Aim: The Dietary Approaches to Stop Hypertension (DASH) diet is recommended for lowering blood pressure (BP). Our previous single-arm trial revealed that the Japanese cuisine-based DASH (J-DASH) diet (supplying NaCl 8.0 g per day) reduced BP and improved cardiometabolic biomarkers. The present study’s primary objective was to test the feasibility of the J-DASH diet based on its effects on the BP and BP variability of subjects with untreated high-normal BP or stage 1 hypertension.

Methods: The 6-month study period was held from December 2015 to August 2016. The participants were recruited through advertisements in local newspapers and our website and from among randomized participants at Yamaguchi University Hospital. The 2-month treatments included the following: the J-DASH-1 diet 1×/day or the J-DASH-2 diet providing a fish hamburger-patty 2×/day (5 days/week respectively). The control group consumed their usual diets. For the subsequent 4 months, all participants consumed their usual diets. The main outcome measure was the feasibility of the J-DASH diet. We also collected the data of clinic BP and home BP (by automatic BP monitor), cardiometabolic biomarkers, and lifestyle and psychosocial parameters during the intervention phase. We examined behavior changes throughout the study period, and the diets’ safety.

Results: Fifty-one participants were recruited; following screening, 48 met the inclusion criteria and were randomized by central allocation. Eight participants were eliminated based on exclusion criteria, and the 40 participants were randomly allocated to the J-DASH 1 and J-DASH 2 groups ( n=13 each) and the usual-diet group (n=14). The participants’ mean age was 50 years, and 44% were women. The three groups’ clinic BP values were not significantly different, but the home BP values were lower in the J-DASH 1 group and lowest in the J-DASH 2 group compared to the usual-diet group and differed significantly among the three groups throughout the study period (p＜0.0001). The home BP variability was significantly lower in the J-DASH groups compared to the usual-diet group throughout the study period ( p＜0.01). The other indices including fish oil showed little differences among the groups throughout the study period.

Conclusions: The J-DASH diet was feasible to improve home BP and stabilize its variability, and it did so more effectively than the participants’ usual diets.

Aim: The relationship of blood pressure (BP) indexes (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse pressure [PP], mean arterial pressure [MAP]) to subclinical cerebrovascular diseases (SCVDs) remains unclear. This study aimed to elucidate the relationship of four BP indexes measured at two visits on SCVDs assessed by magnetic resonance imaging (MRI) in general Japanese men.

Methods: In general Japanese men aged 40–79 years (N=616), office BP indexes were measured at two visits (Visits 1 [2006–2008] and 2 [2010–2014]). MRI images obtained on the third visit (2012–2015) were examined for prevalent SCVDs: lacunar infarction, periventricular hyperintensity (PVH), deep subcortical white matter hyperintensity (DSWMH), microbleeds, and intracranial artery stenosis (ICAS). Using a multivariable logistic regression analysis, we computed and estimated the odds ratio of each prevalent SCVD for one standard deviation higher BP indexes. The same analyses were performed using home BP.

Results: All four office BP indexes at both visits associated with lacunar infarction. Visit 1 and 2 DBP and Visit 1 MAP associated with PVH and DSWMH, and Visit 1 SBP associated with DSWMH. All Visit 2 BP indexes appear to show stronger association with microbleeds than Visit 1 indexes, and Visit 1 and 2 SBP, PP, and MAP showed similar associations with ICAS. Additional analyses using home BP indexes revealed similar relationships; however, the significance of some relationships decreased.

Conclusion: In general Japanese men, BP indexes were associated with most of SCVDs, and BP indexes measured at different periods associated with different SCVDs assessed by MRI.

Aim: This study investigated the relationship between birth physique and cardiovascular risk factors in Japanese urban residents aged 40 years and more.

Methods: A self-administered questionnaire on birth physique was performed among 624 individuals (165 men and 459 women) who participated in the KOBE study. We examined whether self-reported birth physique and available recorded birth weights matched for 72 participants. Then the association between birth physique and risk factors for all participants was examined by gender. Body size at birth in the questionnaire (large, medium, small) was set as an exposure and laboratory values from the baseline survey (2010-2011) were used as outcomes.

