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Abstract ApoA-I amyloidosis is an extremely rare form of systemic amyloidosis that commonly involves the heart, kidneys, and liver. ApoA-I amyloidosis is caused by amyloidogenic variants of APOA1 that are inherited in an autosomal dominant manner. Here, we report a 69-year-old man with sporadic cardiac amyloidosis who was born to consanguineous parents and carried a homozygous variant of p.Leu202Arg in APOA1.

Abstract Background The development of immunohistochemical staining has revealed that gastric adenocarcinoma with the gastric phenotype can be divided into the foveolar, fundic gland, and pyloric gland phenotypes. Gastric adenocarcinoma of the pyloric gland type is difficult to diagnose using biopsy because of its low atypia and rarity. Herein, we describe a case of gastric adenocarcinoma of the pyloric gland type that was diagnosed immunohistochemically after endoscopic resection. Case presentation A 67-year-old man was referred to our hospital for the diagnosis and treatment of a 30-mm elevated lesion on the lesser curvature side of the middle of the gastric body. Although four biopsies were performed, it was difficult to determine whether the lesion was benign or malignant. Therefore, endoscopic submucosal dissection was performed, and the presence of tumor cells infiltrating the submucosa with venous invasions was identified. Immunohistochemical staining revealed that the tumor cells were positive for MUC5AC and MUC6 and negative for Pepsinogen I and H + /K + -ATPase. From the above findings, he was diagnosed as having gastric adenocarcinoma with pyloric gland type. The patient underwent a laparoscopic distal gastrectomy and was discharged without any adverse events. Conclusions Gastric adenocarcinoma of the pyloric gland type is a rare disease, and endoscopic resection can serve as a viable diagnostic option for this condition when it is difficult to diagnose using biopsy. Immunohistochemical pathology images can aid in the diagnosis of gastric adenocarcinoma of the pyloric gland type.

Abstract 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.

Abstract Background Gastrocutaneous fistulas are a rare complication of enterocutaneous fistulas and can be caused by intestinal injury, infection, and anastomotic leakage. They are typically treated conservatively or endoscopically; however, for large or difficult-to-treat gastrocutaneous fistulas, surgical intervention is required. Herein, we present a case of a huge gastrocutaneous fistula that was successfully treated with a two-stage surgery performed using open abdomen management. Case presentation A 61-year-old man with a perforated gastric ulcer underwent omental filling as an emergency surgery. Post-operative leakage led the development of a 10-cm gastrocutaneous fistula. He was transferred to our hospital for the treatment of gastrocutaneous fistula. Furthermore, nutritional therapy was administered for dehydration, electrolyte abnormalities, metabolic acidosis, and acute kidney injury due to the high-output nature of the fistula. Moreover, owing to the intraperitoneal severe adhesion and poor nutritional status, two-stage surgery was planned. In the first stage, extensive dissection of the adhesions, distal gastrectomy reconstruction with Roux-en-Y anastomosis, and jejunostomy were performed. Furthermore, open abdomen management was conducted to check for the presence of unexpected complications due to extensive dissection of the adhesion and anastomotic leakage. Subsequently, in the second stage of the surgery, abdominal closure was performed on the 9th day after gastrectomy. Conclusion Open abdomen management may be effective for huge gastrocutaneous fistulas with extensive adhesions that require surgical intervention.

Abstract Introduction Dotinurad is a newer urate-lowering agent that selectively inhibits urate transporter 1 in the renal proximal tubule and increases urinary urate excretion. Currently, little is known about the clinical efficacies of dotinurad in patients with hyperuricemia and hypertension. The aim of this study was to assess the clinical effects of a selective urate reabsorption inhibitor dotinurad on serum uric acid (SUA) levels and relevant vascular markers in patients with hyperuricemia and treated hypertension. Methods This investigator-initiated, multicenter, prospective, single-arm, open-label, exploratory clinical trial in Japan enrolled patients with hyperuricemia and treated hypertension who received a 24-week dotinurad therapy (a starting dose at 0.5 mg once daily and up-titrated to 2 mg once daily). The primary endpoint was a percentage change in the SUA level from baseline to week 24. The secondary endpoints were cardiovascular and metabolic measurements, including changes in the cardio-ankle vascular index (CAVI) and derivatives of reactive oxygen metabolites (d-ROMs) concentration at week 24. Results Fifty patients (mean age 70.5 ± 11.0 years, with 76.0% being men, and mean SUA level 8.5 ± 1.2 mg/dL) were included in the analysis. The percentage change from baseline in the SUA level at week 24 was − 35.8% (95% confidence interval [CI] − 39.7% to − 32.0%, P

