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Abstract Atrial fibrillation (AF) is an arrhythmic disease. Prediction of AF development in healthy individuals is important before serious complications occur. We aimed to develop a risk prediction score for future AF using participants’ data, including electrocardiogram (ECG) measurements and information such as age and sex. We included 88,907 Japanese participants, aged 30–69 years, who were randomly assigned to derivation and validation cohorts in a ratio of 1:1. We performed multivariate logistic regression analysis and obtained the standardised beta coefficient of relevant factors and assigned scores to them. We created a score based on prognostic factors for AF to predict its occurrence after five years and applied it to validation cohorts to assess its reproducibility. The risk score ranged from 0 to 17, consisting of age, sex, PR prolongation, QT corrected for heart rate prolongation, left ventricular hypertrophy, premature atrial contraction, and left axis deviation. The area under the curve was 0.75 for the derivation cohort and 0.73 for the validation cohort. The incidence of new-onset AF reached over 2% at 10 points of the risk score in both cohorts. Thus, in this study, we showed the possibility of predicting new-onset AF using ECG findings and simple information.

Abstract Background Diabetes mellitus (DM) and hypertension are well-known atherosclerosis risk factors. Furthermore, renal dysfunction is a crucial risk factor for patients with coronary artery disease (CAD), and managing renal function in these patients is complicated because of comorbid conditions and potential side effects during treatment. Therefore, this study aimed to investigate the effect of medications for hypertension on renal function after percutaneous coronary intervention (PCI) between patients with and without DM with statins. Methods In 297 consecutive patients undergoing PCI for stable angina pectoris, cystatin C (CysC) was evaluated at baseline and 9 months after PCI, and the percent change in CysC (%CysC) was calculated. The association of worsening renal function (WRF: %CysC ≥ 0) and baseline characteristics, including medications, was assessed. Results Among 297 hypertensive patients with statins, 196 and 101 were with and without DM, respectively. Angiotensin-converting enzyme inhibitor (ACEI), angiotensin II receptor blocker, and β-blocker were prescribed in 56 (29%), 82 (42%), and 91 (46%) patients in the DM group, and 20 (20%), 52 (51%), and 52 (51%) in the non-DM group, respectively. The patients with WRF after PCI were 100 (51%) and 59 (58%) in the DM and non-DM groups (p = 0.261). Additionally, the %CysC had no significant differences between groups [median: 0%, interquartile range (IQR): -7.9% to 8.5% vs. median: 1.1%, IQR: -6.6% to 9.6%, p = 0.521]. Multivariate logistic analysis for WRF using relevant factors from univariate analysis showed that only β-blocker [odds ratio (OR): 2.76, 95% confidence interval (CI): 1.03–7.90, p = 0.048] was independently associated with WRF in the DM group whereas ACEI (OR: 0.07, 95% CI: 0.01–0.47, p = 0.012) was negatively correlated with WRF in the non-DM group. Conclusion The β-blocker was the independent risk factor for WRF in patients with DM in the late phase after PCI for stable angina pectoris, while the use of ACEI had a renoprotective effect in patients without DM.

Abstract The next‐generation mineralocorticoid receptor blocker (MRB) esaxerenone has favorable antihypertensive effects in patients who do not respond to treatment with first‐line antihypertensive agents and may be beneficial as a second‐line treatment. However, MRBs are currently considered a fourth‐line treatment as there is no clinical evidence comparing the efficacy of esaxerenone with other classes of antihypertensive agents. The multicenter, randomized, open‐label, parallel‐group EXCITE‐HT study will evaluate the efficacy and safety of esaxerenone as a second‐line agent in the treatment of Japanese patients with uncontrolled essential hypertension. After a 4‐week run‐in period, patients will receive either esaxerenone or trichlormethiazide for 12 weeks per the package insert and the Japanese Society of Hypertension Guidelines for the Management of Hypertension. At Weeks 4 and 8, the dose of esaxerenone or trichlormethiazide may be increased. Blood pressure (home [morning and bedtime] and office), serum biomarkers, and urinary biomarkers will be measured. The primary efficacy endpoint is the change from baseline in morning home systolic blood pressure/diastolic blood pressure to the end of treatment. The EXCITE‐HT study is expected to validate the non‐inferiority of esaxerenone to trichlormethiazide and provide the first evidence for the early use of esaxerenone as a second‐line agent in the treatment of Japanese patients with uncontrolled essential hypertension instead of its current use as a fourth‐line agent.

