Nailfold capillaroscopy reveals early peripheral microcirculation abnormalities in children affected by heterozygous familial hypercholesterolemia.

BACKGROUND: nailfold capillaroscopy (NCF) is a non-invasive imaging technique to seek peripheral microcirculation abnormalities in children and adults. Familial hypercholesterolemia is a genetic disorder caused by mutations capable of increasing blood levels of low-density lipoproteins cholesterol (LDL-C), thus triggering early atherosclerosis. The study aims at evaluating peripheral microcirculation in children with heterozygous familial hypercholesterolemia (HeFH) by means of NFC in comparison with healthy peers and at searching for possible correlations between these abnormalities and patients' lipid panel. METHODS: thirty-six HeFH patients were enrolled (13 males and 23 females. Mean age 8 ± 3 years; age range 3-13 years). They had increased levels of total cholesterol (237.9 ± 34.2 mg/dl) and LDL-C (154.2 ± 37.6 mg/dl). Both values were ≥95th gender and age specific centile. All the subjects in the study underwent NFC. RESULTS: In 69.4 % of HeFH children nailfold capillaries were tortuous (p < 0.00001 compared to healthy controls). In 41.6 % the number of capillaries was markedly reduced (<7 capillaries/mm). The mean number of capillaries was 8.4 ± 2.6/mm in HeFH and 12.2 ± 1.4/mm in healthy controls (p < 0.00001). In 100 % of the sample size capillary blood flow was slowed down (p < 0.00001). In 50 % of the sample size a blood "sludge" phenomenon was seen (p < 0.00001). No gender differences were detected. Sludge phenomenon was seen only in those with LDL-C over 99th centile (p < 0.00001). CONCLUSION: NCF allows the identification of an early peripheral microvascular dysfunction in HeFH children which is similar to that already seen in atherosclerotic disease. Prompt identification of these capillary abnormalities may be crucial in implementing early prevention measures.

Lifestyle and awareness of cholesterol blood levels among 29159 community school children in Italy.

BACKGROUND AND AIM: Lifestyle habits including indoor and outdoor activities among community school children, adherence to the Mediterranean diet and awareness about total cholesterol blood levels represent determinant factors in cardiovascular disease (CVD) prevention. The aim of this study was to analyze the relationship between adherence to the Mediterranean diet, total cholesterol blood levels, body composition and hours per day spent in in-house or outdoor among 29,159 Italian 6-14 years-old community school children (50% boys). The KidMed questionnaire, modified to handle missing information on olive oil consumption, was used to assess the adherence to the Mediterranean diet among participants. METHODS AND RESULTS: Associations between variables were tested according to 3 classes of the Mediterranean diet adherence score using analysis of variance. Participants with high adherence to Mediterranean diet were few (1%). Overall awareness of total cholesterol blood levels was low among children (4.5%), slightly higher among parents (26.2 and 24.1% in mothers and fathers, respectively). Among Mediterranean diet adherent children, BMI was significantly (p < 0.001) smaller than among the non-Mediterranean or intermediate adherent children as were the total hours spent per day watching television or playing with videogames (p < 0.001) whereas the hours/day in sport or outdoor activities were more (p < 0.001). These results were confirmed by multiple linear regression with KidMed scored 0 to 8 as dependent variable. CONCLUSION: Although awareness of total cholesterol blood levels and adherence to the Mediterranean diet are rare among community school children, only among these a healthier lifestyle was practiced with a tendency to lower CVD risks. These results are important as the first sized experience of this type in Italy.

Analysis of Children and Adolescents with Familial Hypercholesterolemia.

