Lipid changes in females with familial hypercholesterolemia during the menopausal transition period.

To inform guidelines for screening family members of patients with familial hypercholesterolemia (FH), we designed a clinical trial to compare the yield of cascade screening in FH patients with and without an identifiable pathogenic variant. Participants with hypercholesterolemia (Low-density lipoprotein cholesterol (LDL-C) > 155 mg/dL) underwent sequencing of LDLR, APOB, and PCSK9 and genotyping of six single nucleotide polymorphisms associated with LDL-C followed by calculation of a polygenic score for LDL-C. We identified 24 patients with definite FH (pathogenic variant in one of the three FH genes), 76 patients with probable FH (Dutch lipid clinic network (DLCN) score ≥ 6, no pathogenic variant), and 262 patients with possible FH (DLCN score 3–5, no pathogenic variant). We will enroll 50 patients with definite FH by recruiting an additional 26 from the FH Clinic at Mayo and 50 patients each with probable and possible FH, matching on age and sex. Family members of patients with definite FH will undergo testing for the relevant pathogenic variant using saliva kits and family members of those with probable/possible FH will have a lipid profile checked. We will assess the number of new cases detected (defined as presence of a pathogenic variant in the family member of definite FH patient or LDL-C > 155 mg/dL (>130 mg/dL in children) in family members of probable/possible FH patients, and the cost of detecting a new case. The proposed clinical trial will compare the yield and cost of cascade screening for FH patients with/without an identifiable pathogenic variant, and thereby inform guidelines for cascade screening for FH.

Familial hypercholesterolemia (FH) is an underdiagnosed genetic inherited condition that may lead to premature coronary artery disease (CAD). FH has an estimated prevalence in the general population of about 1:313. However, its prevalence in patients with premature STEMI (ST-elevation myocardial infarction) has not been widely studied. This study aimed to evaluate the prevalence of FH in patients with premature STEMI. Cardiovascular risk factors, LDLc (low-density lipoprotein cholesterol) evolution, and differences between genders were also evaluated. Consecutive patients were referred for cardiac catheterization to our center due to STEMI suspicion in 2018. From the 80 patients with confirmed premature CAD (men < 55 and women < 60 years old with confirmed CAD), 56 (48 men and eight women) accepted to be NGS sequenced for the main FH genes. Clinical information and DLCN (Dutch Lipid Clinic Network) score were analyzed. Only one male patient had probable FH (6–7 points) and no one reached a clinically definite diagnosis. Genetic testing confirmed that the only patient with a DLCN score ≥6 has HF (1.8%). Smoking and high BMI the most frequent cardiovascular risk factors (>80%). Despite high doses of statins being expected to reduce LDLc levels at STEMI to current dyslipidemia guidelines LDL targets (<55 mg/dL), LDLc control levels were out of range. Although still 5.4 times higher than in general population, the prevalence of FH in premature CAD is still low (1.8%). To improve the genetic yield, genetic screening may be considered among patients with probable or definite FH according to clinical criteria. The classical cardiovascular risk factors prevalence far exceeds FH prevalence in patients with premature STEMI. LDLc control levels after STEMI were out range, despite intensive hypolipemiant treatment. These findings reinforce the need for more aggressive preventive strategies in the young and for intensive lipid-lowering therapy in secondary prevention.

Familial hypercholesterolemia (FH) is an inherited disorder characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) associated with premature cardiovascular disease. Using the data from the START (STable Coronary Artery Diseases RegisTry) study, a nationwide, prospective survey on patients with stable coronary artery disease (CAD), we described prevalence and lipid lowering strategies commonly employed in these patients. The study population was divided into "definite/probable FH," defined as a Dutch Lipid Clinic Network (DLCN) score ≥6, "possible FH" with DLCN 3-5, and "unlikely FH" in presence of a DLCN <3. Among the 4030 patients with the DLCN score available, 132 (3.3%) were classified as FH (2.3% with definite/probable and 1.0% with possible FH) and 3898 (96.7%) had unlikely FH. Patients with both definite/probable and possible FH were younger compared to patients not presenting FH. Mean on-treatment LDL-C levels were 107.8 ± 41.5, 84.4 ± 40.9, and 85.8 ± 32.3 (P < 0.0001) and a target of ≤70 mg/dL was reached in 10.9%, 30.0%, and 22.0% (P < 0.0001) of patents with definite/probable, possible FH, and unlikely FH, respectively. Statin therapy was prescribed in 85 (92.4%) patients with definite/probable FH, in 38 (95.0%) with possible FH, and in 3621 (92.9%) with unlikely FH (P = 0.86). The association of statin and ezetimibe, in absence of other lipid-lowering therapy, was more frequently used in patients with definite/probable FH compared to patients without FH (31.5% vs 17.5% vs 9.5%; P < 0.0001). In this large cohort of consecutive patients with stable CAD, FH was highly prevalent and generally undertreated with lipid lowering therapies.

