Sex differences in the association between epicardial adipose tissue volume and left atrial volume index.

BACKGROUND: Sex disparities in the association between epicardial adipose tissue volume (EATV) and cardiovascular disease have been reported. The sex-dependent effects of EATV on left atrial (LA) size have not been elucidated. METHODS: Consecutive 247 subjects (median 65 [interquartile range 57, 75] years; 67% of men) who underwent multi-detector computed tomography without significant coronary artery disease or moderate to severe valvular disease were divided into two groups: patients with sinus rhythm (SR) or atrial fibrillation (AF). Sex differences in the association between the EATV index (EATVI) (mL/m2) and LA volume index (LAVI) in 63 SR (28 men and 35 women) and 184 AF (137 men and 47 women) patients were evaluated using univariate and multivariate regression analyses. RESULTS: In overall that includes both men and women, the relationship between EATVI and LAVI was not significantly correlated for patients with SR and AF. The relationship between EATVI and LAVI differed between men and women in both SR and AF groups. In SR patients, there was a positive relationship between EATVI and LAVI in men, but not in women. In contrast, in patients with AF, a negative relationship was found between EATVI and LAVI in women, whereas no association was found in men. CONCLUSIONS: We evaluated sex differences in the association between EATVI and LAVI in patients with either SR or AF, and found a positive relationship in men with SR and a negative relationship in women with AF. This is the first report to evaluate sex differences in the relationship between EATVI and LAVI, suggesting that EAT may play a role, at least in part, in sex differences in the etiology of AF.

Respiratory Displacement of the Right Adrenal Vein: Comparison of Inspiratory and Expiratory Computed Tomography With Catheter Venography.

OBJECTIVE: The aim of the study is to reveal the respiratory displacement of the right adrenal vein (RAV) to predict the exact location of the RAV during adrenal venous sampling (AVS). METHODS: Computed tomography (CT) scans obtained 45 seconds (breath-hold at inhalation) and 70 seconds (breath-hold at exhalation) after contrast material injection were compared to venograms of the RAV of patients with primary aldosteronism who underwent AVS between January 2016 and December 2020. The craniocaudal distance between the center of the Th11/12 disc and the RAV orifice was measured; the craniocaudal location of the RAV orifice was also specified relative to vertebral bodies and intervertebral discs on inspiratory phase CT (In-CT), expiratory phase CT (Ex-CT), and catheter venography. The transverse and vertical angles of the RAV and the position of the RAV orifice on the inferior vena cava (IVC) circumference were measured on In-CT and Ex-CT. RESULTS: In total, 51 patients (30 males, 21 females; mean age, 54.9 ± 11.1 years) were included. Craniocaudal distances between the center of the Th11/12 disc and RAV orifice were significantly different among the following 3 acquisitions: catheter venography versus In-CT (15.2 ± 8.4 mm); venography versus Ex-CT (5.6 ± 4.1 mm); and In-CT versus Ex-CT (19.6 ± 8.0 mm) (all, P < 0.001). The craniocaudal location of the RAV orifice on venography was significantly closer to that on Ex-CT than on In-CT (P < 0.001); measurements using venograms compared with In-CT and Ex-CT scans were within 1 level difference in 18 (35.3%) and 47 (92.2%) patients, respectively (P < 0.001). The vertical angle of the RAV was significantly more likely to be smaller on In-CT than on Ex-CT (P < 0.001). CONCLUSIONS: RAV locations and angles change with respiratory motion. It is crucial to consider the respiratory phase of CT because it can enable a more accurate prediction of the location of the RAV during AVS.

Rationale and design of an investigator-initiated, multicenter, prospective, placebo-controlled, double-blind, randomized trial to evaluate the effects of finerenone on vascular stiffness and cardiorenal biomarkers in type 2 diabetes and chronic kidney disease (FIVE-STAR).

