Prevalence and Clinical Characteristics of Familial Hypercholesterolemia in Patients with Acute Coronary Syndrome according to the Current Japanese Guidelines: Insight from the EXPLORE-J study

Abstract

Aims: Little data exists for evaluating the prevalence and patient characteristics of familial hypercholesterolemia (FH) according to the latest 2022 guidelines for FH published by the Japan Atherosclerosis Society (JAS), which revised the Achilles tendon thickness (ATT) threshold from 9.0 mm in both sexes to 8.0 mm in men and 7.5 mm in women. This study used a nationwide registry of patients with acute coronary syndrome (ACS) to evaluate the prevalence of FH according to the latest diagnostic criteria for FH and to investigate the application of Achilles tendon imaging in the diagnosis of FH.

A previous prospective observational study at 59 Japanese centers involving consecutive patients with ACS who were managed between April 2015 and August 8, 2016 was conducted to explore lipid management and persistent risk in patients hospitalized for ACS (EXPLORE-J). The study population consisted of 1,944 EXPLORE-J enrollees.

Results: According to the diagnostic criteria for FH in the 2022 JAS guidelines, the prevalence of probable or definite was among patients with ACS was 6.6% (127/1944). Among patients with premature ACS (male, age ＜55 years; female, age ＜65 years), the prevalence of FH was 10.1% (43/427). The mean ages were of the probable FH and definite FH groups were 59.9 and 61.0 years, respectively, while the mean age of the possible-or-unlikely FH group was 66.4 years (significantly older). Relative to the possible-or-unlikely FH group, the low-density lipoprotein cholesterol (LDL-C) levels were similar in the probable FH group and and significantly higher in the definite FH group.

Conclusions: The prevalence of FH was considerably higher than previously reported, especially for patients with premature ACS. The age and LDL-C levels of the patients in the probable FH and definite FH groups were similar.

See editorial vol. 32: 20-22

Introduction

Familial hypercholesterolemia (FH) is an inherited disorder caused by mutations in genes associated with the LDL receptor (LDLR) pathway, including LDLR, proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein B (APOB), and LDL receptor adaptor protein 1 (LDLRAP1)¹⁾. Patients with FH are at high risk of developing premature atherosclerotic cardiovascular disease; hence, early detection and lipid-lowering therapy are important^1-5). Although the worldwide prevalence of FH was previously estimated to be 1/500, recent studies have reported a prevalence of 1/250 ^{6, 7)}. A Japanese study conducted in Hokuriku district reported that the prevalence of FH was 1/208, suggesting that there are approximately 300,000 patients with FH in Japan⁸⁾. However, the actual number of patients diagnosed in Japan was lower than expected because physicians showed a lack of awareness of the guidelines for FH^{9, 10)}. To educate physicians about FH and standardize its diagnosis and treatment, the guidelines for FH published by the Japan Atherosclerosis Society (JAS) have uniquely used the measurement of Achilles tendon thickness (ATT)⁷⁾. However, in the prior guidelines for FH published by the JAS in 2017 (2017 JAS guidelines), the cutoff value of ATT 9 mm in both sexes was based on a single-center study from 1977, and showed low sensitivity and high specificity¹¹⁾. As previously noted, using this threshold value results in low sensitivity in the diagnosis of FH. Therefore, the JAS has revised several items in the latest diagnostic criteria for FH, which were included in the guidelines for FH published by the JAS in 2022 (2022 JAS guidelines). The most important change from the previous guidelines was to establish a more appropriate ATT threshold of ≥ 8.0 mm in males and ≥ 7.5 mm in females based on multicenter data^{12, 13)}. Another important change in the criteria was the establishment of detailed classifications of FH (i.e., definite FH, probable FH, and FH). After the revision of the diagnostic criteria for FH, the prevalence of FH may have changed; therefore, it is essential to more accurately assess the prevalence of FH, particularly in patients with acute coronary syndrome (ACS) who are at high risk for recurrent cardiovascular events. Therefore, the present study aimed to use a nationwide registry of patients with ACS to evaluate the prevalence of FH according to the new diagnostic criteria for FH in patients with ACS and to investigate the diagnosis of FH based on Achilles tendon imaging.