Background Sterile inflammation caused by metabolic disorders impairs endothelial function; however, the underlying mechanism by which hyperglycemia induces inflammation remains obscure. Recent studies have suggested that stimulator of interferon genes (STING), a key cytosolic DNA sensor in the innate immune system, contributes to the pathogenesis of inflammatory diseases. This study examines the role of the STING in endothelial dysfunction in streptozotocin‐induced diabetic mice. Methods and Results Injection of streptozotocin promoted the expression of STING and DNA damage markers in the aorta of wild‐type mice. Streptozotocin elevated blood glucose and lipid levels in both wild‐type and STING‐deficient mice, which showed no statistical differences. Genetic deletion of STING ameliorated endothelial dysfunction as determined by the vascular relaxation in response to acetylcholine (P

Abstract Aims Abnormal left ventricular diastolic response to preload stress can be an early marker of heart failure (HF). The aim of this study was to assess clinical course in patients with HF with preserved ejection fraction (HFpEF) who underwent preload stress echocardiography. In the subgroup analysis, we assessed the prognosis of patients with unstable signs during preload stress classified by treatment strategies. Methods and results We prospectively conducted preload stress echocardiographic studies between January 2006 and December 2013 in 211 patients with HFpEF. Fifty‐eight patients had abnormal diastolic reserve during preload stress (unstable impaired relaxation: unstable IR). Of 58 patients with unstable IR, 19 patients were assigned to additional therapy by increased or additional therapy and 39 patients were assigned to standard therapy. Composite outcomes were prespecified as the primary endpoint of death and hospitalization for deteriorating HF. During a median period of 6.9 years, 19 patients (33%) reached the composite outcome. Unstable group with standard therapy had significantly shorter event‐free survival than stable group. Patients with uptitration of therapy had longer event‐free survival than those with standard therapy group after adjustment of laboratory data (hazard ratio, 0.20, 95% confidence interval, 0.05–0.90; P = 0.036); the 10 year event‐free survival in patients with and without uptitration of therapy was 93% and 51%, respectively (P = 0.023). Conclusions Patients with unstable sign had significantly shorter event‐free survival than patients with stable sign. After additional therapy, the prognosis of patients with unstable signs improved. This technique may impact decision‐making for improving their prognosis.

Abstract Background Esophageal gastrointestinal stromal tumors (GISTs) are rare tumors of the gastrointestinal interstitium, and comprise less than 0.7% of all GISTs. The presentation of esophageal GIST is relatively benign, commonly characterized by symptoms of dysphagia and gastrointestinal bleed. On the contrary, it is highly unusual for these tumors to present as surgical emergencies. Case presentation Here, we describe a case of hemothorax secondary to the rupture of a massive (19 cm) esophageal GIST in a 79-year-old male. The patient presented with mild back pain, vomiting, and hypotension. A CT scan revealed significant mediastinal enlargement and left hemothorax. We conducted an emergency thoracotomy which revealed a 19 × 15 × 7 cm ruptured esophageal tumor that was bleeding profusely into the left thoracic cavity. Piecemeal resection without esophagectomy was performed to achieve hemostasis. Pathological evaluation of resected tissue confirmed the diagnosis of GIST. The patient was provided adjuvant imatinib therapy and remains progression-free at the 10-month follow-up. Conclusions To the best of our knowledge, this is the first reported case of life-threatening hemothorax caused by a ruptured esophageal GIST. Findings from this case may aid in the diagnosis and management of these rare tumors.

Abstract Background The COVID-19 pandemic has caused an unprecedented disruption in medical education. Students and lecturers had to adapt to online education. The current study aimed to investigate the level of satisfaction and future preference for online lectures among clinical clerkship students and elucidated the factors that affect these outcomes. Methods We selected a sample of 114 medical students undergoing clinical clerkship during the COVID-19 pandemic. We conducted onsite lectures before the pandemic and online lectures after the outbreak. A survey was conducted, and the sample included students and 17 lecturers. The average scores of total satisfaction and future preference related to online lectures were computed. Results Students’ scores on total satisfaction with online lectures and their future preference were higher than those for onsite lectures. Scores on the ease of debating dimension were low and those on accessibility of lectures in online lectures were higher than those in onsite lectures. There was no difference between the two groups in the scores on the comprehensibility and ease of asking questions dimensions. Results of the multiple regression analysis revealed that accessibility determined total satisfaction, and future preference was determined by comprehensibility as well as accessibility. Contrary to students’ future preferences, lecturers favored onsite lectures to online ones. Conclusion Online lectures are an acceptable mode of teaching during the COVID-19 pandemic for students undergoing clinical clerkship. Online lectures are expected to become more pervasive to avoid the spread of COVID-19.

