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Highlighted articles November

Volume 278 Issue November 2018

By Simona Negrini and Arnold von Eckardstein (Editor–in-Chief).

Assessment of cardiovascular risk factors is playing a key role in the prevention of atherosclerotic cardiovascular diseases. Traditionally, the presence and extent of risk factors are recorded. Exposure over time is increasingly appreciated as an important factor. In this regard, cardiovascular risk assessment in children and adolescents is getting more and more attention. This issue of Atherosclerosis contains several articles describing risk factors and preclinical manifestations of ASCVD in children and adolescents as well as strategies for early detection.

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Highlighted articles

Sex-specific trajectories of measures of cardiovascular health during childhood and adolescence: A prospective cohort study

Cardiovascular disease (CVD) is a leading cause of death worldwide and its prevalence continues to increase globally. Sex differences in measures of cardiovascular health in adults are well documented. Women and men do not experience cardiometabolic diseases (CVD and type 2 diabetes mellitus (T2DM)) equally. For instance, at the age of 40 years, the remaining lifetime risk of CVD is one in two for women and two in three for men. However, the sex-specific aetiology of cardiovascular health across childhood and adolescence is poorly understood. O’ Keeffe et al. examined sex differences in trajectories of 11 measures of cardiovascular health from birth to 18 years, in a contemporary birth cohort study in England.

Outcomes were measured over varying time spans from birth or mid-childhood to age 18 and with different numbers of repeated measures per outcome. Analyses were performed using fractional polynomial and linear spline multilevel models.
Females had higher mean BMI, height-adjusted fat mass, pulse rate, insulin, triglycerides, and non-high-density lipoprotein cholesterol (HDL-c) and lower mean height-adjusted lean mass from birth or from mid-childhood to age 18. Females had lower levels of glucose from mid-childhood and developed lower systolic blood pressure and higher HDL-c from mid-adolescence onward.

Sex differences in measures of cardiovascular health are apparent from birth or mid-childhood and change during early life. These differences may have implications for sex-specific disease risk in future adult populations


Reference values for cardiometabolic risk scores in children and adolescents: Suggesting a common standard

International reference values for cardiometabolic risk variables, to allow for standardization of continuous risk scores in children, are not currently available. Such standards are needed to identify prevalence and trends of cardiometabolic risk in children and simultaneously aid comparability among studies. Stavnsbo et al. aimed to provide international age- and gender-specific reference values for cardiometabolic risk factors in children and adolescents.

Cohorts of children sampled from different parts of Europe (North, South, Mid and Eastern) and from the United States were pooled. In total, 22,479 subjects, aged 6–18 years were included in the study. Linear mixed-model regression analysis was used to analyze the associations between age and each cardiometabolic risk factor.

Reference values for 14 of the most commonly used cardiometabolic risk variables in clustered risk scores were calculated and presented by age and gender: systolic blood pressure, diastolic blood pressure, waist circumference, body mass index, sum of 4 skinfolds, triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, TC:HDL-C ratio, glucose, insulin, homeostatic model assessment-score, and cardiorespiratory fitness.

This study suggests a common standard to define cardiometabolic risk in children. Adapting this approach makes single risk factors and clustered cardiometabolic disease risk scores comparable to the reference material and to cardiometabolic risk values in studies using the same strategy. This unified approach increases the prospect to estimate and compare prevalence and trends of cardiometabolic risk in children when using continuous cardiometabolic risk scores.

Effects of a cluster-randomized school-based prevention program on physical activity and microvascular function (JuvenTUM 3)

Physical inactivity plays a key role in the development of obesity-related atherosclerotic cardiovascular disease and may represent an important link between obesity, inflammation, insulin resistance and early atherosclerosis in adults. However, only few studies have assessed these associations in children.

The retinal microcirculation offers the opportunity to examine, non-invasively, the effects of physical inactivity or obesity on small brain vessels. In adults, obesity has been associated with a wider retinal venular diameter and a lower arteriolar-to-venular diameter ratio (AVR). Similar to these findings, childhood obesity correlates with retinal venular dilatation and lower AVR, and increased blood pressure is linked to retinal arteriolar narrowing. No study to date has examined the effects of a school-based lifestyle intervention program on obesity, inflammation and microcirculation assessing retinal vessel diameters in children. In this study, Siegrist et al. investigated the impact of school-based lifestyle intervention program JuvenTUM 3 on physical activity, physical fitness, serum biomarkers and microvascular function.

The authors studied 434 children in a cluster-randomized setting over 18 months. The school-based prevention program included weekly lifestyle lessons for children with the aim to increase physical activity in and outside of school, physical fitness and health behavior. Anthropometric measurements and blood sampling were conducted using standard protocols: physical activity was assessed with a questionnaire and physical fitness with a 6-item-test battery. Central retinal arteriolar (CRAE) and venular (CRVE) vessel diameters, as early marker of vascular dysfunction, and the arteriolar-to-venular diameter ratio (AVR) were measured with a non-mydriatic vessel analyser.