Methods

Study Population

Exploration of lipid management and persistent risk in patients hospitalized for ACS in Japan (EXPLORE-J) was performed in a prospective observational study conducted at 59 centers across Japan, which enrolled consecutive patients who presented with ACS between April 2015 and August 2016. The design of this study has been previously described^14-16). Patients of ≥ 20 years of age who presented with ACS, including ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), or unstable angina, at the time of informed consent were eligible for inclusion in the present study. The details of the inclusion and exclusion criteria have been reported previously^14-16). The study population consisted of 1944 patients enrolled in the EXPLORE-J study.

This study was conducted in accordance with the principles outlined in the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects (enacted on December 22, 2014). The ethical review committees of all participating centers approved the study protocol. All patients provided their written informed consent before participation.

Genetic Examination

Informed consent was obtained from all the participants for genetic testing. We have previously described the details of genetic testing¹⁷⁾. We evaluated single-nucleotide variations or insertions/deletions in genes encoding key proteins. Specifically, we analyzed mutations in genes involved in the LDLR endocytic and recycling pathways, namely, LDLR, PCSK9, APOB, and LDLRAP1. The genetic mutations were categorized as follows: nonpathogenic variant (denoted as “−”), indeterminate pathogenic variant (denoted as “±” indicating that it had not been previously reported but could be pathogenic), and pathogenic variant (denoted as “＋” indicating a reported association with FH pathogenicity). To determine the pathogenicity of the variants detected in LDLR or PCSK9, we used various resources, including ClinVar, Leiden Open Variation database, population data from the Exome Aggregation Consortium, Japanese Human Genetic Variation Database, and Tohoku Medical Megabank Organization. In addition, we employed in silico tools/software and functional data based on the guidelines provided by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Definitions of FH

In this study, the definition of FH was based on diagnostic criteria for FH in the 2022 JAS guidelines¹³⁾. Definite FH was diagnosed if ≥ 2 of the following 3 criteria were met: I) untreated LDL cholesterol (LDL-C) ≥ 180 mg/dL, II) presence of tendon xanthomas or cutaneous nodular xanthomas, and III) a family history of FH or premature coronary artery disease (CAD) among first-degree relatives. The diagnosis of Achilles tendon thickening was determined by radiography, with measurements of ≥ 8.0 mm in men and ≥ 7.5 mm in women. Probable FH was strongly suspected if the LDL-C level was ≥ 250 mg/dL or the criteria II) or III) were met and the LDL-C level was ≥ 160 mg/dL, even if some of the criteria were not fulfilled. Furthermore, even if none of the aforementioned conditions were present and if the patient met the criteria I) or II) and had a first-degree relative with an LDL-C level of ≥ 180 mg/dL or a diagnosis or history of premature CAD, the patient was still considered to have FH (possible FH). In this study, we adopted a family history of FH or premature coronary artery disease (CAD) among second-degree relatives, because we collected data on second-degree relatives according to the prior guidelines for FH. In this study, definite and probable FH were defined as FH. In addition, FH can generally be diagnosed if pathogenic genetic mutations are identified.

Assessments

The assessment of FH was based on the highest available LDL-C measurement obtained at visit 1. LDL-C measurements obtained before hospitalization without treatment and the first measurement after hospitalization were included in the analysis, regardless of the method used. LDL-C levels were assessed at visit 1, which occurred at ≤ 14 days of hospitalization for ACS and subsequently at each visit throughout the 2-year observation period. Both the direct and calculated measurements were considered. As previously described, ATT was measured by three highly trained readers who were blinded to the patients’ clinical characteristics¹¹⁾. ATT measurements using radiographs obtained during hospitalization for study registration were performed at each site and at the central reading laboratory. However, the radiographic measurements conducted during visit 3 were deemed acceptable.

