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

Abstract

Background: Familial 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.

Methods: One 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.

Results: hsCRP 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).

Conclusion: The 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.

Keywords: Coronary artery disease; Endothelial activation; Familial hypercholesterolaemia; Inflammation; Oxidative stress.

Fig. 1

Graph of mean concentration of hsCRP in three different groups. Data were expressed as mean ± SEM. FH and RUC groups were higher in hsCRP concentration compared to NC. ## indicated p < 0.001 and # p < 0.05 compared to NC; FH: Familial Hypercholesterolaemia; RUC: Related unaffected controls; NC: normolipaemic subjects

Fig. 2

Graph of mean concentration of sICAM-1 in three different groups. Data were expressed as mean ± SEM. FH and RUC groups were higher in sICAM-1 concentration compared to NC. ## indicated p < 0.001 and # p < 0.01 compared to NC; FH: Familial Hypercholesterolaemia; RUC: Related unaffected controls; NC: normolipaemic subjects

Fig. 3

Graph of mean concentration of E-selectin in three different groups. Data were expressed as mean ± SEM. FH group was higher in E-selectin concentration compared to NC. # indicated p < 0.001 compared to NC; FH: Familial Hypercholesterolaemia; RUC: Related unaffected controls; NC: normolipaemic subjects

Fig. 4

Graph of mean concentration of Ox-LDL in three different groups. Data were expressed as mean ± SEM. FH group was higher in Ox-LDL concentration compared to NC # indicated p < 0.001 compared to NC; FH: Familial Hypercholesterolaemia; RUC: Related unaffected controls; NC: normolipaemic subjects.

Fig. 5

Graph of mean concentration of MDA in three different groups. Data were expressed as mean ± SEM. FH and RUC groups were higher in MDA concentration compared to NC. # indicated p < 0.001 compared to NC; FH: Familial Hypercholesterolaemia; RUC: Related unaffected controls; NC: normolipaemic subjects

Fig. 6

Graph of mean concentration of ISP in two different groups. Data were expressed as mean ± SEM. FH group was higher in ISP concentration compared to NC. # indicated p < 0.001 compared to NC; FH: Familial Hypercholesterolaemia; RUC: Related unaffected controls; NC: normolipaemic subjects