Aims: Programmed cell death-1 (PD-1) and its ligand (PD-L1) regulate T cells, leading to immunotolerance. We previously demonstrated that patients with coronary artery disease (CAD) had increased circulating levels of soluble PD-L1 (sPD-L1). However, the prognostic significance of sPD-L1 on cardiovascular outcomes is unknown. In the present study, we evaluated the association between sPD-L1 and cardiovascular events in patients with CAD.

Methods: We prospectively measured sPD-L1 in patients with CAD admitted to Kumamoto University Hospital between December 2017 and January 2020 and observed their cardiovascular event rate. The primary outcome was a composite of death from non-cardiovascular causes, death from cardiovascular causes, non-fatal myocardial infarction, unstable angina pectoris, revascularization, hospitalization for heart failure, and ischemic stroke.

Results: Finally, 627 patients were enrolled, and 35 patients were lost to follow-up. The median follow-up duration was 522 days. In total, 124 events were recorded. The Kaplan–Meier curve showed that the event rate was higher in the higher sPD-L1 group (median ≥ 136 pg/dL) than in the lower sPD-L1 group (25.0% vs. 16.9%; p=0.028, log-rank test). Univariate Cox proportional hazards analysis showed that high-sensitivity C-reactive protein, an estimated glomerular filtration rate of ＜60 mL/min/1.73m², B-type natriuretic peptide, left ventricular ejection fraction, and sPD-L1 were significantly associated with cardiovascular events. Multivariable Cox proportional hazards analysis of factors that were significant in univariate analysis identified that sPD-L1 was significantly and independently associated with cardiovascular events (hazard ratio: 1.364, 95% confidence interval: 1.018–1.828, p=0.038).

Conclusions: Higher sPD-L1 levels were significantly associated with future cardiovascular events in patients with CAD.

Aim: This study aims to explore the association of cumulative exposure to cardiovascular health behaviors and factors with the onset and progression of arterial stiffness.

Methods: In this study, 24,110 participants were examined from the Kailuan cohort, of which 11,527 had undergone at least two brachial-ankle pulse wave velocity (baPWV) measurements. The cumulative exposure to cardiovascular health behaviors and factors (cumCVH) was calculated as the sum of the cumCVH scores between two consecutive physical examinations, multiplied by the time interval between the two. A logistic regression model was constructed to evaluate the association of cumCVH with arterial stiffness. Generalized linear regression models were used to analyze how cumCVH affects baPWV progression. Moreover, a Cox proportional hazards regression model was used to analyze the effect of cumCVH on the risk of arterial stiffness.

Results: In this study, participants were divided into four groups, according to quartiles of cumCVH exposure levels, namely, quartile 1 (Q1), quartile 2 (Q2), quartile 3 (Q3), and quartile 4 (Q4). Logistic regression analysis showed that compared with the Q1 group, the incidence of arterial stiffness in terms of cumCVH among Q2, Q3, and Q4 groups decreased by 16%, 30%, and 39%, respectively. The results of generalized linear regression showed that compared with the Q1 group, the incidence of arterial stiffness in the Q3 and Q4 groups increased by −25.54 and −29.83, respectively. The results of Cox proportional hazards regression showed that compared with the Q1 group, the incidence of arterial stiffness in cumCVH among Q2, Q3, and Q4 groups decreased by 11%, 19%, and 22%, respectively. Sensitivity analyses showed consistency with the main results.

Conclusions: High cumCVH can delay the progression of arterial stiffness and reduce the risk of developing arterial stiffness.

Aims: We attempted to clarify whether the multiple criteria for metabolic syndrome (MetS) can sufficiently predict cardiovascular disease, whether waist circumference (WC) should be required, and whether sex-specific thresholds for each component are necessary. Only a few large-scale studies among East Asians have addressed the ability of MetS to predict cardiovascular disease.

Methods: We analyzed the data of 330,051 men and 235,028 women aged 18–74 years with no history of coronary artery disease (CAD) or cerebrovascular disease (CVD) from a nationwide Japanese claims database accumulated during 2008–2016. The association of each MetS component with CAD or CVD (CAD/CVD), MetS associated with CAD/CVD according to various criteria, and utility of modified criteria with more specific optimal values for each component were examined using multivariate Cox regression and receiver operating characteristic (ROC) analysis.

Results: During the study, 3,934 men (1.19%) and 893 women (0.38%) developed CAD/CVD. For each current MetS criteria, there was a 1.3- to 2.9-fold increased risk of CAD/CVD. Optimal thresholds for predicting CAD/CVD were WCs of 83 and 77 cm, triglycerides levels of 130 and 90 mg/dl, high-density lipoprotein cholesterol levels of 50 and 65 mg/dl, blood pressures of 130/80 and 120/80 mmHg, and fasting plasma glucose levels of 100 and 90 mg/dl for men and women, respectively. The existing MetS criteria and modified criteria were not significantly different in predicting CAD/CVD, but using the modified criteria markedly increased the prevalence of MetS and percentage of people with MetS developing CAD/CVD.

