IL-1 Receptor Antagonist Blocks the Lipopolysaccharide-Induced Inhibition of Gastric Motility in Freely Moving Conscious Rats

Background and Aims

Endotoxin/lipopolysaccharide (LPS) alters gastrointestinal functions. However, little is known as to whether LPS could change gastric antral contractility in freely moving conscious animals. We tried to clarify this problem and the associated mechanisms.

Methods

In this study, we recorded intraluminal gastric pressure waves in freely moving conscious rats by manometric catheter located in the antrum. Area under the manometric trace was evaluated as motor index (MI).

Results

Intraperitoneal injection of LPS at doses of 0.2?mg/kg or more significantly inhibited MI. The inhibition started immediately after the administration of LPS and lasted over 1?h. Intraperitoneal injection of IL-1β potently decreased MI while neither IL-6 nor TNF-α inhibited gastric motility, suggesting IL-1β specifically reduced gastric motility. Next, we examined the hypothesis that endogenous IL-1 mediates the LPS-induced inhibition of gastric motility. To address the speculation, an IL-1 receptor antagonist (IL-1Ra) was used to block IL-1 signaling. Pretreatment with IL-1Ra at a dose of 20?mg/kg significantly blocked the inhibition of gastric contractility by LPS at a dose of 0.2?mg/kg.

Conclusions

These results suggest for the first time that LPS or IL-1β is capable of inhibiting gastric motility in conscious rats and that endogenously released IL-1 may mediate the LPS-evoked inhibition of gastric antral motility. This evidence also led us to speculate that IL-1Ra may be a therapeutic tool for patients with disturbed gastrointestinal functions under septic conditions.     

Increased levels of inflammatory and extracellular matrix turnover biomarkers persist despite reverse atrial structural remodeling during the first year after atrial fibrillation ablation

Purpose

Left atrial (LA) remodeling associated with atrial fibrillation (AF) is known to be related to inflammation and collagen turnover. We investigated the changes in the biomarkers of inflammation and collagen turnover in relation to LA reverse remodeling during the 1st year after AF ablation.

Methods

Biomarkers of inflammation [high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6)] and collagen turnover [matrix metalloproteinase-2 (MMP-2), tissue inhibitor of MMP-2 (TIMP-2), transforming growth factor beta 1 (TGF-β1)], as well as asymmetric dimethylarginine (ADMA) and adiponectin levels were measured, and echocardiographic measurements were obtained before and 3, 6, and 12 months after ablation in 60 AF patients (49 males; age, 57.6?±?10.9 years).

Results

During a 12.1 (11.5–12.9)-month follow-up period, AF recurred in 29 patients (48 %). Neither the LA volume (LAV) nor the left ventricular ejection fraction (LVEF) changed significantly during the 1st year in this group, but the LAV decreased significantly, and the LVEF increased significantly in the nonrecurrence group. The hs-CRP and IL-6 decreased after ablation but returned near to baseline levels in both groups by 12 months. The MMP-2 remained increased during the 1st year in both groups, whereas the TIMP-2 increased markedly in the nonrecurrence group but did not change substantially in the recurrence group. The TGF-β1 increased in both groups, but the change was less pronounced in the recurrence group. The ADMA and adiponectin levels did not change substantially in either group.

Conclusions

Despite reverse remodeling, the inflammation and collagen turnover biomarker levels are quite progressive during the 1st year after ablation and may explain the late AF recurrence.     

Catheter ablation for atrial fibrillation results in greater improvement in cardiac function in patients with low versus normal left ventricular ejection fraction

Purpose

It is still unknown whether left ventricular ejection fraction (LVEF) might affect the magnitude of improvement after atrial fibrillation (AF) ablation on cardiac function in persistent or longstanding persistent AF (CAF) patients.

Method

We performed echocardiography in 35 patients with CAF before and after catheter ablation (CA). Patients were stratified by LVEF into two groups prior to CA—normal LVEF (≥50 % LVEF, N group, n?=?24) and a low LVEF group (<50 % LVEF, L group, n?=?11). Patients were followed at 1 month, 3 months, 6 months, 1 year, and 2 years after ablation.

Results

After 15.8?±?7.4 months follow-up, the L group showed greater improvement in LVEF and left atrial ejection fraction (LAEF; N group vs L group: LVEF difference (%), 5?±8 vs 20±?13, p?<?0.01; LAEF difference (%), 11?±?12 vs 21?±?10, p?<?0.05). LA maximal volume and E/e′ showed the same tendency after ablation, although the extent of improvement was not statistically significant. Both groups showed almost the same time course of improvement up to 2 years, although the L group showed earlier recovery in LVEF.