OBJECTIVE: To evaluate the effectiveness of criteria based on child-parent assessment in predicting familial hypercholesterolemia (FH)-causative mutations in unselected children with hypercholesterolemia. STUDY DESIGN: LDLR, APOB, and PCSK9 genes were sequenced in 78 children and adolescents (mean age 8.4 ± 3.7 years) with clinically diagnosed FH. The presence of polygenic hypercholesterolemia was further evaluated by genotyping 6 low-density lipoprotein cholesterol (LDL-C)-raising single-nucleotide polymorphisms. RESULTS: Thirty-nine children (50.0%) were found to carry LDLR mutant alleles but none with APOB or PCSK9 mutant alleles. Overall, 27 different LDLR mutations were identified, and 2 were novel. Children carrying mutations showed higher LDL-C (215.2 ± 52.7 mg/dL vs 181.0 ± 44.6 mg/dL, P <.001) and apolipoprotein B levels (131.6 ± 38.3 mg/dL vs 100.3 ± 30.0 mg/dL, P <.004), compared with noncarriers. A LDL-C of ~190 mg/dL was the optimal value to discriminate children with and without LDLR mutations. When different diagnostic criteria were compared, those proposed by the European Atherosclerosis Society showed a reasonable balance between sensitivity and specificity in the identification of LDLR mutations. In children without mutation, the FH phenotype was not caused by the aggregation of LDL-C raising single-nucleotide polymorphisms. CONCLUSIONS: In unselected children with hypercholesterolemia, LDL-C levels >190 mg/dL and a positive family history of hypercholesterolemia appeared to be the most reliable criteria for detecting FH. As 50% of children with suspected FH did not carry FH-causing mutations, genetic testing should be considered.

Circulating miR-200c is up-regulated in paediatric patients with familial hypercholesterolaemia and correlates with miR-33a/b levels: implication of a ZEB1-dependent mechanism.

Hypercholesterolaemia provokes reactive oxygen species (ROS) increase and is a major risk factor for cardiovascular disease (CVD) development. We previously showed that circulating miR-33a/b expression levels were up-regulated in children with familial hypercholesterolaemia (FH). miR-33a/b control cholesterol homoeostasis and recently miR-33b has been demonstrated to directly target the transcription factor zinc finger E-box-binding homeobox 1 (ZEB1). The latter acts in a negative feedback loop with the miR-200 family. Our previous studies showed that the ROS-dependent miR-200c up-regulation induces endothelial dysfunction and provokes a ZEB1-dependent apoptosis and senescence. In the present study, we aimed to verify whether circulating miR-200c was induced in FH children, and whether a correlation existed with miR-33a/b Total RNA was extracted from plasma of 28 FH children and 25 age-matched healthy subjects (HS) and miR-200c levels were measured. We found that miR-200c was up-regulated in FH compared with HS (4.00 ± 0.48-fold increase, P<0.05) and exhibited a positive correlation with miR-33a/b. miR-200c did not correlate with plasma lipids, but correlated with C-reactive protein (CRP) plasma levels and glycaemia (GLI). Ordinary least squares (OLS) regression analysis revealed that miR-200c was significantly affected by GLI and by miR-33a (P<0.01; P<0.001 respectively). Moreover, we found that miR-33 overexpression, in different cell lines, decreased ZEB1 expression and up-regulated both the intracellular and the extracellular miR-200c expression levels. In conclusion, circulating miR-200c is up-regulated in FH, probably due to oxidative stress and inflammation and via a miR-33a/b-ZEB1-dependent mechanism. The present study could provide the first evidence to point to the use of miR-33a/b and miR-200c, as early biomarkers of CVD, in paediatric FH.

Circulating miR-33a and miR-33b are up-regulated in familial hypercholesterolaemia in paediatric age.

Hypercholesterolaemia is one of the major causes of CVD (cardiovascular disease). It is associated with enhanced oxidative stress, leading to increased lipid peroxidation which in turn determines endothelial dysfunction and susceptibility to coronary vasoconstriction and atherosclerosis. Different miRNAs are involved in the pathogenesis of CVD and play an important role in inflammatory process control, therefore, together with atherogenic factors, they can stimulate atherosclerotic degeneration of the vessel walls of arteries. miR-33a and miR-33b play a pivotal role in a variety of biological processes including cholesterol homoeostasis, HDL (high-density lipoprotein)-cholesterol formation, fatty acid oxidation and insulin signalling. Our study aimed to determine whether circulating miR-33a and miR-33b expression was altered in familial hypercholesterolaemic children. Total RNA was extracted from plasma, and miR-33a and miR-33b were measured by quantitative real-time PCR. We found that miR-33a and miR-33b were significantly up-regulated in the plasma of 28 hypercholesterolaemic children compared with 25 healthy subjects (4.49±0.27-fold increase, P<0.001, and 3.21±0.39-fold increase, P<0.05 respectively), and for both miRNAs, a positive correlation with total cholesterol, LDL (low-density lipoprotein)-cholesterol, LDL-cholesterol/HDL-cholesterol ratio, apolipoprotein B, CRP (C-reactive protein) and glycaemia was found. OLS (ordinary least squares) regression analysis revealed that miR-33a was significantly affected by the presence of FH (familial hypercholesterolaemia), glycaemia and CRP (P<0.001, P<0.05 and P<0.05 respectively). The same analysis showed that miR-33b was significantly related to FH and CRP (P<0.05 and P<0.05 respectively). Although it is only explorative, the present study could be the first to point to the use of miR-33a and miR-33b as early biomarkers for cholesterol levels in childhood, once validated in independent larger cohorts.

