Assessments of Atherosclerosis and Treatment Strategies for Heterozygous Familial Hypercholesterolemia

Abstract

Patients with familial hypercholesterolemia (FH) carry an extremely elevated cardiovascular risk because of lifelong exposure to elevated low-density lipoprotein cholesterol (LDL-C). The Japan Atherosclerosis Society (JAS) complies with the clinical guidelines of FH stipulating diagnostic criteria as well as the treatment targets based on their cardiovascular preventive status. These guidelines are expected to improve the FH diagnosis rate and facilitate better LDL-C management, ultimately leading to improved patient outcomes. However, there are no clear instructions on how and when to assess atherosclerosis. In addition, current treatment target goals, especially for adults with heterozygous FH (HeFH) (LDL-C ＜100 mg/dL in primary prevention and LDL-C ＜70 mg/dL in secondary prevention), are sometimes insufficient to fully navigate to prevent cardiovascular events, given that many factors, such as hypertension, diabetes, smoking, lipoprotein (a), cholesterol-year score, coronary artery calcium, and pathogenic mutations are associated with a further increased risk on top of the LDL-C level assessed cross-sectionally. Accordingly, we summarized contemporary strategies for assessing systemic atherosclerosis and treatment options.

Introduction

Familial hypercholesterolemia (FH) is one of the most common inherited diseases, and its prevalence is estimated to be 1 in 300 people in the general population^{1, 2)}. Patients with heterozygous FH (HeFH) typically exhibit extreme elevations of low-density lipoprotein cholesterol (LDL-C), tendon xanthomas, and premature cardiovascular disease. The most critical aspect of this disease is an early diagnosis, since initiating treatment at an earlier stage significantly improves the prognosis^3-5).

In this regard, the Japan Atherosclerosis Society (JAS) complies with the clinical guidelines of FH for adults (≥ 15 years old) and children (＜15 years old), stipulating diagnostic criteria and LDL-C treatment targets^{6, 7)}. We anticipate that the diagnostic rate of FH will increase going forward, as the new version of the clinical criteria for FH accepts the use of genetic testing of FH, which has now been covered by the Japanese National Health Insurance. However, there is no clear indication of assessments of systemic atherosclerosis in FH, particularly concerning the appropriate methods and timing for such evaluations. Furthermore, simple LDL-C target goals alone are sometimes insufficient to prevent cardiovascular events. In fact, numerous clinical conditions, such as hypertension, diabetes, and smoking; additional biomarkers, such as triglycerides, remnant cholesterol, and lipoprotein (a) (Lp[a]); genetic factors beyond FH-related genes; and subclinical atherosclerosis, including coronary artery calcium (CAC), have been associated with further increased risk among patients with FH^8-18).

Several scoring systems or classifications have been developed for further risk stratification among patients with FH, such as the Montreal-FH-SCORE, SAFEHEART-RE, and so-called “severe FH”^19-21). Therefore, we summarized contemporary strategies for assessing systemic atherosclerosis and treatment options.

1. Development of Atherosclerosis among Patients with HeFH

1.1. Systemic Complications (Table 1)

Table 1.Complications associated with HeFH

Complication	Odds ratio	Evidence level
Coronary artery disease	10- to 20-fold	E-1a
Peripheral artery disease	5- to 10-fold	E-1a
Aortic stenosis	up to 8-fold	E-3
Abdominal aortic aneurysm	up to 2-fold	E-3
Cerebrovascular disease	Neutral	E-1a

Coronary artery disease (CAD) is the most frequent and important complication in patients with HeFH. The odds ratio of CAD among patients with HeFH has been shown to be 10–20 times higher than that among individuals without FH²²⁾. Peripheral artery disease (PAD) is more prevalent in individuals with FH than in those without the condition. The odds ratio of PAD among the patients with HeFH has been shown to be 5–10 times higher than that among non-FH individuals²³⁾. Despite the lack of epidemiological evidence, abdominal aortic aneurysm and aortic stenosis have also been suggested as frequent complications^{24, 25)}. However, there is no clear evidence for an association between cerebrovascular disease and HeFH²⁶⁾.

1.2. Development of Atherosclerosis

The next question is whether or not atherosclerotic changes begin to occur in patients with HeFH. Several studies have investigated the development of atherosclerosis in patients with HeFH. For example, it has been shown that differences in intima-media thickness (IMT) assessed by carotid ultrasound among patients with HeFH appear to start as early as eight years old²⁷⁾. Tada et al. showed that carotid plaque, defined as an IMT ≥ 1.2 mm, starts to develop among patients with HeFH at approximately 17 years old in males and 26 years old in females¹¹⁾. In addition. Tada et al. showed that coronary plaque starts to develop in patients with HeFH at approximately 23 years old in males and 34 years old in females⁸⁾. In contrast, CAC among patients with HeFH starts to develop at approximately 21 years old in males and 37 years old in females²⁸⁾. Therefore, carotid ultrasound is the first choice to assess atherosclerosis during childhood, and if carotid plaques are identified, coronary computed tomography (CT) should be considered. However, it is noteworthy that the endothelial function in patients with HeFH appears to be impaired even earlier than these “morphological” atherosclerotic changes²⁹⁾.