Conclusion

The greater improvement in several cardiac functions was seen in patients with greater LV dysfunction, after the CA for CAF.     

Effect of Chronic CPT-1 Inhibition on Myocardial Ischemia-Reperfusion Injury (I/R) in a Model of Diet-Induced Obesity

Purpose

By increasing circulating free fatty acids and the rate of fatty acid oxidation, obesity decreases glucose oxidation and myocardial tolerance to ischemia. Partial inhibition of fatty acid oxidation may improve myocardial tolerance to ischemia/reperfusion (I/R) in obesity. We assessed the effects of oxfenicine treatment on post ischemic cardiac function and myocardial infarct size in obese rats.

Methods

Male Wistar rats were fed a control diet or a high calorie diet which resulted in diet induced obesity (DIO) for 16?weeks. Oxfenicine (200?mg/kg/day) was administered to control and DIO rats for the last 8?weeks. Isolated hearts were perfused and infarct size and post ischemic cardiac function was assessed after regional or global ischemia and reperfusion. Cardiac mitochondrial function was assessed and myocardial expression and activity of CPT-1 (carnitine palmitoyl transferase-1) and IRS-1 (insulin receptor substrate-1) was assessed using Western blot analysis.

Results

In the DIO rats, chronic oxfenicine treatment improved post ischemic cardiac function and reduced myocardial infarct size after I/R but had no effect on the cardiac mitochondrial respiration. Chronic oxfenicine treatment worsened post ischemic cardiac function, myocardial infarct size and basal mitochondrial respiration in control rat hearts. Basal respiratory control index (RCI) values, state 2 and state 4 respiration rates and ADP phosphorylation rates were compromised by oxfenicine treatment.

Conclusion

Chronic oxfenicine treatment improved myocardial tolerance to I/R in the obese rat hearts but decreased myocardial tolerance to I/R in control rat hearts. This decreased tolerance to ischemia of oxfenicine treated controls was associated with adverse changes in basal and reoxygenation mitochondrial function. These changes were absent in oxfenicine treated hearts from obese rats.     

Cytokine Combination Therapy with Erythropoietin and Granulocyte Colony Stimulating Factor in a Porcine Model of Acute Myocardial Infarction

Purpose

Erythropoietin (EPO) and granulocyte colony stimulating factor (GCSF) have generated interest as novel therapies after myocardial infarction (MI), but the effect of combination therapy has not been studied in the large animal model. We investigated the impact of prolonged combination therapy with EPO and GCSF on cardiac function, infarct size, and vascular density after MI in a porcine model.

Methods

MI was induced in pigs by a 90 min balloon occlusion of the left anterior descending coronary artery. 16 animals were treated with EPO+GCSF, or saline (control group). Cardiac function was assessed by echocardiography and pressure-volume measurements at baseline, 1 and 6 weeks post-MI. Histopathology was performed 6 weeks post-MI.

Results

At week 6, EPO+GCSF therapy stabilized left ventricular ejection fraction, (41?±?1% vs. 33?±?1%, p?<?0.01) and improved diastolic function compared to the control group. Histopathology revealed increased areas of viable myocardium and vascular density in the EPO+GCSF therapy, compared to the control. Despite these encouraging results, in a historical analysis comparing combination therapy with monotherapy with EPO or GCSF, there were no significant additive benefits in the LVEF and volumes overtime using the combination therapy.

Conclusion

Our findings indicate that EPO+GCSF combination therapy promotes stabilization of cardiac function after acute MI. However, combination therapy does not seem to be superior to monotherapy with either EPO or GCSF.     

Fragmented QRS complexes after acute myocardial infarction are independently associated with unfavorable left ventricular remodeling

Background

Recovery of left ventricular ejection fraction (LVEF) after acute myocardial infarction (MI) is not universal and is difficult to predict. Fragmented QRS (fQRS) complexes are thought to be markers of myocardial scar. We hypothesized that fQRS complexes on 12?lead surface ECGs during the initial post-MI period would be associated with adverse LV remodeling over the following year.

The Protective Role of Interleukin-11 Against Neutron Radiation Injury in Mouse Intestines via MEK/ERK and PI3K/Akt Dependent Pathways

Background

Neutron irradiation (IR) has been proven to cause more serious damage than gamma IR. Preventing and curing neutron IR damage remains an urgent issue.