Background: Low-density lipoprotein cholesterol (LDL-C) is considered the most important risk factor for coronary artery disease (CAD). Although lipid-lowering therapy using high-intensity statins for patients with stable CAD is one of the cornerstones of medication therapy, there is still a risk of residual cardiovascular events, even after controlling for LDL-C. Recently, attention has focused on the association between small dense LDL-C as a residual risk factor for CAD, and it has been reported that a formula can be used to calculate the small LDL-C. Methods: We investigated the association between estimated small dense LDL-C (Esd LDL-C) and the occurrence of new lesions with myocardial ischemia ≤2 years after percutaneous coronary intervention (PCI) in 537 patients with stable angina who underwent PCI. In this study, all patients had been prescribed statins. This study was based on previously reported data regarding the relationship between non-high-density lipoprotein cholesterol levels and stable angina pectoris after PCI. Results: Revascularization, including new lesions and in-stent restenosis, and new lesions appeared in 130 and 90 patients, respectively, ≤2 years after PCI. Age, diabetes mellitus (DM), LDL-C, and Esd LDL-C were associated with the occurrence of revascularization and new lesions ≤2 years after PCI. Multivariate logistic regression analysis models revealed that Esd LDL-C [odds ratio (OR) 1.03, 95% confidence interval (CI) 1.004–1.048, p = 0.020; and OR 1.03, 95% CI 1.009–1.057, p = 0.007, respectively] were associated with the revascularization and occurrence of new lesions ≤2 years after PCI. Conclusions: As well as total cholesterol and LDL-C, Esd LDL-C was an independent risk factor for the revascularization and occurrence of new lesions ≤2 years after PCI for stable angina in Japanese patients receiving statin therapy. In patients with stable angina who are on lipid-lowering therapy with statins, calculating the Esd LDL-C may provide useful information for predicting revascularization and the occurrence of new lesions.

Abstract Chronic kidney disease (CKD) is a risk factor for end-stage renal disease and contributes to increased risk of cardiovascular disease morbidity and mortality. We aimed to develop a risk prediction score and equation for future CKD using health checkup data. This study included 58,423 Japanese participants aged 30–69 years, who were randomly assigned to derivation and validation cohorts at a ratio of 2:1. The predictors were anthropometric indices, life style, and blood sampling data. In derivation cohort, we performed multivariable logistic regression analysis and obtained the standardized beta coefficient of each factor that was significantly associated with new-onset CKD and assigned scores to each factor. We created a score and an equation to predict CKD after 5 years and applied them to validation cohort to assess their reproducibility. The risk score ranged 0–16, consisting of age, sex, hypertension, dyslipidemia, diabetes, hyperuricemia, and estimated glomerular filtration rate (eGFR), with area under the curve (AUC) of 0.78 for the derivation cohort and 0.79 for the validation cohort. The CKD incidence gradually and constantly increased as the score increased from ≤ 6 to ≥ 14. The equation consisted of the seven indices described above, with AUC of 0.88 for the derivation cohort and 0.89 for the validation cohort. We developed a risk score and equation to predict CKD incidence after 5 years in Japanese population under 70 years of age. These models had reasonably high predictivity, and their reproducibility was confirmed through internal validation.

Objective Colour scanning laser ophthalmoscope (cSLO) offers several advantages, including improved image quality and better visualisation of the retinal structures compared with colour fundus photograph (CFP). This study aimed to identify whether cSLO could be used to predict systemic arterial stiffness.Methods and analysis We retrospectively analysed the data of 54 patients with 103 eyes. In addition to blood pressure and blood data, all patients had cardio-ankle vascular index (CAVI) measurements, as well as images of the fundus acquired using cSLO and CFP. We determined the retinal artery sclerosis (RAS) index from the colour of the retinal artery in cSLO images, the ratio of arterial to venous diameter (A/V ratio), and Scheie’s classification in CFP images. The correlation between each parameter and CAVI was examined using Spearman’s rank correlation coefficient, and the correlation between Scheie’s classification and CAVI was examined using Steel-Dowass tests.Results CAVI showed a significant positive correlation with the RAS index (r=0.679, p

Abstract Background Malnutrition affects the prognosis of cardiovascular disease. Acute myocardial infarction (AMI) has been a major cause of death around the world. Thus, we investigated the impact of malnutrition as defined by Geriatric Nutritional Risk Index (GNRI) on mortality in AMI patients. Methods In 268 consecutive AMI patients who underwent percutaneous coronary intervention (PCI), associations between all-cause death and baseline characteristics including malnutrition (GNRI

