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Background: Physiological and prognostic associations of centrilobular emphysema (CLE) and paraseptal emphysema (PSE) in smokers with and without chronic obstructive pulmonary disease (COPD) have been increasingly recognized, but the associations with extrapulmonary abnormalities, such as muscle wasting, osteoporosis, and cardiovascular diseases, remain unestablished. Objectives: The aim of the study was to investigate whether CLE was associated with extrapulmonary abnormalities independent of concomitant PSE in smokers without airflow limitation. Methods: This retrospective study consecutively enrolled current smokers without airflow limitation who underwent lung cancer screening with computed tomography and spirometry. CLE and PSE were visually identified based on the Fleischner Society classification system. Cross-sectional areas of pectoralis muscles (PM) and adjacent subcutaneous adipose tissue (SAT), bone mineral density (BMD), and coronary artery calcification (CAC) were evaluated. Results: Of 310 current smokers without airflow limitation, 83 (26.8%) had CLE. The PSE prevalence was higher (67.5% vs. 23.3%), and PM area, SAT area, and BMD were lower in smokers with CLE than in those without (PM area (mean), 34.5 versus 38.6 cm2; SAT area (mean), 29.3 versus 36.8 cm2; BMD (mean), 158.3 versus 178.4 Hounsfield unit), while CAC presence did not differ. In multivariable models, CLE was associated with lower PM area but not with SAT area or BMD, after adjusting for PSE presence, demographics, and forced expiratory volume in 1 s. Conclusions: The observed association between CLE and lower PM area suggests that susceptibility to skeletal muscle loss could be high in smokers with CLE even without COPD.

Objectives With an increase in globalization, the number of non-native-speaking citizens and tourists visiting local pharmacies is rapidly growing worldwide, creating linguistic and sociological problems. The aim of this study is to compare the effect of adding our original method, Original MethOd at pharmacy To ENhAnce Support for Health Improvement (OMOTENASHI), to the conventional medication counselling method (CMC) when counselling non-Japanese patients at the pharmacy. Methods The OMOTENASHI consists of tools written in multiple languages and illustrations to clarify the effects and side effects, and to confirm patients’ understanding. 71 non-Japanese patients were recruited and randomly assigned to the OMOTENASHI or to the CMC in a 1:1 ratio. Comprehension and satisfaction level were evaluated. Results The overall comprehension level was significantly higher in the OMOTENASHI than in the CMC (75% vs 38%, p = 0.002), with a prominent difference in the recognition of the name, effects, side effects, precautions, and how to deal with side effects of the prescribed medication. Conclusion The OMOTENASHI to be a helpful tool in providing essential information to non-native-speaking patients. Practice implication The study highlighted the need to ensure every patient’s safety and interests, and to avoid disadvantages caused by limited language proficiency in the globalization era.

Dysanapsis, a mismatch between airway tree caliber and lung size, contributes to a large variation in lung function on spirometry in healthy subjects. However, it remains unclear whether other morphological features of the airway tree could be associated with the variation in lung function independent of dysanapsis. This study used lung cancer screening chest computed tomography (CT) and spirometry data from asymptomatic never smokers. Dysanapsis and the complexity of airway tree geometry were quantified on CT by measuring airway to lung ratio (ALR) and airway fractal dimension (AFD). Moreover, total airway count (TAC), ratio of airway luminal surface area to volume (SA/V), longitudinal tapering and irregularity of the radius of the internal lumen from the central to peripheral airways (Tapering index and Irregularity index) were quantified. In 431 asymptomatic never smokers without a history of lung diseases, lower ALR was associated with lower forced expiratory volume in 1 s (FEV

Among individuals with hypertension, the prevalence of secondary hypertension has been reported to be ≈10%. More than half of individuals with secondary hypertension have associated hyperaldosteronism. However, given the current clinical environment, these patients often remain undiagnosed. We hypothesized that the urinary sodium/potassium ratio (Na/K) could be used as a simple, low-cost method of screening for hyperaldosteronism among individuals with hypertension in primary care and health examination settings. We recruited hypertensive individuals aged 30–69 years old who were not taking any antihypertensive medications from among participants in health examinations. Urinary Na and K were measured using second morning urine samples, and the plasma aldosterone concentration (PAC) was also measured. We evaluated the association of the second morning urine Na/K ratio (SMU Na/K) with a high PAC, defined as ≥90th percentile (24.3 ng/dL), using receiver operating characteristic (ROC) curves. Overall, 160 participants (108 men and 52 women) with a mean age of 54.3 years were eligible for this study. The area under the ROC curve for the relationship between SMU Na/K and high PAC was 0.77 (95% confidence interval [CI]: 0.59–0.95) in men and 0.64 (95% CI: 0.36–0.93) in women. In men, SMU Na/K values

Two spirometry criteria have been proposed for early chronic obstructive pulmonary disease (COPD) in young smokers: 1) forced expiratory volume in 1 s (FEVThis retrospective study analysed medical check-up data from 13,010 consecutive subjects aged50 years who underwent current and 3 previous spirometry tests in Japan. Current ≥10 pack-year smokers were the main focus of analysis; those meeting one or more spirometry criteria were diagnosed with early COPD. Early COPD was categorized into three subtypes: FEVOf the 1579 current ≥ 10 pack-year smokers, 488 (30.9%) met the early COPD criteria. Multivariate multinomial logistic models adjusted for age, sex, height, body mass index (BMI) and smoking history indicated that past BMI increase and low exercise were associated with higher type 2 early COPD incidence (odds ratio (OR) [95% confidence interval (CI)] = 4.30 [3.10, 6.04], and 0.80 [0.69, 0.93], respectively) but not with higher type 1 incidence. A history of asthma was associated with higher type 3 incidence (OR [95% CI] = 1.98 [1.18, 3.07]).The 3 types of spirometry-based early COPD have different clinical factors. Their trajectories should be explored in longitudinal studies.