Aims

The objective of this study was to investigate the radioprotective effects of IL-11 against neutron IR-induced damage in small intestine of mice.

Methods

Mice were exposed to 3-Gy neutron IR whole body and then treated with 500 μg/kg interleukin-11 (IL-11) intraperitoneally every day. Mice were observed at various time-points over 1–5 days after IR. IEC-6 cells were exposed to 4 Gy neutron IR, and 100 ng/mL rhIL-11 was added to culture medium. Cell proliferation activity was estimated by MTT assay and rates of apoptosis were estimated by flow cytometry.

Results

IL-11 slightly alleviated the incidence of diarrhea in the mice and promoted intestinal epithelia regeneration. In the in vitro study, neutron IR activated extracellular signal-regulated kinase (ERK)1/2 phosphorylation in intestinal epithelial cells constitutively, which was initially suppressed and then activated later by IL-11. The MEK-specific inhibitor U0126 could antagonize the positive effect of IL-11 on cell growth. Phosphatidylinositol 3-kinase (PI3K)/Akt pathway activation was suppressed after neutron IR, but could be triggered by IL-11 to protect the cells. The PI3K inhibitor LY294002 suppressed the positive effect of IL-11 on cell growth, and antagonized the protective effect of IL-11 against cell death after neutron IR.

Conclusion

IL-11 increases cell proliferation after neutron IR in MEK and PI3K-dependent signaling pathways, but protects cells against death only in the PI3K-dependent signaling pathway.     

Native QRS narrowing reflects electrical reversal and associates with anatomical reversal in cardiac resynchronization therapy

Purpose

Abbreviation of paced QRS duration has been taken as electrical resynchronization imposed by cardiac resynchronization therapy (CRT). However, little is known about alteration in native QRS duration and its correlation with therapeutic response as well as anatomical remodeling post-CRT.

Methods

Data of 74 consecutive patients with complete ECG records were reviewed. Response was defined as absolute improvement in LVEF by ≥10 % from baseline. Changes in native QRS duration (native ΔQRS) were analyzed to CRT response and to changes in echocardiography.

Results

Over median follow-up of 13 months, 47 patients had response to CRT and 30 subjects had abbreviation in native QRS duration. Native ΔQRS correlated positively with QRS duration pre- and post-CRT as well as with changes in echocardiography. Reversal of electrical remodeling as assessed by native QRS narrowing accompanied with greater improvements in LVEF (20 %?±?11 % vs 10%?±?10 %, p?=?0.000) and LVEDD (14?±?11 mm vs. 4?±?10 mm, p?=?0.000). Multivariate analysis indicated that native ΔQRS was the lone independent factor of ECG in association to response to CRT (OR1.049, 95%CI 1.015–1.085, p?=?0.004): 83.3 % of patients with native QRS reduction were responders. Among the non-responders, 18.5 % had native QRS narrowing at follow-ups.

Conclusions

Native QRS narrowing associated with beneficial response and greater improvements in echocardiography. Abbreviation in native QRS duration could reflect electrical reversal imposed by CRT.     

Ventricular tachycardia and sudden death after primary PCI-reperfusion therapy

Background

Current approaches to coronary artery disease (CAD) and acute myocardial infarction (MI) may not be well represented in most primary prevention trials of sudden cardiac death (SCD).

Methods

The contemporary and ongoing registry of the Rostock infarction network (Drip &; Ship) represents a well-defined cohort of patients subjected to percutaneous coronary intervention (PCI) for ST-elevation infarction (STEMI) and served as the database for both candidates for an ICD for primary prevention of SCD and for sudden death (SCD) or ventricular tachycardia (VT) during follow-up.

Results

A total of 855?consecutive patients were treated with PCI for STEMI or NSTEMI in the region of Rostock (Germany) between 2001 and 2004. While all cause mortality was still 17.2%, the SCD rate was low at 1.3% during 728?±?366?days of follow-up. Within that time 85?patients (9.9%) developed an indication for ICD therapy due to an impaired LV function (LVEF????35%) and heart failure. Univariate predictors of an ICD indication were delayed reperfusion (p?=?0.001), a high creatine kinase (CK) max (p?=?0.009), a persistent wide QRS complex (p?=?0.001), previous cerebrovascular events (p?=?0.033), and chronic renal failure (p?=?0. 001). However, only 16.5% of these patients qualifying for an ICD actually received an ICD; nevertheless, the actual SCD rate was only 3.5%, while 5.4% (46?patients) suffered VTs or ventricular fibrillation (VF). The SCD/VT rate in the entire infarct population was associated with time to reperfusion (0.032), left bundle-branch block (0.002), a longer history of CAD (0.032), and VT during follow-up.

