Clinical practice recommendations on lipoprotein apheresis for children with homozygous familial hypercholesterolaemia: An expert consensus statement from ERKNet and ESPN.

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.

Food Insecurity and Ideal Cardiovascular Health Risk Factors Among US Adolescents.

BACKGROUND: Food insecurity, a social and economic condition of limited availability of healthy food, is a risk factor for adverse cardiovascular health outcomes among adults; few studies have been conducted in adolescents. This study explores the association between food insecurity and cardiovascular health risk factors among a nationally representative sample of US adolescents, adopting the American Heart Association's Life's Essential 8 metric. METHODS AND RESULTS: We analyzed data from 2534 adolescents aged 12 to 19 years from the 2013 to 2018 National Health and Nutrition Examination Surveys. In the sample, 24.8% of adolescents lived in food-insecure households. After multivariable adjustment, food insecurity was associated with a 3.23-unit lower total Life's Essential 8 score (95% CI, -6.32, -0.15) and lower scores on diet quality (ß=-5.39 [95% CI, -8.91, -1.87]) and nicotine exposure (ß=-4.85 [95% CI, -9.24, -0.45]). Regarding diet, food insecurity was associated with 5% lower Healthy Eating Index-2015 scores [95% CI, -7%, -2%], particularly lower intakes of whole grains and seafood/plant proteins and marginally higher intake of added sugar. Regarding nicotine exposure, food insecurity was associated with ever use of a tobacco product among m (odds ratio, 1.74 [95% CI, 1.20-2.53]). Compared with their food-secure counterparts, food-insecure male (odds ratio, 1.98 [95% CI, 1.07-3.65]) and female (odds ratio, 3.22 [95% CI, 1.60-6.45]) adolescents had higher odds of living with a current indoor smoker. CONCLUSIONS: In this nationally representative sample of adolescents, food insecurity was associated with multiple indicators of cardiovascular health risk. These findings underscore the need for public health interventions and policies to reduce food insecurity and improve cardioprotective behaviors during adolescence, with particular efforts targeting diet quality and nicotine exposure.

Social Determinants of Health Including Child Opportunity Index Leading to Gaps in Care for Patients With Significant Congenital Heart Disease.

BACKGROUND: Gaps in care (GIC) are common for patients with congenital heart disease (CHD) and can lead to worsening clinical status, unplanned hospitalization, and mortality. Understanding of how social determinants of health (SDOH) contribute to GIC in CHD is incomplete. We hypothesize that SDOH, including Child Opportunity Index (COI), are associated with GIC in patients with significant CHD. METHODS AND RESULTS: A total of 8554 patients followed at a regional specialty pediatric hospital with moderate to severe CHD seen in cardiology clinic between January 2013 and December 2015 were retrospectively reviewed. SDOH factors including race, ethnicity, language, and COI calculated based on home address and zip code were analyzed. GIC of >3.25 years were identified in 32% (2709) of patients. GIC were associated with ages 14 to 29 years (P<0.001), Black race or Hispanic ethnicity (P<0.001), living ≥150 miles from the hospital (P=0.017), public health insurance (P<0.001), a maternal education level of high school or less (P<0.001), and a low COI (P<0.001). Multivariable analysis showed that GIC were associated with age ≥14 years, Black race or Hispanic ethnicity, documenting <3 caregivers as contacts, mother's education level being high school or less, a very low/low COI, and insurance status (C statistic 0.66). CONCLUSIONS: One-third of patients followed in a regional referral center with significant CHD experienced a substantial GIC (>3.25 years). Several SDOH, including a low COI, were associated with GIC. Hospitals should adopt formal GIC improvement programs focusing on SDOH to improve continuity of care and ultimately overall outcomes for patients with CHD.

Genetic testing for familial hypercholesterolemia.

