The official journal of the Japan Atherosclerosis Society and the Asian Pacific Society of Atherosclerosis and Vascular DiseasesOriginal ArticleAim: Familial hypercholesterolemia (FH) is an underdiagnosed autosomal dominant genetic disorder characterized by high levels of plasma low-density lipoprotein cholesterol (LDL-C) from birth. This study aimed to assess the genetic identification of FH in children with high LDL-C levels who are identified in a universal pediatric FH screening in Kagawa, Japan. Method: In 2018 and 2019, 15,665 children aged 9 or 10 years underwent the universal lipid screening as part of the annual health checkups for the prevention of lifestyle-related diseases in the Kagawa prefecture. After excluding secondary hyper-LDL cholesterolemia at the local medical institutions, 67 children with LDL-C levels of ≥ 140 mg/dL underwent genetic testing to detect FH causative mutations at four designated hospitals. Results: The LDL-C levels of 140 and 180 mg/dL in 15,665 children corresponded to the 96.3 and 99.7 percentile values, respectively. Among 67 children who underwent genetic testing, 41 had FH causative mutations (36 in the LDL-receptor, 4 in proprotein convertase subtilisin/kexin type 9, and 1 in apolipoprotein B). The area under the curve of receiver operating characteristic curve predicting the presence of FH causative mutation by LDL-C level was 0.705, and FH causative mutations were found in all children with LDL-C levels of ≥ 250 mg/dL. Conclusion: FH causative mutations were confirmed in almost 60% of the referred children, who were identified through the combination of the lipid universal screening as a part of the health checkup system and the exclusion of secondary hyper-LDL cholesterolemia at the local medical institutions.

Background: The impairment of short-term heart rate regulation in patients with heart failure with preserved ejection fraction (HFpEF) can cause acute hemodynamic collapse. Detrended fluctuation analysis (DFA) is a useful tool for the diagnosis of heart diseases and the prediction of mortality. In DFA, the short-term scaling exponent a is decreased in heart failure. However, its change in HFpEF patients remains unclear. Methods: Twenty patients diagnosed with HFpEF [defined as brain natriuretic peptide (BNP) >100 pg/ mL, ejection fraction (EF) !50%, and without significant valvular disease], 20 diagnosed with non-HFpEF (BNP > 100 pg/mL and EF < 50%), and 20 control subjects generally matched for age and gender were enrolled. Holter electrocardiography was performed, and heart rate variability was calculated. In the DFA, the scaling exponents in 1000 beats were calculated for each 15-min segment and the average of all segments was used. We compared both the short-term (<11 beats, a1) and long-term (!11 beats, a2) scaling exponents among the three groups.Results: In the HFpEF, non-HFpEF, and control groups, a1 was 0.73 AE 0.27, 0.66 AE 0.29, and 1.01 AE 0.20 (p < 0.01), and a2 was 0.95 AE 0.08, 0.88 AE 0.11, and 0.96 AE 0.07 (p < 0.01), respectively. The a1 exponent was significantly decreased in the HFpEF group (p < 0.01 vs. control) and the non-HFpEF group (p < 0.01 vs. control), while the a2 exponent was significantly decreased in the non-HFpEF group only (p < 0.05 vs. HFpEF and control).Conclusions: Short-term heart rate regulation is impaired in patients with HFpEF, while patients with non-HFpEF have both short-term and long-term impairment.

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Introduction: Familial hypercholesterolemia (FH) is an autosomal hereditary disease found in patients who have elevated low-density lipoprotein cholesterol (LDL-C) levels from birth. Early detection and treatment of FH during childhood potentially reduces the risk of premature cardiovascular events. In Kagawa prefecture, a unique community health system, involving three steps, has been conducted to prevent lifestyle-related diseases for 10-year-old children. This system includes universal lipid screening, selection by pediatricians, and next-generation sequencing (NGS) of FH-related genes in the hospitals. The aim of this study is to investigate whether this system can be effective in detection of FH. Methods: In Kagawa prefecture, the universal lipid screening of children at 10 years of age is performed annually at school, covering over 90% of the target group. After excluding secondary hypercholesterolemia, pediatric clinics introduced children with LDL-C levels >140 mg/dL to four hospitals to perform NGS to detect FH. Results: In 2017, 279 children (3.7%) showed elevated LDL-C >140mg/dL among 7,647 ones who received the screening. We performed NGS for 46 children after excluding secondary hypercholesterolemia by pediatricians (LDL-C 186.0±50.3 mg/dL; M/F 27/19) and 26 children (57%) had FH genetic mutations (23 LDL-R, 3 PCSK9). The children with LDL-C >180mg/dL are recommended to receive statin therapy according to the guideline from the Japanese Atherosclerosis Society (JAS). Children with LDL-C levels ≥180 mg/dL have 74% of positive genetic mutations, and even those with 140-180 mg/dl LDL-C levels have as much as 44%, respectively (Table). Conclusions: The unique community health system in Kagawa can efficiently detect FH of children. Further investigation will be required for the effective prevention of future atherosclerotic cardiovascular diseases.

Introduction: Familial hypercholesterolemia (FH) is an autosomal hereditary disease found in patients who have elevated low-density lipoprotein cholesterol (LDL-C) from birth. Early detection and treatment of FH during childhood potentially reduces the risk of premature cardiovascular events. In Kagawa prefecture, a unique community health system, involving three steps, has been conducted to prevent lifestyle-related diseases for 10-year-old children. This system includes universal lipid screening, selection by pediatricians, and next-generation sequencing (NGS) of FH-related genes in hospitals. The aim of this study is to compare 3 international guidelines to detect pediatric FH with this unique community health system in Kagawa. Methods: In Kagawa prefecture, the universal lipid screening of approximately 8,000 children at 10 years of age is performed annually, covering over 90% of the target group. After excluding secondary hypercholesterolemia, pediatric clinics introduced children with LDL-C >140mg/dL to 4 designated hospitals to perform NGS. We applied the guidelines of the Dutch Lipid Clinic Network (DLCN), Simon Broome (SB), and the Japanese Atherosclerosis Society (JAS) to children who received NGS in the unique community health system in Kagawa. Results: We performed NGS for 46 children from January 2018 to February 2020 (LDL-C 186.0±50.3 mg/dL; Male/F 27/19) and 26 (57%) had FH genetic mutations (23 LDL-R and 3 PCSK9 mutations). Seventeen children met FH criteria for DLCN (35%), 10 for Simon Broome (22%), and 11 for JAS (24%), respectively. The combination of NGS and either of the 3 guidelines increased the number of children diagnosed as FH up to 31 (67%). Conclusion: International guidelines detected only half of pediatric FH who were diagnosed by the unique community health system in Kagawa. Further investigation will be required to build an effective universal screening system for pediatric FH.