SUBOPTIMAL CONTROL OF CHOLESTEROL LEVELS AMONG INDIVIDUALS WITH FAMILIAL HYPERCHOLESTEROLEMIA AND SEVERE HYPERCHOLESTEROLEMIA IN ONTARIO, CANADA

Background Familial hypercholesterolaemia (FH) is underdiagnosed in most countries. We report our first experience from a national pilot project of cascade screening in relatives of FH patients. Methodology Participating specialists recruited consecutive index patients (IP) with Dutch Lipid Clinic Network (DLCN) score ≥6. After informed consent, the relatives were visited by the nurses to collect relevant clinical data and perform blood sampling for lipid profile measurement. FH diagnosis in the relatives was based on the DLCN and/or MEDPED FH (Make-Early-Diagnosis-to-Prevent-Early-Deaths-in-FH) criteria. Results In a period of 18 months, a total of 127 IP (90 with definite FH and 37 with probable FH) were enrolled in 15 centres. Out of the 270 relatives visited by the nurses, 105 were suspected of having FH: 31 with DCLN score >8, 33 with DLCN score 5-8 and 41 with MEDPED FH criteria. In a post-hoc analysis, another set of MEDPED FH criteria established in the Netherlands and adapted to Belgium allowed to detect FH in 51 additional relatives. Conclusion In a country with no national FH screening program, our pilot project demonstrated that implementing a simple phenotypical FH cascade screening strategy using the collaboration of motivated specialists and two nurses, allowed to diagnose FH in 127 index patients and an additional 105 of their relatives over the two-year period. Newly developed MEDPED FH cut-offs, easily applicable by a nurse with a single blood sample, might further improve the sensitivity of detecting FH within families.

Coronary artery calcium score assessment in patients with familial hypercholesterolemia

This study presents an assessment of familial hypercholesterolemia (FH) probability using different algorithms (CatBoost, XGBoost, Random Forest, SVM) and its ensembles, leveraging electronic health record data. The primary objective is to explore an enhanced method for estimating FH probability, surpassing the currently recommended Dutch Lipid Clinic Network (DLCN) Score. The models were trained using the largest Polish cohort of patients enrolled in an FH clinic, all of whom underwent genetic testing for FH-associated mutations. The initial dataset comprised over 100 parameters per patient, which was reduced to 48 clinically accessible features to ensure applicability in routine outpatient settings. To preserve balance, the data were stratified according to DLCN score ranges (&lt;0–2&gt;, &lt;3–5&gt;, &lt;6–8&gt;, and ≥9), representing varying levels of FH likelihood. The dataset was then split into training and test sets with an 80/20 ratio. Machine-learning models were trained, with hyperparameters optimized via grid search. The accuracy of the DLCN score in predicting FH was first evaluated by examining the proportion of patients with positive DNA tests relative to those with a DLCN score of 6 and above, the threshold for genetic testing. The DLCN score demonstrated an accuracy of approximately 40%. In contrast, the CatBoost model and its ensembles achieved over 80% accuracy. While the DLCN score remains a clinically valuable tool, its diagnostic accuracy is limited. The findings indicate that the ML models offer a substantial improvement in the precision of FH diagnosis, demonstrating its potential to enhance clinical decision making in identifying patients with FH.