BACKGROUND: The overactivation of mineralocorticoid receptor (MR) plays a key pathological role in the progression of cardiovascular and renal diseases by promoting pro-inflammatory and pro-fibrotic signaling. Recently, it has been found that finerenone, a novel nonsteroidal selective MR antagonist, can robustly improve cardiorenal outcomes in patients with type 2 diabetes (T2D) and a wide spectrum of chronic kidney disease (CKD). However, the mechanisms underlying the cardiorenal benefits of finerenone are poorly understood. Further, whether the clinical benefits are mediated by an improvement in vascular stiffness is not confirmed. Therefore, the current study aims to evaluate the effects of finerenone on vascular stiffness as assessed using cardio ankle vascular index (CAVI) and relevant cardiorenal biomarkers in patients with T2D and CKD. METHODS: The Effects of Finerenone on Vascular Stiffness and Cardiorenal Biomarkers in Type 2 Diabetes and Chronic Kidney Disease (FIVE-STAR) is an ongoing, investigator-initiated, multicenter, prospective, placebo-controlled, double-blind, randomized clinical trial in Japan. Its target sample size is 100 subjects. Recruitment will be performed from September 2023 to July 2024. After obtaining informed consent, eligible participants with T2D and CKD (25 mL/min/1.73 m2 ≤ estimated glomerular filtration ratio [eGFR] < 90 mL/min/1.73 m2 and 30 mg/g Cr ≤ urinary albumin-to-creatinine ratio [UACR] < 3500 mg/g Cr) will be equally randomized to receive 24-week treatment with either finerenone (starting dose at 10 mg once daily in participants with a baseline eGFR < 60 mL/min/1.73 m2 or at 20 mg once daily in those with a baseline eGFR ≥ 60 mL/min/1.73 m2) or dose-matched placebo. The primary endpoint is the change from baseline in CAVI at 24 weeks. The secondary endpoints are changes from baseline in UACR at 12 and 24 weeks and relevant serum and urinary biomarkers at 24 weeks. As an exploratory endpoint, proteomic analysis using the Olink® Target 96 panels will be also performed. DISCUSSION: FIVE-STAR is the first trial evaluating the therapeutic impact of finerenone on vascular stiffness and relevant cardiorenal biomarkers in patients with T2D and CKD. This study will provide mechanistic insights on the clinical benefits of finerenone based on recent cardiovascular and renal outcome trials. Trial registration Unique Trial Number, NCT05887817 ( https://clinicaltrials.gov/ct2/show/NCT05887817 ) and jRCTs021230011 ( https://jrct.niph.go.jp/latest-detail/jRCTs021230011 ).

Canagliflozin reduces proteinuria by targeting hyperinsulinaemia in diabetes patients with heart failure: A post hoc analysis of the CANDLE trial.

AIM: To investigate factors associated with proteinuria regression in patients with type 2 diabetes mellitus (T2DM) treated with canagliflozin. MATERIALS AND METHODS: This study was a post hoc analysis of the CANDLE trial (UMIN000017669), which compared the effect of 24 weeks of treatment with canagliflozin or glimepiride for changes in N-terminal pro-brain natriuretic peptide in patients with T2DM and chronic heart failure (CHF). Factors associated with regression of proteinuria at 24 weeks were evaluated with multivariate logistic models. RESULTS: The rate of regression of proteinuria was higher (28/102, 27.5% vs. 12/112, 10.7%), and that of progression was lower (9/102, 8.8% vs. 26/112, 23.2%), in the canagliflozin versus the glimepiride group (P = .0001). There were no differences in the change in the estimated glomerular filtration rate category between groups. Insulin level, homeostatic model assessment of ß-cell function, homeostatic model assessment for insulin resistance and estimated plasma volume were decreased at 24 weeks in the regression subclass but not in the progression subclass, suggesting that regression of proteinuria is associated with the declines in these values in the canagliflozin group. Higher insulin level at baseline was solely associated with proteinuria regression in the multivariate logistic regression model (baseline insulin, as per a 1-mlU/L increase, odds ratio 1.24 [1.05-1.47], P = .011). CONCLUSIONS: In patients with T2DM and CHF, regression of proteinuria with canagliflozin treatment was associated with the pretreatment insulin level. These results may provide clinicians with novel mechanistic insights into the beneficial effects of canagliflozin on renal outcomes and may warrant discussion for selecting preferred patient profiles, including pretreatment insulin levels.

Association of polypharmacy with incidence of CKD: a retrospective cohort study.

BACKGROUND: Polypharmacy is common in patients with chronic kidney disease (CKD) and is associated with a decline in kidney function. However, its impact on patients without CKD has not been adequately elucidated. Therefore, we aimed to investigate the association between polypharmacy and the incidence of CKD. METHODS: We conducted retrospective cohort study using 1221 participants who were enrolled in the Fukushima Cohort Study with one or more risk factors of CKD, an estimated glomerular filtration rate (eGFR) of ≥ 60 mL/min/1.73 m2, and without proteinuria. Participants were categorized into three groups based on the number of medications: non-polypharmacy, 0-4 medications; polypharmacy, 5-9 medications; and hyper-polypharmacy, ≥ 10 medications. RESULTS: The median age was 62 years, 49% were men, the median eGFR was 75.4 ml/min/1.73 m2, and the median number of medications was 5. Polypharmacy and hyper-polypharmacy were noted in 506 (41%) and 250 (20%) participants, respectively. During follow-up, 288 participants developed CKD and 67 cardiovascular events were observed. Compared to the non-polypharmacy group, the hyper-polypharmacy group had a higher risk of CKD and cardiovascular events. The adjusted hazard ratios were 1.41 (95% CI1.01-1.99) and 2.24 (95% CI1.05-4.78) for the incidence of CKD and cardiovascular events, respectively. Sensitivity analyses yielded similar findings for the restricted cubic spline function models. CONCLUSIONS: Hyper-polypharmacy is associated with a higher risk of CKD and cardiovascular events.

