Dimethyl Fumarate Ameliorated Cardiorenal Anemia Syndrome and Improved Overall Survival in Dahl/Salt-Sensitive Rats.

Cardiovascular disease, chronic kidney disease, and anemia are known to adversely affect each other. Inflammation is commonly involved in these diseases. Cardiorenal anemia syndrome (CRAS) is the name given to this mutually harmful condition. Dimethyl fumarate (DMF) is a Food and Drug Administration-approved antioxidant and anti-inflammatory agent. The purpose of this study was to investigate the effects of DMF on Dahl/salt-sensitive (DS) rats as a CRAS model. Six-week-old DS rats were divided into three groups: the control group, the high-salt (HS) group, and the HS+DMF group. The HS and HS+DMF groups were fed a high-salt diet (8% NaCl) from 6 weeks of age. In the HS+DMF group, DMF (90 mg/kg per day) was orally administered from 6 to 15 weeks of age. Systolic blood pressure was measured every 2 weeks. The heart and renal injuries were assessed with histopathological analysis. The heart and renal expression of mRNAs was assessed by reverse-transcription polymerase chain reaction. DMF significantly improved overall survival, which was shortened by HS in DS rats. Systolic blood pressure increased in the HS group compared with the control group, and DMF tended to suppress this change. DMF ameliorated the cardiac and renal abnormalities confirmed in the HS group by histopathological analysis. Furthermore, the changes in mRNA expressions associated with disease exacerbation in the HS group were suppressed by DMF. DMF also improved anemia. This study suggests that DMF improves overall survival in DS rats through organ-protective effects and is effective against cardiorenal anemia syndrome. SIGNIFICANCE STATEMENT: Dimethyl fumarate was found to improve overall survival in Dahl/salt-sensitive rats, associated with its ability to ameliorate anemia and induce cardioprotective and renoprotective effects through anti-inflammatory and antifibrotic effects.

Juzentaihoto improves adenine-induced chronic renal failure in BALB/c mice via suppression of renal fibrosis and inflammation.

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-ß, 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.

Endoscopic ultrasound-guided portal pressure gradient with liver biopsy: 6 years of endo-hepatology in practice.

BACKGROUND AND AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Reactive Oxygen Species Cause Exercise-Induced Angina in a Myocardial Ischaemia-Reperfusion Injury 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.

Effects of Weight Loss in Outpatients With Mild Chronic Heart Failure: Findings From the J-MELODIC Study.

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.

Long-term outcomes of endoscopic treatment for duct-to-duct anastomotic strictures after living donor liver transplantation.

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.

Influence of quality of sleep in the first trimester on blood pressure in the third trimester in primipara women.

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 pregnancy in primipara women. Materials and methods: We recruited 128 pregnant women (primipara) who visited the obstetrics and gynecology clinic for medical examination, of which 89 were longitudinally investigated from the first to the third trimester after obtaining informed consent. A survey was conducted in the first, second, and third trimesters to evaluate sleep quality using the Japanese version of the Pittsburgh Sleep Quality Index (PSQI-J). Patients were assigned to either a good sleep quality group (PSQI-J ≤ 5) or a poor sleep quality group (PSQI-J ≥ 6). Blood pressure was measured using a home blood pressure measurement method. We analyzed the relationship between sleep quality in the first trimester and blood pressure during pregnancy. Results: The increase in morning systolic blood pressure from first to third trimester was larger in the poor sleep quality group than in the good sleep quality group (7.1 ± 7.0 vs. 3.0 ± 5.6 mmHg, p < .01). Sleep latency (r = 0.38, ß = 0.43, p = .02) and sleep disturbances (r = 0.24, ß = 0.33, p = .04) in the first trimester affected the increase in systolic blood pressure during pregnancy. Conclusions: Understanding sleep quality at the beginning of pregnancy can help predict a rise in systolic blood pressure in the third trimester. This emphasizes the importance of sleep education during pregnancy.

Neutrophil/lymphocyte ratio elevation in renal dysfunction is caused by distortion of leukocyte hematopoiesis in bone marrow.

