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Assessment of Coronary Atherosclerosis in Patients With Familial Hypercholesterolemia by Coronary Computed Tomography Angiography

Published:January 05, 2015DOI:https://doi.org/10.1016/j.amjcard.2014.12.034
      The aims of this study were (1) to determine whether the accumulation of coronary plaque burden assessed with coronary computed tomography angiography (CCTA) can predict future events and (2) to estimate the onset and progression of coronary atherosclerosis in patients with familial hypercholesterolemia (FH). Consecutive 101 Japanese patients with heterozygous FH (men = 52, mean age 56 ± 16 years, mean low-density lipoprotein cholesterol 264 ± 58 mg/dl) who underwent 64-detector row CCTA without known coronary artery disease were retrospectively evaluated by assigning a score (0 to 5) to each of 17 coronary artery segments according to the Society of Cardiovascular Computed Tomography guidelines. Those scores were summed and subsequently natural log transformed. The periods to major adverse cardiac events (MACE) were estimated using multivariable Cox proportional hazards models. During the follow-up period (median 941 days), 21 MACE had occurred. Receiver operating characteristic curve analyses identified a plaque burden score of 3.35 (raw score 28.5) as the optimal cutoff for predicting a worse prognosis. Multivariate Cox regression analysis identified the presence of a plaque score ≥3.35 as a significant independent predictor of MACE (hazard ratio = 3.65; 95% confidence interval 1.32 to 25.84, p <0.05). The regression equations were Y = 0.68X − 15.6 (r = 0.54, p <0.05) in male and Y = 0.74X − 24.8 (r = 0.69, p <0.05) in female patients with heterozygous FH. In conclusion, coronary plaque burden identified in a noninvasive, quantitative manner was significantly associated with future coronary events in Japanese patients with heterozygous FH and that coronary atherosclerosis may start to develop, on average, at age 23 and 34 years in male and female patients with heterozygous FH, respectively.
      Familial hypercholesterolemia (FH; OMIM #143890) is characterized by the triad of (1) primary hyper–low-density lipoprotein (LDL) cholesterolemia, (2) tendon xanthomas, and (3) premature coronary artery disease (CAD).
      • Goldstein J.L.
      • Hobbs H.H.
      • Brown M.S.
      Familial hypercholesterolemia.
      • Soutar A.K.
      • Naoumova R.P.
      Mechanisms of disease: genetic causes of familial hypercholesterolemia.
      Coronary computed tomography angiography (CCTA), a noninvasive imaging technique that progressed during the last decade, permits accurate detection and exclusion of CAD
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      Diagnostic accuracy of 64-slice computed tomography coronary angiography: a prospective, multicenter, multivendor study.
      • Zeb I.
      • Abbas N.
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      • Budoff M.J.
      Coronary computed tomography as a cost-effective test strategy for coronary artery disease assessment - a systematic review.
      In addition, the prognostic utility of CCTA for the general population has been clearly demonstrated by a number of previous studies.
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      • Murthy R.
      • Kraemer D.F.
      • Percy R.F.
      • Miller A.B.
      • Strom J.A.
      Association of cardiac events with coronary artery disease detected by 64-slice or greater coronary CT angiography: a systematic review and meta-analysis.
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      • Cheng V.
      • Chinnaiyan K.
      • Chow B.J.
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      • Raff G.
      • Shaw L.J.
      • Villines T.
      • Berman D.S.
      CONFIRM Investigators
      Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings results from the International Multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: an International Multicenter Registry) of 23,854 patients without known coronary artery disease.
      However, few data exist regarding the clinical prognostic performance of CCTA in FH. Moreover, such technique could help us to estimate when and how rapidly coronary atherosclerosis in patients with FH develops.
      • Mabuchi H.
      • Koizumi J.
      • Shimizu M.
      • Takeda R.
      Development of coronary heart disease in familial hypercholesterolemia.
      Here, we build on these observations to test 2 hypotheses: (1) plaque burden assessed by CCTA is associated with future coronary events beyond established risk factors in patients with FH and (2) we can estimate the onset and progression of coronary atherosclerosis in patients with FH assuming linear model of plaque progression. We tested these hypotheses in our mutation-determined heterozygous FH cohort without known CAD.