High-intensity statins are recommended for all patients with familial hypercholesterolemia (FH) and non-statin lipid lowering therapies (LLTs) are indicated when there is an inadequate response to statins 1, 2 . In the pre-PCSK9 inhibitor (PCSK9i) era only about 40% of FH patients achieved an LDL-C level 3 . Partly based on the need for additional therapeutic options in high-risk FH patients, PCSK9 inhibitors were approved for treatment of heterozygous and homozygous FH in 2015. Nevertheless, emerging anecdotal data suggest that access to non-statin LLTs has been a challenge for FH patients though this has not been systematically evaluated. The FH Optimal Care of the US (FOCUS) study was designed by The FH Foundation to assess current treatment patterns of FH patients, and allowed us to assess rejection rates of PCSK9 inhibitors in those with FH or ASCVD.

Funding Acknowledgements Type of funding sources: None. Introduction Patients (P) with familial hypercholesterolemia (FH) have considerable elevation in levels of low-density lipoprotein (LDL) cholesterol and a higher risk of premature coronary artery disease (CAD) and acute coronary syndromes (ACS). However, even in a hospital setting with a high volume of ACS P, the diagnosis of FH frequently goes undetected. The aim of this study was to evaluate the application of the Dutch Lipid Clinic Network (DLCN) Criteria in P admitted for ACS and analyse ACS recurrence, hospitalization and mortality in a 30-day follow-up. Methods Retrospective evaluation of P with ACS admitted to a tertiary center from 2005 to 2019. Data from the digital files including family history and laboratory tests was analysed and P were followed up for 30 days for hospitalization, recurrent ACS, all cause mortality and cardiovascular (CV) death. Evaluation of tendinous xanthomata, arcus cornealis and genetic analysis was not undertaken. Results 3811 P were evaluated, mean age 63 ± 13 years, 28% female gender, 1497 P (39%) with active or previous smoking habits, 847 P (22%) with diabetes mellitus, 419 P (11%) with family history of coronary disease, 1340 P (35%) with premature CAD, 53 P (1.4%) with premature cerebral or peripheral vascular disease and 522 (14%) with previous ACS. The mean LDL cholesterol level was 125 ± 43 mg/dL, the mean high-density lipoprotein (HDL) cholesterol level was 40 ± 16 mg/dL and the mean triglyceride level was 132 ± 89 mg/dL. The diagnosis at hospital admission was unstable angina (UA) in 189 P (5%), non-ST-segment elevation myocardial infarction (NSTEMI) in 1024 P (27%) and ST-segment elevation MI (STEMI) in 2598 P (68%). The hospital mortality rate was 4.3% (163P). Applying the DLCN criteria, 3089 P (81%) had a score of &amp;lt;3 ("unlikely FH"), 675 P (17.7%) a score of 3 to 5 ("possible FH"), 41 P (1.1%) a score of 6 to 8 ("probable FH") and 1 P (0.03%) a score of &amp;gt;8 ("definite FH"). Stratifying according to ACS type: among UA, 31 P (16%) had "possible FH" and 4 P (2.1%) had "probable FH". Among NSTEMI, 145 P (14.2%) had "possible FH", 9 P (0.9%) "probable FH" and 1 P (0.03%) had "definite FH". Finally, among STEMI P, 497 P (19.1%) had "possible FH" and 28 P (1.1%) had "probable FH". In a 30-day follow-up, there was an all cause mortality of 2% (78 P) and a CV death of 1.3% (49P), while the all cause hospitalization rate was 3.5% (134P) and the admission rate for recurrent ACS was 1.7% (65P). The DLCN criteria score was significantly correlated with CV death (OR 1.25, CI 95% 1.04-1.50, p = 0.020) and admission for recurrent ACS (OR 1.19, CI 95% 1.04-1.36, p = 0.04). Conclusion Application of the DLCN criteria in P admitted for ACS revealed 675 P (17.7%) with "possible FH" and 41 P (1.1%) with "probable FH" as well as show significant correlation with CV death and recurrent ACS. Routine assessment of these criteria can be an accessible tool to stratify likelihood of FH and proceed accordingly to genetic testing.

