研究者詳細 - 堀　美香

論文 - 堀　美香

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Association between Achilles Tendon Softness and Atherosclerotic Cardiovascular Disease in Patients with Familial Hypercholesterolemia. 査読有り

Michikura M, Ogura M, Hori M, Matsuki K, Makino H, Hosoda K, Harada-Shiba M

Journal of atherosclerosis and thrombosis advpub 巻 ( 0 ) 2022年1月

Circulating Furin-Cleaved Proprotein Convertase Subtilisin/Kexin Type 9 Concentration Predicts Future Coronary Events in Japanese Subjects 査読有り

Kataoka Y., Harada-Shiba M., Hori M., Watanabe M., Kokubo Y., Noguchi T., Yasuda S., Miyamoto Y.

JACC: Asia 1 巻 ( 3 ) 頁： 360 - 368 2021年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JACC: Asia

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) circulates as mature and furin-cleaved forms, which differ in their properties to degrade low-density lipoprotein (LDL) receptors. Objectives: In this study, we sought to investigate whether PCSK9 subtypes associate with atherosclerotic cardiovascular events. Methods: We investigated 1,436 statin-naive Japanese subjects without any cardiovascular disease in the Suita Study, an epidemiologic Japanese cohort study. Total, mature, and furin-cleaved PCSK9 levels were measured by means of enzyme-linked immunosorbent assay. The occurrence of coronary and stroke events were compared in subjects stratified by PCSK9 level tertile. Results: Total, mature, and furin-cleaved PCSK9 levels were associated with non–high-density lipoprotein cholesterol (all P < 0.001) and systolic blood pressure (P = 0.001, P = 0.004, and P < 0.001, respectively). Furthermore, only furin-cleaved PCSK9 level was correlated to high-sensitivity C-reactive protein (hs-CRP) (P < 0.001). During the 13.6-year observational period, furin-cleaved PCSK9 level predicted a greater likelihood of experiencing coronary events (tertile 2: hazard ratio [HR]: 2.84 [95% confidence interval [CI]: 1.21-6.65; P = 0.01]; tertile 3: HR: 2.81 [95% CI: 1.17-6.74; P = 0.02]), but not stroke (tertile 2: HR: 1.31 [95% CI: 0.72-2.40; P = 0.36]; tertile 3: HR: 1.27 [95% CI: 0.68-2.38; P = 0.44]). Total and mature PCSK9 levels were not associated with coronary events (total PCSK9: tertile 2: HR: 1.35 [95% CI: 0.68-2.68; P = 0.39]; tertile 3: HR: 1.13 [95% CI: 0.54-2.34; P = 0.73]; mature PCSK9: tertile 2: HR: 1.02 [95% CI: 0.52-2.02; P = 0.93]; tertile 3: HR: 0.96 [95% CI: 0.47-1.95; P = 0.92]) and stroke events (total PCSK9: tertile 2: HR: 0.90 [95% CI: 0.50-1.61; P = 0.72]; tertile 3: HR: 0.99 [95% CI:0.54-1.80; P = 0.97]; mature PCSK9: tertile 2: HR: 0.86 [95% CI: 0.47-1.57; P = 0.63]; tertile 3: HR: 1.11 [95% CI: 0.61-1.99; P = 0.72]), respectively. Conclusions: Furin-cleaved but not total and mature PCSK9 was associated with both LDL cholesterol and hs-CRP and predicted future coronary events in the primary prevention settings. Our findings provide pathophysiological insights into the properties of PCSK9 subtypes in association with coronary events.

