherogenesis are higher in these subjects and FH also independently predict biomarkers of endothelial activation and oxidative stress. Furthermore, despite not fulfilling the diagnostic criteria for FH, related unaffected family members that may not phenotypically express the mutation may still be at risk of developing CAD as reflected from the enhanced inflammatory and endothelial activation status observed in this group. This highlights the need to not only conduct family tracing in indexed FH cases, but also assess the coronary risk among family members that do not fulfil the FH diagnostic criteria.

Oxidative burden in familial hypercholesterolemia

“…An association between 8-epi PGF 2α excretion and serum cholesterol levels was observed in FH. Accordingly, plasma Badrnya et al (2014) Relation between OS and CRP ↑ CRP in FH and ↓antioxidant defense capacity of the glutathione system Ho et al (2013) Markers of OS in FH ↑ MDA, DNA damage and carotid wall thickness Boroushaki et al (2014); Rahman et al (2017) OxLDL and S1P ↓ S1P content and its beneficial effects on HDL action Frias et al (2017) OxLDL and inflammatory response (MVs production)…”

Molecular mechanisms and genetic regulation in atherosclerosis

“…(LOX-1), stimulating PI3K/Akt which phosphorylate IκB-NF-κB complex to allow NF-κB's translocation to the nucleus. In the nucleus NF-κB stimulate the secretion of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6 transcription, adhesion molecules expression to allow the adhesion of monocyte/macrophage contributing to AS plaque formation [ [21] , [22] , [23] ]. Sirtuin (Sirt) proteins, on the other hand, induce vasorelaxation by enhancing the expression of vasodilation agents such as endothelial nitric oxide synthetase (eNOS) and Akt phosphorylation to inhibit NF-κB mediated inflammatory pathway and secretion of vasoconstriction proteins.…”

Evaluation of Cardiovascular Risk Factors in Patients With Familial Hypercholesterolemia From the North-Eastern Area of Romania

“…Atherosclerosis is a complex multifactorial disorder, consisting in chronic in ammatory response, which causes plaque formation in the intima and media of medium and large arteries (1). Atherosclerosis can affect the vessels throughout the life of an individual, several risk factors being signi cant contributors to the atherosclerotic plaques formation: dyslipidemia, diabetes mellitus, high blood pressure (1).…”