著者
Hayato Tada Hirofumi Okada Atsushi Nohara Masakazu Yamagishi Masayuki Takamura Masa-aki Kawashiri
出版者
The Japanese Circulation Society
雑誌
Circulation Journal (ISSN:13469843)
巻号頁・発行日
vol.85, no.11, pp.2073-2078, 2021-10-25 (Released:2021-10-25)
参考文献数
23
被引用文献数
1 24

Background:Recent studies suggest that cumulative exposure to low-density lipoprotein-cholesterol (LDL-C) leads to the development of atherosclerotic cardiovascular disease (ASCVD). However, few studies have investigated whether this link extends to individuals with familial hypercholesterolemia (FH), a relevant patient population.Methods and Results:We retrospectively investigated the health records of 1,050 patients with clinical FH diagnosis between April 1990 and March 2019. We used Cox proportional hazards models adjusted for established ASCVD risk factors to assess the association between cholesterol-year-score and major adverse cardiovascular events (MACEs), including death from any cause or hospitalization due to ASCVD events. Cholesterol-year-score was calculated as LDL-C max × [age at diagnosis/statin initiation] + LDL-C at inclusion × [age at inclusion − age at diagnosis/statin initiation]. The median follow-up period for MACE evaluation was 12.3 (interquartile range, 9.1–17.5) years, and 177 patients experienced MACEs during the observation period. Cholesterol-year-score was significantly associated with MACEs (hazard ratio, 1.35; 95% confidence interval, 1.07–1.53; P=0.0034, per 1,000 mg-year/dL), independent of other traditional risk factors including age and LDL-C, based on cross-sectional assessment. Cholesterol-year-score improved the discrimination ability of other traditional risk factors for ASCVD events (C-index, 0.901 vs. 0.889; P=0.00473).Conclusions:Cumulative LDL-C exposure was strongly associated with MACEs in Japanese patients with FH, warranting early diagnosis and treatment initiation in these patients.
著者
Hayato Tada Hirofumi Okada Atsushi Nohara Ryuji Toh Amane Harada Katsuhiro Murakami Takuya Iino Manabu Nagao Tatsuro Ishida Ken-ichi Hirata Masayuki Takamura Masa-aki Kawashiri
出版者
The Japanese Circulation Society
雑誌
Circulation Journal (ISSN:13469843)
巻号頁・発行日
pp.CJ-22-0560, (Released:2022-11-26)
参考文献数
33
被引用文献数
4

Background: Recently, the function of high-density lipoprotein (HDL), rather than the HDL cholesterol (HDL-C) level, has been attracting more attention in risk prediction for coronary artery disease (CAD).Methods and Results: Patients with clinically diagnosed familial hypercholesterolemia (FH; n=108; male/female, 51/57) were assessed cross-sectionally. Serum cholesterol uptake capacity (CUC) levels were determined using our original cell-free assay. Linear regression was used to determine associations between CUC and clinical variables, including low-density lipoprotein cholesterol and the carotid plaque score. Multivariable logistic regression analysis was used to test factors associated with the presence of CAD. Among the 108 FH patients, 30 had CAD. CUC levels were significantly lower among patients with than without CAD (median [interquartile range] 119 [92–139] vs. 142 [121–165] arbitrary units [AU]; P=0.0004). In addition, CUC was significantly lower in patients with Achilles tendon thickness ≥9.0 mm than in those without Achilles tendon thickening (133 [110–157] vs. 142 [123–174] AU; P=0.047). Serum CUC levels were negatively correlated with the carotid plaque score (Spearman’s r=0.37; P=0.00018). Serum CUC levels were significantly associated with CAD, after adjusting for other clinical variables (odds ratio=0.86, 95% CI=0.76–0.96, P=0.033), whereas HDL-C was not.Conclusions: HDL function, assessed by serum CUC level, rather than HDL-C level, adds risk stratification information among FH patients.
著者
Hayato Tada Hirofumi Okada Atsushi Nohara Ryuji Toh Amane Harada Katsuhiro Murakami Takuya Iino Manabu Nagao Tatsuro Ishida Ken-ichi Hirata Masayuki Takamura Masa-aki Kawashiri
出版者
The Japanese Circulation Society
雑誌
Circulation Journal (ISSN:13469843)
巻号頁・発行日
vol.87, no.6, pp.806-812, 2023-05-25 (Released:2023-05-25)
参考文献数
33
被引用文献数
4

