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Iron deficiency is linked to worse clinical status and outcomes in heart failure. Although metabolic syndrome contributes to the development of heart failure, the impact of iron deficiency in heart failure complicated with metabolic syndrome remains obscure. KKAy mice were used as a model of metabolic syndrome. Four-week-old male C57BL/6J and KKAy mice were fed either a normal diet or iron-restricted (IR) diet for 12 weeks. During the experiment, 40% of mice died due to pulmonary congestion in KKAy mice with IR diet (KKAy-IR), while no mice died in other groups. Necropsy showed the presence of multiple white lesions on the cardiac surface in those KKAy-IR mice. Echocardiography and histological analyses revealed that KKAy-IR mice exhibited cardiac hypertrophy and cardiac dysfunction with cardiac calcification. Cardiac mRNA of ectonucleotide pyrophosphatase/phosphodiesterase-1 (Enpp1), a key enzyme for bone mineralization, was highly abundant in KKAy-IR mice. Of note, iron restriction-induced cardiac calcification and dysfunction were attenuated by etidronate, an inhibitor of bone mineralization, with decreased cardiac Enpp1 mRNA abundance in KKAy-IR mice. In conclusion, iron deficiency leads to ectopic cardiac calcification and dysfunction with the increase of Enpp1 in metabolic syndrome model mice.

Background: Polypharmacy is associated with poor prognosis of patients with various diseases. However, it has not been precisely addressed how polypharmacy affects the clinical characteristics of the cardiovascular outpatients. The aim of this study is to search for the clinical characteristics related to the number of prescribed drugs in the cardiovascular outpatients. Also, we examine whether the number of the prescribed drugs affects the worsening of renal function. Methods: This retrospective study was conducted using the data of 259 continuous cardiovascular outpatients who were examined complete blood count (CBC) and serum creatinine. Results: In the univariate analysis, the number of prescribed drugs were associated with the number of cardiovascular diseases or their risk factors, age, white blood cells, platelet, body mass index, anemia, and chronic kidney disease stage 3b or higher. In the multivariable analysis, independent variables that significantly correlated with the number of prescribed drugs were the number of cardiovascular diseases or their risk factors, anemia, and chronic kidney disease stage 3b or higher. Among 259 patients, 208 patients received follow-up examination of serum creatinine. The number of prescribed drugs was the only factor that was associated with accelerated deterioration of renal function. Conclusions: Polypharmacy is associated not only with poor renal function but with accelerated deterioration of renal function. Polypharmacy may be causally related with renal dysfunction. Cardiol Res. 2020;11(1):15-21 doi: https://doi.org/10.14740/cr991

The portal pressure gradient (PPG) is a useful predictor of portal hypertension (PH) related complications. We previously showed the feasibility and safety of endoscopic ultrasound guided PPG measurement (EUS-PPG). Now EUS-guided liver biopsy (EUS-bx) has been shown to be a safe and effective alternative to percutaneous or Interventional Radiology-guided liver biopsy for the diagnosis of chronic liver disease (CLD). We aimed to evaluate the correlation between PPG and clinical markers of PH, and assess the feasibility and safety of concomitant, single session EUS-PPG and EUS-bx.This was a retrospective study of patients undergoing EUS-PPG for CLD at a single tertiary endoscopy center between February 2014 and March 2020. EUS-PPG was performed using a 25-gauge needle and compact manometer. Data analysis was performed with SAS version 9.4.Eighty-three patients underwent EUS-PPG with 100% technical success. The mean PPG was 7.06 mmHg (SD 6.09, range 0-27.3). PPG was higher in patients with (vs without) clinical features of cirrhosis (9.46 vs 3.61 mmHg, P 0.0001), esophageal or gastric varices (13.88 vs 4.34 mmHg, P 0.0001), and thrombocytopenia (9.25 vs 4.71 mmHg, P = 0.0022). In the 71 patients (85.5%) who underwent EUS-bx, 70 (98.6%) specimens were deemed adequate by the pathologist for histologic diagnosis. There were no early or late major adverse events.EUS-PPG correlates well with clinical markers of PH. EUS-bx can be performed safely during the same session as EUS-PPG, providing a comprehensive endoscopic evaluation of the patient with CLD.

Left ventricular ejection fraction (LVEF) is critical for determining the prognosis and treatment of patients with heart failure (HF). However, the influence of serial LVEF changes in patients with stable chronic HF (CHF) has not yet been completely investigated. We analyzed data of 263 outpatients with CHF from the J-MELODIC study cohort and evaluated the frequency of cardiac events. We stratified patients into tertiles based on the relative difference in LVEF in 1 year and that at baseline. We found a significant difference in the cardiac event rate among the three groups (log-rank test, p = 0.042). We identified a relative 11% LVEF reduction as the optimal cutoff value based on the receiver operating characteristics analysis. LVEF (OR, 1.04; 95% CI, 1.01–1.07; p = 0.015) and E/e′ (OR, 1.06; 95% CI, 1.01–1.12; p = 0.023) at baseline were predictors of >11% LVEF reduction. After adjusting the variables including age and sex, >11% LVEF reduction was an independent predictor of subsequent cardiac events (HR, 5.79; 95% CI, 2.49–13.2; p 11% LVEF reduction may have subsequent worsening outcomes. Such patients should be carefully followed-up as high risk population for development of cardiac events.