During enrollment, information regarding the family history of CAD, ischemic cerebral infarction, and hypercholesterolemia among first- and second-degree relatives was collected. FH was diagnosed based on a family history of premature CAD.

Statistical Analysis

The details of the statistical analysis and sample size calculations in this study have been reported previously^{14, 18)}. Continuous variables were expressed as the mean±standard deviation (SD) or median with interquartile range (IQR). To compare continuous variables, we performed Student’s t-test or the Wilcoxon rank-sum test, depending on the data distribution. Categorical variables were expressed as frequencies and percentages and were compared using Fisher’s exact test. The Mann–Whitney U-test was used to compare categorical variables as nominal or ordinal.

R version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria) was used to perform all analyses. All reported p values were two-tailed, and p values of ＜0.05 were considered to indicate statistical significance.

Results

Prevalence of FH in Patients with ACS according to the Diagnostic Criteria of the JAS 2017 and JAS 2022 Guidelines

The distribution of ATT is shown in Fig.1. 6.7% of patients met the criteria for Achilles tendon thickening according to the diagnostic criteria of the prior 2017 JAS guidelines, with a cutoff value of 9.0 mm for both sexes. In contrast, 15.6% of patients met the diagnostic criteria of the latest 2022 JAS guidelines, with cutoff values of 8.0 mm in men and 7.5 mm in women (Fig.1).

Fig.1.

Distribution of Achilles tendon thickening

When accounting for the 3 components of the diagnostic criteria for FH, LDL-C, xanthomas, and family history of premature CAD, the prevalence of FH in patients with ACS was 6.6% (127/1944 [definite FH, 4.4%, probable FH: 2.2%]) (Fig.2). When focusing on patients with premature ACS, the prevalence of FH was 10.1% (43/427 [definite FH, 6.6%; probable FH, 3.5%) (Supplemental Fig.1).

Fig.2.

Diagnosis of FH in the (A) 2017 JAS guidelines and (B) 2022 JAS guidelines

Supplemental Fig.1.

Diagnosis of FH between (A) JAS guideline 2017 and (B) JAS guideline 2022 among premature ACS patients

Baseline Characteristics according to the FH Status at the Index Hospitalization for ACS

The mean ages of the probable FH and definite FH groups were 59.9 years and 61.0 years, respectively (Table 1). In contrast, the mean age of the possible-or-unlikely FH group was 66.4 years, which was significantly older in comparison to the probable FH and definite FH groups. The LDL-C levels of the probable FH and definite FH groups were significantly higher in comparison to the possible-or-unlikely FH group. The LDL-C levels of the probable FH and definite FH groups were numerically similar (Table 1).

Table 1.Baseline characteristics of the possible-or-unlikely FH, probable FH, and definite FH groups