Results: Mean (standard deviation) recorded birth weight of 72 participants was 3665 (318), 3051 (300), and 2653 (199) g, in the large, medium, and small group, respectively. In the analysis for all participants, odds ratio for having both hypertension and impaired glucose tolerance were significantly higher in the small versus large birth weight group, which was 7.42 (95% CI 1.75–31.50) for men and 4.44 (95% CI 1.14–17.30) for women after adjusting for age, body mass index, smoking/alcohol/exercise habits, and menstrual status in women. Similar results were observed in participants with recorded birth weight.

Conclusions: The present study indicates that individuals with small physique at birth might be at higher risk for hypertension and impaired glucose tolerance in middle age compared to those with large birth weight.

Aim: ATP-binding cassette (ABC) transporters and endonuclease-exonuclease-phosphatase family domain containing 1 (EEPD1) are reported to regulate cellular cholesterol efflux in macrophages. Bioinformatics analysis has revealed that ABCG1 and EEPD1 might be potential targets of microRNA (miR)-320b. This study aimed to elucidate the roles of miR-320b in cholesterol efflux from macrophages and the pathogenesis of atherosclerosis.

Methods: Microarray was conducted to profile microRNA (miRNA) expression, and quantitative real-time PCR (qPCR) was used to validate the differentially expressed miRNAs in peripheral blood mononuclear cells of coronary artery disease (CAD) patients and healthy controls. Luciferase assay was conducted to evaluate the activity of reporter construct containing the 3´-untranslated region (3´-UTR) of target genes. Besides, NBD-cholesterol efflux induced by high-density lipoprotein (HDL) and lipid-free apolipoprotein A1 (apoA1) was detected using fluorescence intensity, respectively. Apoe^−/− mice were injected with adeno-associated virus (AAV)2-miR-320b or control via tail vein, thereafter fed with 14 week atherogenic diet to study the roles of miR-320b in vivo.

Results: MiR-320b was highly expressed in CAD patients compared with that in the healthy controls in both the microarray analysis and qPCR analysis. In vitro study showed that miR-320b decreased HDL- and apoA1-mediated cholesterol efflux from macrophages partly by directly targeting ABCG1 and EEPD1 genes and partly via suppressing the LXRα-ABCA1/G1 pathway. Consistently, in vivo administration of AAV2-miR-320b into Apoe^−/− mice attenuated cholesterol efflux from peritoneal macrophages, which showed reduced expression of ABCA1/G1 and EEPD1, and increased lipid LDL-C level, with a down-regulation of hepatic LDLR and ABCA1. AAV2-miR-320b treatment also increased atherosclerotic plaque size and lesional macrophage content and enhanced pro-inflammatory cytokines levels through the elevated phosphorylation level of nuclear factor-κB p65 in macrophages.

Conclusion: We identify miR-320b as a novel modulator of macrophage cholesterol efflux and that it might be a promising therapeutic target for atherosclerosis treatment.

Aim: This study aimed to demonstrate the clinical impact of various frailty-related aspects in poor-risk patients undergoing revascularization for chronic limb-threatening ischemia (CLTI).

Methods: We analyzed a clinical database of a prospective multicenter observational study. A total of 562 CLTI patients who required assistance for their daily lives and were candidates for revascularization were included. We examined various measures of frailty severity, including activities of daily living (ADL)/mobility, physical performance, nutritional status, cognitive function, and cardiac function at baseline (before revascularization). Data on inflammatory markers at baseline and ADL/mobility before CLTI onset were also collected.

Results: The patients were aged 77±10 years, 65% were non-ambulatory, and 38% were categorized as mild dementia or severer. The correlation coefficients between the frailty measures ranged from 0.00 to 0.91. The random forest analysis for one-year mortality risk showed that these frailty-related measures, as well as age and inflammatory markers, had a relatively high variable importance compared with comorbidities and limb severity.

Conclusion: The correlations between measures of frailty severity were not always strong but rather widely varied in CLTI patients who required assistance for their daily lives and were candidates for revascularization. Measures of frailty severity, as well as age and inflammatory markers, had a relatively large predictive impact on one-year mortality risk compared with comorbidities and limb severity in the population.