DOI： 10.1016/j.jacasi.2021.09.003

Scopus

Global perspective of familial hypercholesterolaemia: a cross-sectional study from the EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC) 査読有り国際共著

EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC)

The Lancet 398 巻 ( 10312 ) 頁： 1713 - 1725 2021年11月

Switching from lipoprotein apheresis to evolocumab in FH siblings on hemodialysis: case reports and discussion. 査読有り

Ishii T, Ogura M, Nakamori H, Hori M, Harada-Shiba M, Tamura K, Oyama K

CEN case reports 10 巻 ( 4 ) 頁： 592 - 597 2021年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：CEN case reports

Familial hypercholesterolemia (FH) and chronic kidney disease, especially end-stage renal disease (ESRD), are common and put patients at a high risk of developing atherosclerotic cardiovascular disease (ASCVD). ESRD concomitant with FH may further increase the risk of ASCVD. Achieving target levels of low-density lipoprotein cholesterol (LDL-C) is difficult owing to the limitations of statin administration due to its side effects in ESRD. Therefore, some FH patients with ESRD require lipoprotein apheresis for the prevention of secondary ASCVD events. Although proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors may offer a safe and effective option for lowering lipid levels in such patients, no guidelines are available for their use. Here, we report the case of two male siblings with FH in secondary prevention undergoing hemodialysis combined with PCSK9 inhibitor treatment. The siblings, who showed a heterozygous c.1846-1G>A mutation in the LDLR gene, underwent hemodialysis. In combination with the lipoprotein apheresis, siblings were administered evolocumab, a PCSK9 inhibitor. Both the siblings had coronary artery disease, diabetes, and ESRD, and received hemodialysis. Their LDL-C levels did not reach the target values despite administering statin, ezetimibe, and biweekly lipoprotein apheresis. On the introduction of evolocumab treatment, their LDL-C levels were significantly reduced without any adverse effects, resulting in successful withdrawal from lipoprotein apheresis therapy. Although the effects of switching from lipoprotein apheresis to PCSK9 inhibitors for cardiovascular protection remain unclear in FH patients with and without ESRD, our case report will be helpful in guiding future therapeutic decisions.

DOI： 10.1007/s13730-021-00605-x

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PubMed

Current Diagnosis and Management of Abetalipoproteinemia. 査読有り

Takahashi M, Okazaki H, Ohashi K, Ogura M, Ishibashi S, Okazaki S, Hirayama S, Hori M, Matsuki K, Yokoyama S, Harada-Shiba M

Journal of atherosclerosis and thrombosis 28 巻 ( 10 ) 頁： 1009 - 1019 2021年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人日本動脈硬化学会

Abetalipoproteinemia (ABL) is a rare autosomal recessive disorder caused by biallelic pathogenic mutations in the MTTP gene. Deficiency of microsomal triglyceride transfer protein (MTTP) abrogates the assembly of apolipoprotein (apo) B-containing lipoprotein in the intestine and liver, resulting in malabsorption of fat and fat-soluble vitamins and severe hypolipidemia. Patients with ABL typically manifest steatorrhea, vomiting, and failure to thrive in infancy. The deficiency of fat-soluble vitamins progressively develops into a variety of symptoms later in life, including hematological (acanthocytosis, anemia, bleeding tendency, etc.), neuromuscular (spinocerebellar ataxia, peripheral neuropathy, myopathy, etc.), and ophthalmological symptoms (e.g., retinitis pigmentosa). If left untreated, the disease can be debilitating and even lethal by the third decade of life due to the development of severe complications, such as blindness, neuromyopathy, and respiratory failure. High dose vitamin supplementation is the mainstay for treatment and may prevent, delay, or alleviate the complications and improve the prognosis, enabling some patients to live to the eighth decade of life. However, it cannot fully prevent or restore impaired function. Novel therapeutic modalities that improve quality of life and prognosis are awaited. The aim of this review is to 1) summarize the pathogenesis, clinical signs and symptoms, diagnosis, and management of ABL, and 2) propose diagnostic criteria that define eligibility to receive financial support from the Japanese government for patients with ABL as a rare and intractable disease. In addition, our diagnostic criteria and the entry criterion of low-density lipoprotein cholesterol (LDL-C) ＜15 mg/dL and apoB ＜15 mg/dL can be useful in universal or opportunistic screening for the disease. Registry research on ABL is currently ongoing to better understand the disease burden and unmet needs of this life-threatening disease with few therapeutic options.