PURPOSE OF REVIEW: Despite familial hypercholesterolemia (FH) being the most common genetic cause of cardiovascular disease (CVD), genetic testing is rarely utilized in the US. This review summarizes what is known about the clinical utility of genetic testing and its role in the diagnosis and screening of FH. RECENT FINDINGS: The presence of an FH-causative variant is associated with a substantially higher risk of CVD, even when low-density lipoprotein cholesterol (LDL-C) levels are only modestly elevated. Genetic testing can facilitate the identification of FH cases who may be missed by clinical diagnostic criteria, improve risk stratification beyond LDL-C and family history, guide treatment decisions, and improve treatment initiation and adherence. Genetic testing can be incorporated into FH screening and diagnosis algorithms, including cascade, targeted, and universal screening. Integrating genetic testing into cascade screening can enhance the effectiveness of the process. Several models of universal FH screening with coordinated genetic and lipid testing are feasible and effective. SUMMARY: More systematic integration of genetic testing into FH diagnosis and screening can significantly reduce the burden of this condition through early detection and treatment. Further pragmatic implementation studies are needed to determine how to more effectively and affordably integrate genetic testing into clinical lipid screening programs.

Familial Hypercholesterolemia Variant and Cardiovascular Risk in Individuals With Elevated Cholesterol.

Importance: Familial hypercholesterolemia (FH) is a genetic disorder that often results in severely high low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary heart disease (CHD). However, the impact of FH variants on CHD risk among individuals with moderately elevated LDL-C is not well quantified. Objective: To assess CHD risk associated with FH variants among individuals with moderately (130-189 mg/dL) and severely (≥190 mg/dL) elevated LDL-C and to quantify excess CHD deaths attributable to FH variants in US adults. Design, Setting, and Participants: A total of 21 426 individuals without preexisting CHD from 6 US cohort studies (Atherosclerosis Risk in Communities study, Coronary Artery Risk Development in Young Adults study, Cardiovascular Health Study, Framingham Heart Study Offspring cohort, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis) were included, 63 of whom had an FH variant. Data were collected from 1971 to 2018, and the median (IQR) follow-up was 18 (13-28) years. Data were analyzed from March to May 2023. Exposures: LDL-C, cumulative past LDL-C, FH variant status. Main Outcomes and Measures: Cox proportional hazards models estimated associations between FH variants and incident CHD. The Cardiovascular Disease Policy Model projected excess CHD deaths associated with FH variants in US adults. Results: Of the 21 426 individuals without preexisting CHD (mean [SD] age 52.1 [15.5] years; 12 041 [56.2%] female), an FH variant was found in 22 individuals with moderately elevated LDL-C (0.3%) and in 33 individuals with severely elevated LDL-C (2.5%). The adjusted hazard ratios for incident CHD comparing those with and without FH variants were 2.9 (95% CI, 1.4-6.0) and 2.6 (95% CI, 1.4-4.9) among individuals with moderately and severely elevated LDL-C, respectively. The association between FH variants and CHD was slightly attenuated when further adjusting for baseline LDL-C level, whereas the association was no longer statistically significant after adjusting for cumulative past LDL-C exposure. Among US adults 20 years and older with no history of CHD and LDL-C 130 mg/dL or higher, more than 417 000 carry an FH variant and were projected to experience more than 12 000 excess CHD deaths in those with moderately elevated LDL-C and 15 000 in those with severely elevated LDL-C compared with individuals without an FH variant. Conclusions and Relevance: In this pooled cohort study, the presence of FH variants was associated with a 2-fold higher CHD risk, even when LDL-C was only moderately elevated. The increased CHD risk appeared to be largely explained by the higher cumulative LDL-C exposure in individuals with an FH variant compared to those without. Further research is needed to assess the value of adding genetic testing to traditional phenotypic FH screening.

Relationship of Left Ventricular Mass to Lean Body Mass in the Obese Pediatric Population.