Conclusion

While mortality in patients with STEMI is still alarming even with PCI, the risk of SCD may be considerably decreased even in patients with an LVEF below 35%. With the current approach to primary prevention of sudden cardiac death, approximately 10% of postinfarction patients qualify for ICD therapy; however this may only reach a quarter of patients prone to SCD.     

Improvement in Left Ventricular Function with Intracoronary Mesenchymal Stem Cell Therapy in a Patient with Anterior Wall ST-Segment Elevation Myocardial Infarction

Background/Aims

The progression and development of congestive heart failure is still considered a large problem despite the existence of revascularization therapies and optimal, state-of-the-art medical services. An acute myocardial infarction (AMI) is a major cause of congestive heart failure, so researchers are investigating techniques to complement primary percutaneous coronary intervention (PCI) or thrombolytic therapy to prevent congestive heart failure after AMI.

Methods

Twenty-six patients with successful PCI for acute ST-segment elevation anterior wall myocardial infarction were assigned to either a control group (n?=?12) or a bone marrow mesenchymal stem cells (BM-MSC) group (n?=?14). The control group received optimum post-infarction treatment, and the BMSC group received intracoronary delivery of autologous BMSC at 1 month after PCI with the optimum medical treatment. The primary endpoint was a left ventricular ejection fraction (LVEF) change from baseline to 4-month follow-up, as determined via myocardial single-photon emission computed tomography (SPECT).

Results

The global LVEF at baseline (determined 3.5?±?1.5 days after PCI) was 35.4?±?3.0% in the control group and 33.6?±?4.7% in the BM-MSC group. BMSC transfer enhanced left ventricular systolic function primarily in anterior wall myocardial segments adjacent to the LAD infarcted area. Four months later, via SPECT, global LVEF had increased by 4.8?±?1.9% in the control group and 8.8?±?2.9% in the BM-MSC group (p?=?0.031). The cell transfer did not increase the risk of adverse clinical events, in-stent restenosis, or proarrhythmic effects. The echocardiographic evaluation also revealed a significant increase in the LVEF value from baseline to the 4-month (9.0?±?4.7 and 5.3?±?2.6%, p?=?0.023) and 12-month (9.9?±?5.2% and 6.5?±?2.7%, p?=?0.048) follow-up in the BM-MSC group but not in the control group.

Conclusions

Intracoronary administration of autologous BM-MSC was tolerable and safe with significant improvement in LVEF at 4-month (SPECT and echocardiography result) and 12-month (echocardiography result only) follow-up in patients with anterior AMI.

     

Cardioprotection by Farnesol: Role of the Mevalonate Pathway

Purpose

Farnesol is a key metabolite of the mevalonate pathway and known as an antioxidant. We examined whether farnesol treatment protects the ischemic heart.

Methods

Male Wistar rats were treated orally with 0.2, 1, 5, and 50 mg/kg/day farnesol/vehicle for 12 days, respectively. On day 13, the effect of farnesol treatment on cardiac ischemic tolerance and biochemical changes was tested. Therefore, hearts were isolated and subjected either to 30 min coronary occlusion followed by 120 min reperfusion to measure infarct size or to 10 min aerobic perfusion to measure cardiac mevalonate pathway end-products (protein prenylation, cholesterol, coenzyme Q9, coenzyme Q10, dolichol), and 3-nitrotyrosine (oxidative/nitrosative stress marker), respectively. The cytoprotective effect of farnesol was also tested in cardiomyocytes subjected to simulated ischemia/reperfusion.

Results

Farnesol pretreatment decreased infarct size in a U-shaped dose–response manner where 1 mg/kg/day dose reached a statistically significant reduction (22.3?±?3.9 % vs. 40.9?±?6.1 % of the area at risk, p?<?0.05). Farnesol showed a similar cytoprotection in cardiomyocytes. The cardioprotective dose of farnesol (1 mg/kg/day) significantly increased the marker of protein geranylgeranylation, but did not influence protein farnesylation, cardiac tissue cholesterol, coenzyme Q9, coenzyme Q10, and dolichol. While the cardioprotective dose of farnesol did not influence 3-nitrotyrosine, the highest dose of farnesol (50 mg/kg/day) tested did not show cardioprotection, however, it significantly decreased cardiac 3-nitrotyrosine.

