搜索结果：Journal of atherosclerosis and thrombosis

Homozygous Familial hypercholesterolemia (HoFH) is a rare genetic disease characterized by very high levels of low-density lipoprotein cholesterol (LDL-C). Owing to LDL receptor activity being completely or nearly all lost in HoFH, LDL-C levels greatly exceed normal levels, and are even higher than in heterozygous (HeFH), which can cause fatal cardiovascular disease even in infancy. The current study updates differences in clinical characterization, therapeutic strategies and cardiovascular outcomes between HoFH and HeFH. A total of 157 patients who were genetically or clinically diagnosed with FH (HoFH: 15, HeFH: 142) were retrospectively analyzed. Clinical characteristics, lipid profiles and atherosclerotic prognosis were evaluated between HoFH and HeFH patients. Age and sex were similar between the two groups. Untreated LDL-C in HoFH was about double that in HeFH (498.4±164.3 vs. 232.0±60.5 mg/dL, p＜0.001), while on-treatment LDL-C with lipid lowering therapies did not differ significantly (83.8±59.1 vs. 127.1±59.6 mg/dL, p = 0.15). There was wide diversity in lipid lowering therapies between the two groups and a significantly higher prevalence of coronary artery and valvular disease in HoFH. Consequently, HoFH patients were more likely to receive percutaneous and surgical interventions at a younger age compared to HeFH patients. The findings of this observational study show the clinical relevance of FH. Although both HeFH and HoFH are inherited disorders of lipoprotein metabolism, HoFH should be treated with a different, stricter therapeutic strategy to prevent premature ASCVD.

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. 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. 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. 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.

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. 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. 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. 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.

The relationship between omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) and atrial fibrillation (AF) remains unclear. This retrospective study aimed to investigate the association between plasma levels of omega-3 PUFAs (eicosapentaenoic acid [EPA], docosahexaenoic acid [DHA]) and omega-6 PUFAs (arachidonic acid [AA] and dihomo-γ-linolenic acid [DGLA]) and the prevalence of AF. After excluding patients who were prescribed icosapent ethyl (IPE) or were younger than 40 years, data from 9,178 patients at Juntendo University Hospital with plasma EPA, DHA, AA, and DGLA measurements obtained between April 2017 and January 2021 were analyzed. The plasma PUFA levels were divided into quartiles, with the lowest quartile used as the reference. Multivariable logistic regression and restricted cubic spline analyses were performed to assess the association between the PUFA levels and AF. The median age was 69 years (interquartile range [IQR], 59-77 years), and 60.6% of the participants were male. AF was diagnosed in 908 (9.9%) patients. After adjusting for age, sex, and body mass index (BMI), higher plasma levels of EPA, DHA, EPA+DHA, AA, and DGLA were significantly associated with a lower risk of AF (all P＜0.001). In contrast, no significant associations were observed between the PUFA ratios, including (EPA+DHA)/AA, EPA/AA, DHA/AA, and DGLA/AA, and AF. Restricted cubic spline analyses revealed linear inverse associations for EPA, DHA, EPA+DHA, and AA and AF, whereas a nonlinear association for DGLA and AF was observed. Within the physiological ranges, higher plasma levels of EPA, DHA, EPA+DHA, AA, and DGLA were independently and inversely associated with AF risk. However, extremely high EPA concentrations, achieved through pharmacological interventions, have been suggested to be associated with an increased risk of AF.

