26 results on '"Harada-Shiba, Mariko"'
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2. 2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: new treatments and clinical guidance.
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Cuchel M, Raal FJ, Hegele RA, Al-Rasadi K, Arca M, Averna M, Bruckert E, Freiberger T, Gaudet D, Harada-Shiba M, Hudgins LC, Kayikcioglu M, Masana L, Parhofer KG, Roeters van Lennep JE, Santos RD, Stroes ESG, Watts GF, Wiegman A, Stock JK, Tokgözoğlu LS, Catapano AL, and Ray KK
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- Humans, Cholesterol, LDL genetics, Homozygote, Homozygous Familial Hypercholesterolemia, Hyperlipoproteinemia Type II diagnosis, Hyperlipoproteinemia Type II genetics, Hyperlipoproteinemia Type II therapy, Anticholesteremic Agents therapeutic use, Atherosclerosis drug therapy
- Abstract
This 2023 statement updates clinical guidance for homozygous familial hypercholesterolaemia (HoFH), explains the genetic complexity, and provides pragmatic recommendations to address inequities in HoFH care worldwide. Key strengths include updated criteria for the clinical diagnosis of HoFH and the recommendation to prioritize phenotypic features over genotype. Thus, a low-density lipoprotein cholesterol (LDL-C) >10 mmol/L (>400 mg/dL) is suggestive of HoFH and warrants further evaluation. The statement also provides state-of-the art discussion and guidance to clinicians for interpreting the results of genetic testing and for family planning and pregnancy. Therapeutic decisions are based on the LDL-C level. Combination LDL-C-lowering therapy-both pharmacologic intervention and lipoprotein apheresis (LA)-is foundational. Addition of novel, efficacious therapies (i.e. inhibitors of proprotein convertase subtilisin/kexin type 9, followed by evinacumab and/or lomitapide) offers potential to attain LDL-C goal or reduce the need for LA. To improve HoFH care around the world, the statement recommends the creation of national screening programmes, education to improve awareness, and management guidelines that account for the local realities of care, including access to specialist centres, treatments, and cost. This updated statement provides guidance that is crucial to early diagnosis, better care, and improved cardiovascular health for patients with HoFH worldwide., Competing Interests: Conflict of interest Potential conflicts of interest outside the submitted work are summarized as follows. The following authors report participation in trials; receipt of fellowships, or grants for travel, research or staffing support; and/or personal honoraria for consultancy or lectures/speaker’s bureau from: Abbott (K.A.-R., M.K., K.K.R., R.D.S., L.S.T.); Abdi-Ibrahim (M.K., L.S.T.); Acasti (D.G., R.A.H.); Ache (R.D.S.); Actelion (L.S.T.); Aegerion (M.A., E.B., D.G., M.H.-S.); Akcea (M.A., E.B., A.L.C., D.G., R.A.H., K.G.P.); Alexion Pharma France (E.B.); Alfasigma (M.A.); Amarin (M.A., M.Av., A.L.C., L.M.); Amgen (M.A., M.Av., E.B., T.F., D.G., M.H.-S., R.A.H., M.K., L.M., K.G.P., F.J.R., K.K.R., R.D.S., L.S.T., G.F.W., A.W.); Amryt (M.A., M.Av., MC, M.K., L.M., J.E.R.v.L., R.D.S., A.W.); Arrowhead (R.A.H., G.F.W.); Ascent Development (M.H.-S.); Astellas (M.H.-S.); AstraZeneca (A.L.C., D.G., M.K., K.K.R., R.D.S., G.F.W.); Bayer (M.K., L.S.T.); Biolab (R.D.S.); Boehringer Ingelheim (D.G., M.H.-S., K.K.R.); Cerenis (D.G.); CRISPR Therapeutics (K.K.R.); Daiichi-Sankyo (M.Av., E.B., A.L.C., M.H.-S., M.K., L.M., K.G.P., K.K.R., L.S.T.); Dalcor Pharma (D.G.); Danone (E.B.); Deva (M.K.); Esperion (A.L.C., D.G., K.K.R., R.D.S., G.F.W.); Gemphire (D.G.); Genfit (E.B.); Genzyme (A.L.C.); Getz Pharma (R.D.S.); GlaxoSmithKline (D.G.); HDL Therapeutics (D.G.); HLS Therapeutics (R.A.H.); Ionis Pharmaceuticals (E.B., A.L.C., D.G., M.K.); Ironwood (D.G.); Jansen (M.K.); Kowa (A.L.C., D.G., M.H.-S., K.K.R., R.D.S.); LIB Therapeutics (R.A.H., M.K., F.J.R.); Libbs (R.D.S.); Eli Lilly/Lilly (A.L.C., D.G., M.K., K.K.R.); Medpace (M.H.-S., M.K.); Menarini (A.L.C.); Merck (A.L.C., M.K., R.D.S., L.S.T.); MSD (E.B., M.H.-S., K.G.P.); Mylan (M.A., E.B., A.L.C.); Nestlé (D.G.); New Amsterdam (K.K.R.); Novartis (K.A.-R., M.A., M.Av., E.B., A.L.C., T.F., D.G., M.H.-S., R.A.H., M.K., L.M., K.G.P., K.K.R., J.E.R.v.L., F.J.R., R.D.S., L.S.T., G.F.W., A.W.); NovoNordisk (M.K., K.K.R., R.D.S., L.S.T.); Pfizer (M.A., A.L.C., D.G., R.A.H., M.K., K.K.R., R.D.S., L.S.T., G.F.W.); PTC (R.D.S.); Recordati (A.L.C., M.H.-S., M.K., L.S.T.); Regeneron (M.A., A.L.C., MC, D.G., R.A.H., K.G.P., F.J.R., K.K.R., A.W.); REGENXBIO (M.C.); Resverlogix (K.K.R.); Sandoz (A.L.C.); Sanofi (K.A.-R., M.A., A.L.C., T.F., D.G., M.H.-S., R.A.H., M.K., L.M., K.G.P., F.J.R., K.K.R., R.D.S., L.S.T., G.F.W.); Sanofi/Genzyme (M.Av.); Sanofi-Regeneron (E.B.); SCIBE Therapeutics (K.K.R.); Servier (E.B., L.M., L.S.T.); Sigma Tau (A.L.C.); Silence Therapeutics (E.B., K.G.P., K.K.R., G.F.W., A.W.); Sobi Takeda (M.Av.); The Medicine Company (D.G., M.H.-S.); Ultragenyx (R.A.H.); UniQure (D.G.); and Vaxxinity (K.K.R.). ESG Stroes reports honoraria for lectures/advisory board R.D.S. paid to his institution from Amarin, Amgen, Daiichi-Sankyo, Esperion, IONIS/Akcea, Novartis, Novo-Nordisk, and Sanofi-Regeneron. Manuscripts have been published in collaboration with non-academic co-authors by L.S.T. (Fitbit), and G.F.W. (Amgen). T.F. is supported by the project National Institute for Research of Metabolic and Cardiovascular Diseases (Programme EXCELES, ID Project No. LX22NPO5104)—Funded by the European Union—Next Generation EU. D.G. is supported by Canadian Cardiovascular Research Network and the Institut de cardiologie de Montréal. Equity interests are reported by K.K.R. (Cargene Therapeutics and Pemi31 Therapeutics) and J.K.S. (AstraZeneca and GSK). K.K.R. is President of the European Atherosclerosis Society. L.S.T. is Past-President of the European Atherosclerosis Society and an Editorial Board Member, The European Heart Journal. L.C.H. has no disclosures., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)
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- 2023
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3. Guidelines for the Diagnosis and Treatment of Pediatric Familial Hypercholesterolemia 2022.