Abstract Background Bochdalek hernia is a common congenital diaphragmatic defect that usually manifests with cardiopulmonary insufficiency in neonates. It is very rare in adults, and symptomatic cases are mostly left-sided. Diaphragmatic defects generally warrant immediate surgical intervention to reduce the risk of incarceration or strangulation of the displaced viscera. Case presentation A 47-year-old woman presented with dyspnea on exertion. Computed tomography revealed that a large part of the intestinal loop with superior mesenteric vessels and the right kidney were displaced into the right thoracic cavity. Preoperative three-dimensional (3D) simulation software visualized detailed anatomy of displaced viscera and the precise location and size of the diaphragmatic defect. She underwent elective surgery after concomitant pulmonary hypertension was stabilized preoperatively. The laparotomic approach was adopted. Malformation of the liver and the presence of intestinal malrotation were confirmed during the operation. The distal part of the duodenum, jejunum, ileum, colon, and right kidney were reduced into the abdominal cavity consecutively. A large-sized oval defect was closed with monofilament polypropylene mesh. No complications occurred postoperatively. Conclusion Symptomatic right-sided Bochdalek hernia in adults is exceedingly rare and is frequently accompanied by various visceral anomalies. Accurate diagnosis and appropriate surgical repair are crucial to prevent possible incarceration or strangulation. The preoperative 3D simulation provided comprehensive information on anatomy and concomitant anomalies and helped surgeons plan the operation meticulously and perform procedures safely.

Abstract Background Radiofrequency (RF) ablation of typical atrioventricular nodal reentrant tachycardia (tAVNRT) is performed without revealing out the location of antegrade slow pathway (ASp). In this study, we studied a new electrophysiological method of identifying the site of ASp. Methods This study included 19 patients. Repeated series of very high‐output single extrastimulations (VhoSESts) were delivered at the anatomical slow pathway region during tAVNRT. Tachycardia cycle length (TCL), coupling interval (CI), and return cycle (RC) were measured and the prematurity of VhoSESts [ΔPM (= TCL – CI)] and the prolongation of RCs [ΔPL (= RC – TCL)] were calculated. Pacing sites were classified into two categories: (i) ASp capture sites [DSPC(+) sites], where two different RCs were shown, and ASp non‐capture sites [DSPC(‐) sites], where only one RC was shown. RF ablation was performed at DSPC(+) sites and/or sites with catheter‐induced mechanical trauma (CIMT) to ASp. Results DSPC(+) sites were shown in 13 patients (68%). RF ablation was successful in all patients without any degree of atrioventricular block nor recurrence. Total number of RF applications was 1.8 ± 1.1. Minimal distance between successful ablation sites and DSPC(+)/CIMT sites and His bundle (HB) electrogram recording sites was 1.9 ± 0.8 mm and 19.8 ± 6.1 mm, respectively. ΔPL of more than 92.5 ms, ΔPL/TCL of more than 0.286, and ΔPL/ΔPM of more than 1.565 could identify ASp with sensitivity of 100%, 91.1%, and 88.9% and specificity of 92.9%, 97.0%, and 97.6%, respectively. Conclusions Sites with ASp capture and CIMT were close to successful ablation sites and could be useful indicators of tAVNRT ablation.

Background and study aims Response evaluation criteria in solid tumors (RECIST) have been the gold standard to preoperatively predict treatment response and prognosis in patients with gastric cancer (GC) after neoadjuvant chemotherapy (NAC); however, methods for patients without evaluable lesions by RECIST are not yet confirmed. The aim of this study was to assess the utility of preoperative endoscopy for predicting treatment response and prognosis in patients with GC after NAC. Patients and methods This retrospective study included 105 patients with initially resectable GC who underwent NAC followed by surgical treatment. Preoperative factors for predicting treatment response and survival outcomes were analyzed. Results The number of patients classified as responders using preoperative endoscopic assessment, RECIST, and postoperative pathological evaluation were 25 (23.8 %), 28 (26.7 %), and 18 (17.1 %), respectively. Forty-three patients (41 %) were classified as non-targeted disease only, and their treatment responses were not evaluable by RECIST. Multivariate analysis identified endoscopic response as an independent preoperative factor to predict postoperative histological treatment response (odds ratio = 4.556, 95 % CI = 1.169–17.746, P = 0.029). Endoscopic treatment response was the only independent preoperative predictive factor for overall survival (OS) (hazard ratio = 0.419, 95 % confidence interval (CI) = 0.206–0.849, P = 0.016). Further, endoscopic treatment response was available for 33 patients (76.7 %) with non-targeted disease only, which showed significantly different OS between endoscopic responders (80.0 %) and non-responders (43.5 %) (P = 0.025). Conclusions Endoscopic evaluation was an independent preoperative factor to predict treatment response and prognosis in patients with GC after NAC. Endoscopic assessment may be especially valuable for patients who could not be assessed by RECIST.

