Recent data suggest that there is a significant sex difference in diagnosis and treatments for patients with familial hypercholesterolemia (FH). No prior data exist regarding this issue among Japanese FH. Japanese patients with clinically diagnosed heterozygous FH (HeFH) (N=1,273, male/female=614/659) at our university hospital were assessed. We compared variables, including those associated with diagnosis and treatments between male and female. Cox proportional hazards models were used to assess factors associated with major adverse cardiac event (MACEs), including cardiovascular death and any coronary events among both sexes. The median follow-up period was 10.9 years. During the follow-up period, 142 MACEs were observed. We found that the age of diagnosis as HeFH was significantly older in women compared with men (51 years vs. 46 years, respectively, P<0.001). Male sex was significantly associated with MACEs (hazard ratio (HR): 1.64; 95% confidence interval (CI): 1.14–2.14; P<0.001), although LDL cholesterol level at baseline as well as at the follow-up were lower than those of female. No significant differences were observed in terms of factors associated with MACEs in sexes. There are some sex differences in diagnosis and treatments for Japanese HeFH patients. Despite their protective property, we need to diagnose and treat female patients with HeFH much earlier.

Data on the appropriate timing and impact of atherosclerosis assessment in patients with heterozygous familial hypercholesterolemia (HeFH) are limited. We aimed to determine when atherosclerotic changes occur and the utility of triple assessments of carotid plaque, coronary plaque, and coronary artery calcium (CAC) in patients with HeFH. Data from patients with HeFH in the primary prevention setting admitted to a university hospital between 2000 and 2020 who underwent triple atherosclerosis assessment using carotid ultrasound and coronary computed tomography (CT) and were followed up were retrospectively reviewed (n = 622, male = 306, mean age = 54 years). Carotid plaque, coronary plaque, and CAC scores were plotted against age in males and females. We performed log-rank tests to compare cardiovascular events-free survival among different strata of the atherosclerosis group. Regression equations of carotid plaque, coronary plaque, and CAC scores were Y = 0.12X–2.07 (r = 0.35, p < 0.001), Y = 0.36X–9.30 (r = 0.37, p < 0.001), and Y = 2.48X–77.23 (r = 0.34, p < 0.001) in males and Y = 0.12X–3.60 (r = 0.42, p < 0.001), Y = 0.33X–11.75 (r = 0.41, p < 0.001), and Y = 2.23X–89.47 (r = 0.39, p < 0.001) in females, respectively. Significant differences were observed among the groups according to atherosclerotic burden. On average, carotid plaque, coronary plaque, and CAC may develop at ages 17, 26, and 31 in male patients and 30, 36, and 40 in female patients with HeFH, respectively. Furthermore, triple assessments help in risk stratification.

Transthyretin cardiac amyloidosis (ATTR-CM) is a progressive disease where early diagnosis and treatment can significantly improve prognosis. Carpal tunnel syndrome (CTS) often precedes cardiac involvement by 5–10 years, making it a potential early red flag for ATTR-CM. Previous studies have reported stepwise screening for cardiac involvement in cases where amyloid deposits were detected in tenosynovium during carpal tunnel release (CTR). However, comprehensive screening, including cardiac MRI, Technetium-99m pyrophosphate scintigraphy (99mTc-PYP scintigraphy), and genetic testing in all cases, has not been reported. To perform detailed cardiac screening in patients with tenosynovial ATTR amyloid deposits found during CTR, evaluating the prevalence of ATTR-CM and identifying its predictive factors. This prospective study included 81 consecutive patients who underwent CTR for CTS between October 2022 and December 2024. Tenosynovial amyloid deposits were detected in 27 cases (33.3%), all confirmed as ATTR-positive. Among them, 24 patients (mean age 74.1±8.1 years, 11 males) consented to undergo blood tests, echocardiography, cardiac MRI, 99mTc-PYP scintigraphy, and genetic testing. All cases were wild-type ATTR, and 6 cases (28.9%) met the Japanese Cardiac Society 2020 Guideline criteria for probable or definite ATTR-CM (CTS-ATTR-CM). All CTS-ATTR-CM cases exhibited elevated troponin T beyond the normal range (0.028 ng/ml [0.017-0.034]); however, septal wall thickness remained within normal limits in four out of six cases (10.8±2.5 mm). Univariate logistic regression analysis identified extracellular volume fraction (ECV) increase by 1% (p=0.04, OR 1.38) and troponin T increase by 0.01 ng/mL (p=0.032, OR 9.39) as significant predictors of CTS-ATTR-CM, whereas echocardiographic markers such as wall thickness and ejection fraction were not predictive. Comprehensive cardiac screening in patients with tenosynovial ATTR amyloid deposits identified ATTR-CM in 7.4% of all CTR cases. While ECV and troponin T emerged as potential predictors, echocardiographic findings proved insufficient in detecting early-stage ATTR-CM in CTS patients. Proactive screening in this population may facilitate early diagnosis and timely intervention.

