Francesca Abello

The Type of LDLR Gene Mutation Predicts Cardiovascular Risk in Children with Familial Hypercholesterolemia

OBJECTIVE To ascertain whether the molecular characterization of a defect in the low-density lipoprotein (LDL) receptor gene (LDLR) in children with heterozygous familial hypercholesterolemia (heFH) identifies subjects at greater risk of developing premature coronary artery disease (pCAD) later in life. STUDY DESIGN We investigated 264 children with heFH from 201 families, along with 148 affected parents and 100 unaffected siblings. The lipid profile was assessed before any treatment was provided, and genotype analysis was performed to characterize LDLR defects. In a subgroup of children with heFH and controls, we measured aorta and carotid intima-media thickness (aIMT and cIMT). The prevalence of pCAD in parents and/or grandparents with heFH was recorded. RESULTS The children with heFH with a family history of pCAD had higher LDL cholesterol and apolipoprotein B levels and greater aIMT and cIMT than those with negative family history. Compared with carriers of LDLR-defective mutations, carriers of LDLR-negative mutations had a more severe phenotype, in terms of plasma lipid levels and IMT, and a higher prevalence of pCAD in first-degree relatives (36% vs 6.7%; P < .001). CONCLUSIONS The study of heFH in children, in which other risk factors for CAD play a minor role, allows early identification of those at increased risk for developing pCAD, who merit more stringent clinical control and early pharmacologic treatment.

Endothelial activation, inflammation and premature atherosclerosis in children with familial dyslipidemia.

OBJECTIVES Prospective studies demonstrated an increased cardiovascular risk in subjects with high levels of either the endothelial-platelet activation marker P-selectin or high-sensitivity C-reactive protein (hs-CRP). Both children with heterozygous familial hypercholesterolemia (FH) and those with familial combined hyperlipidemia (FCHL) are prone to premature atherosclerosis. Our objective was to investigate in children with either FH or FCHL whether P-selectin and hs-CRP contribute to carotid intima-media thickness (IMT), along with increased plasma lipid levels. METHODS Carotid IMT, serum lipids and soluble P-selectin and hs-CRP levels were measured in 88 children (mean age 10.5+/-4.3 years) including 44 dyslipidemic children (25 with FH and 19 with FCHL) and 44 non-dyslipidemic controls. RESULTS Carotid IMT was significantly higher among dyslipidemic than in control children (0.46+/-0.06mm vs 0.43+/-0.06mm, p=0.003) and serum P-selectin levels as well [129(50-254)ng/mL vs 50(24.5-130)ng/mL, p<0.001]. FH but not FCHL children had higher hs-CRP levels than controls [0.7(0.01-6.9)mg/L vs 0.3(0.1-1.2)mg/L, p=0.006]. In the entire sample of dyslipidemic children, carotid IMT was positively associated with soluble P-selectin levels (rho=0.30, p=0.049), but not with hs-CRP. The association between P-selectin and carotid IMT was independent from confounders, including plasma lipid levels. CONCLUSION Endothelial-platelet activation, more than low-grade systemic inflammation, correlates with premature atherosclerosis among children with familial dyslipidemia, this association being independent from plasma lipid levels.

The treatment of hypercholesterolemic children: Efficacy and safety of a combination of red yeast rice extract and policosanols☆

BACKGROUND AND AIMS The prevention of cardiovascular risk, as occurs in lipoprotein disorders, is required since childhood. Aim of the study was to evaluate, in a group of children affected by primary dyslipidemia, the efficacy, tolerability and safety of a short-term treatment with a dietary supplement containing red yeast rice extract and policosanols. METHODS AND RESULTS 40 children affected by heterozygous Familial Hypercholesterolemia (FH) (n=24) and Familial Combined Hyperlipidemia (FCH) (n=16), aged 8-16 years, were enrolled in a double-blind, randomized, placebo-controlled, cross-over trial. After a 4-week run-in period with only dietary advice, children received a dietary supplement containing 200mg red yeast rice extract, corresponding to 3mg of monacolins, and 10mg policosanols once-daily and placebo for 8 weeks, separated by a 4-week washout period. Lipid profile was assessed after each treatment period. The dietary supplement, compared with the placebo, significantly reduced total cholesterol by 18.5% (p<0.001), LDL-C levels by 25.1% (p<0.001), and apolipoprotein B by 25.3% (p<0.001) when patients were considered as a whole group. Similar results were obtained when FH and FCH were considered separately and no significant difference between groups was detected. No significant differences were observed in HDL-C and apolipoprotein A-I levels. No adverse effects were detected when liver and muscular enzymes (AST, ALT, and CK) were determined. CONCLUSIONS The treatment with a dietary supplement containing red yeast rice extract and policosanols has been for the first time successfully employed in hypercholesterolemic children. Results indicate this strategy as an effective, safe and well tolerated in a short-term trial.