Abstract Background What type of reconstruction procedure should be applied is one of the important issues in surgery for gastric cancer. We have several options for reconstruction procedure after distal gastrectomy. The Billroth II and Roux-en-Y reconstruction have a duodenal stump while the Billroth I does not have it, which is the biggest structural difference in these procedures. An increase in intraduodenal pressure due to the formation of duodenum stump occasionally causes severe complication such as duodenal stump leakage; however, a duodenal diverticulum perforation after the Roux-en-Y reconstruction has not yet been reported. Herein, we report two cases of a perforated duodenal diverticulum after gastrectomy with the Roux-en-Y reconstruction. Case presentation The first case was a 66-year-old man who presented to our hospital with an acute onset right-upper-quadrant abdominal pain. He had undergone laparoscopic distal gastrectomy with the Roux-en-Y reconstruction for the early gastric cancer 15 months before. A large periampullary diverticulum had been detected during the checkup before the gastrectomy. Abdominal contrast-enhanced CT showed a retroperitoneal fluid collection with gas present at the second part of the duodenum. Therefore, a perforated duodenal diverticulum with abdominal abscess was diagnosed, and an emergency laparotomy was performed. Pancreaticoduodenectomy was performed because of severe duodenal inflammation and surrounding tissue damage. The second case was a 52-year-old man who had undergone open distal gastrectomy for locally advanced gastric cancer. Multiple non-ampullary duodenal diverticula had also been identified during the preoperative checkup. On the 2nd postoperative day, he presented with a sudden-onset abdominal pain with peritoneal irritation signs, and intestinal fluid was identified through the intraperitoneal drainage tube placed in a suprapancreatic site during his previous gastrectomy. Therefore, an emergency laparotomy was performed. During laparotomy, a perforated diverticulum at the second part of the duodenum was detected. The perforated duodenum diverticulum was directly sutured with drainage of the retroperitoneal space. Conclusions It is necessary to recognize that the Roux-en-Y reconstruction after gastrectomy for gastric cancer patients with duodenal diverticulum might cause a perforation of the diverticulum.

Objectives There is a high prevalence of left ventricular diastolic dysfunction (LVDD) in systemic sclerosis (SSc) which is associated with high mortality. Thus, early detection of LVDD could be important in management of SSc. We hypothesised that exercise echocardiography in SSc patients with normal resting haemodynamics may expose early phase LVDD, which could affect its prognosis, defined as cardiovascular death and unplanned hospitalisation for heart failure.Methods Between January 2014 and December 2018, we prospectively enrolled 140 patients with SSc who underwent 6-minute walk (6MW) stress echocardiographic studies with normal range of estimated mean pulmonary arterial pressure (mPAP) (1.4 mm Hg/L/min) and impaired pulmonary vascular reserve (ΔmPAP/ΔCO>3.0 mm Hg/L/min) had worse outcomes compared with those without these abnormalities (p

Background The prognosis of patients with cancer‐venous thromboembolism (VTE) is not well known because of a lack of registry data. Moreover, there is also no knowledge on how specific types are related to prognosis. We sought to evaluate the clinical characteristics and outcomes of patients with cancer‐associated VTE, compared with a matched cohort without cancer using real‐world registry data of VTE. Methods and Results This study was based on the Diagnosis Procedure Combination database in the JROAD‐DPC (Japanese Registry of All Cardiac and Vascular Diseases and the Diagnosis Procedure Combination). Of 5 106 151 total patients included in JROAD‐DPC, we identified 49 580 patients who were first hospitalized with VTE from April 2012 to March 2017. Propensity score was estimated with a logistic regression model, with cancer as the dependent variable and 18 clinically relevant covariates. After propensity matching, there were 25 148 patients with VTE with or without cancer. On propensity score‐matched analysis with 25 148 patients with VTE, patients with cancer had higher total in‐hospital mortality within 7 days (1.3% versus 1.1%, odds ratio [OR], 1.66; 95% CI, 1.31–2.11; P