BACKGROUND: Preserved ratio impaired spirometry (PRISm) is a common spirometry finding, but its heterogeneous manifestations and frequent transitions to airflow limitation (AFL), chronic obstructive pulmonary disease, or normal spirometry hinder establishing an appropriate management strategy. This study examined whether transition to AFL and baseline comorbidities are more frequent in subjects with definite PRISm (PRISm confirmed on both current and past two spirometry tests) versus incident PRISm (PRISm confirmed only on a current test with past normal spirometry records) than in normal spirometry. METHODS: Archived medical check-up data of subjects aged ≥40 years (n=10828) with two past spirometry records, in a Japanese hospital, were cross-sectionally analyzed. Among them, data from those with follow-up spirometry after three years (n=6467) were used to evaluate transition to AFL. PRISm was defined as forced volume in 1s (FEV1)/forced vital capacity ≥0.7 and % predicted FEV1

BACKGROUND: The antitumor effect of statins has been highlighted, but clinical study results remain inconclusive. While patients with diabetes are at high risk of cancer, it is uncertain whether statins are effective for cancer chemoprevention in this population. OBJECTIVE: This study evaluated the association between statins and cancer incidence/mortality in patients with type 2 diabetes. DESIGN: This study was a follow-up observational study of the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial, which was a randomized controlled trial of low-dose aspirin in Japanese patients with type 2 diabetes. PARTICIPANTS: This study enrolled 2536 patients with type 2 diabetes, age 30–85 years, and no history of atherosclerotic cardiovascular disease, from December 2002 until May 2005. All participants recruited in the JPAD trial were followed until the day of any fatal event or July 2015. We defined participants taking any statin at enrollment as the statin group (n = 650) and the remainder as the no-statin group (n = 1886). MAIN MEASURES: The primary end point was the first occurrence of any cancer (cancer incidence). The secondary end point was death from any cancer (cancer mortality). KEY RESULTS: During follow-up (median, 10.7 years), 318 participants developed a new cancer and 123 died as a result. Cancer incidence and mortality were 10.5 and 3.7 per 1000 person-years in the statin group, and 16.8 and 6.3 per 1000 person-years in the no-statin group, respectively. Statin use was associated with significantly reduced cancer incidence and mortality after adjustment for confounding factors (cancer incidence: adjusted hazard ratio [HR], 0.67; 95% CI, 0.49–0.90, P = 0.007; cancer mortality: adjusted HR, 0.60; 95% CI, 0.36–0.98, P = 0.04). CONCLUSIONS: Statin use was associated with a reduced incidence and mortality of cancer in Japanese patients with type 2 diabetes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11606-020-06167-5) contains supplementary material, which is available to authorized users.

Aims A sodium glucose cotransporter 2 (SGLT2) inhibitor was recently found to reduce heart failure hospitalization in the EMPA‐REG OUTCOME trial. We have hypothesized that autonomic nerve activity may be modulated by SGLT2 inhibition. The current study aims to investigate the impact of empagliflozin on sympathetic and parasympathetic nerve activity in patients with type 2 diabetes mellitus. Methods and results This ongoing study is a prospective, randomized, open‐label, multicentre investigation of 134 patients with type 2 diabetes mellitus. The patients are randomly allocated to receive either empagliflozin or sitagliptin with the treatment goal of the Japan Diabetes Society guidelines. Ambulatory electrocardiographic monitoring is performed at the baseline and at 12 and 24 weeks of treatment. Analyses of heart rate variability are conducted using the MemCalc method, which is a combination of the maximum entropy method for spectral analysis and the non‐linear least squares method for square analysis. The primary endpoint is the change in the low‐frequency (0.04–0.15 Hz)/high‐frequency (0.15–0.4 Hz) ratio from baseline to 24 weeks. Conclusions This investigation on the effect of EMPagliflozin on cardiac sYmpathetic and parasympathetic neRve activity in JapanEse pAtieNts with type 2 diabetes (EMPYREAN study) offers an important opportunity to understand the impact of SGLT2 inhibition on autonomic nerve activity in patients with type 2 diabetes.

Background: Many studies have reported that dipeptidyl peptidase (DPP)-4 inhibitors do not significantly reduce cardiovascular events (CVE). We sought to evaluate whether DPP-4 inhibitors effected the incidence of CVE in diabetic patients with no history of atherosclerotic events. Methods: The Japanese primary prevention of atherosclerosis with aspirin for diabetes (JPAD) trial was a multicenter, prospective, randomized, open label, blinded, end-point study done from 2002 to 2008. After completion of the JPAD trial, we followed up with the patients until 2019. We defined the cardiovascular events as the following: acute myocardial infarction; stable angina; unstable angina; sudden cardiac death; stroke; transient ischemic attack; heart failure requiring hospitalization; aortic disease; and peripheral artery disease. JPAD patients were divided into a DPP-4 Group and a non-DPP-4 Group based on whether or not they were taking DPP-4 inhibitors at the 2013 follow-up. We investigated the incidence of CVE in 1,107 JPAD patients who had had at least one follow-up by 2019. Results: During the observation period from 2013 to 2019, there were 37 (7%) CVE in the DPP-4 Group (n=520) and 66 (11%) in the non-DPP-4 Group (n=587). The incidence of CVE was significantly lower in the DPP-4 Group than in the non-DPP-4 Group (Log-Rank P=0.0074, Figure). Cox proportional hazards model analysis revealed that use of DPP-4 inhibitors (HR, 0.65: 0.43-0.98, P=0.04) was an independent factor after adjustment for age ≥65 years, hypertension, dyslipidemia, and, insulin usage (Figure). Conclusions: Our study demonstrated that the use of DPP-4 inhibitors was associated with a reduced incidence of CVE after adjustment in diabetic patients without a history of atherosclerotic events. It is necessary to be aware of the cardiovascular event-suppressing effect of DPP-4 inhibitors on diabetic patients.

