AIM: The association between serum fatty acids and atherosclerotic disease remains unclear. In this cross-sectional study, we examined the association of serum fatty acids and the EPA/AA ratio with hypertriglyceridemia (...AIM: The association between serum fatty acids and atherosclerotic disease remains unclear. In this cross-sectional study, we examined the association of serum fatty acids and the EPA/AA ratio with hypertriglyceridemia (HTG), a key metabolic factor underlying atherosclerosis. METHODS: A total of 2,413 adults aged 40-74 years were randomly selected after excluding those with clinically validated myocardial infarction or stroke. We analyzed the serum fatty-acid composition and categorized saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), n-6 polyunsaturated fatty acids (PUFA), n-3 PUFA, and the EPA/AA ratio into quartiles, defined HTG at triglyceride levels ≥ 150 or ≥ 175 mg/dL in fasting or non-fasting samples, respectively, and calculated the adjusted odds ratios (AORs) and 95 % confidence intervals (CIs) using multivariable logistic regression. RESULTS: After adjusting for age, sex, body mass index, social status, lifestyle, and the self-reported medical history of hypertension, diabetes, dyslipidemia, other cardiovascular diseases, and cerebrovascular conditions (excluding validated myocardial infarction or stroke), the odds of HTG were significantly higher in the highest quartile of SFA (AOR, 8.13; 95 % CI, 5.62-11.77) and MUFA (AOR, 64.7; 95 % CI, 31.4-133.2). In contrast, higher n-6 PUFA (AOR, 0.02; 95 % CI, 0.01-0.04) and n-3 PUFA (AOR, 0.36; 95 % CI, 0.26-0.50) levels, and a higher EPA/AA ratio (AOR, 0.64; 95 % CI, 0.46-0.88) were associated with lower odds of HTG. CONCLUSIONS: Higher serum SFA and MUFA were associated with increased odds, while higher n-6 PUFA, n-3 PUFA, and the EPA/AA ratio were associated with decreased odds of HTG.
Kitagawa K, Ishizuka K, Doijiri R
… +24 more, Maruyama K, Sakaguchi M, Hino S, Honma Y, Kimura Y, Iguchi Y, Hirano T, Oda M, Oi K, Toi S, Mizuno T, Arai S, Hosoya M, Wako S, Takahashi S, Saito M, Todo K, Saito T, Kimura K, Ago T, Kitazono T, Sato Y, Hoshino T, Remote Ischemic conditioning for Acute Ischemic Stroke (RICAIS) study group
AIMS: Preclinical studies have shown that remote ischemic conditioning (RIC) has a neuroprotective effect; however, the findings of clinical studies are inconsistent. This study aimed to show the effect of RIC on acute i...AIMS: Preclinical studies have shown that remote ischemic conditioning (RIC) has a neuroprotective effect; however, the findings of clinical studies are inconsistent. This study aimed to show the effect of RIC on acute ischemic stroke while considering its severity at baseline. METHODS: We enrolled 79 patients with ischemic stroke who had National Institute of Health Stroke Scale (NIHSS) scores of 5-20 within 48 h after stroke onset and randomized them into the RIC [n = 43] and control groups [n = 36]. The intervention was performed using an inflatable cuff on one lower extremity. In the RIC group, each treatment consisted of four cycles of 5 min cuff inflation and deflation. The treatment was repeated once daily for at least three days. Based on the NIHSS score, the patients were divided into three groups: mild (NIHSS 5-9), moderate (NIHSS 10-14), and severe (NIHSS 15-20). The primary outcome was a good functional outcome at 90 days, defined as a modified Rankin Scale score of 0-1 in the mild group, 0-2 in the moderate group, and 0-3 in the severe group. RESULTS: Among the 79 patients (mean age, 65.0 years, 40 women), 7 (16.3%) in the RIC group and 8 (22.2%) in the control group had good functional outcomes (odds ratio, 0.73 [95% confidence interval, 0.29-1.82]; P = 0.502). The incidences of major adverse cardiovascular events, aspiration pneumonia, and serious adverse events were similar in both the groups. CONCLUSION: Although this study may have been underpowered, RIC initiated within 48 h of stroke onset did not seem to improve the functional outcomes in acute ischemic stroke.