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Harada-Shiba M, Ohtake A, Sugiyama D, Tada H, Dobashi K, Matsuki K, Minamino T, Yamashita S, and Yamamoto Y
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- Humans, Child, Blood Component Removal, Guidelines as Topic, Cholesterol, LDL, Hyperlipoproteinemia Type II diagnosis, Hyperlipoproteinemia Type II drug therapy, Hyperlipoproteinemia Type II genetics, Atherosclerosis diagnosis, Atherosclerosis drug therapy, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use
- Abstract
As atherosclerosis begins in childhood, early diagnosis and treatment of familial hypercholesterolemia (FH) is considered necessary. The basic diagnosis of pediatric FH (under 15 years of age) is based on hyper-low-density lipoprotein (LDL) cholesterolemia and a family history of FH; however, in this guideline, to reduce overlooked cases, "probable FH" was established. Once diagnosed with FH or probable FH, efforts should be made to promptly provide lifestyle guidance, including diet. It is also important to conduct an intrafamilial survey, to identify family members with the same condition. If the level of LDL-C remains above 180 mg/dL, drug therapy should be considered at the age of 10. The first-line drug should be statin. Evaluation of atherosclerosis should be started using non-invasive techniques, such as ultrasound. The management target level is an LDL-C level of less than 140 mg/dL. If a homozygous FH is suspected, consult a specialist and determine the response to pharmacotherapy with evaluating atherosclerosis. If the response is inadequate, initiate lipoprotein apheresis as soon as possible.
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- 2023
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4. Association between Achilles Tendon Softness and Atherosclerotic Cardiovascular Disease in Patients with Familial Hypercholesterolemia.
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Michikura M, Ogura M, Hori M, Matsuki K, Makino H, Hosoda K, and Harada-Shiba M
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- Humans, Carotid Intima-Media Thickness, Overweight complications, Risk Factors, Achilles Tendon diagnostic imaging, Cardiovascular Diseases etiology, Cardiovascular Diseases complications, Hyperlipoproteinemia Type II complications, Hyperlipoproteinemia Type II diagnosis, Atherosclerosis etiology, Atherosclerosis complications, Carotid Artery Diseases complications, Xanthomatosis complications
- Abstract
Aims: Achilles tendon (AT) xanthomas are a specific physical finding of familial hypercholesterolemia (FH) and AT thickness has been used for its diagnosis and evaluation of its severity. Recently, we reported that the AT of FH patients was softer than that of non-FH patients and the combined use of a cut-off value for AT softness with that for AT thickness improved diagnostic accuracy. However, an association between AT softness and severity of atherosclerosis has not been reported. Accordingly, the present study aimed to investigate whether AT softness was associated with carotid atherosclerosis and presence of atherosclerotic cardiovascular disease (ASCVD) in FH., Methods: The AT of 176 genetically diagnosed FH patients and 98 non-FH patients was examined to measure AT thickness and the elasticity index (EI) as an indicator for assessing AT softness using ultrasonography., Results: Increased age was associated with AT softness, and overweight was negatively related to AT softness. There were significant inverse correlations between EI and maximum and mean intima-media thickness (IMT) within the common carotid artery only among FH patients. In multiple linear regression analysis, although the relationship between EI and mean IMT was attenuated, the association between EI and maximum IMT remained robust. In logistic regression analysis adjusted for age, sex and traditional cardiovascular risk factors (smoking history, presence of hypertension, presence of diabetes mellitus, overweight, LDL-cholesterol, HDL-cholesterol, and Log triglycerides), EI was associated with presence of ASCVD (Odds ratio per 1-SD increase, 0.37; 95% CI, 0.15 - 0.86; P=0.0252)., Conclusion: The degree of lipid deposition in the AT of FH patients could be assessed by its thickness as well as its softness. AT softness is not only useful in diagnosing FH but is also associated with the severity of carotid atherosclerosis and presence of ASCVD. In addition, these findings suggest that AT softness would be helpful in risk assessment for FH patients.
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- 2022
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5. Characterization of Polyvascular Disease in Heterozygous Familial Hypercholesterolemia: Its Association With Circulating Lipoprotein(a) Levels.
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Funabashi S, Kataoka Y, Hori M, Ogura M, Doi T, Noguchi T, and Harada-Shiba M
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- Humans, Lipoprotein(a), Middle Aged, Risk Factors, Atherosclerosis complications, Coronary Artery Disease diagnosis, Hyperlipoproteinemia Type II diagnosis, Hyperlipoproteinemia Type II epidemiology, Hyperlipoproteinemia Type II genetics, Peripheral Arterial Disease complications
- Abstract
Background Heterozygous familial hypercholesterolemia (HeFH) more likely exhibits extensive atherosclerotic disease at multiple vascular beds. Lipoprotein(a) (Lp(a)) is an atherogenic lipoprotein that elevates HeFH-related atherosclerotic cardiovascular disease risks. Whether circulating Lp(a) level associates with polyvascular propagation of atherosclerosis in subjects with HeFH remains uncertain. Methods and Results The current study analyzed 370 subjects with clinically diagnosed HeFH who received evaluation of systemic arteries. Polyvascular disease (polyVD) was defined as more than 2 coexisting atherosclerosis conditions including coronary artery disease, carotid stenosis, or peripheral artery disease. Clinical characteristics and lipid features were analyzed in subjects with HeFH and polyVD; 5.7% of patients with HeFH (21/370) had polyVD. They were more likely to have a clustering of risk factors, tendon ( P <0.001) and skin xanthomas ( P =0.004), and corneal arcus ( P =0.026). Furthermore, an elevated Lp(a) level ( P =0.006) and a greater frequency of Lp(a) level ≥50 mg/dL ( P <0.001) were observed in subjects with HeFH and polyVD. On multivariable analysis adjusting risk factors and lipid-lowering agents, Lp(a) ≥50 mg/dL (odds ratio [OR], 5.66 [95% CI, 1.68-19.0], P =0.005), age, and family history of premature coronary artery disease independently predicted polyVD in subjects with HeFH. Of note, the prevalence of polyVD rose to 33.3% in patients with HeFH and age >58 years old, family history of premature coronary artery disease, and Lp(a) ≥50 mg/dL (OR, 10.3 [95% CI, 3.12-33.4], P <0.001). Conclusions An increased level of circulating Lp(a) levels predicted concomitance of polyVD in patients with HeFH. The current findings suggest subjects with HeFH and Lp(a) ≥50 mg/dL as a high-risk category who require meticulous screening of systemic vascular beds.
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- 2022
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6. Relation of Serum Lipoprotein(a) Levels to Lipoprotein and Apolipoprotein Profiles and Atherosclerotic Diseases in Japanese Patients with Heterozygous Familial Hypercholesterolemia: Familial Hypercholesterolemia Expert Forum (FAME) Study.