Background: We sought to evaluate whether there was a difference in the incidence rate of cardiovascular event (CVD) among different hemoglobin (Hb) A1c levels in diabetic patients without a history of atherosclerotic events. Methods: The Japanese primary prevention of atherosclerosis with aspirin for diabetes (JPAD) trial was a multicenter, prospective, randomized, open label, blinded, end-point study done from 2002 to 2008. After completion of the JPAD trial, we followed up with the patients until 2019. We defined the cardiovascular events as the following: acute myocardial infarction; stable angina; unstable angina; sudden cardiac death; stroke; transient ischemic attack; aortic disease; and peripheral artery disease. Among 2,535 JPAD patients, HbA1c levels of the JPAD patients were recorded on average 8 times. Based on the mean value of HbA1c, we divided the patients into three groups: a High HbA1c Group (n=899, HbA1c ≥7.5%); a Moderate HbA1c Group (n=581, 7.5% >HbA1c ≥7.0 %); or, a Low HbA1c Group (n=1055, 7.0% >HbA1c). We compared the incidence of CVD among the three groups. Results: The mean HbA1c (%) was 8.6 in the High HbA1c Group, 7.4 in the Moderate HbA1c Group, and 6.6 in the Low HbA1c Group on registration. During an 11.56-year follow-up, the incidence of CVD was significantly higher in the High HbA1c Group (P2 , duration of diabetes ≥7.0% years, medications, eGFR ≥60 ml/min/1.73m 2 , and systolic blood pressure ≥140 mm Hg (Figure). Conclusions: Our study demonstrated that HbA1c ≥7.5% was independently associated with the incidence of CVD in diabetic patients without a history of atherosclerotic events while 7.5% >HbA1c ≥7.0 % was not.

There is little evidence of how blood pressure level over 10 years affects the decline of estimated glomerular filtration rate (eGFR) in diabetic patients. The Japanese primary prevention of atherosclerosis with aspirin for diabetes (JPAD) trial was a multicenter, randomized, clinical trial done from 2002 to 2008. After completion of the JPAD trial, we followed up the patients until 2019 as a cohort study. We defined late-stage kidney disease (LSKD) as eGFR 30 ml/min/1.73 m

OBJECTIVE To evaluate and compare the efficacy of long-term use of low-dose aspirin for the prevention of dementia in men and women. RESEARCH DESIGN AND METHODS This study is a follow-up cohort study of the Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) trial, which was a randomized, open-label, standard care–controlled trial examining the effects of low-dose aspirin on cardiovascular events. We followed up 2,536 Japanese patients with type 2 diabetes (T2D) enrolled in the JPAD trial from 2002 to 2017. The primary outcome of this post hoc analysis was the incidence of dementia, which was defined by the prescription of antidementia drugs or admission due to dementia. RESULTS Among the originally enrolled patients, 2,121 (84%) retained their original allocation. During a median follow-up of 11.4 years, 128 patients developed dementia. The overall effect of low-dose aspirin on the prevention of dementia adjusted for age, sex, and other established risk factors was not significant (hazard ratio [HR] 0.82, 95% CI 0.58–1.16). However, a significant reduction was seen in the risk of dementia in women (HR 0.58, 95% CI 0.36–0.95), but not in men (HR 1.27, 95% CI 0.75–2.13) (Pinteraction = 0.03). CONCLUSIONS Long-term use of low-dose aspirin may reduce the risk for dementia in women with T2D.

Background Because of the advanced age of patients with cardiovascular disease (CVD), prevention of sleep disorder and dementia is a priority for cardiac rehabilitation (CR) during their long-term care. This study aimed to investigate the association of physical activity with sleep quality and cognitive function in elderly patients with CVD in the CR maintenance phase. Methods We conducted a multicenter study through the Clinical Exercise Physiology Association Japan network, which included 102 elderly patients (mean age, 74 ± 7.4 years) with CVD undergoing phase III CR at 6 institutions. Physical activity was assessed using a triaxial accelerometer for 7 consecutive days and was classified as locomotive and household activities. Physical fitness was assessed via 6-min walking distance (6MD), hand grip power, 10-m walking speed, one leg standing time with eyes open, and 10 times sit-to-stand tests. Sleep quality and cognitive function were evaluated using the Pittsburgh sleep quality index (PSQI) and mini-mental state examination (MMSE) scores, respectively. Results The patients performed 5506.8 ± 3743.6 steps/day and scored 5.8 ± 3.5 points in the PSQI and 28.4 ± 1.7 points in the MMSE. Sleep latency and MMSE scores correlated with locomotive activity, but not with household activity. Locomotive activity and 6MD were independent predictors of sleep latency and MMSE score, respectively. When patients with heart failure were excluded, the relationship between sleep latency and locomotive activity was preserved, but the relationship between exercise tolerance and cognitive function disappeared. Conclusion Locomotive activity and exercise tolerance are associated with sleep latency and cognitive function in elderly patients with CVD continuing phase III CR. However, in this study, the relationship between exercise tolerance and cognitive function was offset by the presence of heart failure.

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2-I) have beneficial cardiovascular effects, including reduction in hospitalization for heart failure (HF). The aim of this study is to explore the efficacy and safety of canagliflozin compared with standard diabetes treatment in elderly patients with type 2 diabetes (T2DM) and HF with preserved ejection fraction (HFpEF). Methods and Results: This is a multicenter, randomized, open-label, parallel-group comparison study designed to evaluate the effects of canagliflozin on fluid retention and cardiac function in T2DM patients with HFpEF. Eligible participants are patients aged ≥65 years with insufficient glycemic control. Qualified patients will be randomly assigned to treatment with 100 mg of canagliflozin or standard diabetic treatment other than SGLT2-I; both groups will be treated for 24 weeks. The primary endpoints are changes in body weight as an indicator of fluid retention and plasma brain natriuretic peptide as an indicator of cardiac function. The secondary endpoints include cardiovascular event rates, changes in the dose of loop diuretics, echocardiographic left ventricular function, and nutritional status. Conclusions: This study is expected to provide valuable findings regarding the mechanisms of canagliflozin on cardiac function and a potential new therapeutic approach for HFpEF. (UMIN000028668 and jRCTs051180030).

