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Background: Homozygous familial hypercholesterolemia (HoFH) is an orphan metabolic disease characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C), xanthomas, aortic stenosis, and premature atherosclerotic cardiovascular disease (ASCVD). In addition to LDL-C, studies in experimental models and small clinical populations have suggested that other types of metabolic molecules might also be risk factors responsible for cardiovascular complications in HoFH, but definitive evidence from large-scale human studies is still lacking. Herein, we aimed to comprehensively characterize the metabolic features and risk factors of human HoFH by using metabolic systems strategies., Methods: Two independent multi-center cohorts with a total of 868 individuals were included in the cross-sectional study. First, comprehensive serum metabolome/lipidome-wide analyses were employed to identify the metabolomic patterns for differentiating HoFH patients (n = 184) from heterozygous FH (HeFH, n = 376) and non-FH (n = 100) subjects in the discovery cohort. Then, the metabolomic patterns were verified in the validation cohort with 48 HoFH patients, 110 HeFH patients, and 50 non-FH individuals. Subsequently, correlation/regression analyses were performed to investigate the associations of clinical/metabolic alterations with typical phenotypes of HoFH. In the prospective study, a total of 84 HoFH patients with available follow-up were enrolled from the discovery cohort. Targeted metabolomics, deep proteomics, and random forest approaches were performed to investigate the ASCVD-associated biomarkers in HoFH patients., Results: Beyond LDL-C, various bioactive metabolites in multiple pathways were discovered and validated for differentiating HoFH from HoFH and non-FH. Our results demonstrated that the inflammation and oxidative stress-related metabolites in the pathways of arachidonic acid and lipoprotein(a) metabolism were independently associated with the prevalence of corneal arcus, xanthomas, and supravalvular/valvular aortic stenosis in HoFH patients. Our results also identified a small marker panel consisting of high-density lipoprotein cholesterol, lipoprotein(a), apolipoprotein A1, and eight proinflammatory and proatherogenic metabolites in the pathways of arachidonic acid, phospholipid, carnitine, and sphingolipid metabolism that exhibited significant performances on predicting first ASCVD events in HoFH patients., Conclusions: Our findings demonstrate that human HoFH is associated with a variety of metabolic abnormalities and is more complex than previously known. Furthermore, this study provides additional metabolic alterations that hold promise as residual risk factors in HoFH population., (© 2023. The Author(s).)

Background: There is a lack of large-scale data on the clinical and genotype characteristics of homozygous familial hypercholesterolemia (HoFH) patients in Asia., Objective: To define the characteristics of phenotypic and genetic HoFH probands from mainland China., Methods: We collected data from patients with suspected HoFH from ten clinical hospitals across mainland China from 2003 to 2019. Clinical data and DNA testing were obtained in all patients. The Kaplan-Meier method was used to generate survival curves, and the groups were compared with the log-rank test., Results: A total of 108 unrelated probands with suspected HoFH (mean age 14.9 years) were included. The three most common variants were W483X (c.1448 G>A), A627T (c.1879 G>A), H583Y (c.1747 C>T). The majority (64.8%) were compound heterozygotes (n = 70), 23 (21.3%) were true HoFH patients. True HoFH showed higher LDL-C levels compared to compound HoFH (16.8±3.6 mmol/L vs. 15.0±3.1 mmol/L, P = 0.022). During follow-up, only 21.2% patients exhibited an LDL-C reduction of more than 50%. Kaplan-Meier analysis showed that the true HoFH probands had significantly worse survival rates compared to other genotype probands (13-year survival; 20.3% vs. 76.7%, respectively; P = 0.016). In addition, true HoFH shows that 2.8-fold (P = 0.022) increase any death and 3.0-fold (P = 0.023) increase cardiovascular death risk in relative to other FH., Conclusions: This report shows that HoFH has devastating consequences, and that patients are often only diagnosed after they have been exposed to severely elevated LDL-C for years. Systematic screening and early intensive treatment are an absolute requirement for these young individuals with HoFH., (Copyright © 2022. Published by Elsevier Inc.)

Background: Coronary flow velocity reserve (CFVR) can provide useful quantitative information on the functional status of coronary artery circulation, and an impaired CFVR (< 2.0) was associated with a significant increase in the occurrence of cardiac events. Coronary artery disease (CAD) is the leading cause of death in homozygous familial hypercholesterolemia (HoFH), but the relationship between impaired CFVR and outcome in HoFH has never been discussed before METHODS: To explore the long-term prognostic value of CFVR in patients with HoFH, 39 HoFH patients with CFVR data (mean age with 16.7 years) were enrolled from the Genetic and Imaging of Familial Hypercholesterolemia in Han Nationality Study. All patients were divided into impaired CFVR (CFVR < 2.0, n = 17) and preserved CFVR (CFVR≥2.0, n = 22) group. Follow-up was performed until a major adverse cardiac event (MACE) occurred or up to June 30, 2020 RESULTS: During a median follow-up of 89 months, 16 events were registered, 12 of which were occurred in the impaired CFVR group and four occurred in the preserved CFVR group. The event-free survival rate of impaired CFVR group was significantly lower than that in the preserved CFVR group (29.4% vs 81.8%, P < .001), and CFVR < 2.0 was independently associated with prognosis before and after adjustment for related risk factors (HR 5.197, 95% CI 1.669 to 16.178, P = .004 and HR 5.488, 95% CI 1.470 to 20.496, P = .011, respectively) CONCLUSIONS: an impaired CFVR predicts a worse outcome in HoFH. CFVR shows an independent value in the prediction of long-term outcome in HoFH., (© 2021 Wiley Periodicals LLC.)