According to the latest Japanese Guidelines for the Prevention of Atherosclerotic Disease in 2022, the target for secondary prevention of low-density lipoprotein cholesterol (LDL-C) in patients with a history of coronary heart disease is LDL-C <100 mg/dL, and in patients with acute coronary syndrome (ACS), familial hypercholesterolemia (FH), diabetes, or atherothrombotic stroke is LDL-C <70 mg/dL. However, it is still unclear 1) if the LDL-C treatment target attainment rates are in upward trend, and 2) what are the factors associated with LDL-C treatment target attainment. We aimed to investigate 1) trends of LDL-C treatment target attainment rates and 2) factors associated with LDL-C treatment target attainment in the general population of Japan. Using the Health Checkup data in our city obtained in 2008(n=38,546), 2012(n=45,719), 2017(n=51,969), and 2022(n=48,636) when the Japanese Guidelines for Prevention of Atherosclerotic Diseases had been revised, we analyzed 1) the trends of secondary prevention of LDL-C treatment target attainment rates in patients with a history of heart disease by Cochran-Armitage trend test. Additionally, we analyzed 2) factors associated with LDL-C treatment target attainment by logistic regression analysis using patient basic variables, blood test results, and lifestyle questionnaires from the 2022 health examination. The LDL-C treatment target attainment rates were 24.6% in 2008, 30.2% in 2012, 33.0% in 2017, and 34.7% in 2022. We found that there was a significantly upward trend over time (P<0.001). Nextly, we also found that, male sex (odds ratio[OR]: 2.64, 95% confidence interval[CI]: 1.72-4.06, P<0.001), systolic blood pressure (OR: 0.99, 95% CI: 0.98-1.00, P=0.015), ALT (OR: 1.01, 95% CI: 1.00-1.03, P=0.044), uric acid (OR: 0.79, 95% CI: 0.72-0.88, P<0.001), use of medication to reduce blood pressure (OR: 1.92, 95% CI: 1.48-2.49, P<0.001), use of medication to reduce blood sugar or insulin injection (OR: 0.38, 95% CI: 0.24-0.58, P<0.001), weight gain of 10 kg or more since age 20 (OR: 0.71, 95% CI: 0.53-0.93, P=0.015), walking or any equivalent amount of physical activity for more than one hour a day in daily life (OR: 0.73, 95% CI: 0.57-0.92, P=0.009), and eating speed quicker than others (OR: 1.31, 95% CI: 1.03-1.67, P=0.027), were significantly associated with LDL-C treatment target attainment. The LDL-C treatment target attainment rates among Japanese patients under secondary prevention tended to increase over time. However, there are several clinical as well as lifestyle factors associated with LDL-C treatment target attainment. Interventions for specific lifestyles and more intensive treatments for women should be considered to achieve better LDL-C control among patients with preexisting coronary heart disease.

Abstract Backgrounds Achilles tendon thickening (ATT) can be regressed through LDL-lowering in patients with familial hypercholesterolemia (FH). The Japan Atherosclerosis Society (JAS) determined the threshold of ATT as ≥8.0 mm in male and ≥7.5 mm in female. Purpose We aimed to determine clinical impact of changes of ATT in development of major adverse cardiovascular events (MACE). Methods Patients with clinically diagnosed FH (N=1,273, male/female=614/659) with ATT data using X-ray were assessed. We divided the patients into 4 groups (group 1: patients without ATT from baseline to their follow-up, group 2: patients without ATT at baseline, but developed ATT at follow-up, group 3: patients with ATT at baseline, but regressed at follow-up, group 4: patients with ATT from baseline to their follow-up). Cox proportional hazards models were used to assess factors associated with MACE, including cardiovascular death and any coronary events. Results The median follow-up period was 10.9 years. During the follow-up period, 142 MACEs were observed, and median ATT was regressed from 7.8 to 7.6 mm. We found that there was more significant positive correlation between cholesterol-year score and ATT among patients with and without MACE (p <0.001; Spearman’s r=0.33, and p <0.001; Spearman’s r=0.35, respectively). Under these circumstances, changes of ATT were significantly associated with the occurrence of MACE (hazard ratio (HR): 2.73; 95% confidence interval (CI): 1.33–4.13; p<0.001, HR: 2.18; 95% CI: 1.08–3.28; p<0.001, HR: 6.34; 95% CI: 3.10–9.58; p<0.001, in group 2, group 3, and group 4, respectively when group 1 was considered as reference). Conclusion Assessments of ATT condition represent diagnostic values and risk stratification information among patients with FH.