Anthropometric indices are not satisfactory predictors of metabolic comorbidities in obese children and adolescents.

OBJECTIVE: To assess the accuracy of body mass index (BMI), Z score of the BMI, waist circumference, and waist-to-height ratio in selecting obese children with fasting metabolic impairments or impaired glucose tolerance. STUDY DESIGN: In a cohort of 883 obese children and adolescents (age 8-18 years), we assessed the associations of anthropometric indices with traditional metabolic complications of obesity (impaired fasting glucose, impaired glucose tolerance, hypertension, high triglycerides, low high-density lipoprotein-cholesterol). The accuracy of anthropometric indices as markers of metabolic impairment was assessed by receiver operating characteristic analysis and the areas under the receiver operating characteristics curves (AUROCs) of anthropometric indices were compared with each other by the DeLong test. RESULTS: BMI, Z score of the BMI, waist circumference, and waist-to-height ratio were associated with metabolic impairments but showed low to moderate accuracy in discriminating both single and clustered metabolic impairments. The AUROCs ranged from 0.55-0.70. The 4 anthropometric indices did not show significantly different AUROCs as predictors of clustered metabolic risk factors (all P values of DeLong tests: >.05). CONCLUSIONS: Commonly used anthropometric indices are not satisfactory markers of metabolic comorbidity among obese children and adolescents and should not be adopted as screening tools for the metabolic assessment of this category of patients.

Apolipoprotein B and Lipid Profile in Italian Children and Adolescents.

RATIONALE: The prevention of cardiovascular (CV) disease is mandatory from childhood onwards. Among biochemical markers related to the clinical cardiovascular outcome, LDL cholesterol (LDL-C), non-HDL-C and apolipoprotein B (ApoB) are recognized as main target parameters. Emphasis on ApoB concentrations is growing, as representative of any class of atherogenic lipoprotein. This consideration allows checking of subjects under 18 years of age when the CV risk occurs. The aim of this study is to evaluate ApoB levels in a sample of Italian hyperlipidemic children and adolescents, and their siblings, to test any relationship with their lipid profile. METHODS: A retrospective study, including 1877 children and adolescents (aged 0-18 years), was performed. Clinical and biochemical data were selected from a database, including the lipid profile, ApoB analysis and anthropometric parameters of any proband. Participants had been checked as potentially hyperlipidemia affected, the suspicion raised by familial CV risk or because the dyslipidemia was already known. Data from the first visit at the University Hospitals in Rome and Turin were collected. Patients affected by secondary hyperlipidemia or obesity were excluded. Blood test analysis was performed in fasting conditions by automated commercial kits. Participants were classified according to gender, age (stratified in subgroups: 0-5, 6-10, 11-14, and 15-18 years old) and anthropometric parameters, referred to as weight in Kg and height in cm, and BMI calculated. Lipid profile results were stratified in relation to acceptable, borderline, or increased levels, as indicated by NCEP, and any potential relation with ApoB established. Statistics were performed by Epi-Info 7 programs to evaluate the variance analysis. Either parent could sign the informed consent. RESULTS: Among the whole sample n.1010 and n.867 participants were females and males, respectively. TC values acceptable (≤170 mg/dL), borderline (171-200 mg/dL) and elevated (≥201 mg/dL) were found in 411 (22%), 585 (31%) and 881 (47%) participants, respectively. The LDL-C cut-off considered was 110 mg/dL (90° percentile). Mean ApoB progressively increased from 65 to 110 mg/dL according to TC levels and resulted in significant correlation when any age subgroup and gender was considered. The highest ApoB values, TC and LDL-C related, were found in the youngest subgroup, regardless of gender. CONCLUSION: ApoB results increase progressively and in parallel with TC and LDL-C and represent a further parameter to distinguish between normal and hyperlipidemic subjects. Serum levels are close to 70 mg/dL and to 100 mg/dL in the former and latter group, respectively.

The Association between Mid-Upper Arm Circumference and Blood Pressure in an Italian Population of School-Aged Children and Adolescents with Lipid Disorders.

