Randomized comparison of TAVI valves: The Compare-TAVI trial.

INTRODUCTION: Based on technical advancements and clinical evidence, transcatheter aortic valve implantation (TAVI) has been widely adopted. New generation TAVI valve platforms are continually being developed. Ideally, new valves should be superior or at least non-inferior regarding efficacy and safety, when compared to best-in-practice contemporary TAVI valves. METHODS AND ANALYSIS: The Compare-TAVI trial (ClinicalTrials.gov NCT04443023) was launched in 2020, to perform a 1:1 randomized comparison of new vs contemporary TAVI valves, preferably in all comers. Consecutive cohorts will be launched with sample sizes depending on the choice of interim analyses, expected event rates, and chosen superiority or non-inferiority margins. Enrollment has just been finalized in cohort B, comparing the Sapien 3/Sapien 3 Ultra Transcatheter Heart Valve (THV) series (Edwards Lifesciences, Irvine, California, USA) and the Myval/Myval Octacor THV series (Meril Life Sciences Pvt. Ltd., Vapi, Gujarat, India) balloon expandable valves. This non-inferiority study was aimed to include 1062 patients. The 1-year composite safety and efficacy endpoint comprises death, stroke, moderate-severe aortic regurgitation, and moderate-severe valve deterioration. Patients will be followed until withdrawal of consent, death, or completion of 10-year follow-up, whichever comes first. Secondary endpoints will be monitored at 30 days, 1, 3, 5, and 10 years. SUMMARY: The Compare-TAVI organization will launch consecutive cohorts wherein patients scheduled for TAVI are randomized to one of two valves. The aim is to ensure that the short- and long-term performance and safety of new valves being introduced is benchmarked against what achieved by best-in-practice contemporary valves.

Increasing Levels of Positive End-expiratory Pressure Cause Stepwise Biventricular Stroke Work Reduction in a Porcine Model.

BACKGROUND: Positive end-expiratory pressure (PEEP) is commonly applied to avoid atelectasis and improve oxygenation in patients during general anesthesia but affects cardiac pressures, volumes, and loading conditions through cardiorespiratory interactions. PEEP may therefore alter stroke work, which is the area enclosed by the pressure-volume loop and corresponds to the external work performed by the ventricles to eject blood. The low-pressure right ventricle may be even more susceptible to PEEP than the left ventricle. The authors hypothesized that increasing levels of PEEP would reduce stroke work in both ventricles. METHODS: This was a prospective, observational, experimental study. Six healthy female pigs of approximately 60 kg were used. PEEP was stepwise increased from 0 to 5, 7, 9, 11, 13, 15, 17, and 20 cm H2O to cover the clinical spectrum of PEEP. Simultaneous, biventricular invasive pressure-volume loops, invasive blood pressures, and ventilator data were recorded. RESULTS: Increasing PEEP resulted in stepwise reductions in left (5,740 ± 973 vs. 2,303 ± 1,154 mmHg · ml; P < 0.001) and right (2,064 ± 769 vs. 468 ± 133 mmHg · ml; P < 0.001) ventricular stroke work. The relative stroke work reduction was similar between the two ventricles. Left ventricular ejection fraction, afterload, and coupling were preserved. On the contrary, PEEP increased right ventricular afterload and caused right ventriculo-arterial uncoupling (0.74 ± 0.30 vs. 0.19 ± 0.13; P = 0.01) with right ventricular ejection fraction reduction (64 ± 8% vs. 37 ± 7%, P < 0.001). CONCLUSIONS: A stepwise increase in PEEP caused stepwise reduction in biventricular stroke work. However, there are important interventricular differences in response to increased PEEP levels. PEEP increased right ventricular afterload leading to uncoupling and right ventricular ejection fraction decline. These findings may support clinical decision-making to further optimize PEEP as a means to balance between improving lung ventilation and preserving right ventricular function.

Automated detection of cardiac rest period for trigger delay calculation for image-based navigator coronary magnetic resonance angiography.

BACKGROUND: Coronary magnetic resonance angiography (coronary MRA) is increasingly being considered as a clinically viable method to investigate coronary artery disease (CAD). Accurate determination of the trigger delay to place the acquisition window within the quiescent part of the cardiac cycle is critical for coronary MRA in order to reduce cardiac motion. This is currently reliant on operator-led decision making, which can negatively affect consistency of scan acquisition. Recently developed deep learning (DL) derived software may overcome these issues by automation of cardiac rest period detection. METHODS: Thirty individuals (female, n = 10) were investigated using a 0.9 mm isotropic image-navigator (iNAV)-based motion-corrected coronary MRA sequence. Each individual was scanned three times utilising different strategies for determination of the optimal trigger delay: (1) the DL software, (2) an experienced operator decision, and (3) a previously utilised formula for determining the trigger delay. Methodologies were compared using custom-made analysis software to assess visible coronary vessel length and coronary vessel sharpness for the entire vessel length and the first 4 cm of each vessel. RESULTS: There was no difference in image quality between any of the methodologies for determination of the optimal trigger delay, as assessed by visible coronary vessel length, coronary vessel sharpness for each entire vessel and vessel sharpness for the first 4 cm of the left mainstem, left anterior descending or right coronary arteries. However, vessel length of the left circumflex was slightly greater using the formula method. The time taken to calculate the trigger delay was significantly lower for the DL-method as compared to the operator-led approach (106 ± 38.0 s vs 168 ± 39.2 s, p < 0.01, 95% CI of difference 25.5-98.1 s). CONCLUSIONS: Deep learning-derived automated software can effectively and efficiently determine the optimal trigger delay for acquisition of coronary MRA and thus may simplify workflow and improve reproducibility.