1.3. Development of Cardiovascular Events

Now that we understand when atherosclerotic changes in patients with HeFH start to develop, the next question is when cardiovascular events, such as myocardial infarction or unstable angina, start to occur in this population. In 1989, Mabuchi et al. reported that myocardial infarction starts to occur around 30 years old in males, and around 50 years old in female^s30). This particular observational study contains several important aspects of this disease: 1) all of the patients in this study were statin-naïve, as it was conducted before the release of statins; 2) the timing of myocardial infarction onset appears to differ between males and females; and 3) the significant cardiovascular risk associated with this disease is evident even from a simple observational study with a small sample size.

2. Assessments of Clinical and Subclinical Atherosclerosis among Patients with HeFH

2.1. Carotid Ultrasound

The usefulness of carotid ultrasound in assessing subclinical atherosclerosis has been demonstrated since the 1990s³¹⁾. This technique has great advantages over other methods of assessing systemic atherosclerosis in several aspects: 1) it can assess carotid atherosclerosis non-invasively, 2) it can assess the degree of atherosclerosis directly, 3) its standardized assessment methods allow for periodic use in follow-up evaluations, and 4) it can be used for further risk stratification. In fact, the carotid IMT and/or plaque score assessed by carotid ultrasound have been associated with not only the severity of systemic atherosclerosis but also future cardiovascular events beyond traditional clinical risk factors, such as hypertension, diabetes, smoking, and LDL-C, among the general population³²⁾. The same was true for patients with HeFH. We previously showed that the carotid plaque score assessed by carotid ultrasound is significantly associated with future cardiovascular events among patients with HeFH¹¹⁾. In addition, as described above, we have shown that carotid plaques (defined as an IMT ≥ 1.2 mm) in patients with HeFH start to develop at around 17 years old in males and 26 years old in females¹¹⁾.

2.2. The Ankle-Brachial Index (ABI)/Pulse Wave Velocity (PWV)

The ankle-brachial index (ABI)/pulse-wave velocity (PWV) is also a noninvasive method for assessing systemic atherosclerosis that should be indicated for patients with HeFH. If the ABI is ≤ 0.9, then PAD is highly suspected. This should be considered in patients with HeFH, as PAD is one of the most frequent complications, as described above. Furthermore, the PWV, which can also be assessed simultaneously with the ABI, is used to assess sclerosis of the systemic arteries³³⁾. The ABI/PWV is useful for evaluating the existence of PAD as well as assessing sclerosis, for not only the general population but also patients with HeFH. We have shown that arterial stiffness assessed by the PWV is significantly associated with cardiovascular events in patients with HeFH³⁴⁾.

2.3. Cardiac CT

Cardiac CT has proven a promising tool for assessing coronary atherosclerosis since the 1990s, with its utility increasing with improvements in the resolution of CT³⁵⁾. Currently, cardiac CT has three major roles: (1) the assessment of coronary artery stenosis (morphologically), (2) the estimation of coronary artery stenosis (functionally), and (3) the assessment of CAC. Although it is more invasive than carotid ultrasound, cardiac CT can also be used to evaluate the presence of coronary atherosclerosis, including the signs of ischemia via the assessment of fractional-flow reserve. If “positive” findings are noted on cardiac CT, then we move to introduce coronary angiography, which is more invasive than cardiac CT. The degree of CAC can also be assessed using cardiac CT³⁶⁾. The most commonly used method, known as the “Agatston Score,” allows for the quantitative assessment of CAC. This score has been useful in not only the general populations but also patients with HeFH²⁸⁾.

2.4. Coronary Angiography

Despite the development of less invasive strategies, coronary angiography has been the “gold standard” for assessing coronary atherosclerosis. Coronary angiography enables the assessment of not only morphological coronary atherosclerosis but also functional ischemia using designated pressure wires, allowing clinicians to determine the need for revascularization. Coronary ectasia may be a specific morphological change in patients with FH³⁷⁾. In other words, we should always consider the possibility of FH when encountering such a clinical scenario. We proposed a flowchart for the assessment of clinical and subclinical atherosclerosis in patients with HeFH.

2.5. Strategies for Assessing Systemic Atherosclerosis among Patients with HeFH

We proposed strategies for assessing systemic atherosclerosis in patients with HeFH (Fig.1). When diagnosing patients with HeFH, it is important to assess the symptoms of angina. The standard method of assessing angina contains three items: 1) constricting discomfort in the front of the chest or in the neck, jaw, shoulder, or arm; 2) precipitation by physical exertion; and 3) relieved by rest of nitrates within 5 minutes³⁸⁾. If a patient has symptoms that meet two or more criteria, they should be considered to have typical angina; otherwise, the symptoms can be considered non-anginal. When a patient with HeFH has angina, coronary angiography should be indicated in addition to assessments of subclinical atherosclerosis via the ABI/PWV and carotid ultrasound. In patients with HeFH ≥ 20 years old who do not present with typical angina, cardiac CT should be considered unless contraindicated, and assessments, such as the ABI/PWV and carotid ultrasound, are recommended. In patients with HeFH ≤ 19 years old who do not have typical angina, ABI/PWV and carotid ultrasound assessments should be indicated.