Background: It is known that epicardial adipose tissue (EAT) volume is linked to cardiac dysfunction. However, it is unclear whether EAT volume (EATV) is closely linked to abnormal LV strain. We examined the relationship between EATV and global longitudinal strain (GLS), global circumferential strain (GCS), and global radial strain (GRS) in patients with preserved LV function.Methods: Notably, 180 consecutive subjects (68 ± 12 years; 53% men) underwent 320-slice multi-detector computed tomography coronary angiography and were segregated into coronary artery disease (CAD) (≥1 coronary artery branch stenosis ≥50%) and non-CAD groups. GLS, GCS, and GRS were evaluated by 2-dimensional speckle tracking in patients with preserved left ventricular (LV) ejection fraction (LVEF) ≥50%.Results: First, GLS, but not GRS and GCS, was lower in the high EATV group though the LVEF was comparable to the low EATV group. Frequency of GLS ≤18 was higher in the high EATV group. Second, multiple regression model showed that EATV, age, male sex, and CAD, were determinants of GLS. Third, the cutoff points of EATV were comparable (~116–117 mL) in both groups. The cutoff of EATV ≥116 showed a significant correlation with GLS ≤18 in overall subjects.Conclusions: Increasing EATV was independently associated with global longitudinal strain despite the preserved LVEF and lacking obstructive CAD. Our findings suggest an additional role of EAT on myocardial systolic function by impaired LV longitudinal strain.

Objectives. Cilnidipine, an L-/N-type calcium channel blocker (CCB), has unique organ-protective properties due to suppression of hyperactivity in the sympathetic nervous system and renin-angiotensin system (RAS). In this study, we hypothesized that cilnidipine might exert a renoprotective effect by suppressing the RAS. Methods. A total of 25 hypertensive patients receiving a RAS inhibitor were randomly assigned to a cilnidipine (n = 12) or amlodipine (n = 13) group. The effects of cilnidipine on proteinuria and angiotensin II–renin feedback were assessed. Results. After 6 months of treatment, both systolic and diastolic blood pressures were significantly reduced to a similar extent in both groups. The urine albumin-to-creatinine ratio was significantly lower in the cilnidipine group (p

Background: Echocardiography requires a high degree of skill on the part of the examiner, and the skill may be more improved in larger volume centers. This study investigated trends and outcomes associated with the use and volume of echocardiographic exams from a real-world registry database of heart failure (HF) hospitalizations. Methods: This study was based on the Diagnosis Procedure Combination database in the Japanese Registry of All Cardiac and Vascular Datasets (JROAD-DPC). A first analysis was performed to assess the trend of echocardiographic examinations between 2012 and 2016. A secondary analysis was performed to assess whether echocardiographic use was associated with in-hospital mortality in 2015. Results: During this period, the use of echocardiography grew at an average annual rate of 6%. Patients with echocardiography had declining rates of hospital mortality, and these trends were associated with high hospitalization costs. In the 2015 sample, a total of 52,832 echocardiograms were examined, corresponding to 65.6% of all HF hospital admissions for that year. We found that the use and volume of echocardiography exams were associated with significantly lower odds of all-cause hospital mortality in heart failure (adjusted odds ratio (OR): 0.48 for use of echocardiography and 0.78 for the third tertile; both p < 0.001). Conclusions: The use of echocardiography was associated with decreased odds of hospital mortality in HF. The volumes of echocardiographic examinations were also associated with hospital mortality.

Abstract Background It is unknown whether canagliflozin, a selective sodium glucose co-transporter 2 inhibitor, reduces epicardial adipose tissue (EAT) thickness, which is associated with insulin resistance and is a risk factor for coronary artery disease. Methods and results We administered 100 mg of canagliflozin for 6 months to 13 patients with type 2 diabetes mellitus. We evaluated glycemic control, visceral adipose tissue (VAT) area and subcutaneous adipose tissue (SAT) area, and skeletal muscle mass by using impedance methods, and EAT thickness by using echocardiography. Canagliflozin treatment for 6 months decreased hemoglobin A1c level from 7.1 ± 0.5% to 6.7 ± 0.6% (P

