Recombinant tissue plasminogen activator (rt-PA), specifically alteplase, remains the standard treatment for acute cerebral infarction across all stroke subtypes. However, per recent randomized controlled trials (RCTs), individuals with mild cerebral infarction, medical management alone without rt-PA can yield functional outcomes comparable to those achieved with thrombolytic therapy. This has sparked ongoing debate regarding the necessity of rt-PA administration in cases of mild stroke. Nonetheless, certain individuals with mild cerebral infarction derive clear benefits from rt-PA therapy. Therefore, an individualized treatment approach should be prioritized over a uniform thrombolytic strategy in these cases. This review examines the therapeutic efficacy and limitations of rt-PA therapy for mild cerebral infarction, integrating evidence from prior clinical studies with the authors’ perspectives.

Aims: The Pemafibrate for Prevention of Atherosclerotic Diseases in Stroke (PPAR Stroke) study aimed to assess the effects of pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, on the progression of cerebrovascular atherosclerosis in patients with stroke and hypertriglyceridemia.

Methods: Ninety-nine patients (mean age, 65.6 years; male, 74.7%) with hypertriglyceridemia and a history of stroke or transient ischemic attack of non-cardioembolic origin were included in this prospective single-arm study. Hypertriglyceridemia was defined as a fasting serum triglyceride (TG) level ≥ 150 mg/dL. All patients were treated with pemafibrate (0.2 mg or 0.1 mg/day) for 2 years. The primary outcome was change in carotid intima-media thickness (IMT) from baseline at 2 years, as assessed using carotid ultrasonography. The secondary outcomes were changes in blood biomarker levels and progression of intracranial artery stenosis on magnetic resonance angiography.

Results: The mean TG level significantly decreased from 269 mg/dL at baseline to 139 mg/dL at 2 years (P＜0.001) and high-density lipoprotein cholesterol level increased from 49 to 54 mg/dL (P＜0.001), whereas low-density lipoprotein cholesterol level remained unchanged. Significant reductions in high-sensitivity C-reactive protein and interleukin-6 levels were also observed (P=0.003 and P=0.002, respectively). With regard to mean IMT in the internal carotid arteries, the difference was significant for the left side (1.59 mm at baseline vs. 1.52 mm at 2 years; P=0.009) and borderline significant for the right side (1.32 mm at baseline vs. 1.28 mm at 2 years; P=0.053). Among the 48 stenotic lesions in the intracranial arteries, regression and progression was observed in 9 (18.8%) and 4 (8.3%) cases, respectively.

Conclusions: Pemafibrate was observed to have TG-lowering and anti-inflammatory effects and could attenuate atherosclerosis progression in the intra- and extracranial arteries of patients with stroke and hypertriglyceridemia.

Aims: Direct oral anticoagulants (DOACs) are used to treat venous thromboembolism (VTE). However, their impact on thrombus regression and the clinical outcomes after 2-week post-therapy computed tomography (CT) monitoring remains unexplored. This study aimed to elucidate the characteristics of patients with VTE treated with individual DOACs, assess the incidence of clinical events, and evaluate their impact on pulmonary artery thrombus regression.

Methods: This prospective, multicenter study in Japan included 175 patients with VTE treated with rivaroxaban, apixaban, and edoxaban. We employed 2-week post-therapy CT monitoring to compare thrombus regression rates, patient backgrounds, and clinical outcomes.

Results: Rivaroxaban users had higher body weight, hemoglobin levels, pulmonary embolism prevalence, and larger thrombus volume, but a lower prevalence of active cancer than apixaban and edoxaban users. The median thrombus regression rate after approximately 2 weeks of treatment was 89.9%, with no significant differences between the DOACs. During the 13.5-month follow-up, the recurrence or aggravation of symptomatic VTE did not differ significantly among the groups; however, the apixaban group exhibited a slightly higher major bleeding rate. Among the 95 patients receiving rivaroxaban intensive therapy, 34 (35.8%) experienced early termination due to sufficient thrombus resolution within 2 weeks compared to the standard duration group. This did not increase VTE recurrence, aggravation, or mortality.

