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Background: Changes in cholesterol absorption and cholesterol synthesis may promote dyslipidemia and cardiovascular disease in individuals with type 2 diabetes mellitus (T2DM)., Objective: To assess cholesterol synthesis and absorption in lean individuals, obese individuals, and individuals with T2DM., Methods: We measured lathosterol and lanosterol (markers of cholesterol synthesis) as well as campesterol and β-sitosterol (markers of cholesterol absorption) in the serum of 15 to 26 years old individuals with T2DM (n = 95), as well as their lean (n = 98) and obese (n = 92) controls., Results: Individuals with T2DM showed a 51% increase in lathosterol and a 65% increase in lanosterol compared to lean controls. Similarly, obese individuals showed a 31% increase in lathosterol compared to lean controls. Lathosterol and lanosterol were positively correlated with body mass index, fasting insulin and glucose, serum triglycerides, and C-reactive protein, and negatively correlated with HDL-cholesterol. In contrast, campesterol and β-sitosterol were not altered in individuals with T2DM. Moreover, campesterol and β-sitosterol were negatively correlated with body mass index, fasting insulin, and C-reactive protein and were positively correlated with HDL-cholesterol., Conclusions: Adolescents and young adults with T2DM show evidence of increased cholesterol synthesis compared to non-diabetic lean controls. These findings suggest that T2DM may promote cardiovascular disease by increasing cholesterol synthesis, and provide additional rationale for the use of cholesterol synthesis inhibitors in this group., (© 2020 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Background: To optimize treatment and prevent cardiovascular disease in subjects with type 1 diabetes, it is important to determine how cholesterol metabolism changes with type 1 diabetes., Objective: The objective of the study was to compare plasma levels of campesterol and β-sitosterol, markers of cholesterol absorption, as well as lathosterol, a marker of cholesterol synthesis, in youth with and without type 1 diabetes., Methods: Serum samples were obtained from adolescent subjects with type 1 diabetes (n = 175, mean age 15.2 years, mean duration of diabetes 8.2 years) and without diabetes (n = 74, mean age 15.4 years). Campesterol, β-sitosterol, and lathosterol, were measured using targeted liquid chromatography tandem mass spectrometry, compared between groups, and correlated with the available cardiometabolic variables., Results: Campesterol and β-sitosterol levels were 30% higher in subjects with type 1 diabetes and positively correlated with hemoglobin A1c levels. In contrast, lathosterol levels were 20% lower in subjects with type 1 diabetes and positively correlated with triglycerides, body mass index, and systolic blood pressure., Conclusion: Plasma markers suggest that cholesterol absorption is increased, whereas cholesterol synthesis is decreased in adolescent subjects with type 1 diabetes. Further studies to address the impact of these changes on the relative efficacy of cholesterol absorption and synthesis inhibitors in subjects with type 1 diabetes are urgently needed., (Copyright © 2019 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Importance: Favorable trends occurred in the lipid levels of US youths through 2010, but these trends may be altered by ongoing changes in the food supply, obesity prevalence, and other factors., Objective: To analyze trends in levels of lipids and apolipoprotein B in US youths during 18 years from 1999 through 2016., Design, Setting, and Participants: Serial cross-sectional analysis of US population-weighted data for youths aged 6 to 19 years from the National Health and Nutrition Examination Surveys for 1999 through 2016. Linear temporal trends were analyzed using multivariable regression models with regression coefficients (β) reported as change per 1 year., Exposures: Survey year; examined periods spanned 10 to 18 years based on data availability., Main Outcomes and Measures: Age- and race/ethnicity-adjusted mean levels of high-density lipoprotein (HDL), non-HDL, and total cholesterol. Among fasting adolescents (aged 12-19 years), mean levels of low-density lipoprotein cholesterol, geometric mean levels of triglycerides, and mean levels of apolipoprotein B. Prevalence of ideal and adverse (vs borderline) levels of lipids and apolipoprotein B per pediatric lipid guidelines., Results: In total, 26 047 youths were included (weighted mean age, 12.4 years; female, 51%). Among all youths, the adjusted mean total cholesterol level declined from 164 mg/dL (95% CI, 161 to 167 mg/dL) in 1999-2000 to 155 mg/dL (95% CI, 154 to 157 mg/dL) in 2015-2016 (β for linear trend, -0.6 mg/dL [95% CI, -0.7 to -0.4 mg/dL] per year). Adjusted mean HDL cholesterol level increased from 52.5 mg/dL (95% CI, 51.7 to 53.3 mg/dL) in 2007-2008 to 55.0 mg/dL (95% CI, 53.8 to 56.3 mg/dL) in 2015-2016 (β, 0.2 mg/dL [95% CI, 0.1 to 0.4 mg/dL] per year) and non-HDL cholesterol decreased from 108 mg/dL (95% CI, 106 to 110 mg/dL) to 100 mg/dL (95% CI, 99 to 102 mg/dL) during the same years (β, -0.9 mg/dL [95% CI, -1.2 to -0.6 mg/dL] per year). Among fasting adolescents, geometric mean levels of triglycerides declined from 78 mg/dL (95% CI, 74 to 82 mg/dL) in 1999-2000 to 63 mg/dL (95% CI, 58 to 68 mg/dL) in 2013-2014 (log-transformed β, -0.015 [95% CI, -0.020 to -0.010] per year), mean levels of low-density lipoprotein cholesterol declined from 92 mg/dL (95% CI, 89 to 95 mg/dL) to 86 mg/dL (95% CI, 83 to 90 mg/dL) during the same years (β, -0.4 mg/dL [95% CI, -0.7 to -0.2 mg/dL] per year), and mean levels of apolipoprotein B declined from 70 mg/dL (95% CI, 68 to 72 mg/dL) in 2005-2006 to 67 mg/dL (95% CI, 65 to 70 mg/dL) in 2013-2014 (β, -0.4 mg/dL [95% CI, -0.7 to -0.04 mg/dL] per year). Favorable trends were generally also observed in the prevalence of ideal and adverse levels. By the end of the study period, 51.4% (95% CI, 48.5% to 54.2%) of all youths had ideal levels for HDL, non-HDL, and total cholesterol; among adolescents, 46.8% (95% CI, 40.9% to 52.6%) had ideal levels for all lipids and apolipoprotein B, whereas 15.2% (95% CI, 13.1% to 17.3%) of children aged 6 to 11 years and 25.2% (95% CI, 22.2% to 28.2%) of adolescents aged 12 to 19 years had at least 1 adverse level., Conclusions and Relevance: Between 1999 and 2016, favorable trends were observed in levels of lipids and apolipoprotein B in US youths aged 6 to 19 years.