Abstract Background Anemia is a common comorbidity in older patients with heart failure (HF)1 and atrial fibrillation (AF)2, associated with an increased risk of adverse events. This study evaluated the prognostic effects of longitudinal changes in anemia status on clinical outcomes in patients with AF, as limited data are available on this aspect. Methods and Results We prospectively evaluated data of 1,388 patients with AF obtained from the Hokuriku-Plus AF registry (1,010 men, 72.3±9.7 years) and recorded the incidence of cardiovascular death (CVD), HF, thromboembolism, and major bleeding. Finally, 1,233 patients with AF with baseline and first year of follow up hemoglobin levels were evaluated. Patients were categorized into 3 groups based on the longitudinal changes in 1-year anemia status: AF without anemia (group 1), AF with improved anemia (group 2), and AF with sustained or new-onset anemia (group 3). During 1–5-year follow up, the incidences of CVD, HF, thromboembolism, and major bleeding were significantly higher in patients with AF and anemia than in those without (Figure1). Additionally, the incidence of CVD or HF was significantly higher in group 3 than in groups 1 and 2 (Figure 2). Multivariate analysis revealed no anemia or improvement from anemia in 1 year as an independent predictor for reducing CVD and HF. Conclusions Recovery from anemia may be associated with a favorable clinical course in AF.

Background and Aims: Familial hypercholesterolemia (FH) is an autosomal dominant monogenic disease characterized by high low-density lipoprotein cholesterol (LDL-C) levels. Although carrying causative FH variants is associated with coronary heart disease (CHD), it remains unclear whether disclosing its associated cardiovascular risk affects outcomes in patients with FH. Here, we evaluated the efficacy of providing future cardiovascular risk based on genetic testing in addition to a standard FH education program. Methods: We conducted a randomized, wait-list controlled, open-label, single-center trial. In the intervention group, we reported a future cardiovascular risk based on the genetic testing adding to standard FH education at week 0. In the wait-list control group, we only disseminated standard FH education according to the guidelines at week 0; they later received a genetic testing-based cardiovascular risk assessment at week 24. The primary endpoint of this study was the plasma LDL-C level at week 24. Results: Fifty eligible patients with clinically diagnosed FH, without a history of CHD, were allocated to the intervention group (n=24) or the wait-list control group (n=26). At week 24, the intervention group had a significantly greater reduction in LDL-C levels than the wait-list control group (mean changes, -13.1 mg/dL vs. 6.6 mg/dL; difference, -19.7 mg/dL; 95% confidence interval, -34 to -5.6; p=0.009). This interventional effect was consistent with FH causative variant carriers but not with non-carriers. Conclusions: In addition to standard FH care, providing future cardiovascular risk based on genetic testing can further reduce plasma LDL-C levels, particularly among FH causal variant carriers.

Objective: The early diagnosis and treatment initiation for children with familial hypercholesterolemia (FH) has been recommended in guidelines. However, there is limited data on the impact of early treatments on the prognosis of children with FH. To investigate if the early initiation of lipid-lowering therapies among Japanese pediatric patients with FH reduced the occurrence of cardiovascular disease (CVD) events in them. Methods: We retrospectively investigated the occurrence of CVD events (myocardial infarction, unstable angina, or coronary artery revascularization) in patients with FH (N = 1050, male/female = 490/560), including 106 children below 20 years. We compared a variety of phenotypes, including genetic backgrounds, other complications, LDL cholesterol, medical therapies, and their prognoses between the patients’ diagnoses before the age of 20 years (children, mean age = 15 years) and after that age (adults, mean age = 52 years). Overall, 290 patients (27.6%) had a history of prior CVD events. Results: The median follow-up duration was 12.6 [9.5–17.9] years. The baseline LDL cholesterol level, 239 mg/dL, dropped to 112 mg/dL with the treatments. The Achilles tendon thickness was significantly lower in children than that of adults (7.2 vs. 8.9 mm, P < 0.001). Over the follow-up duration, 119 CVD events were observed. Importantly, no CVD event was observed in children despite their median LDL cholesterol level at follow-up being significantly higher than that of adults (122 vs. 111 mg/dL, P < 0.001). Conclusion: The likelihood of CVD events in those with FH diagnosed and treated in childhood is low.

