Reperfusion therapy has profoundly transformed acute ischemic stroke (AIS) care. Initially, treatment decisions relied primarily on time from symptom onset. However, growing evidence has shown that the extent of irreversibly injured tissue and the presence of salvageable brain tissue determine the efficacy and safety of reperfusion therapy. This caused a paradigm shift from time-based selection toward tissue-based assessment, placing neuroimaging at the center of clinical decision-making. This narrative review traces the evolution of imaging-based stroke assessment in the reperfusion era. We review the development and clinical impact of the Alberta Stroke Program Early Computed Tomography Score (ASPECTS) and diffusion-weighted imaging (DWI)-ASPECTS, which translated the pathophysiological concept of the ischemic core into a practical, reproducible, routine clinical tool. We discuss the emergence of imaging and clinical mismatch concepts, including perfusion-based ischemic core–penumbra mismatch, as well as clinical–diffusion, MRA–diffusion, and DWI–FLAIR mismatches, which address the limitations of strict time-based criteria and expand treatment opportunities, particularly in patients with unknown onset time. Finally, we examine the growing role of artificial intelligence (AI)-driven automated imaging platforms in acute stroke care, enabling rapid, standardized, and quantitative assessment of ischemic core, penumbra, and vascular pathology. These tools support clinical decision-making under severe time constraints and reduce inter-reader and inter-institutional variability. This iterative process of trial and refinement has shaped the current framework of tissue-based, data-driven stroke care. We discuss how integrating established imaging concepts with emerging AI technologies may further advance precision reperfusion therapy and improve equity and outcomes in AIS treatment.

Aim: Notch signaling is a fundamental signal that regulates morphogenesis and cell differentiation during the embryonic period, and it plays a crucial role in macrophage differentiation. Macrophage-mediated inflammation promotes atherosclerosis from the initial lesion formation to acute thrombotic complications in advanced plaques. However, their role in atherosclerosis remains unclear. We herein focused on the Notch ligand Delta-like ligand 1 (Dll1), and examined its role in the pathobiology of atherosclerosis.

Methods: In Apoe^−/− mice, a blocking antibody against Dll1 (Dll1 Ab) was administered for 12 weeks from 8 weeks (early phase) or 20 weeks (late phase) of age.

Results: Dll1 blockade suppressed both initial lesion development and plaque vulnerability compared with lesions in mice treated with non-immune IgG. Dll1 Ab decreased lipid accumulation in advanced lesions and increased the collagen content. In ex vivo cultured macrophages, the blockade of Dll1-Notch signaling by Dll1 blocking antibodies suppressed the mRNA expression of Tnf and the release of activated matrix metalloproteinase 9, which increased plaque vulnerability. In contrast, the stimulation of Dll1-Notch by recombinant Dll1 induced Il1b, Il6, and Tnf expression in macrophages, as well as NF-κB activation. An exploratory transcriptome analysis of atherosclerotic arteries suggested that Dll1-Notch signaling regulates the expression of genes associated with inflammation and mitosis.

Conclusions: These results indicate that Dll1 promotes the pathobiology of atherosclerosis from the initial lesion development to plaque destabilization in advanced atherosclerotic lesions.

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/m², 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.

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_LDL-C (plus rare variants) and MRS_LDL-C showed a higher correlation between the predicted and measured values (r = 0.272, P = 3.7×10⁻¹²) than those using PRS_LDL-C alone (r = 0.106, P = 0.008) and PRS_LDL-C plus rare variants (r = 0.263, P = 1.9×10⁻¹¹). 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.

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.

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/1.73m²) 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.

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.

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.

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: 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.