BackgroundPredicting metabolic syndrome (MetS) is important for identifying high-risk cardiovascular disease individuals and providing preventive interventions. We aimed to develop and validate an equation and a simple MetS score according to the Japanese MetS criteria.MethodsIn total, 54,198 participants (age, 54.5±10.1 years; men, 46.0%), with baseline and 5-year follow-up data were randomly assigned to 'Derivation' and 'Validation' cohorts (ratio: 2:1). Multivariate logistic regression analysis was performed in derivation cohort and scores were assigned to factors corresponding to β-coefficients. We evaluated predictive ability of the scores using area under the curve (AUC), then applied them to validation cohort to assess reproducibility.ResultsThe primary model ranged 0-27 points had an AUC of 0.81 (sensitivity: 0.81, specificity: 0.81, cut-off score: 14), and consisted of age, sex, blood pressure (BP), body mass index (BMI), serum lipids, glucose measurements, tobacco smoking, and alcohol consumption. The simplified model (excluding blood tests) ranged 0-17 points with an AUC of 0.78 (sensitivity: 0.83, specificity: 0.77, cut-off score: 15) and included: age, sex, systolic BP, diastolic BP, BMI, tobacco smoking, and alcohol consumption. We classified individuals with a score ConclusionWe developed a primary score, an equation model, and a simple score. The simple score is convenient, well-validated with acceptable discrimination, and could be used for early detection of MetS in high-risk individuals.

Abstract Background Pulmonary vein (PV) reconnection is the main cause of atrial fibrillation (AF) recurrence. This study aimed to examine the effect of first‐pass PV isolation (PVI) on PV reconnection frequency during the procedure and on AF ablation outcomes. Methods This retrospective study included 446 patients with drug‐refractory AF (370 men, aged 64 ± 10 years) who underwent initial PVI using an open‐irrigated contact force catheter between January 2015 and October 2016. We investigated the effect of first‐pass PVI on PV reconnection during spontaneous PV reconnection and dormant conduction after an adenosine triphosphate challenge. Results First‐pass PVI was achieved in 69% (617/892) of ipsilateral PVs, of which we observed PV reconnection during the procedure in 134 (22%) PVs. This value was significantly lower than that observed in those without first‐pass PVI (50%, 138/275) (P

Abstract Background Stable coronary artery disease (CAD) patients with myocardial damage have a poor prognosis compared to those without myocardial damage. Recently, malnutrition has been reported to affect the prognosis of cardiovascular diseases. However, the effects of malnutrition on prognosis of CAD patients with myocardial damage remains uncertain. We investigated the effects of malnutrition on prognosis of CAD patients with myocardial damage who received percutaneous coronary intervention (PCI). Methods Subjects comprised 241 stable CAD patients with myocardial damage due to myocardial ischemia or infraction. Patients underwent successful revascularization for the culprit lesion by PCI using second-generation drug-eluting stents and intravascular ultrasound. The geriatric nutritional risk index (GNRI), which is widely used as a simple method for screening nutritional status using body mass index and serum albumin, was used to assess nutritional status. Associations between major cardiovascular and cerebrovascular events (MACCE) and patient characteristics were assessed. Results Mean GNRI was 100 ± 13, and there were 55 malnourished patients (23%; GNRI

Background: Chair stand performance is a good predictor of future disability onset among older adults. This study aimed to establish reference values of five-times chair-stand test stratified by age and gender, and to determine the association of chair stand performance with mild cognitive impairment (MCI) status and multidimensional cognitive function among community-dwelling older adults. Methods: This cross-sectional study included 604 community-dwelling older adults (mean age, 74.0; women, 63.1%). The five-times chair-stand test was measured, and the mean and SD were calculated as reference values for each age category in intervals of five years. Participants were classified into three groups based on tertiles (good, medium, and poor) in the five-times chair-stand test in each age group. Results: Mean (SD) values of the five-times chair-stand test in men and women were 8.2 s (2.6 s) and 8.2 s (2.9 s). Chair stand performance declined with advancing age and a significant decline in participants aged 80 years and older was observed. Poor chair stand performance (the lowest performance tertile) was significantly associated with MCI (Odds Ratio (OR) 2.18, 95% CI 1.41–3.36), lower attention (OR 2.36, 95% CI 1.28–4.37), executive function (OR 2.69, 95% CI 1.63–4.45), and processing speed (OR 2.80, 95% CI 1.18–6.67) after controlling for covariates. Conclusions: Similar mean values of the five-times chair-stand test, 8.2 s were presented in older men and women, poor performance of chair stand was associated with MCI, specific domains of attention, executive function, and processing speed. Chair stand performance would be useful for case-finding with a greater risk of cognitive impairment among community-dwelling older adults.

Abstract The association between 18F-fluorodeoxyglucose (18F-FDG) myocardial uptake and clinical presentations in cardiac sarcoidosis (CS) has not yet been clarified. The Patlak slope, Ki, which represents the rate of 18F-FDG uptake is a quantitative index of 18F-FDG metabolism. This study aims to investigate the usefulness of standardized uptake value (SUV) and Patlak Ki images (Ki images) extracted from dynamic 18F-FDG-PET/CT for evaluating the risk of clinical events (CEs) in CS. The SUV and Ki myocardial images were generated from 30 dynamic 18F-FDG-PET/CT scans of 21 CS patients. The SUV and Ki images both were rated as positive in 19 scans and negative in 11 scans with the same incidence of CEs which were significantly higher in positive than negative scans [cardiac dysfunction: 78.9% (15/19) vs. 27.2% (3/11); arrhythmic events: 65.5% (10/19) vs. 0% (0/11)]. In 19 positive scans, the three Ki parameters (Ki max, Ki mean and Ki volume) were significantly higher in scans for patients with arrhythmic events than in those without. Logistic regression analysis showed that the Ki volume alone was significantly associated with the risk of arrhythmic events. Our study suggests that Ki images may add value to SUV images for evaluating the risk of CEs in CS patients.