Our primary aim was to investigate the relationship between LVM and anthropometric measures including lean body mass (LBM) in obese pediatric subjects compared to normal weight controls. A retrospective chart review identified subjects 2-18 years old who were normotensive and had normal echocardiograms between 1995 and 2020 at Boston Children's Hospital. LVM was calculated with the 5/6 area length rule from 2D echocardiograms. LBM was calculated with equations derived from dual-energy X-ray absorptiometry. Of the 2217 subjects who met inclusion criteria, 203 were obese and 2014 had normal weight. The median age was 11.9 (2.0-18.9); 46% were female. The median LVM was 94.5 g (59.3-134.3) in obese subjects vs. 78.0 g (51.5-107.7) in controls. The median LBM was 37.2 kg (18.9-50.6) in obese subjects vs. 30.5 kg (17.6-40.8) in controls. In control and obese subjects, LBM had the strongest correlation to LVM (R2 0.86, P < 0.001) and (R2 0.87, P < 0.001), respectively. There was at most a modest correlation between tissue Doppler velocity z-scores and LV mass, and the largest was Septal E' z-score in obese subjects (r = - 0.31, P = 0.006). In this cohort, LBM was found to have the strongest relationship to LVM in obese subjects. The largest correlation between tissue Doppler velocity z-scores and LV mass was Septal E' z-score. Future studies will evaluate which measurements are more closely aligned with clinical outcomes in obese children.

Elevation of IL-17 Cytokines Distinguishes Kawasaki Disease From Other Pediatric Inflammatory Disorders.

OBJECTIVE: Kawasaki disease (KD) is a systemic vasculitis of young children that can lead to development of coronary artery aneurysms. We aimed to identify diagnostic markers to distinguish KD from other pediatric inflammatory diseases. METHODS: We used the proximity extension assay to profile proinflammatory mediators in plasma samples from healthy pediatric controls (n = 30), febrile controls (n = 26), and patients with KD (n = 23), multisystem inflammatory syndrome in children (MIS-C; n = 25), macrophage activation syndrome (n = 13), systemic and nonsystemic juvenile idiopathic arthritis (n = 14 and n = 10, respectively), and juvenile dermatomyositis (n = 9). We validated the key findings using serum samples from additional patients with KD (n = 37) and febrile controls (n = 28). RESULTS: High-fidelity proteomic profiling revealed distinct patterns of cytokine and chemokine expression across pediatric inflammatory diseases. Although KD and MIS-C exhibited many similarities, KD differed from MIS-C and other febrile diseases in that most patients exhibited elevation in one or more members of the interleukin-17 (IL-17) cytokine family, IL-17A, IL-17C, and IL-17F. IL-17A was particularly sensitive and specific, discriminating KD from febrile controls with an area under the receiver operator characteristic curve of 0.95 (95% confidence interval 0.89-1.00) in the derivation set and 0.91 (0.85-0.98) in the validation set. Elevation of all three IL-17-family cytokines was observed in over 50% of KD patients, including 19 of 20 with coronary artery aneurysms, but was rare in all other comparator groups. CONCLUSION: Elevation of IL-17 family cytokines is a hallmark of KD and may help distinguish KD from its clinical mimics.

Clinical practice recommendations on lipoprotein apheresis for children with homozygous familial hypercholesterolemia: an expert consensus statement from ERKNet and ESPN.

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 well established since three decades, lowering serum LDL-C levels by more than 70% per session. 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 targets and follow-up of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia and on the role of lipoprotein(a) and liver transplantation.

International Atherosclerosis Society guidance for implementing best practice in the care of familial hypercholesterolaemia.