Fig.1. Strategies for assessing systemic atherosclerosis among patients with HeFH

First, it is important to assess the presence of angina, which should be done using three items.

3. Basic treatment strategies for patients with HeFH

3.1. Statins

Since their advent, statins have been the central component of treatment strategies for not only general hyperLDL-Cemia but also patients with HeFH³⁹⁾. Statin administration should begin at a standard dose with titration to the maximum or maximum tolerated dose, while carefully observing the efficacy and checking for potential side effects. Some patients show statin intolerance⁴⁰⁾, where statins cannot be tolerated because of side effects. In such cases, other agents listed below should be considered to sufficiently lower LDL-C levels. In real-world settings, multidrug combinations are usually required to achieve treatment targets.

3.2. Ezetimibe

Ezetimibe is an important LDL-lowering option for patients with HeFH. In fact, combination therapy with statins and ezetimibe has been the “standard” medication, as LDL-C levels in HeFH are typically too high to be adequately reduced by statins alone. Currently, several combinations of statins and ezetimibe are used in Japan⁴¹⁾.

3.3. Colestimide

Colestimide is also a useful option for lowering LDL-C levels in patients with HeFH⁴²⁾. Triple therapy using statins, ezetimibe, and colestimide can reduce LDL-C by 66.4%, and 44% of patients with HeFH reportedly achieved LDL-C ＜100 mg/dL⁴³⁾.

3.4. Probcol

In Japan, a retrospective study suggested that the use of probucol delays the recurrence of CAD in HeFH⁴⁴⁾; however, its potential side effects, such as QT prolongation, should also be carefully considered.

3.5. PCSK9-Inhibitors

The combination of evolocumab or alirocumab in HeFH already treated with statins (and ezetimibe) has been shown to be relatively safe, with an additional reduction in LDL-C (approximately 60%) and Lp(a)^{45, 46)}, and its long-term safety has been confirmed up to approximately 3 years of treatment^{47, 48)}. In addition to combination therapy with statins, PCSK9 inhibitors have been shown to be useful in reducing LDL-C levels in patients with statin intolerance. In Japan, PCSK9 inhibitors can be administered without background statin therapy if the patients exhibit statin intolerance. Currently, inclisiran, a small interfering RNA (siRNA) that targets PCSK9 synthesis specifically in hepatocytes, can also be used.

3.6. Lipoprotein Apheresis

For patients with HeFH, the use of statins in combination with ezetimibe and PCSK9 inhibitors has made it possible to achieve LDL-C control targets in many cases in recent years; however, implementing lipoprotein apheresis should be considered if the patient is drug-resistant and has advanced CAD. For patients with HeFH, the Japanese National Health Insurance covers treatment in cases where the serum LDL-C level remains above 370 mg/dL in a steady state (with stable body weight and serum albumin levels) despite diet therapy, does not fall below 170 mg/dL, and in cases where coronary atherosclerosis is evident along with the presence of xanthoma. In addition, lipoprotein apheresis can be combined with PCSK9 inhibitors; however, since anti-PCSK9 antibodies are removed during lipoprotein apheresis, subcutaneous injections should be administered after lipoprotein apheresis treatment if the combination is used. In contrast, the combination of lipoprotein apheresis and treatment with a PCSK9 inhibitor reportedly enabled approximately 63% of patients to be weaned off of lipoprotein apheresis while safely achieving effective LDL-C control⁴⁹⁾.

4. Advanced Treatment Strategies (Personalized Medicine) for Patients with HeFH (Table 2)

Table 2.Risk factors for atherosclerosis among patients with HeFH

Risk factor	Impact on atherosclerosis	Modifiable
Hypertension	+++	Yes
Diabetes	++	Yes
Smoking	+++	Yes
TG/remnant cholesterol	++	Yes
Lp(a)	++	Yes
CRP	++	No
IMT/carotid plaque score	+ to +++	No
ABI/PWV	+ to +++	No
CAC	+ to +++	No
FH-mutation	+++	No
Rare-mutation(s) other than FH-gene	+ to ++	No
PRS (CAD)	+ to ++	No
Cholesterol-year score	+ to +++	No

TG: triglyceride, Lp(a): lipoprotein (a), CRP: C-reactive protein, IMT: intima-media thickness, ABI: ankle brachial index, PWV: pulse wave velocity, CAC: coronary artery calcium, PRS: polygenic risk score, CAD: coronary artery disease.

4.1. Classical Risk Factors

Classical atherosclerotic risk factors, such as hypertension, diabetes, and smoking, are associated with a further increased risk beyond the already elevated risk due to extremely high LDL-C levels among patients with HeFH. These classical risk factors are associated with a 2- to 3-fold increase in CAD among patients with HeFH⁵⁰⁾. This strongly suggests the need to assess these conditions and consider them in risk stratification and management, in addition to appropriately treating each of these comorbidities.