Conclusions: Although various criteria for MetS similarly predicted CAD/CVD, the new criteria greatly reduced the number of high-risk individuals, especially women, overlooked by the current criteria.

Aims: Past observational studies have reported on the association between antipsychotic drugs and venous thromboembolism (VTE); however, the conclusions remain controversial, and its mechanisms are yet to be fully understood. Thus, in this study, we aim to determine the associations of antipsychotic drugs with VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE), and their potential mechanisms.

Methods: We first mined the adverse event signals of VTE, DVT, and PE caused by antipsychotic drugs in Food and Drug Administration Adverse Event Reporting System (FAERS). Next, we used two-sample Mendelian randomization (MR) method to investigate the association of antipsychotic drug target gene expression with VTE, DVT, and PE, using single-nucleotide polymorphisms as genetic instruments. We not only used the expression of all antipsychotic drug target genes as exposure to perform MR analyses but also analyzed the effect of single target gene expression on the outcomes.

Results: In the FAERS, 1694 cases of VTE events were reported by 16 drugs. However, using the MR approach, no significant association was determined between the expression of all antipsychotic target genes and VTE, DVT, or PE, either in blood or brain tissue. Although the analysis of single gene expression data showed that the expression of nine genes was associated with VTE events, these targets lacked significant pharmacological action.

Conclusions: Adverse event mining results have supported the claim that antipsychotic drugs can increase the risk of VTE. However, we failed to find any genetic evidence for this causal association and potential mechanisms. Thus, vigilance is still needed for antipsychotic drug-related VTE despite the limited supporting evidence.

Aims: The progression of atherosclerosis and decline in physical function are poor prognostic factors in patients with cardiovascular disease (CVD). The ankle–brachial index (ABI) is a widely used indicator of the degree of progression of atherosclerosis, which may be used to identify patients with CVD who are at risk of poor physical function. This study examined the association between ABI and poor physical function in patients with CVD.

Methods: We reviewed the data of patients with CVD who completed the ABI assessment and physical function tests (6-min walking distance, gait speed, quadriceps isometric strength, and short physical performance battery). Patients were divided into five categories according to the level of ABI, and the association between ABI and poor physical function was examined using multiple logistic regression analysis. Additionally, restricted cubic splines were used to examine the nonlinear association between ABI and physical function.

Results: A total of 2982 patients (median [interquartile range] age: 71[62–78] years, 65.8% males) were included in this study. Using an ABI range of 1.11–1.20 as a reference, logistic regression analysis showed that ABI ≤ 1.10 was associated with poor physical function. The restricted cubic spline analysis showed that all physical functions increased with an increase in ABI level. The increase in physical function plateaued at an ABI level of approximately 1.1.

Conclusions: ABI may be used to identify patients with poor physical function. ABI levels below 1.1 are potentially associated with poor physical function in patients with CVD.

Aim: The carotid sinuses and aortic arch are baroreceptor-resident arteries (BRAs) and atherosclerosis-susceptible sites of brain-supplying arteries, which would impair baroreflex-mediated blood pressure (BP) regulation and prompt coronary atherosclerosis. We sought to determine the relationship between total atherosclerosis burden (TAB) of BRAs and coronary atherosclerosis burden (AB) in patients with ischemic cerebrovascular disease (ICVD) and explore the potential contribution of BP profiles to this relationship.

Methods: In this cross-sectional analysis of patients with ICVD who simultaneously undertook computed tomography angiography and 24-hour ambulatory BP monitoring, TAB of BRAs was scored based on the atherosclerotic vessel circumference ratio of the carotid sinuses and aortic arch, while the ABs of the intracranial, cervical, aortic, and coronary arteries were scored based on stenosis severity and plaque complexity as routine.

Results: Among the 230 patients analyzed, coronary AB was significantly correlated with TAB of BRAs, independently of, and more tightly than the ABs of the intracranial, cervical, and aortic arteries, and the stenosis- and complexity-based AB of BRA-located arteries (bilateral common and extracranial internal carotid arteries and aortic arch). Both coronary AB and TAB of BRAs were negatively associated with the night-to-day BP dipping ratios, which was quite different from the relationship between intracranial AB and 24-hour BP characteristics. These findings were also true for patients with ICVD without a history of coronary artery disease.

Conclusion: Evaluating TAB of BRAs might provide a new link between atherosclerosis of brain- and heart-supplying arteries, connected partially by BP circadian rhythm. It might facilitate identifying patients with ICVD with heavy coronary AB and comprehensively managing vascular risk.