Purpose: Guidelines recommend cholesterol screening for all adolescents and young adults (AYAs) ages 17-21 years. Little is known about how screening results impact perceptions of AYA health., Methods: We recruited 37 AYAs and 35 parents of AYAs with differing risk for abnormal cholesterol results: (1) familial hypercholesterolemia; (2) obesity; and (3) generally healthy. Participants completed quantitative health status ratings using visual analog scales (VASs) and semistructured interviews regarding three hypothetical cholesterol screening scenarios: (1) high likelihood of cardiovascular disease (CVD) before age 40 years ("high risk"); (2) some risk of CVD before age 70 years ("moderate risk"); and (3) low risk for CVD despite a strong family history of CVD ("low risk"). We analyzed VAS data with logistic regression and qualitative data with a priori and emergent coding using multiple coders., Results: Each group perceived all three cholesterol screening scenarios as comparatively less than perfect health; the high-risk result fell furthest from perfect health. Although there was no significant difference between AYAs and parents in VAS ratings, qualitative analyses revealed AYAs were more likely than parents to discount the impact of moderate-risk results because of longer length of time before predicted CVD., Conclusions: AYAs' and parents' perceptions of the impact of cholesterol screening results on AYA health varied by presented scenario, ranging from mild to significant decreases in perceptions of AYA health. As universal cholesterol screening continues to be adopted in this age group, further studies of the real-life impact on AYA risk perceptions and subsequent behavior are warranted., (Copyright © 2016 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Lower socioeconomic status has been associated with adverse lipid levels in adult populations. Childhood dyslipidemia is a risk factor for future cardiovascular disease. However, studies examining relationships between socioeconomic indicators and lipid levels in children are limited. To examine the relationship between income level and lipid levels in childhood., Methods: We conducted a retrospective chart review of primary care patients, ages 2 to 18 years, who had lipid levels drawn at two large pediatric practices in Boston, MA between August 01, 2008 and August 31, 2010. Income level was determined using geocoding census tract data. Analysis was performed using t-test, Anova and Spearman correlation coefficients. BMI percentile, age, sex, race/ethnicity, and site were adjusted for on multivariate analyses., Results: Reviewing 930 charts of patients with measured lipid levels, 730 had a valid address, no previously diagnosed lipid disorder and met other study eligibility criteria. Mean total cholesterol level did not vary by income level (low 155.5 mg/dl ±26.9, moderate 153.5 mg/dl ±30.4, middle 155.3 mg/dl ±26.6 and high income 155.5 mg/dl ±27.9; p = .87) on multivariate analysis. Income level was not related to LDL, HDL, or triglycerides., Conclusions: In this analysis of children cared for in two urban pediatric primary practices, there was no association between income level determined by census tract and lipid levels in childhood. If confirmed in prospective investigations in other geographical locations, income level may not be a key driver of childhood lipid levels.

