Aim: Recent studies have demonstrated that selective sodium–glucose cotransporter 2 inhibitors (SGLT2is) reduce cardiovascular events, although their mechanism remains obscure. We examined the effect of canagliflozin, an SGLT2i, on atherogenesis and investigated its underlying mechanism.

Method: Canagliflozin (30 mg/kg/day) was administered by gavage to streptozotocin-induced diabetic apolipoprotein E-deficient (ApoE^－/－) mice. Sudan IV staining was performed at the aortic arch. Immunostaining, quantitative RT-PCR, and vascular reactivity assay were performed using the aorta. In vitro experiments using human umbilical vein endothelial cells (HUVECs) were also performed.

Result: Canagliflozin decreased blood glucose (P＜0.001) and total cholesterol (P＜0.05) levels. Sudan IV staining showed that 12-week canagliflozin treatment decreased atherosclerotic lesions (P＜0.05). Further, 8-week canagliflozin treatment ameliorated endothelial dysfunction, as determined by acetylcholine-induced vasodilation (P＜0.05), and significantly reduced the expressions of inflammatory molecules such as ICAM-1 and VCAM-1 in the aorta at the RNA and protein levels. Canagliflozin also reduced the expressions of NADPH oxidase subunits such as NOX2 and p22phox in the aorta and reduced urinary excretion of 8-OHdG, suggesting a reduction in oxidative stress. Methylglyoxal, a precursor of advanced glycation end products, increased the expressions of ICAM-1 and p22phox in HUVECs (P＜0.05, both). Methylglyoxal also decreased the phosphorylation of eNOS^Ser1177 and Akt but increased the phosphorylation of eNOS^Thr495 and p38 MAPK in HUVECs.

Conclusion: Canagliflozin prevents endothelial dysfunction and atherogenesis in diabetic ApoE^－/－ mice. Anti-inflammatory and antioxidative potential due to reduced glucose toxicity to endothelial cells might be its underlying mechanisms.

Aim: Glycemic index (GI) and glycemic load (GL) influence postprandi al glucose concentrations and insulin responses. This study aims to ascertain the connection between GI, GL, and carotid atherosclerotic stenosis and cardiovascular disease (CVD) risk factors.

Methods: A total of 669 patients with ischemic stroke within 7 days were enrolled. GI and GL were assessed with a validated food frequency questionnaire from patients. Computed tomography angiography (CTA) was used for the evaluation of carotid atherosclerotic stenosis. Traditional risk factors such as total cholesterol, triglycerides, LDL-C, HDL-C, C-reactive protein, homocysteine, neutrophil to lymphocyte ratio (NLR), fasting plasma glucose, and hemoglobin A1c were measured. GI/GL and its association with CVD risk factors and carotid stenosis were explored with Spearman analysis and multivariable logistic regression, respectively.

Results: The prevalence of carotid stenosis was 63.2% of all 669 participants. The mean value of GI/GL was 49.3/137. Spearman test did not detect significant relationships between GI/GL and CVD risk factors. In multivariable regression models, GI (4^th vs. 1^st quartile, OR=2.11; 95% CI, 1.30–3.42) and GL (4^th vs. 1^st quartile, OR=1.82; 95% CI, 1.12–2.96) were observed a significant association with carotid stenosis after adjustment for major confounding factors. The association between GL and carotid stenosis became more pronounced among yo ungers (4^th vs. 1^st quartile, OR=2.42; 95% CI, 1.13–4.76) and women (4^th vs. 1^st quartile, OR=3.81; 95% CI, 1.45–5.05).

Conclusion: Higher GI and GL were positively associated with a higher degree of carotid stenosis in these Chinese cerebral infarction patients, especially in younger patients and women.

Aim: To construct a risk prediction model for cardiovascular disease (CVD) based on the Suita study, an urban Japanese cohort study, and compare its accuracy against the Framingham CVD risk score (FRS) model.

Methods: After excluding participants with missing data or those who lost to follow-up, this study consisted of 3,080 men and 3,470 women participants aged 30–79 years without CVD at baseline in 1989–1999. The main outcome of this study was incidence of CVD, defined as the incidence of stroke or coronary heart disease. Multivariable Cox proportional hazards models with stepwise selection were used to develop the prediction model. To assess model performance, concordance statistics (C-statistics) and their 95% confidence intervals (CIs) were calculated using a bootstrap procedure. A calibration test was also conducted.