Background Toll‐like receptor (TLR) 9 recognizes bacterial DNA, activating innate immunity, whereas it also provokes inflammation in response to fragmented DNA released from mammalian cells. We investigated whether TLR9 contributes to the development of vascular inflammation and atherogenesis using apolipoprotein E–deficient (Apoe−/−) mice. Methods and Results Tlr9‐deficient Apoe−/− (Tlr9−/−Apoe−/−) mice and Apoe−/− mice on a Western‐type diet received subcutaneous angiotensin II infusion (1000 ng/kg per minute) for 28 days. Angiotensin II increased the plasma level of double‐stranded DNA, an endogenous ligand of TLR9, in these mice. Genetic deletion or pharmacologic blockade of TLR9 in angiotensin II–infused Apoe−/− mice attenuated atherogenesis in the aortic arch (P

A broad range of chronic conditions, including heart failure (HF), have been associated with vitamin D deficiency. Existing clinical trials involving vitamin D supplementation in chronic HF patients have been inconclusive. We sought to evaluate the outcomes of patients with vitamin D supplementation, compared with a matched cohort using real-world big data of HF hospitalization. This study was based on the Diagnosis Procedure Combination database in the Japanese Registry of All Cardiac and Vascular Datasets (JROAD-DPC). After exclusion criteria, we identified 93,692 patients who were first hospitalized with HF between April 2012 and March 2017 (mean age was 79 ± 12 years, and 52.2% were male). Propensity score (PS) was estimated with logistic regression model, with vitamin D supplementation as the dependent variable and clinically relevant covariates. On PS-matched analysis with 10,974 patients, patients with vitamin D supplementation had lower total in-hospital mortality (6.5 vs. 9.4%, odds ratio: 0.67, p < 0.001) and in-hospital mortality within 7 days and 30 days (0.9 vs. 2.5%, OR, 0.34, and 3.8 vs. 6.5%, OR: 0.56, both p < 0.001). In the sub-group analysis, mortalities in patients with age < 75, diabetes, dyslipidemia, atrial arrhythmia, cancer, renin-angiotensin system blocker, and β-blocker were not affected by vitamin D supplementation. Patients with vitamin D supplementation had a lower in-hospital mortality for HF than patients without vitamin D supplementation in the propensity matched cohort. The identification of specific clinical characteristics in patients benefitting from vitamin D may be useful for determining targets of future randomized control trials.

Background: Peripheral artery disease causes significant functional disability and results in impaired quality of life. Ischemic tissue injury releases various endogenous ligands for Toll-like receptors (TLRs), suggesting the involvement of TLRs in blood flow recovery. However, the role of TLR9, which was originally known as a sensor for bacterial DNA, remains unknown. This study investigated the role of TLR9 in blood flow recovery in the ischemic limb using a mouse hind-limb ischemia model.Methods and Results: Unilateral femoral artery ligation was performed in TLR9-deficient (Tlr9−/−) mice and wild-type mice. In wild-type mice, femoral artery ligation significantly increased mRNA expression of TLR9 in the ischemic limb (P < 0.001) and plasma levels of cell-free DNA (cfDNA) as determined by single-stranded DNA (ssDNA) (P < 0.05) and double-stranded DNA (dsDNA) (P < 0.01), which are endogenous ligands for TLR9, compared with the sham-operated group. Laser Doppler perfusion imaging demonstrated significantly improved ratio of blood flow in the ischemic to non-ischemic limb in Tlr9−/− mice compared with wild-type mice at 2 weeks after ligation (P < 0.05). Tlr9−/− mice showed increased capillary density and reduced macrophage infiltration in ischemic limb. Genetic deletion of TLR9 reduced the expression of TNF-α, and attenuated NF-κB activation in ischemic muscle compared with wild-type mice (P < 0.05, respectively) at 3 days after the surgery. ODN1826, a synthetic agonistic oligonucleotide for TLR9, or plasma obtained from mice with ischemic muscle promoted the expression of TNF-α in wild-type macrophages (P < 0.05), but not in Tlr9−/− macrophages. ODN1826 also activated NF-κB signaling as determined by the degradation of IκBα in wild-type macrophages (P < 0.05), but not in Tlr9−/− macrophages. In vitro experiments using human umbilical vein endothelial cells demonstrated that TNF-α, or conditioned medium obtained from wild-type macrophages treated with ODN1826 accelerated cell death as determined by MTS assay (P < 0.05 and P < 0.01, respectively).Conclusion: Our results suggest that ischemic muscle releases cfDNA, which activates TLR9 and enhances inflammation, leading to impairment of blood flow recovery in the ischemic limb. cfDNA-TLR9 signaling may serve as a potential therapeutic target in ischemic limb disease.