Pediatric cholesterol disorders are common, affecting 1 in 5 adolescents, although most are mild or moderate abnormalities. Because cholesterol values during childhood are moderately predictive of adult cholesterol levels, and are associated with atherosclerosis by pathology and by vascular testing, and because familial hyperlipidemias are associated with early cardiovascular events, cholesterol screening is recommended during childhood. Identified lipid abnormalities are an indication for lifestyle improvement and, in rare cases, pharmacotherapy. However, many gaps in the pediatric knowledge base remain about the benefits and risk, the optimal method for lipid screening, and about appropriate indications for pharmacotherapy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose of Review: Adolescence is a common time for the identification of cardiovascular disease risk factors, including elevated cholesterol. Guidelines for the detection and treatment of hypercholesterolemia differ for children and adults. This review highlights these differences and discusses special considerations for cholesterol management in the adolescent population., Recent Findings: Several longitudinal studies have confirmed that the number of cardiovascular risk factors present in adolescence, including elevated cholesterol, lead to atherosclerosis in adults. There is increased awareness that other chronic medical conditions, including diabetes, congenital heart disease, inflammatory diseases, and childhood cancer, can accelerate this process. There is a move to screen and treat more young patients with elevated cholesterol to prevent future cardiovascular disease. New markers of atherosclerosis are being used to quantify cardiovascular disease risk in adolescents in research populations. The safety and efficacy of several interventions, including drug therapy, is increasingly established., Summary: Comprehensive cardiovascular risk assessment is important for adolescent health and includes assessment of family history and tobacco use along with measurement of body mass index and blood pressure. Additionally, cholesterol screening is recommended for overweight adolescents or those with an unknown family history and for all patients by the age of 20. Providers caring for adolescents should be familiar with both the pediatric and adult cholesterol screening and treatment guidelines as well as how common adolescent conditions affect cholesterol levels.

BackgroundBlood pressure (BP) and cholesterol are major modifiable risk factors for cardiovascular disease (CVD), but effects of exposures during young adulthood on later life CVD risk have not been well quantified.ObjectiveThe authors sought to evaluate the independent associations between young adult exposures to risk factors and later life CVD risk, accounting for later life exposures.MethodsThe authors pooled data from 6 U.S. cohorts with observations spanning the life course from young adulthood to later life, and imputed risk factor trajectories for low-density lipoprotein (LDL) and high-density lipoprotein cholesterols, systolic and diastolic BP starting from age 18 years for every participant. Time-weighted average exposures to each risk factor during young (age 18 to 39 years) and later adulthood (age ≥40 years) were calculated and linked to subsequent risks of coronary heart disease (CHD), heart failure (HF), or stroke.ResultsA total of 36,030 participants were included. During a median follow-up of 17 years, there were 4,570 CHD, 5,119 HF, and 2,862 stroke events. When young and later adult risk factors were considered jointly in the model, young adult LDL ≥100 mg/dl (compared with