Introduction: Blood pressure (BP) is a significant predictor for chronic kidney disease (CKD). Hypothesis: We sought to evaluate whether the progression of CKD in diabetic patients, without a history of atherosclerotic events, is dependent on BP control. Methods: The Japanese primary prevention of atherosclerosis with aspirin for diabetes (JPAD) trial was a multicenter, prospective, randomized, open label, blinded, end-point study done from 2002 to 2008. After completion of the JPAD trial, we followed up the patients until 2019. We defined late-stage kidney disease (LSKD) as estimated glomerular filtration rate (eGFR) 2 or hemodialysis. Among 2,536 JPAD patients, 27 patients were excluded for eGFR 2 on registration. BP of the JPAD patients was recorded on average 8 times. Based on the mean value of systolic BP (SBP), we divided the patients into three groups: a High BP Group (n=607, SBP≥140 mm Hg); a Moderate BP Group (n=989, 140>SBP≥130 mm Hg); or a Low BP Group (n=913, SBP Results: The mean eGFR (ml/min/1.73m 2 ) was 75.1 in the High BP Group, 72.6 in the Moderate BP Group, and 75.7 in the Low BP Group on registration. During a 11.2-year follow-up, the incidence of LSKD was significantly higher in the High BP and Moderate BP Groups than in the Low BP Group (P2 , duration of diabetes ≥7.0 years, statin usage, aspirin usage, eGFR≥60 ml/min/1.73m 2 , and hemoglobin A1c ≥7.2 % (Figure). Conclusions: Our study demonstrated that SBP was independently associated with the progression to LSKD in diabetic patients, without a history of atherosclerotic events. SBP less than 130 mm Hg is recommended for diabetic patients to prevent progression to LSKD.

Air pollution causes hypertension, cardiovascular disease, and mortality. Asian dust (AD) reportedly induces asthma or acute myocardial infarction along with air pollution, but its impact on blood pressure (BP) is unknown. We investigated the association between short-term AD exposure and BP fluctuations in 300,952 individuals whose BP was measured during April 2005–March 2015 and divided them into AD and non-AD groups based on visitation for AD-related events. AD’s occurrence, air pollutants’ concentration (suspended particulate matter, SO2, NO2, photochemical oxidants), and meteorological variables (mean ambient temperature, relative humidity) were obtained from a monitoring station; AD events correlated with decreased visibility (< 10 km). We observed 61 AD days, with 3897 participants undergoing medical check-ups. Short-term AD exposure at lag day-0 was significantly associated with higher systolic BP (SBP), diastolic BP (DBP), and pulse rate (PR) risk (β = 1.85, 95% confidence interval (CI) 1.35–2.35 for SBP, β = 2.24, 95% CI 1.88–2.61 for DBP, β = 0.52, 95% CI 0.14–0.91 for PR) using multi-pollutant model. Population-attributable fractions exposed to AD were 11.5% for those with elevated SBP (SBP ≥ 120 mmHg) and 23.7% for those with hypertension (SBP ≥ 140 mmHg or DBP ≥ 90 mmHg). This study showed a strong association between short-term AD exposure and increased SBP and DBP.

Among individuals with hypertension, the prevalence of secondary hypertension has been reported to be ≈10%. More than half of individuals with secondary hypertension have associated hyperaldosteronism. However, given the current clinical environment, these patients often remain undiagnosed. We hypothesized that the urinary sodium/potassium ratio (Na/K) could be used as a simple, low-cost method of screening for hyperaldosteronism among individuals with hypertension in primary care and health examination settings. We recruited hypertensive individuals aged 30-69 years old who were not taking any antihypertensive medications from among participants in health examinations. Urinary Na and K were measured using second morning urine samples, and the plasma aldosterone concentration (PAC) was also measured. We evaluated the association of the second morning urine Na/K ratio (SMU Na/K) with a high PAC, defined as ≥90th percentile (24.3 ng/dL), using receiver operating characteristic (ROC) curves. Overall, 160 participants (108 men and 52 women) with a mean age of 54.3 years were eligible for this study. The area under the ROC curve for the relationship between SMU Na/K and high PAC was 0.77 (95% confidence interval [CI]: 0.59-0.95) in men and 0.64 (95% CI: 0.36-0.93) in women. In men, SMU Na/K values1.0 could detect hyperaldosteronism with a sensitivity of 45.5%, a specificity of 97.9%, a positive predictive value of 71.4%, and a negative predictive value of 94.1%. The use of the urinary Na/K ratio may be appropriate as a method of screening for hyperaldosteronism in hypertensive men.

Aim: Measurement of B-type natriuretic peptide (BNP) is widely used as a diagnostic and risk assessment tool for cardiovascular disease. Recent studies have demonstrated that BNP-32 and its precursor proBNP circulate in the blood stream, and that most commercial BNP immunoassays measure both forms. However, recombinant or synthetic BNP-32 is used as the standard for those BNP immunoassays. This gap between clinical samples and the standard might be a potential source of variation in BNP measurements among assays. The purpose of this study is to validate a more suitable calibrator for BNP immunoassays. Methods: External BNP calibrators containing both BNP-32 and glycosylated proBNP were prepared at two concentration levels. Target BNP concentrations of the low and high levels were 40 and 160 pg/mL, respectively. And to reflect clinical samples, the molar ratios of BNP-32 to glycosylated proBNP in these concentration levels were adjusted to 50:50 and 25:75, respectively. BNP concentrations of plasma samples along with the external BNP calibrators were measured at two commercial labs and using an automated analyzer MI02 Shionogi® BNP (MI02). These samples and the calibrators were also measured using an immunoradiometric assay (IRMA) as a standard assay procedure. Concentrations of the plasma samples measured at the labs or using the MI02 were adjusted according to a comparison of the measured concentrations of the external BNP calibrators with the IRMA. Results: After measured concentrations of the plasma samples were adjusted using the external BNP calibrators, the correlation between each measurement and the IRMA was improved. The range of the slopes according to Passing-Bablok regression analysis narrowed from 0.628 - 0.955 to 0.911 - 1.005. Conclusions: Our data suggests that a mixture of BNP-32 and glycosylated proBNP at different ratios by concentration level is suitable for calibration to minimize variations in BNP measurements among immunoassays.