4.2. Emerging Risk Factors

In addition to these established risk factors, there are other “emerging” risk factors that need to be assessed in patients with HeFH. Triglycerides or remnant cholesterol have been associated with cardiovascular events independent of LDL-C in patients with HeFH¹⁰⁾. In addition, Lp(a) appears to be associated with further increased risk for cardiovascular events, especially in patients with increased C-reactive protein (CRP) among patients with HeFH¹⁸⁾. In fact, it has been shown that Lp(a) levels among patients with HeFH are approximately 2-fold higher than those in patients without FH⁵¹⁾. Accordingly, we need to consider reducing these emerging biomarkers because they are likely to be causal risk factors for atherosclerosis according to genetic analyses^52-54).

4.3. Subclinical Atherosclerosis

As described above, assessments of subclinical atherosclerosis in patients with HeFH are strongly recommended, not only for the simple diagnosis of systemic atherosclerosis but also for further risk stratification. For example, carotid plaque scores assessed using carotid ultrasound have been associated with increased cardiovascular events¹⁰⁾. Arterial wall stiffness assessed by the PWV has also been associated with CAD in patients with HeFH³⁴⁾. Furthermore, CAC has been associated with future cardiovascular events in patients with HeFH²⁸⁾. Notably, the absence of CAC was a significant predictor of a cardiovascular event-free prognosis. Accounting for these factors, we should consider the intensity of LDL-lowering therapy and its target goals.

4.4. Genetic Factors

FH is a Mendelian lipid disorder, and genetic testing for FH-related genes has been covered by Japanese National Health Insurance since 2022. It is useful for not only the definitive diagnosis but also further risk stratification. In fact, the presence of pathogenic FH-mutations has been associated with 3- to 4-fold higher odds for CAD than in FH-mutation-negative patients⁹⁾. In addition, loss-of-function mutations in the LDL receptor (LDLR) appear to be associated with a further increased risk compared to missense mutations⁵⁵⁾. These facts clearly suggest that we may account for the genetic background of FH in LDL-lowering therapy and treatment target goals.

In addition to FH mutation, several other genetic factors are associated with cardiovascular risk among patients with HeFH. For example, rare genetic variations that are known to be associated with LDL-C, such as rare genetic variations in ATP-binding cassette sub-family G member 5 (ABCG5), ATP-binding cassette sub-family G member 8 (ABCG8), and apolipoprotein E (APOE), have been shown as additional risk factors for HeFH^{12, 13, 56)}. The polygenic risk score for CAD comprising multiple common single nucleotide variations (SNV) has also been associated with cardiovascular events, independent of FH mutations⁵⁷⁾. Importantly, an “acquired” better lifestyle can offset at least a portion of the increased “congenital” risk, even among patients with HeFH⁵⁸⁾.

4.5. Cholesterol-Year Score at the Diagnosis

Recently, life-long exposure to elevated LDL-C levels has attracted considerable attention⁵⁹⁾. Under this concept, cardiovascular events in patients with HeFH occur on reaching the “threshold” of LDL-C accumulation (integral value of LDL-C over the years). This threshold may be affected by other risk factors listed above. Tada et al. investigated the “threshold” of LDL-C accumulation among Japanese HeFH patients and found approximately 10,000 mg/dL× years appear to be viable⁶⁰⁾. This finding supports the concepts of “the earlier the better” and “the lower the better.”

4.6. Advanced Treatment Strategies (Personalized Medicine)

Based on the considerations described above, we propose a flowchart outlining advanced treatment strategies (personalized medicine) for patients with HeFH (Fig.2). Please keep in mind that there are “modifiable” risk factors that should be managed on top of LDL-lowering therapies, such as hypertension and diabetes, but also other “non-modifiable” risk factors, such as FH-mutation and the polygenic risk score. In cases with a high burden of “non-modifiable” risk factors, we should consider further LDL reduction beyond the “standard” LDL-C treatment target goal.

Fig.2.

Advanced treatment strategies (personalized medicine) among patients with HeFH

Conclusion

In this review article, we aimed to provide a straightforward summary of the current understanding of the assessments of systemic atherosclerosis and advanced treatment strategies for patients with HeFH. It should be noted that the most important aspect of this disease should be the early diagnosis and treatment. We hope that this article will inspire greater motivation for the early diagnosis of FH and adoption of advanced assessment and treatment strategies for this relatively common disease.

Acknowledgements

None declared.

Sources of Funding

This work was supported by scientific research grants from the Health, Labour, and Welfare Sciences Research Grant for Research on Rare and Intractable Diseases.

Conflicts of Interest

Mariko Harada-Shiba has stock options from Liid Pharma. Mariko Harada-Shiba received honoraria from Amgen, MEDPACE, Novartis, Protosera, BML and Kowa.