	Entire (N = 1944)	Possible-or- unlikely FH (N = 1817)	Probable FH (N = 42)	Definite FH (N = 85)	p value	Number of patients evaluated
Age (years), mean (SD)	66.0±12.2	66.4±12.1	59.9±12.3	61.0±12.2	＜0.001	1944
Men, n (%)	1561 (80%)	1457 (80%)	34 (81%)	70 (82%)	0.63	1944
BMI (kg/m2), mean (SD)	24.2±3.6	24.2±3.6	24.9±3.5	24.8 ±3.5	0.16	1937
PCSK9 (ng/mL), median (Min, Max)	355 (103–1158)	353 (103–1158)	355 (199–636)	372 (153–810)	0.20	1887
LDL-C (mg/dL), mean (SD)
Highest available level at baseline (1, 2, 3, or 4)	127.2±39.5	122.7±34.4	185.8±39.4	192.1±56.5	＜0.001	1924
1) Measurement without medication before hospitalization	132.6±38.2	128.6±35.0	172.4±55.4	174.0±40.5	＜0.001	380
2) First measurement after hospitalization	121.3±40.0	117.0±35.0	166.7±42.7	184.6±60.2	＜0.001	1827
3) Direct method	101.8±33.2	99.0±29.2	125.2±36.3	145.7±60.5	＜0.001	1439
4) Calculated	99.4±31.9	96.9±28.6	128.6±42.7	137.9±52.8	＜0.001	1797
ACS type, n (%)					0.87	1944
STEMI	1195 (62%)	1116 (61%)	25 (60%)	54 (64%)
NSTEMI	309 (16%)	287 (16%)	9 (21%)	13 (15%)
Unstable angina	440 (23%)	414 (23%)	8 (19%)	18 (21%)
Medical history, n (%)
Coronary artery disease	355 (18%)	342 (18.8%)	2 (4.8%)	11 (12.9%)	0.07	1944
Cerebrovascular accident	149 (7.7)	141 (7.8%)	1 (2.4%)	7 (8.2%)	0.60	1944
Peripheral artery disease	37 (1.9)	31 (1.7%)	1 (2.4%)	5 (5.9%)	0.11	1944
Diabetes mellitus	679 (35%)	637 (35%)	10 (23.8%)	32 (37.7%)	0.27	1944
Hypertension	1427 (73%)	1344 (74.0%)	25 (59.5%)	58 (68.2%)	0.06	1944
Dyslipidemia	1512 (78%)	1393 (76.7%)	39 (92.9%)	80 (94.1%)	＜0.001	1944
Therapy before hospitalization						1944
Any LMT, n (%)	625 (32%)	595 (32.8%)	12 (28.6%)	18 (21.2%)	0.07	1944
Statin	530 (27%)	506 (27.9%)	9 (21.4%)	15 (17.7%)	0.08	1944
High-intensity statin	30 (1.5%)	30 (1.7%)	0 (0.0%)	0 (0.0%)	0.82	1944
Fibrates	35 (1.8%)	33 (1.8%)	1 (2.4%)	1 (1.2%)	0.84	1944
EPA/DHA	70 (3.6%)	69 (3.8%)	0 (0.0%)	1 (1.2%)	0.31	1944
Ezetimibe	40 (2.1%)	37 (2.0%)	1 (2.4%)	2 (2.4%)	0.65	1944
Antiglycemic (except insulin)	382 (20%)	365 (20.1%)	6 (14.3%)	11 (12.9%)	0.20	1944
Antiglycemic (insulin)	77 (4.0%)	75 (4.1%)	1 (2.4%)	1 (1.2%)	0.45	1944
Genetic testing	430 (22%)	399 (22%)	11 (26%)	20 (24%)	0.77	1944
Pathogenic variants	10/430	9/399	0/11	1/20
Intermediated variants	25/430	21/399	2/11	2/20

FH, familial hypercholesterolemia; BMI, body mass index; PCSK9, proprotein convertase subtilisin/kexin type 9; LDL-C: LDL cholesterol; ACS, acute coronary syndrome; STEMI, ST-elevation myocardial infarction; NSTEMI, non-ST-elevation myocardial infarction; LMT, left main trunk; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid.

Regarding lipid-lowering treatment before hospitalization, only 18% of the patients in the definite FH group and 21% of the patients in the probable FH group took statins. None of the patients received a high-intensity statin before the index hospitalization (Table 1).

Genetic Characteristics

Among the entire cohort, 430 patients underwent genetic screening and were analyzed. Pathogenic variants were identified in 25 patients (5.8%), as previously described¹⁷⁾. Among the patients with a pathogenic variant, 10 (40.0%) had a pathogenic LDLR variant and 15 (60.0%) had a pathogenic PCSK9 variant (Supplementary Table 1). An indeterminate variant was identified in 10 (2.3%) patients (Supplementary Table 2). Among patients with an indeterminate variant, 5 (50.0%) had indeterminate LDLR variants and another 5 (50.0%) had indeterminate PCSK9 variants. According to the diagnostic criteria of the 2017 JAS guidelines, none of the patients with either pathogenic or intermediate variants fulfilled the diagnostic criteria for FH. In contrast, of 2/25 (8%) patients with a pathogenic variant fulfilled the diagnostic criteria of the 2022 JAS guidelines (Supplemental Table 1). In addition, 10% (1/10) of patients with an indeterminate variant fulfilled the diagnostic criteria of the 2022 JAS guidelines (Supplemental Table 2).