Abstract Aims This study was designed to examine the association between coronary artery calcium (CAC) and major adverse cardiac events (MACEs) and to estimate CAC progression in patients with familial hypercholesterolemia (FH) in primary prevention settings. Methods and results Data of patients with FH admitted to our university hospital between 2000 and 2020, who underwent CAC measurement and were followed up (N = 622, male = 306), were retrospectively reviewed. Risk factors for MACEs were determined using the Cox proportional hazard model. The median follow-up duration was 13.2 years (interquartile range: 9.8–18.4 years). We observed 132 MACEs during the follow-up period. The event rate per 1,000 person-years for CAC scores of 0 (N = 283 [45.5%]), 1–100 (N = 260 [41.8%]), and >100 (N = 79 [12.7%]) was 1.2, 17.0, and 78.8, respectively. Log (CAC score+1) was a significant predictor of the occurrence of MACEs (hazard ratio: 3.24; 95% confidence interval: 1.68–4.80; p = 5.6×10−5) in the multivariate Cox regression analysis, independent of other factors. The risk discrimination of MACEs was enhanced by adding CAC information to other conventional risk factors (C-statistics: 0.833–0.934; p = 1.4×10−15). The regression equations between age and the CAC score in male and female were Y = 0.074X–1.52 and Y = 0. 087X–3.21, respectively. Conclusion CAC score helps in further risk stratification in patients with FH. Furthermore, the average age of CAC onset was 21 years in male and 37 years in females.

Background and aims: No previous study has investigated the association between attainment of low-density li-poprotein (LDL) cholesterol treatment target and better prognosis in patients with familial hypercholesterolemia (FH). The current research aimed to examine the association between attainment of LDL cholesterol treatment target and major adverse cardiac events (MACEs) in patients with FH to validate the current LDL cholesterol treatment targets in primary (<100 mg/dL) and secondary (<70 mg/dL) prevention settings.Methods: The data of patients with FH who were admitted to Kanazawa University Hospital between 2000 and 2020 and who were followed-up were retrospectively reviewed. The number of MACEs, including mortality associated with cardiovascular disease, unstable angina, and myocardial infarction per 1000 person-years, was calculated for each stratum for the attainment of LDL cholesterol target.Results: The median follow-up duration was 12.6 years. In total, 132 MACEs were recorded during the follow-up period. The numbers of patients who attained the LDL cholesterol target in the primary and secondary prevention groups were 228 (31.9%) and 40 (11.9%), respectively. The event rates per 1000 person-years for LDL cholesterol levels of <100 and >= 100 mg/dL in the primary prevention group were 2.6 and 4.4, respectively. The event rates per 1000 person-years for LDL cholesterol levels of <70 and >= 70 mg/dL in the secondary prevention group were 15.3 and 27.5, respectively.Conclusions: Attainment of the LDL cholesterol target is associated with better prognosis in patients with FH. However, the attainment rate is currently inadequate among Japanese.

Abstract Aims Recent studies suggest that cumulative exposure to LDL-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. We aimed to determine whether cholesterol-year-score, an indicator of cumulative exposure to LDL-C, is associated with ASCVD events among Japanese patients with FH Methods and results We retrospectively investigated the health records of 1,050 patients with clinical FH diagnosis who were referred to our institute 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 [HR], 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 versus 0.889; P=0.00473). Conclusion Cumulative LDL-C exposure was strongly associated with MACEs in Japanese patients with FH, warranting early diagnosis and treatment initiation in these patients. Funding Acknowledgement Type of funding sources: None.