Hematological parameters of anemia and prognosis of non-dialysis-dependent chronic kidney disease: the Fukushima CKD cohort study.

BACKGROUND: Mean corpuscular volume (MCV) and red cell distribution width (RDW), as well hemoglobin, are reported to be associated with mortality in various populations. However, associations between such hematological parameters and adverse outcomes in patients with CKD have not been sufficiently elucidated. METHODS: A total of 1,320 participants enrolled in the Fukushima CKD Cohort Study were examined to investigate associations between hematological parameters of anemia (MCV and RDW) and adverse outcomes, such as ESKD, all-cause death, and cardiovascular events, in patients with non-dialysis-dependent CKD. Baseline hematological parameters were grouped as follows: hemoglobin into 3 categories (< 11.0 g/dL, 11.0 ≤ - < 13.0 g/dL [reference], and ≥ 13.0 g/dL); MCV into 5 categories (< 90 fL, ≥ 90 - < 94 fL [reference], ≥ 94 - < 98 fL, ≥ 98 - < 102 fL, and ≥ 102 fL); and RDW into 2 categories (< 13.6% [reference] vs ≥ 13.6%). RESULTS: During the median observational period of 4.7 years, 120 patients developed ESKD, 160 developed cardiovascular events, and 122 died. Hemoglobin < 11 g/dL (hazard ratio [HR] 1.56, 95% confidence interval [CI], 1.00-2.42), MCV < 90 fL (HR 2.01, 95% CI 1.14-3.54), and RDW ≥ 13.6% (HR 1.57, 95% CI 1.01-2.42) were significantly associated with higher risks of ESKD. Hemoglobin < 11 g/dL, MCV ≥ 98 fL, and RDW ≥ 13.6% were significantly associated with higher risks of all-cause death. No significant associations between hematological parameters and risk of cardiovascular events were confirmed. CONCLUSION: In patients with non-dialysis-dependent CKD, MCV, RDW, and hemoglobin were associated with increased risks of ESKD and all-cause mortality.

Influence of post-disaster evacuation on childhood obesity and liver dysfunction: The Fukushima Health Management Survey.

BACKGROUND: After the Great East Japan Earthquake and subsequent Fukushima Daiichi Nuclear Power Plant accident in 2011, the Fukushima Prefectural Government launched a long-term health management survey for the population of Fukushima. Results of the Comprehensive Health Check (CHC) showed that some children aged 6-15 years, who resided in the evacuation area at the time of the disaster, had obesity, hyperlipidemia, liver dysfunction, and/or renal dysfunction from as early as 2011. The aim of the present study was to determine the long-term trend of obesity and hepatic enzyme abnormalities in Fukushima children. METHODS: We evaluated the changes in body mass index standard deviation score (BMI-SDS), aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transpeptidase from 2011 to 2018. RESULTS: Obesity (BMI-SDS ≥ 2) was significantly associated with hepatobiliary enzyme abnormalities. The mean BMI-SDS was significantly higher in 2011 after the disaster, but then soon showed a gradual decrease. The frequency of obesity did not increase significantly after the disaster. There were no significant differences in the prevalence of hepatobiliary enzyme abnormalities in the children aged 6-15 years of either sex from 2011 to 2018. CONCLUSIONS: In the present study, we found that the increase in the mean BMI-SDS after the disaster was temporary, suggesting that the frequency of obesity and liver dysfunction might not have been significantly influenced by the disaster.

Obesity and glucose metabolism abnormalities by post-disaster evacuation.