Background and aims The anastomotic biliary stricture is a clinically important complication after living donor liver transplantation (LDLT) with a duct-to-duct anastomosis. Although endoscopic management of post-LDLT biliary strictures using balloon dilation (BD) and plastic stents (PSs) has provided acceptable short-term outcomes, long-term outcomes and prognostic factors for treatment success remain unclear. Methods We included 96 patients with post-LDLT biliary strictures who were endoscopically managed between 2003 and 2016. BD was utilized as a first-line treatment strategy, and PS placement was carried out for refractory cases. Potential prognostic factors for biliary stricture resolution were analysed using logistic regression analyses. Results Endoscopic treatment was technically successful in 84 patients (87.5%). The overall rate of biliary stricture resolution was 44.8% (43 of 96 patients) with a median follow-up duration of 90.9 months (interquartile range, 30.9-122.3 months). Bile duct kinking was associated with a lower rate of biliary stricture resolution (odds ratio, 0.33; 95% confidence interval, 0.13-0.87). After successful endoscopic treatment, biliary strictures recurred in 22 patients (57.9%) after BD, and in one patient (4%) after PS treatment. Conclusions Despite a high technical success rate, endoscopic treatment only provided a low rate of resolution of anastomotic biliary strictures among LDLT patients and required prolonged treatment duration. Alternative strategies including the use of a covered metal stent should be evaluated to further improve the treatment outcomes of post-LDLT biliary strictures, particularly in those accompanied by the bile duct kinking.

Due to increasing opportunities for abdominal imaging studies, bile duct stones are occasionally diagnosed without any symptoms. However, there has been no consensus on the management of asymptomatic bile duct stones. We conducted a retrospective longitudinal cohort study to investigate the natural history of asymptomatic bile duct stones and clinical outcomes according to the timing of endoscopic removal. We identified consecutive patients who were diagnosed with asymptomatic common bile duct stones and categorized into those who were followed up with stones in situ (wait-and-see group) and those who received early endoscopic stone removal (intervention group). Cumulative incidence functions of biliary complications were estimated and compared between the groups. We included 191 patients (114 patients in the wait-and-see group and 77 patients in the intervention group). In the wait-and-see group, the cumulative incidence of biliary complications was 6.1% at 1 year, 11% at 3 years, and 17% at 5 years. Asymptomatic disappearance of stones was observed in 22 patients (19%). Procedure-related adverse events of early endoscopic stone removal of asymptomatic stones were observed in 25 (32%) patients including 4 (5.2%) with severe pancreatitis. The cumulative incidence function of biliary complications did not differ by treatment strategies (P = 0.55). Biliary complications occurred in a substantial proportion of patients with asymptomatic bile duct stones, but early endoscopic removal appeared to have little effect on the prevention of further biliary complications. Given the risk of procedure-related pancreatitis, the wait-and-see strategy may become a management option of asymptomatic stones.

Although surgical or endoscopic treatment is effective for pain control in symptomatic calcified chronic pancreatitis, it is still unknown whether early intervention in mild symptomatic pancreatic stones would reduce the frequency of acute exacerbation and improve long-term outcomes. The aim of this randomized-controlled trial was to explore the efficacy of early endotherapy for mild symptomatic pancreatic stones in comparison with the wait-and-see policy.Patients with mild symptoms because of pancreatic stones were assigned randomly to the endotherapy or the wait-and-see group. The wait-and-see group received endotherapy only when they developed refractory exacerbation or intractable pain. The primary outcome was the cumulative incidence of intolerable pain attacks and acute exacerbation. The secondary outcomes were the development of pancreatic insufficiency and the progression of pancreatic atrophy.A total of 20 patients were enrolled between March 2008 and March 2011. The study was terminated prematurely because of the poor patient enrollment. Early endotherapy tended to reduce the cumulative incidence of pain attacks and exacerbation, (P=0.17) with the composite incidence of pain attacks and exacerbation of 30% in the endotherapy group and 60% in the wait-and-see group. There were no significant differences in terms of diabetic status and the presence of steatorrhea. The thickness of the pancreas decreased significantly in the wait-and-see group (9.2-6.8 mm, P=0.041), but not in the endotherapy group (8.7-9.0 mm, P=0.60).In a small group of patients, early endotherapy in mild symptomatic chronic pancreatitis was associated with a trend toward a minor number of acute attacks and atrophy progression of the pancreas.

Purpose: The purpose of this study was to clarify the relationship between decreased sleep quality during the first trimester and a rise in blood pressure during an otherwise normal course of pregn...

Background Weight loss is a strong prognostic factor in chronic heart failure (CHF); however, little is known about its effects in patients with mild CHF. Therefore, we investigated the effects of weight loss in patients with mild CHF. Methods and Results We analyzed a total of 242 outpatients with mild CHF from the J-MELODIC study cohort. Weight loss was defined as ≥5% weight loss in 1 year. Twenty-seven patients (11.2%) lost ≥5% weight in 1 year. Weight loss was associated with higher rates of underweight and worsening renal function in 1 year compared with the absence of ≥5% weight loss. The predictors of weight loss included edema, B-type natriuretic peptide, and diabetes mellitus at baseline. Although weight loss was significantly associated with subsequent cardiovascular death or hospitalization for HF (log-rank P = .002) and subsequent death from any cause (log-rank P = .002), underweight was not associated with these outcomes (log-rank P = .356 and P = .168, respectively). Even after adjusting for covariates, weight loss was a significant and independent risk factor for subsequent cardiovascular death or hospitalization for HF (hazard ratio 3.22, 95% confidence interval 1.10–8.41; P = .034). Conclusions In patients with mild CHF, ≥5% weight loss was a significant predictor for subsequent cardiovascular death or hospitalization for HF.