Abstract Funding Acknowledgements Type of funding sources: None. Background Although I-123 meta-iodobenzylguanidine (mIBG) has been applied to patients with chronic heart failure (CHF), a diagnostic tool for differential prediction of fatal arrhythmic events (ArE) and heart-failure death (HFD) has been pursued. Purpose The aim of this study was to create a calculator of mortality risk for differentiating mode of cardiac death using a machine learning (ML) method, and to test the accuracy in a new cohort of patients with CHF. Methods A total of 529 patients with CHF was used as the training database for ML. The ArE group consisted of patients with arrhythmic death, sudden cardiac death and appropriate therapy by implantable cardioverter defibrillator. A heart-to-mediastinum ratio (H/M) standardized to the medium-energy collimator condition was calculated with a planar anterior mIBG scintigram. The best classifier models for predicting HFD and ArE were determined by four-fold cross validation. Input variables included age, sex, New York Heart Association (NYHA) functional class, left ventricular ejection fraction, ischemic etiology, mIBG H/M and washout rate, and b-type natriuretic peptide (BNP) or NT Pro BNP, estimated glomerular filtration rate, hemoglobin, and complications such as diabetes and hypertension. After creating the ML-based model, the constructed classifier functions for ArE, HFD, and survival were exported for subsequent use. A new cohort of patients (n = 312, age 67 ± 13 years, 2015 or later) was used to test the ML-based model. Results The training database included 141 events (27%) with ArE (7%) and HFD (20%). Receiver-operating characteristic analysis by four-fold validation showed area under the curve value of 0.90 for HFD and 0.73 for ArE. Among various ML methods, the logistic regression method demonstrated the most stable calculation of the probability of ArE followed by random forest and gradient boosted tree methods. Therefore, the logistic-regression method was used for calculating both HFD and ArE probabilities. In the test cohort, patients with a high HFD probability >8% resulted in 6.3-fold higher HFD than those with low probability (≤ 8%). Patients with high ArE probability >8% showed 2.5-fold higher ArE than those with low probability (≤ 8%). Conclusion The ML-based mortality risk calculator could be used for stratifying patients at high and low risks, which might be useful for estimating appropriate treatment strategy.

Recent observational studies have suggested that catheter ablation for atrial fibrillation (AF) is significantly associated with reduced risk for stroke, cardiovascular events and all-cause death. However, little is known whether late recurrence of AF after catheter ablation is associated with worse clinical outcomes. We aimed to clarify whether late recurrence of AF after catheter ablation is associated with major adverse cardiac and cerebrovascular events (MACCE). We retrospectively investigated 2,737 participants (74.4% men, mean age 63.4±10.3 years, 62.7% paroxysmal AF) who received first catheter ablation for AF and completed follow-up more than 3 months after the procedure from AF Frontier Ablation Registry, a multicenter cohort study in Japan. We evaluated an association between late recurrence of AF after catheter ablation and first MACCE in cox-regression hazard models adjusted for known risk factors. MACCE were defined as stroke/transient ischemic attack (TIA), cardiovascular events or all-cause death. Late recurrence was defined as AF relapse more than 3 months after the procedure. During a mean follow-up period of 25.2 months, 2,070 patients (75.6%) were free from AF after catheter ablation and 122 patients (4.5%) had MACCE (ischemic stroke 18 [14.8%], hemorrhagic stroke 16 [13.1%], TIA 7 [5.7%], hospitalization for heart failure 19 [15.6%], acute coronary syndrome 19 [15.6%], hospitalization for other cardiovascular events 24 [20%] and all-cause death 19 [15.6%]). The MACCE occurred significantly more frequently in the recurrence group than in non-recurrence group (7.5% vs. 3.5%; hazard ratio [HR] 1.85; 95% confidence interval [CI] 1.28–2.65; P=0.001) (Figure). Multivariate analysis revealed that baseline age (HR 1.05; 95% CI 1.03–1.08; P<0.001), heart failure (HR 1.76; 95% CI 1.17–2.66; P=0.007), old myocardial infarction (HR 4.49; 95% CI 2.59–7.81; P<0.001), non-ischemic cardiomyopathy (HR 2.56; 95% CI 1.47–4.46; P=0.001), left atrial diameter (HR 1.22 per 5-mm increase; 95% CI, 1.06–1.41; P=0.006) and recurrence of AF (HR 1.69; 95% CI 1.17–2.44; P=0.005) were independently associated with the incidence of MACCE after catheter ablation. In the Japanese multicenter cohort of AF ablation, late recurrence of AF was independently associated with increased MACCE, suggesting the significance of sinus rhythm maintenance by catheter ablation. Kaplan-Meier curves for MACCE Type of funding source: None