References

• 1)  Beheshti SO, Madsen CM, Varbo A, Nordestgaard BG. Worldwide Prevalence of Familial Hypercholesterolemia: Meta-Analyses of 11 Million Subjects. J Am Coll Cardiol, 2020; 75: 2553-2566
• 2)  Hu P, Dharmayat KI, Stevens CAT, Sharabiani MTA, Jones RS, Watts GF, Genest J, Ray KK, Vallejo-Vaz AJ. Prevalence of Familial Hypercholesterolemia Among the General Population and Patients With Atherosclerotic Cardiovascular Disease: A Systematic Review and Meta-Analysis. Circulation, 2020; 141: 1742-1759
• 3)  Harada-Shiba M, Sugisawa T, Makino H, Abe M, Tsushima M, Yoshimasa Y, Yamashita T, Miyamoto Y, Yamamoto A, Tomoike H, Yokoyama S. Impact of statin treatment on the clinical fate of heterozygous familial hypercholesterolemia. J Atheroscler Thromb, 2010; 17: 667-674
• 4)  Luirink IK, Wiegman A, Kusters DM, Hof MH, Groothoff JW, de Groot E, Kastelein JJP, Hutten BA. 20-Year Follow-up of Statins in Children with Familial Hypercholesterolemia. N Engl J Med, 2019; 381: 1547-1556
• 5)  Tada H, Okada H, Nomura A, Nohara A, Yamagishi M, Takamura M, Kawashiri MA. Prognostic Impact of Cascade Screening for Familial Hypercholesterolemia on Cardiovascular Events. J Clin Lipidol, 2021; 15: 358-365
• 6)  Harada-Shiba M, Arai H, Ohmura H, Okazaki H, Sugiyama D, Tada H, Dobashi K, Matsuki K, Minamino T, Yamashita S, Yokote K; Joint Working Group of the Japan Atherosclerosis Society for the Development of Guidelines for the Treatment of Adult Familial Hypercholesterolemia. Guidelines for the Diagnosis and Treatment of Adult Familial Hypercholesterolemia 2022. J Atheroscler Thromb, 2023; 30: 558-586
• 7)  Harada-Shiba M, Ohtake A, Sugiyama D, Tada H, Dobashi K, Matsuki K, Minamino T, Yamashita S, Yamamoto Y; Joint Working Group of the Japan Pediatric Society and the Japan Atherosclerosis Society for the Development of Guidelines for Pediatric Familial Hypercholesterolemia. Guidelines for the Diagnosis and Treatment of Pediatric Familial Hypercholesterolemia 2022. J Atheroscler Thromb, 2023; 30: 531-557
• 8)  Tada H, Kawashiri MA, Okada H, Teramoto R, Konno T, Yoshimuta T, Sakata K, Nohara A, Inazu A, Kobayashi J, Mabuchi H, Yamagishi M, Hayashi K. Assessment of coronary atherosclerosis in patients with familial hypercholesterolemia by coronary computed tomography angiography. Am J Cardiol, 2015; 115: 724-729
• 9)  Tada H, Kawashiri MA, Nohara A, Inazu A, Mabuchi H, Yamagishi M. Impact of clinical signs and genetic diagnosis of familial hypercholesterolaemia on the prevalence of coronary artery disease in patients with severe hypercholesterolaemia. Eur Heart J, 2017; 38: 1573-1579
• 10)  Tada H, Kawashiri MA, Nohara A, Sakata K, Inazu A, Mabuchi H, Yamagishi M, Hayashi K. Remnant-like particles and coronary artery disease in familial hypercholesterolemia. Clin Chim Acta, 2018; 482: 120-123
• 11)  Tada H, Kawashiri MA, Okada H, Nakahashi T, Sakata K, Nohara A, Inazu A, Mabuchi H, Yamagishi M, Hayashi K. Assessments of Carotid Artery Plaque Burden in Patients With Familial Hypercholesterolemia. Am J Cardiol, 2017; 120: 1955-1960
• 12)  Tada H, Kawashiri MA, Nomura A, Teramoto R, Hosomichi K, Nohara A, Inazu A, Mabuchi H, Tajima A, Yamagishi M. Oligogenic familial hypercholesterolemia, LDL cholesterol, and coronary artery disease. J Clin Lipidol, 2018; 12: 1436-1444
• 13)  Tada H, Okada H, Nomura A, Yashiro S, Nohara A, Ishigaki Y, Takamura M, Kawashiri MA. Rare and Deleterious Mutations in ABCG5/ABCG8 Genes Contribute to Mimicking and Worsening of Familial Hypercholesterolemia Phenotype. Circ J, 2019; 83: 1917-1924
• 14)  Tada H, Okada H, Nohara A, Yamagishi M, Takamura M, Kawashiri MA. Effect of Cumulative Exposure to Low-Density Lipoprotein-Cholesterol on Cardiovascular Events in Patients With Familial Hypercholesterolemia. Circ J, 2021; 85: 2073-2078
• 15)  Tada H, Takamura M, Kawashiri MA. Individualized Treatment for Patients With Familial Hypercholesterolemia. J Lipid Atheroscler, 2022; 11: 39-54