This sub-group analysis evaluated the long-term efficacy and safety of evinacumab, an angiopoietin-like 3 inhibitor, in adolescent and adult Japanese patients with homozygous familial hypercholesterolemia (HoFH) who were enrolled in the open-label, single-arm, extension of the Phase 3 ELIPSE HoFH pivotal trial. Patients aged ≥ 12 years with HoFH on stable lipid-lowering therapies received intravenous evinacumab 15 mg/kg every 4 weeks and weekly/biweekly lipoprotein apheresis. Final results are reported. Eleven patients were enrolled and received at least 1 dose of evinacumab at baseline, including 9 adults who participated in the evinacumab pivotal study (evinacumab-continue) and 2 newly enrolled adolescent patients (evinacumab-naïve). Mean (standard error) percent decrease in LDL-C from baseline to Week 24 was 42.9% (7.4) in the overall cohort (n = 9) and 37.1% (7.9) in the evinacumab-continue group (n = 7), with reductions in LDL-C observed as early as Week 8 and persisting through Week 168. Evinacumab treatment was also associated with reductions in other lipid parameters measured, including apolipoproteins A1 and B, non-high density lipoprotein cholesterol (HDL-C), HDL-C, total cholesterol, fasting triglycerides, and lipoprotein(a). Similar lipid-lowering results were seen in the evinacumab-naïve group (n = 2). Treatment-emergent adverse events (TEAEs) occurred in all 11 patients. Serious TEAEs occurred in 3 (27.3%) patients, and none were treatment related. Evinacumab treatment resulted in sustained reductions in LDL-C and other lipid parameters in Japanese patients ≥ 12 years with HoFH, including those undergoing lipoprotein apheresis, and was generally well tolerated.

Adenosine triphosphate (ATP) is well known as the major intracellular energy carrier. It also functions as a potent extracellular signaling molecule. In atherosclerosis, both intracellular and extracellular ATP have been increasingly implicated in the disease pathophysiology. The intracellular ATP levels are closely regulated by the balance among the metabolic pathways, including glycolysis and oxidative phosphorylation (OXPHOS), and they play diverse and cell type-specific roles in atherosclerotic plaques. In contrast, the extracellular ATP released from these cells binds to purinergic P2 receptors and activates downstream signaling cascades primarily in an autocrine or paracrine manner, thereby regulating various cellular functions during disease progression. These two contrasting ATP-associated pathways are involved in a wide range of atherosclerosis-related processes including inflammation, vascular tone and barrier function, cell proliferation, migration and differentiation, and calcification, some of which are shared or highly context-dependent. This review summarizes the fundamental aspects of ATP biology, discusses the current approaches for measuring ATP concentrations in atherosclerotic plaques, and highlights the functions of intra- and extracellular ATP in major atherosclerosis-related cell types, including endothelial cells, macrophages and vascular smooth muscle cells (VSMCs), to clarify these intricately intertwined pathophysiological processes. Finally, this overview provides insights into the current challenges in ATP biology research and outlines therapeutic opportunities targeting intra- or extracellular ATP in atherosclerotic disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent worldwide. Conventional fibrates effectively lower triglycerides but may elevate liver enzymes and creatinine, limiting long-term use. Pemafibrate, a selective PPARα modulator (SPPARMα), offers potent triglyceride reduction with favorable hepatic and renal safety. This study evaluated the effects of switching from conventional fibrates to pemafibrate on lipid profiles, liver enzyme, fibrosis indices(Fibrosis-4 index) with particular emphasis on renal safety in clinical practice. We retrospectively analyzed 144 patients with dyslipidemia, including those with MASLD or chronic kidney disease, who were switched from bezafibrate 200mg (N = 24) or 400mg (N = 30), or fenofibrate 80mg (N = 51) or 160mg (N = 39), to pemafibrate (0.2mg/day). Laboratory parameters were assessed at baseline and 6 months post-switch. Triglycerides decreased significantly, particularly in the bezafibrate 200 mg and fenofibrate 80 mg groups, while other lipid profiles remained stable. Serum alanine aminotransferase decreased significantly with bezafibrate 200mg (29±27 to 17±13U/L, p＜0.05) and fenofibrate 80mg (26±18 to 20±10 U/L, p＜0.05), whereas treatment with bezafibrate (400mg) and fenofibrate (160mg) showed a trend toward reduction. The glutamyl transferase showed a similar trend. The Fibrosis-4 index showed reductions across all groups, reaching statistical significance in bezafibrate200mg (1.51±0.63→1.36±0.47, p = 0.02) and fenofibrate 80mg (1.17±0.37→1.07±0.33, p = 0.001). Renal function remained stable across all groups, with no clinically significant deterioration in estimated glomerular filtration rate, supporting the renal safety of pemafibrate. Switching from conventional fibrates to pemafibrate improved triglyceride levels, liver enzymes, and fibrosis indices in patients with MASLD, while maintaining a favorable renal safety profile.