      Methods

      A total of 104 consecutive patients with FH without known CAD exhibiting a single mutation in the LDL receptor or proprotein convertase subtilisin/kexin type 9 (PCSK9) gene who underwent 64-detector row CCTA from January 2008 to December 2012 because of any clinical indications, including chest symptom, signs of cardiac diseases, peripheral artery disease, cerebrovascular disease, or multiple coronary risk factors were retrospectively analyzed. Of the 104 patients with heterozygous FH, 3 subjects with poor images (2.9%) were excluded; thus, 101 subjects with heterozygous FH whose ages range from 22 to 84 years remained in this analysis (men = 52, mean age 56 ± 16 years, mean LDL-C 264 ± 58 mg/dl). The characteristics of the study subjects are listed in Table 1 and Supplementary Table 1. Median follow-up period was 941 days. We defined major adverse cardiac events (MACE) as cardiac death, ST-elevated myocardial infarction, non–ST-elevated myocardial infarction, unstable angina pectoris, staged percutaneous coronary intervention, or coronary artery bypass grafting.
      Table 1Baseline characteristics divided by the presence of major adverse cardiac event
      VariableMajor adverse cardiac eventp value
      YES (n=21)NO (n=80)
      Age (years)59.4±14.850.1±13.7< 0.05
      Men12 (57%)40 (50%)n.s.
      Hypertension19 (79%)15 (19%)< 0.05
      Diabetes mellitus11 (52%)11 (14%)< 0.05
      Smoker17 (81%)19 (24%)< 0.05
      BMI (kg/m2)25.8±3.823.4±2.9< 0.05
      Total cholesterol (mg/dL)339±54347±62n.s.
      Low-density lipoprotein cholesterol (mg/dL)265 ± 65260±55n.s.
      High-density lipoprotein cholesterol (mg/dL)43±1057±14< 0.05
      Triglyceride (mg/dL)147±60132±80n.s.
      Plaque burden score3.64±0.332.13±1.25< 0.05
      Statins15 (71%)52 (65%)n.s.
      Statins duration (years)9±9.37.2±8.6n.s.
      Hypertension was defined as systolic blood pressure of at least 140 mm Hg, diastolic blood pressure of at least 90 mm Hg, or use of antihypertensive medication. Presence of diabetes was defined as previously described by Japan Diabetes Society
      • Seino Y.
      • Nanjo K.
      • Tajima N.
      • Kadowaki T.
      • Kashiwagi A.
      • Araki E.
      • Ito C.
      • Inagaki N.
      • Iwamoto Y.
      • Kasuga M.
      • Hanafusa T.
      • Haneda M.
      • Ueki K.
      Committee of the Japan Diabetes Society on the Diagnostic Criteria of Diabetes Mellitus
      Report of the committee on the classification and diagnostic criteria of diabetes mellitus.
      or the use of diabetes medication. Body mass index (BMI) was defined as body weight in kilograms divided by the square of height measured in meters. Serum concentrations of total cholesterol, triglyceride, and high-density lipoprotein cholesterol (HDL-C) were determined enzymatically. LDL-C concentrations were calculated using the Friedewald formula.
      • Friedewald W.T.
      • Levy R.I.
      • Fredrickson D.S.
      Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.
      Genomic DNA was isolated from peripheral white blood cells according to standard procedures and was used for polymerase chain reaction. Genotypes of all the participants in this study were determined as previously described.
      • Noguchi T.
      • Katsuda S.
      • Kawashiri M.A.
      • Tada H.
      • Nohara A.
      • Inazu A.
      • Yamagishi M.
      • Kobayashi J.
      • Mabuchi H.
      The E32K variant of PCSK9 exacerbates the phenotype of familial hypercholesterolemia by increasing PCSK9 function and concentration in the circulation.
      • Tada H.
      • Kawashiri M.A.
      • Ikewaki K.
      • Terao Y.
      • Noguchi T.
      • Nakanishi C.
      • Tsuchida M.
      • Takata M.
      • Miwa K.
      • Konno T.
      • Hayashi K.
      • Nohara A.
      • Inazu A.
      • Kobayashi J.
      • Mabuchi H.
      • Yamagishi M.
      Altered metabolism of low-density lipoprotein and very-low-density lipoprotein remnant in autosomal recessive hypercholesterolemia: results from stable isotope kinetic study in vivo.
      • Mabuchi H.
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      • Noguchi T.
      • Kobayashi J.
      • Kawashiri M.A.
      • Inoue T.
      • Mori M.
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      • Nakanishi C.
      • Yagi K.
      • Yamagishi M.
      • Ueda K.
      • Takegoshi T.
      • Miyamoto S.
      • Inazu A.
      • Koizumi J.
      Hokuriku FH Study Group