Abstract Background Pericardiocentesis is frequently performed when fluid needs to be removed from the pericardial sac, for both therapeutic and diagnostic purposes, however, it can still be a high-risk procedure in inexperienced hands and/or an emergent setting. Case presentation A 78-year-old male made an emergency call complaining of the back pain. When the ambulance crew arrived at his home, he was in a state of shock due to cardiac tamponade diagnosed by portable echocardiography. The pericardiocentesis was performed using a puncture needle on site, and the patient was immediately transferred to our hospital by helicopter. Contrast-enhanced computed tomography showed a small protrusion of contrast media on the inferior wall of the left ventricle, suggesting cardiac rupture due to acute myocardial infarction. Emergency coronary angiography was then performed, which confirmed occlusion of the posterior descending branch of the left circumflex coronary artery. In addition, extravasation of contrast medium due to coronary artery perforation was observed in the acute marginal branch of the right coronary artery. We considered that coronary artery perforation had occurred as a complication of the pericardial puncture. We therefore performed transcatheter coil embolization of the perforated branch, and angiography confirmed immediate vessel sealing and hemostasis. After the procedure, the patient made steady progress without a further increase in pericardial effusion, and was discharged on the 50th day after admission. Conclusions When performing pericardial drainage, it is important that the physician recognizes the correct procedure and complications of pericardiocentesis, and endeavors to minimize the occurrence of serious complications. As with the patient presented, coil embolization is an effective treatment for distal coronary artery perforation caused by pericardiocentesis.

Objective: Vinegar has been reported to have a hypotensive effect. We aimed to investigate the relationship between the consumption of vinegar-based side dishes and blood pressure. Research methods & procedures: This cross-sectional study included 746 individuals (257 men and 489 women) aged ≥40 years from Tarumizu, Kagoshima, Japan. Nutrient intake was estimated based on the brief-type self-administered diet history questionnaire. The intake frequency of vinegar-based side dishes (Sunomono and pickles) was determined using a self-administered diet history questionnaire. Participants who did not consume vinegar-based side dishes for a month were defined as having no Sunomono or pickle eating habit. Blood pressure was categorized into four groups according to the Japanese Society of Hypertension Guidelines for the Management of Hypertension. The association between the intake of vinegar-based side dishes and blood pressure categories was analyzed using ordinal logistic regression analysis adjusted for age, body mass index, smoking history, excessive alcohol intake, living situation, energy intake, protein intake, sodium intake, potassium intake, and seaweed intake. Results: Approximately 13.6% men and 6.1% women had no Sunomono eating habits. In men, eating Sunomono, but not pickles, was significantly related to blood pressure categories (estimate, −0.702; 95% CI, −1.122 to −0.310), whereas more frequent consumption of Sunomono did not show an improvement in the blood pressure category. The relationship between eating Sunomono and blood pressure categories was not recognized in women. Conclusion: This was the first study assessing the association between consumption of vinegar-based side dishes and blood pressure categories. We highlighted the effect of Sunomono consumption on blood pressure categories in men. Consumption of Sunomono may improve blood pressure in men.

The heart is dependent on ATP production in mitochondria, which is closely associated with cardiovascular disease because of the oxidative stress produced by mitochondria. Mitochondria are highly dynamic organelles that constantly change their morphology to elongated (fusion) or small and spherical (fission). These mitochondrial dynamics are regulated by various small GTPases, Drp1, Fis1, Mitofusin, and Opa1. Mitochondrial fission and fusion are essential to maintain a balance between mitochondrial biogenesis and mitochondrial turnover. Recent studies have demonstrated that mitochondrial dynamics play a crucial role in the development of cardiovascular diseases and senescence. Disruptions in mitochondrial dynamics affect mitochondrial dysfunction and cardiomyocyte survival leading to cardiac ischemia/reperfusion injury, cardiomyopathy, and heart failure. Mitochondrial dynamics and reactive oxygen species production have been associated with endothelial dysfunction, which in turn causes the development of atherosclerosis, hypertension, and even pulmonary hypertension, including pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Here, we review the association between cardiovascular diseases and mitochondrial dynamics, which may represent a potential therapeutic target.