BACKGROUND: The objectives of this study were to determine the longer-term trends in childhood obesity and glucose metabolism abnormalities among residents of Fukushima Prefecture 5 years after the Great East Japan Earthquake. METHODS: We evaluated the changes in height, weight, body mass index (BMI), BMI SD score, fasting plasma glucose (FPG) concentration, and hemoglobin A1c (HbA1c) among elementary and junior high school residents who had lived in the evacuation zone between 2011 and 2015. RESULTS: Of the residents, 11,112 received health checks in 2011, while in 2012, 2013, 2014, and 2015, 5,737, 4522, 4297 and 3405 received health checks, respectively. The mean BMI SD score for all participants in 2011 was 0.149, and this score gradually decreased from 2011 to 2015. FPG levels and HbA1c levels for all participants with a BMI value +2SD or more in 2011 were higher than those in residents with a BMI value of less than +2SD. The frequency of participants with a FPG level of 126 mg/dl or more and the frequency of participants with a HbA1c level of 6.5% or more in 2011 were higher than those in 2012, 2013, and 2015. CONCLUSIONS: These results suggest that a number of pediatric residents suffered from obesity and glucose metabolism abnormalities. However, the longer-term observations indicated an improvement in obesity and glucose metabolism abnormalities. There was a strong association observed between obesity and glucose metabolism, thus, it is important to continue with health checks for children with obesity and strive to improve their health.

Blood data trends of children in Fukushima after the Great East Japan Earthquake: Fukushima health management survey.

BACKGROUND: After the Great East Japan Earthquake on March 11, 2011 and the subsequent accident at the Tokyo Electric Power Company-operated Daiichi Nuclear Power Plant, the Fukushima Prefecture government initiated the Fukushima Health Management Survey (FHMS) to assess the long-term health effects of the disaster on Fukushima residents. The blood tests of children aged ≤15 years between 2011 and 2012 did not reveal any changes regarding peripheral blood data; however, long-term monitoring is still necessary. Therefore, this study aimed to investigate the long-term health status of children aged ≤15 years who had evacuated the Fukushima Prefecture. METHODS: From 2011 to 2018, 71,250 evacuees aged 15 years or younger participated in the FMHS and were subjected to blood tests. By analyzing the data of the comprehensive health check survey managed by the FHMS, we examined the changes in hemoglobin (Hb) levels, white blood cell (WBC) counts, including fractions, and platelet (PLT) counts among children from 2011 to 2018. RESULTS: Minor fluctuations in Hb levels, PLT counts, and WBC counts were observed during the study period, but the central 95% intervals of distribution of the laboratory values were generally within previously reported reference intervals. In particular, there was no increase in the proportions of patients with anemia, polycythemia, or deviating WBC counts. CONCLUSION: From 2011 to 2018, there was no increase in the percentages of children with anemia, polycythemia, or deviating WBC counts among the Fukushima Prefecture evacuees.

[Clinical Features of Endocrine Disorders with Immune Checkpoint Inhibitor in Patients with Non-Small Cell Lung Cancer].

Immune checkpoint inhibitors(ICIs)could cause immune-related adverse events(irAEs), of which endocrine disorders are relatively common. Symptoms include fatigue, anorexia, and shock, making diagnosis and treatment difficult. This study aimed to analyze the characteristics of patients with non-small cell lung cancer concomitant with endocrine disorders as irAEs. In total, 83 patients who were administered ICIs for advanced or postoperative recurrent non-small cell lung cancer between February 2016 and February 2021 were identified. We retrospectively studied the clinical course and findings of 7 patients who developed endocrine disorders after treatment. Four patients had hypopituitarism, and 3 patients had thyroid dysfunctions. There were 6 male patients and 1 female patient. Regarding anticancer agents, 5 patients received ICI alone, and 2 patients received ICI plus cytotoxic chemotherapies. The patients received treatment from the irAE treatment team in our hospital, and 5 of 7 patients could were able to be readministered ICIs. Endocrine disorders as irAEs require collaboration with specialized departments for early diagnosis and treatment.

Association between serum insulin levels and heart failure-related parameters in patients with type 2 diabetes and heart failure treated with canagliflozin: a post-hoc analysis of the randomized CANDLE trial.