OBJECTIVE: We investigate the mechanism of neutrophil/lymphocyte ratio (NLR) elevation, a useful prognostic marker in patients with cardiovascular diseases (CVDs). METHODS: In this clinical study, we retrospectively searched for factors associated with NLR elevation in cardiovascular outpatients. In animal experiments using mice with adenine-induced nephropathy, we further examined the hematopoietic process in bone marrow and explored the mechanism of NLR elevation. RESULT: In patients with CVDs or their risk factors, multiple regression analysis revealed that decrease in estimated glemerular filtration rate and increase in white blood cell count were significantly associated with increase in NLR. In mice with adenine-induced nephropathy, NLR and serum indoxyl sulfate (IS) levels were increased. Fluorescence-activated cell sorting revealed the increase in the number of myeloid progenitors and decrease in the number of common lymphoid progenitors, suggesting biased granulocyte side in the hematopoietic process in bone marrow. Treatment with oral charcoal adsorbent AST-120 decreased serum concentration of IS and normalized NLR and bone marrow abnormalities in mice with adenine-induced nephropathy. CONCLUSION: Renal function was a strong determinant of NLR in cardiovascular outpatients. NLR elevation due to renal impairment is caused by distortion of the hematopoietic process in bone marrow. IS plays a significant role in these processes.

Endoscopic papillary large balloon dilation and endoscopic papillary balloon dilation both without sphincterotomy for removal of large bile duct stones: A propensity-matched analysis.

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.

Impact of serum cholesterol esterification rates on the development of diabetes mellitus in a general population.

BACKGROUND: Lecithin:cholesterol acyltransferase (LCAT) plays an important role in cholesterol esterification in serum. Serum LCAT activity is elevated in patients with serum high triglyceride and low high-density lipoprotein-cholesterol (HDL-C) concentrations, both of which are related to metabolic syndrome and subsequent diabetes mellitus, referred to as lipotoxicity. We hypothesized that increased serum LCAT activity could predict future risk of diabetes mellitus in a general Japanese population. METHODS: We prospectively studied 1496 individuals aged 20-86 years without histories of diabetes mellitus at baseline. Serum lipid concentrations, glucose parameters, and LCAT activity measured as the serum cholesterol esterification rate, were evaluated. RESULTS: During 11 years of follow-up, 46 newly diagnosed patients with diabetes mellitus were reported. After adjustment for plasma glycosylated hemoglobin A1c (HbA1c) levels, the relative risks (RRs) for the development of diabetes mellitus were 5.45 [95% confidence interval (95% CI) 2.37-12.55; P <  0.001] for body-mass index, 0.22 (95% CI, 0.09-0.53; P = 0.001) for HDL-C, 4.81 (95% CI, 1.96-11.77; P = 0.001) for triglyceride, and 4.64 (95% CI, 1.89-11.41; P = 0.001) for LCAT activity. After adjustment for HbA1c, total cholesterol, triglyceride, HDL-C, phospholipid, and free fatty acid levels, the RR of LCAT activity for future risk of diabetes mellitus remained significant (RR, 4.93; 95% CI,1.32-18.41; P = 0.018). In this analysis, we found a significant association between LCAT activity and risk of diabetes mellitus in men but not in women. CONCLUSION: Increased serum cholesterol esterification rate is a potent predictor for future diabetes mellitus.

EUS-guided portal pressure gradient measurement with a simple novel device: a human pilot study.

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.

Altered expression of intestinal duodenal cytochrome b and divalent metal transporter 1 might be associated with cardio-renal anemia syndrome.

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.

Changes in brain natriuretic peptide in chronic heart failure patients treated with long-acting versus short-acting loop diuretics: J-MELODIC subanalysis.