AIM: This study explored the association between retinol-binding protein 4 (RBP4) and cardiovascular events in patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI). METHODS: A to...AIM: This study explored the association between retinol-binding protein 4 (RBP4) and cardiovascular events in patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI). METHODS: A total of 736 AMI patients who underwent successful PCI were prospectively enrolled between January 2020 and January 2022. The baseline RBP4 levels were measured by ELISA and categorized into quartiles. The incidence of major adverse cardiovascular events (MACEs), including all-cause mortality, recurrent myocardial infarction, revascularization, heart failure, and stroke, was assessed at the 1- and 3-year follow-up. Multivariate Cox proportional hazards models were used to evaluate the association between RBP4 and MACEs. A receiver operating characteristic (ROC) curve analysis was performed to determine the predictive efficiency of RBP4 for predicting the 1-year and 3-year MACEs. RESULTS: During follow-up, 110 (14.95%) and 165 (22.42%) patients developed MACEs at one and three years, respectively. Elevated RBP4 (the fourth quartile vs. the first quartile) was associated with an increased risk of MACEs (HR = 2.18, 95%CI = 1.42~4.37, P = 0.007) and heart failure (HR = 3.89, 95%CI = 1.68~5.75, P＜0.001) at the 1-year follow-up. Additionally, the elevated RBP4 were associated with an increased risk of MACEs (HR = 4.41, 95%CI = 2.57~7.31, P＜0.001), revascularization (HR = 3.43, 95%CI = 1.82~4.87, P＜0.001) and heart failure (HR = 7.12, 95%CI = 3.78~11.92, P＜0.001) at 3-year follow-ups. An ROC curve analysis revealed that the serum RBP4 cutoff for predicting the 1-year MACEs was 46.3 ng/mL (AUC = 0.74, 95%CI = 0.69~0.78, P＜0.001), and for predicting the 3-year MACEs, it was 43.9 ng/mL (AUC = 0.81, 95%CI = 0.77~0.85, P＜0.001). A Stratified Cox regression analysis suggested that the renal function did not significantly modify the association between RBP4 and MACEs. CONCLUSION: Elevated RBP4 levels are independently associated with an increased risk of MACEs in patients with AMI post-PCI, thus highlighting its potential as a prognostic biomarker for risk stratification.
Yoshida T, Emoto T, Yamamoto H
… +15 more, Takaya T, Sawada T, Murphy SL, Shoda M, Nakamura K, Taniguchi M, Sasaki N, Fukuishi Y, Toba T, Ohkawa T, Furuyashiki T, Kawai H, Hirata KI, Otake H, Yamashita T
J Atheroscler Thromb
· 2026 Jun · PMID 41850847
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AIM: Acute coronary syndrome (ACS) and ischemic stroke are major life-threatening conditions caused by atherosclerosis. Although the mechanisms of atherosclerosis appear to be broadly similar across different vascular be...AIM: Acute coronary syndrome (ACS) and ischemic stroke are major life-threatening conditions caused by atherosclerosis. Although the mechanisms of atherosclerosis appear to be broadly similar across different vascular beds, growing evidence suggests that there are morphological and histological differences between coronary and carotid atherosclerosis. To identify disease-specific therapeutic strategies, we aimed to compare ACS and chronic coronary syndrome (CCS) in coronary artery disease, and symptomatic and asymptomatic carotid artery disease. METHODS: We analyzed our own single-cell RNA sequencing dataset for coronary artery disease (GSE184073) and a publicly available dataset for carotid artery disease (GSE253903). Myeloid cells were extracted from these datasets and comparative analyses were performed using metabolic profiling and an RNA velocity analysis. RESULTS: By integrating multiple velocity-inference approaches, including the original and dynamic RNA velocity models, TFvelo using transcription factor regulatory information, and CellRank, we consistently identified a differentiation trajectory toward interleukin-1B (IL1B) inflammatory macrophages marked by high expression of matrix metalloproteinase 19 (MMP19). This trajectory was accompanied by the activation of the glycolytic and glycosaminoglycan degradation pathways. A similar directional flow toward IL1B inflammatory macrophages was also observed in symptomatic carotid artery plaques. However, unlike coronary lesions, carotid lesions activated the glycolytic pathway in SPP1 foamy macrophages expressing MMP19. CONCLUSIONS: Our findings revealed a shared differentiation trajectory into IL1B inflammatory macrophages in carotid and coronary artery diseases, which is associated with plaque vulnerability. Notably, the distinct activation of the glycolytic pathway in a separate macrophage subset suggests that tailored therapeutic strategies may be necessary to effectively address plaque vulnerability in each vascular bed.