Previous reports have found evidence that the lung uptake of iodine-123-metaiodobenzylguanidine (123I-MIBG) represents pulmonary vascular endothelial function. Therefore, it was believed that the reduced lung uptake of 123I-MIBG in patients with pulmonary artery hypertension may indicate poor pulmonary vascular endothelial function in those patients. In our previous report, we analyzed the lung uptake of 123I-MIBG in patients with pulmonary hypertension, and demonstrated that it is lower in patients with pulmonary arterial hypertension (PAH) than in those with chronic thromboembolic pulmonary hypertension and controls, suggesting that reduced uptake of 123I-MIBG in patients with PAH indicates endothelial dysfunction of the pulmonary artery. In the current report, we describe a 46-year-old woman diagnosed with scleroderma whose lung uptake of 123I-MIBG was decreased on admission, but she was not diagnosed with pulmonary artery hypertension at that time because her pulmonary artery pressure during right heart catheterization was not elevated. However, she was diagnosed with borderline PAH 2 years later. The lung uptake of 123I-MIBG was reduced before a reduction in %DLCO was observed. This report suggests that the lung uptake of 123I-MIBG may be useful for the early diagnosis of pulmonary artery hypertension.

Aim: To compare the understanding of hypertension and antihypertensive treatment in Japanese patients (aged 50% of these patients had little knowledge of hypertension and poor understanding of their physician’s explanation of it. Conclusions: Elderly patients with hypertension (aged ≥75 years) require daily BP monitoring and detailed and repeated explanation of hypertension and BP targets.

The number of patients with heart failure (HF) is rapidly increasing. Although hypertension is related to onset of HF, antihypertensive treatment status for these patients has not been fully examined. We conducted a claims-based study to discern the treatment status of Japanese hypertensive patients with HF. Two Japanese databases (2008–2016) from acute care hospitals and health insurance societies were used to analyze prescription rates for antihypertensive drug class or category of diuretics in all hypertensive patients and the subset of patients with HF. Totals of hypertensive patients and those with HF in each database in 2015 were 4,191,666 and 1,404,008 patient-months, and 1,382,732 and 148,194 patient-months, respectively. In the acute care hospitals database, calcium channel blockers (CCBs) (55.0–56.5%) and angiotensin II receptor blockers (49.4–54.7%) were prescribed most. β-blockers (38.7–48.0%) and diuretics (42.3–45.6%) were prescribed more for hypertensive patients with HF than for all hypertensive patients (21.5–24.8% and 25.5–26.7%, respectively). Loop diuretics were also prescribed more often for hypertensive patients with HF (68.3–76.0% from acute care hospitals and 47.8–55.8% from health insurance societies) than for all hypertensive patients (56.7–61.7% and 16.4–18.3%). The size of medical institution had a greater effect on drug selection than patient age in both patient groups. Given recommendations in guidelines for hypertensive patients with HF, the differences in drug choice in comparison with all hypertensive patients appear reasonable. However, some deviations, such as the high rate of CCBs in frontline and preference for angiotensin II receptor blockers over angiotensin-converting enzyme inhibitors, did not appear to follow guidelines.

Lectin-like oxidized low-density lipoprotein (ox-LDL) causes vascular senescence and atherosclerosis. It has been reported that ox-LDL scavenger receptor-1 (LOX-1) is associated with the angiotensin II type 1 receptor (AT1R). While mitochondria play a crucial role in the development of vascular senescence and atherosclerosis, they also undergo quality control through mitochondrial dynamics and autophagy. The aim of this study was to investigate (1) whether LOX-1 associates with AT1R, (2) if this regulates mitochondrial quality control, and (3) whether AT1R inhibition using Candesartan might ameliorate ox-LDL-induced vascular senescence. We performed in vitro and in vivo experiments using vascular smooth muscle cells (VSMCs), and C57BL/6 and apolipoprotein E-deficient (ApoE KO) mice. Administration of oxidized low-density lipoprotein (ox-LDL) to VSMCs induced mitochondrial dysfunction and cellular senescence accompanied by excessive mitochondrial fission, due to the activation of fission factor Drp1, which was derived from the activation of the Raf/MEK/ERK pathway. Administration of either Drp1 inhibitor, mdivi-1, or AT1R blocker candesartan attenuated these alterations. Electron microscopy and immunohistochemistry of the co-localization of LAMP2 with TOMM20 signal showed that AT1R inhibition also increased mitochondrial autophagy, but this was not affected by Atg7 deficiency. Conversely, AT1R inhibition increased the co-localization of LAMP2 with Rab9 signal. Moreover, AT1R inhibition-induced mitochondrial autophagy was abolished by Rab9 deficiency, suggesting that AT1R signaling modulated mitochondrial autophagy derived from Rab9-dependent alternative autophagy. Inhibition of the Raf/MEK/ERK pathway also decreased the excessive mitochondrial fission, and Rab9-dependent mitochondrial autophagy, suggesting that AT1R signaling followed the Raf/MEK/ERK axis modulated both mitochondrial dynamics and autophagy. The degree of mitochondrial dysfunction, reactive oxygen species production, vascular senescence, atherosclerosis, and the number of fragmented mitochondria accompanied by Drp1 activation were all higher in ApoE KO mice than in C57BL/6 mice. These detrimental alterations were successfully restored, and mitochondrial autophagy was upregulated with the administration of candesartan to ApoE KO mice. The association of LOX-1 with AT1R was found to play a crucial role in regulating mitochondrial quality control, as cellular/vascular senescence is induced by ox-LDL, and AT1R inhibition improves the adverse effects of ox-LDL.