BACKGROUND: Insulin resistance and hyperinsulinemia in patients with type 2 diabetes (T2D) are adversely associated with the development and worsening of heart failure (HF). Herein, we sought to investigate the effect of canagliflozin on insulin concentrations and the associations of changes in insulin concentrations with HF-related clinical parameters in patients with T2D and HF. METHODS: This was a post-hoc analysis of the investigator-initiated, multicenter, open-label, randomized, controlled CANDLE trial for patients with T2D and chronic HF (UMIN000017669). The endpoints were the effects of 24 weeks of canagliflozin treatment, relative to glimepiride treatment, on insulin concentrations and the relationship between changes in insulin concentrations and clinical parameters of interest, including New York Heart Association (NYHA) classification. The effects of canagliflozin on those parameters were also analyzed by baseline insulin level. RESULTS: Among the participants in the CANDLE trial, a total of 129 patients (canagliflozin, n = 64; glimepiride, n = 65) who were non-insulin users with available serum insulin data both at baseline and week 24 were included in this analysis. Overall, the mean age was 69.0 ± 9.4 years; 75% were male; the mean HbA1c was 6.8 ± 0.7%; and the mean left ventricular ejection fraction was 59.0 ± 14.1%, with parameters roughly balanced between treatment groups. Canagliflozin treatment significantly reduced insulin concentrations at week 24 (p < 0.001), and the between-group difference (canagliflozin minus glimepiride) in those changes was - 3.52 mU/L (95% confidence interval, - 4.85 to - 2.19; p < 0.001). Decreases in insulin concentrations, irrespective of baseline insulin level, were significantly associated with improvement in NYHA class in patients treated with canagliflozin. CONCLUSION: Our findings suggest that canagliflozin treatment in patients with T2D and HF ameliorated excess insulin overload, contributing to the improvement of clinical HF status. TRIAL REGISTRATION: University Medical Information Network Clinical Trial Registry, number 000017669, Registered on May 25, 2015.

Effects of External Radiation Exposure Resulting From the Fukushima Daiichi Nuclear Power Plant Accident on the Health of Residents in the Evacuation Zones: the Fukushima Health Management Survey.

BACKGROUND: Associations have been reported between lifestyle-related diseases and evacuation after the Great East Japan Earthquake (GEJE). However, the relationship between lifestyle-related diseases and the effective radiation dose due to external exposure (EDEE) after the GEJE remains unclear. METHODS: From among 72,869 residents of Fukushima Prefecture (31,982 men; 40,887 women) who underwent a comprehensive health check in fiscal year (FY) 2011, the data of 54,087 residents (22,599 men; 31,488 women) aged 16 to 84 years were analyzed. The EDEE data of 25,685 residents with incomplete results from the basic survey, performed to estimate the external radiation exposure dose, were supplemented using multiple imputation. The data were classified into three groups based on EDEE (0 to <1, 1 to <2, and ≥2 mSv groups and associations between the incidence of diseases and EDEE from FY2011 to FY2017 were examined using a Cox proportional hazards model, with FY2011 as the baseline. RESULTS: A higher EDEE was associated with a greater incidence of hypertension, diabetes mellitus, dyslipidemia, hyperuricemia, liver dysfunction, and polycythemia from FY2011 to FY2017 in the age- and sex-adjusted model. However, after further adjustment for evacuation status and lifestyle-related factors, the significant associations disappeared. No association was found between EDEE and other lifestyle-related diseases. CONCLUSION: EDEE was not directly associated with the incidence of lifestyle-related diseases after the GEJE. However, residents with higher external radiation doses in Fukushima Prefecture might suffer from lifestyle-related diseases related to evacuation and the resultant lifestyle changes.

Trends in Lifestyle-related Diseases and Their Risk Factors After the Fukushima Daiichi Nuclear Power Plant Accident: Results of the Comprehensive Health Check in the Fukushima Health Management Survey.

Residents were forced to evacuate owing to the radiation released after the Fukushima Nuclear Power Plant (NPP) accident following the Great East Japan Earthquake on 11/03/2021; thus, their lifestyles drastically changed. The Comprehensive Health Check (CHC) of the Fukushima Health Management Survey (FHMS) was performed to evaluate health statuses and prevent lifestyle-related diseases in evacuation area residents. The first part of the CHC survey is a retrospective analysis of pre- and post-disaster data on health check-ups of evacuation area residents. The second part is a cross-sectional, prospective analysis of post-disaster (fiscal year (FY) 2011-2017) data on health check-ups. Subjects were men and women living in 13 municipalities in areas surrounding the NPP in Fukushima Prefecture. Post-disaster (FY 2011-2012) overweight, hypertension, dyslipidemia, diabetes mellitus, metabolic syndrome, liver dysfunction, hyperuricemia, polycythemia and atrial fibrillation cases increased from the pre-disaster (FY 2008-2010) levels. This tendency was strongest among residents who were forced to evacuate. Proportion of overweight people remained unchanged, the prevalence of liver dysfunction decreased and the proportion of people with treated hypertension and dyslipidemia increased during FY 2011-2017. Meanwhile, the prevalence of diabetes mellitus and mean levels of HbA1c increased. Furthermore, Evacuees showed higher risks of diabetes mellitus, dyslipidemia, chronic kidney diseases and liver dysfunction than non-evacuees. Therefore, residents in the evacuation area, especially evacuees, are at high risk of developing lifestyle-related diseases, especially cardiovascular diseases; therefore, it is necessary to observe health statuses and implement measures to prevent lifestyle-related diseases.