This work addressed laser-induced spark ignition (LSI) of dimethyl ether (DME)-air mixtures in a microgravity environment which was simulated in a laboratory-scale drop tower, to study fundamental ignition characteristics in microgravity. A laser-induced spark was adopted as a pilot source because LSI has potential benefits as compared to conventional electrical spark ignition: no wall effects, no heat-loss to electrodes, etc. Ignition characteristics, therefore, can be investigated without effects of ignition source via LSI. DME-air mixtures filled in a combustion chamber on a framework package were ignited during free-fall. The ignition energy and flame kernel development were investigated with varying the equivalence ratio and the laser pulse energy. The minimum ignition energy (MIE) was calculated statistically via the logistic regression method. Comparing MIE and flame kernel development between normal gravity and microgravity, MIE in microgravity was lower than that in normal gravity over tested equivalence ratios ranging from 0.575 to 0.675. The difference of MIE became significant with decreasing the equivalence ratio, the maximum value of which was 7.0 mJ at the lowest equivalence ratio. Flame kernel was deformed in normal gravity due to buoyant force. The flame kernel in the bottom region was often not able to develop against buoyant force. Ignition succeeded consequently when only the top of flame kernel developed into a self-sustaining flame to propagate throughout the entire chamber. This flame deformation was noticeable as the equivalence ratio decreased because the flame propagation speed also decreased. On the other hand, in microgravity, reduced buoyant force allowed the flame kernel to stably develop into a self-sustaining flame. This is the first time that both MIE and flame kernel development via LSI were found experimentally to be well affected by gravity.

Renal inflammation and fibrosis are observed in underlying diseases associated with the pathological progression of chronic kidney disease (CKD). The inhibition of renal inflammation and fibrosis is one method to suppress the progression of CKD. Juzentaihoto (TJ-48), a Kampo medicine, effectively relieves chronic wasting diseases and fatigue and has been reported to decrease inflammation. In this study, we investigated whether TJ-48 has a renal protective effect and its underlying mechanism in mice with adenine-induced CKD. BALB/c mice were divided into four groups for examination: (1) control, (2) dietary restriction, (3) adenine, and (4) adenine + TJ-48. Biochemical and histological analyses, gene expression analysis, and complete blood counts were performed. TJ-48 treatment decreased tubular damage and fibrosis. TJ-48 also decreased creatinine levels exacerbated by adenine, suppressed the mRNA expression of tumor necrosis factor-α, chemokine ligand 2, transforming growth factor-β, and kidney injury molecule-1, and decreased the neutrophil/lymphocyte ratio increased by adenine. TJ-48 exerts a renoprotective effect possibly via the suppression of fibrosis and inflammation.

We studied the mechanisms of anemia and the influence of anemia on renal pathology in Dahl/Salt Sensitive (Dahl/SS) rat, a model of cardio-renal-anemia syndrome. Erythrocyte lifespan was shortened and associated with decreased hemoglobin level in the Dahl/SS rats given high-salt diet. Serum haptoglobin decreased, reticulocytes increased, and erythropoiesis in the bone marrow and extramedullary hematopoiesis in the spleen was markedly stimulated by increased serum erythropoietin in them. As a mechanism of hemolysis, we investigated the incidence of eryptosis, suicidal death of erythrocytes. Eryptosis was increased, and red blood cell-derived microparticles, small particle which are generated in hemolytic disease, were also increased in Dahl/SS rats fed with high-salt diet. Deposition of hemosiderin and mitochondrial morphologic abnormality, a sign of ferroptosis, in proximal renal tubules was associated with intravascular hemolysis. Treatment with deferasirox, an oral iron chelator, reduced the renal proximal tubular injury and the glomerular sclerosis in Dahl/SS rats fed with high-salt diet. In conclusion, reduced half-life of erythrocytes induced by hemolysis is the major cause of anemia in Dahl/SS rat. Iron accumulation induced by hemolysis causes renal proximal tubule injury and accelerates renal damage in this model.

Percutaneous coronary intervention (PCI) effectively treats obstructive coronary artery syndrome. However, 30–40% patients continue to have angina after a successful PCI, thereby reducing patient satisfaction. The mechanisms underlying persistent angina after revascularisation therapy are still poorly understood; hence, the treatment or guideline for post-PCI angina remains unestablished. Thus, this study aimed to investigate the mechanisms underlying effort angina in animals following myocardial ischaemia-reperfusion (I/R) injury. Phosphorylated extracellular signal-regulated kinase (p-ERK), a marker for painful stimulation-induced neuronal activation, was used for the investigation. After a forced treadmill exercise (FTE), the number of p-ERK-expressing neurons increased in the superficial dorsal horn of the I/R model animals. Moreover, FTE evoked hydrogen peroxide (H2O2) production in the I/R-injured heart, inducing angina through TRPA1 activation on cardiac sensory fibres. Notably, the treatment of a TEMPOL, a reactive oxygen species scavenger, or TRPA1−/− mice successfully alleviated the FTE-induced p-ERK expression in the dorsal horn. The production of H2O2, a reactive oxygen species, through physical exercise contributes to angina development following I/R. Hence, our findings may be useful for understanding and treating angina following revascularisation therapy.

Aims Cardiac function varies in the population of patients with heart failure (HF) with preserved left ventricular ejection fraction (LVEF; HFpEF). This study investigated the heterogeneity of clinical features associated with HF and the prognostic value of BNP levels in patients with HFpEF. Methods and results The study enrolled 288 patients with stable HF and serum creatinine 40%, n = 205). Patients with HFpEF were further categorized as having relatively low LVEF (HFrlEF; EF 40–60%, n = 107) or as having relatively high LVEF (HFrhEF; EF ≥ 60%, n = 98). We defined cardiovascular death and hospitalization for HF as adverse events and evaluated the prognostic value of the BNP levels in each group. There was no significant difference in event-free survival between HFpEF and HFrEF patients or between HFrhEF and HFrlEF patients. A multivariate Cox proportional hazards model revealed that the BNP level was an independent predictor of adverse events in HFrEF patients (hazard ratio: 4.088, 95% confidence interval: 1.178–14.179, P = 0.027) and in HFrlEF patients (hazard ratio: 14.888, 95% confidence interval: 4.969–44.608, P