Objective: To describe enrollment characteristics of youth in the Cascade Screening for Awareness and Detection of FH Registry.Study Design: This is a cross-sectional analysis of 493 participants aged <18 years with heterozygous familial hypercholesterolemia recruited from US lipid clinics (n = 20) between April 1, 2014, and January 12, 2018. At enrollment, some were new patients and some were already in care. Clinical characteristics are described, including lipid levels and lipid-lowering treatments.Results: Mean age at diagnosis was 9.4 (4.0) years; 47% female, 68% white and 12% Hispanic. Average (SD) highest Low-density lipoprotein cholesterol (LDL-C) was 238 (61) mg/dL before treatment. Lipid-lowering therapy was used by 64% of participants; 56% were treated with statin. LDL-C declined 84 mg/dL (33%) among those treated with lipid-lowering therapy; statins produced the greatest decline, 100 mg/dL (39% reduction). At enrollment, 39% had reached an LDL-C goal, either <130 mg/dL or ≥50% decrease from pre-treatment; 20% of those on lipid-lowering therapy reached both goals.Conclusions: Among youth enrolled in the Cascade Screening for Awareness and Detection of FH Registry, diagnosis occurred relatively late, only 77% of children eligible for lipid-lowering therapy were receiving treatment, and only 39% of those treated met their LDL-C goal. Opportunities exist for earlier diagnosis, broader use of lipid-lowering therapy, and greater reduction of LDL-C levels. [ABSTRACT FROM AUTHOR]

Objective: Insulin resistance (IR) is a hallmark of obesity and metabolic disease. Circulating extracellular RNAs (ex-RNAs), stable RNA molecules in plasma, may play a role in IR, though most studies on ex-RNAs in IR are small. We sought to characterize the relationship between ex-RNAs and metabolic phenotypes in a large community-based human cohort.Research Design and Methods: We measured circulating plasma ex-RNAs in 2,317 participants without diabetes in the Framingham Heart Study (FHS) Offspring Cohort at cycle 8 and defined associations between ex-RNAs and IR (measured by circulating insulin level). We measured association between candidate ex-RNAs and markers of adiposity. Sensitivity analyses included individuals with diabetes. In a separate cohort of 90 overweight/obese youth, we measured selected ex-RNAs and metabolites. Biology of candidate microRNAs was investigated in silico.Results: The mean age of FHS participants was 65.8 years (56% female), with average BMI 27.7 kg/m2; participants in the youth cohort had a mean age of 15.5 years (60% female), with mean BMI 33.8 kg/m2. In age-, sex-, and BMI-adjusted models across 391 ex-RNAs in FHS, 18 ex-RNAs were associated with IR (of which 16 were microRNAs). miR-122 was associated with IR and regional adiposity in adults and IR in children (independent of metabolites). Pathway analysis revealed metabolic regulatory roles for miR-122, including regulation of IR pathways (AMPK, target of rapamycin signaling, and mitogen-activated protein kinase).Conclusions: These results provide translational evidence in support of an important role of ex-RNAs as novel circulating factors implicated in IR. [ABSTRACT FROM AUTHOR]

Background: The prevalence of familial hypercholesterolemia (FH) is commonly reported as 1 in 500. European reports suggest a higher prevalence; the US FH prevalence is unknown.Methods and Results: The 1999 to 2012 National Health and Nutrition Examination Survey (NHANES) participants ≥20 years of age (n=36 949) were analyzed to estimate the prevalence of FH with available Dutch Lipid Clinic criteria, including low-density lipoprotein cholesterol and personal and family history of premature atherosclerotic cardiovascular disease. Prevalence and confidence intervals of probable/definite FH were calculated for the overall population and by age, sex, obesity status (body mass index ≥30 kg/m(2)), and race/ethnicity. Results were extrapolated to the 210 million US adults ≥20 years of age. The estimated overall US prevalence of probable/definite FH was 0.40% (95% confidence interval, 0.32-0.48) or 1 in 250 (95% confidence interval, 1 in 311 to 209), suggesting that 834 500 US adults have FH. Prevalence varied by age, being least common in 20 to 29 year olds (0.06%, 1 in 1557) and most common in 60 to 69 year olds (0.85%, 1 in 118). FH prevalence was similar in men and women (0.40%, 1 in 250) but varied by race/ethnicity (whites: 0.40%, 1 in 249; blacks: 0.47%, 1 in 211; Mexican Americans: 0.24%, 1 in 414; other races: 0.29%, 1 in 343). More obese participants qualified as probable/definite FH (0.58%, 1 in 172) than nonobese (0.31%, 1 in 325).Conclusions: FH, defined with Dutch Lipid Clinic criteria available in NHANES, affects 1 in 250 US adults. Variations in prevalence by age and obesity status suggest that clinical criteria may not be sufficient to estimate FH prevalence. [ABSTRACT FROM AUTHOR]