Background: Recently, the function of high-density lipoprotein (HDL), rather than the HDL cholesterol (HDL-C) level, has been attracting more attention in risk prediction for coronary artery disease (CAD).Methods and Results: Patients with clinically diagnosed familial hypercholesterolemia (FH; n=108; male/female, 51/57) were assessed cross-sectionally. Serum cholesterol uptake capacity (CUC) levels were determined using our original cell-free assay. Linear regression was used to determine associations between CUC and clinical variables, including low-density lipoprotein cholesterol and the carotid plaque score. Multivariable logistic regression analysis was used to test factors associated with the presence of CAD. Among the 108 FH patients, 30 had CAD. CUC levels were significantly lower among patients with than without CAD (median [interquartile range] 119 [92–139] vs. 142 [121–165] arbitrary units [AU]; P=0.0004). In addition, CUC was significantly lower in patients with Achilles tendon thickness ≥9.0 mm than in those without Achilles tendon thickening (133 [110–157] vs. 142 [123–174] AU; P=0.047). Serum CUC levels were negatively correlated with the carotid plaque score (Spearman’s r=0.37; P=0.00018). Serum CUC levels were significantly associated with CAD, after adjusting for other clinical variables (odds ratio=0.86, 95% CI=0.76–0.96, P=0.033), whereas HDL-C was not.Conclusions: HDL function, assessed by serum CUC level, rather than HDL-C level, adds risk stratification information among FH patients.
著者
Hayato Tada Hirofumi Okada Akihiro Nomura Satoshi Yashiro Atsushi Nohara Yasushi Ishigaki Masayuki Takamura Masa-aki Kawashiri
出版者
The Japanese Circulation Society
雑誌
Circulation Journal (ISSN:13469843)
巻号頁・発行日
vol.83, no.9, pp.1917-1924, 2019-08-23 (Released:2019-08-23)
参考文献数
21
被引用文献数
55 55

Background:A substantial proportion of patients clinically diagnosed as having familial hypercholesterolemia (FH) do not manifest causative mutation(s) in the FH genes such asLDLR,APOB, andPCSK9. We aimed to evaluate the effect of rare and deleterious mutation(s) inABCG5/ABCG8on hyper-low-density lipoprotein (LDL) cholesterolemia in individuals who meet the clinical criteria for FH.Methods and Results:We compared the LDL cholesterol (LDL-C) values among 487 subjects with FH; the subjects were grouped according to the presence of mutation(s) in FH andABCG5/ABCG8genes. We identified 276 individuals with a deleterious mutation in 1 FH gene (57%, monogenic FH), but found no causative mutations in 156 individuals (32%, mutation-negative). A total of 37 individuals had deleterious mutations inABCG5orABCG8, but not in FH genes (8%,ABCG5/ABCG8mutation carriers). Among these, 3 individuals had sitosterolemia (0.6%) with double mutations. We also identified 18 individuals with deleterious mutations in an FH gene andABCG5orABCG8(4%,ABCG5/ABCG8-oligogenic FH). Subjects without mutations had significantly higher polygenic scores than those in any other groups. LDL-C levels in oligogenic FH subjects were significantly higher than in the monogenic FH subjects. Moreover, sitosterol/lathosterol levels were significantly affected by those mutations.Conclusions:The results suggested that rare and deleterious mutations inABCG5/ABCG8contribute substantially to mimicking and exacerbation of the FH phenotype.
著者
Hayato Tada Hirofumi Okada Akihiro Nomura Soichiro Usui Kenji Sakata Atsushi Nohara Masakazu Yamagishi Masayuki Takamura Masa-aki Kawashiri
出版者
The Japanese Circulation Society
雑誌
Circulation Journal (ISSN:13469843)
巻号頁・発行日
pp.CJ-20-0901, (Released:2020-12-03)
参考文献数
21
被引用文献数
11

Background:This study is aimed to compare the efficacy of the 2017 Japan Atherosclerosis Society (JAS) familial hypercholesterolemia (FH) criteria, which focuses on only 3 essential clinical manifestations, with that of Dutch Lipid Clinic Network (DLCN) FH criteria, which adopts a scoring system of multiple elements.Methods and Results:A total of 680 Japanese dyslipidemic participants (51% men) were enrolled between 2006 and 2018, all of whom had full evaluations of low-density lipoprotein (LDL) cholesterol, Achilles tendon X-rays, family history records, and genetic analysis of FH-associated genes (LDLR,APOB, andPCSK9). Predictive values for the existence of FH mutations by both clinical criteria were evaluated. Overall, 173 FH patients were clinically diagnosed by using the 2017 JAS criteria and 100, 57, 156, and 367 subjects were also diagnosed as having definite, probable, possible, and unlikely FH by the DLCN FH criteria, respectively. The positive and negative likelihood ratio predicting the presence of FH mutations by using the 2017 JAS FH criteria were 19.8 and 0.143, respectively; whereas, using the DLCN criteria of definite, probable, and possible FH, the ratios were 29.2 and 0.489, 9.70 and 0.332, and 3.43 and 0.040, respectively.Conclusions:Among Japanese patients, the JAS 2017 FH criteria is considered superior to diagnose FH mutation-positive patients and simultaneously rule out FH mutation-negative patients compared with the DLCN FH criteria.