      Genotypic and phenotypic features in homozygous familial hypercholesterolemia caused by proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutation.
      The institutional review board approved the study protocol. All patients gave written informed consent.
      CCTA was performed with a dual-source 64-slice (Somatom Definition Flash; Siemens Medical System, Erlangen, Germany). A non–contrast-enhanced scan was performed to assess coronary calcium and defined the anatomic range for subsequent CCTA. This scan was automatically triggered and performed using the following scan parameters: collimation 0.6 mm; gantry rotation time 280 ms; tube voltage 120 kV; and tube current 100 mA. For the contrast-enhanced scan, collimation was 0.6 mm and gantry rotation time was 280 ms. The tube voltage and current were 120 kV and 340 mA, respectively. Fifty to eighty milliliters of nonionic iodinated contrast (370 mg iodine/ml, Iopamidol-370; Bayer Healthcare Pharmaceuticals, Osaka, Japan) was injected using a dual-flow injector (Dual Shot GX; Nemoto Kyorindo, Tokyo, Japan) through an antecubital vein. The iodine load was based on body weight. Image acquisition was manually triggered on arrival of contrast in the left main coronary trunk. Patients with a heart rate >100 beats/min and with no contraindications to β blockers received intravenous β-blocker therapy (landiolol hydrochloride 0.125 mg/kg) just before the computed tomographic (CT) scan. Multiple phases were used to assess the images of different arteries. In addition, we constructed 3-dimensional rotation images to assess the diagonal and other small branches.
      Two experienced radiologists, blinded with regard to the clinical status, evaluated all CCTA scans separately. Despite our efforts, the segments that were uninterpretable were scored as the same as most proximal segment which was interpretable (72 segments of a total of 1,717 segments: 4.2%). Discrepancies in evaluation were resolved during a consensus reading. Angiographic analysis by coronary computed tomography was performed according to a 17-segment American Heart Association classification.
      • Austen W.G.
      • Edwards J.E.
      • Frye R.L.
      • Gensini G.G.
      • Gott V.L.
      • Griffith L.S.
      • McGoon D.C.
      • Murphy M.L.
      • Roe B.B.
      A reporting system on patients evaluated for coronary artery disease. Report of the Ad Hoc Committee for Grading of Coronary Artery Disease, Council on Cardiovascular Surgery, American Heart Association.
      Coronary plaque burden was assessed by assigning a score (0 to 5) to each of 17 coronary artery segments according to the Society of Cardiovascular Computed Tomography (SCCT) guidelines (0, Normal: absence of plaque and no luminal stenosis; 1, Minimal: plaque with <25% stenosis; 2, Mild: 25% to 49% stenosis; 3, Moderate: 50% to 69% stenosis; 4, Severe: 70% to 99% stenosis; 5, Occluded).
      • Leipsic J.
      • Abbara S.
      • Achenbach S.
      • Cury R.
      • Earls J.P.
      • Mancini G.J.
      • Nieman K.
      • Pontone G.
      • Raff G.L.
      SCCT guidelines for the interpretation and reporting of coronary CT angiography: a report of the Society of Cardiovascular Computed Tomography Guidelines Committee.
      Those scores were summed and natural log-transformed, because of its skewed distribution.
      Categorical variables were expressed as percentages. Fisher's exact test or chi-square test was used as appropriate. Continuous variables with a normal distribution were shown as mean (±SD) and were compared using unpaired Student t tests. The plaque burden score cut-off value was determined on the basis of receiver operating characteristic (ROC) curve analysis. The cumulative fraction of events was estimated as 1 minus the Kaplan–Meier estimate of survival free of MACE. Differences in the cumulative fraction of events between subgroups were assessed by the log-rank test according to the cutoff. We initially analyzed all available risk factors using a univariate model; then, multivariate Cox regression analysis was performed using only the covariates that were significantly associated with MACE in the univariate analysis. Intraobserver or interobserver variability among readers was assessed using the Bland–Altmann method and coefficient of variation (CV) with 20 randomly selected subjects. All statistical analyses were conducted using R.
      R Core Team
      R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing.
      All p values <0.05 were considered statistically significant.

