Intracranial branch atheromatous disease (BAD) is a pathological condition characterized by the occlusion of a relatively large perforating branch (700–800 µm) near the orifice of a parent artery due to atherosclerotic plaque-based thrombus (microatheroma). BAD is refractory to treatment and follows a course of progressive exacerbation, especially motor paralysis. Uniform treatment for common atherothrombotic cerebral infarction or lacunar infarction does not prevent the progressive exacerbation of BAD, and consequently affects functional prognosis. To date, various combinations of treatments have been investigated and proposed to attenuate the worsening symptoms of BAD. However, no therapy with established efficacy is yet available for BAD. Since it is the most difficult condition to treat in the area of cerebral infarction, the establishment of optimal treatment methods for BAD is keenly awaited. This review presents an overview of the acute treatments available for BAD and discusses the prospects for optimal treatment.

The Hisayama Study is an ongoing epidemiological study of stroke, coronary artery disease (CAD), and other noncommunicable diseases in a general Japanese population established in 1961. According to the longitudinal data from the Hisayama Study, average levels of systolic blood pressure among hypertensive individuals have decreased with time since 1961. In contrast, the prevalence of metabolic risk factors such as obesity, hypercholesterolemia, and glucose intolerance has increased with time. The incidence rates of ischemic stroke in this population have declined significantly as a result of improvement in hypertension management, but the proportion of atherothrombotic brain infarction (ATBI) and embolic stroke among the total ischemic stroke cases have increased probably due to the increased prevalence of metabolic risk factors and the increased number of patients with atrial fibrillation (AF) with super-aging population. Therefore, a strategy to reduce the risks of ATBI and embolic stroke by comprehensive management of their risk factors is necessary.

In this review, we first show the secular trends in the incidence of stroke and the prevalence of its risk factors using the data from the Hisayama Study. Then, the studies for the association of traditional risk factors with stroke development in the Hisayama Study are introduced. Finally, we developed risk prediction models to estimate the absolute risk of atherosclerotic cardiovascular disease (ASCVD; including ATBI and CAD) and AF, that may be used for the stratification of future risk of ATBI and AF-related stroke in clinical practice or health examination.

Advances in immunosuppressive therapy; posttransplant management of allograft rejection; and measures against infectious diseases, cardiovascular diseases, and malignancy dramatically improved graft and patient survival after kidney transplantation (KT). Among them, kidney allograft biopsy is an important tool and the gold standard for the diagnosis of various kidney allograft injuries, including allograft rejection, virus-induced nephropathy, calcineurin inhibitor toxicity, and posttransplant glomerular diseases. The Banff Conference on Allograft Pathology has contributed to establishing the diagnostic criteria for kidney allograft rejection and polyomavirus-associated nephropathy that are used as a common standard worldwide. In addition to the for-cause biopsy, many transplant centers perform protocol biopsies in the early and late posttransplant periods to detect and treat allograft injury earlier. Preimplantation biopsy in deceased-donor KT has also been performed, especially in the marginal donor, and attempts have been made to predict the prognosis in combination with clinical information and the renal resistance of hypothermic machine perfusion. Regarding the preimplantation biopsy from a living kidney donor, it can provide useful information on aging and/or early changes in lifestyle diseases, such as glomerulosclerosis, tubulointerstitial changes, and arterial and arteriolar sclerosis, and be used as a reference for the subsequent management of living donors. In this review, morphologic features of important kidney allograft pathology, such as allograft rejection and polyomavirus-associated nephropathy, according to the latest Banff classification and additional information derived from protocol biopsy, and future perspectives with recently developed technologies are discussed.

Aim: Risk of cardiovascular disease is increased in patients with diabetes mellitus (DM). Cholesterol metabolism (hepatic synthesis and intestinal absorption) is known to be associated with cardiovascular risk. Next, we examined the association of DM with cholesterol absorption/synthesis.

Methods: The CACHE Consortium, which is comprised of 13 research groups in Japan possessing data of lathosterol (Latho, synthesis marker) and campesterol (Campe, absorption marker) measured by gas chromatography, compiled the clinical data using the REDCap system. Among the 3597 records, data from 2944 individuals were used for several analyses including this study.

Results: This study analyzed data from eligible 2182 individuals including 830 patients with DM; 42.2% were female, median age was 59 years, and median HbA1c of patients with DM was 7.0%. There was no difference in Latho between DM and non-DM individuals. Campe and Campe/Latho ratio were significantly lower in DM individuals than in non-DM individuals. When the associations of glycemic control markers with these markers were analyzed with multivariable-adjusted regression model using restricted cubic splines, Campe and Campe/Latho ratio showed inverse associations with glucose levels and HbA1c. However, Latho showed an inverted U-shaped association with plasma glucose, whereas Latho showed a U-shaped association with HbA1c. These associations remained even after excluding statin and/or ezetimibe users.