Yoshioka N, Tokuda T, Tanaka A
… +9 more, Kojima S, Yamaguchi K, Yanagiuchi T, Ogata K, Takei T, Morita Y, Nakama T, Morishima I, LEADers PAD investigators
AIMS: Data on recurrence and its patterns after paclitaxel-coated balloon (PCB) angioplasty for femoropopliteal artery disease are limited. We evaluated the incidence and predictors of re-recurrence according to the retr...AIMS: Data on recurrence and its patterns after paclitaxel-coated balloon (PCB) angioplasty for femoropopliteal artery disease are limited. We evaluated the incidence and predictors of re-recurrence according to the retreatment strategy (PCB or scaffold) and recurrence pattern (restenosis or reocclusion) in patients with recurrence after primary PCB therapy. METHODS: This multicenter retrospective study included 276 limbs of 246 patients who underwent repeat endovascular therapy (EVT) using either PCB (PCB group, n = 217) or a scaffold (scaffold group, n = 59) for primary PCB recurrence. The primary endpoint was 1-year freedom from re-recurrence, and secondary analyses identified the predictors of re-recurrence. RESULTS: In the PCB group, 174 restenotic and 43 reoccluded lesions were treated with PCBs. In the scaffold group, 32 restenotic and 27 reoccluded lesions were treated with scaffolds. In both groups, reoccluded lesions had significantly lower freedom from re-recurrence rates than restenotic lesions (PCB: 43.0% vs. 68.6%, p＜0.001; scaffold: 52.6% vs. 81.5%, p = 0.033). Freedom from re-reocclusion was also significantly lower in reoccluded lesions than in restenotic lesions (PCB: 48.5% vs. 88.6%, p＜0.001; scaffold: 65.8% vs. 93.2%, p = 0.033). The independent predictors of re-recurrence after PCB treatment were male sex (hazard ratio [HR] 2.01, p = 0.010), reoccluded lesions (HR 2.71, p = 0.001), poor BK run-off (HR 1.97, p = 0.020), use of first-generation low-dose PCB (HR 2.32, p = 0.017), and residual stenosis ＞30% (HR 2.60, p = 0.009). After scaffold treatment, reoccluded lesions were also identified as a significant predictor of re-recurrence (HR 2.99, p = 0.043). CONCLUSION: Reocclusion after PCB therapy was strongly associated with subsequent re-recurrence, including re-reocclusion, regardless of the retreatment strategy.