We have previously reported that a long-acting loop diuretic, azosemide, reduces cardiovascular risks in patients with chronic heart failure (CHF) as compared with a short-acting one, furosemide, in Japanese Multicenter Evaluation of LOng- versus short-acting Diuretics In Congestive heart failure (J-MELODIC). However, the mechanisms of the difference have not been elucidated. This study aimed to examine whether there is a difference in the reduction in plasma brain natriuretic peptide (BNP) level and in left ventricular (LV) functional recovery between the CHF patients treated with the long-acting diuretic (the azosemide group) and the short-acting diuretic (the furosemide group). We reviewed changes in plasma BNP level and echo-assessed LV functional parameters from baseline to a year after the entry in 288 CHF patients with New York Heart Association class II or III symptoms that joined J-MELODIC. The decrease in plasma BNP levels was larger in the azosemide group than in the furosemide group (p < 0.01). The changes in echocardiographic parameters were not more favorable in the azosemide group than in the furosemide group. In conclusion, the decrease in plasma BNP levels was larger in the azosemide group than in the furosemide group. These findings may account for the better prognosis in CHF patients treated with azosemide than those with furosemide in J-MELODIC.

EUS-guided portal pressure gradient measurement with a novel 25-gauge needle device versus standard transjugular approach: a comparison animal study.

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.

Cholecystectomy after endoscopic papillary balloon dilation for bile duct stones reduced late biliary complications: a propensity score-based cohort analysis.

BACKGROUND: Cholecystectomy after endoscopic sphincterotomy for bile duct stones with concomitant gallstones is known to reduce late biliary complications. Endoscopic papillary balloon dilation for bile duct stones develops fewer late biliary complications than endoscopic sphincterotomy, but no randomized controlled trials have been conducted about the role of cholecystectomy after endoscopic papillary balloon dilation. Therefore, we conducted this propensity score-matched analysis to compare cholecystectomy and wait-and-see approach after endoscopic papillary balloon dilation. METHODS: Propensity score matching extracted 147 pairs of patients with cholecystectomy after endoscopic papillary balloon dilation and with gallbladder left in situ with stones (wait-and-see) from 725 patients who underwent endoscopic papillary balloon dilation for bile duct stones. Late biliary complications such as recurrent bile duct stones and cholecystitis were evaluated. Cumulative incidence of late biliary complications was calculated treating death without biliary complications as a competing risk, and its prognostic factor was evaluated. RESULTS: The rates of late biliary complications were 5.4 and 25.2 % in the cholecystectomy after endoscopic papillary balloon dilation and wait-and-see groups: Recurrent bile duct stones rates were 4.1 and 19.0 %, and cholecystitis rates were 0.7 and 6.1 %. The cumulative incidences of biliary complications in the cholecystectomy after endoscopic papillary balloon dilation and wait-and-see approach were 3.1 versus 13.0 % at 1 year and 5.7 versus 28.0 % at 5 year after endoscopic papillary balloon dilation (p = 0.008). Subdistribution hazard ratio of late biliary complications in the wait-and-see group was 5.1 (p = 0.020). CONCLUSION: Cholecystectomy after endoscopic papillary balloon dilation for choledocholithiasis was associated with fewer late biliary complications. Prophylactic cholecystectomy should be offered to all surgically fit patients after endoscopic papillary balloon dilation for bile duct stones with concomitant gallstones.

Changes in collagen metabolism account for ventricular functional recovery following beta-blocker therapy in patients with chronic heart failure.

While beta blockade improves left ventricular (LV) function in patients with chronic heart failure (CHF), the mechanisms are not well known. This study aimed to examine whether changes in myocardial collagen metabolism account for LV functional recovery following beta-blocker therapy in 62 CHF patients with reduced ejection fraction (EF). LV function was echocardiographically measured at baseline and 1, 6, and 12 months after bisoprolol therapy along with serum markers of collagen metabolism including C-terminal telopeptide of collagen type I (CITP) and matrix metalloproteinase (MMP)-2. Deceleration time of mitral early velocity (DcT) increased even in the early phase, but LVEF gradually improved throughout the study period. Heart rate (HR) was reduced from the early stage, and CITP gradually decreased. LVEF and DcT increased more so in patients with the larger decreases in CITP (r = -0.33, p < 0.05; r = -0.28, p < 0.05, respectively), and HR (r = -0.31, p < 0.05; r = -0.38, p < 0.05, respectively). In addition, there were greater decreases in CITP, MMP-2 and HR from baseline to 1, 6, or 12 months in patients with above-average improvement in LVEF than in those with below-average improvement in LVEF. Similar results were obtained in terms of DcT. There was no significant correlation between the changes in HR and CITP. In conclusion, improvement in LV systolic/diastolic function was greatest in patients with the larger inhibition of collagen degradation. Changes in myocardial collagen metabolism are closely related to LV functional recovery somewhat independently from HR reduction.