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Naito R, Daida H, Masuda D, Harada-Shiba M, Arai H, Bujo H, Ishibashi S, Koga N, Oikawa S, and Yamashita S
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- Apolipoproteins therapeutic use, Apolipoproteins A therapeutic use, Apolipoproteins B, Apolipoproteins E, Humans, Japan epidemiology, Lipoprotein(a), Male, Atherosclerosis complications, Atherosclerosis etiology, Cardiovascular Diseases complications, Hyperlipoproteinemia Type II
- Abstract
Aims: Lipoprotein(a) [Lp(a)] is a plasma lipoprotein consisting of a low-density lipoprotein (LDL)-like particle with apolipoprotein (Apo)(a), attached via a disulfide bond to Apo B100. Previous studies have shown that high Lp(a) levels are associated with an increased risk of cardiovascular disease in patients with familial hypercholesterolemia (FH). To date, limited data are available as to distribution of Lp(a) in FH and associations of Lp(a) with other lipid profiles and cardiovascular disease. Our study aimed to investigate serum Lp(a) levels in relation to other lipid profiles and clinical conditions in the national largest-ever cohort of Japanese FH patients., Methods: This study is a secondary analysis of the Familial Hypercholesterolemia Expert Forum (FAME) Study that includes a Japanese nationwide cohort of FH patients. In 399 patients under treatment for heterozygous FH who had a baseline measurement of serum Lp(a), the present study examined the distribution of Lp(a) levels and associations of Lp(a) with other lipid profiles and clinical conditions including coronary artery disease (CAD)., Results: The distribution of Lp(a) was skewed to the right with a median of 20.8 mg/dL, showing a log-normal distribution. Serum Apo B and Apo E levels were positively associated with Lp(a) levels. Age-adjusted mean of Apo B was 8.77 mg/dL higher and that of Apo E was 0.39 mg/dL higher in the highest category (40+ mg/dL) of Lp(a) than in the lowest category (<20 mg/dL). LDL-C levels did not show such an association with Lp(a) levels. A tendency towards a positive relationship between Lp(a) and prevalent CAD was observed in men., Conclusion: Our study demonstrated a distribution pattern of Lp(a) in Japanese FH patients and positive relationships of Lp(a) with Apo B and Apo E levels.
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- 2022
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7. Familial Hypercholesterolemia in Patients with Acute Coronary Syndrome: Genetic Insights from EXPLORE-J.
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Harada-Shiba M, Ako J, Hirayama A, Nakamura M, Nohara A, Sato K, Murakami Y, Koshida R, Ozaki A, and Arai H
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- Humans, Mutation, Phenotype, Proprotein Convertase 9 genetics, Prospective Studies, Receptors, LDL genetics, Risk Factors, Acute Coronary Syndrome diagnosis, Acute Coronary Syndrome genetics, Atherosclerosis, Hyperlipoproteinemia Type II diagnosis, Hyperlipoproteinemia Type II epidemiology, Hyperlipoproteinemia Type II genetics
- Abstract
Aim: Genetic testing can provide a definitive diagnosis of familial hypercholesterolemia (FH). However, accessibility of genetic testing may be limited in certain countries where it is not considered "standard of care," including Japan. In addition, mutations responsible for FH cannot be identified in approximately 30% of patients., Methods: EXPLORE-J is a multicenter, prospective, observational study of patients presenting with acute coronary syndrome (ACS). The genetic data were analyzed and adjudicated as pathogenic, indeterminate, or nondetectable pathogenic variant., Results: Of 1,944 patients, 431 underwent genetic screening. Overall, most patients had nonpathogenic variants of LDLR, LDLRAP1, or PCSK9 (n=396, 91.9%). Of the 25 (5.8%) patients with pathogenic variants, variants of the LDLR gene and the PCSK9 gene were seen in 10 and 15 patients, respectively. Indeterminate variants were observed in 10 (2.3%) patients. Of the 431 patients, eight (1.9%) met the criteria for a diagnosis of FH using the Japanese Atherosclerosis Society (JAS) 2017 guidelines. When genetic data were incorporated, 33 (7.7%) patients met the JAS guidelines. No patients with FH pathogenic variants satisfied the JAS clinical criteria for a diagnosis of FH., Conclusions: The results revealed a higher prevalence of genetic mutations of FH among Japanese patients with ACS and a low sensitivity of the FH diagnostic criteria of the JAS 2017 guidelines. These findings highlight the difficulties of FH diagnosis in patients with ACS in the acute phase and suggest the importance of genetic testing and family history.
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- 2022
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8. How Can We Identify Very High-Risk Heterozygous Familial Hypercholesterolemia?
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Kataoka Y, Funabashi S, Doi T, and Harada-Shiba M
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- Biomarkers, Cholesterol, LDL, Humans, Atherosclerosis diagnosis, Atherosclerosis drug therapy, Atherosclerosis etiology, Hypercholesterolemia, Hyperlipoproteinemia Type II diagnosis, Hyperlipoproteinemia Type II drug therapy, Hyperlipoproteinemia Type II genetics
- Abstract
Heterozygous familial hypercholesterolemia (HeFH) is a genetic disorder that elevates low-density lipoprotein cholesterol and increases the risk of premature atherosclerotic cardiovascular disease (ASCVD). However, despite their atherogenic lipid profiles, the cardiovascular risk of HeFH varies in each individual. Their variety of phenotypic features suggests the need for better risk stratification to optimize their therapeutic management. The current review summarizes three potential approaches, including (1) definition of familial hypercholesterolemia (FH)-related risk scores, (2) genetic analysis, and (3) biomarkers. The International Atherosclerosis Society has recently proposed a definition of severe FH to identify very high-risk HeFH subjects according to their clinical characteristics. Furthermore, published studies have shown the association of FH-related genetic phenotypes with ASCVD, which indicates the genetic analysis's potential to evaluate individual cardiovascular risks. Biomarkers reflecting disease activity have been considered to predict the formation of atherosclerosis and the occurrence of ASCVD in HeFH subjects. Incorporating these risk stratifications will be expected to allocate adequate intensity of lipid-lowering therapies in HeFH subjects, which ultimately improves cardiovascular outcomes.
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- 2022
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9. Achilles Tendon Thickness Assessed by X-ray Predicting a Pathogenic Mutation in Familial Hypercholesterolemia Gene.
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Tada H, Hori M, Matsuki K, Ogura M, Nohara A, Kawashiri MA, and Harada-Shiba M
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- Female, Humans, Male, Mutation, Proprotein Convertase 9 genetics, Receptors, LDL genetics, X-Rays, Achilles Tendon diagnostic imaging, Atherosclerosis genetics, Hyperlipoproteinemia Type II diagnostic imaging, Hyperlipoproteinemia Type II genetics
- Abstract
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.
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- 2022
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10. Effectiveness and Safety of Lipid-Lowering Drug Treatments in Japanese Patients with Familial Hypercholesterolemia: Familial Hypercholesterolemia Expert Forum (FAME) Study.