Prevalence of genetically verified familial hypercholesterolemia among young (<45 years) Norwegian patients hospitalized with acute myocardial infarction

A Clinically Validated Genetic Screening for Familial Hypercholesterolemia in Quebec

Familial hypercholesterolemia (FH) and type 1 diabetes (T1D) are both common and without adequate treatment, lead to premature atherosclerosis and cardiovascular events. We identified children with T1D and probable FH and analyzed their lipid-lowering therapy (LLT). This retrospective cohort study was based on the Diabetes Prospective Follow-Up registry, analyzing data of 41,992 children (2014-2023) with pediatric T1D from 384 European centers. Classification of probable FH was >2× LDL cholesterol (LDL-C) >4.9 mmol/L and of possible FH, >2× LDL-C >4.1 mmol/L and ≤4.9 mmol/L. A total of 31,862 patients consistently had LDL-C <4.1 mmol/L, 416 (1.2%) had possible FH, and 195 (0.56%) had probable FH. Compared with the LDL-C <4.1 mmol/L cohort, the possible FH and probable FH groups had higher BMI standard deviation scores (0.73 and 0.55 vs. 0.27, P < 0.00001) and higher HbA1c (8.2% [66 mmol/mol]) and 8.3% [67 mmol/L] vs. 7.5% [58 mmol/mol], P < 0.00001) and were more often female (57% and 62% vs. 44%, P < 0.00001). Odds ratios for LDL-C 2× >4.9 mmol/L were 3.85 (95% CI 2.6-5.7) for HbA1c >9% (>75 mmol/mol), 2.12 (1.48-3.04) for HbA1c 7.5-9% (58-75 mmol/mol), 2.10 (1.56-2.81) for female sex, and 1.47 (1.08-2.02) for BMI >70th percentile. In the possible FH and probable FH groups, 20% and 29% were receiving LTT, respectively. The prevalence of probable FH was high (1 in 215 children) in pediatric T1D. We assume that the majority are affected by genetic FH, modified by HbA1c and BMI. Despite the very high risk for premature atherosclerosis in patients with FH and T1D, only one-third receive LLT.

Introduction: Prior reports of the genetic etiology of hypercholesterolemia are affected by referral bias, inclusion of individuals with secondary hypercholesterolemia and variability in identifying pathogenic variants. We sought to assess the prevalence of monogenic and polygenic etiologies in a community based cohort of adults with primary hypercholesterolemia (LDL-C ≥155 mg/dL after excluding secondary causes). Methods: We identified 1719 individuals aged 18-70 years with primary hypercholesterolemia from SE Minnesota. The Dutch Lipid Clinic Network (DLCN) score was ascertained by an electronic health record (EHR) based algorithm followed by manual review. Familial hypercholesterolemia (FH) was considered present with a DLCN score ≥6 whereas a DLCN score of 3-5 was considered possible FH. Participants underwent sequencing of FH genes ( LDLR, APOB, PCSK9 ) and genotyping of 12 SNPs known to be associated with LDL-C. Rare (frequency &lt;0.1%) and putatively functional variants were identified and pathogenicity was assigned based on the ACMG guidelines using relevant database, literature and EHR review. A polygenic score (PGS) for LDL-C (derived from 12 SNPs) &gt;90 th percentile was considered an indicator of polygenic etiology. Results: A pathogenic/likely pathogenic variant (16 in LDLR , 1in APOB and 2 in PCSK9 ) was present in 24 (1.3%) individuals, a PGS &gt;90 th percentile was present in 265 (15.4%) and 4 (0.2%) had both a monogenic and polygenic etiology. The overall prevalence of an identifiable genetic etiology was 17%. Based on clinical criteria the overall prevalence of FH (DLCN ≥6) was 7.0% (6.1% probable and 0.9% definite) and that of possible FH was 30.0%. In the possible, probable and definite FH categories, a monogenic etiology was present in 2.4%, 9.5% and 26.7% and a polygenic etiology in 19.1%, 21.0% and 13.3% respectively. 52.0% of those with a monogenic etiology and 9.7% of those with a polygenic etiology met the DLCN criteria for FH. Conclusions: This study provides for the first time estimates of monogenic and polygenic etiology of hypercholesterolemia in adults from the community, excluding cases of secondary hypercholesterolemia and using standardized methods of variant annotation.