Background Silent events with newly developed Q waves in electrocardiogram (ECG) [silent myocardial infarction (MI)] in diabetic patients is reported to be independently associated with an increased risk of fatal MI. However, the incidence rate of silent MI in diabetic patients has yet to be clarified. We sought to determine the incidence rate of first symptomatic MI and silent MI in diabetic patients. Methods We conducted a prospective cohort study on patients enrolled in the Japanese primary prevention of atherosclerosis with aspirin for diabetes (JPAD) trial which was started in 2002. It is a randomized controlled trial to examine the efficacy of low-dose aspirin therapy for the primary prevention of atherosclerotic events in type 2 diabetic patients. No patients had Q waves in their ECG before entry to the JPAD trial. We followed-up 1825 patients until July 2015 after completion of the JPAD trial in 2008. The median follow-up period was 10.3 years. We collected 1648 patients’ ECGs to identify patients with silent MI. Results Symptomatic MI occurred in 65 patients and silent MI occurred in 22 patients. The incidence rate of symptomatic MI was 4.26 per 1000 patient-years and 1.44 for silent MI in diabetic patients. Thus, 25% of total MIs were silent. Cause-specific Cox proportional hazard model indicated that age (hazard ratio 1.06, 95% confidence interval; 1.03–1.10, p = 0.0004) and long history of diabetes (1.00, 1.01–1.07, p = 0.01) were independently associated with symptomatic MI, but these were not associated with silent MI. Conclusions We demonstrated that incidence rate of first silent MI and that proportion of silent MI to all MIs was 25% in diabetic patients without a history of atherosclerotic events. Diabetic patients frequently need ECG screening for detection of silent MI.

Rheumatoid arthritis (RA) patients often have altered body composition including reduced muscle mass and increased fat mass. Some RA patients are likely to increase visceral fat without obesity [Body Mass Index (BMI) ≥ 25]. The objective of the study was to determine the association between obesity and/or visceral adiposity and the risk for atherosclerosis in Japanese RA patients. Obesity was evaluated using the BMI, with visceral adiposity evaluated using the visceral fat area (VFA) and the visceral/subcutaneous fat ratio (V/S ratio), quantified using the dual bioelectrical impedance method. Atherosclerosis was evaluated based on the intima–media thickness (IMT) and Plaque score (PS) of the carotid artery, measured using ultrasonography. Multivariate analysis was performed to determine the factors associated with IMT and PS. IMT and PS were compared among groups of patients sub-classified according to BMI and VFA levels. The V/S ratio was higher in RA patients than healthy controls, after adjustment for age, BMI, and waist circumference. On multivariate analysis, the V/S ratio, but not the BMI, was independently associated with the IMT and PS. Among the sub-classifications for BMI and VFA, non-obese patients with a high visceral adiposity (18.5 ≤ BMI

OBJECTIVE This study analyzed the efficacy of low-dose aspirin in cancer chemoprevention in patients with diabetes. RESEARCH DESIGN AND METHODS This study was a posttrial follow-up of the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial. Participants in the JPAD trial (2,536 Japanese patients with type 2 diabetes and without preexisting cardiovascular disease) were randomly allocated to receive aspirin (81 or 100 mg daily) or no aspirin. After that trial ended in 2008, we followed up with the participants until 2015, with no attempt to change the previously assigned therapy. The primary end point was total cancer incidence. We investigated the effect of low-dose aspirin on cancer incidence. RESULTS During the median follow-up period of 10.7 years, a total of 318 cancers occurred. The cancer incidence was not significantly different between the aspirin and no-aspirin groups (log-rank, P = 0.4; hazard ratio [HR], 0.92; 95% CI, 0.73–1.14; P = 0.4). In subgroup analyses, aspirin did not affect cancer incidence in men, women, or participants aged ≥65 years. However, it decreased cancer incidence in participants aged CONCLUSIONS Low-dose aspirin did not reduce cancer incidence in Japanese patients with type 2 diabetes.

Background: A sodium glucose cotransporter 2 (SGLT2) inhibitor was recently found to reduce heart failure hospitalization in the EMPA-REG OUTCOMES trial. We have hypothesized that autonomic nerve activity may be modulated by SGLT2 inhibition. The current study aims to investigate the impact of empagliflozin on sympathetic and parasympathetic nerve activity in patients with type 2 diabetes mellitus.Methods: This ongoing study is a prospective, randomized, open-label, multicenter investigation of 134 patients with type 2 diabetes mellitus. The patients are randomly allocated to receive either empagliflozin or sitagliptin with the treatment goal of the Japan Diabetes Society guidelines. Ambulatory electrocardiographic monitoring is performed at the baseline and at 12 and 24 weeks of treatment. Analyses of heart rate variability are performed using the MemCalc method, which is a combination of the maximum entropy method for spectral analysis and the non-linear least squares method for square analysis. The primary endpoint is the change in the low frequency (LF; 0.04-0.15 Hz) / high frequency (HF; 0.15-0.4 Hz) ratio from baseline to 24 weeks.Discussion: This investigation on the effect of EMPagliflozin on cardiac sYmpathetic and parasympathetic neRve activity in JapanEse pAtieNts with type 2 diabetes (EMPYREAN study) offers an important opportunity to understand the impact of SGLT2 inhibition on autonomic nerve activity in patients with type 2 diabetes.Trial Registration: UMIN Clinical Trials Registry identifier UMIN000029194. Registered 19 September 2017, https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000033375