Results: During a median follow-up period of 16.9 years, 351 men and 241 women developed CVD. We formulated risk models with and without electrocardiogram (ECG) data that included age, sex, systolic blood pressure, diastolic blood pressure, high-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, diabetes mellitus, smoking, and urinary protein as risk factors. The C-statistics of the Suita CVD risk models with ECG data (0.782; 95% CI, 0.766–0.799) and without ECG data (0.781; 95% CI, 0.765–0.797) were significantly higher than that of the FRS model (0.768; 95% CI, 0.750–0.785).

Conclusions: The Suita CVD risk model is feasible to use and improves predictability of the incidence of CVD relative to the FRS model in Japan.

Aim: Intracerebral hemorrhage (ICH) is one of the most severe complications of thrombolysis. Symptomatic ICHs are associated with adverse outcomes. It has been reported that symptomatic ICHs most commonly occur within the first few hours after the initiation of intravenous thrombolysis. Our aim here was to determine the risk factors for early ICH (within 12 h) after thrombolysis.

Methods: We analyzed patients with acute ischemic stroke who received intravenous alteplase at two hospitals affiliated to Wenzhou Medical University between March 2008 and November 2017. The ICH diagnosis time was defined as the time from the intravenous administration of alteplase to the first detection of hemorrhage on computed tomography. Demographic data, medical history, clinical features, and laboratory examination results were collected. Univariate analysis followed by multivariable logistic regression analysis was performed to determine the predictors of early ICH (within 12 h) after thrombolysis.

Results: Among 197 patients, early ICH (within 12 h) after thrombolysis occurred in 13 patients (6.6%). In the univariate analysis, patients with early ICHs were significantly correlated with prior stroke (P=0.04). After adjusting for potential confounders in the multivariate analysis, prior stroke (odds ratio [OR]: 5.752, 95% confidence interval [CI]: 1.487–22.248; P=0.011) and atrial fibrillation (OR: 5.428, 95% CI: 1.427–20.640; P=0.013) were associated with early ICH.

Conclusions: Prior stroke and atrial fibrillation are independent risk factors for early ICHs (within 12 h) after intravenous thrombolysis with alteplase.

Aims: Profiling of lipoproteins can predict risk of cardiovascular disease; gel permeation high-performance liquid chromatography (HPLC) improves prediction accuracy by providing detailed data for specific lipoprotein subclasses. This study applied HPLC to examine the effects of evolocumab, which effectively treats hyperlipidemia and mixed dyslipidemia, on lipoprotein subclasses, specifically the number and size of lipoprotein particles.

Methods: This post-hoc analysis used patient blood samples from YUKAWA-2, a phase 3 trial evaluating the efficacy of evolocumab in Japanese adult patients with hyperlipidemia or mixed dyslipidemia and at high risk for cardiovascular disease. We used HPLC to assess observed values and percent change from baseline in cholesterol and triglyceride (TG) concentrations, number of particles in lipoprotein subclasses to week 12, and mean observed values and mean percent change from baseline in variables to weeks 10 and 12. HPLC was also compared with conventional methods in assessing low-density lipoprotein (LDL) cholesterol (LDL-C) values.

Results: Data for all 404 patients were analyzed. Evolocumab significantly decreased cholesterol and TG concentrations, and total particle count, in very low-density lipoprotein (VLDL) and LDL subclasses. Particle size increased slightly in LDL, high-density lipoprotein (HDL), and VLDL, but data varied widely. At very low LDL-C, HPLC measurements were higher than those from conventional methods.

Conclusion: This research used HPLC to assess the effects of evolocumab in 20 lipid subclasses. By lowering lipid content and improving the lipid profile, evolocumab may reduce atherogenicity. This reduction is better quantified by HPLC than by conventional methods in the very low LDL-C range.

Aim: Evidence is lacking about whether urinary stones are associated with the subsequent risk of cardiovascular diseases. Herein, we investigated the association between history of urinary stones and the risk of coronary heart disease (CHD) and stroke among middle-aged Japanese.

Methods: This cohort study included 89,037 Japanese men and women (45–74 years) registered in the Japan Public Health Center-based prospective study. Cox proportional hazard models were used to calculate the hazard ratios (HRs) and their 95% confidence intervals (CIs) for incident CHD and stroke among Japanese adults with a self-reported history of urinary stones compared with those without it. The following covariates were included in the regression models: age, sex, area, body mass index, and histories of hypertension, diabetes, hyperlipidemia, smoking habit, alcohol intake, and physical activity.