Conclusion: We demonstrated that DM and hyperglycemia were independent factors for lower cholesterol absorption marker levels regardless of statin/ezetimibe use.

Aims: Aortic diseases (ADs), including aortic dissection, aortic aneurysm, and aortic rupture, are fatal, with extremely high mortality rates. A body shape index (ABSI), an anthropometric measure calculated as waist circumference adjusted by height and weight, improves the predictive capacity for mortality. However, whether ABSI is a risk factor for AD-related mortality in the general population remains unclear.

Methods: We used a nationwide database of 630,842 individuals (aged 40–75 years) who participated in the annual “Specific Health Check and Guidance in Japan” between 2008 and 2010.

Results: During the follow-up period of 3.8 years, 159 AD-related deaths occurred, including 105 aortic dissections and 54 aortic aneurysm ruptures. The subjects were divided into three groups based on ABSI tertiles. Kaplan–Meier analysis demonstrated that the 3^rd tertile (with the highest ABSI) had the greatest risk among the three groups. Multivariate Cox proportional hazard regression analysis demonstrated that ABSI was significantly associated with AD-related death after adjusting for confounding risk factors. Neither waist circumference nor body mass index consistently predicted AD-related death in the multivariate model. The prediction capacity was significantly improved by the addition of ABSI to the confounding risk factors.

Conclusions: We demonstrated for the first time that ABSI, a surrogate marker for abdominal visceral fat tissue, was associated with AD-related deaths in the general population, suggesting the importance of central adiposity in the development of AD.

Aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising new target for reducing low-density lipoprotein cholesterol (LDL-C) and cardiovascular events in high-risk patients. However, the influence of circulating PCSK9 concentration on atherosclerotic plaque formation in the general population remains unknown. We assessed the relationship between serum PCSK9 concentration and coronary artery calcium (CAC) prevalence in the general population.

Methods: Community-dwelling Japanese men (n=622) aged 46–82 years without a history of cardiovascular disease and lipid-lowering medications were included. Serum PCSK9 concentration and CAC score were measured using the Agatston method, and the multivariable analysis was used to assess their association. CAC was defined as an Agatston score of ＞10. We conducted further analysis stratified by age (＜60, 60–69, and ≥ 70 years).

Results: The average age, LDL-C, and median serum PCSK9 concentration were 68 years, 122 mg/dL, and 240 ng/mL, respectively. After multivariable adjustment for traditional cardiovascular risk factors, no significant association was observed between serum PCSK9 concentration and CAC prevalence (adjusted relative risk [aRR] 1.05, 95% confidence interval [CI] 0.97–1.13). With age stratification, serum PCSK9 concentration was significantly associated with CAC prevalence in men aged ＜60 years (aRR 1.38, 95% CI 1.01–1.88) but not in men aged 60–69 years (aRR 0.96, 95% CI 0.85–1.10) or ≥ 70 years (aRR 1.08, 95% CI 0.99–1.19).

Conclusions: A higher serum PCSK9 concentration was associated with a higher CAC prevalence in men aged ＜60 years, which was independent of traditional cardiovascular risk factors.

Aims: This study aimed to examine the relationship between physical performance and peripheral artery disease (PAD) in different age groups of Chinese older adults.

Methods: We enrolled 1357 relatively healthy ≥ 65 years old participants of Chinese ethnicity. We classified the participants into two age categories, the pre-old group (65–74 years, n=968) and the old group (≥ 75 years, n=389). We assessed the cross-sectional association of the ankle–brachial index (ABI), which is used for the classification of patients with PAD (ABI ≤ 0.9). Physical performance mainly focused on muscle strength, mobility, and balance, which were measured via hand grip, 4 m walking speed, and the Timed Up and Go Test.

Results: A total of 125 (9.2%) patients met the diagnostic criteria and were defined as having PAD. After multivariate adjustment, we found that grip strength and 4 m walking speed were correlated negatively with PAD (odds ratio (OR)=0.953, 95% confidence interval (CI)=0.919–0.989; OR=0.296, 95% CI=0.093–0.945) in pre-old participants, whereas balance (OR=1.058, 95% CI=1.007–1.112) was correlated positively with PAD only in older participants.

Conclusion: Our study further confirmed the association between physical performance and PAD in community-dwelling older Chinese adults. Muscle strength and mobility correlated negatively with PAD, and balance was positively associated with PAD in older participants. These findings might help with better early screening and management of PAD.

Aims: Renal dysfunction is an independent predictor of adverse outcomes in patients with coronary artery disease (CAD). However, the prognostic impact of mid-term changes in renal dysfunction status remains unclear. This study aimed to investigate the impact of mid-term changes in renal dysfunction status on long-term clinical outcomes in CAD patients who underwent percutaneous coronary intervention (PCI).