      Results

      The clinical characteristics of patients with or without subsequent MACE are shown in Table 1. The frequencies of the traditional coronary risk factors, such as age, hypertension, diabetes mellitus, smoking habits, and BMI, were significantly greater, whereas HDL-C was significantly less in patients with FH with MACE compared to those without MACE. Interestingly, plaque burden was significantly greater in patients with FH with MACE than those without MACE. The genetic backgrounds of the study participants are provided in Supplementary Table 1. A nonsense mutation (c.2431A>T) in the LDL receptor gene was common (40%), and the remaining participants carried 26 other different gene mutations, including PCSK9.
      Intraobserver and interobserver reproducibility for measurements of plaque burden scores is shown in Figure 1. Bland–Altman analysis demonstrated good agreements between both within intraobserver with a CV of 9.1% (Figure 1) and within interobserver with a CV of 9.9% (Figure 1) measurements.
      Figure thumbnail gr1
      Figure 1Bland–Altman analysis for the measurement of plaque burden score Bland–Altman analysis demonstrated good agreements between the measurements (A) within intraobserver and (B) within interobserver.
      To evaluate if coronary plaque burden and traditional risk factors were determinants of the occurrence of MACE, univariate analysis was performed (Table 2). The median of the coronary plaque burden score was 2.78 (raw score 16.1). As a result, age, hypertension, diabetes mellitus, smoking, BMI, and plaque burden score ≥ median were significant predictors for MACE (Table 2). In addition, multivariate analysis showed that the presence of hypertension and a plaque burden score ≥ median were significant independent prognostic factors (Table 2).
      Table 2Univariate and multivariate Cox regression analysis of risk factors for major adverse cardiac event
      VariableUnivariate analysisMultivariate analysis
      Hazard ratio95% CIp valueHazard ratio95% CIp value
      Age1.0381.006-1.072< 0.05
      Men0.9860.413-2.354n.s.
      Hypertension20.824.842-89.55< 0.057.5211.581-37.76< 0.05
      Diabetes mellitus3.8331.620-9.066< 0.05
      Smoker6.3362.214-18.9< 0.05
      Body mass index1.1711.037-1.324< 0.05
      Total cholesterol1.0040.9972-1.011n.s.
      Low-density lipoprotein cholesterol1.0050.9978-1.012n.s.
      High-density lipoprotein cholesterol0.97730.9449-1.011n.s.
      Triglyceride1.0020.9966-1.007n.s.
      plaque burden score ≥ median (2.78)13.934.082-47.51< 0.055.4241.411-20.85< 0.05
      Statins1.0060.9594-1.055n.s.
      On the basis of the ROC curve analysis, the optimal plaque burden score cut-off value for developing MACE was 3.35 (raw score 28.5), the sensitivity and specificity of which were 85.7% and 82.5%, respectively, with a area under the ROC curve of 0.90 (Figure 2). Table 3 compares the clinical profiles of patients with a plaque burden score ≥3.35 and those with <3.35. The frequencies of the traditional coronary risk factors, such as age, hypertension, diabetes mellitus, and smoking habit, were greater in patients with a plaque burden score ≥3.35 than those with a score <3.35. Moreover, BMI and the duration under statin therapy were greater in patients with a plaque burden score ≥3.35 than those with a score <3.35.
      Figure thumbnail gr2