Background: Many anthropometric measurements have been investigated concerning their association with blood pressure (BP) in paediatric age groups. This study aims to find a relationship between mid-upper arm circumference (MUAC) and BP in a population of children and adolescents aged 1-18 years. Methods: 5853 subjects (2977 females and 2876 males) were studied. MUAC, body mass index (BMI), and BP were measured. The individuals in the study were subdivided and grouped by gender and type of school attended in Italy: 1-5 years (pre-school), 6-10 years (primary school), 11-13 years (secondary school), 14-18 years (high school). Results: In the age range of 6-13 years, all the subjects with MUAC > 50th percentile had systolic and diastolic BP significantly higher than children with MUAC below 50th percentile (p < 0.0001). In the age range 14-18 years, the relationship persisted only in females (p < 0.001 and p < 0.05 for diastolic and systolic BP, respectively). A linear relationship was found between MUAC and BMI. Conclusions: In Italian children of both genders aged 6-13, arm distribution of body fat is strongly associated with increased systolic and diastolic BP. As such, a simple anthropometric measurement like MUAC might represent a tool to identify young subjects who are at risk for HTN.

Hypertension in children and adolescents attending a lipid clinic.

UNLABELLED: This study aims to investigate prevalence of hypertension and cardiovascular risk factor clustering in children and adolescents attending a lipid clinic as well as the relationship of their hypertensive status with indicators of fat distribution and parental fat distribution and blood pressure (BP). In this cross-sectional primary prevention study, data on indicators of fat distribution (waist, hip, and middle-upper arm circumferences), body mass index (BMI), BP, high-sensitivity C-reactive protein (hsCRP), lipid and glucose profile of 370 children and adolescents (180 M, 190 F, mean age 9.5 years, (range 6-14 years)) were collected. Parents (502, 251 M, 251 F, age range 28-36 years), who gave their informed consent, underwent BMI, fat distribution, and BP measurements. There were 131 (35.4 %) hypercholesterolemic subjects and 72 (19.5 %) hypertensives. Using tests on medians, in comparison with 298 normotensives, the 72 hypertensives had higher levels of insulin (p<0.005) and no differences in cholesterol levels, age, and height. BMI and all the indicators of fat distribution were significantly higher (all p<0.01) in hypertensives than normotensives. BMI and waist circumferences were higher (both p<0.05) in the mothers of hypertensives, but not in the fathers. Hypertensive subjects' BMI was related to mothers' hip and waist circumferences (r=0.28 and 0.21, respectively). CONCLUSIONS: In this study, children's hypertension was a component of the metabolic syndrome, but uric acid and hsCRP levels were not contributive. This hemodynamic and metabolic disorder was related to maternal fat distribution and BMI suggesting an epigenetic etiology.

Familial Hypercholesterolaemia in Children and Adolescents: Current and Future Perspectives.

Familial hypercholesterolemia (FH) is a genetic disease, the underlying cause of which is represented by mutations capable of influencing the metabolism of low-density lipoproteins (LDL). The distinguishing characteristic of FH has increased LDL cholesterol blood levels since birth, triggering early development of atherosclerosis-related diseases. Diagnosis of FH is frequently either missed or made with a considerable delay. Prompt identification of the disease is pivotal in implementing early prevention measures. Safe and effective drugs have been approved for use in children and adolescents, with statins, with or without ezetimibe, representing first-line therapy. At times, however, these medications may not be sufficient to achieve the therapeutic target, particularly in homozygous FH patients. Lipoprotein apheresis, which has proved safe and efficient, is strongly suggested in such cases. New drugs still at the investigational stage may represent a promising and personalised therapy. Lowering cholesterol levels in childhood hampers the formation of arterial atherosclerotic plaques, thus reducing cardiovascular events later in life. Accordingly, early detection, diagnosis, and therapy in FH subjects are priority aims.

Cardiovascular prevention in childhood: a consensus document of the Italian Society of Cardiology Working Group on Congenital Heart Disease and Cardiovascular Prevention in Paediatric Age.