Homozygous familial hypercholesterolemia (HoFH) is a rare, life-threatening genetic disorder characterized by an extremely elevated serum level of low-density lipoprotein cholesterol (LDL-C) and accelerated premature atherosclerotic cardiovascular diseases (ASCVD). However, the detailed mechanism of how the pathogenic mutations of HoFH trigger the acceleration of ASCVD is not well understood. Therefore, we performed high-throughput RNA and small RNA sequencing on the peripheral blood RNA samples of six HoFH patients and three healthy controls. The gene and miRNA expression differences were analyzed, and seven miRNAs and six corresponding genes were screened out through regulatory network analysis. Validation through quantitative PCR of genes and miRNAs from 52 HoFH patients and 20 healthy controls revealed that the expression levels of hsa-miR-486-3p, hsa-miR-941, and BIRC5 were significantly upregulated in HoFH, while ID1, PLA2G4C, and CACNA2D2 were downregulated. Spearman correlation analysis found that the levels of ID1, hsa-miR-941, and hsa-miR-486-3p were significantly correlated with additional ASCVD risk factors in HoFH patients. This study represents the first integrated analysis of transcriptome and miRNA expression profiles in patients with HoFH, a rare disease, and as a result, six differentially expressed miRNAs/genes that may be related to atherosclerosis in HoFH are reported. The miRNA-mRNA regulatory network may be the critical regulation mechanism by which ASCVD is accelerated in HoFH., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Homozygous familial hypercholesterolemia (HoFH) is a rare inborn-errors-of-metabolism disorder characterized by devastatingly elevated low-density lipoprotein cholesterol (LDL-C) and premature cardiovascular disease. The gold standard for screening and diagnosing HoFH is genetic testing. In China, it is expensive and is always recommended for the most likely HoFH subjects with aggressive LDL-C phenotype. However, the LDL-C levels of HoFH patients and a substantial proportion of heterozygous FH (HeFH) patients overlapped considerably. Here, we performed a cost-effective metabolomic profiling on genetically diagnosed HoFH (n = 69) and HeFH patients (n = 101) with overlapping LDL-C levels, aiming to discovery a unique metabolic pattern for screening homozygotes in patients with severe FH. We demonstrated a differential serum metabolome profile in HoFH patients compared to HeFH patients. Twenty-one metabolomic alterations showed independent capability in differentiating HoFH from severe HeFH. The combined model based on seven identified metabolites yielded a corrected diagnosis in 91.3% of HoFH cases with an area under the curve value of 0.939. Collectively, this study demonstrated that metabolomic profiling serves as a useful and economical approach to preselecting homozygotes in FH patients with severe hypercholesterolemia and may help clinicians to conduct selective genetic confirmation testing and familial cascade screening. [ABSTRACT FROM AUTHOR]

Abstract: Homozygous familial hypercholesterolemia (HoFH) is a rare disorder characterized by the early onset of atherosclerosis and usually occurs at the ostia of coronary arteries. In this study, we used transthoracic Doppler echocardiography (TTDE) to evaluate the dynamic changes of coronary flow in HoFH patients and to detect aortic and coronary atherosclerosis by dual-source computed tomography (DSCT). We studied 20 HoFH patients (12 females, 8 males, mean age 13.1 ± 5.3 years, with a mean low density lipoprotein (LDL) cholesterol of 583 ± 113 mg/dL) and 15 control patients (8 females, 7 males, mean age 15.2 ± 6.9 years, with a mean LDL cholesterol 128 ± 71 mg/dL) using TTDE and DSCT. None of the patients showed evidence of ischemia with standard exercise testing. Though the baseline coronary flow was similar between HoFH patients and normal controls, the hyperemic flow velocities and, thus, the coronary flow velocity reserve (CFVR) were significantly lower in those with HoFH. All HoFH patients had aortic plaques, nine of them with the coronary artery ostia simultaneously, who had significantly higher LDL-cholesterol and lower CFVR than those without ostia plaques. Our data demonstrated that TTDE together with DSCT could be a useful noninvasive method for detection of coronary flow dynamics and atherosclerosis specifically in HoFH subjects with coronary ostia. (E-mail: lizhian_anzhen@yahoo.com.cn) [Copyright &y& Elsevier]