BACKGROUND: Current clinical biomarkers for the programmed cell death 1 (PD-1) blockade therapy are insufficient because they rely only on the tumor properties, such as programmed cell death ligand 1 expression frequency and tumor mutation burden. Identifying reliable, responsive biomarkers based on the host immunity is necessary to improve the predictive values. METHODS: We investigated levels of plasma metabolites and T cell properties, including energy metabolism markers, in the blood of patients with non-small cell lung cancer before and after treatment with nivolumab (n = 55). Predictive values of combination markers statistically selected were evaluated by cross-validation and linear discriminant analysis on discovery and validation cohorts, respectively. Correlation between plasma metabolites and T cell markers was investigated. RESULTS: The 4 metabolites derived from the microbiome (hippuric acid), fatty acid oxidation (butyrylcarnitine), and redox (cystine and glutathione disulfide) provided high response probability (AUC = 0.91). Similarly, a combination of 4 T cell markers, those related to mitochondrial activation (PPARγ coactivator 1 expression and ROS), and the frequencies of CD8(+)PD-1(hi) and CD4(+) T cells demonstrated even higher prediction value (AUC = 0.96). Among the pool of selected markers, the 4 T cell markers were exclusively selected as the highest predictive combination, probably because of their linkage to the abovementioned metabolite markers. In a prospective validation set (n = 24), these 4 cellular markers showed a high accuracy rate for clinical responses of patients (AUC = 0.92). CONCLUSION: Combination of biomarkers reflecting host immune activity is quite valuable for responder prediction. FUNDING: AMED under grant numbers 18cm0106302h0003, 18gm0710012h0105, and 18lk1403006h0002; the Tang Prize Foundation; and JSPS KAKENHI grant numbers JP16H06149, 17K19593, and 19K17673.

Introduction Asian dust (AD) is one of the health care problems because AD increases risk for mortality, respiratory, and cardiovascular disease. Previous animal studies showed that particulate matter from AD induced oxidative stress and systemic inflammation, increased blood pressure and heart rate, and decreased cardiac contraction. However, few reports show association of AD with increased blood pressure in human healthy subjects. Purpose The aim of this study was to investigate effects of AD on blood pressure and blood cell counts in human. Methods Using generalized linear models, we estimated the association between short-term exposure to AD and systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR) and white blood cell (WBC) count in 296,168 participants aged 20 and older (men n=168,579, 56.9%) who underwent medical check-ups and had no anti-hypertensive agents between April 2005 and March 2015 in a health check-up center in Japan. AD days were the days on which AD events occurred, which were defined as decreased visibility ( Results During study period, 61 AD days were observed, and there were 4,670 participants undergoing medical check-ups on AD days. In the propensity score matched population (n=4,670, each), short-term exposure to AD was significantly associated with an increased risk of higher SBP, DBP, HR, or WBC count [β=1.303, 95% confidence interval (CI) 0.577 to 2.029 for SBP, β=0.630, 95% CI 0.122 to 1.138 for DBP, β=0.987, 95% CI 0.410 to 1.563 for HR, β=150.0, 95% CI 64.9 to 235.1 for WBC]. These significant associations were also observed in two-pollutant models. In subgroup analysis according to age, AD exposure had greater impact on SBP, DBP, and HR in younger people (20 to 40 years old), but WBC count in middle-high age (51 years and older). GLM analysis according to age category Conclusions The present study showed that short-term exposure to AD was associated with higher SBP, DBP, HR and WBC count. Short-term exposure to AD may exacerbate sympathetic nervous system for the young and immune system for the elderly.

Albuminuria is a risk factor for cardiovascular events in diabetic patients, but it is unknown whether proteinuria is also a risk factor for cardiovascular events in these patients.The Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial was performed between 2002 and 2008 to examine the efficacy of low-dose aspirin therapy for the primary prevention of cardiovascular events in type 2 diabetes patients. After the JPAD trial was completed, we continued to follow up the patients until 2015. Among the 2536 patients participating in the JPAD study, 42 were excluded because proteinuria was not checked at registration. We divided the patients into two groups: proteinuria group (n = 446; proteinuria ± or greater) and non-proteinuria groups (n = 2048; proteinuria -). We compared the incident rate of cardiovascular events between the two groups.During the observation period [median, 10.3 (10.2-10.5) years], 332 patients had a first cardiovascular event. Among 332 patients, 136 patients had cerebrovascular events and 54 patients had acute myocardial infarction. The incidence rate of cardiovascular events was significantly higher in the proteinuria group compared with the non-proteinuria group (HR 1.75, 95%CI 1.36-2.23, p 0.0001). The incidence rate of cerebrovascular events was also significantly higher in the proteinuria group than in the non-proteinuria group (HR 1.71, 95%CI 1.14-2.49, p = 0.0064). The Cox proportional hazards model revealed that proteinuria was independently associated with cardiovascular events in diabetic patients without a history of cardiovascular events after adjusting for age, gender, body mass index, hemoglobin A1c level, duration of diabetes, and estimated glomerular filtration rate.Proteinuria was independently associated with the incidence of primary cardiovascular events in diabetic patients. Proteinuria detected by the dipstick test, which is simple and inexpensive, is useful as a first step in the risk assessment of diabetic patients.