This contemporary, international, evidence-informed guidance aims to achieve the greatest good for the greatest number of people with familial hypercholesterolaemia (FH) across different countries. FH, a family of monogenic defects in the hepatic LDL clearance pathway, is a preventable cause of premature coronary artery disease and death. Worldwide, 35 million people have FH, but most remain undiagnosed or undertreated. Current FH care is guided by a useful and diverse group of evidence-based guidelines, with some primarily directed at cholesterol management and some that are country-specific. However, none of these guidelines provides a comprehensive overview of FH care that includes both the lifelong components of clinical practice and strategies for implementation. Therefore, a group of international experts systematically developed this guidance to compile clinical strategies from existing evidence-based guidelines for the detection (screening, diagnosis, genetic testing and counselling) and management (risk stratification, treatment of adults or children with heterozygous or homozygous FH, therapy during pregnancy and use of apheresis) of patients with FH, update evidence-informed clinical recommendations, and develop and integrate consensus-based implementation strategies at the patient, provider and health-care system levels, with the aim of maximizing the potential benefit for at-risk patients and their families worldwide.

Contemporary Homozygous Familial Hypercholesterolemia in the United States: Insights From the CASCADE FH Registry.

Background Homozygous familial hypercholesterolemia (HoFH) is a rare, treatment-resistant disorder characterized by early-onset atherosclerotic and aortic valvular cardiovascular disease if left untreated. Contemporary information on HoFH in the United States is lacking, and the extent of underdiagnosis and undertreatment is uncertain. Methods and Results Data were analyzed from 67 children and adults with clinically diagnosed HoFH from the CASCADE (Cascade Screening for Awareness and Detection) FH Registry. Genetic diagnosis was confirmed in 43 patients. We used the clinical characteristics of genetically confirmed patients with HoFH to query the Family Heart Database, a US anonymized payer health database, to estimate the number of patients with similar lipid profiles in a "real-world" setting. Untreated low-density lipoprotein cholesterol levels were lower in adults than children (533 versus 776 mg/dL; P=0.001). At enrollment, atherosclerotic cardiovascular disease and supravalvular and aortic valve stenosis were present in 78.4% and 43.8% and 25.5% and 18.8% of adults and children, respectively. At most recent follow-up, despite multiple lipid-lowering treatment, low-density lipoprotein cholesterol goals were achieved in only a minority of adults and children. Query of the Family Heart Database identified 277 individuals with profiles similar to patients with genetically confirmed HoFH. Advanced lipid-lowering treatments were prescribed for 18%; 40% were on no lipid-lowering treatment; atherosclerotic cardiovascular disease was reported in 20%; familial hypercholesterolemia diagnosis was uncommon. Conclusions Only patients with the most severe HoFH phenotypes are diagnosed early. HoFH remains challenging to treat. Results from the Family Heart Database indicate HoFH is systemically underdiagnosed and undertreated. Earlier screening, aggressive lipid-lowering treatments, and guideline implementation are required to reduce disease burden in HoFH.

Lack of Age-Appropriate Reference Intervals Causing Potentially Missed Alerts in Clinical Reports of Dyslipidemia.

This study shows that only 12.5% of laboratory reports (2/16) included age-appropriate pediatric reference ranges for all lipid and lipoproteins. The use of erroneous reference range(s) could lead to missed alerts of dyslipidemia in up to 97.3% (total cholesterol), 93.6% (high-density lipoprotein cholesterol), 94.8% (low-density lipoprotein cholesterol), and 87.8% (triglycerides) of youth in the population-based National Health and Nutrition Examination Survey cohort. These findings highlight the potential missed opportunities for reinforcing lifestyle counseling for dyslipidemia in addition to obesity in youth.

Estimated Yield of Screening for Heterozygous Familial Hypercholesterolemia With and Without Genetic Testing in US Adults.