Conclusions: Substantial thrombus regression and a low incidence of VTE and bleeding support the effectiveness of DOACs. Terminating intensive therapy in one-third of the rivaroxaban group after 2-week CT monitoring did not increase the occurrence of VTE events, thereby suggesting suitability for patients at a high risk of bleeding.

Aims: The impact of a reduced renal function on the risk of venous thromboembolism (VTE) remains controversial. The association between VTE and the renal function, as well as genetic susceptibility, requires further clarification in a large population.

Methods: This study included 358,723 participants with non-renal failure from the UK Biobank. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of VTE incidence associated with the renal function at baseline were estimated using the Cox proportional hazards model. In addition, the relationship between the renal function and cumulative risk of VTE was visualized using Kaplan-Meier curves and restricted cubic spline (RCS). Furthermore, this study investigated the combined effects and interactions between the renal function and genetic susceptibility on the risk of VTE onset.

Results: Renal function biomarkers in the highest quartile levels for urine creatinine, serum creatinine, urea, urate, cystatin C, and urine microalbumin and lowest quartile levels for the estimated glomerular filtration rate (eGFR) were associated with an elevated risk of VTE onset. For the joint analysis with genetic susceptibility, participants with both high levels of renal function biomarkers (a low eGFR) and high genetic risk had the highest risk of developing VTE, with an HR (95% CI) of 2.83 (2.46-3.26) for urine creatinine, 2.72 (2.37-3.13) for serum creatinine, 2.49 (2.18-2.84) for urea, and 2.63 (2.26-3.05) for urate, 3.52 (3.01-4.13) for cystatin C, 2.90 (2.33-3.60) for urine microalbumin, and 3.37 (2.86-3.98) for the eGFR.

Conclusions: A decreased renal function increases the risk of VTE and genetic susceptibility has a positive additive effect on VTE risk. This suggests that biomarkers of the renal function may be used as predictors of VTE, especially in populations with genetic susceptibility to VTE.

Aims: There is a lack of evidence regarding the sex-specific impact of arterial stiffness on the incidence of chronic kidney disease (CKD). This study assessed the relationship between arterial stiffness based on brachial-ankle pulse wave velocity (baPWV) and incident CKD in men and women.

Methods: Individuals who participated in health checkups and underwent concomitant baPWV measurement between 2006 and 2019 were included. They were free of CKD at baseline. The participants were categorized into 4 groups based on their baPWV values (cm/s) as follows: ＜1,200 cm/s for normal, ≥ 1,200 and ＜1,400 for high normal, ≥ 1,400 and ＜1,800 for borderline, and ≥ 1,800 cm/s. The primary outcome was CKD development (estimated glomerular filtration rate ＜60 mL/min/1.73 m²).

Results: A total of 130,100 participants were enrolled, with a mean age of 40.5±8.2 years old. During the mean of 5.6 years of follow-up, 906 (0.7%) participants developed incident CKD. The cumulative incidence of CKD was 0.3%, 0.5%, 1.4%, and 6.2% in the normal, high normal, borderline, and abnormal groups, respectively. In the multivariable-adjusted model including systolic blood pressure, compared with the normal baPWV group, abnormal baPWV group demonstrated a significantly increased risk of incident CKD in women. However, among men, any other baPWV groups were not associated with a significantly elevated risk of incident CKD.

Conclusions: Increased arterial stiffness, as measured by baPWV, was associated with an increased risk of incident CKD, with notable sex-specific differences. These findings underscore the utility of baPWV for identifying CKD risk in women and offer valuable insights into sex-specific differences in arterial stiffness and CKD development.

Aims: Plasma S-adenosylhomocysteine (SAH) level is positively associated with cardiovascular risk. However, the relationship between plasma SAH levels and the risk of all-cause and cardiovascular mortality remains unknown. This study aimed to explore the relationship between plasma SAH levels and the risk of all-cause and cardiovascular mortality in patients with coronary artery disease (CAD).

Methods: Plasma SAH levels were measured in 1553 patients with CAD. The association between plasma SAH level and the risk of all-cause and cardiovascular mortality was estimated using Cox Proportional hazards regression models.