Long-term effects of L- and N-type calcium channel blocker on uric acid levels and left atrial volume in hypertensive patients.

Left ventricular (LV) diastolic dysfunction is associated with hypertension and hyperuricemia. However, it is not clear whether the L- and N-type calcium channel blocker will improve LV diastolic dysfunction through the reduction of uric acid. The aim of this study was to investigate the effects of anti-hypertensive therapy, the L- and N-type calcium channel blocker, cilnidipine or the L-type calcium channel blocker, amlodipine, on left atrial reverse remodeling and uric acid in hypertensive patients. We studied 62 patients with untreated hypertension, randomly assigned to cilnidipine or amlodipine for 48 weeks. LV diastolic function was assessed with the left atrial volume index (LAVI), mitral early diastolic wave (E), tissue Doppler early diastolic velocity (E') and the ratio (E/E'). Serum uric acid levels were measured before and after treatment. After treatment, systolic and diastolic blood pressures equally dropped in both groups. LAVI, E/E', heart rate and uric acid levels decreased at 48 weeks in the cilnidipine group but not in the amlodipine group. The % change from baseline to 48 weeks in LAVI, E wave, E/E' and uric acid levels were significantly lower in the cilnidipine group than in the amlodipine group. Larger %-drop in uric acid levels were associated with larger %-reduction of LAVI (p < 0.01). L- and N-type calcium channel blocker but not L-type calcium channel blocker may improve LV diastolic function in hypertensive patients, at least partially through the decrease in uric acid levels.

Use of proton pump inhibitors is associated with anemia in cardiovascular outpatients.

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 B12 deficiency. 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<0.001). On multivariate analysis female sex (P<0.001), peripheral artery disease (P=0.003), PPI (P=0.003), low white blood cell count (P=0.004), old age (P=0.007), and low estimated glomerular filtration rate (P=0.010) were independently associated with low Hb. Among these patients, we investigated the change in Hb after the initiation of PPI in 36 patients for whom data on Hb level within 1 year before and within 1 year after the initiation of PPI were available. Mean decrease in Hb after the initiation of PPI was 0.38 ± 0.87 g/dl (95% confidence interval: -0.67 to -0.09 g/dl). CONCLUSIONS: Use of PPI was associated with anemia in Japanese cardiovascular outpatients.

Detection of painless pancreatitis by computed tomography in patients with post-endoscopic retrograde cholangiopancreatography hyperamylasemia.

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.

Increased serum cholesterol esterification rates predict coronary heart disease and sudden death in a general population.

OBJECTIVE: Lecithin:cholesterol acyltransferase (LCAT) is thought to be important in reverse cholesterol transport. However, its association with coronary heart disease (CHD) and sudden death is controversial. APPROACH AND RESULTS: We prospectively studied 1927 individuals from the general population. Serum concentrations of apolipoprotein A-I, A-II, B, C-II, C-III, E, and LCAT activity measured as a serum cholesterol esterification rate were evaluated. We documented 61 events of CHD and sudden death during 10.9 years of follow-up. After adjustment for age and sex, LCAT activity was significantly associated with the risk of CHD and sudden death (hazard ratio, 3.02; 95% confidence interval, 1.49-6.12; P=0.002). In multivariate analysis adjusted for age, sex, current smoking status, history of diabetes mellitus, body mass index, systolic blood pressure, serum total cholesterol, and serum high-density lipoprotein cholesterol concentrations, the hazard ratio of LCAT activity for the risk of CHD and sudden death remained significant (hazard ratio, 3.07; 95% confidence interval, 1.35-7.01; P=0.008). However, when it was analyzed for men and women separately, this association remained significant only in women. CONCLUSIONS: Increased LCAT activity measured as a serum cholesterol esterification rate was a risk for CHD and sudden death in a Japanese general population.