Familial hypercholesterolemia (FH) is one of the most common genetic disorders characterized by a predominant elevation in plasma low-density lipoprotein (LDL) cholesterol (LDL-C) concentration and higher incidence of premature atherosclerotic cardiovascular disease (ASCVD). It has been reported that the long-term coronary artery disease (CAD) and ASCVD risk in the US adults with the FH phenotype are up to approximately five-fold higher than that in the general population.[1] It has also been estimated that there is an important long-term burden of ASCVD in phenotypic but undiagnosed FH patients in the US, with the acceleration of CAD risk by 20–30 years.[1] In recent years, the features of under-diagnosis and under-treatment of FH patients has attained an intensive attention worldwide.[2] This increased risk is age dependent, with the highest relative risk in younger index ages. Notably, several atherosclerosis-related international academic organizations or societies have issued statements or guidelines consequently, which call for the actions to improve the diagnosis and treatment of this unique, treatable disease globally.[3–6] In the Asia Pacific region, FH is estimated to affect at least 15 million people.[7] Among them, China alone may account for more than half of the FH patients as it is the world's most populous country. The general knowledge regarding FH is not very unfamiliar for medical professionals. Premature ASCVD is a great concern in FH patients due to the extremely high plasma LDL-C concentration. If homozygous FH (HoFH) is left untreated, tendon xanthomas may usually be detected.[2] Since the 1950s, FH patients have been divided into heterozygous FH (HeFH) and HoFH, and diagnosing HeFH and HoFH based on the phenotypic features of ASCVD or xanthomas has frequently been difficult without the DNA analysis of FH genes.[3] With the development of genetic testing technology, multiple studies revealed that a severe defect in the ability to bind and internalize LDL particles was caused by mutations in both alleles of the gene encoding the LDL receptor (LDLR).[8] Recent genetic insights indicate that besides LDLR (approximately 75%–95%), mutations in alleles of other genes including apolipoprotein B (ApoB), proprotein convertase subtilin/kexin9 (PCSK9), and LDLR adapter protein 1 (LDLRAP1) may also be a cause in few FH patients, which can result in impaired LDL metabolism, leading to life-long elevations in LDL-C and increased risk for premature ASCVD.[8–10] Currently, it is estimated that this unique disease of abnormal cholesterol metabolism presents in all racial and ethnic groups affecting 1 of 200–500 individuals worldwide and is now increasingly recognized as a global health issue.[5,6] From the perspectives of theory and clinical practice, FH as a major global public health challenge is even more serious in China. First, China is the largest country in the world and accounts for nearly one-fifth (18.84%) of the total 6.7 billion of the world's population. A commonly cited estimation of the frequency of HeFH is 1/500 (0.2%), which was calculated from the FH frequency in survivors of myocardial infarction (MI), of <60 years of age in a single study with some assumptive frequencies, including the prevalence of CAD in the population of the US.[4] However, contemporary data have suggested a higher frequency, highlighting that the burden of the disease is increasing including in the Chinese population.[9,10] According to the recently published 2016 Chinese guidelines for the management of dyslipidemia in adults (2016 revised version), the prevalence of dyslipidemia in Chinese adults reaches as high as 40.4% and covered approximately 160 million individuals.[11] This implies that at least seven millions of Chinese individuals may be classified as HeFH according to the commonly cited overall frequency estimation. Furthermore, a Chinese FH patients’ study with a large sample size from Beijing Fuwai hospital has recently reported that 3.5% of the patients were identified with definite/probable FH phenotype (definite, 1.0% and probable, 2.5%).[9] This study enrolled 8,050 consecutive patients undergoing coronary angiography (CAG) due to angina-like chest pain, and FH was diagnosed made using Dutch Lipid Clinic Network (DLCN) criteria and target exome sequencing in LDLR, ApoB, and PCSK9 genes. Simultaneously, another study by the same researchers showed that in 1843 consecutive patients with myocardial infraction (MI), the prevalence of definite/probable FH was 3.9% (7.1% in patients with premature MI and 0.9% in those with non-premature MI).[10] The authors concluded that the prevalence of FH among Chinese patients with MI or undergoing CAG appeared to be common, particularly among those with premature MI. These data strongly emphasize that FH is not uncommon in China. Therefore, FH should be considered as a condition of high concern, and more efforts are needed for its management. Another challenge is the change in the pattern of lipids during the past several years in China. Although the serum LDL-C concentration and the frequency of CAD may be slightly lower in the Chinese population than those before. With rapid economic growth and lifestyle changes, Chinese populations are experiencing increased cardiovascular risk and cardiovascular disease has become the leading cause of death.[11] A national prospective cohort study performed between 1991 and 2000 reported that 43.8% of deaths in Chinese adults of ≥ 40 years of age were attributable to CAD and stroke.[12] A report from the China National Diabetes and Metabolic Disorders Study (CNDMDS) comprising 46,232 Chinese adults suggests an alarm that levels of total cholesterol (TC) and LDL-C are considerably higher than those previously reported in the general Chinese population.[13] Accordingly, the increasing cholesterol levels have changed the FH phenotype in China, which may be another challenge in its diagnosis. Moreover, early diagnosis as well as effective treatment strategies in affected children with FH are challenges among experts, especially in China due to the single-child policy.[14] Single-child policy which lasted for more than half of a century, resulted in many single-child families. This phenomenon has a high impact on the family in terms of economics burden, psychological stress, healthcare issues, and domestic happiness. Hence, earlier screening of FH individuals including parent-mediated early diagnosis and intervention is important for single-child families.[15] Hence, parent-mediated early diagnosis and treatment for young children are the best strategies for prevention of premature ASCVD and improvement of survival in FH, especially in HoFH patients in the single-child society setting. Furthermore, improving public and healthcare professionals’ awareness of FH is another way for early diagnosis of FH. It is worth emphasizing that Chinese medical professionals should be obliged to actively take part in a global call for FH management.