Background: Less than 45% of U.S. children meet the 60 min.d-1 physical activity (PA) guideline. Structured after-school PA programing is one approach to help increase activity levels. This study aimed to evaluate the feasibility and short-term impact of a supervised after-school PA and nutrition education program on activity levels. Methods: Forty-two 3rd-5th graders from an inner-city school in Boston, MA were randomly assigned to a 10-wk after-school program of either: 1) weekly nutrition education, or 2) weekly nutrition education plus supervised PA 3 d.wk-1 at a community-based center. At baseline and follow-up, PA was measured using accelerometry and fitness (VO2max) was estimated using the PACER 15-m shuttle run. Additional measures obtained were non-fasting finger stick total cholesterol (TC) and glucose levels, waist circumference (WC), body mass index (BMI), percent body fat (%BF), and blood pressure (BP). Values are presented as mean±SE, unless noted otherwise. Results: Thirty-six participants completed the study (mean±SD; age 9.7±0.9 years). Participants attended >80% of the sessions. After adjusting for accelerometer wear time and other design factors, light and moderate-to-vigorous PA (MVPA) increased in the nutrition+PA group (+21.5±14.5 and +8.6±8.0 min.d-1, respectively) and decreased in the nutrition only group (-35.2±16.3 and -16.0±9.0 min.d-1, respectively); mean difference between groups of 56.8±21.7 min.d-1 (light PA, p = 0.01) and 24.5±12.0 min.d-1 (MVPA, p = 0.04). Time spent in sedentary behaviors declined in the nutrition+PA group (-14.8±20.7 min.d-1) and increased in the nutrition only group (+55.4±23.2 min.d-1); mean difference between groups of -70.2±30.9 min.d-1 (p = 0.02). Neither group showed changes in TC, BP, WC, %BF, BMI percentile, or fitness (p>0.05). Conclusions: The supervised afterschool community-based nutrition and PA program was well accepted and had high attendance. The changes in light PA and MVPA has potential to promote weight maintenance in inner-city elementary school children, however longer term studies with larger samples are needed. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

The article presents a study which examined the levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) in patients with type 1 diabetes (T1D) and its role in maintaining plasma cholesterol levels. The variables considered include correlations between PCSK9 and age, body mass index (BMI), insulin level, blood glucose and pressure, triglycerides and cholesterol. The effect of PCSK9 in male and female patients is discussed.

Background. Omega-3 fatty acids supplements lower triglyceride (TG) levels in adults; little pediatric information is available. We evaluated their effect in hypertriglyceridemic adolescents. Methods. Twenty-five patients aged 10 to 19 years with TG levels 150 to 1000 mg/dL were randomized to 6 months double-blind trial of Lovaza (~3360 mg docosahexaenoic acid + eicosapentaenoic acid per day) versus placebo. Results. Baseline mean TG levels were 227 mg/dL (standard deviation = 49). TG levels declined at 3 months in the Lovaza group by 54 ± 27 mg/dL (mean ± standard error; P = .02) and by 34 ± 26 mg/dL (P = .16) in the placebo group. The difference in TG lowering between groups was not significant (P = .52). There were no between-group differences in endothelial function, blood pressure, body mass index, C-reactive protein, or side effects. Conclusions. High-dose omega-3 fatty acid supplements are well tolerated in adolescents. However, declines in TG levels did not differ significantly from Placebo in this small study. [ABSTRACT FROM PUBLISHER]