Background: The Japan-Multi-domain Intervention Trial for Prevention of Dementia in Older Adults with Diabetes (J-MIND-Diabetes) is an 18-month, multi-centered, open-labeled, randomized controlled trial designed to identify whether multi-domain intervention targeting modifiable risk factors for dementia could prevent the progression of cognitive decline among older adults with type 2 diabetes mellitus (T2DM). This manuscript describes the study protocol for the J-MIND-Diabetes trial.Materials and Methods: Subjects of this trial will comprise a total of 300 T2DM outpatients aged 70–85 years with mild cognitive impairment. Subjects will be centrally randomized into intervention and control groups at a 1:1 allocation ratio using the stratified permuted-block randomization methods. The intervention group will participate in multi-domain intervention programs aimed at: (1) management of metabolic and vascular risk factors; (2) physical exercise and self-monitoring of physical activity; (3) nutritional guidance; and (4) social participation. The control group will receive usual T2DM care and general instructions on dementia prevention. The primary and secondary outcomes will be assessed at baseline, at 6- and 18-month follow-up. The primary outcome is change from baseline at 18 months in a global composite score combining several neuropsychological domains, including global cognitive function, memory, attention, executive function, processing speed and language. Secondary outcomes include: (1) cognitive changes in neuropsychological tests; (2) changes in geriatrics assessments; (3) metabolic control and diabetic complications; (4) changes in blood and urinary markers.Discussion: This trial will be the first trial to demonstrate the effectiveness of multi-domain intervention in preventing cognitive decline in older adults with T2DM at increased risk of dementia in Japan.Trial Registration: UMIN000035911; Registered on the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) 18 February 2019. (https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000040908).

Background The risk of cardiovascular disease is known to increase after menopause. Mitochondria, which undergo quality control via mitochondrial autophagy, play a crucial role in the regulation of cellular senescence. The aim of this study was to investigate whether the effect of estrogen‐mediated protection from senescence on arteries is attributed to the induction of mitochondrial autophagy. Methods and Results We used human umbilical vein cells, vascular smooth muscle cells, and 12‐week‐old female C57BL/6 mice. The administration of 17β‐estradiol (E2) to cells inhibited cellular senescence and mitochondrial dysfunction. Furthermore, E2 increased mitochondrial autophagy, maintaining mitochondrial function, and retarding cellular senescence. Of note, E2 did not modulate LC3 (light chain 3), and ATG7 (autophagy related 7) deficiency did not suppress mitochondrial autophagy in E2‐treated cells. Conversely, E2 increased the colocalization of Rab9 with LAMP2 (lysosomal‐associated membrane protein 2) signals. The E2‐mediated effects on mitochondrial autophagy were abolished by the knockdown of either Ulk1 or Rab9. These results suggest that E2‐mediated mitochondrial autophagy is associated with Rab9‐dependent alternative autophagy. E2 upregulated SIRT1 (sirtuin 1) and activated LKB1 (liver kinase B1), AMPK (adenosine monophosphate‐activated protein kinase), and Ulk1, indicating that the effect of E2 on the induction of Rab9‐dependent alternative autophagy is mediated by the SIRT1/LKB1/AMPK/Ulk1 pathway. Compared with the sham‐operated mice, ovariectomized mice showed reduced mitochondrial autophagy and accelerated mitochondrial dysfunction and arterial senescence; these detrimental alterations were successfully rescued by the administration of E2. Conclusions We showed that E2‐induced mitochondrial autophagy plays a crucial role in the delay of vascular senescence. The Rab9‐dependent alternative autophagy is behind E2‐induced mitochondrial autophagy.