[16] In China, many people are unaware of FH, even among medical professionals who are working in well-known hospitals located in the first line cities. To improve the awareness, knowledge, and perception of FH among practitioners and hospitalized patients, a FH survey was recently performed in multiple cardiovascular centers including Beijing, Shanghai, Guangzhou, Wuhan, and Changchun (unpublished data). Surprisingly, among 345 cardiologists and 1,083 hospitalized patients with CAD, <10% of doctors recognized that an individual with plasma LDL-C >6.5 mmol/L might be considered as a diagnosis of FH (probable), and 3% of them answered that a person whose plasma LDL-C levels are > 8.5 mmol/L should be diagnosed as FH. Although as high as 82% of hospitalized patients vaguely considered that lipid disorders could be genetically inherited, only 0.7% of them learned about FH through consultation of a health website before hospitalization. More importantly, <50% of the investigated patients did not recognize that consistent elevated plasma LDL-C level was a risk factor of CAD. Therefore, a program of FH course for professionals and more propaganda for the population are urgently needed to improve the management of FH in China. Besides early diagnosis, early intervention of FH is crucial for the prevention of CAD. FH represents a major gap in preventive medicine and is clearly a public health problem. Considering the public health challenges that FH poses, gaps in care are currently being addressed by clinicians and researchers worldwide. Treatment of elevated LDL-C concentration in FH involves dietary and lifestyle management and pharmacotherapy. Statins are the mainstay pharmacotherapy and are supported by new evidence. A proportion of patients may need additional therapy with ezetimibe or bile-acid sequestrants. Furthermore, PCSK9 inhibitors are also recommended to treat FH. Without treatment, approximately 50% of men and 30% of women experience an ASCVD-related event by age 50 and 60 years, respectively. Evidence has shown that young adults with 20 years of statin therapy started in childhood had lower rates of both ASCVD-related events (1%) and death (0%) than their affected parent at a comparable age (26% and 7%, respectively), who started statin therapy later in life. According to previous studies,[17,18] 750,000 cases of CAD onset and 10,500 CAD deaths could be prevented if early intervention be employed based on the estimated seven million HeFH patients in China. Hence, early and appropriate intervention is of high importance. In addition, although China has already developed its own diagnostic criteria for FH, which is simpler and more convenient for clinically early diagnosis, more efforts are needed for its popularization and application. During the past several decades, there were scarce studies focusing on FH in China, which were mainly presented as case reports.[19] More recently, a novel modified system of simplified Chinese criteria for FH has been developed.[20] In this criteria, definite FH could be diagnosed in patients who meet any two out of the three items: LDL-C > 4.8 mmol/L, tendon xanthomas, and DNA mutation, which has similar sensitivity and specificity with the Simon Broome (SB) criteria and the Dutch Lipid Clinic Network (DLCN) criteria demonstrated by a large Chinese cohort.[20] However, these novel criteria need to be generalized in Chinese population. Studies in Chinese general population are required to test and confirm these novel FH criteria. Finally, China needs more joint efforts to respond to FH-related global call to arms due to the basic features of developing countries and imbalance in economics. As well-known, there is a great difference of health insurance system and economic growth between urban and rural areas in China, which may influence the early-diagnosis of FH in children and adolescents.[16] Early detection of FH is difficult due to lack of conventional physical examination, especially in vast rural areas of rural China. Universal lipid screening is not conventionally used in some parts of rural area. More efforts are needed for FH screening, early diagnosis, and early treatment, such as establishing a special network and foundation, performing a registry study, and strengthening the publicity.[21] The professionals, society, and even government should pay attention to this issue. Universal lipid screening FH in children between the ages of 9 and 11 years and common genetic cascade screening for FH in patients with premature CAD or LDL-C > 4.9 mg/dL may be the most effective strategies to improve the efficacy of early identification and management of FH in China.[1,2] China may bear a heavy health burden as the most populous country in the world.[22,23] Conclusion FH is a common genetic disease characterized by premature ASCVD, which is associated with higher cardiovascular events but is preventable and treatable. With one-sixth of the world's population of individuals who are living with FH residing in China, the time has come to action for FH individuals. The phenotype of FH in China and other Chinese populations is now comparable to that in Western countries and the prevalence of FH in the general population is also similar. However, only a very small proportion of cases has been identified and treated. Although intensive statin treatment or statin plus ezetimibe or PCSK9 inhibitor is recommended for Chinese FH patients, the LDL-C target is often not achieved. Despite a high progress in FH management in China during the last decade, more efforts are needed to improve the current situation of our patients with FH, including engaging healthcare professionals, developing public awareness campaigns, and establishing national FH alliances. Universal lipid screening in children and common or expanded genetic cascade screening for FH in patients with premature CAD or LDL-C > 4.9 mg/dL may be the most effective strategies. Finally, optimization of patient care pathways is critical to improve both the rate of diagnosis and the management of FH patients. In summary, although the progress in FH management has been made in China during the past years, greater efforts are still needed in the future. Funding This work was partially supported by the Capital Health Development Fund (201614035), and CAMS Major Collaborative Innovation Project (2016-I2M-1-011) awarded to Dr Jianjun Li, MD, PhD. Conflict of interest statement The author has no conflict of interest with regard to the content of this manuscript.