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Yamashita S, Masuda D, Harada-Shiba M, Arai H, Bujo H, Ishibashi S, Daida H, Koga N, and Oikawa S
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- Cholesterol, Cholesterol, LDL, Ezetimibe therapeutic use, Humans, Japan epidemiology, Male, Probucol therapeutic use, Anticholesteremic Agents adverse effects, Atherosclerosis drug therapy, Hydroxymethylglutaryl-CoA Reductase Inhibitors adverse effects, Hyperlipoproteinemia Type II drug therapy, Hyperlipoproteinemia Type II epidemiology, Hyperlipoproteinemia Type II genetics, Xanthomatosis complications
- Abstract
Aims: Familial hypercholesterolemia (FH) is a genetic disorder characterized by high serum levels of low-density lipoprotein (LDL)-cholesterol (LDL-C), tendon and skin xanthomas, and premature coronary artery disease (CAD). In Japan, detailed information on the current status of drug therapies for patients with FH has not been reported so far, and their efficacy and safety have not been clarified. After the introduction of ezetimibe, which can further reduce serum LDL-C levels on top of statins, the changes of management for FH patients with these drugs are of particular interest. The current study aimed to evaluate the clinical status of FH heterozygotes and homozygotes, especially focusing on the real-world lipid-lowering drug therapy, attained serum LDL-C levels, and cardiovascular events at registration and during the follow-up., Methods: The FAME Study enrolled 762 heterozygous (including 17 newly diagnosed cases) and 7 homozygous FH patients from hospitals and clinics nationwide. Diagnosis of FH was based upon the criteria defined in the Study Report in 2008 of the Research Committee on Primary Hyperlipidemia supported by Grants-in-Aid for Scientific Research from the Japanese Ministry of Health, Labor and Welfare. Data analysis was primarily carried on heterozygous FH patients., Results: Xanthoma or thickening of the Achilles tendon was observed in more than 80% of the patients. CAD was recorded in 23% of patients. Patients with parental and sibling CAD accounted for 47% and 24%, respectively. At baseline, patients without CAD who had LDL-C <100 mg/dL accounted for 12.3% and those with CAD who had attained the target (LDL-C <70 mg/dL) in the secondary prevention accounted for only 1.8%. In the multiple logistic analysis, male sex, age >40, heterozygous FH score >20, hypertension, and sibling CAD were significantly and positively associated with prevalent CAD, whereas serum HDL-cholesterol levels showed a significant inverse association with CAD. Patients treated with statin alone, statin+ezetimibe, statin+resin, or statin+probucol accounted for 31.1%, 26.3%, 4.0%, and 3.7%, respectively. Patients treated with three-drug combination (statin+ezetimibe+resin or statin+ezetimibe+probucol) accounted for 7.5%. Statins and ezetimibe were used in 88.0% and 48.0% at the baseline, respectively. Although high-intensity statins were mainly prescribed, statin doses were much lower than those reported in Western countries. The addition of ezetimibe resulted in ~20% reduction in serum LDL-C. CAD was diagnosed in 17 patients with 21 episodes during follow-up. The Cox hazard model analysis demonstrated that male sex, CAD at the baseline, and parental CAD were related to the development of atherosclerotic cardiovascular disease (ASCVD) events. Furthermore, an increase in serum HDL-C was associated with a significant reduction of ASCVD events, while serum LDL-C and triglyceride levels were not related to ASCVD events., Conclusion: The prevalence of CAD in Japanese patients with heterozygous FH is still very high. In most of the cases, the target level of serum LDL-C was not achieved for primary and secondary prevention of CAD, suggesting that a more aggressive LDL-C lowering and appropriate management of residual risks are necessary.
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- 2022
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11. Circulating Mature PCSK9 Level Predicts Diminished Response to Statin Therapy.
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Kuyama N, Kataoka Y, Takegami M, Nishimura K, Harada-Shiba M, Hori M, Ogura M, Otsuka F, Asaumi Y, Noguchi T, Tsujita K, and Yasuda S
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- Aged, Anticholesteremic Agents therapeutic use, Atherosclerosis drug therapy, Biomarkers blood, Coronary Artery Disease drug therapy, Dose-Response Relationship, Drug, Drug Therapy, Combination, Female, Follow-Up Studies, Humans, Male, Middle Aged, Prospective Studies, Treatment Outcome, Atherosclerosis blood, Coronary Artery Disease blood, Ezetimibe therapeutic use, Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage, Proprotein Convertase 9 blood
- Abstract
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.
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- 2021
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12. Familial Hypercholesterolemia and Lipoprotein Apheresis.
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Makino H, Koezuka R, Tamanaha T, Ogura M, Matsuki K, Hosoda K, and Harada-Shiba M
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- Humans, Hyperlipoproteinemia Type II blood, Atherosclerosis prevention & control, Hyperlipoproteinemia Type II therapy, Lipoproteins blood
- Abstract
Lipoprotein apheresis has been developed as the treatment for refractory familial hypercholesterolemia (FH) to remove low-density lipoprotein (LDL), which is the main pathogenic factor. Currently, three procedures are available in Japan, including the plasma exchange, double-membrane filtration, and selective LDL adsorption. Selective LDL adsorption, which was developed in Japan, has been one of the most common treatment methods in the world. Lipoprotein apheresis enabled the prevention of atherosclerosis progression even in homozygous FH (HoFH) patients. However, in our observational study, HoFH patients who started lipoprotein apheresis in adulthood had a poorer prognosis than those who started in childhood. Therefore, HoFH patients need to start lipoprotein apheresis as early as possible. Although the indication for lipoprotein apheresis in heterozygous FH (HeFH) patients has been decreasing with the advent of strong statins, our observational study showed that HeFH patients who discontinued lipoprotein apheresis had a poorer prognosis than patients who continued apheresis therapy. These results suggest that it is beneficial for very-high-risk HeFH patients to be treated by lipoprotein apheresis even if their LDL cholesterol is controlled well by lipid-lowering agents. Since launching a new class of lipid-lowering agents, proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody and microsome triglyceride transfer protein inhibitors, the indication for lipoprotein apheresis in FH has been changing. However, despite the development of these drugs, lipoprotein apheresis is still an option with a high therapeutic effect for FH patients with severe atherosclerotic cardiovascular disease.
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- 2019
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13. Humoral factors secreted from adipose tissue-derived mesenchymal stem cells ameliorate atherosclerosis in Ldlr-/- mice.
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Takafuji Y, Hori M, Mizuno T, and Harada-Shiba M
- Subjects
- Animals, Aorta pathology, Aortic Diseases genetics, Aortic Diseases metabolism, Aortic Diseases pathology, Atherosclerosis genetics, Atherosclerosis metabolism, Atherosclerosis pathology, Cell Adhesion Molecules metabolism, Cells, Cultured, Coculture Techniques, Culture Media, Conditioned metabolism, Cytokines metabolism, Diet, High-Fat, Disease Models, Animal, Endothelial Cells metabolism, Endothelial Cells pathology, Extracellular Vesicles metabolism, Hepatocyte Growth Factor metabolism, Humans, Inflammation Mediators metabolism, Macrophages metabolism, Macrophages pathology, Male, Mice, Inbred C57BL, Mice, Knockout, Receptors, LDL genetics, Signal Transduction, Adipose Tissue cytology, Aorta metabolism, Aortic Diseases prevention & control, Atherosclerosis prevention & control, Mesenchymal Stem Cells metabolism, Paracrine Communication, Plaque, Atherosclerotic, Receptors, LDL deficiency
- Abstract
Aims: Atherosclerosis is a chronic inflammatory disease of the vasculature. Mesenchymal stem cells (MSCs) exert immunomodulatory and immunosuppressive effects by secreting humoral factors; however, the intravascular MSC administration presents a risk of vascular occlusion. Here, we investigated both the effect of conditioned medium from cultured MSCs (MSC-CM) on atherosclerosis and the underlying mechanism., Methods and Results: Low-density lipoprotein receptor-deficient (Ldlr-/-) mice were fed a high-fat diet and received intravenous injections of either MSC-CM from adipose tissue-derived MSCs or control medium 2×/week for 13 weeks. MSC-CM treatment decreased the atherosclerotic plaque area in the aorta and aortic root of Ldlr-/- mice by 41% and 30%, respectively, with no change in serum lipoprotein levels. Histopathologically, the MSC-CM treatment decreased the expression of cell adhesion molecules (CAMs) and the accumulation of macrophages on the vascular walls. Extracellular vesicles (EVs) and supernatant (MSC-CM supernatant) were separated from the MSC-CM by ultracentrifugation. In tumour necrosis factor-α stimulated human aortic endothelial cells (HAOECs), both the MSC EVs and MSC-CM supernatant decreased CAM expression by inhibiting the mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NFκB) pathways. In macrophages, the MSC-CM supernatant decreased the lipopolysaccharide-induced increases in M1 marker expression by inhibiting both the MAPK and NFκB pathways and increased the expression of M2 markers by activating the signal transducer and activator of transcription 3 pathway. In co-culture, inflamed HAOECs pretreated with MSC-CM supernatant and MSC EVs exhibited decreased monocyte adhesion to HAOECs. In addition, the neutralization of hepatocyte growth factor (HGF) in MSC-CM or MSC-CM supernatant attenuated their abilities to suppress monocyte adhesion to HAOECs in co-culture., Conclusion: MSC-CM ameliorated atherosclerosis in Ldlr-/- mice and suppressed CAM expression and macrophage accumulation in the vascular walls. Humoral factors, including HGF and EVs from MSCs, hold promise as therapeutic agents to reduce the residual risk of coronary artery diseases., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2019
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14. Crude α-Mangostin Suppresses the Development of Atherosclerotic Lesions in Apoe -Deficient Mice by a Possible M2 Macrophage-Mediated Mechanism.