J Atheroscler Thromb
· 2026 Jun · PMID 41795932
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AIMS: Hyperglycemia and glycemic variability (GV) are predictors of adverse outcomes in critically ill patients; however, their roles in pulmonary embolism (PE) remain unclear. This study investigated the association bet...AIMS: Hyperglycemia and glycemic variability (GV) are predictors of adverse outcomes in critically ill patients; however, their roles in pulmonary embolism (PE) remain unclear. This study investigated the association between the mean blood glucose (MBG), GV, and mortality in patients with PE. METHODS: A retrospective cohort study of patients with PE was conducted using the MIMIC-IV 3.0. GV was quantified using the coefficient of variation (CV). Patients were stratified according to tertiles of MBG and CV. Multivariable logistic regression, restricted cubic splines (RCS), and ROC curves were used to evaluate the associations with ICU and in-hospital mortality, supplemented by the threshold effect, sensitivity, and subgroup analyses. RESULTS: Among the 1,493 PE patients, the ICU and in-hospital mortality rates were 12.99% and 20.90%, respectively. A higher MBG or CV was significantly associated with an increased risk of ICU mortality and in-hospital mortality. RCS revealed a linear association between MBG and mortality, whereas CV exhibited an inverted U-shaped relationship with inflection points at 38.523% (ICU) and 37.038% (in-hospital). For every 1% increase in CV to the left of the inflection point, the relative risks of ICU and in-hospital mortality increased by 0.035. The combined model (MBG + CV + ERS (European Respiratory Society)) achieved AUCs of 0.735 (ICU) and 0.693 (in-hospital) for mortality prediction. CONCLUSIONS: MBG and CV are independent predictors of mortality in critically ill patients with PE, suggesting that optimal glycemic control may benefit this population.
Kanazawa K, Miyamoto N, Ueno H
… +15 more, Tsutsumi S, Saito R, Tokugawa J, Ueno Y, Yamashiro K, Yamamoto M, Yasumoto Y, Hishii M, Yamamoto T, Maruki C, Urabe T, Kondo A, Arai H, Hattori N, Tanaka R
J Atheroscler Thromb
· 2026 Jun · PMID 41795922
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AIM: A reduction in low-density lipoprotein cholesterol (LDL-C) is beneficial for vascular diseases; however, lower LDL-C levels may be associated with an increased risk of spontaneous intracerebral hemorrhage (sICH). Th...AIM: A reduction in low-density lipoprotein cholesterol (LDL-C) is beneficial for vascular diseases; however, lower LDL-C levels may be associated with an increased risk of spontaneous intracerebral hemorrhage (sICH). The present study investigated the relationship between the LDL-C levels and in-hospital mortality after sICH using data from the Juntendo Registry of Spontaneous Intra-Cerebral Hemorrhage (J-ICH registry). METHODS: Patients aged ≥ 20 years with non-traumatic sICH admitted to five Juntendo-affiliated hospitals between September 2016 and December 2019 were enrolled in this study. The relationships between the LDL-C levels and in-hospital mortality, statin therapy, and antithrombotic therapy were analyzed. RESULTS: Among the 1,017 patients with sICH, lower LDL-C levels were associated with older age, a lower BMI, a larger hematoma volume, more severe neurological deficits, and a higher in-hospital mortality. A logistic regression analysis confirmed that LDL-C ＜100 mg/dL independently increased the risk of in-hospital death, along with age, the NIHSS score, hematoma volume, and intraventricular hemorrhage. Subgroup analyses showed that the association between low LDL-C levels and mortality was particularly evident in patients with deep/infratentorial intracerebral hemorrhage, those managed without surgery, and those without prior statin use. Prior statin use was associated with a potential protective effect against in-hospital mortality and hematoma volume. CONCLUSION: This study demonstrated that lower LDL-C levels were associated with a higher in-hospital mortality after sICH, whereas prior statin use was not associated with poorer outcomes and may instead offer a protective effect.