Aim: Low-density lipoprotein cholesterol (LDL-C) level reduction is highly effective in preventing the occurrence of a cardiovascular event. Contrariwise, an inverse association exists between LDL-C levels and prognosis in some patients with cardiovascular diseases—the so-called “cholesterol paradox.” This study aimed to investigate whether the LDL-C level on admission affects the long-term prognosis in patients who develop acute coronary syndrome (ACS) and to examine factors associated with poor prognosis in patients with low LDL-C levels.

Methods: We enrolled 410 statin-naïve patients with ACS, whom we divided into low- and high-LDL-C groups based on an admission LDL-C cut-off (obtained from the Youden index) of 122 mg/dL. Endothelial function was assessed using the reactive hyperemia index 1 week after statin initiation. The primary composite endpoint included all-cause death, as well as myocardial infarction and ischemic stroke occurrences.

Results: During a median follow-up period of 6.1 years, 76 patients experienced the primary endpoint. Multivariate Cox regression analysis revealed that patients in the low LDL-C group had a 2.3-fold higher risk of experiencing the primary endpoint than those in the high LDL-C group (hazard ratio, 2.34; 95% confidence interval, 1.29–4.27; p=0.005). In the low LDL-C group, slow gait speed (frailty), elevated chronic-phase high-sensitivity C-reactive protein levels (chronic inflammation), and endothelial dysfunction were significantly associated with the primary endpoint.

Conclusions: Patients with low LDL-C levels at admission due to ACS had a significantly worse long-term prognosis than those with high LDL-C levels; frailty, chronic inflammation, and endothelial dysfunction were poor prognostic factors.

Aims: Although physiological effects of hydrophilic- (H-) and lipophilic- (L-) antioxidant capacities (AOCs) are suggested to differ, the association of an antioxidant-rich diet and chronic kidney disease (CKD) incidence has not been examined. We therefore explored the association between the H- or L-AOC of a whole Japanese diet and CKD risk in a general population.

Methods: A total of 922 individuals without CKD (69.2% women; mean age, 59.5 years old) from Ohasama Town, Japan, were examined. CKD incidence was defined as the presence of proteinuria and/or an estimated glomerular filtration rate (eGFR) of ＜60 ml/min/1.73 m². Consumption of H-/L-AOC was determined based on the oxygen radical absorbance capacity in a specially developed Japanese food AOC database. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for new-onset CKD using a Cox proportional hazards model.

Results: During the median follow-up of 9.7 years, 137 CKD incidents were recorded. After adjusting for potential confounding variables, the highest quartile of L-AOC was significantly associated with a 51% reduced CKD risk among only women. An increased L-AOC intake was more effective in preventing eGFR reduction than in preventing proteinuria in women. These associations were not seen for H-AOC intake in both sexes and L-AOC intake in men.

Conclusions: A high intake of lipophilic antioxidants may be associated with a reduced CKD risk. The balance between dietary antioxidant intake and pro-oxidants induced by unhealthy lifestyles may be crucial for preventing future kidney deterioration.

Aim: There is little information on the relationships of serum small dense low-density lipoprotein cholesterol (sdLDL-C) levels and serum triglyceride (TG) levels with cardiovascular events in patients with coronary artery disease (CAD) and type 2 diabetes mellitus (DM) who are receiving statins. The aim of this study was to evaluate the relationships of serum TG levels and sdLDL-C levels as residual risks for cardiovascular events in patients with CAD and type 2 DM who were being treated with statins.

Methods: The subjects were divided into four groups based on TG levels and sdLDL-C levels: sdLDL-C of ＜40.0 mg/dL and TG of ＜150 mg/dL, sdLDL-C of ≥ 40.0 mg/dL and TG of ＜150 mg/dL, sdLDL-C of ＜40.0 mg/dL and TG of ≥ 150 mg/dL, and sdLDL-C of ≥ 40.0 mg/dL and TG of ≥ 150 mg/dL. During a median follow-up period of 1419 days, cardiovascular events occurred in 34 patients.

Results: The incidences of cardiovascular events were significantly higher in patients with sdLDL-C of ≥ 40.0 mg/dL and TG of ＜150 mg/dL and in patients with sdLDL-C of ≥ 40.0 mg/dL and TG of ≥ 150 mg/dL, but not in patients with sdLDL-C of ＜40.0 mg/dL and TG of ≥ 150 mg/dL, than in patients with sdLDL-C of ＜40.0 mg/dL and TG of ＜150 mg/dL.

Conclusions: Under the condition of treatment with statins, patients with CAD and type 2 DM who had sdLDL-C levels of ≥ 40.0 mg/dL had a high risk for cardiovascular events even though serum TG levels were controlled at ＜150 mg/dL.