BackgroundAn elevated level of serum uric acid (SUA) is associated with an increased risk of cardiovascular disease. Pharmacological intervention with urate-lowering agents, such as the conventional purine analogue xanthine oxidase (XO) inhibitor, allopurinol, has been used widely for a long period of time in clinical practice to reduce SUA levels. Febuxostat, a novel non-purine selective inhibitor of XO, has higher potency for inhibition of XO activity and greater urate-lowering efficacy than conventional allopurinol. However, clinical evidence regarding the effects of febuxostat on atherosclerosis is lacking. The purpose of the study was to test whether treatment with febuxostat delays carotid intima-media thickness (IMT) progression in patients with asymptomatic hyperuricemia.Methods and findingsThe study was a multicenter, prospective, randomized, open-label, blinded-endpoint clinical trial undertaken at 48 sites throughout Japan between May 2014 and August 2018. Adults with both asymptomatic hyperuricemia (SUA >7.0 mg/dL) and maximum IMT of the common carotid artery (CCA) ≥1.1 mm at screening were allocated equally using a central web system to receive either dose-titrated febuxostat (10-60 mg daily) or as a control-arm, non-pharmacological lifestyle modification for hyperuricemia, such as a healthy diet and exercise therapy. Of the 514 enrolled participants, 31 were excluded from the analysis, with the remaining 483 people (mean age 69.1 years [standard deviation 10.4 years], female 19.7%) included in the primary analysis (febuxostat group, 239; control group, 244), based on a modified intention-to-treat principal. The carotid IMT images were recorded by a single sonographer at each site and read in a treatment-blinded manner by a single analyzer at a central core laboratory. The primary endpoint was the percentage change from baseline to 24 months in mean IMT of the CCA, determined by analysis of covariance using the allocation adjustment factors (age, gender, history of type 2 diabetes, baseline SUA, and baseline maximum IMT of the CCA) as the covariates. Key secondary endpoints included changes in other carotid ultrasonographic parameters and SUA and the incidence of clinical events. The mean values (± standard deviation) of CCA-IMT were 0.825 mm ± 0.173 mm in the febuxostat group and 0.832 mm ± 0.175 mm in the control group (mean between-group difference [febuxostat - control], -0.007 mm [95% confidence interval (CI) -0.039 mm to 0.024 mm; P = 0.65]) at baseline; 0.832 mm ± 0.182 mm in the febuxostat group and 0.848 mm ± 0.176 mm in the control group (mean between-group difference, -0.016 mm [95% CI -0.051 mm to 0.019 mm; P = 0.37]) at 24 months. Compared with the control group, febuxostat had no significant effect on the primary endpoint (mean percentage change 1.2% [95% CI -0.6% to 3.0%] in the febuxostat group (n = 207) versus 1.4% [95% CI -0.5% to 3.3%] in the control group (n = 193); mean between-group difference, -0.2% [95% CI -2.3% to 1.9%; P = 0.83]). Febuxostat also had no effect on the other carotid ultrasonographic parameters. The mean baseline values of SUA were comparable between the two groups (febuxostat, 7.76 mg/dL ± 0.98 mg/dL versus control, 7.73 mg/dL ± 1.04 mg/dL; mean between-group difference, 0.03 mg/dL [95% CI -0.15 mg/dL to 0.21 mg/dL; P = 0.75]). The mean value of SUA at 24 months was significantly lower in the febuxostat group than in the control group (febuxostat, 4.66 mg/dL ± 1.27 mg/dL versus control, 7.28 mg/dL ± 1.27 mg/dL; mean between-group difference, -2.62 mg/dL [95% CI -2.86 mg/dL to -2.38 mg/dL; P < 0.001]). Episodes of gout arthritis occurred only in the control group (4 patients [1.6%]). There were three deaths in the febuxostat group and seven in the control group during follow-up. A limitation of the study was the study design, as it was not a placebo-controlled trial, had a relatively small sample size and a short intervention period, and only enrolled Japanese patients with asymptomatic hyperuricemia.ConclusionsIn Japanese patients with asymptomatic hyperuricemia, 24 months of febuxostat treatment did not delay carotid atherosclerosis progression, compared with non-pharmacological care. These findings do not support the use of febuxostat for delaying carotid atherosclerosis in this population.Trial registrationUniversity Hospital Medical Information Network Clinical Trial Registry UMIN000012911.

Few studies have investigated the relationship between nutritional status and comprehensive assessment of oral hypofunction, especially protein intake-related sarcopenia. Thus, we explored these relationships in a large-scale cross-sectional cohort study using the seven-item evaluation for oral hypofunction and Diet History Questionnaire for nutritional assessment. We used the data from 1004 individuals who participated in the 2019 health survey of the residents of Tarumizu City, Kagoshima Prefecture, Japan for analysis. We found that individuals with oral hypofunction were significantly older with a lower skeletal muscle index. Although there were few foods that had a significant difference between the groups with and without oral hypofunction, the consumption of beans and meats was significantly lower in women and men in the oral hypofunction group, respectively. According to the lower limit of the tentative dietary goal defined in Japan, comprehensive evaluation of oral hypofunction was significantly and independently associated with protein intake in both men and women (odds ratio, 1.70; 95% confidence interval, 1.21–2.35). In conclusion, we found that oral hypofunction was associated with targeted protein intake for sarcopenia and frailty prevention in middle-aged and older community-dwelling adults. Comprehensive evaluation of oral function with intervention in cases of hypofunction could inform clinicians to better prevent sarcopenia.