Conclusions

This is the first demonstration that oral farnesol treatment reduces infarct size. The cardioprotective effect of farnesol likely involves increased protein geranylgeranylation and seems to be independent of the antioxidant effect of farnesol.     

SGLT-2 Inhibition with Dapagliflozin Reduces the Activation of the Nlrp3/ASC Inflammasome and Attenuates the Development of Diabetic Cardiomyopathy in Mice with Type 2 Diabetes. Further Augmentation of the Effects with Saxagliptin,a DPP4 Inhibitor

Purpose

We assessed whether (1) dapagliflozin (Dapa, an SGLT2-inhibitor) attenuates the deterioration of heart function Nlrp3 and inflammasome activation in diabetic mice. (2) The effects can be augmented with saxagliptin (Saxa), a DDP4-inhibitor. (3) Dapa effect is possibly SGLT2-independent on cardiofibroblasts in vitro.

Methods

Type 2 diabetic (BTBR ob/ob) and wild-type (WT) mice received vehicle, Dapa, or Dapa+Saxa for 8 weeks. Glucose tolerance test and echocardiogram were performed. Cardiofibroblasts from WT and BTBR hearts were incubated with Dapa and exposed to LPS.

Results

Left ventricular ejection fraction (LVEF) was 81 ± 1% in the WT and 53 ± 1% in the T2D-cont mice. Dapa and Dapa+Saxa improved LVEF to 68 ± 1 and 74.6 ± 1% in the BTBR mice (p < 0.001). The mRNA levels of NALP3, ASC, IL-1β, IL-6, caspase-1, and TNFα were significantly higher in the BTBR compared to the WT hearts; and Dapa and Dapa+Saxa significantly attenuated these levels. Likewise, protein levels of NLRP3, TNFα, and caspase-1 were higher in the BTBR compared to the WT hearts and Dapa, and to a greater extent Dapa+Saxa, attenuated the increase in the BTBR mice. Collagen-1 and collagen-3 mRNA levels significantly increased in the BTBR mice and these increases were attenuated by Dapa and Dapa+Saxa. P-AMPK/total-AMPK ratio was significantly lower in the BTBR mice than in the WT mice. Dapa and Dapa+Saxa equally increased the ratio in the BTBR mice. This in vitro study showed that NALP3, ASC, IL-1β, and caspase-1 mRNA levels were higher in the BTBR cardiofibroblasts and attenuated with Dapa. The effect was AMPK-dependent and SGLT1-independent.

Conclusions

Dapa attenuated the activation of the inflammasome, fibrosis, and deterioration of LVEF in BTBR mice. The anti-inflammatory, anti-fibrotic effects are likely SGLT2- and glucose-lowering-independent, as they were replicated in the in vitro model. The effects on remodeling were augmented when Saxa was added to Dapa. Yet, adding Saxa to Dapa did not result in a greater effect on myocardial fibrosis and collagen levels.

     

Mal-effects of obstructive sleep apnea on the heart

Objective

This study aims to examine the impact of chronic intermittent hypoxia on hearts in patients with obstructive sleep apnea (OSA).

Methods

Two hundred twenty patients were divided into groups based on (1) severity of the disease, (2) years of disease history, and (3) with or without secondary hypertension. All subjects underwent blood pressure measurements, polysomnogram monitoring, and cardiac Doppler ultrasound examinations.

Results

The left ventricular ejection fraction (LVEF), fractional shortening (FS), and the ratio of early to late diastolic filling (E/A) in patients with severe OSA were lower than in those with moderate OSA and in healthy controls. The inner diameters of the main pulmonary artery (inD of MPA), the inner diameters of the right cardiac ventricle (inD of RV), and the thickness of anterior wall of the right ventricle (TAW of RV) were increased in patients with severe OSA compared to those with moderate disease and worsened as a function of time with disease. The tissue Doppler imaging-derived Tei index and pulmonary artery systolic pressure were also increased along with the severity of OSA. LVEF and FS in patients who had suffered from OSA for >10?years were decreased compared with those suffering from OSA for a shorter time. LVEF and FS in patients with secondary hypertension were decreased significantly relative to non-hypertensive OSA patients and healthy controls. E/A was decreased in OSA patients whether they had secondary hypertension or not.

Conclusion

OSA affected the left ventricular diastolic function in the early stage of the disease. Extended exposure to OSA resulted in left ventricular dysfunction with increased hypertension. Right ventricle dysfunction and abnormalities became more severe as the disease progressed.     