The interaction among heart failure (HF), chronic kidney disease (CKD), and anemia is called cardio-renal anemia syndrome. The mechanism of anemia in cardio-renal anemia syndrome is complex and remains completely unknown. We have previously reported that impaired intestinal iron transporters may contribute to the mechanism of anemia in HF using in vivo HF model rats. In this study, we assessed intestinal iron transporters in CKD model rats to investigate the association of intestinal iron transporters in the mechanism of cardio-renal anemia syndrome. CKD was induced by 5/6 nephrectomy in Sprague-Dawley rats. Sham-operated rats served as a control. After 24-week surgery, CKD rats exhibited normocytic normochromic anemia and normal serum erythropoietin levels despite of anemia. Serum iron levels were decreased in CKD rats compared with the controls. Of interest, intestinal expression of critical iron importers, such as duodenal cytochrome b (Dcyt-b) and divalent metal transporter 1 (DMT-1), was decreased in CKD rats compared with the controls. On the other hand, intestinal expression of ferroportin, an intestinal iron exporter, was not different in the control and CKD groups. Moreover, hepatic expression of hepcidin, a regulator of iron homeostasis, did not differ between the control and CKD groups. These results suggest that impaired intestinal expression of Dcyt-b and DMT-1 might be associated with the reduction of an iron uptake in CKD. Taken together, impaired these intestinal iron transporters may become a novel therapeutic target for cardio-renal anemia syndrome.

We report a case of metastatic pancreatic-head mucinous carcinoma (with multiple lymph node and bone metastases) and review the relevant literature. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) was useful for diagnosis, and a satisfactory outcome was achieved after systemic chemotherapy with FOLFIRINOX followed by resection of the primary lesion as conversion surgery. The patient was a 55-year-old man. Hematological findings included elevated serum tumor marker levels: CEA 12.7 ng/mL, DUPAN-2 400 U/mL. Findings from several imaging modalities and EUS-FNA confirmed a clinicopathological diagnosis of metastatic pancreatic mucinous carcinoma with multiple bone and lymph node metastases. Five courses of modified FOIFIRINOX (m-FFX) were given as systemic chemotherapy, which had an antitumor effect. Subtotal stomach-preserving pancreaticoduodenectomy and extensive lymph-node dissection were thus performed. Histopathological analysis showed invasive ductal carcinoma, muc (pT3, pN1b, cM1). After surgery, the clinical course was notable for the absence of complications. Tegafur/gimeracil/oteracil (S-1) was started as maintenance adjuvant chemotherapy postoperatively, and no disease progression has been observed at 10 months after surgery.

Background and Aims Portal hypertension (PH) is a serious adverse event of liver cirrhosis. The hepatic venous pressure gradient (HVPG) accurately reflects the degree of PH and is the single best prognostic factor in liver disease. Currently, portal pressure gradient (PPG) measurement is performed at interventional radiology (IR) with a standard transjugular approach requiring radiation and intravenous contrast. The aim of this study was to develop a novel EUS-guided system using a 25G FNA needle and compact manometer to directly measure PPG and to evaluate its performance and clinical feasibility. Methods Experiments were performed in 3 swine that were under general anesthesia. Manometry was performed in venous (baseline and PH) and arterial (aorta) systems. The PH model was created by rapid Dextran-40 infusion peripherally. Under EUS guidance a 25G FNA needle with attached manometer was used to puncture (transgastric-transhepatic approach) and measure pressures in the portal vein, right hepatic vein (RHV), inferior vena cava (IVC), and aorta. With the IR approach, RHV (free and wedged), IVC, and aorta pressure were measured with an occlusion balloon. Pressure correlation was divided into 3 groups; low pressure (baseline), medium pressure (noncirrhotic portal hypertensive model), and high pressure (arterial). Correlation between the 2 methods of measurement was charted in scatter plots, and the Pearson's correlation coefficient (R) was calculated. Results EUS identification, access, and manometry was successful in all targeted vessels. There was excellent correlation (R, .985-.99) between EUS and IR methods in all pressure ranges. No adverse event occurred. Conclusions This novel technique of EUS-PPG measurement using a 25G needle and novel manometer was feasible and demonstrated excellent correlation with the standard transjugular method throughout low, medium, and high pressure ranges.

Iron is a catalyst in the formation of reactive oxygen species. Oxidative stress is associated with the pathogenesis of both human and experimental animal models of renovascular hypertension. We hypothesized that iron is involved in the pathogenesis of renovascular hypertension and that iron restriction may affect the pathogenesis of renovascular hypertension via the inhibition of oxidative stress. Herein, we investigated the effect of iron restriction on hypertension and renal damage in a rat model of two-kidney one-clip (2K1C) renovascular hypertension. Renovascular hypertension was induced by 2K1C in male Sprague-Dawley rats. At the day of clipping, 2K1C rats were divided into untreated (2K1C) and dietary iron-restricted groups (2K1C+IR). The 2K1C rats showed hypertension after the day of clipping, whereas dietary iron restriction attenuated the development of hypertension. Vascular hypertrophy and the increased fibrotic area were suppressed in the 2K1C+IR group. The clipped kidney developed renal atrophy in both the 2K1C and 2K1C+IR groups after clipping. However, the unclipped kidney showed renal hypertrophy in the 2K1C and 2K1C+IR groups, and the extent was less in the 2K1C+IR group. The 2K1C rats exhibited glomerulosclerosis and tubulointerstitial fibrosis in the unclipped kidney, whereas these changes were attenuated by an iron-restricted diet. Importantly, proteinuria was decreased in the 2K1C+IR group, along with decreased urinary 8-hydroxy-2'-deoxyguanosine excretion and superoxide production of the unclipped kidney. Moreover, the expression of nuclear mineralocorticoid receptor in the unclipped kidney of the 2K1C rats was attenuated by iron restriction. These data indicate a novel effect of iron restriction on hypertension and renal damage in renovascular hypertension.