DOI： 10.5551/jat.RV17056

PubMed

Current Diagnosis and Management of Primary Chylomicronemia. 査読有り

Okazaki H, Gotoda T, Ogura M, Ishibashi S, Inagaki K, Daida H, Hayashi T, Hori M, Masuda D, Matsuki K, Yokoyama S, Harada-Shiba M

Journal of atherosclerosis and thrombosis 28 巻 ( 9 ) 頁： 883 - 904 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Atherosclerosis and Thrombosis

Primary chylomicronemia (PCM) is a rare and intractable disease characterized by marked accumulation of chylomicrons in plasma. The levels of plasma triglycerides (TGs) typically range from 1,000 - 15,000 mg/dL or higher. PCM is caused by defects in the lipoprotein lipase (LPL) pathway due to genetic mutations, autoantibodies, or unidentified causes. The monogenic type is typically inherited as an autosomal recessive trait with loss-offunction mutations in LPL pathway genes (LPL, LMF1, GPIHBP1, APOC2, and APOA5). Secondary/environmental factors (diabetes, alcohol intake, pregnancy, etc.) often exacerbate hypertriglyceridemia (HTG). The signs, symptoms, and complications of chylomicronemia include eruptive xanthomas, lipemia retinalis, hepatosplenomegaly, and acute pancreatitis with onset as early as in infancy. Acute pancreatitis can be fatal and recurrent episodes of abdominal pain may lead to dietary fat intolerance and failure to thrive. The main goal of treatment is to prevent acute pancreatitis by reducing plasma TG levels to at least less than 500-1,000 mg/dL. However, current TG-lowering medications are generally ineffective for PCM. The only other treatment options are modulation of secondary/environmental factors. Most patients need strict dietary fat restriction, which is often difficult to maintain and likely affects their quality of life. Timely diagnosis is critical for the best prognosis with currently available management, but PCM is often misdiagnosed and undertreated. The aim of this review is firstly to summarize the pathogenesis, signs, symptoms, diagnosis, and management of PCM, and secondly to propose simple diagnostic criteria that can be readily translated into general clinical practice to improve the diagnostic rate of PCM. In fact, these criteria are currently used to define eligibility to receive social support from the Japanese government for PCM as a rare and intractable disease. Nevertheless, further research to unravel the molecular pathogenesis and develop effective therapeutic modalities is warranted. Nationwide registry research on PCM is currently ongoing in Japan with the aim of better understanding the disease burden as well as the unmet needs of this life-threatening disease with poor therapeutic options.

DOI： 10.5551/jat.RV17054

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PubMed

Substantially Elevated Atherosclerotic Risks in Japanese Severe Familial Hypercholesterolemia Defined by the International Atherosclerosis Society 査読有り国際誌 Open Access

Funabashi S., Kataoka Y., Hori M., Ogura M., Nakaoku Y., Nishimura K., Doi T., Nishikawa R., Tsuda K., Noguchi T., Harada-Shiba M.

JACC: Asia 1 巻 ( 2 ) 頁： 245 - 255 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JACC: Asia