This prospective study assessed the clinical application of a nonfasting low-density lipoprotein cholesterol measure in a pediatric primary care population. A homogenous direct low-density lipoprotein cholesterol assay was tested in healthy children, aged 4 to 12 years, at risk for hyperlipidemia, as defined by American Academy of Pediatrics, and including patients with incomplete family histories. This nonfasting homogeneous assay was comparable to modified ß quantification, the gold standard reference method of measuring low-density lipoprotein cholesterol, and the current recommended screening method, total cholesterol. Results from the study suggest that this nonfasting assay can provide more direct low-density lipoprotein cholesterol measurements for healthy children, with improved clinical utility and greater overall patient convenience in testing for important cholesterol abnormalities. [ABSTRACT FROM AUTHOR]

Abstract: Cardiovascular disease (CVD) is multifactorial in etiology. Traditional cardiovascular risk factors, such as increased cholesterol concentrations and blood pressure, are used to assess CVD risk. Recently, better understanding of the role of inflammation in atherosclerosis has prompted many to propose the measurement of various inflammatory markers to better identify those who are at increased risk. C-reactive protein (CRP) is found in endothelial atherosclerotic lesions, and evidence suggests that it may play a role in atherogenesis. Of candidate serum markers that might add information to clinical risk assessment, high-sensitivity C-reactive protein (hsCRP) measurement has the most potential for clinical use for multiple reasons: (a) high hsCRP is associated with a twofold to a threefold increase in the prevalence of myocardial infarction, stroke, and peripheral vascular disease, and it predicts incident cardiovascular events in those with and without preexisting CVD; (b) the increased risk associated with high hsCRP is independent of other established risk factors; (c) hsCRP augments the predictive capacity of the Framingham Risk Score; (d) hsCRP assays are standardized, and this analyte is biologically stable over time; (e) various risk-reducing interventions also reduce hsCRP, and research is underway to assess whether specifically targeting hsCRP reduces CVD risk. National guidelines regarding the clinical utility of hsCRP in primary and secondary prevention settings have been recently issued. [Copyright &y& Elsevier]

Objectives: To describe muscle-related statin adverse effects in real-world pediatric practice.Study Design: Using prospectively collected quality improvement data from a pediatric preventive cardiology practice, we compared serum creatine kinase (CK) levels among patients prescribed and not prescribed statins, and pre-/poststatin initiation. Multivariable mixed-effect models were constructed accounting for repeated measures, examining the effect of statins on log-transformed CK (lnCK) levels adjusted for age, sex, weight, season, insurance type, and race/ethnicity.Results: Among 1501 patients seen over 3.5 years, 474 patients (14?±?4 years, 47% female) had at least 1 serum CK measured. Median (IQR) CK levels of patients prescribed (n?=?188 patients, 768 CK measurements) and not prescribed statins (n?=?351 patients, 682 CK measurements) were 107 (83) IU/L and 113 (81) IU/L, respectively. In multivariable-adjusted models, lnCK levels did not differ based on statin use (??=?0.02 [SE 0.05], P?=?.7). Among patients started on statins (n?=?86, 130 prestatin and 292 poststatin CK measurements), median CK levels did not differ in adjusted models (? for statin use on lnCK?=?.08 [SE .07], P?=?.2). There was a clinically insignificant increase in CK over time (??=?.08 [SE .04], P?=?.04 per year). No muscle symptoms or rhabdomyolysis were reported among patients with high CK levels.Conclusions: In a real-world practice, pediatric patients using statins did not experience higher CK levels, nor was there a meaningful CK increase with statin initiation. These data suggest the limited utility to checking CK in the absence of symptoms, supporting current guidelines. [ABSTRACT FROM AUTHOR]

In this article the author comments on the study "Trends in serum lipids among US youths aged 6 to 19 years, 1988-2010" by Kit B. K. and colleagues, published in the current issue of the journal. The study reports that that total cholesterol (TC) declined in children aged 6 to 19 years over the past 2 decades. It also showed that low-density lipoprotein (LDL) and triglyceride levels both declined in adolescents aged 12-19 years with available fasting serum specimen.