Abstract Background High plasma B-Type natriuretic peptide (BNP) level is associated with cardiac events or stroke in patients with atrial fibrillation (AF). However, it is still unknown whether BNP predicts worse clinical outcomes after catheter ablation ofAF. Purpose We aimed to see if plasma BNP level is associated with major adverse cardiac and cerebrovascular events (MACCE) after catheter ablation of AF. Methods We retrospectively analyzed 1,853 participants (73.1% men, mean age 63.3±10.3 years, 60.7% paroxysmal AF) who received first catheter ablation of AF with pre-ablation plasma BNP level measurement and completed follow-up more than 3 months after the procedure from AF Frontier Ablation Registry, a multicenter cohort study in Japan. We evaluated an association between plasma BNP level before catheter ablation and first MACCE in cox-regression hazard models adjusted for known risk factors. MACCE were defined as stroke/transient ischemic attack (TIA), cardiovascular events or all-cause death. Results The mean plasma BNP level was 120.2±3.7 pg/mL. During a mean follow-up period of 21.9 months, 57 patients (3.1%) suffered MACCE (ischemic stroke 8 [14.0%], hemorrhagic stroke 5 [8.8%], TIA 5 [8.8%], hospitalization for heart failure 11 [19.2%], acute coronary syndrome 9 [15.8%], hospitalization for other cardiovascular events 8 [14.0%] and all-cause death 11 [19.2%]). Plasma BNP level of patients with MACCE were significantly higher than those without MACCE (291.7±47.0 vs 114.7±3.42 pg/mL, P<0.001). Multivariate analysis revealed that plasma BNP level (hazard ratio [HR] per 10 pg/mL increase 1.014; 95% confidence interval [CI] 1.005–1.023; P=0.001), baseline age (HR 1.052; 95% CI 1.022–1.084; P=0.001), heart failure (HR 2.698; 95% CI 1.512–4.815; P=0.001), old myocardial infarction (HR 3.593; 95% CI 1.675–7.708; P=0.001) and non-ischemic cardiomyopathy (HR 2.676; 95% CI 1.337 - 5.355; P=0.005) were independently associated with MACCE. At receiver-operating characteristic curve analysis, plasma BNP level before catheter ablation ≥162.7 pg/mL was the best threshold to predict MACCE (area under the curve: 0.71). Kaplan-Meier curve analysis (Figure) showed that the cumulative incidence of MACCE was significantly higher in patients with a BNP ≥162.7 pg/mL than in those with a BNP below 162.7 pg/mL (HR 4.85; 95% CI 2.86–8.21; P<0.001). Conclusions Elevation of plasma BNP level was independently related to the increased risk of MACCE after catheter ablation ofAF. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Bristol-Meiers Squibb

Abstract Background Sitosterolemia, which is caused by ABCG5 or ABCG8 genetic mutations, is involved with marked increased concentrations of cholesterol as well as non-cholesterol plant sterols including sitosterol. Assessments of serum sitosterol level is critical to discriminate this disease from familial hypercholesterolemia (FH), which exhibits similar phenotypes except for elevated sitosterol levels. However, no prior data exist regarding the optimal cutoff value of serum sitosterol predicting the presence of sitosterolemia with double pathogenic mutations in ABCG5 or ABCG8 genes. Methods We retrospectively investigated consecutive 253 Japanese dyslipidemic subjects (mean age = 47.02 yr, male = 48.6%) with the assessments of serum sitosterol level as well as the presence of ABCG5 or ABCG8 genetic mutations in our institute since 2009 to 2018. Exome lesions of those 2 genes were sequenced, and pathogenicity of the identified genetic variants were determined using standard variant filtering schema, including minor allele frequency, in silico annotation tools. We divided the subjects into 3 groups based on the number of pathogenic mutations in ABCG5 or ABCG8 genes. We compared serum lipid values, including LDL cholesterol as well as serum sitosterol among those groups, and tried to determine the optimal cutoff value discriminating patients of sitosterolemia with double mutations from others. Results We identified 11 individuals with sitosterolemia with double mutations, 27 individuals with a single mutation, and 215 individuals without any mutations. Distribution of serum sitosterol exhibited skewed to the right (Figure). There was no significant correlation between serum sitosterol and other lipids, including LDL cholesterol. As expected, serum sitosterol level of patients with sitosterolemia exhibited significantly higher than those of any other groups (52.0 vs. 7.9 μg/ml, p=2.22×10–6, 52.0 vs. 2.8 μg/ml, p=2.275×10–8). 15 μg/ml was the optimal cut-off value, the sensitivity and specificity of which were 100%, and 99.6%, respectively. Histgram of serum sitosterol Conclusion We suggest the cutoff sitosterol value of 15 μg/ml predicting the presence of sitosterolemia with double pathogenic ABCG5 or ABCG8 genetic mutations.