Cardiovascular diseases (CVD) may be manifested from a very early age. Genetic and environmental (epigenetic) factors interact to affect development and give rise to an abnormal phenotypical expression of genetic information, although not eliciting changes in the nucleotide sequence of DNA. It has been scientifically proven that increased oxidative stress (OS) caused by disease (overweight, obesity, diabetes), nutritional imbalances, unhealthy lifestyles (smoking, alcohol, substance abuse) in the mother during pregnancy may induce placental dysfunction, intrauterine growth restriction, prematurity, low birth weight, postnatal adiposity rebound, metabolic alterations and consequent onset of traditional cardiovascular risk factors. OS represents the cornerstone in the onset of atherosclerosis and manifestation of CVD following an extended asymptomatic period. OS activates platelets and monocytes eliciting the release of pro-inflammatory, pro-atherogenic and pro-oxidising substances resulting in endothelial dysfunction, decrease in flow-mediated arterial dilatation and increase in carotid intima-media thickness. The prevention of CVD is defined as primordial (aimed at preventing risk factors development), primary (aimed at early identification and treatment of risk factors), secondary (aimed at reducing risk of future events in patients who have already manifested a cardiovascular event), and tertiary (aimed at limiting the complex outcome of disease). Atherosclerosis prevention should be implemented as early as possible. Appropriate screening should be carried out to identify children at high risk who are apparently healthy and implement measures including dietary and lifestyle changes, addition of nutritional supplements and, lastly, pharmacological treatment if risk profiles fail to normalise. Reinstating endothelial function during the reversible stage of atherosclerosis is crucial.

Should We Be Screening for Ischaemic Heart Disease Earlier in Childhood?

Ischaemic heart disease is the most common cause of death in males and the second in the female gender. Yet we often only focus on identification and treatment of this foremost cause of death in adulthood. The review asks the question what form of coronary disease do we encounter in childhood, what predisposing factors give rise to atherosclerosis and what strategies in childhood could we employ to detect and reduce atherosclerosis development in later life.

Long-term outcome of a patient with Transcobalamin deficiency caused by the homozygous c.1115_1116delCA mutation in TCN2 gene: a case report.

BACKGROUND: Transcobalamin deficiency is a rare autosomal recessive inborn error of cobalamin transport (prevalence: < 1/1000000) which clinically manifests in early infancy. CASE PRESENTATION: We describe the case of a 31 years old woman who at the age of 30 days presented with the classical clinical and laboratory signs of an inborn error of vitamin B12 metabolism. Family history revealed a sister who died at the age of 3 months with a similar clinical syndrome and with pancytopenia. She was started on empirical intramuscular (IM) cobalamin supplements (injections of hydroxocobalamin 1 mg/day for 1 week and then 1 mg twice a week) and several transfusions of washed and concentrated red blood cells. With these treatments a clear improvement in symptoms was observed, with the disappearance of vomiting, diarrhea and normalization of the full blood count. At 8 years of age injections were stopped for about two and a half months causing the appearance of pancytopenia. IM hydroxocobalamin was then restarted sine die. The definitive diagnosis could only be established at 29 years of age when a genetic evaluation revealed the homozygous c.1115_1116delCA mutation of TCN2 gene (p.Q373GfsX38). Currently she is healthy and she is taking 1 mg of IM hydroxocobalamin once a week. CONCLUSIONS: Our case report highlights that early detection of TC deficiency and early initiation of aggressive IM treatment is likely associated with disease control and an overall favorable outcome.

Plasma non-cholesterol sterols: a useful diagnostic tool in pediatric hypercholesterolemia.

Current guidelines strongly recommend the identification of genetic forms of hypercholesterolemia (HC) during childhood.The usefulness of non-cholesterol sterols (NCS) in the diagnosis of genetic HC has not been fully explored. Plasma NCS were measured by gas chromatography/mass spectrometry (GC/MS) in 113 children with hypercholesterolemia affected by: autosomal dominant hypercholesterolemia (ADH), familial combined hyperlipidemia(FCHL), polygenic hypercholesterolemia (PHC), and in 79 controls to evaluate: i) plasma NCS profile in different genetic HC and ii) the usefulness of NCS for the diagnosis of HC beyond current clinical criteria. ADH was characterized by raised lathosterol/total cholesterol (TC) and reduced phytosterols/TC ratios, indicative of increased cholesterol synthesis. FCHL showed a slight increase of lathosterol/TC ratio, whereas PHC showed increased phytosterols/TC ratios, indicative of increased cholesterol absorption. In a post hoc discriminant analysis of patients with HC, lipid values correctly classified the 73% (14 of 19) of ADH, whereas the inclusion of plasma sterols allowed the correct identification of all 19 patients with ADH. FCHL was not differentiated from PHC (62 versus 69%).In conclusion, NCS measurement showed that cholesterol plasma levels are related to the cholesterol synthesis in ADH and to cholesterol absorption in PHC. NCS improve the detection of ADH in pediatric patients, whereas FCHL diagnosis is not improved.