• 16)  Tada H, Okada H, Nohara A, Toh R, Harada A, Murakami K, Iino T, Nagao M, Ishida T, Hirata KI, Takamura M, Kawashiri MA. Impact of High-Density Lipoprotein Function, Rather Than High-Density Lipoprotein Cholesterol Level, on Cardiovascular Disease Among Patients With Familial Hypercholesterolemia. Circ J, 2023; 87: 806-812
• 17)  Ogura M, Harada-Shiba M, Masuda D, Arai H, Bujo H, Ishibashi S, Daida H, Koga N, Oikawa S, Yamashita S. Factors Associated with Carotid Atherosclerosis and Achilles Tendon Thickness in Japanese Patients with Familial Hypercholesterolemia: A Subanalysis of the Familial Hypercholesterolemia Expert Forum (FAME) Study. J Atheroscler Thromb, 2022; 29: 906-922
• 18)  Tada H, Kojima N, Yamagami K, Nomura A, Nohara A, Usui S, Sakata K, Fujino N, Takamura M, Kawashiri MA. Synergistic effect of lipoprotein (a) and C-reactive protein on prognosis of familial hypercholesterolemia. Am J Prev Cardiol, 2022; 12: 100428
• 19)  Paquette M, Dufour R, Baass A. The Montreal-FH-SCORE: A new score to predict cardiovascular events in familial hypercholesterolemia. J Clin Lipidol, 2017; 11: 80-86
• 20)  Gallo A, Charriere S, Vimont A, Chapman MJ, Angoulvant D, Boccara F, Cariou B, Carreau V, Carrié A, Bruckert E, Béliard S; French REgistry of Familial hypERCHOLesterolemia (REFERCHOL) investigators. SAFEHEART risk-equation and cholesterol-year-score are powerful predictors of cardiovascular events in French patients with familial hypercholesterolemia. Atherosclerosis, 2020; 306: 41-49
• 21)  Funabashi S, Kataoka Y, Hori M, Ogura M, Nakaoku Y, Nishimura K, Doi T, Nishikawa R, Tsuda K, Noguchi T, Harada-Shiba M. Substantially Elevated Atherosclerotic Risks in Japanese Severe Familial Hypercholesterolemia Defined by the International Atherosclerosis Society. JACC Asia, 2021; 1: 245-255
• 22)  Hu P, Dharmayat KI, Stevens CAT, Sharabiani MTA, Jones RS, Watts GF, Genest J, Ray KK, Vallejo-Vaz AJ. Prevalence of Familial Hypercholesterolemia Among the General Population and Patients With Atherosclerotic Cardiovascular Disease: A Systematic Review and Meta- Analysis. Circulation, 2020; 141: 1742-1759
• 23)  Hutter CM, Austin MA, Humphries SE. Familial hypercholesterolemia, peripheral arterial disease, and stroke: a HuGE minireview. Am J Epidemiol, 2004; 160: 430-435
• 24)  Kita Y, Shimizu M, Sugihara N, Shimizu K, Miura M, Koizumi J, Mabuchi H, Takeda R. Abdominal aortic aneurysms in familial hypercholesterolemia--case reports. Angiology, 1993; 44: 491-499
• 25)  Nishikawa T, Tada H, Nakagawa-Kamiya T, Niwa S, Yoshida S, Mori M, Sakata K, Nohara A, Higashikata T, Kato H, Ino K, Takemura H, Takamura M, Kawashiri MA. A case with familial hypercholesterolemia complicated with severe systemic atherosclerosis intensively treated for more than 30 years. J Cardiol Cases, 2020; 22: 216-220
• 26)  Svendsen K, Olsen T, Vinknes KJ, Mundal LJ, Holven KB, Bogsrud MP, Leren TP, Igland J, Retterstøl K. Risk of stroke in genetically verified familial hypercholesterolemia: A prospective matched cohort study. Atherosclerosis, 2022; 358: 34-40
• 27)  Kusters DM, Wiegman A, Kastelein JJ, Hutten BA. Carotid intima-media thickness in children with familial hypercholesterolemia. Circ Res, 2014; 114: 307-310
• 28)  Tada H, Kojima N, Yamagami K, Nomura A, Nohara A, Usui S, Sakata K, Hayashi K, Fujino N, Takamura M, Kawashiri MA. Coronary artery calcium among patients with heterozygous familial hypercholesterolaemia. Eur Heart J Open, 2023; 3: oead046
• 29)  Vlahos AP, Naka KK, Bechlioulis A, Theoharis P, Vakalis K, Moutzouri E, Miltiadous G, Michalis LK, Siamopoulou-Mavridou A, Elisaf M, Milionis HJ. Endothelial dysfunction, but not structural atherosclerosis, is evident early in children with heterozygous familial hypercholesterolemia. Pediatr Cardiol, 2014; 35: 63-70
• 30)  Mabuchi H, Koizumi J, Shimizu M, Takeda R. Development of coronary heart disease in familial hypercholesterolemia. Circulation, 1989; 79: 225-232
