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.

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.

Aims: The global distribution of lipoprotein(a) [Lp(a)] levels varies due to racial and ethnic differences. However, the clinical relevance of Lp(a) levels in Japanese patients has not been fully explored.

Methods: We investigated the association of Lp(a) levels, the Suita score, and the presence of high-risk plaque (HRP) as well as that of ≥ 50% stenosis, quantitative plaque volume, and the value of coronary artery calcium score in coronary computed tomographic angiography (CCTA), among 272 Japanese patients (mean age: 65 years) in whom serum Lp(a) levels were measured due to suspected coronary artery disease. HRP was defined as positive remodeling and/or low attenuation. Plaque volume was quantified as the percent plaque volume.

Results: HRP was identified in 33 (12.1%) patients. The prevalence of HRP, ≥ 50% stenosis, and percent plaque volume progressively increased with higher Lp (a) levels and Suita scores. In multivariate analyses, Lp(a) and the Suita score independently predicted HRP when assessed as continuous (p = 0.02, p＜0.001, respectively) or categorical variables (p = 0.005, p = 0.007, respectively). Patients in the highest tertile of Lp(a) and classified as high- or intermediate-risk by the Suita score had the highest HRP risk, whereas those in the lower 2 tertiles and low-risk group had the lowest. Incorporating Lp(a) into the Suita score improved the prediction of HRP beyond the Suita score alone (p = 0.005).

Conclusions: The combinatorial value of assessing Lp(a) levels and Suita score may provide useful insight regarding Japanese patients undergoing CCTA for the prediction of HRP.

Aim: Achilles tendon xanthomas are a characteristic feature of familial hypercholesterolemia (FH). Achilles tendon thickness (ATT) has been associated with the severity of coronary artery disease (CAD) in FH. However, its relevance in non-FH remains unclear. Therefore, we assessed the relationship between ATT and CAD severity in patients with acute coronary syndrome (ACS) without FH.

Methods: A total of 194 patients (mean age: 69.1±11.9 years) with ACS without FH were retrospectively investigated and divided into two groups: single-vessel disease (SVD) or multivessel disease (MVD). ATT was measured using ultrasonography (US-ATT) and radiography (Xp-ATT). The association between ATT and CAD severity was evaluated.

Results: Of the total, 107 patients (55.2%) had SVD, and 87 (44.8%) had MVD. Mean US-ATT and Xp-ATT values were 5.0±0.6 mm and 6.4±1.2 mm, respectively. ATT was significantly greater in the MVD group than in the SVD group (US-ATT: 5.2 mm vs. 4.8 mm, p＜0.01; Xp-ATT: 6.6 mm vs. 6.1 mm, p = 0.01) and correlated with the SYNTAX score (US-ATT: r = 0.30, p＜0.01; Xp-ATT: r = 0.19, p = 0.02). Multivariable analysis identified US-ATT as an independent predictor of MVD (odds ratio: 2.71; 95% confidence interval: 1.46–5.01; p＜0.01).

Conclusion: In patients with ACS without FH, ATT was significantly associated with CAD severity. This suggests that ATT, particularly US-ATT, may serve as a practical, non-invasive marker for cardiovascular risk stratification.

Aim: Specific Health Checkups (SHCs) and Specific Health Guidance (SHG) were launched in 2008, but the factors related to their effectiveness have not been clarified. We examined the mean reduction in body weight (BW) and waist circumference (WC) of participants eligible for active support under SHG. Body size was considered, as well as the number of support points given during SHG, which indicates the amount of support they received.

Methods: A dataset of participants (aged 40–64) who were eligible for SHG and had SHC results collected between 2011 and 2012 was analyzed (n = 76,565). The mean changes in BW and WC between 2011 and 2012 were compared among participants based on their participation status (did not participate, dropped out, finished) and the number of support points for those who finished. Participants were also stratified by sex and BMI (kg/m²): normal weight, overweight, and obese.