AIMS: Small dense low-density lipoprotein cholesterol (sdLDLC) has been suggested to be more harmful for cardiovascular outcomes than total LDLC. This study aimed to clarify the prognostic significance of the estimated s...AIMS: Small dense low-density lipoprotein cholesterol (sdLDLC) has been suggested to be more harmful for cardiovascular outcomes than total LDLC. This study aimed to clarify the prognostic significance of the estimated sdLDLC for the incidence of coronary artery diseases (CAD). METHODS: We analyzed the clinical information obtained at an annual health checkup of 365,083 adults aged 40-74 years enrolled in the National Health Insurance system in Japan. The incidence of CAD was determined using the health insurance claims data. Additionally, we calculated Japanese-specific coefficients of the sdLDLC estimation equation using general population data, where the measured sdLDLC value was available (n = 9,558). RESULTS: The estimated sdLDLC level calculated from the total LDLC and triglyceride levels was correlated with the measured sdLDLC level (coefficient of determination = 0.768) and it was significantly associated with the CAD incidence (hazard ratio per 10 mg/dL = 1.21, p＜0.001). Although the total LDLC showed a similar association, the estimated sdLDLC ≥ 30 mg/dL (hazard ratio = 1.97, p = 0.016) and ≥ 40 mg/dL (hazard ratio = 2.57, p = 0.001) were significantly associated with CAD, even in participants with normal LDLC levels (＜120 mg/dL). The cross-sectional association of the measured sdLDLC with the pulse wave velocity of the large artery (β = 0.034, p＜0.001) was significant, while that of the estimated sdLDLC (β = 0.014, p = 0.057) was not. CONCLUSION: The estimated sdLDLC may be a straightforward and cost-effective marker for identifying individuals with normal LDLC levels at risk of CAD. However, the measured sdLDLC may be a more favorable marker than the estimated sdLDLC.
J Atheroscler Thromb
· 2026 May · PMID 41780950
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Patients with chronic kidney disease (CKD) face a markedly elevated risk of death from cardiovascular disease (CVD); in particular, those requiring hemodialysis have a 10- to 30-fold higher risk than the general populati...Patients with chronic kidney disease (CKD) face a markedly elevated risk of death from cardiovascular disease (CVD); in particular, those requiring hemodialysis have a 10- to 30-fold higher risk than the general population. This extremely increased risk of CVD death reflects the coexistence of multiple traditional and nontraditional risk factors. The present narrative review considers two distinct steps: first, the occurrence of a CVD event, and second, death resulting from an inability to recover from the CVD event. Patients undergoing hemodialysis are at an increased risk for both of these steps, accounting for the dramatically higher risk of CVD death in this population. High risk for the second step-death following a CVD event-may be driven by conditions called decreased physical resilience and increased frailty. Studies of patients on hemodialysis show that predictors for death at this stage include key components of malnutrition-inflammation-atherosclerosis syndrome-also called the malnutrition-inflammation-complex-syndrome or protein-energy wasting-such as lower body mass index, lower serum albumin, and higher C-reactive protein. Other important contributors include higher age, longer dialysis duration, diabetic kidney disease, phosphate, calcium, serum calcification propensity (T50), and insulin-like growth factor 1 levels. Notably, some of these factors also predict death following infection, suggesting that the risk predictors for the second step are shared between CVD and infection. Recognizing these steps may facilitate prevention and greater preparedness for CVD, infection, and other stressful events among patients with CKD.
Fujimoto S, Iguchi Y, Yamagami H
… +20 more, Koga M, Itabashi R, Yakushiji Y, Kowata K, Kimura N, Terasawa Y, Shimizu T, Miyazaki Y, Oki K, Masuo O, Matsuoka H, Arakawa S, Ueda T, Tanaka R, Hashimoto W, Abe S, Kato G, Furugori T, Kimura K, ACUTE-PRAS Investigators
J Atheroscler Thromb
· 2026 Jun · PMID 41780949