Supplemental Table 1.Characteristics of patients with pathogenic variants

Age, years	Sex	FH diagnosis by the JAS criteria 2022	Premature CAD family history	Highest LDL-C level, mg/dL	ATT, mm	Gene	Mutation	Amino Acid
50–59	Male	No	No	119	7.9	PCSK9	c.94G > A	p. E32K
50–59	Male	No	N/A	136	6.2	LDLR	c.344G > A	p. R115H
60–69	Male	No	N/A	146	8.2	PCSK9	c.94G > A	p. E32K
50–59	Male	No	N/A	154	6.2	LDLR	c.344G > A	p. R115H
70–79	Male	No	No	78	8.8	PCSK9	c.94G > A	p. E32K
70–79	Male	No	No	109	5.8	LDLR	c.344G > A	p. R115H
70–79	Female	No	No	245	6.2	PCSK9	c.94G > A	p. E32K
60–69	Male	No	No	221	5.6	PCSK9	c.94G >A	p. E32K
40–49	Male	No	No	168	8.9	LDLR	c.1845 + 2T > C	N/A
80–89	Male	No	No	136	6.9	PCSK9	c.94G > A	p. E32K
60–69	Male	No	No	204	6.1	PCSK9	c.94G > A	p. E32K
60–69	Male	No	No	151	N/A	PCSK9	c.94G > A	p. E32K
70–79	Female	Definite FH	Yes	113	7.8	LDLR	c.810C > A	p. C270X
50–59	Female	No	No	290	5.3	PCSK9	c.1486C > T	p. R496W
60–69	Female	No	No	98	7.4	LDLR	c.1784G > A	p. R595Q
70–79	Female	No	No	153	17.5	LDLR	c.2390-2A > T	N/A
60–69	Male	No	No	126	5.7	PCSK9	c.94G > A	p. E32K
60–69	Male	No	No	188	6.4	LDLR	c.1747C > T	p. H583Y
30–39	Male	Definite FH	No	300	8.2	PCSK9	c.94G > A	p. E32K
60–69	Male	No	N/A	103	6.7	LDLR	c.1783C > T	p. R595W
60–69	Male	No	N/A	173	6.3	PCSK9	c.94G > A	p. E32K
70–79	Male	No	N/A	122	N/A	LDLR	c.1702C > G	p. L568V
70–79	Male	No	N/A	121	7.2	PCSK9	c.94G > A	p. E32K
60–69	Female	No	No	108	12.8	PCSK9	c.94G > A	p. E32K
60–69	Male	No	No	167	6.8	PCSK9	c.94G > A	p. E32K

Supplemental Table 2.Characteristics of patients with intermediate variants

Age, years	Sex	FH diagnosis by the JAS criteria 2022	Premature CAD family history	Highest LDL-C level, mg/dL	ATT, mm	Gene	Mutation	Amino Acid
50–59	Male	No	No	141	7.7	PCSK9	c.1765G> A	p. V589M
60–69	Male	Definite FH	No	191	8.7	LDLR	c.211G> A	p. G71R
60–69	Male	No	N/A	142	6.3	LDLR	c.211G> A	p. G71R
70–79	Male	No	Yes	115	N/A	PCSK9	c.212C> T	p. P71L
80–89	Female	No	No	112	6.6	PCSK9	c.1954A> G	p. N652D
80–89	Male	No	No	91	5.3	PCSK9	c.1975C> G	p. R659G
80–89	Female	No	N/A	89	N/A	PCSK9	c.1727C> T	p. P576L
70–79	Female	No	No	166	6.2	LDLR	c.2257C> T	p. P753S
50–59	Male	No	No	158	7.4	LDLR	c.1546G> A	p. G516S
50–59	Male	No	No	150	10.2	LDLR	c.1834G> T	p. A612

Among the 430 patients who underwent genetic testing, the prevalence of definite and probable FH diagnosed according to both clinical criteria and genetic testing was 12.6% (Supplemental Fig.2).