Results: The mean BW change (95% CI) for those who did not participate and finished SHG was −0.45 kg (−0.47, −0.43) and −1.32 kg (−1.39, −1.25) in men, and −0.66 kg (−0.72, −0.60) and −1.68 kg (−1.87, −1.49) in women, respectively. Higher support points and larger body sizes correlated with greater reductions in BW in men (P＜0.001), but the associations were not significant in women. The reduction in WC was greater in women with normal weight than in obese women.

Conclusion: Sex differences were observed in the association between BW/WC reduction and body size or the amount of support given during SHG.

Aim: We evaluated the association between the dietary fiber intake and the risk of dementia.

Methods: We performed a prospective study within the Japan Public Health Center-based Prospective Study involving 41,467 Japanese individuals aged 45–74 years between 1995-1998. Information regarding food intake was collected using a food frequency questionnaire. Disabling dementia was detected using the National Long-term Insurance System between 2006 and 2016. We calculated the hazard ratios and 95% confidence intervals for disabling dementia according to quartiles of soluble, insoluble, and total fiber intake and dietary fiber intake from food groups (cereals, potatoes and starches, soybeans, vegetables, and fruits) intake by sex.

Results: During an average follow-up period of 9.4, 4910 cases of disabling dementia were documented. The total fiber intake was inversely associated with the risk of disabling dementia in both men and women. The multivariable hazard ratios (95% confidence intervals: CIs) of disabling dementia for the highest versus lowest quartiles of total fiber intake were 0.82 (0.73-0.91) in women (p for trend ＜0.001) and 0.86 (0.74-1.00) in men (p for trend = 0.03). Similar inverse associations between soluble and insoluble fiber intake and the risk of disabling dementia were observed. The dietary fiber intake from cereals, potatoes, starches, vegetables, and fruits, but not soybeans, was inversely associated with the risk of disabling dementia, with some variation by sex.

Conclusions: The dietary intake of total, soluble, and insoluble fiber was associated with a lower risk of disabling dementia. The associations did not vary materially according to the food source of the fiber.

Aims: Physical exercise exerts antiatherosclerotic effects through several mechanisms. One anti-inflammatory effect of exercise is directly exerted on vascular endothelial cells by β-aminoisobutyric acid (BAIBA), which is released from the skeletal muscles during physical activity. The increased expression of estrogen-related receptor α (ERRα) and peroxisome proliferator-activated receptor-gamma co-activator (PGC)-1β also plays a role in these mechanisms. However, the underlying mechanisms remain unknown, and we aimed to explore the effects of PGC-1β on the endothelial function.

Methods: We generated human umbilical vein endothelial cells (HUVECs) with PGC-1β knockdown using siRNA or by inducing the overexpression of PGC-1β using an adenovirus. We then examined the expression of inflammation-related genes induced by tumor necrosis factor α (TNFα) using qRT-PCR and the expression of endothelial nitric oxide synthase (eNOS) and its activation-related proteins using a western blot analysis.

Results: BAIBA treatment suppressed the TNFα-induced expression of inflammation-related molecules in HUVECs. However, these protective effects were diminished following PGC-1β knockdown, which correlated with decreased levels of IκBα protein. Additionally, in PGC-1β knockdown-HUVECs, the total and phosphorylated levels of eNOS decreased along with the levels of active AMP-activated protein kinase (AMPK) and protein kinase B (Akt). Conversely, the overexpression of PGC-1β in HUVECs resulted in the opposite effect.

Conclusion: These results suggest that BAIBA exerts various protective effects on vascular endothelial cells through the PGC-1β-NFκB and PGC-1β-AMPK-Akt-eNOS axes.

Aim: T50 is the time required for primary calciprotein particles (CPPs) to transform into secondary CPPs in vitro, reflecting serum calcification propensity, and used as a biomarker for calcification stress. Since secondary CPPs induce inflammation and oxidative stress, they may promote atherosclerosis. We investigated whether or not T50 was associated with carotid artery intima-media thickness (IMT).