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AIM: To explore whether the antiplatelet effects of prasugrel and clopidogrel vary according to patient background factors in the ACUTE-PRAS study. METHODS: This was a post hoc, hypothesis-generating, exploratory analysi...AIM: To explore whether the antiplatelet effects of prasugrel and clopidogrel vary according to patient background factors in the ACUTE-PRAS study. METHODS: This was a post hoc, hypothesis-generating, exploratory analysis of the multicenter, open-label, randomized controlled ACUTE-PRAS study, in which 176 patients with acute atherothrombotic stroke or high-risk TIA received prasugrel or clopidogrel within 48 h of symptom onset. High platelet reactivity (HPR; platelet reaction units [PRU] ＞208) and absolute PRU were assessed on Day 5 in subgroups stratified by ABCD-GENE score, age, body mass index (BMI), chronic kidney disease (CKD), diabetes mellitus (DM), hypertension, dyslipidemia, time from stroke onset to treatment, National Institutes of Health Stroke Scale (NIHSS) score, and prior ischemic stroke. RESULTS: Patients with prasugrel had numerically lower rates of HPR than those with clopidogrel in the high-risk stratum of ABCD-GENE score ≥ 10 (OR 2.73, p = 0.076), and favorable trends in prasugrel were also observed for CKD (8.06, p = 0.012), age ＞75 years (5.02, p = 0.025), BMI ＜25 kg/m² (4.61, p = 0.012), dyslipidemia (4.73, p = 0.009), DM (3.86, p = 0.038), treatment initiation ≤ 24 h (3.31, p = 0.010), and NIHSS ≤ 3 (2.77, p = 0.036) or ≥ 4 (9.00, p = 0.025). Prasugrel also reduced PRU numerically more than clopidogrel across most subgroups, except in patients with BMI ≥ 25 kg/m, treatment initiation ＞24 hours, or prior ischemic stroke, where only numerical differences were observed. CONCLUSIONS: Prasugrel provided favorable early platelet inhibition, particularly in subgroups characterized by advanced age, CKD, low BMI, metabolic comorbidities, or very early treatment start.
Hirata A, Harada S, Iida M
… +15 more, Matsumoto M, Miyagawa N, Toki R, Edagawa S, Shibuki T, Kuwabara K, Kohsaka S, Izawa Y, Sawano M, Takizawa T, Shoji S, Katsumata M, Sugiyama D, Okamura T, Takebayashi T
J Atheroscler Thromb
· 2026 Jun · PMID 41780931
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AIMS: The association between alcohol consumption and the risk of cardiovascular disease (CVD) varies according to the presence of underlying cardiovascular risk factors. Incorporating such risk factors may be important...AIMS: The association between alcohol consumption and the risk of cardiovascular disease (CVD) varies according to the presence of underlying cardiovascular risk factors. Incorporating such risk factors may be important to effectively reduce harmful alcohol use through health guidance. However, whether the risk of alcohol consumption is affected due to renal impairment remains unclear. METHODS: A total of 10,583 community-dwelling Japanese adults (mean age 59.4 (SD 10.1) years; 46% men) were followed for 10 years. Alcohol consumption was categorized into five groups for men: never drinkers, former drinkers, light drinkers (＜20 g/day), moderate drinkers (20-39 g/day), and heavy drinkers (≥ 40 g/day), and four groups for women with moderate and heavy combined. Cox proportional hazards models estimated hazard ratios for incident CVD stratified by the presence or absence of reduced estimated glomerular filtration rate (eGFR) (＜60 mL/min/1.73m) and proteinuria, with adjustment for confounders. RESULTS: Among men with proteinuria, alcohol consumption was associated with a higher risk of atherosclerotic CVD, whereas an inverse association was observed in men without proteinuria [hazard ratio (95% confidence interval): moderate drinkers without proteinuria, 0.58 (0.34-0.97); moderate drinkers with proteinuria, 3.49 (1.15-10.56)]. Moderate to heavy drinking increased the risk of intracerebral hemorrhage irrespective of the renal status. In women, moderate to heavy drinking was associated with an increased CVD risk only when proteinuria was present. In contrast, a reduced eGFR did not clearly affect the association in either sex. CONCLUSIONS: The CVD risk associated with alcohol consumption may differ according to the renal status, particularly depending on the presence or absence of proteinuria.