BackgroundPredictive factors for the efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors for lowering glycosylated hemoglobin (HbA1c) remain unclear in patients with type 2 diabetes mellitus. The aim of this study is therefore to clarify predictive factors of the efficacy of DPP-4 inhibitors for lowering HbA1c after 12 months of treatment.MethodsA total of 191 consecutive type 2 diabetic patients (male sex 55%, mean age, 68.3±35.8 years), who had been treated with DPP-4 inhibitors for 12 months, were enrolled in this study and evaluated retrospectively.ResultsAfter 12 months of DPP-4 inhibitor treatment, random blood glucose level, and HbA1c level, decreased from 167±63 to 151±49 mg/dL (P

Natriuretic peptides have been proposed as biomarkers of cardiovascular disease, especially heart failure. Brain natriuretic peptide (BNP) has also been shown to be upregulated at the transcriptional and translational levels by pro-inflammatory cytokines in cardiac myocytes. Although we often measure plasma BNP levels in cancer patients, it remains unknown whether cancer-related inflammation affects the plasma BNP levels. We investigated the relationship between the BNP and human cancers.We retrospectively studied 2,923 patients in whom the plasma BNP levels and serum C-reactive protein (CRP) were measured and echocardiography was performed. Patients with clinically evident heart failure (NYHA II or higher), heart disease requiring medical treatment or surgery, renal dysfunction, and inflammatory disease were excluded. There were 234 patients in the final analysis. Blood sampling was performed before surgery and chemotherapy. In addition, we evaluated the relationship between the inflammation and plasma BNP levels in mouse models of colon cancer.Of the 234 patients, 80 were diagnosed with cancer. Both the plasma BNP and serum CRP levels were significantly higher in cancer patients than those without. There were no significant differences in the echocardiographic parameters. There was a significant positive correlation between the plasma BNP and serum CRP levels in cancer patients (r = 0.360, P

Traditional and non-traditional risk factors for atherosclerotic cardiovascular disease (ASCVD) are different between men and women. Gender-linked impact of epicardial adipose tissue volume (EATV) in patients undergoing coronary artery bypass grafting (CABG) remains unknown.Gender-linked impact of EATV, abdominal fat distribution and other traditional ASCVD risk factors were compared in 172 patients (men: 115; women: 57) who underwent CABG or non-coronary valvular surgery (non-CABG).In men, EATV, EATV index (EATV/body surface area) and the markers of adiposity such as body mass index, waist circumference and visceral fat area were higher in the CABG group than in the non-CABG group. Traditional ASCVD risk factors were also prevalent in the CABG group. In women, EATV and EATV index were higher in the CABG group, but other adiposity markers were comparable between CABG and non-CABG groups. Multivariate logistic regression analysis showed that in men, CABG was determined by EATV Index and other ASCVD risk factors including hypertension, dyslipidemia, adiponectin, high sensitive C-reactive protein (hsCRP) and type 2 diabetes mellitus (Corrected R2 = 0.262, p < 0.0001), while in women, type 2 diabetes mellitus is a single strong predictor for CABG, excluding EATV Index (Corrected R2 = 0.266, p = 0.005).Our study found that multiple risk factors, including epicardial adipose tissue volume and traditional ASCVD factors are determinants for CABG in men, but type 2 diabetes mellitus was the sole determinant in women. Gender-specific disparities in risk factors of CABG prompt us to evaluate new diagnostic and treatment strategies and to seek underlying mechanisms.

Background: Endothelial dysfunction caused by increased oxidative stress is a critical initiator of macro- and micro-vascular disease development in diabetic patients. Ipragliflozin, a selective sodium glucose co-transporter 2 (SGLT2) inhibitor, offers a novel approach for the treatment of diabetes by enhancing urinary glucose excretion. The aim of the present study was to examine whether ipragliflozin attenuates endothelial dysfunction in diabetic mice.Methods: Eight-week-old male C57BL/6 mice were treated with streptozotocin (150 mg/kg) by a single intraperitoneal injection to induce diabetes mellitus. At three days of injection, ipragliflozin (3 mg/kg/day) was administered via gavage for 3 weeks. Vascular function was assessed by isometric tension recording. Human umbilical endothelial cells (HUVEC) were used for in vitro experiments. RNA and protein expression were examined by quantitative RT-PCR (qPCR) and western blot, respectively. Oxidative stress was determined by measuring urine 8-hydroxy-2'-deoxyguanosine (8-OHdG) level.Results: Ipragliflozin administration significantly reduced blood glucose level (P