- Author
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Shibata MA, Harada-Shiba M, Shibata E, Tosa H, Matoba Y, Hamaoka H, Iinuma M, and Kondo Y
- Subjects
- Animals, Apolipoproteins E genetics, Apolipoproteins E metabolism, Atherosclerosis blood, Atherosclerosis genetics, Cholesterol blood, Macrophages drug effects, Male, Mice, Mice, Knockout, Plaque, Atherosclerotic blood, Plaque, Atherosclerotic drug therapy, Plaque, Atherosclerotic genetics, Plaque, Atherosclerotic metabolism, Xanthones chemistry, Atherosclerosis drug therapy, Atherosclerosis metabolism, Macrophages metabolism, Xanthones therapeutic use
- Abstract
Lifestyle choices play a significant role in the etiology of atherosclerosis. Male Apoe
-/- mice that develop spontaneous atherosclerotic lesions were fed 0%, 0.3%, and 0.4% mangosteen extracts, composed largely of α-mangostin (MG), for 17 weeks. Body weight gains were significantly decreased in both MG-treated groups compared to the control, but the general condition remained good throughout the study. The levels of total cholesterol (decreased very-low-density lipoprotein in lipoprotein profile) and triglycerides decreased significantly in the MG-treated mice in conjunction with decreased hepatic HMG-CoA synthase and Fatty acid transporter . Additionally, increased serum lipoprotein lipase activity and histopathology further showed a significant reduction in atherosclerotic lesions at both levels of MG exposure. Real-time PCR analysis for macrophage indicators showed a significant elevation in the levels of Cd163 , an M2 macrophage marker, in the lesions of mice receiving 0.4% MG. However, the levels of Nos2 , associated with M1 macrophages, showed no change. In addition, quantitative immunohistochemical analysis of macrophage subtypes showed a tendency for increased M2 populations (CD68⁺/CD163⁺) in the lesions of mice given 0.4% MG. In further analysis of the cytokine-polarizing macrophage subtypes, the levels of Interleukin13 ), associated with M2 polarization, were significantly elevated in lesions exposed to 0.4% MG. Thus, MG could suppress the development of atherosclerosis in Il13 ), associated with M2 polarization, were significantly elevated in lesions exposed to 0.4% MG. Thus, MG could suppress the development of atherosclerosis in Apoe-/- mice, possibly through an M2 macrophage-mediated mechanism.- Published
- 2019
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15. LDL apheresis in Japan.
- Author
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Makino H, Tamanaha T, and Harada-Shiba M
- Subjects
- Humans, Japan, Atherosclerosis therapy, Blood Component Removal methods, Cholesterol, LDL blood, Hyperlipoproteinemia Type II therapy, Peripheral Arterial Disease therapy
- Abstract
LDL apheresis has been developed as the treatment for refractory familial hypercholesterolemia (FH). Currently, plasma exchange, double membrane filtration, and selective LDL adsorption are available in Japan, and selective LDL adsorption is most common method. LDL apheresis can prevent atherosclerosis progression even in homozygous (HoFH). However, in our observational study, HoFH who started LDL apheresis from adulthood had poor prognosis compared with patients who started from childhood. Therefore, as far as possible, HoFH patients need to start LDL apheresis from childhood. Although indication of LDL apheresis in heterozygous FH (HeFH) has been decreasing with the advent of strong statin, our observational study showed that HeFH patients who were discontinued LDL apheresis therapy had poor prognosis compared with patients who were continued apheresis therapy. These results suggest that high risk HeFH need to be treated by LDL apheresis even if their LDLC is controlled by lipid-lowering agents. However, by launching new class of lipid lowering agents, that is, PCSK-9 antibody and MTP inhibitor, indication of LDL-apheresis in FH may be changed near the future. LDL-apheresis can provide symptom relief of peripheral artery disease (PAD). Therefore, PAD patients who have insufficient effect by other therapeutic approach including revascularization are also treated by LDL apheresis. Thus, LDL apheresis is still one of good therapeutic options for severe atherosclerotic diseases in Japan., (Copyright © 2017. Published by Elsevier Ltd.)
- Published
- 2017
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16. Pathological and molecular analyses of atherosclerotic lesions in ApoE-knockout mice.
- Author
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Shibata MA, Shibata E, Maemura K, Kondo Y, and Harada-Shiba M
- Subjects
- Animals, Apolipoproteins E metabolism, Atherosclerosis blood, Atherosclerosis diagnostic imaging, Carotid Intima-Media Thickness, Immunohistochemistry, Lipids blood, Male, Matrix Metalloproteinases metabolism, Mice, Inbred C57BL, Mice, Knockout, Real-Time Polymerase Chain Reaction, Scavenger Receptors, Class E, Apolipoproteins E deficiency, Atherosclerosis genetics, Atherosclerosis pathology
- Abstract
The establishment of consistent and reliable methods for the analysis of atherosclerosis molecular pathways and for testing the efficiency of new therapeutics is of utmost importance. Here, we fed ApoE-knockout (KO) mice with high-fat diet to for 16 weeks to induce atherosclerosis. Atherosclerotic lesions in mice were methodically investigated using pathologic analyses and molecular biology tools. These lesions were histopathologically classified into three categories: early, progressive, and combined lesions. Immunohistochemical analyses showed that both F4/80 (macrophage marker) and tenascin-C are expressed in these lesions. Real-time PCR analysis conducted using formalin-fixed paraffin-embedded tissues with atherosclerotic lesions demonstrated an increase in the levels of many inflammatory chemokines, including Cxcl16, while antibody arrays performed using frozen atherosclerotic tissue samples showed elevated TIMP-1 expression. Subsequent immunohistochemical analyses showed that the expression of CXCL16, TIMP-1, MMP-9, MMP-8, and LOX-1 is localized in the atherosclerotic lesions. We confirmed that the expression of these proteins is localized to atherosclerotic lesion, which suggests their roles in the development of the lesions in ApoE-KO mice. Therefore, this mouse model represents an appropriate tool for elucidating molecular mechanisms underlying the development of atherosclerosis, and a model for the evaluation of therapeutic efficiency of novel drugs.