Aim: Matrix metalloproteinases (MMPs) play critical roles in acute myocardial infarction (AMI). This trial was conducted to determine the potential effects of higher-dose rosuvastatin on circulating MMP levels in patients with AMI.

Methods: This was a multicenter, open-label, 1:1 randomized, parallel-group study. Patients with AMI were randomly assigned to the appropriate-dose group (10 mg rosuvastatin once daily) or the low-dose group (2.5 mg rosuvastatin once daily) within 24 hours after percutaneous coronary intervention. MMP-2 and MMP-9 levels were measured on day 1 and at week 4, 12, and 24 after enrollment. The primary endpoint was the change in MMP levels at 24 weeks after enrollment. The secondary endpoints were change in MMP levels at day 1 and weeks 4 and 12 after enrollment.

Results: Between August 2017 and October 2018, 120 patients with AMI from 19 institutions were randomly assigned to either the appropriate-dose or the low-dose group. There were 109 patients who completed the 24-week follow-up. The primary endpoint for both MMP-2 and MMP-9 was not significantly different between the two groups. The change in the active/total ratio of MMP-9 at week 12 after baseline was significantly lower in the appropriate-dose group compared with the low-dose group (0.81 [−52.8–60.1]% vs. 70.1 [−14.5–214.2]%, P=0.004), while the changes in MMP-2 were not significantly different between the two groups during the study period.

Conclusions: This study could not demonstrate the superiority of appropriate-dose of rosuvastatin in inhibiting serum MMPs levels in patients with AMI.

Aim: This study aimed to determine the association between serum 25-hydroxyvitamin D (25(OH)D) levels and vascular endothelial function in patients with type 2 diabetes (T2D).

Methods: This retrospective study included 113 patients with poorly controlled T2D who were admitted for in-hospital diabetes educational program and underwent measurements of serum 25(OH)D levels and reactive hyperemia index (RHI).

Results: Serum 25(OH)D levels significantly correlated with RHI in T2D patients. Receiver operating characteristic (ROC) curve analysis showed that serum 25(OH)D level of 16.5 ng/mL is the optimal cutoff level for predicting vascular endothelial dysfunction (RHI＜1.67), with a sensitivity of 68.5%, specificity of 67.9%, and area under the ROC curve of 0.668 (95% confidence interval [CI]: 0.566–0.770, p=0.002). The mean RHI was significantly lower (1.70±0.54) in patients with low 25(OH)D levels (n=56, 25(OH)D levels ＜16.5 ng/mL) than that (1.99±0.58; p＜0.001) in patients with high 25(OH)D levels (n=57, 25(OH)D level ≥ 16.5 ng/mL). The proportion of patients with RHI＜1.67 was higher in the low 25(OH)D group than in the high 25(OH)D group (38% vs. 18%; p＜0.001). Multivariate logistic regression analysis identified that serum 25(OH)D level ＜16.5 ng/mL was associated with increased odds of RHI ＜1.67 (odds ratio 4.598, 95% CI 1.961–10.783, p＜0.001).

Conclusion: The results demonstrated the association of serum 25(OH)D levels with endothelial function in poorly controlled T2D patients and identified serum 25(OH)D level of ＜16.5 ng/mL as a predictor of RHI ＜1.67. Serum 25(OH)D level is a potentially useful marker of vascular endothelial dysfunction in poorly controlled T2D patients.

Aim: We investigated the influence of weight change on concurrent changes in predicted cardiovascular disease (CVD) risk and individual CVD risk factors over time.

Methods: A total of 2,140 community-dwellers aged 40–74 years participated in both 2002 and 2007 health examinations. Obesity was defined as body mass index ≥ 25 kg/m². Weight trajectories were classified as: “stable obese” (obese at both examinations), “obese to nonobese” (obese in 2002 but nonobese in 2007), “nonobese to obese” (nonobese in 2002 but obese in 2007), or “stable nonobese” (nonobese at both examinations). We compared changes in the model-predicted risk for CVD and individual CVD risk factors across weight-change categories.