Background Heterozygous familial hypercholesterolemia (FH) is a common genetic disorder causing premature cardiovascular disease. Despite this, there is no national screening program in the United States to identify individuals with FH or likely pathogenic FH genetic variants. Methods and Results The clinical characteristics and FH variant status of 49 738 UK Biobank participants were used to develop a regression model to predict the probability of having any FH variants. The regression model and modified Dutch Lipid Clinic Network criteria were applied to 39 790 adult participants (aged ≥20 years) in the National Health and Nutrition Examination Survey to estimate the yield of FH screening programs using Dutch Lipid Clinic Network clinical criteria alone (excluding genetic variant status), genetic testing alone, or combining clinical criteria with genetic testing. The regression model accurately predicted FH variant status in UK Biobank participants (observed prevalence, 0.27%; predicted, 0.26%; area under the receiver-operator characteristic curve, 0.88). In the National Health and Nutrition Examination Survey, the estimated yield per 1000 individuals screened (95% CI) was 3.7 (3.0-4.6) FH cases with the Dutch Lipid Clinic Network clinical criteria alone, 3.8 (2.7-5.1) cases with genetic testing alone, and 6.6 (5.3-8.0) cases by combining clinical criteria with genetic testing. In young adults aged 20 to 39 years, using clinical criteria alone was estimated to yield 1.3 (95% CI, 0.6-2.5) FH cases per 1000 individuals screened, which was estimated to increase to 4.2 (95% CI, 2.6-6.4) FH cases when combining clinical criteria with genetic testing. Conclusions Screening for FH using a combination of clinical criteria with genetic testing may increase identification and the opportunity for early treatment of individuals with FH.

SARS-CoV-2 Infection and Associated Cardiovascular Manifestations and Complications in Children and Young Adults: A Scientific Statement From the American Heart Association.

Coronavirus disease 2019 (COVID-19) resulted in a global pandemic and has overwhelmed health care systems worldwide. In this scientific statement, we describe the epidemiology, pathophysiology, clinical presentations, treatment, and outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and multisystem inflammatory syndrome in children and young adults with a focus on cardiovascular manifestations and complications. We review current knowledge about the health consequences of this illness in children and young adults with congenital and acquired heart disease, the public health burden and health disparities of this infection in these populations, and vaccine-associated myocarditis.

Follow-up cardiac magnetic resonance in children with vaccine-associated myocarditis.

Myocarditis is a rare complication of the COVID-19 mRNA vaccine. We previously reported a case series of 15 adolescents with vaccine-associated myocarditis, 87% of whom had abnormalities on initial cardiac magnetic resonance (CMR), including late gadolinium enhancement (LGE) in 80%. We performed follow-up CMRs to determine the trajectory of myocardial recovery and better understand the natural history of vaccine-associated myocarditis. Case series of patients age < 19 years admitted to Boston Children's Hospital with acute vaccine-associated myocarditis following the BNT162b2 vaccine who had abnormal CMR at the time of initial presentation, and underwent follow-up testing. CMR assessment included left ventricular (LV) ejection fraction, T2-weighted myocardial imaging, LV global native T1, LV global T2, extracellular volume (ECV), and late gadolinium enhancement (LGE). Ten patients (9 male, median age 15 years) with vaccine-associated myocarditis underwent follow-up CMR at a median of 92 days (range 76-119) after hospital discharge. LGE was persistent in 80% of patients, though improved from prior in all cases. Two patients (20%) had abnormal LV global T1 at presentation, which normalized on follow-up. ECV decreased between acute presentation and follow-up in 6/10 patients; it remained elevated at follow-up in 1 patient and borderline in 3 patients. CONCLUSION: CMR performed ~3 months after admission for COVID-19 vaccine-associated myocarditis showed improvement of LGE in all patients, but persistent in the majority. Follow-up CMR 6-12 months after acute episode should be considered to better understand the long-term cardiac risks. WHAT IS KNOWN: • Myocarditis is a rare side effect of COVID-19 mRNA vaccine. •Late gadolinium enhancement is present on most cardiac magnetic resonance at the time of acute presentation. WHAT IS NEW: •Late gadolinium enhancement improved on all repeat cardiac magnetic resonance at 3-month follow-up. •Most patients still had a small amount of late gadolinium enhancement, the clinical significance of which is yet to be determined.

Insulin Prevents Hypercholesterolemia by Suppressing 12α-Hydroxylated Bile Acids.

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.