Relationship Between Risk of Hyper-Low-density Lipoprotein Cholesterolemia and Evacuation After the Great East Japan Earthquake.

BACKGROUND: The Great East Japan Earthquake and the Fukushima Daiichi nuclear disaster forced the evacuation of residents and led to many changes in lifestyle for the evacuees. The Comprehensive Health Check was implemented to support the prevention of lifestyle-related disease and we analyzed the effect of prolonged evacuation (average of 3.0 years) on the new onset of hyper-LDL cholesterolemia. METHODS: The study participants were Japanese adults living near the Fukushima Daiichi nuclear power plant in Fukushima Prefecture. Annual health checkups focusing on metabolic syndromes were conducted for persons ≥40 years by the Specific Health Checkup. Based on data from annual checkups from 2011 or 2012, we followed 18,670 participants without hyper-LDL cholesterolemia who underwent at least one other annual checkup during 2013-2015. RESULTS: We found that the new onset of hyper-LDL cholesterolemia was 31% higher in evacuees than in non-evacuees. Evacuees had a significantly higher prevalence of obesity, hypertension, and diabetes, and higher frequency of weight change. Furthermore, logistic regression model analysis showed that the evacuation was significantly associated with the new onset of hyper-LDL cholesterolemia after adjusting age, gender, body mass index, smoking habit, alcohol consumption, diabetes, weight change, sleep deprivation, and exercise. CONCLUSION: The findings of the present study suggest that prolonged evacuation after a disaster is a risk factor for the new onset of hyper-LDL cholesterolemia, and lead to an increase in cardiovascular disease. It is therefore important to follow-up evacuees and recommend lifestyle changes where necessary.

STING, a cytosolic DNA sensor, plays a critical role in atherogenesis: a link between innate immunity and chronic inflammation caused by lifestyle-related diseases.

AIMS: Lifestyle-related diseases promote atherosclerosis, a chronic inflammatory disease; however, the molecular mechanism remains largely unknown. Endogenous DNA fragments released under over-nutrient condition provoke sterile inflammation through the recognition by DNA sensors. Here, we investigated the role of stimulator of interferon genes (STING), a cytosolic DNA sensor, in atherogenesis. METHODS AND RESULTS: Apolipoprotein E-deficient (Apoe-/-) mice fed a western-type diet (WTD), a hypercholesterolaemic mouse model, showed higher STING expression and markers for DNA damage such as γH2AX, p53, and single-stranded DNA (ssDNA) accumulation in macrophages in the aorta compared with wild-type (WT) mice. The level of cGAMP, a STING agonist, in the aorta was higher in Apoe-/- mice. Genetic deletion of Sting in Apoe-/- mice reduced atherosclerotic lesions in the aortic arch, lipid, and macrophage accumulation in plaques, and inflammatory molecule expression in the aorta compared with the control. Pharmacological blockade of STING using a specific inhibitor, C-176, ameliorated atherogenesis in Apoe-/- mice. In contrast, bone marrow-specific STING expression in Apoe-/- mice stimulated atherogenesis. Expression or deletion of STING did not affect metabolic parameters and blood pressure. In vitro studies revealed that STING activation by cGAMP or mitochondrial DNA accelerated inflammatory molecule expression (e.g. TNF-α or IFN-ß) in mouse and human macrophages. Activation of nuclear factor-κB and TANK binding kinase 1 was involved in STING-associated vascular inflammation and macrophage activation. Furthermore, human atherosclerotic lesions in the carotid arteries expressed STING and cGAMP. CONCLUSION: Stimulator of interferon genes stimulates pro-inflammatory activation of macrophages, leading to the development of atherosclerosis. Stimulator of interferon genes signalling may serve as a potential therapeutic target for atherosclerosis.

Reduction of estimated fluid volumes following initiation of empagliflozin in patients with type 2 diabetes and cardiovascular disease: a secondary analysis of the placebo-controlled, randomized EMBLEM trial.