Background: The long-term efficacy and safety of low-dose aspirin for primary prevention of cardiovascular events in patients with type 2 diabetes mellitus are still inconclusive. Methods: The JPAD trial (Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes) was a randomized, open-label, standard care–controlled trial examining whether low-dose aspirin affected cardiovascular events in 2539 Japanese patients with type 2 diabetes mellitus and without preexisting cardiovascular disease. Patients were randomly allocated to receive aspirin (81 or 100 mg daily; aspirin group) or no aspirin (no-aspirin group) in the JPAD trial. After that trial ended in 2008, we followed up with the patients until 2015, with no attempt to change the previously assigned therapy. Primary end points were cardiovascular events, including sudden death, fatal or nonfatal coronary artery disease, fatal or nonfatal stroke, and peripheral vascular disease. For the safety analysis, hemorrhagic events, consisting of gastrointestinal bleeding, hemorrhagic stroke, and bleeding from any other sites, were also analyzed. The primary analysis was conducted for cardiovascular events among patients who retained their original allocation (a per-protocol cohort). Analyses on an intention-to-treat cohort were conducted for hemorrhagic events and statistical sensitivity. Results: The median follow-up period was 10.3 years; 1621 patients (64%) were followed up throughout the study; and 2160 patients (85%) retained their original allocation. Low-dose aspirin did not reduce cardiovascular events in the per-protocol cohort (hazard ratio, 1.14; 95% confidence interval, 0.91–1.42). Multivariable Cox proportional hazard model adjusted for age, sex, glycemic control, kidney function, smoking status, hypertension, and dyslipidemia showed similar results (hazard ratio, 1.04; 95% confidence interval, 0.83–1.30), with no heterogeneity of efficacy in subgroup analyses stratified by each of these factors (all interaction P >0.05). Sensitivity analyses on the intention-to-treat cohort yielded consistent results (hazard ratio, 1.01; 95% confidence interval, 0.82–1.25). Gastrointestinal bleeding occurred in 25 patients (2%) in the aspirin group and 12 (0.9%) in the no-aspirin group ( P =0.03), and the incidence of hemorrhagic stroke was not different between groups. Conclusions: Low-dose aspirin did not affect the risk for cardiovascular events but increased risk for gastrointestinal bleeding in patients with type 2 diabetes mellitus in a primary prevention setting. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00110448.

Aim Previous studies have reported that patients with rheumatoid arthritis (RA) have a higher risk of developing cardiovascular disease (CVD) than the general population. A major cause of CVD is atherosclerosis, which can be evaluated with carotid ultrasonography (US). As far as we know, there have been no large-scale carotid artery US studies in Japanese patients with RA. The aim of this study was to identify the risk factors for atherosclerosis in Japanese patients with RA. Methods The study subjects underwent physical examinations, laboratory tests and US examination, and answered a questionnaire about their lifestyle. Carotid US was performed to measure the maximum carotid intima media thickness (max cIMT) and to detect plaques. Results Atherosclerosis was detected in 238 patients (52%). Age, hypertension, and total/high-density lipoprotein cholesterol ratio were positively related to max cIMT. Presence of plaques was related to age, Disease Activity Score of 28 joints-erythrocyte sedimentation rate (DAS28-ESR), smoking, and any biological treatment. DAS28-ESR correlated positively not with cIMT but with the development of plaques in our patients with low disease activity (average DAS28-ESR of 2.7). Conclusion Disease Activity Score of 28 joints-erythrocyte sedimentation rate was related to the size and number of plaques, whereas only traditional risk factors were related to max cIMT. This indicated that the inflammatory conditions of RA could affect the formation of atherosclerotic plaques. For the management of CVD in patients with RA, it may be important to control not only traditional risk factors, but also RA disease activity.

Approximately, 70 % of acute myocardial infarctions are known to develop from mild atherosclerotic lesions. Therefore, it is important to evaluate mild coronary plaques to prevent acute coronary syndrome (ACS). The aim of the present study was to investigate the effects of exercise-based cardiac rehabilitation (CR) on mild coronary atherosclerosis in non-culprit lesions in patients with ACS. Forty-one men with ACS who underwent emergency percutaneous coronary interventions and completed a 6-month follow-up were divided into CR and non-CR groups. Quantitative coronary angiography (QCA) was performed using the automatic edge detection program. The target lesion was a mild stenotic segment (10–50 % stenosis) at the distal site of the culprit lesion, and the segment to be analyzed was determined at a segment length ranging from 10 to 15 mm. The plaque area was significantly decreased in the CR group after 6 months, but was significantly increased in the non-CR group (P

Aim This subanalysis aimed to clarify whether intensive lipid-lowering therapy with statins slows the progression of atherosclerosis in Japanese subjects under treatment for primary prevention of cardiovascular disease. Methods This was a subanalysis of the Justification for Atherosclerosis Regression Treatment (JART) Study. We compared the efficacy of intensive lipid-lowering therapy and conventional therapy with respect to changes in the mean intima-media thickness (IMT) and serum lipid levels. We also evaluated changes in the mean IMT over 24 months of treatment and assessed the relationship between these changes and reductions in the LDL-C levels using a post-hoc analysis. Results Intensive lipid-lowering therapy with rosuvastatin was associated with significantly smaller changes in the mean IMT and a greater reduction in the serum lipid levels in comparison to conventional therapy with pravastatin. The average net change in the mean IMT was 0.010 mm (n=121) at 12 months and -0.004 mm (n=56) at 24 months. A decrease in LDL-C was found to be associated with a smaller change in the mean IMT (p=0.0009; Jonckheere-Terpstra trend test). A greater reduction in serum LDL-C was found to be associated with a smaller change in the mean IMT. Similar associations were observed for the serum TC and non-HDL-C levels and LDL-C/HDL-C ratio. There were no notable differences in the incidence of serious adverse events among the LDL-C quartiles. Conclusions Lowering the LDL-C level with intensive lipid-lowering therapy is associated with reduced changes in the IMT among Japanese subjects at moderate to high risk under treatment for primary prevention. Subjects suitable for primary prevention may receive cardiovascular benefits from intensive lipid-lowering therapy, in association with significantly slower IMT progression than that observed with conventional therapy.