Enhanced NOX-2 derived oxidative stress in offspring of patients with early myocardial infarction.

BACKGROUND: Offspring of patients with early myocardial infarction have a higher risk to develop cardiovascular events; the underlying physiopathology is still unclear. Several lines of evidence support a role for oxidative stress in atherogenesis and NADPH oxidase-2 (NOX-2) is considered a major source of O2- in human. Furthermore, oxidative stress regulates arachidonic acid metabolism via activation of platelet phospholipase-A2. The aim of this study was to address NOX-2 activity as well as serum thromboxane B2 (TXB2) and 8-isoPGF2-alpha in offspring of patients with premature myocardial infarction. METHODS: Ninety-two consecutive subjects, including 46 offspring of patients with premature myocardial infarction and 46 healthy subjects (HS) matched for age and gender, were recruited. A cross sectional study was performed to compare serum activity of soluble NOX-2-dp (sNOX-2-dp), blood levels of isoprostanes and serum TXB2 in these two groups. RESULTS: Compared with HS, offspring of patients with early myocardial infarction had higher values of serum TxB2, isoprostanes and sNOX-2-dp. Bivariate analysis in the overall population showed that serum sNOX-2-dp levels were significantly associated with serum isoprostanes and TXB2. A multiple linear regression analysis was performed to define the independent predictors of sNOX-2-dp. Serum isoprostanes (SE: 0.07; standardized coefficient ß: 0.579; P < 0.001) and TXB2 levels (SE: 0.06; standardized coefficient ß: 0.211; P < 0.001) were significantly associated to sNOX-2-dp (R2: 0.42). CONCLUSION: This study shows that Nox-2 activation is a key determinant of oxidative stress and platelet activation in offspring of patients with premature myocardial infarction.

Mediterranean diet and physical activity impact on metabolic syndrome among children and adolescents from Southern Italy: Contribution from the Calabrian Sierras Community Study (CSCS).

OBJECTIVES: The aim of this study was to assess the impact of Mediterranean diet (MD) and physical activity on metabolic syndrome (MS) prevalence in children and adolescents. MATERIAL AND METHODS: This cross-sectional study was carried out in 863 boys and 780 girls, 6-14years old, from primary and secondary schools in a 14-town Southern Italian community. We modified the KIDMED questionnaire to adapt it to the local reality. RESULTS: Poor adherence to MD was seen in 18.4% of children and adolescents, while 81.6% had a medium-high compliance and the prevalence of MS was 6.6% and 3.7% respectively (OR: 1.8; 95% C.I.: 1.06-3.11; p=0.013). When participants had less physical activity, MS was more frequent as compared to those more active (5.3% versus 2.3%; OR: 2.3; 95% C.I.: 1.3-4.3; p=0.0068) which had a parallel counterpart when comparing those accustomed to seeing television for less or more than 5h per day and MS prevalence was 12.3% versus 3.8% (OR: 3.38; 95% C.I.: 1.66-6.86, p=0.0008), respectively. Finally, there was a specific abnormality in triglyceride levels, both in girls and boys, when participants were classified according to bad lifestyles, based on the combined evaluation of scarce adherence to MD and less extracurricular physical activity, accompanied by a 7-fold increased prevalence of MS as compared to those with the best lifestyle (11.0% versus 1.6%; p=0.025). CONCLUSIONS: There is an apparent importance of healthier lifestyle habits including physical activity and adherence to the MD also among children and adolescents.

Epigenetics and cardiovascular risk in childhood.

Cardiovascular disease (CVD) can arise at the early stages of development and growth. Genetic and environmental factors may interact resulting in epigenetic modifications with abnormal phenotypic expression of genetic information without any change in the nucleotide sequence of DNA. Maternal dietary imbalance, inadequate to meet the nutritional needs of the fetus can lead to intrauterine growth retardation, decreased gestational age, low birth weight, excessive post-natal growth and metabolic alterations, with subsequent appearance of CVD risk factors. Fetal exposure to high cholesterol, diabetes and maternal obesity is associated with increased risk and progression of atherosclerosis. Maternal smoking during pregnancy and exposure to various environmental pollutants induce epigenetic alterations of gene expression relevant to the onset or progression of CVD. In children with hypercholesterolemia and/or obesity, oxidative stress activates platelets and monocytes, which release proinflammatory and proatherogenic substances, inducing endothelial dysfunction, decreased Doppler flow-mediated dilation and increased carotid intima-media thickness. Primary prevention of atherosclerosis should be implemented early. It is necessary to identify, through screening, high-risk apparently healthy children and take care of them enforcing healthy lifestyle (mainly consisting of Mediterranean diet and physical activity), prescribing nutraceuticals and eventual medications, if required by a high-risk profile. The key issue is the restoration of endothelial function in the reversible stage of atherosclerosis. Epigenetics may provide new markers for an early identification of children at risk and thereby develop innovative therapies and specific nutritional interventions in critical times.