      Figure 2ROC curve analysis and survival analysis. (A) ROC curve analysis revealed a plaque burden score of 3.35 as the optimal cutoff for predicting MACE, the sensitivity and specificity of which were 85.7% and 82.5%, respectively, with a area under the ROC curve of 0.90. (B) Cumulative event rates according to the cutoff. Blue dotted line indicates subjects with a plaque burden score ≥3.35. Red solid line indicates subjects with a plaque burden score <3.35.
      Table 3Baseline characteristics divided by the plaque score cut-off value
      VariablePlaque burden scorep value
      ≥ 3.35 (n=32)< 3.35 (n=69)
      Age (years)61.0±13.748.0±12.8< 0.05
      Men15 (47%)37 (54%)n.s.
      Hypertension23 (72%)11 (16%)< 0.05
      Diabetes mellitus15 (47%)7 (10%)< 0.05
      Smoker19 (59%)17 (25%)< 0.05
      Body mass index (kg/m2)25.7±3.323.1±2.9< 0.05
      Total cholesterol (mg/dL)341±49346±59n.s.
      Low-density lipoprotein cholesterol (mg/dL)262±70264±53n.s.
      High-density lipoprotein cholesterol (mg/dL)44±1256±13< 0.05
      Triglyceride (mg/dL)129±84138±99n.s.
      Plaque burden score3.68±0.221.86±1.15< 0.05
      Statins25 (78%)42 (61%)n.s.
      Statins duration (years)10.5±9.26.2±8.2< 0.05
      The cumulative event rate curve revealed that those patients with a plaque burden score ≥3.35 had a significantly higher event rate than those with a score <3.35 (Figure 2). Table 4 summarizes the MACE during the follow-up period. As many as 18 of 30 patients with a plaque burden score ≥3.35 had MACE during the follow-up period.
      Table 4Major adverse cardiac event during the follow-up period
      VariablePlaque burden scoreP value
      ≥ 3.35 (n=32)< 3.35 (n=69)
      Composite endpoint
       All major adverse cardiac event18 (56%)3 (4%)< 0.05
       Acute coronary syndrome-related event5 (16%)0 (0%)n.s.
      Coronary events
       Cardiac death1 (3%)0 (0%)n.s.
       ST elevated myocardial infarction2 (6%)0 (0%)n.s.
       Unstable angina pectoris/non-ST elevated myocardial infarction2 (6%)0 (0%)n.s.
       Staged-PCI/CABG13 (41%)3 (4%)< 0.05
      CABG = coronary artery bypass grafting; PCI = percutaneous coronary intervention.
      There was no one who exhibited coronary ostial stenosis associated with supravalvular stenosis which is specific to FH. However, as much as 26 of 101 (26%) patients with heterozygous FH exhibited aortic valve calcification detected by CCTA.
      We also investigated whether the particular mutation status (c.2431A>T) could affect any risk factors, including lipids, and the outcomes; however, there is no difference observed in the group with this mutation and that with other mutations (Supplementary Tables 2 and 3).
      Finally, we evaluated the correlation coefficient between age and raw plaque burden score in each gender (Figure 3). The regression equations were Y = 0.68X − 15.6 (r = 0.54, p <0.05) in male and Y = 0.74X − 24.8 (r = 0.69, p <0.05) in female patients with heterozygous FH even after accounting for other risk factors, such as LDL-C, HDL-C, hypertension, diabetes, and smoking. These results suggest that coronary atherosclerosis may start to develop, on average, at ages 23 and 34 years in male and female patients with heterozygous FH, respectively.
      Figure thumbnail gr3
      Figure 3Plots of correlation between age (X) and plaque burden score (Y) in male (A) and female (B) patients with heterozygous FH. The regression equations are Y = 0.68X − 15.6 (r = 0.54, p <0.05) in male heterozygotes and Y = 0.74X − 24.8 (r = 0.69, p <0.05) in female heterozygotes, respectively. The solid lines indicate the regression line. The dotted lines indicate 95% CI. Plaque burden score was obtained by assigning scores (0 to 5) to each of 17 coronary artery segments; the highest possible plaque burden score is 60.