Attenuation of indomethacin-induced gastric mucosal injury by prophylactic administration of sake yeast-derived thioredoxin

Background

Indomethacin is one of the group of nonsteroidal anti-inflammatory drugs, which often cause gastric mucosal injury as a side effect. Infiltration and activation of inflammatory cells, production of proinflammatory cytokines and chemokines, generation of reactive oxygen species, and activation of apoptotic signaling are involved in the pathogenesis of indomethacin-induced gastric injury. We examined whether sake yeast-derived thioredoxin (a small redox-active protein with anti-oxidative activity and various redox-regulating functions) reduced indomethacin-induced gastric injury.

Methods

Gastric injury was produced by the intraperitoneal administration of indomethacin (40?mg/kg body weight) to C57BL/6 mice. Prior to the administration of indomethacin, the mice were offered food pellets containing non-genetically modified sake yeast-derived thioredoxin (thioredoxin 200?μg/g) for 3?days. Histological examinations, assessment of myeloperoxidase activity, and analysis of the gene expressions of proinflammatory cytokines and a chemokine (interleukin [IL]-1β, IL-6, and CXCL1) were statistically evaluated. Indomethacin cytotoxicity was determined by lactate dehydrogenase release from murine gastric epithelial GSM06 cells induced by 24-h treatment with 200 and 400?μM indomethacin after 1-h preincubation with 100?μg/ml sake yeast-derived thioredoxin.

Results

Macroscopic (edema, hemorrhage, and ulcers) and histological (necrosis, submucosal edema, neutrophil infiltration) findings induced by indomethacin were significantly reduced by pretreatment with food pellets containing thioredoxin. Gastric myeloperoxidase activity and the gene expressions of proinflammatory cytokines (IL-1β and IL-6) were also significantly reduced by this pretreatment compared with findings in the mice not pretreated with thioredoxin-containing food pellets. The administration of sake yeast-derived thioredoxin significantly reduced indomethacin-induced cytotoxicity in GSM06 cells.

Conclusions

We conclude that oral administration of sake yeast-derived thioredoxin reduces indomethacin-induced gastric injury. Sake yeast-derived thioredoxin may have therapeutic potential against indomethacin-induced gastric injury.     

Allicin Ameliorates Cardiac Hypertrophy and Fibrosis through Enhancing of Nrf2 Antioxidant Signaling Pathways

Aim

To evaluate the protective effects of allicin on Ang II-induced cardiac hypertrophy.

Methods

Sprague?CDawley male rats were randomized into 3 groups:1)sham group (saline)(n?=?12), 2) Ang II group(n?=?9), 3) allicin group (Ang II + allicin)(n?=?9). They received infusions of either saline or Ang II (250?ng/kg body weight per min) through mini-osmotic pumps implanted subcutaneously for 2?weeks and given a diet containing 180?mg/kg/day of allicin for 8 consecutive weeks. Hemodynamic, morphological, histological, and biochemical changes were evaluated at corresponding time points.

Results

Ang II infusion increased blood pressure, heart rate and heart weight to body weight ratio, and resulted in anatomical and functional changes, such as increased LV mass, posterior wall thickness and LV end-diastolic diameter, and decreased fractional shortening and EF compared with sham rats. Nrf2 and HO-1 in the hearts of rats in the Ang II group were moderately elevated at both mRNA and protein levels compared to sham group mice, but NQO1 and??-GCS were significantly lower. GPx activities, levels of GSH and T-AOC in the hearts of the rats in the Ang II group were also significantly lower, and the levels of TBARS, reactive oxygen species and protein carbonyl were significant increased. Allicin attenuated LV mass, posterior wall thickness and LV end-diastolic diameter (1.10?±?0.04 vs. 1.37?±?0.05, 2.26?±?0.08 vs. 2.96?±?0.12, 7.27?±?0.36 vs. 8.56?±?0.41, respectively; all P?<?0.05), and increased fractional shortening and EF (28.30?±?3.21 vs. 25.40?±?2.57, 60.27?±?5.63 vs. 51.30?±?4.78, respectively; both P?<?0.05) in the Ang II-induced hypertrophic rats compared to the untreated Ang II rats. Furthermore, allicin treatment attenuated the accumulation of interstitial collagen and collagen I/III (P?<?0.01 vs. the untreated Ang II group), decreased the levels of reactive oxygen species, protein carbonyl and TBARS and increased GPx activities. Moreover, allicin significantly increased mRNA expression and protein levels of Nrf2, NQO1, and ??-GCS ( P?<?0.01, P?<?0.05 vs. the untreated Ang II group).