School-based physical activity increased in 41% of the children from the intervention schools compared to 19% in controls. Improvements in vascular parameters were observed for AVR and CRVE, also in overweight children.

The school-based prevention program JuvenTUM 3 increased physical activity at school inducing favorable effects on retinal microvasculature function. These findings underline the importance of early lifestyle interventions in children for primary prevention of cardiovascular disease.

Serum non-cholesterol sterols and cholesterol metabolism in childhood and adolescence

Cholesterol is an essential lipid for development and growth, but it also plays an important role in the development of early atherosclerotic lesions already during childhood. Since there is no information on cholesterol metabolism in children from birth to adolescence, Gylling at al. evaluated biomarkers of cholesterol adsorption and cholesterol synthesis in healthy children and adolescents.

The study population consisted of 96 children divided into age groups: <1, 1–5, 6–10, and 11–15 years. Precursors of cholesterol and plant sterols were measured by with gas-liquid chromatography as biomarkers of cholesterol synthesis and absorption, respectively.

Serum non-cholesterol sterol ratios to cholesterol did not differ between genders. Cholesterol precursors squalene, cholestenol, and desmosterol were higher in the <1 year age group compared to the older- age groups, while lathosterol was highest in the 11–15 year old age group. Plant sterols were low in the age group <1 year, after which they did not differ among groups. Cholestanol was not age-dependent. From the age of 1 year, cholesterol homeostasis was intact. Cholesterol absorption prevailed cholesterol synthesis from 1 to 10 years of age.

The results show that serum non-cholesterol sterols have different individual profiles by age in childhood and adolescence. From 1 to 10 years of age, cholesterol absorption prevails cholesterol synthesis. This finding emphasizes the importance of a healthy diet from early childhood.

Detecting familial hypercholesterolemia earlier in life by actively searching for affected children: The DECOPIN project

In Europe, it is estimated that approximately 4.5 million individuals are affected by familial hypercholesterolemia (FH), of whom 20–25% are children and adolescents. Of those, less than 10% are diagnosed. FH is underdiagnosed, and generally detected late in adults, precluding any early management of lifestyle education during childhood or early pharmacological therapy. As such, detection of FH in children remains a major challenge and it is of primary importance to implement strategies for screening methods in this population. Ibarretxe et al. assessed a combination of two methods: the first aimed to detect hypercholesteraemic children and then study the parents (Children-to-parent pathway- Ch-P), and the second one aimed to study the offspring of FH-affected parents (Parent-to-Child pathway, P-Ch).

In the Ch-P path, primary care paediatricians were asked to include lipid profiling, or total cholesterol (TC) and then lipid profiling, in any clinically indicated blood test, if TC was higher than 5.2 mmol/L. Children with low-density lipoprotein cholesterol (LDL-C) ≥ 3.5 mmol/L, plus either a family history of early cardiovascular disease or one parent with severe hypercholesterolemia, were referred to the lipid unit where the parents, rather than their children, were studied. In parents with definite, clinical FH, a genetic study was performed. Focused genetic testing was performed on all offspring of genetically positive parents. The P-Ch path consisted of the active study of children from definite FH adults.
Fifty-nine paediatricians covering a total population of 63,616 children agreed to participate in the project. Of the 216 children who were ultimately referred to the lipid unit, 87 children with FH were identified. Additionally, 41 parents were newly diagnosed with FH. Forty-nine different mutations were detected: 46 in LDLR, 2 in PCSK9 and 1 in APOB gene.

The implementation of active strategies to detect FH in children, in close collaboration with primary care paediatricians, provides a high-performance method for early FH detection.


Screening for lysosomal acid lipase deficiency: A retrospective data mining study and evaluation of screening criteria

Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive lysosomal storage disorder caused by mutations of the LIPA gene. The mutations cause impairment of lysosomal acid lipase enzyme activity which leads to the lysosomal accumulation of cholesteryl esters and triglycerides in cells of several organs, particularly in the liver, spleen, adrenal glands and gut. In severe cases, it can cause life-threatening organ failure due to lipid substrates accumulation. Mild phenotypes are also observed. Draijer et al. aimed to determine the number of missed LAL-D patients in a large pediatric hospital population.

In a retrospective data mining study, the medical files of children with high plasma low density lipoprotein cholesterol (LDL-C) levels, who visited the outpatient clinic at a university hospital between 2000 and 2016, were evaluated. Previously developed LAL-D screening criteria, with lipid and alanine aminotransferase (ALT) values adjusted for children, were used to detect children suspicious of having LAL-D. For suspicion of LAL-D, at least 3 of 5 screening criteria had to be met. Subsequently, data on presentation and follow-up were collected to determine if the clinical picture was compatible with LAL-D.

The authors identified 2037 children with high LDL-C levels. Of those, 36 children complied with ≥3 screening criteria. Only one of them was affected with true LAL-D.
This study shows that retrospective data mining is unlikely to yield a significant number of LAL-D cases in children. The screening algorithm adjusted for children seems useful and accurate in the selection of children for further testing, suggesting that it can be applied prospectively. However, further validation is warranted.


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