Abstract Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors are reported to have BP-lowering effect in addition to blood glucose-lowering effect, however, its mechanism is still unknown. This study aimed to investigate the mechanism of blood pressure (BP) lowering effects of SGLT2 inhibitors using 24-h urinary collection in obese type 2 diabetes patients. Methods Twenty patients with type 2 diabetes (age 48.2 ± 10.7 years, BMI 33.0 ± 4.9 kg/m2) were enrolled. Urine volume, 24-h urinary glucose and sodium excretion, and BP at baseline and 2 weeks and 6 months after administration were measured. Body weight, glycosylated hemoglobin, and BP were evaluated before and 1, 3, and 6 months after SGLT2 inhibitor administration. We evaluated the changes in urine volume and urinary excretion of glucose and sodium as well as correlations among urine volume and urinary sodium glucose excretion at 2 weeks and 6 months after administration of the SGLT2 inhibitors. Furthermore, we investigated the correlations between changes in BP and urinary excretion of sodium and glucose at the same time. Results Two weeks after administration, systolic BP (SBP) significantly decreased (128.5 ± 11.0 to 123.2 ± 9.8 mmHg, P = 0.0314), but diastolic BP (DBP) did not (74.4 ± 10.4 to 73.4 ± 8.5 mmHg, P = 0.5821). The decreased SBP significantly correlated with increased urinary glucose excretion (R = −0.62, P = 0.0073), but not increased urinary sodium excretion. At 6 months, SBP (118.6 ± 11.0 mmHg, P = 0.0041) and DBP (68.4 mmHg, P = 0.0363) significantly decreased. The decreased SBP significantly correlated with increased urinary sodium excretion (R = −0.60, P = 0.0014), but not increased urinary glucose excretion. Conclusions SGLT2 inhibitors significantly decreased SBP after 1 month and DBP after 6 months in obese patients with type 2 diabetes. The main mechanism of the BP-lowering effect may be plasma volume reduction by osmotic diuresis at 2 weeks and by natriuresis at 6 months after SGLT2 inhibitor administration.

Atrial fibrillation (AF) is the most common cardiac arrhythmia in the world and has a high risk of thromboembolism. The most effective approach, catheter ablation, requires evaluation by electrocardiography. The aim of our study was to investigate novel clinical markers that predict restoration of sinus rhythm (SR) after catheter ablation. Seventy-eight consecutive patients with AF underwent catheter ablation and were separated into 2 groups: restored SR and recurrent AF. The levels of 4 blood proteins (serum or plasma) and 3 mature microRNAs (miRNAs) and their primary miRNAs (pri-miRNAs) in serum were measured before and after ablation, and the associations between each parameter were analyzed statistically. Soluble thrombomodulin (s-TM) and plasminogen activator inhibitor-1 (PAI-1) levels increased above baseline after ablation in both the restored SR (s-TM 11.55 [2.92] vs 13.75 [3.38], P < .001; PAI-1 25.74 [15.25] vs 37.79 [19.56], P < .001) and recurrent AF (s-TM 10.28 [2.78] vs 11.67 [3.37], P < .001; PAI-1 26.16 [15.70] vs 40.74 [22.55], P < .001) groups. Levels of C-reactive protein and asymmetric dimethylarginine were not significantly changed. Pri-miR-126 levels significantly decreased after ablation in the recurrent AF group, but the other miRNAs and pri-miRNAs did not. The measurement of s-TM and pri-miR-126 in blood was a useful tool to reflect the condition of AF patients with catheter ablation.

The aim of this cross-sectional study was to examine the association between diet variety and physical frailty in community-dwelling older adults. Data of 577 older adults (mean age: 74.0 ± 6.3 years, women: 62.5%) were analyzed. Diet variety was assessed using the Food Frequency Score (FFS) (maximum, 30 points). The FFS assessed the one-week consumption frequency of ten foods (meat, fish/shellfish, eggs, milk & dairy products, soybean products, green & yellow vegetables, potatoes, fruits, seafood, and fats & oil). Physical frailty was assessed using Fried’s component (slowness, weakness, exhaustion, low physical activity, and weight loss). The participants were classified into frail, pre-frail, and non-frail groups. The prevalence of physical frailty was 6.6%. This study found significant associations between physical frailty and low FFS after adjusting for covariates (odds ratio (OR) 0.90, 95% confidence interval (CI) 0.84–0.97, p < 0.01). The optimal cutoff point of the FFS for physical frailty was ≤16 points. FFS lower than the cutoff point were significantly associated with physical frailty after adjusting for covariates (OR 3.46, 95% CI 1.60–7.50, p < 0.01). Diet variety assessed using the FFS cutoff value of ≤16 points was related to the physical frailty status in community-dwelling older adults.