Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Improving risk assessment for post-surgical low cardiac output syndrome in patients without severely reduced ejection fraction undergoing open aortic valve replacement. The role of global longitudinal strain and right ventricular free wall strain

Low cardiac output syndrome (LCOS) after surgical aortic valve replacement (SAVR) is related to increased mortality and treatment related costs. We aimed to evaluate whether echocardiography-derived left ventricular global longitudinal strain (LV-GLS) relates to the occurrence of postoperative LCOS in patients undergoing SAVR. We prospectively enrolled 75 patients with symptomatic severe aortic stenosis, left ventricular ejection fraction (LVEF) > 40%, NYHA Class <IV, without other significant valve disease. Echocardiographic examination, including LV-GLS assessment was performed before SAVR. In a subgroup of patients right ventricular free wall strain (RVFWS) was also measured. The main outcome was the occurrence of LCOS. Secondary outcome was 30-day mortality. Patients were divided according to LCOS occurrence, which was found in 41% of the population. Baseline clinical characteristics were similar between groups except for LVEF, and LV-GLS. We found LV-GLS to be related to 30-day mortality (OR 1.3, p <0.041, 95% CI 1.02-1.69). After multivariate analysis for variables related to LCOS, only age (p = 0.034), LVEF (p = 0.037) and LV-GLS (p = 0.040) independently predicted LCOS. Mean RVFWS was lower in patients in whom the primary outcome occurred (-12.8 +/- 4.3 vs. -17.1 +/- 3.9, p = 0.0081). In ROC curves analysis a RVFWS of -15% yielded a sensitivity of 81.2% and specificity of 71.4% for the occurrence of LCOS. LV-GLS is a useful parameter for risk stratification in patients with severe aortic stenosis without severely depressed LVEF, and is independently associated with LCOS occurrence. RVFWS wall strain may be useful for risk stratification in patients undergoing AVR

The effects of caffeine on sleep and maturational markers in the rat

Adolescence is a critical period for brain maturation during which a massive reorganization of cortical connectivity takes place. In humans, slow wave activity (<4.5 Hz) during NREM sleep was proposed to reflect cortical maturation which relies on use-dependent processes. A stimulant like caffeine, whose consumption has recently increased especially in adolescents, is known to affect sleep wake regulation. The goal of this study was to establish a rat model allowing to assess the relationship between cortical maturation and sleep and to further investigate how these parameters are affected by caffeine consumption. To do so, we assessed sleep and markers of maturation by electrophysiological recordings, behavioral and structural readouts in the juvenile rat. Our results show that sleep slow wave activity follows a similar inverted U-shape trajectory as already known in humans. Caffeine treatment exerted short-term stimulating effects and altered the trajectory of slow wave activity. Moreover, caffeine affected behavioral and structural markers of maturation. Thus, caffeine consumption during a critical developmental period shows long lasting effects on sleep and brain maturation