Supplemental Fig.2.

Diagnosis of FH among patients who underwent genetic testing

Discussion

The key findings of this study are as follows: 1) According to the diagnostic criteria of the 2022 JAS guidelines, the prevalence of FH (definite or probable) was 6.6% (127/1944). 2) Among patients with premature ACS, the prevalence of FH (definite or probable) was 10.1% (43/427). 3) Among the patients with pathogenic variants, only 8% fulfilled the diagnostic criteria for FH in the 2022 JAS guidelines.

FH is an inherited disorder associated with an elevated risk of premature cardiovascular events^1-5). Rigorous lipid management is crucial, especially in patients with FH ACS¹³⁾. However, FH is often underdiagnosed because of the limited dissemination of guidelines for FH among physicians^{9, 10)}. In response, the diagnostic criteria for FH in the 2017 JAS guidelines established three diagnostic criteria, including ATT assessment, recognizing that LDL-C levels could transiently decrease in serious conditions such as acute myocardial infarction⁷⁾. However, the 2017 JAS guidelines set the cutoff value of the ATT at 9 mm in both sexes based on a study published in 1977. This threshold showed that had low sensitivity and high specificity. Consequently, many patients missed the opportunity to be diagnosed with FH. To address this, the diagnostic criteria for FH in the latest 2022 JAS guidelines used recent data to change the cutoff value to 8.0 mm in males and 7.5 mm in females, which was one of the most significant changes to the diagnostic criteria^{12, 13)}. In this study, we found that patients newly diagnosed according to the JAS 2022 criteria showed a similar phenotype to patients diagnosed using the JAS 2017 criteria. Moreover, the age and LDL-C level of probable FH patients were similar to those of definite FH patients. These results indicate the appropriateness of the latest criteria for FH, and we believe that the new criteria should help estimate the prevalence of FH more accurately.

The findings revealed that modifications to the guidelines led to a notable increase in the prevalence of Achilles tendon thickening detected by X-ray, increasing from 6.7% to 15.6% among patients with ACS. Furthermore, within the cohort definitively diagnosed with FH, the occurrence of xanthomas significantly increased from 85% to 93%, with only 7% of patients without xanthomas receiving a diagnosis of FH. Similarly, the proportion of patients with xanthomas was highest in the probable FH group, indicating the importance of continuing physical examinations and testing for suspected FH.

In addition, by adapting the latest 2022 JAS guidelines, the prevalence of FH increased from 4.5% to 6.6%, reaching as high as 10% among premature ACS patients. In contrast, even with the revised criteria in 2022, only 8% of the genetically confirmed FH cases fulfilled the phenotypic diagnostic criteria for FH. Although we argue that underestimation has been mitigated by the updated criteria, we stress the importance of actively trying to diagnose patients with FH by performing genetic testing, particularly in cases of premature ACS, even if the specified diagnostic criteria are not met. This recommendation is crucial, considering the prevalence of FH observed in the present study. Considering that potential LDL-C fluctuations in serious conditions¹⁹⁾ including ACS and the diagnosis of definite FH are also made in the presence of pathogenic gene mutations associated with FH, the actual prevalence of FH might be higher.