Background and Aims Portal hypertension (PH) is a serious adverse event of liver cirrhosis. The hepatic venous pressure gradient or portal pressure gradient (PPG) accurately reflects the degree of PH and is the single best prognostic indicator in liver disease. This is usually obtained by interventional radiology (IR), although it is not routinely performed. Recently, we developed a simple novel technique for EUS-guided PPG measurement (PPGM). Our animal studies showed excellent correlation between EUS-PPGM and IR-PPGM. We present the first human pilot study of EUS-PPGM in patients with liver disease. Methods EUS-PPGM was performed by experienced endosonographers using a linear echoendoscope, a 25-gauge fine-needle aspiration needle, and a novel compact manometer. The portal vein and hepatic vein (or inferior vena cava) were targeted using a transgastric–transduodenal approach. Clinical parameters of PH were evaluated in each patient. Feasibility was defined as successful PPGM in each patient. Safety was based on adverse events captured in a postprocedural interview. Results Twenty-eight patients underwent EUS-PPGM with 100% technical success and no adverse events. PPG ranged from 1.5 to 19 mm Hg and had excellent correlation with clinical parameters of portal hypertension including the presence of varices ( P = .0002), PH gastropathy ( P = .007), and thrombocytopenia ( P = .036). PPG was increased in patients with high clinical evidence of cirrhosis ( P = .005). Conclusion This novel technique of EUS-PPGM using a 25-gauge needle and compact manometer is feasible and appears safe. Given the availability of EUS and the simplicity of the manometry setup, EUS-guided PPG may represent a promising breakthrough for procuring indispensable information in the management of patients with liver disease.

BACKGROUND AND AIM Endoscopic papillary large balloon dilation (EPLBD) without endoscopic sphincterotomy (EST) may facilitate extraction of large bile duct stones through achieving adequate dilation of the ampulla. However, contrary to favorable long-term outcomes after endoscopic papillary balloon dilation (EPBD), that of EPLBD without EST has been little investigated. Therefore, we conducted the current study to evaluate short- and long-term outcomes of EPLBD without EST and EPBD after removal of large bile duct stones (LBDS; ≥10 mm). METHODS This retrospective study included patients without a previous history of EST, EPBD or EPLBD who underwent EPLBD without EST or EPBD for removal of LBDS. Each patient in the EPLBD without EST group was matched to a patient in the EPBD group using propensity scores. RESULTS Forty-four patients in each group were matched for the analysis. Baseline characteristics were balanced after propensity matching. Rate of complete stone removal in a single session was higher (80% vs 16%, P < 0.001), number of ERCP sessions (1.3 ± 0.7 vs 2.4 ± 1.5, P < 0.001) and rate of lithotripsy use (30% vs 80%, P < 0.001) were smaller in the matched EPLBD without EST group. Contrary to null between-group differences in early adverse events (P = 0.99), a cumulative rate of late biliary complications was higher in the EPLBD without EST group (P = 0.02). CONCLUSION EPLBD without EST showed higher efficacy for removal of LBDS but was associated with worse long-term outcomes when compared to EPBD.

Background Iron is associated with the pathophysiology of several cardiovascular diseases, including pulmonary hypertension (PH). In addition, disrupted pulmonary iron homeostasis has been reported in several chronic lung diseases. Transferrin receptor 1 (TfR1) plays a key role in cellular iron transport. However, the role of TfR1 in the pathophysiology of PH has not been well characterized. In this study, we investigate the role of TfR1 in the development of hypoxia-induced pulmonary vascular remodeling. Methods PH was induced by exposing wild-type (WT) mice and TfR1 hetero knockout mice to hypoxia for 4 weeks and evaluated via assessment of pulmonary vascular remodeling, right ventricular (RV) systolic pressure, and RV hypertrophy. In addition, we assessed the functional role of TfR1 in pulmonary artery smooth muscle cells in vitro. Results The morphology of pulmonary arteries did not differ between WT mice and TfR1 hetero knockout mice under normoxic conditions. In contrast, TfR1 hetero knockout mice exposed to 4 weeks hypoxia showed attenuated pulmonary vascular remodeling, RV systolic pressure, and RV hypertrophy compared with WT mice. In addition, the depletion of TfR1 by RNA interference attenuated human pulmonary artery smooth muscle cells proliferation induced by platelet-derived growth factor-BB (PDGF-BB) in vitro. Conclusions These results suggest that TfR1 plays an important role in the development of hypoxia-induced pulmonary vascular remodeling.

Pancreatic cystic lesions (PCLs) are increasingly identified with the widespread use of imaging modalities. The precise diagnosis of PCLs remains a challenge despite the use of CT, MRI, and EUS-FNA. Confocal laser endomicroscopy (CLE) is a new endoscopic imaging modality that provides real-time, very high magnification images. A smaller CLE probe, which can be passed through a 19-gauge FNA needle, is now available. Needle-based CLE during EUS has recently been examined to evaluate PLCs, and the specific criteria of nCLE for the diagnosis of PLCs have been proposed.