Background: The International Atherosclerosis Society (IAS) has proposed “severe familial hypercholesterolemia” (FH) as a phenotype with the highest cardiovascular risk. However, whether this criteria could appropriately stratify a high-risk Japanese patient with FH remains unknown. Objectives: This study sought to characterize atherosclerotic cardiovascular diseases in IAS-defined Japanese subjects with severe FH. Methods: This study analyzed 380 clinically diagnosed subjects with heterozygous FH without any history of atherosclerotic cardiovascular diseases. Severe FH was defined as untreated low-density lipoprotein cholesterol >400 mg/dL, >310 mg/dL plus 1 high-risk feature, or >190 mg/dL plus 2 high-risk features according to IAS-proposed statement. The occurrence of first and subsequent composite outcomes (cardiac [cardiac death + coronary artery disease + coronary revascularization] and noncardiac events [stroke + peripheral artery disease] was compared between subjects with severe (n = 135) and non-severe (n = 227) FH. Results: Severe FH was identified in 40.3% of study population. They had higher low-density lipoprotein cholesterol (P < 0.001) and lipoprotein(a) (P = 0.03) levels. Moreover, they more frequently received high-intensity statin (P < 0.001), PCSK9 inhibitor (P < 0.001), and lipoprotein apheresis (P = 0.01) than nonsevere FH subjects did, which resulted in a lower on-treatment low-density lipoprotein cholesterol level of subjects with severe FH (113 ± 47.2 vs 130 ± 53.9 mg/dL; P = 0.007). However, during the 7.4-year observational period, subjects with severe FH exhibited a 9.3-, 15.4-, and 5.9-fold greater risk for first composite (P < 0.001), cardiac (P < 0.001), and noncardiac outcomes (P = 0.02), respectively. Multivariate Cox proportional hazard model consistently revealed the 7.8- and 7.9-fold elevated risks of first (P < 0.001) and of subsequent (P < 0.001) composite outcomes in subjects with severe FH. Conclusions: Japanese subjects with severe FH present profound risks of both first and subsequent atherosclerotic cardiovascular diseases in the primary prevention settings. These findings support the clinical applicability of IAS-defined severe FH in Japanese patients, which identifies those who require further stringent antiatherosclerotic management.

DOI： 10.1016/j.jacasi.2021.07.004

Open Access

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PubMed

Can We Clarify the Causative Gene/Variants Underlying Familial Hypercholesterolemia and Improve Genetic Diagnosis Rate? 招待有り査読有り

Hori M

Journal of atherosclerosis and thrombosis 2021年8月

Current Diagnosis and Management of Tangier Disease. 査読有り

Koseki M, Yamashita S, Ogura M, Ishigaki Y, Ono K, Tsukamoto K, Hori M, Matsuki K, Yokoyama S, Harada-Shiba M

Journal of atherosclerosis and thrombosis 28 巻 ( 8 ) 頁： 802 - 810 2021年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Atherosclerosis and Thrombosis

Tangier disease is a genetic disorder characterized by an absence or extremely low level of high-density lipoprotein (HDL)-cholesterol (HDL-C). It is caused by a dysfunctional mutation of the ATP-binding cassette transporter A1 (ABCA1) gene, the mandatory gene for generation of HDL particles from cellular cholesterol and phospholipids, and it appears in an autosomal recessive hereditary profile. To date, 35 cases have been reported in Japan and 109 cases outside Japan. With dysfunctional mutations in both alleles (homozygotes or compound heterozygotes), the HDL-C level is mostly less than 5 mg/dL and there is 10 mg/dL or less of apolipoprotein A-I (apoA-I), the major protein component of HDL. In patients with Tangier disease, major physical findings are orange-colored pharyngeal tonsils, hepatosplenomegaly, corneal opacity, lymphadenopathy, and peripheral neuropathy. Although patients tend to have decreased low-density lipoprotein (LDL)-cholesterol (LDL-C) levels, premature coronary artery disease is frequently observed. No specific curative treatment is currently available, so early identification of patients and preventing atherosclerosis development are crucial. Management of risk factors other than low HDL-C is also important, such as LDL-C levels, hypertension and smoking. Additionally, treatment for glucose intolerance might be required because impaired insulin secretion from pancreatic beta cells has occasionally been reported.

DOI： 10.5551/jat.RV17053

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Diagnosis and Management of Sitosterolemia 2021. 査読有り

Tada H, Nomura A, Ogura M, Ikewaki K, Ishigaki Y, Inagaki K, Tsukamoto K, Dobashi K, Nakamura K, Hori M, Matsuki K, Yamashita S, Yokoyama S, Kawashiri MA, Harada-Shiba M

Journal of atherosclerosis and thrombosis 28 巻 ( 8 ) 頁： 791 - 801 2021年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Atherosclerosis and Thrombosis

Sitosterolemia is an inherited metabolic disorder characterized by increased levels of plant sterols, such as sitosterol. This disease is caused by loss-of-function genetic mutations in ATP-binding cassette (ABC) subfamily G member 5 or member 8 (ABCG5 or ABCG8, respectively), both of which play important roles in selective excretion of plant sterols from the liver and intestine, leading to failure to prevent absorption of food plant sterols. This disorder has been considered to be extremely rare. However, accumulated clinical data as well as genetics suggest the possibility of a much higher prevalence. Its clinical manifestations resemble those observed in patients with familial hypercholesterolemia (FH), including tendon xanthomas, hyper LDL-cholesterolemia, and premature coronary atherosclerosis. We provide an overview of this recessive genetic disease, diagnostic as well as therapeutic tips, and the latest diagnostic criteria in Japan.