BACKGROUNDS/AIM: Sodium glucose co-transporter 2 inhibitors promote osmotic/natriuretic diuresis and reduce excess fluid volume, and this improves cardiovascular outcomes, including hospitalization for heart failure. We sought to assess the effect of empagliflozin on estimated fluid volumes in patients with type 2 diabetes and cardiovascular disease (CVD). METHODS: The study was a post-hoc analysis of the EMBLEM trial (UMIN000024502), an investigator-initiated, multi-center, placebo-controlled, double-blinded, randomized-controlled trial designed primarily to evaluate the effect of 24 weeks of empagliflozin treatment on vascular endothelial function in patients with type 2 diabetes and established CVD. The analysis compared serial changes between empagliflozin (10 mg once daily, n = 52) and placebo (n = 53) in estimated plasma volume (ePV), calculated by the Straus formula and estimated the extracellular volume (eEV), determined by the body surface area, measured at baseline and 4, 12, and 24 weeks after initiation of treatment. Correlations were examined between the changes from baseline to week 24 in each estimated fluid volume parameter and several clinical variables of interest, including N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration. RESULTS: In an analysis using mixed-effects models for repeated measures, relative to placebo empagliflozin reduced ePV by - 2.23% (95% CI - 5.72 to 1.25) at week 4, - 8.07% (- 12.76 to - 3.37) at week 12, and - 5.60% (- 9.87 to - 1.32) at week 24; eEV by - 70.3 mL (95% CI - 136.8 to - 3.8) at week 4, - 135.9 mL (- 209.6 to - 62.3) at week 12, and - 144.4 mL (- 226.3 to - 62.4) at week 24. The effect of empagliflozin on these parameters was mostly consistent across various patient clinical characteristics. The change in log-transformed NT-proBNP was positively correlated with change in ePV (r = 0.351, p = 0.015), but not with change in eEV. CONCLUSIONS: Our data demonstrated that initiation of empagliflozin treatment substantially reduced estimated fluid volume parameters in patients with type 2 diabetes and CVD, and that this effect was maintained for 24 weeks. Given the early beneficial effect of empagliflozin on cardiovascular outcomes seen in similar patient populations, our findings provide an important insight into the key mechanisms underlying the clinical benefit of the drug. Trial registration University Medical Information Network Clinical Trial Registry, number 000024502.

Comparison of the clinical effect of empagliflozin on glycemic and non-glycemic parameters in Japanese patients with type 2 diabetes and cardiovascular disease treated with or without baseline metformin.

BACKGROUND: The most recent treatment guidelines for type 2 diabetes (T2D) recommend sodium-glucose cotransporter 2 (SGLT2) inhibitors should be considered preferentially in patients with T2D with either a high cardiovascular risk or with cardiovascular disease (CVD), regardless of their diabetes status and prior use of conventional metformin therapy. Whether the therapeutic impact of SGLT2 inhibitors on clinical parameters differs according to the use of metformin therapy however remains unclear. METHODS: The study was a post hoc analysis of the EMBLEM trial (UMIN000024502). All participants (n = 105; women 31.4%; mean age 64.8 years) had both T2D and CVD and were randomized to either 24 weeks of empagliflozin 10 mg daily or placebo. Analysis of the data assessed the effect of empagliflozin on changes from baseline to 24 weeks in glycemic and non-glycemic clinical parameters, according to the baseline use of metformin. RESULTS: Overall, 53 (50.5%) patients received baseline metformin. In the 52 patients treated with empagliflozin (48.1% with baseline metformin), the decrease in systolic blood pressure from baseline levels was greater in patients receiving metformin, compared to that observed in metformin-naïve patients (group difference - 8.5 [95% confidence interval (CI) - 17.7 to 0.6 mmHg], p = 0.066). Reduction in body mass index (BMI) was significantly greater in patients receiving baseline metformin, relative to nonusers (- 0.54 [95% CI - 1.07 to - 0.01] kg/m2, p = 0.047). The group ratio (baseline metformin users vs. nonusers) of proportional changes in the geometric mean of high-sensitivity Troponin-I (hs-TnI) was 0.74 (95% CI 0.59 to 0.92, p = 0.009). No obvious differences were observed in glycemic parameters (fasting plasma glucose, glycohemoglobin, and glycoalbumin) between the baseline metformin users and nonusers. CONCLUSION: Our findings suggest 24 weeks of empagliflozin treatment was associated with an improvement in glycemic control, irrespective of the baseline use of metformin therapy. The effects of empagliflozin on reductions in BMI and hs-TnI were more apparent in patients who received baseline metformin therapy, compared to that observed in metformin-naïve patients. Trial registration University Medical Information Network Clinical Trial Registry, number 000024502.

Evacuation after the Great East Japan Earthquake is an independent factor associated with hyperuricemia: The Fukushima Health Management Survey.