Background/Aims: Endoscopic papillary balloon dilation (EPBD) is a possible alternative to endoscopic sphincterotomy (EST) for common bile duct (CBD) stones. To date, 10- and 8-mm EPBD have not been fully compared. Patients and Methods: Patients who underwent EPBD for CBD stones at two Japanese tertiary care centers between May 1994 and January 2014 were identified. Matched pairs with 10- and 8-mm EPBD were generated. Short- and long-term outcomes were compared between the two groups. Results: A total of 869 patients were identified (61 and 808 patients for 10- and 8-mm EPBD, respectively), and 61 well-balanced pairs were generated. The rate of complete stone removal within a single session was higher in the 10-mm EPBD group than in the 8-mm EPBD group (69% vs. 44%, P < 0.001), and use of lithotripsy was less frequent in the 10-mm EPBD group (23% vs. 56%, P < 0.001). The rates of post-ERCP pancreatitis were similar between the 10- and 8-mm EPBD groups (11% vs. 8%). Cumulative biliary complication-free rates were not statistically different between the two groups: 88% [95% confidence interval (CI): 79–97%] and 94% (95% CI: 88–100%) at 1 year and 69% (95% CI: 56–85%) and 80% (95% CI: 69–93%) at 2 years in the 10- and 8-mm EPBD groups, respectively. In the 10-mm EPBD group, ascending cholangitis was not observed, and pneumobilia was found in 5% of cases during the follow-up period. Conclusions: EPBD using a 10-mm balloon for CBD stones is safe and more effective than 8-mm EPBD. The sphincter function is highly preserved after 10-mm EPBD.

The pathobiology of degenerative aortic valve stenosis (AS) is complex and involves multiple features such as fibrosis, inflammation, oxidative stress, angiogenesis, hemorrhage, and osteogenic differentiation. We summarize the mechanism of valve calcification and angiogenesis which is necessary for calcifying processes. A promising therapeutic target is nuclear factor (NF)-κB which activates bone morphogenetic protein (BMP)2 via interleukin-6. BMP2 activates Wnt signaling via msh homeobox 2 causing osteogenic differentiation. BMP2 also activates Runx2/Cbfa1 which is an osteoblast-specific transcription factor. Signals in the hypoxia-inducible factor-2 axis activated by the NF-κB signaling pathway also play important role in calcifying processes including angiogenesis. The reason why angiogenesis takes place in avascular valves is still unknown, but it is likely angiogenesis and angiogenesis-related hemorrhage play critical roles in the progression of AS.

Living donor liver transplantation (LDLT) is an effective alternative to deceased liver transplantation (DDLT) for end-stage liver disease. Although advances in surgical techniques, immunosuppressive management, and post-transplant care have improved the overall outcomes of LDLT, biliary strictures remain the major unsolved problem. Endoscopic retrograde cholangiopancreatography (ERCP) is currently considered the first-line therapy for biliary strictures following LDLT with duct-to-duct reconstruction, with percutaneous and surgical interventions reserved for patients with unsuccessful management via ERCP. Endoscopic management of biliary strictures is technically more challenging in LDLT than in DDLT because of the complexity of the biliary anastomosis, in addition to the tortuous and angulated biliary system. Placement of one or more plastic stents after balloon dilation has been the standard strategy for post-LDLT stricture, but this requires multiple stent exchange to prevent stent occlusion until stricture resolution. Inside stents might prevent duodenobiliary reflux and thus have longer stent patency, obviating the need for multiple ERCPs. Newly developed covered self-expandable metallic stents with anti-migration systems are alternatives to the placement of multiple plastic stents. With the advent of deep enteroscopy, biliary strictures in LDLT patients with Roux-en-Y hepaticojejunostomy are now treatable endoscopically. In this review, we discuss the short- and long-term outcomes of endoscopic management of post-LDLT strictures as well as recent advances in this field.

Background and study aims Endoscopic papillary balloon dilation (EPBD) is a method of bile duct stone removal that has a better long-term outcome but a high risk of post-ERCP pancreatitis (PEP). Recent studies have suggested that 5-minute EPBD can reduce the incidence of PEP. This study aimed to examine the safety and effectiveness of longer duration EPBD compared with shorter duration EPBD (5 minutes vs. 15 seconds after disappearance of the waist of a dilation catheter). Patients and methods Patients without a history of endoscopic sphincterotomy or EPBD who underwent EPBD to remove bile duct stones were selected retrospectively from five centers. The incidence of PEP, other early adverse events, and outcomes of EPBD were compared between the groups. A multivariable analysis of risk factors for PEP was performed. Results A total of 607 patients (157 and 450 in the 5-minute and 15-second EPBD groups, respectively) were included. There were no statistically significant differences between the groups in terms of the incidence of PEP (8.3 % and 8.9 % in the 5-minute and 15-second EPBD groups, respectively; P = 0.871) and the incidence of overall early adverse events (P = 0.999). Although 5-minute EPBD elongated the procedure time (45 vs. 37 minutes, P Conclusions Compared with 15-second EPBD, 5-minute EPBD did not reduce the incidence of PEP.

Aims Cardiac function varies in the population of patients with heart failure (HF) with preserved left ventricular ejection fraction (LVEF; HFpEF). This study investigated the heterogeneity of clinical features associated with HF and the prognostic value of BNP levels in patients with HFpEF. Methods and results The study enrolled 288 patients with stable HF and serum creatinine 40%, n = 205). Patients with HFpEF were further categorized as having relatively low LVEF (HFrlEF; EF 40–60%, n = 107) or as having relatively high LVEF (HFrhEF; EF ≥ 60%, n = 98). We defined cardiovascular death and hospitalization for HF as adverse events and evaluated the prognostic value of the BNP levels in each group. There was no significant difference in event‐free survival between HFpEF and HFrEF patients or between HFrhEF and HFrlEF patients. A multivariate Cox proportional hazards model revealed that the BNP level was an independent predictor of adverse events in HFrEF patients (hazard ratio: 4.088, 95% confidence interval: 1.178–14.179, P = 0.027) and in HFrlEF patients (hazard ratio: 14.888, 95% confidence interval: 4.969–44.608, P

A subpopulation of patients with pancreas divisum experience symptomatic events such as recurrent acute pancreatitis and chronic pancreatitis. Minor papilla sphincterotomy has been reported as being an effective treatment. The aim of this study was to evaluate the safety and efficacy of endoscopic balloon dilation for the minor papilla.Between 2000 and 2012, 16 patients were retrospectively included in this study. After endoscopic balloon dilation for the minor papilla was received, a pancreatic stent or a nasal pancreatic drainage catheter was placed for 1 week. If a stricture or obstruction was evident, it was treated with balloon dilation followed by long-term stent placement (1 year). When an outflow of pancreatic juice was disturbed by a pancreatic stone, endoscopic stone extraction was performed.Balloon dilation and stent placement were achieved and were successful in all the cases (16/16; 100%). Clinical improvement was achieved in 7 (84.7%) of the 9 patients with recurrent acute pancreatitis and in 6 (85.7%) of the 7 patients with chronic pancreatitis. Early complications were observed in 1 (6.3%) patient. Pancreatitis or bleeding related to balloon dilation was not observed.Endoscopic balloon dilation for the minor papilla is feasible for the management of symptomatic pancreas divisum.