DOI： 10.5551/jat.RV17052

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PubMed

Homozygous Familial Hypercholesterolemia. 査読有り

Nohara A, Tada H, Ogura M, Okazaki S, Ono K, Shimano H, Daida H, Dobashi K, Hayashi T, Hori M, Matsuki K, Minamino T, Yokoyama S, Harada-Shiba M

Journal of atherosclerosis and thrombosis 28 巻 ( 7 ) 頁： 665 - 678 2021年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Atherosclerosis and Thrombosis

Familial hypercholesterolemia (FH) is an inherited disorder with retarded clearance of plasma LDL caused by mutations of the genes involved in the LDL receptor-mediated pathway and most of them exhibit autosomal dominant inheritance. Homozygotes of FH (HoFH) may have plasma LDL-C levels, which are at least twice as high as those of heterozygous FH (HeFH) and therefore four times higher than normal levels. Prevalence of HoFH had been estimated as 1 in 1,000,000 before but more recent genetic analysis surveys predict 1 in 170,000 to 300,000. Since LDL receptor activity is severely impaired, HoFH patients do not or very poorly respond to medications to enhance activity, such as statins, and have a poorer prognosis compared to HeFH. HoFH should therefore be clinically distinguished from HeFH. Thorough family studies and genetic analysis are recommended for their accurate diagnosis. Fatal cardiovascular complications could develop even in the first decade of life for HoFH, so aggressive lipid-lowering therapy should be initiated as early as possible. Direct removal of plasma LDL by lipoprotein apheresis has been the principal measure for these patients. However, this treatment alone may not achieve stable LDL-C target levels and combination with drugs should be considered. The lipid-lowering effects of statins and PCSK9 inhibitors substantially vary depending on the remaining LDL receptor activity of individual patients. On the other hand, the action an MTP inhibitor is independent of LDL receptor activity, and it is effective in most HoFH cases. This review summarizes the key clinical issues of HoFH as well as insurance coverage available under the Japanese public healthcare system.

DOI： 10.5551/jat.RV17050

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PubMed

Current Status of Familial LCAT Deficiency in Japan. 査読有り

Kuroda M, Bujo H, Yokote K, Murano T, Yamaguchi T, Ogura M, Ikewaki K, Koseki M, Takeuchi Y, Nakatsuka A, Hori M, Matsuki K, Miida T, Yokoyama S, Wada J, Harada-Shiba M

Journal of atherosclerosis and thrombosis 28 巻 ( 7 ) 頁： 679 - 691 2021年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Atherosclerosis and Thrombosis

Lecithin cholesterol acyltransferase (LCAT) is a lipid-modification enzyme that catalyzes the transfer of the acyl chain from the second position of lecithin to the hydroxyl group of cholesterol (FC) on plasma lipoproteins to form cholesteryl acylester and lysolecithin. Familial LCAT deficiency is an intractable autosomal recessive disorder caused by inherited dysfunction of the LCAT enzyme. The disease appears in two different phenotypes depending on the position of the gene mutation: familial LCAT deficiency (FLD, OMIM 245900) that lacks esterification activity on both HDL and ApoB-containing lipoproteins, and fish-eye disease (FED, OMIM 136120) that lacks activity only on HDL. Impaired metabolism of cholesterol and phospholipids due to LCAT dysfunction results in abnormal concentrations, composition and morphology of plasma lipoproteins and further causes ectopic lipid accumulation and/or abnormal lipid composition in certain tissues/cells, and serious dysfunction and complications in certain organs. Marked reduction of plasma HDL-cholesterol (HDL-C) and corneal opacity are common clinical manifestations of FLD and FED. FLD is also accompanied by anemia, proteinuria and progressive renal failure that eventually requires hemodialysis. Replacement therapy with the LCAT enzyme should prevent progression of serious complications, particularly renal dysfunction and corneal opacity. A clinical research project aiming at gene/cell therapy is currently underway.