Results: Relative to participants in the lowest quartile of plasma SAH levels, those in the highest quartile of plasma SAH levels had a higher risk of all-cause death (adjusted Hazard Ratio [HR], 2.15; 95% CI, 1.54-3.01; P＜0.001) and cardiovascular death (adjusted HR, 2.20; 95% CI, 1.49-3.25; P=0.001) in the age- and sex-adjusted model. The results of the multivariable adjusted analysis were similar (all-cause death [adjusted HR, 1.81; 95% CI, 1.27-2.58; P=0.002] and cardiovascular death [adjusted HR, 1.84; 95% CI, 1.21-2.79; P=0.031]). The age- and sex-adjusted HRs for each 1 SD increase in plasma SAH level were 1.30 (95% CI, 1.22-1.38) for all-cause mortality, and 1.34 (95% CI, 1.25-1.43) for cardiovascular mortality, respectively. A 1 SD increase in the SAH level was associated with a 25% higher risk of total death (adjusted HR, 1.25; 95% CI, 1.17-1.34) and a 29% greater risk of cardiovascular death (adjusted HR, 1.29; 95% CI, 1.20-1.39) in multivariable adjusted analysis.

Conclusions: We found that the plasma SAH level is positively correlated with the risk of all-cause and cardiovascular mortality in patients with CAD in both age- and sex-adjusted and multivariable-adjusted models.

Aim: Previous studies have shown that higher educational levels are associated with slower progression of arterial stiffness; however, evidence from Asian countries is lacking. We aimed to examine the association between educational level and arterial stiffness measured using the cardio-ankle vascular index (CAVI) over time in a sample of Japanese men and women.

Methods: A total of 1381 participants (453 men and 928 women) were included in the present study. Arterial stiffness was measured using the CAVI at baseline (2009–2012) and 5 years later (2014–2018). The educational level was divided into two groups (junior or senior high school vs. junior college, professional school, college, or higher) based on a self-administered questionnaire. A mixed-effects model was used to analyze the association between education and the CAVI at baseline and its change over 5 years. The participants were stratified by sex and age (＜65 vs. ≥ 65 years).

Results: The CAVI at baseline did not differ significantly according to education in any of the four subgroups accorded to age and sex. However, among women of ≥ 65 years of age, the change in the CAVI over 5 years was significantly smaller in the higher education group (p=0.04). No such association was found in women of ＜65 years of age or men.

Conclusions: Education is a factor that affects arterial stiffness in women of ≥ 65 years of age. These results suggest that educational level affects arterial stiffness, depending on sex and age.

Aim: Patients with type 2 diabetes mellitus (T2D) are prone to develop vascular calcification. Fetuin-A protects against vascular calcification but it increases insulin resistance. T50 calciprotein crystallization (also called serum calcification propensity) is a novel marker of calcification stress. This study examined whether T2D affects T50 and the potential role of fetuin-A in the relationship between T2D and T50.

Methods: This cross-sectional study included 101 individuals with T2D and 101 individuals without diabetes (controls). T50 and fetuin-A levels were measured using the established nephelometric method and an enzyme-linked immunosorbent assay, respectively.

Results: Although fetuin-A levels were higher in the T2D group, T50 was not significantly different between the T2D and control groups. In multivariable-adjusted analyses of the total population, T50 was not independently associated with the presence of T2D, fasting plasma glucose, or HbA1c, whereas T50 was significantly associated with fetuin-A, phosphate, and calcium levels. The association between T50 and fetuin-A was modified by the presence of T2D. A subgroup analysis revealed that the positive association between T50 and fetuin-A was significant but smaller in the T2D group, and that the associations of T50 with serum phosphate and calcium were more evident in the T2D group. Additional analyses showed that T50/fetuin-A ratio was lower in the T2D group and that T50/fetuin-A ratio was inversely correlated with fasting glucose and HbA1c levels.

Conclusions: T2D itself was not significantly associated with T50 but T2D modified the association between T50 and fetuin-A in favor of developing vascular calcification in T2D.