Conclusion

Allicin could prevent the development of cardiac remodeling and the progression of cardiac hypertrophy to cardiac dysfunction caused by enhancing the Nrf2 antioxidant signaling pathways.     

Effect of periodic pacemaker optimization on left atrial reverse remodeling in long-term cardiac resynchronization therapy

Purpose

Few data exist about the effect of cardiac resynchronization therapy (CRT) on left atrial (LA) reverse remodeling and function, and whether echocardiographic (echo)-guide pacemaker optimization of atrioventricular and interventricular delays could beneficially affect LA reverse remodeling in long-term CRT therapy.

Methods

Effect of periodic pacemaker optimization on LA reverse remodeling induced by CRT was analyzed in 113 consecutive patients (mean age, 60?±?11 years) and stratified according to periodic pacemaker optimization (group 1) and nonperiodic pacemaker optimization (group 2). Left atrial volumes index percent changes were assessed at every continuing 6-month follow-up visit. The primary endpoint was LA reverse remodeling. The secondary endpoint included left ventricular reverse remodeling and left ventricular ejection fraction.

Results

There is no significant difference of follow-up duration in subgroups (42.43?±?18.94 months in group 1 vs 37.76?±?20.24 months in group 2, p?=?0.228). The responder’s rate of subgroups showed similar after follow-up of 12 months (60.0 vs 53.2 %, p?=?0.483). After 24-month follow-up, the mean reduction of LAV index was similar in two groups (10.34 vs 7.53 %, p?=?0.257). The improvement effect of LA reverse remodeling induced by CRT was sustained during 24-month follow-up to the end of current study in periodic pacemaker optimization group. The degree of LAV index percent reduction was directly correlated to periodic pacemaker optimization at end of current analysis (17.13 vs 10.35 %, p?=?0.047).

Conclusions

Periodic echo-guide pacemaker optimization of atrioventricular and interventricular delays plays a positive role on LA reverse remodeling in long-term CRT therapy.     

Soluble Epoxide Hydrolase Gene Deficiency or Inhibition Attenuates Chronic Active Inflammatory Bowel Disease in IL-10(?/?) Mice

Background

Soluble epoxide hydrolase (sEH) metabolizes anti-inflammatory epoxyeicosatrienoic acids (EETs) into their much less active dihydroxy derivatives dihydroxyeicosatrienoic acids. Thus, targeting sEH would be important for inflammation.

Aims

To determine whether knockout or inhibition of sEH would attenuate the development of inflammatory bowel disease (IBD) in a mouse model of IBD in IL-10(?/?) mice.

Methods

Either the small molecule sEH inhibitor trans/-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) or sEH knockout mice were used in combination with IL-10(?/?) mice. t-AUCB was administered to mice in drinking fluid. Extensive histopathologic, immunochemical, and biochemical analyses were performed to evaluate effect of sEH inhibition or deficiency on chronic active inflammation and related mechanism in the bowel.

Results

Compared to IL-10 (?/?) mice, sEH inhibition or sEH deficiency in IL-10(?/?) mice resulted in significantly lower incidence of active ulcer formation and transmural inflammation, along with a significant decrease in myeloperoxidase-labeled neutrophil infiltration in the inflamed bowel. The levels of IFN-γ, TNF-α, and MCP-1, as well VCAM-1 and NF-kB/IKK-α signals were significantly decreased as compared to control animals. Moreover, an eicosanoid profile analysis revealed a significant increase in the ratio of EETs/DHET and EpOME/DiOME, and a slightly down-regulation of inflammatory mediators LTB₄ and 5-HETE.

Conclusion

These results indicate that sEH gene deficiency or inhibition reduces inflammatory activities in the IL-10 (?/?) mouse model of IBD, and that sEH inhibitor could be a highly potential in the treatment of IBD.     

Serum levels of cytokines in systemic lupus erythematosus

Background

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by abnormal production of autoantibodies and proinflammatory cytokines. The clear pathogenesis of SLE has not been fully elucidated. Cytokine-mediated immunity has been showed to be involved in the pathogenesis of SLE.

Objectives

The aim of this study was to investigate serum levels of cytokines (IL-19, IL-24, IL-26, IL-31, IL-32, IL-36) in SLE patients, in comparison with normal controls in a Chinese population.