- Published
- 2017
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17. Serum FABP5 concentration is a potential biomarker for residual risk of atherosclerosis in relation to cholesterol efflux from macrophages.
- Author
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Furuhashi M, Ogura M, Matsumoto M, Yuda S, Muranaka A, Kawamukai M, Omori A, Tanaka M, Moniwa N, Ohnishi H, Saitoh S, Harada-Shiba M, Shimamoto K, and Miura T
- Subjects
- Aged, Atherosclerosis diagnostic imaging, Atherosclerosis metabolism, Biomarkers blood, C-Reactive Protein metabolism, Carotid Arteries diagnostic imaging, Carotid Arteries metabolism, Carotid Intima-Media Thickness, Female, Humans, Japan, Male, Middle Aged, Atherosclerosis diagnosis, Cholesterol, HDL metabolism, Fatty Acid-Binding Proteins blood, Macrophages metabolism
- Abstract
Cholesterol efflux capacity (CEC) from macrophages, the first step in the reverse cholesterol transport pathway, is inversely associated with residual risk for atherosclerotic cardiovascular disease. Fatty acid-binding protein 4 (FABP4) and FABP5 are expressed in both adipocytes and macrophages and play significant roles in the development of insulin resistance and atherosclerosis. Both FABP4 and FABP5 are secreted from cells, and their circulating levels are associated with insulin resistance and atherosclerosis. We investigated the association between CEC and levels of FABP4 and FABP5 in 250 subjects without any medications. CEC was positively correlated with HDL cholesterol level and negatively correlated with concentrations of high-sensitivity C-reactive protein (hsCRP) and FABP5, but not FABP4. Multiple regression analysis demonstrated that FABP5 concentration was an independent predictor of CEC after adjustment of age, gender and levels of HDL cholesterol and hsCRP. In 129 of the 250 subjects who underwent carotid ultrasonography, mean intima-media thickness was negatively correlated with CEC and was positively correlated with concentrations of FABP4 and FABP5. In conclusion, in contrast to FABP4, circulating FABP5 is associated with decreased CEC and carotid atherosclerosis, suggesting that FABP5 level is a regulatory factor of CEC and a potential biomarker for residual risk of atherosclerosis.
- Published
- 2017
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18. Association Between Cholesterol Efflux Capacity and Atherosclerotic Cardiovascular Disease in Patients With Familial Hypercholesterolemia.
- Author
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Ogura M, Hori M, and Harada-Shiba M
- Subjects
- Achilles Tendon diagnostic imaging, Adult, Aged, Arcus Senilis blood, Arcus Senilis etiology, Arcus Senilis genetics, Asymptomatic Diseases, Atherosclerosis blood, Atherosclerosis diagnosis, Atherosclerosis genetics, Biomarkers blood, Carotid Artery Diseases blood, Carotid Artery Diseases etiology, Carotid Artery Diseases genetics, Carotid Intima-Media Thickness, Cross-Sectional Studies, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Hyperlipoproteinemia Type II blood, Hyperlipoproteinemia Type II genetics, Linear Models, Logistic Models, Male, Middle Aged, Mutation, Odds Ratio, Phenotype, Proprotein Convertase 9, Proprotein Convertases genetics, Radiography, Receptors, LDL genetics, Serine Endopeptidases genetics, Atherosclerosis etiology, Cholesterol, HDL blood, Hyperlipoproteinemia Type II diagnosis
- Abstract
Objective: Patients with familial hypercholesterolemia (FH) are at high risk for premature atherosclerotic cardiovascular disease (ASCVD), especially because of long-term exposure to high low-density lipoprotein cholesterol levels. It has been reported that low-density lipoprotein-lowering therapy delays the onset of ASCVD. However, it still remains difficult to prevent it. Therefore, novel biomarkers and therapeutic targets are necessary to evaluate and prevent atherosclerosis in FH. The aim of this study was to investigate associations of cholesterol efflux capacity with the presence of ASCVD and clinical features in patients with heterozygous FH., Approach and Results: We measured cholesterol efflux capacity in 227 patients with heterozygous FH under pharmaceutical treatment. Seventy-six (33.5%) of them were known to have ASCVD. In a logistic-regression analysis adjusted for risk factors, increased efflux capacity was associated with decreased risk of ASCVD even after the addition of high-density lipoprotein cholesterol level as a covariate (odds ratio per 1-SD increase, 0.95; 95% confidence interval, 0.90-0.99; P<0.05). Decreased cholesterol efflux capacity was associated with the presence of corneal arcus after adjusting for age and sex. In addition, inverse relationships between cholesterol efflux capacity and Achilles tendon thickness, as well as carotid intima-media thickness, were observed after adjustment for age, sex, and traditional cardiovascular risk factors., Conclusions: Cholesterol efflux capacity was independently and inversely associated with the presence of ASCVD in heterozygous FH. In view of residual risks after treatment with statins, cholesterol efflux capacity might be a novel biomarker and a therapeutic target for preventing atherosclerosis in patients with FH., (© 2015 American Heart Association, Inc.)
- Published
- 2016
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19. Proteomic analysis of proteins eliminated by low-density lipoprotein apheresis.
- Author
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Yuasa Y, Osaki T, Makino H, Iwamoto N, Kishimoto I, Usami M, Minamino N, and Harada-Shiba M
- Subjects
- Apolipoprotein C-III blood, Electrophoresis, Gel, Two-Dimensional methods, Enzyme-Linked Immunosorbent Assay, Female, Humans, Male, Mass Spectrometry methods, Proteins metabolism, Vitronectin blood, Atherosclerosis prevention & control, Blood Component Removal methods, Cholesterol, LDL blood, Proteomics methods
- Abstract
Low-density lipoprotein apheresis (LDL-A) treatment has been shown to decrease serum LDL cholesterol levels and prevent cardiovascular events in homozygous patients with familial hypercholesterolemia. Recently, LDL-A treatment has been suggested to have beneficial effects beyond the removal of LDL particles. In this study, to clarify the preventive effects of LDL-A treatment on atherosclerosis, the waste fluid from the adsorption columns was analyzed. The waste fluid of LDL adsorption columns was analyzed by two-dimensional electrophoresis followed by mass spectrometry. Serum concentrations of the newly identified proteins before and after LDL-A treatment were measured by enzyme-linked immunosorbent assay. We identified 48 kinds of proteins in the waste fluid of LDL adsorption columns, including coagulation factors, thrombogenic factors, complement factors, inflammatory factors and adhesion molecules. In addition to the proteins that were reported to be removed by LDL-A treatment, we newly identified several proteins that have some significant roles in the development of atherosclerosis, including vitronectin and apolipoprotein C-III (Apo C-III). The serum levels of vitronectin and Apo C-III decreased by 82.4% and 54.8%, respectively, after a single LDL-A treatment. While Apo C-III was removed with very low-density lipoprotein (VLDL) and LDL, vitronectin was removed without association with lipoproteins. The removal of proteins observed in the waste fluid has a certain impact on their serum levels, and this may be related to the efficacy of LDL-A treatment. Proteomic analysis of the waste fluid of LDL adsorption columns may provide a rational means of assessing the effects of LDL-A treatment., (© 2013 The Authors. Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis.)
- Published
- 2014
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20. Increase in secretory sphingomyelinase activity and specific ceramides in the aorta of apolipoprotein E knockout mice during aging.