Metabolic syndrome among children and adolescents from Southern Italy: contribution from the Calabrian Sierras Community Study (CSCS).

Among 1657 children and adolescents aged 6 to 14 years (787, 47% girls and 870, 53% boys) from primary and secondary schools in a 14-town Southern Italian community, HDL cholesterol (54 ± 15 mg/dl), triglycerides (61 ± 29 mg/dl), blood glucose (78 ± 10 mg/dl), systolic (101 ± 11 mm Hg) and diastolic (62 ± 10 mm Hg) blood pressures, waist circumference (WC) (66 ± 10 cm) and WC/height (0.46 ± 0.006) and triglycerides/HDL cholesterol (1.31 ± 0.99) ratios were measured. The distributions were similar in both genders. Age did not affect triglycerides/HDL cholesterol ratio, whereas there was a slightly positive correlation (p<0.00001) between WC/height and triglycerides/HDL cholesterol ratios. We present individual gender and age specific percentile distributions (as Supplementary materials). Using percentile cut-offs (≤ 10th for HDL cholesterol and ≥ 90th for the other components), there were 183 (11%) children or adolescents with low HDL cholesterol, 162 (9.77%) with high triglycerides, 178 (10.74%) with high blood glucose, 178 (10.74%) with high WC, 244 (20.76%) with high systolic or diastolic BP and 126 (7.6%) with high systolic and diastolic BP. Abnormally high BP was seen in 470 (28.36%) children or adolescents. Using abnormal percentile values of 3 of 5 of its components, metabolic syndrome (MS) was diagnosed in 70 (4.2%) subjects, similarly in both genders. To assess out-of-limit distributions of all 5 individual MS components in children and adolescents gender- and age-distributions derived from local epidemiological data should be used: these distributions are presented and they might now be used both for comparative and applicative purposes at least in Southern Europe.

Early myocardial deformation changes in hypercholesterolemic and obese children and adolescents: a 2D and 3D speckle tracking echocardiography study.

Dyslipidemia and obesity are considered strong risk factors for premature atherosclerotic cardiovascular disease and increased morbidity and mortality and may have a negative impact on myocardial function.Our purpose was to assess the presence of early myocardial deformation abnormalities in dyslipidemic children free from other cardiovascular risk factors, using 2-dimensional speckle tracking echocardiography (2DSTE) and 3-dimensional speckle tracking echocardiography (3DSTE).We studied 80 consecutive nonselected patients (6-18 years of age) with hypercholesterolemia (low-density lipoprotein [LDL] cholesterol levels >95th percentile for age and sex). Forty of them had normal weight and 40 were obese (body mass index >95th percentile for age and sex). Forty healthy age-matched children were selected as controls. Left ventricular (LV) global longitudinal, circumferential, and radial strains were calculated by 2DSTE and 3DSTE. Global area strain (GAS) was calculated by 3DSTE as percentage of variation in surface area defined by the longitudinal and circumferential strain vectors. Right ventricular (RV) global and free-wall longitudinal strain and LV and RV diastolic strain rate parameters were obtained. Data analysis was performed offline.LV global longitudinal strain and GAS were lower in normal-weight and obese dyslipidemic children compared with normal controls and reduced in obese patients compared with normal-weight dyslipidemic children. LV early diastolic strain rate was lower compared with normals. RV global and free-wall longitudinal strain was significantly reduced in obese patients when compared with the control group. A significant inverse correlation was found between LV strain, LDL cholesterol levels, and body mass index.2DSTE and 3DSTE show LV longitudinal strain and GAS changes in dyslipidemic children and adolescents free from other cardiovascular risk factors or structural cardiac abnormalities. Obesity causes an additive adverse effect on LV strain parameters and RV strain impairment.