Objective Clinical studies have suggested the beneficial effects of statin therapy on diastolic heart failure. However, the mechanism of the beneficial effects of statin on diastolic heart failure remains unknown. We examined the effect of atorvastatin on the cardiac function of Dahl salt-sensitive rat, a model of hypertensive diastolic heart failure. Methods Dahl salt-sensitive rats were divided into three groups: the low-salt group (given standard diet), the high-salt group (given 8% NaCl diet from 7 weeks of age), and the high-salt + atorvastatin (HS + Ato) group (given 8% NaCl diet from 7 weeks of age and atorvastatin from 17 weeks of age). We evaluated left ventricular hypertrophy (LVH), fibrosis, and function by using echocardiography and histology. We also examined the expression of molecules related to fibrosis in the hearts of Dahl salt-sensitive rats and cultured rat cardiac fibroblasts. Results Left ventricular hypertrophy, diastolic dysfunction, and cardiac fibrosis were observed in the high-salt group. Atorvastatin ameliorated cardiac fibrosis and normalized left ventricular diastolic function without altering blood pressure. Atorvastatin also decreased the expression of heat shock protein 47 (HSP47), an essential chaperone for type 1 collagen processing, without changing in expression of transforming growth factor beta. In rat cardiac fibroblast cells, atorvastatin also reduced HSP47 level induced by transforming growth factor beta. The effect of atorvastatin was reversed by mevalonate and geranylgeranyl-pyrophosphate and mimicked by Rho kinase inhibitor. Conclusion Atorvastatin administration ameliorates cardiac fibrosis and improves left ventricular diastolic function in Dahl salt-sensitive rats. Lowering HSP47 by atorvastatin via inhibition of Rho-Rho kinase pathway is suggested as a mechanism.

a b s t r a c t Background: Plasma aldosterone concentration (PAC) is related to cardiac remodeling in patients with hypertension. However, we do not know the detailed relationship between changes in PAC and regression of left atrial (LA) volume following long-term treatment with angiotensin II receptor blocker (ARB) or calcium-channel blocker (CCB). Objective: The aim of this study was to investigate the effects of anti-hypertensive monotherapy, an ARB irbesartan or a CCB amlodipine, on PAC and LA reverse remodeling in hypertensive patients. Methods: A total of 48 patients with untreated hypertension were randomly assigned to irbesartan (ARB group, n = 26) and amlodipine (CCB group, n = 22). We examined the correlation between LA volume index (LAVI) and other echocardiographic parameters or PAC (n = 40) at the baseline and after 12 months of treatment. Results: After 12 months, blood pressure (BP) decreased similarly in both groups. LAVI and PAC signifi- cantly decreased in the ARB group, but not in the CCB group (−16 ± 8% vs. 22 ± 9%, p < 0.01, −16 ± 9% vs. 11 ± 9%, p < 0.05). Larger %-decrease in PAC was associated with larger %-reduction of LAVI in the ARB group (r = 0.54, p < 0.05), but not in the CCB group. Conclusions: While BP reduction was similar between the two groups, decrease in LA volume was larger in the ARB group than in the CCB group. Decrease in LA volume was larger in patients with a greater decrease in PAC than in those with smaller decrease in PAC. ARB may facilitate reverse remodeling of LA through decreases in PAC in hypertensive patients.

Background:Proton pump inhibitors (PPI) are frequently prescribed in combination with aspirin for preventing peptic ulcer in patients with atherosclerotic diseases. In contrast, long-term use of PPI has been suggested to be associated with iron or vitamin B12deficiency. The effect of PPI on hemoglobin (Hb) concentration, however, has not been clarified in cardiovascular outpatients.Methods and Results:We retrospectively investigated the clinical characteristics of 278 continuous outpatients who received blood test including complete blood count and serum creatinine concentration (mean age, 69.9±10.8 years; male, 68.7%). The frequency of anemia was 51% in patients receiving PPI and 19% in those not receiving PPI (chi-squared test, P

Objectives Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis is diagnosed on the basis of pancreatic pain and hyperamylasemia. However, because the diagnosis of abdominal pain is not objective, there may be some cases of painless pancreatitis among patients with post-ERCP hyperamylasemia (PEH). We reviewed the computed tomography (CT) findings of PEH cases to determine the incidence of painless pancreatitis. Methods Between July, 2005 and December, 2011, CT was performed in 91 patients with hyperamylasemia 18 h after ERCP. We reviewed the CT findings and graded the severity of pancreatitis according to the Balthazar grading system. Grades C, D, and E were defined as pancreatitis. Results Thirty-four patients (37%) had pancreatitis according to the CT findings. There was a significant difference in the serum amylase levels between the positive- and negative-CT finding groups (1306 ± 833 vs. 786 ± 315 IU/L, respectively; p = 0.0012). Receiver operating characteristic curve analysis showed that the amylase cut-off value for discriminating between the 2 groups was 795 IU/L (6.36 times the upper normal limit). Conclusions Thirty-seven percent of PEH patients had painless pancreatitis. CT is useful to determine pancreatitis in patients taking analgesics, steroids, or anti-immunological drugs and those with diabetes mellitus and 18-h serum amylase levels of >6 times the normal upper limit.