- Author
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Kobayashi K, Nagata E, Sasaki K, Harada-Shiba M, Kojo S, and Kikuzaki H
- Subjects
- Aging blood, Aging genetics, Animals, Atherosclerosis blood, Atherosclerosis genetics, Disease Models, Animal, Female, Liver enzymology, Mice, Mice, Inbred C57BL, Mice, Knockout, Aging metabolism, Aorta enzymology, Apolipoproteins E genetics, Atherosclerosis enzymology, Ceramides blood, Sphingomyelin Phosphodiesterase metabolism
- Abstract
Atherosclerosis is caused by many factors, one of which is oxidative stress. We recently demonstrated that systemic oxidative stress increased secretory sphingomyelinase (sSMase) activity and generated ceramides in the plasma of diabetic rats. In addition, we also showed that the total ceramide level in human plasma correlated with the level of oxidized low-density lipoprotein. To investigate the relationship between ceramide species and atherogenesis during aging, we compared age-related changes in ceramide metabolism in apolipoprotein E knock out mice (apoE(-/-)) and wild type mice (WT). Although the total plasma ceramide level was higher in apoE(-/-) than that in WT at all ages, it decreased with increasing age. sSMase activity increased at 65 weeks (w) of age in both strains of mice. When apoE(-/-) developed atherosclerosis at 15 w of age, C18:0, C22:0, and C24:0 ceramide levels in the apoE(-/-) aorta significantly increased. Furthermore, at 65 w of age C16:0 and C24:1 ceramide levels were significantly higher than those in WT. These results suggested that elevation in levels of specific ceramide species due to sSMase activity contributed to atherogenesis during aging.
- Published
- 2013
- Full Text
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21. Familial hypercholesterolemia with multiple large tendinous xanthomas and advanced coronary artery atherosclerosis.
- Author
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Terasaki F, Morita H, Harada-Shiba M, Ohta N, Otsuka K, Nogi S, Miyamura M, Suzuki S, Ito T, Shimomura H, Katsumata T, Miyamoto Y, and Ishizaka N
- Subjects
- Achilles Tendon pathology, Adult, Atherosclerosis complications, Atherosclerosis surgery, Coronary Artery Bypass, Coronary Artery Disease complications, Coronary Artery Disease surgery, Humans, Hyperlipoproteinemia Type II complications, Hyperlipoproteinemia Type II surgery, Male, Xanthomatosis complications, Xanthomatosis surgery, Atherosclerosis diagnosis, Coronary Artery Disease diagnosis, Hyperlipoproteinemia Type II diagnosis, Xanthomatosis diagnosis
- Abstract
We herein report the case of a 53-year-old man with severe coronary ischemia who underwent successful coronary artery bypass surgery. Of note, he had hypercholesterolemia and presented with multiple large tendinous xanthomas and thickened Achilles tendons that had been present for more than two decades. Together with a family history of dyslipidemia, the patient was diagnosed as having familial hypercholesterolemia. Irrespective of an extensive search for possible mutations in the genes presumably involved in the patient's pathophysiology, including low-density lipoprotein receptor (LDLR), proprotein convertase subtilisin/kexin type 9 (PCSK9), autosomal recessive hypercholesterolemia (ARH) and apolipoprotein B (APOB), we were not able to identify the gene mutations responsible for the phenotype observed in the present case.
- Published
- 2013
- Full Text
- View/download PDF
22. Association of ceramides in human plasma with risk factors of atherosclerosis.
- Author
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Ichi I, Nakahara K, Miyashita Y, Hidaka A, Kutsukake S, Inoue K, Maruyama T, Miwa Y, Harada-Shiba M, Tsushima M, and Kojo S
- Subjects
- Apolipoprotein B-100 blood, Atherosclerosis epidemiology, Cholesterol blood, Cholesterol, LDL blood, Humans, Japan epidemiology, Mass Screening, Middle Aged, Predictive Value of Tests, Risk Factors, Spectrometry, Mass, Electrospray Ionization, Triglycerides blood, Atherosclerosis blood, Ceramides blood
- Abstract
Atherosclerosis is a multifactorial disorder. Recent studies indicate that the plasma level of sphingomyelin, which yields ceramide, correlates with the risk of coronary heart disease. Therefore, ceramide, a well-known lipid causing apoptosis in various cell types, may contribute to atherogenesis. We examined the relationship between ceramide concentration and risk factors of atherosclerosis in normal human plasma using electrospray tandem mass spectrometry (LC-MS/MS). Major ceramides in human plasma were C24:0 and C24:1. The ceramide concentration showed a significant positive correlation with total cholesterol (TC) and triglycerides (TG). In addition, plasma ceramide level increased drastically at a high level of LDL cholesterol (more than 170 mg/dL). Our previous studies demonstrated that the sum of fragmented and conjugated apolipoprotein B-100 proteins (B-ox), which were products of a radical reaction of LDL as well as plasma, was a reliable index of atherosclerosis. B-ox showed a significant positive correlation with the plasma ceramide level. Based on these results, we propose that the ceramide level in human plasma is a risk factor at the early stages of atherosclerosis.
- Published
- 2006
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23. Humoral factors secreted from adipose tissue-derived mesenchymal stem cells ameliorate atherosclerosis in Ldlr−/− mice.
- Author
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Takafuji, Yoshimasa, Hori, Mika, Mizuno, Toshihide, and Harada-Shiba, Mariko
- Subjects
VASCULAR cell adhesion molecule-1 ,MESENCHYMAL stem cells ,CELL adhesion molecules ,HEPATOCYTE growth factor ,NF-kappa B ,MITOGEN-activated protein kinases - Abstract
Aims Atherosclerosis is a chronic inflammatory disease of the vasculature. Mesenchymal stem cells (MSCs) exert immunomodulatory and immunosuppressive effects by secreting humoral factors; however, the intravascular MSC administration presents a risk of vascular occlusion. Here, we investigated both the effect of conditioned medium from cultured MSCs (MSC-CM) on atherosclerosis and the underlying mechanism. Methods and results Low-density lipoprotein receptor-deficient (Ldlr
− / − ) mice were fed a high-fat diet and received intravenous injections of either MSC-CM from adipose tissue-derived MSCs or control medium 2×/week for 13 weeks. MSC-CM treatment decreased the atherosclerotic plaque area in the aorta and aortic root of Ldlr− / − mice by 41% and 30%, respectively, with no change in serum lipoprotein levels. Histopathologically, the MSC-CM treatment decreased the expression of cell adhesion molecules (CAMs) and the accumulation of macrophages on the vascular walls. Extracellular vesicles (EVs) and supernatant (MSC-CM supernatant) were separated from the MSC-CM by ultracentrifugation. In tumour necrosis factor-α stimulated human aortic endothelial cells (HAOECs), both the MSC EVs and MSC-CM supernatant decreased CAM expression by inhibiting the mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NFκB) pathways. In macrophages, the MSC-CM supernatant decreased the lipopolysaccharide-induced increases in M1 marker expression by inhibiting both the MAPK and NFκB pathways and increased the expression of M2 markers by activating the signal transducer and activator of transcription 3 pathway. In co-culture, inflamed HAOECs pretreated with MSC-CM supernatant and MSC EVs exhibited decreased monocyte adhesion to HAOECs. In addition, the neutralization of hepatocyte growth factor (HGF) in MSC-CM or MSC-CM supernatant attenuated their abilities to suppress monocyte adhesion to HAOECs in co-culture. Conclusion MSC-CM ameliorated atherosclerosis in Ldlr− / − mice and suppressed CAM expression and macrophage accumulation in the vascular walls. Humoral factors, including HGF and EVs from MSCs, hold promise as therapeutic agents to reduce the residual risk of coronary artery diseases. [ABSTRACT FROM AUTHOR]- Published
- 2019
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24. Prevalence of familial hypercholesterolemia in patients with acute coronary syndrome in Japan: Results of the EXPLORE-J study.