Watanabe Y, Naganuma T, Matsuoka S
… +1 more, Hozawa K
J Atheroscler Thromb
· 2026 Jun · PMID 41765402
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AIMS: The aim of this study is to evaluate the impact of each level atherosclerotic lesion subset on clinical outcomes following EVT in CLTI patients. METHODS: We identified 705 consecutive CLTI patients undergone succes...AIMS: The aim of this study is to evaluate the impact of each level atherosclerotic lesion subset on clinical outcomes following EVT in CLTI patients. METHODS: We identified 705 consecutive CLTI patients undergone successful EVT between January 2010 and December 2019 at our hospital in Japan. The technical success was defined as the acquisition of one straight line flow to the ulcerated or gangrenous region. We excluded 15 patients with follow up ＜30days. The primary endpoint was major adverse limb event (MALE) at 2 years after EVT. MALE was defined as composite of all cause death and major amputation (MA). MA was defined as an above-the-ankle amputation. RESULTS: The median follow-up duration was 24.4 months. MALE rate was significantly higher in BK group (adjusted HR 1.48, 95% CI, 1.04-2.10 p = 0.028). Cardiovascular mortality was significantly higher in BK group (adjusted HR 1.94, 95% CI, 1.06-3.56 p = 0.031). Isolated BK lesions were identified an independent predictor of MA (adjusted HR 2.12, 95% CI, 1.01-4.48 p = 0.048). CONCLUSION: In CLTI patients who received EVT, those with BK lesions were associated with poorer clinical outcomes after EVT than those without BK lesion, mainly due to increased cardiovascular death. Additionally, isolated BK lesion was associated with higher MA rate after EVT than both FP and BK lesions or isolated FP lesions in our study population.
Takeuchi F, Yamamoto M, Nakatochi M
… +14 more, Takano K, Okazaki A, Emoto S, Tabara Y, Katsuya T, Yamamoto K, Isono M, Mori K, Matsubara T, Ichihara S, Yokota M, Hara H, Hiroi Y, Kato N
J Atheroscler Thromb
· 2026 Jun · PMID 41708081
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AIMS: This study aimed to develop a model to simultaneously assess the genetic and epigenetic contributions to plasma lipids. METHODS: The study used two cardiovascular risk groups: individuals with high low-density lipo...AIMS: This study aimed to develop a model to simultaneously assess the genetic and epigenetic contributions to plasma lipids. METHODS: The study used two cardiovascular risk groups: individuals with high low-density lipoprotein cholesterol (LDL-C) levels (N = 296) and coronary artery disease (CAD) (N = 315), in contrast to the reference (max N = 3,801) and non-CAD individuals (N = 164). For genetic predisposition, rare pathological variants in five target genes related to familial hypercholesterolemia (FH) were screened, while common variants were characterized to calculate a polygenic risk score (PRS). The methylation risk score (MRS) was also calculated for the epigenetic profile based on the DNA methylation levels at the 17 CpG sites. The relationship between each lipid level and these variables was analyzed using regression and quantile models. RESULTS: Functionally significant rare variants were identified more frequently in patients with high LDL-C or CAD than in the general Japanese population (3.8% vs. 2.3%). For LDL-C, the model incorporating both PRS (plus rare variants) and MRS showed a higher correlation between the predicted and measured values (r = 0.272, P = 3.7×10) than those using PRS alone (r = 0.106, P = 0.008) and PRS plus rare variants (r = 0.263, P = 1.9×10). PRS and MRS had the most significant impact on high-density lipoprotein cholesterol and triglycerides, respectively; the two risk scores had additive effects on these lipid traits, as well as LDL-C. CONCLUSION: Our results provide a proof-of-concept that assesses the relative contribution of genetic predisposition and DNA methylation levels, which may help individuals refine their dyslipidemia treatment.