Abstract Background Lipoprotein (a) [Lp(a)] has been shown to be associated with the development of chronic kidney disease (CKD) among various ethnicities. In addition, recent Mendelian randomization studies have suggested that Lp(a) seems to be causally associated with CKD. However, few data exist regarding this issue among Japanese population. Purpose We aimed to investigate the association between serum Lp(a) and the CKD among Japanese population. Methods We retrospectively investigated 6,130 subjects whose serum Lp(a) had been measured for any reason (e.g. any operations which needs bed rest for a long duration, risk factors for atherosclerosis such as hypertension or diabetes) at our University Hospital from April 2004 to March 2014. We excluded 1,895 subjects due to the lack clinical data. We assessed their Lp(a), LDL cholesterol, HDL cholesterol, triglycerides, presence of hypertension, diabetes, chronic kidney disease, smoking, body mass index, presence of coronary artery disease (CAD), and presence of CKD (stage 3 or greater). Results When the study subjects were divided into 5 groups based on their CKD stage, there was a significant trend among their serum Lp(a) levels (P-trend = 2.7×10–13). Under these conditions, multiple regression analysis showed that Lp(a) was significantly associated with CKD [odds ratio (OR): 1.12, 95% confidence interval (CI): 1.08–1.17; p=1.3×10–7: per 10mg/dL)., independent of other classical risk factors, including age, gender, body mass index, hypertension, diabetes, smoking, LDL cholesterol and triglycerides. Under these conditions, Lp(a) was significantly associated with CAD [OR: 1.11, 95% CI: 1.06–1.16; p=1.7×10–6: per 10mg/dL), independent of the presence of CKD. Conclusion Serum Lp(a) was associated with the development of CKD independent of other classical risk factors among Japanese population as well.

Abstract Background Use of ezetimibe on top of statin therapy has been shown to be effective to reduce LDL cholesterol level in hypercholesterolemic patients. However, little is known regarding the individual variety of the effectiveness of ezetimibe. We hypothesized that hypercholesterolemic patients with a mutation in ABCG5 or ABCG8 gene exhibit better response to ezetimibe that those without, based on the fact that ezetimibe is hyper-effective for in patients with sitosterolemia caused by ABCG5 or ABCG8 genetic mutations. Methods Electronical medical record were reviewed in a total of 321 hypercholesterolemic patients (baseline LDL cholesterol = 192±46 mg/dl) prescribed ezetimibe 10 mg daily on top of atorvastatin 10mg daily who had undergone genetic analysis of ABCG5 or ABCG8 gene in our institute since 2006 to 2017. Pathogenicity of the variants were determined using standard variant filtering schema, including minor allele frequency, in silico annotation tools. Patients were divided into 2 groups based on the presence of ABCG5 or ABCG8 mutation. We compared the percent reduction of LDL cholesterol as well as the achieved LDL cholesterol levels between these 2 groups. Results We found 26 (8%) individuals who exhibit deleterious mutations in ABCG5 or ABCG8 gene. Baseline characteristics under the atorvastatin 10mg therapy were comparable in age, gender, and LDL cholesterol level between 2 groups. Under these conditions, percent reduction of LDL cholesterol in mutation positive group was significantly larger than that of mutation negative group (28±16% vs. 39±21%, p<0.05). As a result, the achieved LDL cholesterol level in mutation positive group was significantly lower than that of mutation negative group (87±29 mg/dl vs. 72±26% mg/dl, p<0.05). Conclusion These results suggest that ezetimibe-atorvastatin combination therapy might be more beneficial in hypercholesterolemic patients with a mutation in ABCG5 or ABCG8 gene.