Results: The predicted risk for CVD increased during 5 years in all groups; the increment in the predicted risk for CVD was smallest in the obese to nonobese participants and steepest in the nonobese to obese subjects. Compared with the stable obese participants, the obese to nonobese participants had greater favorable changes in waist circumferences, blood pressure, fasting plasma glucose, serum high-density lipoprotein cholesterol, serum triglycerides, and liver enzymes. For all these parameters, opposite trends were observed when comparing the nonobese to obese participants with the stable nonobese group.

Conclusions: We demonstrated the favorable association of losing weight in obese people and avoiding excessive weight gain in nonobese people with global risk of future CVD and individual CVD risk factors in a real-world setting. The findings could improve behavioral lifestyle interventions that provide information on the health consequences of weight change at health checkups.

Aim: To evaluate the prognostic value of triglyceride-glucose (TyG) index in nondiabetic patients with acute coronary syndrome (ACS) with low-density lipoprotein cholesterol (LDL-C) below 1.8 mmol/L.

Methods: A total of 1655 nondiabetic patients with ACS with LDL-C below 1.8 mmol/L were included in the analysis. Patients were stratified into two groups. The incidence of acute myocardial infarction (AMI), infarct size in patients with AMI, and major adverse cardiac and cerebral event during a median of 35.6-month follow-up were determined and compared between the two groups. The TyG index was calculated using the following formula: ln [fasting triglycerides (mg/dL)×fasting plasma glucose (mg/dL)/2].

Results: Compared with the TyG index ＜8.33 group, the TyG index ≥ 8.33 group had a significantly higher incidence of AMI (21.2% vs. 15.2%, p=0.014) and larger infarct size in patients with AMI [the peak value of troponin I: 10.4 vs. 4.8 ng/ml, p=0.003; the peak value of Creatine kinase MB: 52.8 vs. 22.0 ng/ml, p=0.006; the peak value of myoglobin: 73.7 vs. 46.0 ng/ml, p=0.038]. Although there was no significant difference in mortality between the two groups, the incidence of revascularization of the TyG index ≥ 8.33 group was significantly higher than that of the TyG index ＜8.33 group (8.9% vs. 5.0%, p=0.035). A multivariable Cox regression revealed that the TyG index was positively associated with revascularization [hazard ratio, 1.67; 95% confidence interval, 1.02–2.75; p=0.043].

Conclusions: In nondiabetic patients with ACS with LDL-C below 1.8 mmol/L, a high TyG index level was associated with higher incidence of AMI, larger infarct size, and higher incidence of revascularization. A high TyG index level might be a valid predictor of subsequent revascularization.

Aims: The utility of carotid intima-media thickness (cIMT) as a marker for coronary heart disease is under heavy debate. This is predominantly due to the lack of a standard definition of cIMT, leading to inconsistent results. We investigated and compared the relationships of five different measures of cIMT with coronary calcium.

Methods: Japanese men aged 40-79y ( n=869) from Shiga Epidemiological Study of Subclinical Atherosclerosis were examined. Mean cIMT was measured in three segments of the carotid arteries: common carotid artery (CCA_mean), internal carotid artery (ICA_mean) and bifurcation (Bif_mean). Mean cIMT of average values (Mean cIMT) and mean cIMT of maximum values (Mean-Max cIMT) of all segments combined were assessed. Coronary calcium was assessed as coronary artery calcification (CAC). Ordinal logistic regression was used to determine the odds ratio (OR) of higher CAC per 1 standard deviation higher cIMT measure. Analyses were adjusted for cardiovascular covariates and stratified by age quartiles.

Results: All cIMT measures had positive associations with CAC (p＜0.001): [OR, 95% Confidence Interval]: ICA_mean [1.23, 1.07-1.42], CCA_mean [1.27, 1.08-1.49], Bif_mean [1.33, 1.15-1.53], Mean cIMT [1.42, 1.22-1.66], and Mean-Max [1.50, 1.28-1.75]. In age-stratified analyses, only Mean-Max cIMT maintained a significant relationship with CAC in every age quartile (p＜0.05), while CCA_mean had some of the weakest associations among age quartiles.

Conclusions: Mean-Max cIMT had consistently stronger associations with coronary calcium, independent of important confounders, such as age. The most oft-used measure, CCA_mean, was no longer associated with coronary calcium after age-adjustment and stratification.