Waist circumference (WC) is widely used as a marker of central obesity in the diagnosis of metabolic syndrome (MetS) and it plays an important role in cardiovascular disease (CVD) risk screening. In Japan, the MetS diagnostic criteria established in 2005 require abdominal obesity as a mandatory component, with WC cutoff values of 85 cm for men and 90 cm for women. These criteria are also applied in the national Specific Health Checkup and Specific Health Guidance programs to identify individuals at a high risk of CVD. However, the scientific basis and clinical implications of these thresholds remain controversial.This review summarizes the epidemiological evidence on WC cutoff values in the Japanese population and their relevance to CVD risk. A literature search of PubMed and Ichushi-Web identified studies examining WC thresholds in relation to visceral fat accumulation, clustering of cardiometabolic risk factors, and incident CVD. The evidence was organized into four themes: (1) WC cutoffs based on visceral fat area, (2) prediction of cardiometabolic risk factor clustering, (3) the association between WC and incident CVD, and (4) associations between MetS definitions and CVD risk.Available evidence suggests that the WC thresholds corresponding to visceral fat accumulation and cardiometabolic risk clustering are generally lower than the current Japanese criterion for women. Prospective studies examining WC alone have reported inconsistent associations with incident CVD, particularly among women. Overall, the evidence suggests that CVD risk stratification frameworks requiring abdominal obesity based on WC thresholds may have limitations. Future screening strategies in Japan may benefit from greater emphasis on clustering and the overall burden of cardiometabolic risk factors.

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.

Liver dysfunction may affect chronic limb-threatening ischemia (CLTI) outcomes, but its impact on survival and lipid profiles is unclear. To assess the association of liver dysfunction using the Albumin-Bilirubin (ALBI) score, with survival, liver fibrosis, and cholesterol in CLTI patients. We retrospectively analyzed single-center data of CLTI patients with below-knee lesions between 2008-2018. ALBI scores were calculated from serum albumin and total bilirubin. Optimal cutoff for 3-year overall survival (OS) was determined by receiver operating characteristic (ROC) analysis, dividing patients into high and low ALBI groups. Patient characteristics, cholesterol, and liver fibrosis (FIB-4 index) were compared, with primary endpoint being 3-year OS. Among 263 patients, high ALBI patients (≥ -2.36, n = 135) were older (80 vs. 72 years), included fewer males (55% vs. 71%), had higher prevalence of bed-ridden status (44% vs. 2%) and heart failure (25% vs. 8%; all P＜0.01). They had higher FIB-4 index (2.49 vs. 1.76), lower total cholesterol (147 vs. 173 mg/dL), HDL-C (43 vs. 56 mg/dL), LDL-C (83 vs. 108 mg/dL), and higher LDL-C/HDL-C ratio (2.57 vs. 2.20; P＜0.01). Three-year OS was lower in high ALBI group (36% vs. 57%; P＜0.01) and remained lower after propensity matching (43% vs. 55%; P = 0.04). Multivariate analysis identified low body mass index (BMI), heart failure, high ALBI score and high FIB-4 index (≥ 1.3) and low LDL-C (＜100 mg/dL) as predictors of poor OS. High ALBI scores in CLTI patients links to liver fibrosis, disturbed lipid profiles, and reduced survival.