BACKGROUND AND AIMS: On March 11, 2011, the Great East Japan Earthquake occurred in Japan, with a nuclear accident subsequently occurring at the Fukushima Daiichi Nuclear Power Plant. The disaster forced many evacuees to change particular aspects of their lifestyles. This study assessed the association between evacuation and hyperuricemia based on the Fukushima Health Management Survey from a lifestyle and socio-psychological perspective. METHODS AND RESULTS: This cross-sectional study included 22,812 residents (9391 men and 13,297 women) who underwent both the Comprehensive Health Check and the Mental Health and Lifestyle Survey in fiscal year 2011. Associations between hyperuricemia and lifestyle- and disaster-related factors including evacuation were estimated using a logistic and liner regression analysis. With hyperuricemia defined as uric acid levels >7.0 mg/dL for men and >6.0 mg/dL for women, significant associations were observed between evacuation and hyperuricemia in men (the multivariate-adjusted odds ratio 1.20, 95% confidence interval, 1.05-1.36, p = 0.005), but not in women. In the multivariate-adjusted multiple liner regression analysis, evacuation had significant and positive associations with uric acid levels both in men (ß = 0.084, p = 0.002) and women (ß = 0.060, p < 0.001). CONCLUSION: Evacuation after a natural disaster is an independent factor associated with hyperuricemia.

Association between serum potassium levels and adverse outcomes in chronic kidney disease: the Fukushima CKD cohort study.

BACKGROUND: Serum potassium disorders, commonly observed in chronic kidney disease (CKD), are reportedly associated with higher mortality, but their impact on renal outcomes is still controversial. METHODS: The present study used the longitudinal data of the Fukushima CKD cohort study to investigate the relationships between hypokalemia and hyperkalemia and adverse outcomes such as renal outcomes and all-cause mortality in Japanese patients with non-dialysis-dependent CKD. The study involved 1330 CKD patients followed-up for 2.8 years. The primary endpoint of the present study was a kidney event, defined as a combination of doubling of baseline serum creatinine and end-stage kidney disease. RESULTS: Hyperkalemia (≥ 5.0 mmol/L) was noted in 10.6% and hypokalemia (< 4.0 mmol/L) in 16.4% of the study population. Significant U-shaped associations were observed between potassium levels and both kidney events and all-cause mortality on univariate Cox regression analyses. After adjustment for covariates, both hypokalemia and hyperkalemia were significantly associated with an increased risk of kidney events, with the lowest risk at a serum potassium of 4.0-4.4 mmol/L. Compared with a reference level of 4.0-4.4 mmol/L, the adjusted hazard ratio for kidney events was 2.49 (1.33-4.66) for serum potassium < 4.0 mmol/L, 1.72 (1.00-2.96) for 4.5-4.9 mmol/L, and 2.16 (1.15-4.06) for ≥ 5.0 mmol/L. There was no significant association between serum potassium levels and mortality after multivariate adjustment. CONCLUSION: Hypokalemia and hyperkalemia were associated with an increased risk of CKD progression, but not with mortality in Japanese patients with non-dialysis-dependent CKD.

Retrospective exploratory analyses on gender differences in determinants for incidence and progression of diabetic retinopathy in Japanese patients with type 2 diabetes mellitus.

Gender differences in risks for macrovascular complications in type 2 diabetes mellitus (T2DM) have been well established. However, the impact of gender differences on diabetic retinopathy (DR) has not been fully elucidated. We therefore retrospectively explored gender-specific determinants for DR in patients with T2DM in a small sized Japanese cohort in Okinawa. There were 214 patients who were diagnosed as no DR (n = 142) and non-proliferative DR (n = 72) in 2009. During the follow-up of median 7 years, 41/142 of incidence, 26/72 of progression, and 67/214 of incidence and progression were observed, respectively. DR was assessed using the modified international clinical DR severity scales. The risks for incidence, progression as well as incidence and progression of DR were comparable between men and women, respectively. Cox proportional hazard models in multivariate analyses demonstrated that the only common determinant in both men and women for DR was the duration of T2DM. Regarding gender-specific determinants, lower level of serum albumin in men as well as higher HbA1c, lower level of estimated glomerular filtration rate, and lower level of serum uric acid in women were extracted, respectively. Although precise mechanisms for such gender-specific determinants of DR still remain unsolved, the present study would highlight a couple of factors associated with gender-specific determinants for DR in a limited numbers of Japanese cohort. Prospective observational studies on gender-specific determinants of DR in a large scale cohort are warranted to further clarify underlying mechanisms.