Detection of brain lesions after catheter ablation depends on imaging criteria: insights from AXAFA-AFNET 5 trial.

AIMS: Left atrial catheter ablation is well established in patients with symptomatic atrial fibrillation (AF) but associated with risk of embolism to the brain. The present analysis aims to assess the impact of diffusion-weighted imaging (DWI) slice thickness on the rate of magnetic resonance imaging (MRI)-detected ischaemic brain lesions after ablation. METHODS AND RESULTS: AXAFA-AFNET 5 trial (NCT02227550) participants underwent MRI using high-resolution (hr) DWI (slice thickness: 2.5-3 mm) and standard DWI (slice thickness: 5-6 mm) within 3-48 h after ablation. In 321 patients with analysable brain MRI (mean age 64 years, 33% female, median CHA2DS2-VASc 2), hrDWI detected at least one acute brain lesion in 84 (26.2%) patients and standard DWI in 60 (18.7%; P < 0.01) patients. High-resolution diffusion-weighted imaging detected more lesions compared to standard DWI (165 vs. 104; P < 0.01). The degree of agreement for lesion confirmation using hrDWI vs. standard DWI was substantial (κ = 0769). Comparing the proportion of DWI-detected lesions, lesion distribution, and total lesion volume per patient, there was no difference in the cohort of participants undergoing MRI at 1.5 T (n = 52) vs. 3 T (n = 269). CONCLUSION: The pre-specified AXAFA-AFNET 5 sub-analysis revealed significantly increased rates of MRI-detected acute brain lesions using hrDWI instead of standard DWI in AF patients undergoing ablation. In comparison to DWI slice thickness, MRI field strength had a no significant impact in the trial. Comparing the varying rates of ablation-related MRI-detected brain lesions across previous studies has to consider these technical parameters. Future studies should use hrDWI, as feasibility was demonstrated in the multicentre AXAFA-AFNET 5 trial.

Remodeling after myocardial infarction and effects of heart failure treatment investigated by hyperpolarized [1-13 C]pyruvate magnetic resonance spectroscopy.

PURPOSE: Hyperpolarized [1-13 C]pyruvate MRS can measure cardiac metabolism in vivo. We investigated whether [1-13 C]pyruvate MRS could predict left ventricular remodeling following myocardial infarction (MI), long-term left ventricular effects of heart failure medication, and could identify responders to treatment. METHODS: Thirty-five rats were scanned with hyperpolarized [1-13 C]pyruvate MRS 3 days after MI or sham surgery. The animals were re-examined after 30 days of therapy with ß-blockers and ACE-inhibitors (active group, n = 12), placebo treatment (placebo group, n = 13) or no treatment (sham group, n = 10). Furthermore, heart tissue mitochondrial respiratory capacity was assessed by high-resolution respirometry. Metabolic results were compared between groups, over time and correlated to functional MR data at each time point. RESULTS: At 30 ± 0.5 days post MI, left ventricular ejection fraction (LVEF) differed between groups (sham, 77% ± 1%; placebo, 52% ± 3%; active, 63% ± 2%, P < .001). Cardiac metabolism, measured by both hyperpolarized [1-13 C]pyruvate MRS and respirometry, neither differed between groups nor between baseline and follow-up. Three days post MI, low bicarbonate + CO2 /pyruvate ratio was associated with low LVEF. At follow-up, in the active group, a poor recovery of LVEF was associated with high bicarbonate + CO2 /pyruvate ratio, as measured by hyperpolarized MRS. CONCLUSION: In a rat model of moderate heart failure, medical treatment improved function, but did not on average influence [1-13 C]pyruvate flux as measured by MRS; however, responders to heart failure medication had reduced capacity for carbohydrate metabolism.

Effect of remote ischaemic conditioning on infarct size and remodelling in ST-segment elevation myocardial infarction patients: the CONDI-2/ERIC-PPCI CMR substudy.