• 31)  Salonen JT, Salonen R. Ultrasound B-mode imaging in observational studies of atherosclerotic progression. Circulation, 1993; 87: II56-65
• 32)  Stein JH, Korcarz CE, Hurst RT, Lonn E, Kendall CB, Mohler ER, Najjar SS, Rembold CM, Post WS; American Society of Echocardiography Carotid Intima-Media Thickness Task Force. Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. Endorsed by the Society for Vascular Medicine. J Am Soc Echocardiogr, 2008; 21: 93-111
• 33)  Tomiyama H, Shiina K. State of the Art Review: Brachial-Ankle PWV. J Atheroscler Thromb, 2020; 27: 621-636
• 34)  Tada H, Kawashiri MA, Nohara A, Inazu A, Mabuchi H, Yamagishi M. Assessment of arterial stiffness in patients with familial hypercholesterolemia. J Clin Lipidol, 2018; 12: 397-402
• 35)  Abdelrahman KM, Chen MY, Dey AK, Virmani R, Finn AV, Khamis RY, Choi AD, Min JK, Williams MC, Buckler AJ, Taylor CA, Rogers C, Samady H, Antoniades C, Shaw LJ, Budoff MJ, Hoffmann U, Blankstein R, Narula J, Mehta NN. Coronary Computed Tomography Angiography From Clinical Uses to Emerging Technologies: JACC State-of-the-Art Review. J Am Coll Cardiol, 2020; 76: 1226-1243
• 36)  Golub IS, Termeie OG, Kristo S, Schroeder LP, Lakshmanan S, Shafter AM, Hussein L, Verghese D, Aldana-Bitar J, Manubolu VS, Budoff MJ. Major Global Coronary Artery Calcium Guidelines. JACC Cardiovasc Imaging, 2023; 16: 98-117
• 37)  Murase Y, Yagi K, Kobayashi J, Nohara A, Asano A, Koizumi J, Mabuchi H. Association of coronary artery ectasia with plasma insulin levels in Japanese men of heterozygous familial hypercholesterolemia with the low-density lipoprotein receptor gene mutation K790X. Clin Chim Acta, 2005; 355: 33-39
• 38)  Knuuti J, Wijns W, Saraste A, Capodanno D, Barbato E, Funck-Brentano C, Prescott E, Storey RF, Deaton C, Cuisset T, Agewall S, Dickstein K, Edvardsen T, Escaned J, Gersh BJ, Svitil P, Gilard M, Hasdai D, Hatala R, Mahfoud F, Masip J, Muneretto C, Valgimigli M, Achenbach S, Bax JJ; ESC Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J, 2020; 41: 407-477
• 39)  Brandts J, Ray KK. Familial Hypercholesterolemia: JACC Focus Seminar 4/4. J Am Coll Cardiol, 2021; 78: 1831-1843
• 40)  Bytyçi I, Penson PE, Mikhailidis DP, Wong ND, Hernandez AV, Sahebkar A, Thompson PD, Mazidi M, Rysz J, Pella D, Reiner Ž, Toth PP, Banach M. Prevalence of statin intolerance: a meta-analysis. Eur Heart J, 2022; 43: 3213-3223
• 41)  Kastelein JJ, Akdim F, Stroes ES, Zwinderman AH, Bots ML, Stalenhoef AF, Visseren FL, Sijbrands EJ, Trip MD, Stein EA, Gaudet D, Duivenvoorden R, Veltri EP, Marais AD, de Groot E; ENHANCE Investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med, 2008; 358: 1431-1443
• 42)  Mabuchi H, Sakai T, Sakai Y, Yoshimura A, Watanabe A, Wakasugi T, Koizumi J, Takeda R. Reduction of serum cholesterol in heterozygous patients with familial hypercholesterolemia. Additive effects of compactin and cholestyramine. N Engl J Med, 1983; 308: 609-613
• 43)  Kawashiri MA, Nohara A, Noguchi T, Tada H, Nakanishi C, Mori M, Konno T, Hayashi K, Fujino N, Inazu A, Kobayashi J, Mabuchi H, Yamagishi M. Efficacy and safety of coadministration of rosuvastatin, ezetimibe, and colestimide in heterozygous familial hypercholesterolemia. Am J Cardiol, 2012; 109: 364-369
• 44)  Yamashita S, Hbujo H, Arai H, Harada-Shiba M, Matsui S, Fukushima M, Saito Y, Kita T, Matsuzawa Y. Long-term probucol treatment prevents secondary cardiovascular events: a cohort study of patients with heterozygous familial hypercholesterolemia in Japan. J Atheroscler Thromb, 2008; 15: 292-303
• 45)  Raal FJ, Stein EA, Dufour R, Turner T, Civeira F, Burgess L, Langslet G, Scott R, Olsson AG, Sullivan D, Hovingh GK, Cariou B, Gouni-Berthold I, Somaratne R, Bridges I, Scott R, Wasserman SM, Gaudet D. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet, 2015; 385: 331-340