Methods: We enrolled 382 consecutive patients with CAD who underwent PCI. Renal dysfunction was defined as a reduced estimated glomerular filtration rate (eGFR) of ＜60 mL/min/1.73m². Renal dysfunction status was evaluated at baseline and 1-year follow-up after PCI. We divided the study population into three groups: persistent renal dysfunction, new-onset renal dysfunction, and no or improved renal dysfunction at 1-year follow-up as compared with on baseline. The endpoints of this study were composite events, including all-cause death, acute coronary syndrome, target vessel revascularization, and stroke.

Results: At baseline, renal dysfunction was observed in 77 patients (20%). At the 1-year follow-up, new-onset renal dysfunction was observed in 46 patients (12%), and 59 patients (15%) had persistent renal dysfunction. Kaplan-Meier analysis revealed a significantly higher event rate in patients with persistent renal dysfunction and new-onset renal dysfunction (log-rank test, P=0.0003). In the multivariate Cox proportional hazards analysis, persistent renal dysfunction and new-onset renal dysfunction were independently associated with composite events after adjusting for confounding factors (adjusted hazard ratios 4.08 and 2.64, 95% confidence intervals 1.72-9.57 and 1.03-6.31, P=0.0016, P=0.0045, respectively).

Conclusion: Persistent and new-onset renal dysfunction at 1-year follow-up were associated with unfavorable outcomes in patients with CAD who underwent PCI.

Aim: We aimed to investigate the associations of serum alkaline phosphatase (ALP) levels with incident cardiovascular disease (CVD), coronary heart disease (CHD), and stroke, as well as their subtypes, among men and women in a prospective cohort study.

Methods: A total of 11,408 men and 14,981 women were included to evaluate the associations between ALP levels and incident CVD. Participants were divided into four groups according to the quartiles of serum ALP levels in men and women separately. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: During an average follow-up of 7.3 years, 7,015 incident CVDs (5,561 CHDs and 1,454 strokes) were documented. After adjustments for age, body mass index, smoking status, drinking status, diabetes, hyperlipidemia, hypertension, physical activity, aspirin usage, anticoagulants usage, menopausal status (women only), family history of CVD, estimated glomerular filtration rate, white blood cell counts, and admission batch and comparing the lowest quartile of ALP, the adjusted HRs (95% CIs) of participants in the highest quartile were 1.22 (1.11–1.34) for CVD, 1.14 (1.02–1.28) for CHD, 1.43 (1.18–1.73) for stroke, 1.31 (1.09–1.57) for acute coronary syndrome (ACS), 1.37 (1.11–1.70) for ischemic stroke, and 1.75 (1.10–2.79) for hemorrhagic stroke in men and 1.12 (1.01–1.23) for CVD, 1.10 (0.99–1.23) for CHD, 1.18 (0.92–1.51) for stroke, 1.23 (1.03–1.47) for ACS, 1.10 (0.83–1.45) for ischemic stroke, and 1.54 (0.90–2.65) for hemorrhagic stroke in women. The ALP–CVD associations remained significant even within the normal ranges of ALP levels (40–150 U/L). Moreover, linear dose–response relationships were found between ALP levels and incident CVD.

Conclusions: Higher ALP levels, even within the normal range, were significantly associated with increased risks of CVD, in a dose-dependent manner. These findings suggested that regular monitoring of ALP levels may help in improving the early identification of the population at higher CVD risk.

Aims: Oral health is associated with atherosclerotic cardiovascular disease (ACVD). We previously identified the salivary microbiota characteristics of patients with ACVD. However, whether salivary microbiota is characteristic under impaired vascular endothelial function before ACVD onset remains unclear. Therefore, we aimed to evaluate the characteristics of salivary microbiota associated with peripheral microvascular endothelial dysfunction.

Methods: We collected saliva samples from 172 community-dwelling elderly individuals without a history of ACVD and performed 16S rRNA metagenomic analysis. We assessed the peripheral microvascular endothelial function using reactive hyperemia index (RHI) and compared the salivary microbiota in the groups with normal (RHI ≥ 2.10), borderline, and abnormal (RHI ＜1.67) peripheral endothelial function. Furthermore, we applied machine learning techniques to evaluate whether salivary microbiota could discriminate between individuals with normal and abnormal endothelial function.

Results: The number of operational taxonomic units (OTUs) was higher in the abnormal group than in the normal group (p=0.037), and differences were found in the overall salivary microbiota structure (unweighted UniFrac distances, p=0.038). The linear discriminant analysis (LDA) effect size (LEfSe) algorithm revealed several significantly differentially abundant bacterial genera between the two groups. An Extra Trees classifier model was built to discriminate between groups with normal and abnormal vascular endothelial function based on the microbial composition at the genus level (AUC=0.810).

Conclusions: The salivary microbiota in individuals with endothelial dysfunction was distinct from that in individuals with normal endothelial function, indicating that the salivary microbiota may be related to endothelial function.