- Author
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Harada-Shiba, Mariko, Ako, Junya, Arai, Hidenori, Hirayama, Atsushi, Murakami, Yoshitaka, Nohara, Atsushi, Ozaki, Asuka, Uno, Kiyoko, and Nakamura, Masato
- Subjects
- *
HYPERCHOLESTEREMIA , *CORONARY disease , *LIPIDS , *ACHILLES tendon , *ATHEROSCLEROSIS - Abstract
Abstract Background and aims Prevalence of familial hypercholesterolemia (FH), a common genetic disorder with a high risk for coronary artery disease (CAD), is high among CAD patients; however, data on FH prevalence among acute coronary syndrome (ACS) patients are limited. EXPLORE-J is the largest registry to diagnose FH among Japanese ACS patients using the 2012 Japan Atherosclerosis Society guidelines. Methods This prospective study consecutively recruited patients between April 2015 and August 2016 at 59 sites. Low-density lipoprotein cholesterol (LDL-C) levels, family history of premature CAD, presence of tendon xanthomas, and Achilles tendon radiograms were recorded at baseline. The prevalence rate of FH in patients with ACS was estimated with 95% CI. Results Of 1944 analyzed patients (mean age, 66.0 years; men, 80.3%), 52 (2.7% [95% CI: 2.0–3.5]) had FH. Thirty-one (1.6%) had LDL-C ≥180 mg/dL and Achilles tendon thickness (ATT) ≥9 mm, 8 (0.4%) had LDL-C ≥180 mg/dL and family history of premature CAD, 10 (0.5%) had ATT ≥9 mm and family history of premature CAD, and 3 (0.2%) met all the criteria. FH patients were younger than those without FH (59.5 [12.5] vs. 66.2 [12.1] years; p < 0.001). More patients with premature ACS (men, <55 years; women, <65 years) than without (4.7% [95% CI: 2.9–7.2] vs. 2.1% [1.4–3.0]) had FH. Conclusions FH prevalence is at least five-fold higher in ACS patients than in the general population, especially in patients with premature ACS onset and ATT ≥9 mm. FH screening in ACS patients is therefore clinically important and critical. Highlights • Data on the prevalence of FH, a genetic disorder, among ACS patients are limited. • EXPLORE-J is the largest registry to diagnose FH among Japanese ACS patients. • FH was diagnosed using the 2012 Japan Atherosclerosis Society guidelines. • FH prevalence is higher in ACS patients than the general population (2.7% vs. 0.2%). • Prevalence is especially high in patients with premature ACS onset and ATT ≥9 mm. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
25. Apheresis Technology for Prevention and Regression of Atherosclerosis.
- Author
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Yamamoto, Akira, Harada-Shiba, Mariko, Kawaguchi, Akito, and Tsushima, Motoo
- Subjects
- *
HEMAPHERESIS , *ATHEROSCLEROSIS risk factors , *HYPERCHOLESTEREMIA - Abstract
Familial hypercholesterolemia (FH) is a congenital disorder of cholesterol metabolism, which is due to a deficiency in low-density lipoprotein (LDL) receptors. The homozygous form of FH is especially liable to coronary artery disease (CAD) in youth because of the very high LDL-cholesterol levels. It is resistant to drug therapy, and LDL-apheresis is the only practical way of treatment for these patients. Some patients with heterozygous FH also have high LDL-cholesterol levels that cannot be brought down into the optimum range by any combination drug therapy. We have treated or are treating 10 homozygous and 28 heterozygous FH patients in our hospital or in affiliated hospitals expert in blood purification. Among the 10 homozygous patients, 2 died of myocardial infarction. Only one young female patient is still free of symptoms, and the other patients have been suffering from regurgitation through the aortic valve although they have not experienced myocardial infarction. Rapid rebound of LDL-cholesterol after each apheresis treatment limits the period during which LDL-cholesterol is in the optimum range. The use of atorvastatin at a high dose (40 mg/day) was attempted to suppress this rebound. In contrast with good results in receptor-defective-type patients, receptor-negative-type patients did not show a response in LDL-cholesterol levels to the statin therapy although there was a slight increase in high-density lipoprotein (HDL)-cholesterol with a decrease in very-low-density lipoprotein-triglyceride and -cholesterol. Follow-up study of the patients with heterozygous FH revealed that LDL-apheresis was effective in lengthening the life expectancy of the patients with pre-existing CAD, especially those who had received intervention coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA). It was also shown that the use of probucol in combination with LDL-apheresis was effective in reducing coronary events as shown by the... [ABSTRACT FROM AUTHOR]
- Published
- 2001
- Full Text
- View/download PDF
26. Abstract 12861: Elasticity of Achilles Tendon as a Tool for Improving Diagnostic Accuracy and a Novel Marker for Atherosclerosis in Familial Hypercholesterolaemia.
- Author
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Harada-Shiba, Mariko, Michikura, Masahito, Ogura, Masatsune, Fuke, Chizuru, and Hori, Mika
- Subjects
- *
ACHILLES tendon , *FAMILIAL hypercholesterolemia , *ACHILLES tendon rupture , *ELASTICITY , *LOGISTIC regression analysis , *CORONARY disease , *ATHEROSCLEROSIS - Abstract
Introduction: Achilles tendon xanthoma is one of the major characteristics of familial hypercholesterolaemia (FH) and is used for its diagnosis and evaluation of its severity. However, there are some patients such as females and young individuals who lack AT xanthoma, which results in underdiagnosis of FH.. To improve diagnostic accuracy of FH and evaluation of severity of FH, we measured elasticity as well as thickness of Achilles tendon using ultrasonography. Hypothesis: Elasticity of the Achilles tendon may reflect cholesterol accumulation in FH and can be a marker for diagnosis of FH and evaluation of coronary risk. Methods: One-hundred and ten FH patients diagnosed by genetic testing and 121 non-FH patients were enrolled in this cross-sectional study. Achilles tendon thickness was measured by using ultrasonography. Elasticity was performed by using elastography. Results: The thickness of Achilles tendon was 7.9 (5.8 - 11.0) mm, 5.0 (4.6- 5.6) mm in FH and non-FH, respectively (p<0.01). The elastic index (EI) was 4.1 (3.8 - 4.7), 4.9 (4.5 - 5.1)) in FH and non-FH, respectively (p<0.01). Achilles tendon of FH was thicker and softer than those of non-FH patients, and an inverse relationship between Achilles tendon thickness (ATT) and EI was observed only among FH patients. Cut-off values of EI for the diagnosis of FH derived from receiver-operating curves were 4.6. Although 22 of 110 patients were not diagnosed as FH using the cut-off values for ATT only, we were additively able to diagnose 7 patients who had lower ATT than the cut-off values correctly by using cut-off value for EI. Additionally, decreased EI was associated with increased carotid intima-media thickness. Furthermore, in a logistic regression analysis adjusted for traditional cardiovascular risk factors, decreased EI value, rather than increased ATT was associated with the presence of coronary artery disease, suggesting that EI is not only a diagnostic criterion but also a useful risk marker for atherosclerosis in FH. Conclusions: Our findings should help distinguishing FH patients without Achilles tendon thickening, which could encourage clinicians to diagnose FH more actively. Moreover, EI might be also a novel useful marker for atherosclerosis among FH patients. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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