DOI： 10.5551/jat.RV17051

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PubMed

Achilles Tendon Thickness Assessed by X-ray Predicting a Pathogenic Mutation in Familial Hypercholesterolemia Gene. 査読有り

Tada H, Hori M, Matsuki K, Ogura M, Nohara A, Kawashiri MA, Harada-Shiba M

Journal of atherosclerosis and thrombosis 2021年7月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人日本動脈硬化学会

Aim: The 2017 Japan Atherosclerosis Society (JAS) familial hypercholesterolemia (FH) criteria adopt a cut-off value of ≥ 9 mm of Achilles tendon thickness (ATT) detected by X-ray as one of the three key items. This threshold was determined based on an old data evaluating the ATT of 36 non-FH individuals that was published in 1977. Although the specificity of these clinical criteria is extremely high due to a strict threshold, there are a significant number of patients with FH whose ATT ＜9 mm. We aimed to determine a cut-off value of ATT detected by X-ray to differentiate FH and non-FH based on genetic diagnosis. Methods: The individuals (male/female=486/501) with full assessments of genetic analyses for FH-genes (LDLR and PCSK9), serum lipids, and ATT detected by X-ray at the Kanazawa University Hospital and National Cerebral and Cardiovascular Center Research Institute were included in this study. Receiver operating characteristic (ROC) analyses were conducted to determine a better cut-off value of ATT that predicts the pathogenic mutation of FH. Results: The ROC analyses revealed that the best cut-off values of ATT are 7.6 mm for male and 7.0 mm for female, with the sensitivities/specificities of 0.83/0.83 for male and 0.86/0.85 for female, respectively. If the thresholds of ATT of 8.0/7.5 mm and 7.5/7.0 mm were applied to the diagnosis of male/female FH, the sensitivities/specificities predicting the pathogenic mutation of FH by the 2017 JAS FH clinical criteria would be 0.82/0.90 and 0.85/0.88, respectively. Conclusions: These results suggest that the cut-off value of ATT detected by X-ray is obviously lower than 9.0 mm, which was adopted by the 2017 JAS FH clinical criteria.

DOI： 10.5551/jat.62869

PubMed

Achilles Tendon Softness as a New Tool for Diagnosing Familial Hypercholesterolemia. 査読有り国際誌

Michikura M, Ogura M, Hori M, Furuta K, Hosoda K, Harada-Shiba M

JACC. Cardiovascular imaging 14 巻 ( 7 ) 頁： 1483 - 1485 2021年7月

Circulating Mature PCSK9 Level Predicts Diminished Response to Statin Therapy. 査読有り

Kuyama N, Kataoka Y, Takegami M, Nishimura K, Harada-Shiba M, Hori M, Ogura M, Otsuka F, Asaumi Y, Noguchi T, Tsujita K, Yasuda S

Journal of the American Heart Association 10 巻 ( 11 ) 頁： e019525 2021年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of the American Heart Association