The prevalence of definite or probable FH was 12.6% among patients who underwent genetic testing. Therefore, FH should be considered in patients with premature ACS, even in those with normal LDL-C levels. We emphasized that components of the diagnostic criteria for FH other than the LDL-C level are more important in the diagnosis of FH in patients with ACS, considering that LDL levels tend to be lower in patients with ACS. Therefore, it is recommended that information on components other than LDL-C be carefully collected, with genetic testing performed as appropriate.

Although the diagnostic criteria for FH in the 2022 JAS guidelines indicate that the prevalence of FH is considerably higher than previously estimated, only 8% of the pathogenic variants meet these latest diagnostic criteria. One reason is that LDL-C is reported to temporarily decrease during the acute phase of ACS, potentially leading to the underestimation of LDL-C levels. The second reason pertains to the difficulty in obtaining a comprehensive family history in patients with FH. This inquiry may not have been thorough, given that a detailed inquiry focused on FH is necessary for an accurate family history assessment. A third reason is that half of the pathological mutations in genes are associated with a particular PCSK9 gain-of-function variant (p.E32K), with milder phenotypes than those of the LDLR variants²⁰⁾. Although the current 2022 JAS guidelines have reduced underestimation relative to the previous guidelines, there was still a limitation regarding the individual components of the diagnostic criteria for FH in the current study. To address this issue, the diagnostic criteria in the most recent 2022 JAS guidelines considered premature ACS alone as a diagnostic factor for possible FH.

Limitations

The present study was associated with several limitations that should be considered when interpreting our results.. First, some of the constraints associated with our research include limited availability of data on untreated LDL-C levels and a lack of information regarding the family history of FH. Second, registry data are inherently susceptible to bias. Nevertheless, we mitigated the selection bias by enrolling consecutive patients. Third, in the 2022 JAS guidelines, the diagnostic criteria for FH include FH or premature CAD in first-degree relatives. However, we only had data on second-degree relatives. However, considering each component of the FH criteria, the prevalence rates of a family history of FH or premature CAD was lower than that of the other components. Therefore, we believe that there was no significant effect on the estimates of the prevalence of definite or probable FH. Finally, this study exclusively focused on the Japanese population, thereby limiting its global applicability. Despite these limitations, EXPLORE-J is the largest registry study to use Achilles tendon imaging results to investigate the diagnosis of FH. The prevalence of FH in patients with ACS was higher in comparison to previous studies.

Conclusion

According to the diagnostic criteria for FH in the latest 2022 JAS guidelines, the prevalence of FH is considerably higher than that reported in previous studies, especially for patients with premature ACS. The age and LDL-C levels of the probable FH and definite FH groups were similar.

Acknowledgements

The authors thank Junya Ako (Kitasato University), Hidenori Arai (National Center for Geriatrics and Gerontology), Atsushi Hirayama (Nihon University School of Medicine), Atsushi Nohara (Ishikawa Prefectural Central Hospital), and Masato Nakamura (Toho University Ohashi Medical Center) for organizing this study.

Sources of Funding

This study was sponsored by Sanofi and Regeneron Pharmaceuticals, Inc.

Conflicts of Interest

AT is an employee of Sanofi K.K. MHS received honoraria from Astellas Amgen, Astellas, Sanofi, Aegerion, Kaneka Kowa, and MSD and research grants from Astellas Amgen, Astellas, Sanofi, Aegerion, and MSD. YT, HT, and MT had no COI.

Author contributions

Yasuaki Takeji contributed to the data analysis, drafting, and revision of the manuscript. Hayato Tada contributed to the revision of the manuscript for important intellectual content. Masayuki Takamura contributed to the revision of the manuscript for important intellectual content. Akiyoshi Tomura contributed to the data analysis, drafting, and revision of the manuscript. Mariko Harada-Shiba contributed to drafting and revised the manuscript. All authors approved the final version of the manuscript and agreed to be accountable for all aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved.

Data Statement

The data in this trial are available from the corresponding author upon reasonable request.

Declaration of Generative AI and AI-Assisted Technologies in the Writing Process

AI and AI-assisted technologies were not used in the writing of this manuscript.

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