Background Familial hypercholesterolemia is a common autosomal dominant disease, caused by mutations leading to elevated low-density lipoprotein (LDL) cholesterol and, if untreated, to premature cardiovascular disease. Methods Patients (young adults with a family history of hypercholesterolaemia or premature cardiovascular disease) with LDL cholesterol concentration ≥4.9 mmol/l, after excluding Familial Combined Hyperlipidaemia, were evaluated for causative mutations, Dutch Lipid Clinic Network score calculation and non-invasive ultrasound examination of carotid arteries. Results Of the 263 patients, 210 were heterozygotes for LDL receptor ( LDLR) mutations, four had APOB gene mutations, one PCSK9 gene mutation, while 48 had no evidence of mutations. Among 194 unrelated index cases 149 had mutations (77%). Among patients with LDLR mutations ( n = 145), there were five compound heterozygotes, 75 patients with null mutations and 65 with missense mutations. As many as 178 patients underwent a follow-up and treatment (statin ± ezetimibe), achieving a mean reduction of 49% in LDL cholesterol, with 21% of patients reaching the LDL goal of 2.6 mmol/l. In a multivariate analysis, carotid plaques, at ultrasound examination, were associated with the presence of genetic mutation ( p = 0.001), LDL cholesterol ( p < 0.001), Dutch Lipid Clinic Network score ( p < 0.001), independently of age, gender, smoking habits and systolic blood pressure. The presence of carotid plaque ( p = 0.017), LDL cholesterol ( p < 0.003), Dutch Lipid Clinic Network score ( p < 0.001) were independently associated with premature cardiovascular disease. Conclusions We identified patients with causative mutations in 82% of the cases under study. In addition to LDL cholesterol and Dutch Lipid Clinic Network score, carotid plaques in ultrasound evaluation provide direct evidence of premature vascular disease and are associated with high risk for cardiovascular events.