BACKGROUND: Statin-mediated efficacy of lowering low-density lipoprotein (LDL) cholesterol varies in each individual, and its diminished response is associated with worse outcomes. However, there is no established approach to predict hyporesponse to statins. PCSK9 (proprotein convertase subxilisin/kexin type 9) is a serine-protease associated with LDL metabolism, which circulates as mature and furin-cleaved PCSK9. Since mature PCSK9 more potently degrades the LDL receptor, its evaluation may enable the identification of statin hyporesponders. METHODS AND RESULTS: We analyzed 101 statin-naive patients with coronary artery disease who commenced a statin. PCSK9 subtypes at baseline and 1 month after statin use were measured by ELISA. Hyporesponse to statins was defined as a percent reduction in LDL cholesterol <15%. The relationship between each PCSK9 subtype level and hyporesponse to statins was investigated. Statins significantly lowered LDL cholesterol level (percent reduction, 40%±21%), whereas 11% of study participants exhibited a hyporeseponse to statins. Multivariable logistic regression analysis demonstrated that baseline mature PCSK9 level was an independent predictor for hyporesponse to statins even after adjusting clinical characteristics (mature PCSK9 per 10-ng/mL increase: odds ratio [OR], 1.12; 95% CI, 1.01–1.24 [P=0.03]), whereas furin-cleaved level was not (per 10-ng/mL increase: OR, 1.37; 95% CI, 0.73–2.58 [P=0.33]). Receiver operating characteristic curve analysis identified mature PCSK9 level of 228 ng/mL as an optimal cutoff to predict hyporesponse to statins (area under the curve, 0.73 [sensitivity, 0.91; specificity, 0.56]). CONCLUSIONS: Baseline mature PCSK9 level >228 ng/mL is associated with hyporesponse to statins. This finding suggests that mature PCSK9 might be a potential determinant of hyporesponse to statins.

DOI： 10.1161/JAHA.120.019525

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A Resuscitated Case of Acute Myocardial Infarction with both Familial Hypercholesterolemia Phenotype Caused by Possibly Oligogenic Variants of the PCSK9 and ABCG5 Genes and Type I CD36 Deficiency. 査読有り

Nishikawa R, Furuhashi M, Hori M, Ogura M, Harada-Shiba M, Okada T, Koseki M, Kujiraoka T, Hattori H, Ito R, Muranaka A, Kokubu N, Miura T

Journal of atherosclerosis and thrombosis 2021年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人日本動脈硬化学会

A 56-year-old postmenopausal woman with out-of-hospital cardiac arrest caused by acute myocardial infraction was successfully resuscitated by intensive treatments and recovered without any neurological disability. She was diagnosed as having familial hypercholesterolemia (FH) based on a markedly elevated low-density lipoprotein cholesterol (LDL-C) level and family history of premature coronary artery disease. Genetic testing in her family members showed that a variant of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene (c.2004C＞A, p.S668R), which had been previously reported as having uncertain significance, was associated with FH, indicating that the variant is a potential candidate for the FH phenotype. Next-generation sequencing analysis for the proband also showed that there was a heterozygous mutation of the ATP-binding cassette sub-family G member 5 (ABCG5) gene (c.1166G＞A, R389H), which has been reported to increase LDL-C level and the risk of cardiovascular disease. She was also diagnosed as having type 1 CD36 deficiency based on a lack of myocardial uptake of 123 I-labeled 15-(p-iodophenyl)-3-R,S-methyl-pentadecanoic acid in scintigraphy and the absence of CD36 antigen in both monocytes and platelets in flow cytometry. She had a homozygous mutation of the CD36 gene (c.1126-5_1127delTTTAGAT), which occurs in a canonical splice site (acceptor) and is predicted to disrupt or distort the normal gene product. To our knowledge, this is the first report of a heterozygous FH phenotype caused by possibly oligogenic variants of the PCSK9 and ABCG5 genes complicated with type I CD36 deficiency caused by a novel homozygous mutation. Both FH phenotype and CD36 deficiency might have caused extensive atherosclerosis, leading to acute myocardial infarction in the present case.

DOI： 10.5551/jat.58909

PubMed

Patients With LDLR and PCSK9 Gene Variants Experienced Higher Incidence of Cardiovascular Outcomes in Heterozygous Familial Hypercholesterolemia. 査読有り国際誌

Doi T, Hori M, Harada-Shiba M, Kataoka Y, Onozuka D, Nishimura K, Nishikawa R, Tsuda K, Ogura M, Son C, Miyamoto Y, Noguchi T, Shimokawa H, Yasuda S

Journal of the American Heart Association 10 巻 ( 4 ) 頁： e018263 - 11 2021年2月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of the American Heart Association