Background/Aims: Stent migration occurs frequently, but the prevention of complications resulting from covered self- expandable metal stents (C-SEMSs) remains unresolved. We prospectively assessed a newly developed C-SEMS, a modi- fied covered Zeo stent (m-CZS), in terms of its antimigration effect. Methods:�Between February 2010 and January 2011, an m-CZS was inserted into 42 patients (31 initial drainage cases and 11 reintervention cases) at a tertiary referral center and three affiliated hospitals. The laser-cut stent was flared for 1.5 cm at both ends, with a 1 cm raised bank located 1 cm in from each flared end. The main outcome of this study was the rate of stent migration, and second- ary outcomes were the rate of recurrent biliary obstruction (RBO), the time to RBO, the frequencies of complications, and overall survival. Results:�Of the 31 patients with initial drainage, stent migration occurred in four (12.9%, 95% con- fidence interval, 5.1% to 29.0%), with a mean time of 131 days. RBO occurred in 18 (58%), with a median time to RBO of 107 days. Following previous C-SEMS migration, seven of 10 patients (70%) did not experience m-CZS migration until death. Conclusions:�m-CZSs with antimigration properties ef- fectively, although not completely, prevented stent migration after stent insertion. (GutLiver�2013;7:725-730)

OBJECTIVE Iron accumulation is associated with the pathogenesis of chronic kidney disease (CKD). However, little is known about the effects of isolated iron restriction against CKD. We have recently reported that iron restriction prevents the development of renal damage in the well established 5/6 nephrectomy rat model of CKD. Herein, we investigated the therapeutic effects of iron restriction on preexisting hypertension and renal damage in a rat model of CKD. METHODS CKD was induced by 5/6 nephrectomy in Sprague-Dawley rats. After surgery, 5/6 nephrectomized rats were given an iron-restricted diet from 1 day to 16 weeks for prevention protocol or from 8 to 16 weeks for rescue protocol. Other CKD rats were given a normal diet. RESULTS At 16 weeks after surgery, CKD rats developed hypertension and renal damage. Early intervention with iron restriction prevented the development of hypertension and vascular remodeling. By contrast, late intervention with iron restriction did not remarkably ameliorate preexisting hypertension and vascular remodeling in CKD rats. On the contrary, late intervention with iron restriction prevented further progression of preexisting renal damage in CKD rats. Interestingly, iron restriction led to increased urinary sodium and decreased urinary potassium excretions in CKD rats. Moreover, iron restriction markedly attenuated renal expression of nuclear mineralocorticoid receptor and Rac1 activity in CKD rats. CONCLUSION Iron restriction prevented further deterioration of preexisting renal damage. The beneficial effects of iron restriction on renal damage seem to be associated with inhibition of renal mineralocorticoid receptor signaling.

Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling leading to right ventricular (RV) failure. Recently, iron deficiency is reported to be prevalent in patients with PH. However, the mechanism by which iron deficiency occurs in patients with PH remains unknown. Here, we investigated the effects of dietary iron restriction on the development of monocrotaline-induced pulmonary vascular remodeling and the involved mechanisms. Male Sprague–Dawley rats were subcutaneously injected with monocrotaline (60 mg/kg). Afterwards, monocrotaline - injected rats were randomly divided into two groups and were given a normal diet ( n = 6) or an iron-restricted diet ( n = 6) for 4 weeks. Saline-injected rats given a normal diet were served as controls ( n = 6). Monocrotaline-injected rats showed pulmonary vascular remodeling, increased RV pressure, RV hypertrophy, and decreased RV ejection fraction, followed by RV failure after 4 weeks. In contrast, iron restriction attenuated the development of pulmonary vascular remodeling and RV failure. Of interest, expression of cellular iron transport protein, transferrin receptor 1 was increased in the pulmonary remodeled artery and the failing right ventricle of monocrotaline-injected rats, as compared with the controls. Moreover, a key regulator of iron homeostasis, hepcidin gene expression was increased in the failing right ventricle of monocrotaline-injected rats. Iron restriction attenuated the development of monocrotaline-induced pulmonary vascular remodeling and RV failure. Cellular iron transport might be involved in the pathophysiology of PH and PH induced RV failure.

Background Self-expandable metallic stent (SEMS) placement is widely carried out for distal malignant biliary obstruction, and survival analysis is used to evaluate the cumulative incidences of SEMS dysfunction (e.g. the Kaplan–Meier [KM] method and the log–rank test). However, these statistical methods might be inappropriate in the presence of ‘competing risks’ (here, death without SEMS dysfunction), which affects the probability of experiencing the event of interest (SEMS dysfunction); that is, SEMS dysfunction can no longer be observed after death. A competing risk analysis has rarely been done in studies on SEMS. Patients and Methods We introduced the concept of a competing risk analysis and illustrated its impact on the evaluation of SEMS outcomes using hypothetical and actual data. Our illustrative study included 476 consecutive patients who underwent SEMS placement for unresectable distal malignant biliary obstruction. Results A significant difference between cumulative incidences of SEMS dysfunction in male and female patients via theKM method (P = 0.044 by the log–rank test) disappeared after applying a competing risk analysis (P = 0.115 by Gray's test). In contrast, although cumulative incidences of SEMS dysfunction via the KM method were similar with and without chemotherapy (P = 0.647 by the log–rank test), cumulative incidence of SEMS dysfunction in the non-chemotherapy group was shown to be significantly lower (P = 0.031 by Gray's test) in a competing risk analysis. Conclusion Death as a competing risk event needs to be appropriately considered in estimating a cumulative incidence of SEMS dysfunction, otherwise analytical results may be biased.