      Discussion

      In this study, we evaluated plaque burden score assessed with CCTA in mutation-determined patients with heterozygous FH and found that such score was associated with future coronary events beyond established risk factors and that we can estimate the onset and progression of coronary atherosclerosis in patients with FH assuming a linear model of plaque progression.
      Heterozygous FH have a mutant allele of either of 3 FH-associated genes (FH genes), namely LDL receptor, apolipoprotein B-100, or PCSK9 genes
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      and the frequency of which is estimated to be at least 1 in 500 general populations worldwide.
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      Those patients exhibit premature coronary atherosclerosis because of extremely high LDL-C levels; thus, their risk of future coronary events needs to be assessed. In the present study, plaque burden score assessed with CCTA successfully estimated future MACE. In addition to those prognostic values of plaque burden score, calculating those scores quantitatively based on SCCT guideline instead of adopting any other published dichotomized scoring system,
      • Zeb I.
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      we could estimate the onset and progression of CAD in patients with FH assuming linear model of plaque progression. The regression lines from age and plaque score suggested that coronary atherosclerosis might start to develop at ages 23 and 34 years in male and female patients with FH, respectively, even under statin therapy. In contrast, our previous study, conducted before the approval of statins in 1989 showed that coronary artery stenosis detectable by conventional angiography occurred around 17 and 25 years of age in male and female patients with FH, respectively.
      • Mabuchi H.
      • Koizumi J.
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      • Takeda R.
      Development of coronary heart disease in familial hypercholesterolemia.
      These differences in age (6 years in men and 9 years in women) might reflect a delay in the development of coronary atherosclerosis using statin in patients with FH. We may consider the examination by CCTA around such ages in patients with FH.
      There are only a few reports from Brazil, Spain, and the Netherlands investigating the clinical application of CCTA for FH.
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      Although those reports demonstrated that CCTA could detect substantial coronary plaque burden in FH, especially in mutation-positive FH, few of them addressed the simple issue regarding the predictive prognostic value of this modality.
      This study has several limitations. (1) This study was a retrospective analysis of data from a single center with a relatively small sample size; thus, our results need to be validated through prospective multicenter studies. (2) Because some patients with FH were not examined by CCTA because of physicians' and patients' selection, there is likely to be some bias. (3) Although we have validated the reproducibility of this measurement, the assessments of stenotic severity of calcified plaque by CCTA were still difficult, leaving the possibility that plaque burden was overestimated. (4) Measurement of the Agatston score, which is widely used to assess the burden of coronary artery calcium in a quantitative manner,
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      • Detrano R.
      Quantification of coronary artery calcium using ultrafast computed tomography.
      was not routinely available in this cohort. (5) Our assumption of the development of coronary atherosclerosis in FH is based on linear model (and on the findings from the age 22 to 84 years), which may not be applicable to the younger patients with FH. (6) Most events occurred close after the CT scan, which reflected that the findings of CCTA could lead to the coronary angiogram and the coronary revascularization procedure.

      Acknowledgment

      The authors express special thanks to Kazuko Honda and Sachio Yamamoto (staff of Kanazawa University) and Tohru Noguchi, PhD (former staff of Kanazawa University) for their outstanding technical assistance.

      Disclosures

      Hayato Tada has received research grants from Banyu Life Science Foundation International , SENSHIN Medical Research Foundation , and The Uehara Memorial Foundation . Masa-aki Kawashiri has received payments for lectures from Shionogi & Co., Ltd., Daiichi-Sankyo Co., Ltd., Astellas Pharma Inc., AstraZeneca K.K., Kissei Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd., and Kyowa Hakko Kirin, Co., Ltd. Atsushi Nohara and Hiroshi Mabuchi have received research grants from MSD K.K. , Sanofi K.K. , Shionogi & Co., Ltd. , Kowa Co., Ltd. , Astellas Pharma Inc. , AstraZeneca K.K. , Keiai-Kai Medical Corp. , and Biopharm of Japan Co . Masakazu Yamagishi has received research grants from MSD K.K. , Astellas Pharma Inc. , Daiichi-Sankyo Co., Ltd. , and Otsuka Pharmaceutical Co., Ltd. and he has received payments for lectures from Astellas Pharma Inc., Daiichi-Sankyo Co., Ltd., Shionogi & Co., Ltd., and Kowa Co., Ltd. Other authors have no financial or other relations that could lead to a conflict of interest.

      Supplementary Data

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