BACKGROUND: Patients with familial hypercholesterolemia who harbored both low-density lipoprotein receptor (LDLR) and PCSK9 (proprotein convertase subtilisin/kexin type 9) gene variants exhibit severe phenotype associated with substantially high levels of low-density lipoprotein cholesterol. In this study, we investigated the cardiovascular outcomes in patients with both LDLR and PCSK9 gene variants. METHODS AND RESULTS: A total of 232 unrelated patients with LDLR and/or PCSK9 gene variants were stratified as follows: patients with LDLR and PCSK9 (LDLR/PCSK9) gene variants, patients with LDLR gene variant, and patients with PCSK9 gene variant. Clinical demographics and the occurrence of primary outcome (nonfatal myocardial infarction) were compared. The observation period of primary outcome started at the time of birth and ended at the time of the first cardiac event or the last visit. Patients with LDLR/PCSK9 gene variants were identified in 6% of study patients. They had higher levels of low-density lipoprotein cholesterol (P=0.04) than those with LDLR gene variants. On multivariate Cox regression model, they experienced a higher incidence of nonfatal myocardial infarction (hazard ratio, 4.62; 95% CI, 1.66–11.0; P=0.003 versus patients with LDLR gene variant). Of note, risk for nonfatal myocardial infarction was greatest in male patients with LDLR/PCSK9 gene variants compared with those with LDLR gene variant (86% versus 24%; P<0.001). CONCLUSIONS: Patients with LDLR/PCSK9 gene variants were high-risk genotype associated with atherogenic lipid profiles and worse cardiovascular outcomes. These findings underscore the importance of genetic testing to identify patients with LDLR/ PCSK9 gene variants, who require more stringent antiatherosclerotic management.

DOI： 10.1161/JAHA.120.018263

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PubMed

Cerebrotendinous Xanthomatosis: Molecular Pathogenesis, Clinical Spectrum, Diagnosis, and Disease-Modifying Treatments 査読有り

Koyama Shingo, Sekijima Yoshiki, Ogura Masatsune, Hori Mika, Matsuki Kota, Miida Takashi, Harada-Shiba Mariko

JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS 28 巻 ( 9 ) 頁： 905 - 925 2021年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Atherosclerosis and Thrombosis

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disorder caused by mutations in the CYP27A1 gene, which encodes the mitochondrial enzyme sterol 27-hydroxylase. Decreased sterol 27-hydroxylase activity results in impaired bile acid synthesis, leading to reduced production of bile acids, especially chenodeoxycholic acid (CDCA), as well as elevated serum cholestanol and urine bile alcohols. The accumulation of cholestanol and cholesterol mainly in the brain, lenses, and tendons results in the characteristic clinical manifestations of CTX. Clinical presentation is characterized by systemic symptoms including neonatal jaundice or cholestasis, refractory diarrhea, juvenile cataracts, tendon xanthomas, osteoporosis, coronary heart disease, and a broad range of neuropsychiatric manifestations. The combinations of symptoms vary from patient to patient and the presenting symptoms, especially in the early disease phase, may be nonspecific, which leads to a substantial diagnostic delay or underdiagnosis. Replacement of CDCA has been approved as a first-line treatment for CTX, and can lead to biochemical and clinical improvements. However, the effect of CDCA treatment is limited once significant neuropsychiatric manifestations are established. The age at diagnosis and initiation of CDCA treatment correlate with the prognosis of patients with CTX. Therefore, early diagnosis and subsequent treatment initiation are essential.

DOI： 10.5551/jat.RV17055

Organoid-based ex vivo reconstitution of Kras-driven pancreatic ductal carcinogenesis. 査読有り

Matsuura T, Maru Y, Izumiya M, Hoshi D, Kato S, Ochiai M, Hori M, Yamamoto S, Tatsuno K, Imai T, Aburatani H, Nakajima A, Hippo Y

Carcinogenesis 41 巻 ( 4 ) 頁： 490-501 2020年6月

The first Japanese cases of familial hypercholesterolemia due to a known pathogenic APOB gene variant, c.10580 G>A: p.(Arg3527Gln). 査読有り

2020年5月

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