Okada T, Yamashita S, Tada H
… +9 more, Tsukamoto K, Togo M, Kawashiri MA, Nakamura K, Dobashi K, Ikewaki K, Yoshida H, Harada-Shiba M, Committee on Primary Dyslipidemia under the Research Program on Rare and Intractable Disease of the Ministry of Health, Labour and Welfare of Japan
J Atheroscler Thromb
· 2026 May · PMID 41672494
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AIM: Since comprehensive data on the pathogenic variants of ABCG5 and ABCG8 and clinical features in sitosterolemia remain limited, we aimed to compile a catalog through an extensive literature search of case reports fro...AIM: Since comprehensive data on the pathogenic variants of ABCG5 and ABCG8 and clinical features in sitosterolemia remain limited, we aimed to compile a catalog through an extensive literature search of case reports from 2002 to 2024, as well as an evaluation of variants reported in review articles. METHODS: We compiled 155 cases of sitosterolemia from 133 families with nonsynonymous variants in ABCG5 and ABCG8, along with data on clinical information from case reports. Pathogenic variants were defined either as 1) protein-truncating variants, 2) classified as pathogenic or likely pathogenic variants according to the ACMG guidelines, or 3) serum sitosterol level of the case was measured at ≥ 1 mg/dL. RESULTS: Xanthoma was observed in 69.2% of patients, ischemic heart disease in 14.2%, and hematologic abnormalities in 57.9%. Fifty-three variants in ABCG5 and 52 in ABCG8 were evaluated for their pathogenicity, in which 33 in ABCG5 and 29 in ABCG8 were protein-truncating variants. Additionally, based on the ACMG criteria and serum sitosterol levels, 50 variants in ABCG5 and 51 variants in ABCG8 were finally classified as pathogenic. Among them, the frequently observed R446X and R389H in ABCG5 were highly prevalent in East Asians, while W361X and S107X in ABCG8 were predominantly found in Europeans. CONCLUSION: We provided the largest catalog of clinical features and pathogenic variants of ABCG5 and ABCG8 in the world. This study may help clarify the pathogenicity of variants in ABCG5 and ABCG8 and provide a valuable reference for the genetic diagnosis of sitosterolemia.
Ishii M, Fujisue K, Kaikita K
… +22 more, Yamanaga K, Hanatani S, Matsuzawa Y, Miura M, Kudo T, Shimomura H, Takae M, Shirahama Y, Yamamoto N, Ito T, Tsunoda R, Horio E, Sakamoto T, Rokutanda T, Morihisa K, Noda K, Tanaka H, Matsuura Y, Yamamoto E, Izumiya Y, Tsujita K, PEMA-TAS Investigators
J Atheroscler Thromb
· 2026 Jun · PMID 41656092
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AIMS: Pemafibrate effectively reduces the triglyceride levels in patients with coronary artery disease (CAD). However, its effect on the fibrinogen levels in these patients remains unclear. This study aimed to investigat...AIMS: Pemafibrate effectively reduces the triglyceride levels in patients with coronary artery disease (CAD). However, its effect on the fibrinogen levels in these patients remains unclear. This study aimed to investigate the effects of pemafibrate on thrombogenicity and the plasma fibrinogen levels in patients complicated by hypertriglyceridemia. METHODS: This multicenter, randomized, controlled trial enrolled 101 patients with hypertriglyceridemia (fasting triglycerides ≥ 150 mg/dL) and CAD who received antiplatelet monotherapy and statin therapy. After exclusion, 98 participants were randomly assigned to receive either pemafibrate 0.1 mg twice daily (intervention group) or standard care without any additional lipid-lowering therapy (control group), and 96 patients were analyzed. The fibrinogen levels were assessed at the baseline and after 12 weeks of treatment. The primary endpoint was the change in the fibrinogen level from baseline to week 12. The secondary endpoints included thrombogenicity measured using the Total Thrombus-formation Analysis System (T-TAS). RESULTS: Among the 96 patients, the median baseline fasting triglyceride, HDL cholesterol, LDL cholesterol, and fibrinogen levels were 175 mg/dL, 45 mg/dL, 72 mg/dL, and 299 mg/dL, respectively. The median decrease in triglycerides from baseline to 12 weeks was greater in the pemafibrate group than in the control group (-62 mg/dL vs. -5 mg/dL, p＜0.001), as was the median decrease in fibrinogen (-58 mg/dL vs. 9 mg/dL, p＜0.001). CONCLUSIONS: Pemafibrate significantly reduced fibrinogen levels in patients with CAD and hypertriglyceridemia, thus highlighting its primary benefit in lowering thrombotic risk.