Familial chylomicronemia syndrome (FCS) is a rare disorder characterized by the accumulation of chylomicrons in the circulation due to genetic defects or autoantibodies affecting lipoprotein lipase (LPL), the key enzyme responsible for the metabolism of chylomicrons and very-low-density lipoproteins (VLDL), or its associated proteins, including apolipoprotein (apo) C-II, apoA-V, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), and lipase maturation factor 1 (LMF1). This condition is associated with markedly elevated serum triglyceride (TG) levels and, in severe cases, recurrent episodes of pancreatitis and eruptive xanthomas. Among these etiologies, genetic deficiency of GPIHBP1 is exceedingly rare. We aimed to clarify the clinical and genetic basis and treatment strategies of a patient with GPIHBP1 deficiency. A 47-year-old woman with a childhood diagnosis of FCS presented with severe epigastric pain and was admitted to Rinku General Medical Center for emergency management of acute pancreatitis secondary to severe chylomicronemia. She had a history of severe hypertriglyceridemia complicated by pancreatitis during her first pregnancy and extreme hypertriglyceridemia exceeding 6,000 mg/dL during her second pregnancy without the development of pancreatitis. DNA sequence analysis was performed as a clinical diagnostic test and outsourced to KUBIX Inc. (Hakusan, Ishikawa, Japan). Laboratory evaluation revealed marked hypertriglyceridemia (1,262 mg/dL) with a type V hyperlipoproteinemia pattern. Serum preheparin LPL mass was markedly reduced, and circulating GPIHBP1 was undetectable. Genetic analysis identified a novel homozygous frameshift mutation in the GPIHBP1 gene (NM_178172.4:c.20del [p.Val7AlafsTer73]), which has not been previously reported in public databases. No pathogenic variants were detected in other LPL-related genes. Acute pancreatitis improved rapidly with fasting and intravenous fluid therapy. Strict dietary fat restriction, followed by the addition of the selective PPARα modulator pemafibrate, successfully maintained TG levels below 500 mg/dL during follow-up. We report an extremely rare case of FCS caused by a novel homozygous mutation in the GPIHBP1 gene, in which pregnancy served as a major trigger for severe hypertriglyceridemia. Early diagnosis and strict lipid control are essential to prevent recurrent pancreatitis in patients with GPIHBP1 deficiency.

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. 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. 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. MBG and CV are independent predictors of mortality in critically ill patients with PE, suggesting that optimal glycemic control may benefit this population.

Children with elevated low-density lipoprotein cholesterol (LDL-C) levels, suspected familial hypercholesterolemia (FH), and elevated lipoprotein(a) (Lp(a)) levels are considered to have a particularly high lifetime risk of atherosclerotic cardiovascular disease. Nevertheless, the distribution of Lp(a) levels among children with elevated LDL-C levels remains unclear. This study aimed to clarify the distribution of Lp(a) levels and their association with pathogenic FH variants in children with elevated LDL-C levels. A total of 97 children with LDL-C levels ≥ 140 mg/dL suspected of having FH who underwent genetic testing at Kagawa University Hospital between January 2018 and May 2025 were analyzed. Lp(a) levels were measured using the Lp(a) Latex "DAIICHI" assay and converted from mass units (mg/dL) to molar units (nmol/L) using the calibration-based conversion formula. Clinical and lipid parameters were compared according to Lp(a) levels (≥ 105 vs. ＜105 nmol/L) and the presence of pathogenic FH variants. Lp(a) levels exhibited a right-skewed distribution, with a median of 57.6 nmol/L (15.9 mg/dL) and an interquartile range of 24.0-93.4 nmol/L (7.0-25.4 mg/dL), and 21.6% of children had levels ≥ 105 nmol/L. Pathogenic FH variants were identified in 44 children. No significant differences were observed in either clinical or lipid parameters according to Lp(a) levels (≥ 105 vs. ＜105 nmol/L) or the presence of pathogenic FH variants (P = 0.672). Regardless of the presence of pathogenic FH variants, approximately 20% of the children had Lp(a) levels ≥ 105 nmol/L. These findings emphasize the importance of early lipid management and suggest that Lp(a) measurement may contribute to future cardiovascular risk stratification.

Reducing low-density lipoprotein cholesterol (LDL-C) levels is crucial for preventing atherosclerotic cardiovascular disease (ASCVD). Recommended lipid-lowering therapy (LLT) includes both oral (e.g., statins) and injectable agents. However, patient awareness of LDL-C management and adherence to it remain uncertain. This cross-sectional study surveyed 415 Japanese patients with ASCVD using a web-based platform. The participants reported their understanding of LDL-C target values and the effects of LLT. Medication adherence was evaluated using the Extent of Nonadherence scale, and a binomial logistic regression analysis was performed to identify the factors associated with nonadherence. Approximately 58.1%-60.2% of the participants reported confidence in knowing their correct lipid target values and managing dyslipidemia appropriately. However, only 22.2% reported LDL-C targets of ＜50 or ＜70 mg/dL, and 43.4% believed their targets to be ＜50, ＜70, or ＜100 mg/dL. In contrast, 56.7% either reported LDL-C targets of ＜120, ＜140, or ＜160 mg/dL or did not know their targets. Regarding LLT, 65.8% were unaware that extreme lowering of LDL-C levels with LLT had no disadvantages, and 74.2% were unaware that injectable LLTs were available. Overall, 39.0% of the participants were nonadherent. Higher out-of-pocket costs (≥ 3,001 yen; adjusted odds ratio [OR]: 1.83, p = 0.024) and experience with self-injections (adjusted odds ratio: 2.34, p = 0.027) were significantly associated with nonadherence. Our findings highlight a considerable gap in patient knowledge and adherence to dyslipidemia management strategies. Interventions that promote patient education and shared decision-making are essential for improving adherence and achieving optimal LDL-C targets.