Background:Little is known about the differences between standard-dose statins effects on glucose level and lipids in Japanese patients with diabetes mellitus (DM).Methods and Results:The 1,049 patients were randomly assigned to either the rosuvastatin group or atorvastatin group. There were no significant differences between the 2 groups in the effect on non-high-density lipoprotein cholesterol (non-HDL-C) and HbA1c at 12 months. However, physicians tended to switch to more intensive therapy for DM in the atorvastatin group.Conclusions:Rosuvastatin 5 mg and atorvastatin 10 mg have a similar lowering effect on non-HDL-C, but might be different in terms of adverse effect on glucose levels. (Circ J 2014; 78: 2512–2515)

Background: Recently, it was reported from the Justification for Atherosclerosis Regression Treatment (JART) Study that intensive therapy with rosuvastatin significantly slowed progression of carotid intima-media thickness (IMT) compared with conventional therapy with pravastatin at 12 months. To assess the long-term efficacy of intensive therapy, the present extension study was conducted. Methods and Results: Subjects in the intensive therapy group of the JART Study were asked to participate in the extension study and to continue rosuvastatin treatment. A total of 113 subjects were enrolled into the extension study and were included in the analysis. At 24 months, the mean daily dose of rosuvastatin (±SD) was 7.9±2.9mg. Mean change in mean IMT was –0.005mm (range, –0.024 to 0.015mm) at 24 months (P=0.633, compared with baseline). Rosuvastatin lowered low-density lipoprotein cholesterol (mean±SD) by 46.4±13.8% and elevated high-density lipoprotein cholesterol (mean±SD) by 8.9±24.0% at 24 months compared with baseline. Gray scale median was measured in 25 subjects. It increased by 16.93±33.12 (mean±SD) % at 12 months and by 22.50±52.83% at 24 months from baseline (P=0.017, P=0.044, respectively). Conclusions: Two-year treatment with rosuvastatin inhibited progression of carotid IMT. Rosuvastatin also improved the plaque composition, and this qualitative change occurred relatively early after starting therapy. (Circ J 2013; 77: 1526–1533)

SummaryBackground and purposeThere have been no large-scale studies on the impact of diabetes mellitus (DM) on outcomes in Japanese patients undergoing coronary artery bypass grafting (CABG).Methods and subjectsA multi-institutional retrospective cohort study was conducted in 14 Japanese centers. All adult patients who underwent isolated CABG from 2007 to 2008 were included (n=1522, mean age: 68.5years). The definitions of DM were all patients admitted with diagnosis of DM and preoperative glycated hemoglobin (Hb) A1c≥6.5%. Univariate and multivariate analyses were performed to identify the risk of morbidity and mortality.ResultsThere were 849 DM and 572 non-DM patients. Preoperative mean HbA1c were 7.1% in the DM group and 5.7% in the non-DM group (p

Aim In Japan, heart disease and cerebral ischemic disease are major causes of death. A decrease in the level of low-density lipoprotein cholesterol (LDL-C) through intensive treatment with statins positively correlates with a reduction in the volume of plaques in patients with cardiovascular disease. The METEOR trial, evaluating the effect of rosuvastatin on carotid intima-media thickness (IMT), was conducted only in Europe and the US. Here we planned another trial, the Justification for Atherosclerosis Regression Treatment (JART) study, to clarify the efficacy of intensive lipid-lowering therapy with rosuvastatin in Japanese with atherosclerosis. Methods and results Four hundred patients with hypercholesterolemia (LDL-C >or=140 mg/dL) and a maximum IMT of >or=1.1 mm will be treated for 24 months either with intensive lipid-lowering therapy with rosuvastatin (target LDL-C levels: 80 mg/dL for primary prevention, and 70 mg/dL for secondary prevention) or conventional lipid-lowering therapy with pravastatin (target LDL-C level: complying with JASGL2007). The primary endpoint will be the percent change of mean-IMT and the objectives of the study are to compare the two protocols. Conclusion The JART trial is a prospective, randomized, open-label, blinded end-point evaluation, multi-center, parallel-group, comparative study to examine the regressive effect of intensive lipid-lowering therapy with statins on atherosclerosis by evaluating IMT in the Japanese population.

Endothelium-derived nitric oxide (NO) plays an important role in the prevention of platelet aggregation and adhesion to the vascular wall. Endothelial nitric oxide synthase (eNOS) and L-arginine/NO pathway are both present in human platelets. Platelet-derived NO inhibits excessive activation and aggregation of platelets. However, the expression level of the eNOS gene in human platelets has yet to be elucidated. The current study investigates the individual expression level of platelet eNOS mRNA using the real-time reverse transcriptase-polymerase chain reaction (RT-PCR) detection method. eNOS mRNA expression was examined in platelets isolated from 50 subjects: 11 male smokers, 15 male nonsmokers, and 24 female non-smokers. After extraction of platelet total RNA, eNOS (target) and GAPDH (internal control) mRNA expression levels were quantitated using real-time RT-PCR. The expression levels of eNOS mRNA (relative copy numbers) were significantly lower in male smokers (59±17) than in male nonsmokers (195±71, P < .03), and higher in female nonsmokers (285±60) than in the male nonsmokers (195±71, P < .03). By multiple linear regression analysis, cigarette smoking ( P = .008) and diabetes mellitus ( P = .047) were found to be significantly negative predictors, and antioxidant (vitamin E) treatment ( P = .01) was a significantly positive predictor of platelet eNOS mRNA expression. Age, other medications, and other risk factors for coronary artery disease were not significant. Using this method, eNOS mRNA abundance in human platelets was detected and quantitated in real-time. The intraplatelet eNOS mRNA expression levels were significantly decreased in cigarette smokers. Low platelet NO synthesis in smokers may result in the augmentation of platelet aggregation and thrombus formation, developing into acute coronary syndromes.