Impact of nutrition since early life on cardiovascular prevention

The cardiovascular disease represents the leading cause of morbidity and mortality in Western countries and it is related to the atherosclerotic process. Cardiovascular disease risk factors, such as dyslipidemia, hypertension, insulin resistance, obesity, accelerate the atherosclerotic process which begins in childhood and progresses throughout the life span. The cardiovascular disease risk factor detection and management through prevention delays the atherosclerotic progression towards clinical cardiovascular disease. Dietary habits, from prenatal nutrition, breastfeeding, complementary feeding to childhood and adolescence nutrition play a basic role for this topic.The metabolic and neuroendocrine environment of the fetus is fundamental in the body’s “metabolic programming”. Further several studies have demonstrated the beneficial effects of breastfeeding on cardiovascular risk factors reduction. Moreover the introduction of complementary foods represents another important step, with particular regard to protein intake. An adequate distribution between macronutrients (lipids, proteins and carbohydrates) is required for correct growth development from infancy throughout adolescence and for prevention of several cardiovascular disease risk determinants in adulthood.The purpose of this review is to examine the impact of nutrition since early life on disease.La malattia cardiovascolare rappresenta la principale causa di morbilità e mortalità dei paesi occidentali ed è correlata a degenerazione vascolare aterosclerotica. I fattori di rischio cardiovascolari quali dislipidemia, ipertensione, insulino resistenza e obesità accelerano tale processo il cui esordio è noto sin dell’età pediatrica ed evolve nel corso della vita. L’individuazione e la cura dei fattori di rischio cardiovascolari mediante la prevenzione dei fattori causali ritardano la progressione dell’aterosclerosi e l’insorgenza dei sintomi cardiovascolari. La nutrizione svolge un ruolo preventivo fondamentale sin dall’epoca prenatale e nelle diverse età della crescita.La condizione metabolica e neuro-endocrino cui è sottoposto il feto è rilevante per la “programmazione metabolica”. E’ dimostrata inoltre l’importanza delle modalità di allattamento e divezzamento con particolare interesse per l’assunzione di proteine nel controllo dei fattori di rischio cardiovascolari. La corretta distribuzione di macronutrienti (lipidi, proteine e carboidrati) dall’infanzia all’adolescenza favorisce una crescita corretta e risulta utile a prevenire l’insorgenza dei determinanti di rischio di malattia cardiovascolare in età adulta.Nella presente review verrà esaminato l’impatto della nutrizione dalle più precoci fasi delle vita sul rischio cardiovascolare.

Lipoprotein(a) and family history of cardiovascular disease in children with familial dyslipidemias.

OBJECTIVE To investigate in children and adolescents with familial dyslipidemias the association between lipoprotein(a) [Lp(a)] level and family history of cardiovascular disease (CVD), and whether this association is independent of the disturbed lipid profile. STUDY DESIGN Lp(a) level, lipid profile, and a 2-generation genealogic tree to detect cardiovascular events were evaluated in 231 patients with familial dyslipidemias. Lp(a) levels were stratified according to presence, age of occurrence, and number and type of cardiovascular events in the patients kindreds. RESULTS Lp(a) and other plasma lipid fractions did not differ between patients with and those without a family history of cardiovascular events. However, the percentage of patients with elevated Lp(a) level (≥85th percentile) was higher in those with a positive family history for early cardiovascular events (P = .01). Lp(a) level was a significant independent predictor of the number of premature cardiovascular events (β = 0.17; P = .01) and of cerebrovascular events in kindreds (OR, 2.5; 95% CI, 1.05-6.03; P = .039), independent of plasma lipid fractions and other cardiovascular risk factors. CONCLUSIONS In children and adolescents with familial dyslipidemias, the overall association between Lp(a) level and family history of early CVD may be due to a threshold effect in those with the highest Lp(a) levels. However, multiple cardiovascular events and cerebrovascular events are predicted by any increase in plasma Lp(a) level, independent of other cardiovascular risk factors.