AIMS: Mechanisms regulating adiponectin expression have not been fully clarified. MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression, are involved in biological processes, including obesity and insulin resistance. We evaluated whether the miRNA-378 pathway is involved in regulating adiponectin expression. METHODS AND RESULTS: First, we determined a putative target site for miRNA-378 in the 3 prime untranslated region (3'UTR) of the adiponectin gene by in silico analysis. The levels of adiponectin mRNA and protein were decreased in 3T3-L1 cells overexpressing the mimic of miRNA-378. Luminescence activity in HEK293T cells expressing a renilla-luciferase-adiponectin-3'UTR sequence was inhibited by overexpressing the mimic of miRNA-378, and the decrease was reversed by adding the inhibitor of miRNA-378. Moreover, we confirmed the inhibitory effects of the mimic were cancelled in a deleted mutant of the miR-378 3'-UTR binding site. Addition of tumor necrosis factor-α (TNFα) led a upregulation of miR-378 and downregulation of adiponectin at mRNA and protein levels in 3T3-L1 cells. Level of miR-378 was higher and mRNA level of adiponectin was lower in diabetic ob/ob mice than those of normal C57BL/6 mice and levels of miR378 and adiponectin were negatively well correlated (r = -0.624, p = 0.004). CONCLUSIONS: We found that levels of miRNA-378 could modulate adiponectin expression via the 3'UTR sequence-binding site. Our findings warrant further investigations into the role of miRNAs in regulating the adiponectin expression.

Cardiovascular disease and renal disease have a close relationship that forms a vicious cycle as a cardiorenal syndrome (CRS). Oxidative stress, endothelial dysfunction, and vascular inflammation could be therapeutic targets when the renin-angiotensin-aldosterone system is activated by accumulation of conventional cardiovascular risk factors; however, a strategy for management of CRS has not been established yet. Statins, HMG-CoA reductase inhibitors, have not only cholesterol-lowering effects but also pleiotropic effects on cardiovascular systems, including anti-inflammatory and antioxidant effects and improvement of nitric oxide bioavailability. Since recent studies have indicated that statins have beneficial effects on chronic kidney disease and heart failure as well as coronary artery disease in cholesterol-lowering-dependent/independent manners, treatment with statins might be a successful strategy for preventing deterioration of CRS.

MicroRNAs (MiRNAs) are short, non-coding RNA that regulate a variety of cellular functions by suppressing target protein expression. We hypothesized that a set of microRNA regulate tumor responses to hypoxia by inhibiting components of the hypoxia signaling pathway. We found that miR-22 expression in human colon cancer is lower than in normal colon tissue. We also found that miR-22 controls hypoxia inducible factor 1α (HIF-1α) expression in the HCT116 colon cancer cell line. Over-expression of miR-22 inhibits HIF-1α expression, repressing vascular endothelial growth factor (VEGF) production during hypoxia. Conversely, knockdown of endogenous miR-22 enhances hypoxia induced expression of HIF-1α and VEGF. The conditioned media from cells over-expressing miR-22 contain less VEGF protein than control cells, and also induce less endothelial cell growth and invasion, suggesting miR-22 in adjacent cells influences endothelial cell function. Taken together, our data suggest that miR-22 might have an anti-angiogenic effect in colon cancer.

Aortic valve calcification (AVC), which causes aortic stenosis (AS), is more common in elderly persons. Controlling for conventional risk variables did not, however, reduce the incidence of AS. Thus, residual risk factors of AS should be identified. We enrolled 513 patients who underwent coronary angiography with computed tomography because of suspicion of coronary artery disease (CAD) or ruling out of CAD before aortic valve replacement. Calcium volume was calculated with a commercially available application. Conventional and lipid-related risk factors including serum levels of Lp(a) were evaluated for all patients. Calcium volume and Lp(a) levels were significantly higher in patients who underwent aortic valve replacement than in those who did not. A single regression analysis showed that the calcium volume was positively associated with age and the Lp(a) levels and negatively associated with the estimated glomerular filtration rate. No statistical significance was observed for other risk factors, including oxidized low-density lipoprotein, omega-3 fatty acids levels. The multiple regression analysis revealed that age (P < 0.001), female sex (P < 0.05), Lp(a) (P < 0.01), and hemoglobin A1c (P < 0.01) were determinants of the calcium volume. The area under the curve in receiver operating characteristic analysis of Lp(a) for implementation of AVR was 0.65 at an Lp(a) cut-off level of 16 mg/dL. In conclusion, the serum Lp(a) level is a potent risk factor of AVC in patients with high risk of atherosclerosis. [ABSTRACT FROM AUTHOR]