Familial hypercholesterolemia (FH) is an autosomal dominant disorder of low-density lipoprotein (LDL) metabolism leading to high LDL cholesterol (LDL-C) and accelerated atherosclerosis. The rare homozygous form is associated with physical examination findings and coronary heart disease during childhood. The more common heterozygous form (hetFH) is asymptomatic until adulthood, when those affected develop premature cardiovascular disease (CVD) events, often in early adulthood. Identification of hetFH is key because of the relatively high prevalence, 1 in 200 to 500, and the opportunity to lower LDL-C and reduce CVD outcomes. Selective screening based on family history can identify affected individuals, but many with hetFH are missed by relying on this strategy and go undiagnosed during childhood, leading to the recommendation by the National Heart, Lung, and Blood Institute Expert Panel for universal lipid screening between ages 9 and 11 y and again at ages 17 to 21 y. Diagnosis should lead to treatment with lifestyle modification and pharmacotherapy when appropriate because lowering LDL-C in youth has beneficial effects on subclinical atherosclerosis and likely reduces premature CVD events. This article reviews what is known about the epidemiology and pathophysiology of FH as it relates to the care of children and adolescents. Approaches to identification and treatment of FH during childhood are presented, including both recommendations from published guidelines and clinical experience. A clinical case is used to illustrate various points. [ABSTRACT FROM AUTHOR]

Background Adolescents and young adults (AYAs) with familial hypercholesterolemia (FH) are at high risk for underdiagnosis and inadequate treatment. Yet, little is known about the factors that influence the medical decision making of AYAs with FH and their families. Objective This study explores how family medical history, family narratives of medical experiences, and AYA medical experiences together function as “experiential evidence” and influence screening and treatment decisions. Methods Twenty-four parents and AYAs affected by FH from a pediatric preventive cardiology practice responded to a survey and a semistructured qualitative interview. Transcribed interviews were analyzed using a modified grounded theory approach. Study design, instruments, and interpretation of results were informed by a 20-member stakeholder panel. Results AYAs and parents reported extensive personal and family experiences with cholesterol and cardiovascular conditions and treatments, sometimes distinct from FH, which were used as evidence to inform their own perceptions of FH risk and treatment. This experiential evidence impacted perceptions of: (1) hereditary risk for FH diagnoses, (2) risk for future cardiovascular disease, (3) risks associated with treatments, and (4) capacity to comply with recommended treatments. Although experiences of family members initially informed screening and treatment decisions, the subsequent personal experiences of AYAs led to new experiential evidence that informed future decisions. Conclusions Family cardiovascular history related to and distinct from FH influenced screening and treatment decisions of AYAs and parents affected by FH. Additional clinical assessment of personal and family medical experiences may enhance understanding of the decision-making processes among AYAs and ultimately improve adherence to screening and treatment recommendations. [ABSTRACT FROM AUTHOR]

A response by Samuel R. Vinci and colleagues to a letter to the editor about their article, which provides insights into the rates of cholesterol screening of youth in the U.S., published in the previous issue, is presented.

Homozygous familial hypercholesterolaemia is a life-threatening genetic condition, which causes extremely elevated LDL-C levels and atherosclerotic cardiovascular disease very early in life. It is vital to start effective lipid-lowering treatment from diagnosis onwards. Even with dietary and current multimodal pharmaceutical lipid-lowering therapies, LDL-C treatment goals cannot be achieved in many children. Lipoprotein apheresis is an extracorporeal lipid-lowering treatment, which is used for decades, lowering serum LDL-C levels by more than 70% directly after the treatment. Data on the use of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia mainly consists of case-reports and case-series, precluding strong evidence-based guidelines. We present a consensus statement on lipoprotein apheresis in children based on the current available evidence and opinions from experts in lipoprotein apheresis from over the world. It comprises practical statements regarding the indication, methods, treatment goals and follow-up of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia and on the role of lipoprotein(a) and liver transplantation. [Display omitted] • Early intervention is vital to prevent cardiovascular disease in homozygous familial hypercholesterolaemia (HoFH). • This consensus statement provides guidance on performing lipoprotein apheresis in children with HoFH. • Using the Delphi method involving 40 international experts, 22 statements were developed. • Statements cover indication, methods, treatment goals and follow-up of lipoprotein apheresis in children with HoFH. • Furthermore, the role of lipoprotein(a) and liver transplantation in children with HoFH is discussed. [ABSTRACT FROM AUTHOR]