This study aimed to develop a model to simultaneously assess the genetic and epigenetic contributions to plasma lipids. 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. 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 PRSLDL-C (plus rare variants) and MRSLDL-C showed a higher correlation between the predicted and measured values (r = 0.272, P = 3.7×10-12) than those using PRSLDL-C alone (r = 0.106, P = 0.008) and PRSLDL-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. 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.

Intracranial arterial stenosis is a major cause of ischemic stroke worldwide, particularly in the Asian population. Although traditionally regarded as a manifestation of atherosclerotic disease, increasing evidence suggests that non-atherosclerotic arteriopathies also contribute substantially to its pathogenesis. These conditions, including arterial dissection, inflammatory vasculopathies, and moyamoya disease, often share overlapping clinical and imaging features, thus making precise differentiation challenging in routine practice.This phenotypic overlap highlights the heterogeneity of intracranial arterial stenosis and suggests that it may represent a spectrum of vascular disorders, rather than a single disease entity. Recent studies have highlighted the role of genetic susceptibility as a factor underlying this diversity. Among these, RNF213, originally identified as a susceptibility gene for moyamoya disease, has been implicated in a subset of intracranial arterial diseases beyond the classical diagnostic categories. These observations have led to the concept of RNF213-related vasculopathy, which extends beyond intracranial circulation and provides a framework for understanding diverse vascular phenotypes within a broader context. In addition, a two-hit model has been proposed in which genetic susceptibility interacts with environmental and acquired factors to influence the disease onset and progression.This narrative review summarizes the current understanding of intracranial arterial stenosis beyond the conventional atherosclerosis-centered paradigm and discusses emerging concepts integrating vascular heterogeneity, genetic susceptibility, and environmental modifiers with potential implications for disease classification and individualized therapeutic strategies.

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. 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. 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. 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.

The quantitative flow ratio (QFR)-derived pullback pressure gradient (PPG) characterizes the pathophysiological patterns of coronary atherosclerosis. This study investigated the plaque morphologies associated with these disease patterns. This study used the institutional QFR-PPG database registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000056097). Patients who underwent elective stenting with pre-procedural optical coherence tomography and near-infrared spectroscopy intravascular ultrasound were included. Offline QFR and QFR-PPG analyses were performed, and the lesions were stratified into tertiles. A total of 168 de novo lesions were analyzed in this study. The QFR tertiles were defined as severe (＜0.61), moderate (0.61-0.71), and mild (＞0.71); the QFR-PPG tertiles were defined as diffuse (＜0.66), intermediate (0.66-0.79), and focal (＞0.79). The Severe QFR tertiles exhibited a smaller minimum lumen area (MLA) and higher frequencies of thin-cap fibroatheroma (TCFA) and layered plaque. In contrast, across the QFR-PPG tertiles, MLA and TCFA frequencies were similar, whereas the diffuse group exhibited more layered plaques and larger calcium angles. The maximum lipid-core burden index did not vary across the QFR-PPG tertiles. A multivariable analysis identified MLA and TCFA as independent predictors of QFR, while layered plaque and calcium angle independently predicted QFR-PPG. However, the lipidic features were not independent predictors of QFR. Multimodal intracoronary imaging demonstrated that QFR reflects luminal narrowing and the features of vulnerable plaques. Conversely, QFR-PPG reflects disease diffuseness, characterized by layered plaques and calcium burden rather than lipid-rich features.

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. 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. 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). Reocclusion after PCB therapy was strongly associated with subsequent re-recurrence, including re-reocclusion, regardless of the retreatment strategy.