Methods: This was a cross-sectional study of 202 health examinees. T50 was measured by the established nephelometric method. Carotid artery IMT was measured by high-resolution ultrasonography. The association between T50 and IMT was evaluated by a multivariable-adjusted linear regression analysis.

Results: In a univariate analysis, IMT was not significantly correlated with T50. A multivariable-adjusted linear regression analysis showed that IMT was independently associated with age, sex, diabetes mellitus, dyslipidemia, and fetuin-A but not with T50 in the total subjects. However, when stratified by the estimated glomerular filtration rate (eGFR), T50 was independently and inversely associated with IMT in the subgroup with an eGFR ＜60 mL/min/1.73 m² (β = −0.418, P = 0.013), whereas it was not in the subgroup with an eGFR ≥ 60 mL/min/1.73 m².

Conclusion: T50 was independently and inversely associated with IMT in health examinees with a reduced kidney function, suggesting a novel link between calcification stress and atherosclerosis, particularly in those with chronic kidney disease.

Aim: Chronic kidney disease (CKD) is linked to accelerated vascular remodeling, characterized by medial thickening and fibrosis; however, the molecular mechanisms driving this process remain unclear.

Methods: We investigated the role of toll-like receptor 4 (TLR4) in CKD-associated vascular remodeling using a 5/6 nephrectomy mouse model. TLR4 signaling was selectively inhibited by the long-term administration of TAK-242, a small-molecule-specific inhibitor of TLR4.

Results: TLR4 blockade decreased aortic medial thickening and perivascular fibrosis independent of blood pressure. Immunostaining revealed that blockade of TLR4 decreased Mac-3-positive macrophage accumulation and Ki-67-positive proliferating cells in the aorta. The mRNA expression of IL-6 was suppressed in aortas treated with TAK-242. Disulfide HMGB1 induced the expression of IL-6 in macrophages. Serum from CKD mice induced the expression of IL-6 in RAW264.7 cells and promoted in vitro vascular smooth muscle cell growth, both of which were attenuated with serum from TAK-242-treated CKD mice.

Conclusion: These findings suggest that TLR4-mediated sterile inflammation may contribute to vascular remodeling in CKD and that modulation of TLR4 signaling could be explored as a potential therapeutic strategy to mitigate cardiovascular complications in CKD patients.

Aim: Apolipoprotein CIII (ApoC-III) is a lipid-associated protein crucial for the lipid metabolism. Recent studies have shown that ApoC-III also plays a role in vascular dysfunction and the development of coronary heart disease (CHD). This study examined the hypothesis that the serum ApoC-III concentration is associated with the future risk of CHD in a general Japanese population.

Methods: We prospectively studied 1,676 individuals (1,005 women, 671 men; mean age 57.1 years) in a rural community in Japan. In the 1993 baseline survey, anthropometric examinations, current smoking status, blood pressure, and serum concentrations of lipids and apolipoproteins were assessed. During the follow-up period of 10.9 years (interquartile range 10.8 – 11.1), 48 participants developed CHD, including 18 fatal and non-fatal myocardial infarction patients and 30 sudden death cases.

Results: In the age- and sex-adjusted analysis, we did not find any association between the baseline serum ApoC-III concentration and the risk of CHD and sudden death (HR 2.11, CI 0.88 – 5.03, P = 0.094). However, in a multivariable analysis adjusted for age, sex, the presence of hypertension, presence of diabetes mellitus, current smoking status, total cholesterol, high-density lipoprotein cholesterol, and triglycerides, serum ApoC-III concentration was significantly associated with the risk of CHD and sudden death (HR 3.59, CI 1.05 – 12.3, P = 0.041).

Conclusion: Serum ApoC-III concentration was independently associated with the risk of CHD and sudden death in a general Japanese population.