• 46)  Kastelein JJ, Ginsberg HN, Langslet G, Hovingh GK, Ceska R, Dufour R, Blom D, Civeira F, Krempf M, Lorenzato C, Zhao J, Pordy R, Baccara-Dinet MT, Gipe DA, Geiger MJ, Farnier M. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J, 2015; 36: 2996-3003
• 47)  Farnier M, Hovingh GK, Langslet G, Dufour R, Baccara-Dinet MT, Din-Bell C, Manvelian G, Guyton JR. Long-term safety and efficacy of alirocumab in patients with heterozygous familial hypercholesterolemia: An open-label extension of the ODYSSEY program. Atherosclerosis, 2018; 278: 307-314
• 48)  Santos RD, Stein EA, Hovingh GK, Blom DJ, Soran H, Watts GF, López JAG, Bray S, Kurtz CE, Hamer AW, Raal FJ. Long-Term Evolocumab in Patients With Familial Hypercholesterolemia. J Am Coll Cardiol, 2020; 75: 565-574
• 49)  Moriarty PM, Parhofer KG, Babirak SP, Cornier MA, Duell PB, Hohenstein B, Leebmann J, Ramlow W, Schettler V, Simha V, Steinhagen-Thiessen E, Thompson PD, Vogt A, von Stritzky B, Du Y, Manvelian G. Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial. Eur Heart J, 2016; 37: 3588-3595
• 50)  Pérez de Isla L, Alonso R, Mata N, Saltijeral A, Muñiz O, Rubio-Marin P, Diaz-Diaz JL, Fuentes F, de Andrés R, Zambón D, Galiana J, Piedecausa M, Aguado R, Mosquera D, Vidal JI, Ruiz E, Manjón L, Mauri M, Padró T, Miramontes JP, Mata P; SAFEHEART Investigators. Coronary Heart Disease, Peripheral Arterial Disease, and Stroke in Familial Hypercholesterolaemia: Insights From the SAFEHEART Registry (Spanish Familial Hypercholesterolaemia Cohort Study). Arterioscler Thromb Vasc Biol, 2016; 36: 2004-2010
• 51)  Tada H, Kawashiri MA, Yoshida T, Teramoto R, Nohara A, Konno T, Inazu A, Mabuchi H, Yamagishi M, Hayashi K. Lipoprotein(a) in Familial Hypercholesterolemia With Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Gain-of-Function Mutations. Circ J, 2016; 80: 512-518
• 52)  Tada H, Fujino N, Hayashi K, Kawashiri MA, Takamura M. Human genetics and its impact on cardiovascular disease. J Cardiol, 2022;79: 233-239
• 53)  Tada H. Personalized Medicine beyond Low-Density Lipoprotein Cholesterol to Combat Residual Risk for Coronary Artery Disease. J Atheroscler Thromb, 2021; 28: 1130-1132
• 54)  Tada H, Usui S, Sakata K, Takamura M, Kawashiri MA. Challenges of Precision Medicine for Atherosclerotic Cardiovascular Disease Based on Human Genome Information. J Atheroscler Thromb, 2021; 28: 305-313
• 55)  Tada H, Kojima N, Yamagami K, Nomura A, Nohara A, Usui S, Sakata K, Fujino N, Takamura M, Kawashiri MA. Effects of Different Types of Pathogenic Variants on Phenotypes of Familial Hypercholesterolemia. Front Genet, 2022; 13: 872056
• 56)  Tada H, Yamagami K, Kojima N, Shibayama J, Nishikawa T, Okada H, Nomura A, Usui S, Sakata K, Takamura M, Kawashiri MA. Prevalence and Impact of Apolipoprotein E7 on LDL Cholesterol Among Patients With Familial Hypercholesterolemia. Front Cardiovasc Med, 2021; 8: 625852
• 57)  Fahed AC, Wang M, Homburger JR, Patel AP, Bick AG, Neben CL, Lai C, Brockman D, Philippakis A, Ellinor PT, Cassa CA, Lebo M, Ng K, Lander ES, Zhou AY, Kathiresan S, Khera AV. Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions. Nat Commun, 2020; 11: 3635
• 58)  Tada H, Kojima N, Yamagami K, Nomura A, Nohara A, Usui S, Sakata K, Hayashi K, Fujino N, Takamura M, Kawashiri MA. Impact of Healthy Lifestyle in Patients With Familial Hypercholesterolemia. JACC Asia, 2023; 3: 152-160
• 59)  Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, Wiklund O, Hegele RA, Raal FJ, Defesche JC, Wiegman A, Santos RD, Watts GF, Parhofer KG, Hovingh GK, Kovanen PT, Boileau C, Averna M, Borén J, Bruckert E, Catapano AL, Kuivenhoven JA, Pajukanta P, Ray K, Stalenhoef AF, Stroes E, Taskinen MR, Tybjærg-Hansen A; European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J, 2013; 34: 3478-2490a
• 60)  Tada H, Kojima N, Yamagami K, Nomura A, Nohara A, Usui S, Sakata K, Takamura M, Kawashiri MA. Early diagnosis and treatments in childhood are associated with better prognosis in patients with familial hypercholesterolemia. Am J Prev Cardiol, 2022; 12: 100434