Background: The risk of cardiovascular disease in type 1 diabetes remains extremely high, despite marked advances in blood glucose control and even the widespread use of cholesterol synthesis inhibitors. Thus, a deeper understanding of insulin regulation of cholesterol metabolism, and its disruption in type 1 diabetes, could reveal better treatment strategies.Methods: To define the mechanisms by which insulin controls plasma cholesterol levels, we knocked down the insulin receptor, FoxO1, and the key bile acid synthesis enzyme, CYP8B1. We measured bile acid composition, cholesterol absorption, and plasma cholesterol. In parallel, we measured markers of cholesterol absorption and synthesis in humans with type 1 diabetes treated with ezetimibe and simvastatin in a double-blind crossover study.Results: Mice with hepatic deletion of the insulin receptor showed marked increases in 12α-hydroxylated bile acids, cholesterol absorption, and plasma cholesterol. This phenotype was entirely reversed by hepatic deletion of FoxO1. FoxO1 is inhibited by insulin and required for the production of 12α-hydroxylated bile acids, which promote intestinal cholesterol absorption and suppress hepatic cholesterol synthesis. Knockdown of Cyp8b1 normalized 12α-hydroxylated bile acid levels and completely prevented hypercholesterolemia in mice with hepatic deletion of the insulin receptor (n=5-30), as well as mouse models of type 1 diabetes (n=5-22). In parallel, the cholesterol absorption inhibitor, ezetimibe, normalized cholesterol absorption and low-density lipoprotein cholesterol in patients with type 1 diabetes as well as, or better than, the cholesterol synthesis inhibitor, simvastatin (n=20).Conclusions: Insulin, by inhibiting FoxO1 in the liver, reduces 12α-hydroxylated bile acids, cholesterol absorption, and plasma cholesterol levels. Thus, type 1 diabetes leads to a unique set of derangements in cholesterol metabolism, with increased absorption rather than synthesis. These derangements are reversed by ezetimibe, but not statins, which are currently the first line of lipid-lowering treatment in type 1 diabetes. Taken together, these data suggest that a personalized approach to lipid lowering in type 1 diabetes may be more effective and highlight the need for further studies specifically in this group of patients. [ABSTRACT FROM AUTHOR]

Background: In nephrotic syndrome, damage to the podocytes of the kidney produces severe hypercholesterolemia for which novel treatments are urgently needed. PCSK9 (proprotein convertase subtilisin/kexin type 9) has emerged as an important regulator of plasma cholesterol levels and therapeutic target. Here, we tested the role of PCSK9 in mediating the hypercholesterolemia of nephrotic syndrome.Methods: PCSK9 and plasma lipids were studied in nephrotic syndrome patients before and after remission of disease, mice with genetic ablation of the podocyte (Podocyte Apoptosis Through Targeted Activation of Caspase-8, Pod-ATTAC mice) and mice treated with nephrotoxic serum (NTS), which triggers immune-mediated podocyte damage. In addition, mice with hepatic deletion of Pcsk9 were treated with NTS to determine the contribution of PCSK9 to the dyslipidemia of nephrotic syndrome.Results: Patients with nephrotic syndrome showed a decrease in plasma cholesterol and plasma PCSK9 on remission of their disease (P<0.05, n=47-50). Conversely, Pod-ATTAC mice and NTS-treated mice showed hypercholesterolemia and a 7- to 24-fold induction in plasma PCSK9. The induction of plasma PCSK9 appeared to be attributable to increased secretion of PCSK9 from the hepatocyte coupled with decreased clearance. Interestingly, knockout of Pcsk9ameliorated the effects of NTS on plasma lipids. Thus, in the presence of NTS, mice lacking hepatic Pcsk9 showed a 40% to 50% decrease in plasma cholesterol and triglycerides. Moreover, the ability of NTS treatment to increase the percentage of low-density lipoprotein-associated cholesterol (from 9% in vehicle-treated Flox mice to 47% after NTS treatment), was lost in mice with hepatic deletion of Pcsk9 (5% in both the presence and absence of NTS).Conclusions: Podocyte damage triggers marked inductions in plasma PCSK9, and knockout of Pcsk9 ameliorates dyslipidemia in a mouse model of nephrotic syndrome. These data suggest that PCSK9 inhibitors may be beneficial in patients with nephrotic syndrome-associated hypercholesterolemia. [ABSTRACT FROM AUTHOR]