Endothelial activation, inflammation and premature atherosclerosis in children with familial dyslipidemia
Introduction
Children with heterozygous familial hypercholesterolemia (FH) are prone to premature atherosclerosis development and progression, although broad variation occurs in both time of onset and severity of the atherosclerotic disease [1]. Also, children with the phenotype of familial combined hyperlipidemia (FCHL) develop early in their life endothelial dysfunction that is improved by antioxidant vitamins C and E [2].
Abnormal cholesterol levels certainly contribute to premature atherosclerosis and cardiovascular events in these dyslipidemic individuals [3], being evidence that cholesterol plays a direct causal role in atherogenesis strongly supported by a large body of experimental, epidemiological and clinical studies [4], [5]. High plasma cholesterol levels also enhance the expression of cellular adhesion molecules, proinflammatory genes and cytokines, thus promoting a low-grade systemic inflammatory status [6], [7] which in turn exposes hypercholesterolemic patients to an additive risk for cardiovascular events [8].
Endothelial activation and dysfunction are currently considered in the early stage in the pathogenesis of atherosclerosis, anticipating the formation of structural atherosclerotic changes [8], [9]. Binding of circulating leukocytes to the vascular endothelium by their interaction with cell adhesion molecules, like P-selectin, is considered a crucial step leading to the initial recruitment of leukocytes into the vascular wall, low-grade systemic inflammation and atherogenesis [8], [9], [10], [11], [12], [13]. Prospective epidemiological studies have demonstrated an increased vascular risk in individuals with increased P-selectin levels [14], [15], [16]. In addition, high plasma hs-CRP levels are able to predict an increased risk of cardiovascular events in different clinical settings [17], [18], although the relationship between plasma hs-CRP and carotid IMT remains controversial [19], [20]. Thus, the presence of increased plasma P-selectin and hs-CRP levels, along with abnormal lipid concentrations, might contribute to the risk of early atherosclerosis development and future cardiovascular risk in children with familial dyslipidemias.
Carotid IMT is a reliable measure of early atherosclerosis and cardiovascular risk [21]; among dyslipidemic patients measurement of carotid IMT increases the power of traditional risk factors to predict cardiovascular events [22].
Children with FH have impaired endothelial function and increased arterial IMT [23], [24]. Also, increased plasma hs-CRP levels have been found in children with FH [25]. Although there is enough evidence of an increased carotid IMT in adults with FCHL [26], [27], such data in children with FCHL are still lacking. Moreover, while the relationship between markers of endothelial-platelet activation, systemic inflammation and carotid IMT has been demonstrated in adults [16], [20], the same associations in the setting of familial dyslipidemic children have not been explored so far.
Hence, the aim of our research was to investigate in children with either FH or FCHL the relationship between soluble P-selectin, hs-CRP and carotid IMT.
Section snippets
Patients
Forty-four children with familial dyslipidemias (25 with FH and 19 with FCHL) attending our Pediatric Lipid Clinic were recruited for the study. Diagnosis of FH was defined according to the presence of LDL cholesterol levels above the 95th age- and sex-specific percentile and normal plasma triglycerides below the 75th age- and sex-specific percentile and at least one parent with type IIA phenotype and/or premature coronary artery disease (CAD) and/or xanthomata. Diagnosis of FH was further
Results
Baseline characteristics of the study participants (n.88, mean age 10.5 ± 4.3 years) are summarized in Table 1. Family history for CAD was positive in 84% and 79% FH and FCHL patients, respectively. Carotid IMT was higher in dyslipidemic than in control children (0.46 ± 0.06 mm vs 0.43 ± 0.06 mm, p = 0.003) (Table 1); particularly, carotid IMT was highest among FH children (0.47 ± 0.07 mm), intermediate among FCHL children (0.45 ± 0.03 mm) and lowest among normolipidemic controls (0.43 ± 0.06 mm). Fig. 1
Discussion
Subclinical inflammation and endothelial activation have been frequently observed in adults with non-familial dyslipidemias [29], [30]. Among dyslipidemic adults hs-CRP and P-selectin, two prototypic markers of low-grade systemic inflammation and endothelial-platelet activation respectively, have been associated with carotid atherosclerosis [16], [20], [31]. Also, increased plasma hs-CRP levels have been found in children with FH [25]. Hence, current evidence suggests that inflammation and
Conflict of interest
All authors have no conflicts of interest.
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