Results: In total, 1.31% of Japanese adults reported a positive history of urinary stones. Throughout a median follow-up period of 12 years, 1.16% of Japanese adults developed CHD, and 4.96% developed stroke. No associations were detected between history of urinary stones and the risk of CHD (HR 1.04; 95% CI: 0.64–1.67), stroke (HR 0.92; 95% CI: 0.71–1.20), or total CVD (HR 0.95; 95% CI: 0.75–1.19). Younger urinary stone formers (45–59 years) tended to have a higher, though statistically insignificant, risk of CHD than older urinary stone formers (60–74 years): [(HR 1.15; 95% CI: 0.61–2.15) versus (HR 0.83; 95% CI: 0.40–1.76)], respectively.

Conclusion: The history of urinary stones was shown to be not associated with the risk of CVD among Japanese adults.

Aims: We evaluated the relationship between the ratios of eicosapentaenoic acid and arachidonic acid (EPA/AA), docosahexaenoic acid (DHA)/AA, and delta-5 desaturase activity (D5D) and atherogenic lipid profiles (ALP) and coronary atherosclerosis.

Methods: Polyunsaturated fatty acids (PUFA) and ALP were assessed in 436 men with the first episode of acute coronary syndrome (ACS) not take any lipid-lowering drugs. D5D was estimated as the ratio of AA to dihomogamma-linolenic acid (DGLA). These biomarkers were compared between the lower and higher levels of EPA/AA (0.41) or DHA/AA (0.93) according to the levels in Japanese general population. The thrombolysis in myocardial infarction flow (TIMI) grade of the culprit coronary artery was visually estimated during the initial angiography.

Results: Approximately 70% of patients had low EPA/AA or DHA/AA. Serum levels of LDL-cholesterol, apolipoprotein B (apoB), and remnant lipoprotein cholesterol (RL-C) were significantly higher in the low EPA/AA or DHA/AA groups, while those of triglycerides and malondialdehyde-modified LDL (MDA-LDL) were significantly higher in the low EPA/AA group alone. The levels of EPA, EPA/AA, DHA/AA, and HbA1c increased and those of DGLA and apoA1 decreased with increasing number of stenotic vessels. Patients with three stenotic coronary vessels or TIMI grade ≥ 1 had significantly higher EPA levels compared with the others. The levels of LDL-cholesterol, non-HDL-cholesterol, triglycerides, small dense LDL-cholesterol, RL-C, MDA-LDL, apoB, and apoE decreased progressively and those of EPA, DHA, EPA/AA and HDL-cholesterol increased as D5D increased.

Conclusions: The EPA/AA is a superior risk marker than DHA/AA in term of correlation with ALP in ACS patients.

Aims: Cigarette smoking provokes deleterious influences on cardiovascular and pulmonary systems, although the underlying relationship has not been sufficiently investigated especially in early-stage disease. The present study investigated possible associations between subclinical atherosclerosis and pulmonary function in middle-aged male smokers.

Methods: Male smokers undergoing their periodic health check-up were enrolled in this study (n=3,775, 45±8 years). Pulmonary function was evaluated using spirometry by calculating forced vital capacity (FVC) as a percentage of predicted value (FVC%-predicted), forced expiratory volume in one second (FEV1) as a percentage of predicted value (FEV1%-predicted), and the ratio of FEV1 to FVC (FEV1/FVC). Subclinical atherosclerosis was assessed based on ankle-brachial pressure index (ABI), cardio-ankle vascular index (CAVI), ultrasound examination of the carotid intima-media thickness (IMT), and presence of plaque.

Results: Multivariate regression analysis showed that ABI was positively associated with FVC%-predicted and FEV1%-predicted after adjustment for confounders including smoking intensity, while CAVI or carotid IMT was inversely associated with both. Participants with chronic obstructive pulmonary disease (COPD, n=256) showed reduced ABI and increased CAVI or carotid IMT compared with those without COPD, and participants with carotid plaque had lower pulmonary function than those without plaque. Reduced FEV1/FVC was an independent determinant of carotid plaque and decreased ABI was an independent determinant of COPD, as revealed by logistic regression analysis with the endpoint of carotid plaque presence or a diagnosis of COPD revealed.

Conclusions: Middle-aged male smokers showed a close association between subclinical atherosclerosis and pulmonary function, implying that smoking induced-vascular and pulmonary damage are interacting in early-stage disease.