Materials and methods

A total of 65 patients with SLE and 65 healthy volunteers were recruited for the current study. All serum levels of cytokines were measured by enzyme-linked immunosorbent assay (ELISA) kits.

Results

Serum levels of IL-19, IL-24, IL-26, IL-31, IL-32 and IL-36 in SLE patients were not significantly different from the normal controls (all p?>?0.05).

Conclusion

Serum levels of IL-19, IL-24, IL-26, IL-31, IL-32 and IL-36 in SLE patients were not markedly different from the normal controls. However, functional research should be discussed in future studies to elucidate the roles of these cytokines in SLE.     

Effects of Candesartan on Left Ventricular Function, Aldosterone and BNP in Chronic Heart Failure

Purpose

Heart failure (HF) is characterized by activation of neurohormonal systems such as aldosterone and natriuretic peptides. In the absence of published data, CandHeart trial was designed to assess the effects on left ventricular (LV) function, aldosterone and brain natriuretic peptide (BNP) of candesartan in patients with HF and preserved (LVEF ?? 40%) or depressed (LVEF <40%) LV systolic function.

Methods

A total of 514 patients with stable symptomatic NYHA II-IV HF and any left ventricular ejection fraction (LVEF)were randomized to candesartan (target dose 32?mg once daily) as add-on therapy or standard medical therapy alone. Standardized echocardiographic exams were performed locally under central quality control, whereas biomarkers were assayed in a core laboratory.

Results

The majority of patients (73.3%) were NYHA II and on ACE inhibitors (91.8%) and beta-blockers (85.4%). Mean age was 66?±?11?years. Mean LVEF was 36.2?±?9.7% and 24.9% of patients had LVEF ?? 40%. LVEF increased significantly more in the candesartan group (p?=?0.09 at 12?weeks and p?=?0.01 at 48?weeks) and left ventricular end-diastolic diameter decreased in candesartan group (p?=?0.05 at 12?weeks). Candesartan significantly reduced aldosterone at 48?weeks (p?=?0.009). BNP was reduced similarly over time in both study groups (p?=?0.35 and p?=?0.98 at 12 and 48?weeks, respectively). There were 6.6% of discontinuations of candesartan for adverse events.

Conclusions

In CandHeart, the addition of candesartan to standard medical treatment did not reduce circulating BNP more than standard therapy (primary endpoint), but it significantly improved LV function and produced a marked decrease in aldosterone levels at study end.     

Interleukin‐1 and tumor necrosis factor α blockade treatment of experimental polymyositis in mice

Objective

Histologic studies of the muscles suggest that cytokines are involved in inflammatory myopathy. The therapeutic effects of cytokine blockade are controversial, with anecdotal reports of clinical efficacy. The aim of this study was to discern the significance of interleukin‐1 (IL‐1) and tumor necrosis factor α (TNFα) as therapeutic targets in polymyositis (PM) by studying their involvement and the effects of their blockade in C protein–induced myositis (CIM), a murine model of PM.

Methods

C57BL/6 mice were immunized with recombinant skeletal C protein fragments to induce CIM. The expression of IL‐1 and TNFα in the muscles of mice with CIM was detected using immunohistochemical and real‐time polymerase chain reaction analyses. After the onset of myositis, the mice with CIM were treated with recombinant IL‐1 receptor antagonist (IL‐1Ra), anti–IL‐1R monoclonal antibody, recombinant TNF receptor (p75)–fusion protein (TNFR‐Fc), or anti‐TNFα monoclonal antibody. The muscles were examined histologically for the severity of myositis.

Results

IL‐1α– and TNFα‐positive macrophages were observed in the muscle tissue of mice with CIM as early as 7 days after immunization. IL‐1α, IL‐1β, and TNFα expression in the muscles increased as the severity of myositis peaked, at both the messenger RNA and protein levels. Continuous subcutaneous delivery of IL‐1Ra resulted in suppression of established CIM. Intermittent delivery (1‐day intervals) of anti–IL‐1R monoclonal antibody suppressed myositis, while intermittent delivery of IL‐1Ra did not suppress myositis. Treatment with anti‐TNFα monoclonal antibody and with TNFR‐Fc also reduced the severity of CIM.

Conclusion

IL‐1 and TNF blockade ameliorated CIM after disease onset and should potentially be a new strategy for the treatment of inflammatory myopathy. As IL‐1 blockade, treatment with anti–IL‐1R monoclonal antibody appeared more feasible than the other approaches.