The effect of limb remote ischaemic conditioning (RIC) on myocardial infarct (MI) size and left ventricular ejection fraction (LVEF) was investigated in a pre-planned cardiovascular magnetic resonance (CMR) substudy of the CONDI-2/ERIC-PPCI trial. This single-blind multi-centre trial (7 sites in UK and Denmark) included 169 ST-segment elevation myocardial infarction (STEMI) patients who were already randomised to either control (n = 89) or limb RIC (n = 80) (4 × 5 min cycles of arm cuff inflations/deflations) prior to primary percutaneous coronary intervention. CMR was performed acutely and at 6 months. The primary endpoint was MI size on the 6 month CMR scan, expressed as median and interquartile range. In 110 patients with 6-month CMR data, limb RIC did not reduce MI size [RIC: 13.0 (5.1-17.1)% of LV mass; control: 11.1 (7.0-17.8)% of LV mass, P = 0.39], or LVEF, when compared to control. In 162 patients with acute CMR data, limb RIC had no effect on acute MI size, microvascular obstruction and LVEF when compared to control. In a subgroup of anterior STEMI patients, RIC was associated with lower incidence of microvascular obstruction and higher LVEF on the acute scan when compared with control, but this was not associated with an improvement in LVEF at 6 months. In summary, in this pre-planned CMR substudy of the CONDI-2/ERIC-PPCI trial, there was no evidence that limb RIC reduced MI size or improved LVEF at 6 months by CMR, findings which are consistent with the neutral effects of limb RIC on clinical outcomes reported in the main CONDI-2/ERIC-PPCI trial.

Pulmonary vasodilation by sildenafil in acute intermediate-high risk pulmonary embolism: a randomized explorative trial.

BACKGROUND: To investigate if acute pulmonary vasodilation by sildenafil improves right ventricular function in patients with acute intermediate-high risk pulmonary embolism (PE). METHODS: Single center, explorative trial. Patients with PE were randomized to a single oral dose of sildenafil 50 mg (n = 10) or placebo (n = 10) as add-on to conventional therapy. The time from hospital admission to study inclusion was 2.3 ± 0.7 days. Right ventricular function was evaluated immediately before and shortly after (0.5-1.5 h) randomization by right heart catheterization (RHC), trans-thoracic echocardiography (TTE), and cardiac magnetic resonance (CMR). The primary efficacy endpoint was cardiac index measured by CMR. RESULTS: Patients had acute intermediate-high risk PE verified by computed tomography pulmonary angiography, systolic blood pressure of 135 ± 18 (mean ± SD) mmHg, increased right ventricular/left ventricular ratio 1.1 ± 0.09 and increased troponin T 167 ± 144 ng/L. Sildenafil treatment did not improve cardiac index compared to baseline (0.02 ± 0.36 l/min/m2, p = 0.89) and neither did placebo (0.00 ± 0.34 l/min/m2, p = 0.97). Sildenafil lowered mean arterial blood pressure (- 19 ± 10 mmHg, p < 0.001) which was not observed in the placebo group (0 ± 9 mmHg, p = 0.97). CONCLUSION: A single oral dose of sildenafil 50 mg did not improve cardiac index but lowered systemic blood pressure in patients with acute intermediate-high risk PE. The time from PE to intervention, a small patient sample size and low pulmonary vascular resistance are limitations of this study that should be considered when interpreting the results. TRIAL REGISTRATION: The trial was retrospectively registered at www.clinicaltrials.gov (NCT04283240) February 2nd 2020, https://clinicaltrials.gov/ct2/show/NCT04283240?term=NCT04283240&draw=2&rank=1 .

The hemodynamic and metabolic effects of spironolactone treatment in acute kidney injury assessed by hyperpolarized MRI.

Renal ischemia-reperfusion injury (IRI) is one of the most common types of acute kidney injury. Spironolactone has shown promising kidney protective effects in renal IRI in rats. We investigated the hemodynamic and metabolic effects of spironolactone (100 mg/kg) administered immediately after 40 min unilateral kidney ischemia in rats. Hyperpolarized MRI using co-polarized [1-13 C]pyruvate and [13 C,15 N2 ]urea as well as 1 H dynamic contrast-enhanced (DCE) MRI was performed 24 h after induction of ischemia. We found a significant decrease in renal blood flow (RBF) in the ischemic kidney compared with the contralateral one measured using DCE and [13 C,15 N2 ]urea. The RBF measured using [1-13 C]pyruvate and [13 C,15 N2 ]urea was significantly altered by spironolactone. The RBFs in the ischemic kidney compared with the contralateral kidney were decreased similarly as measured using both [13 C,15 N2 ]urea and [1-13 C]pyruvate in the spironolactone-treated group. Spironolactone treatment increased the perfusion-corrected pyruvate metabolism by 54% in both the ischemic and contralateral kidney. Furthermore, we showed a correlation between vascular permeability using a histological Evans blue analysis and the ratio of the volumes of distribution (VoDs), ie VoD-[13 C,15 N2 ]urea/VoD-[1-13 C]pyruvate. This suggests that [13 C,15 N2 ]urea/[1-13 C]pyruvate VoD ratio may be a novel indicator of renal vascular permeability associated with renal damage in rodents.

Intermittent restraint-induced sympathetic activation attenuates hepatic steatosis and inflammation in a high-fat diet-fed mouse model.

Nonalcoholic fatty liver disease (NAFLD) is very prevalent worldwide and is associated with insulin resistance and metabolic syndrome. Stress is a physiological and biological response to maintain homeostasis of the body against stressors while severe stress response is an important contributor to various illnesses, including metabolic syndrome and brain disorders. We have evaluated the effects of intermittent restraint stress on NAFLD in a high-fat diet (HFD)-fed mouse model. C57/BL6 mice had free access to a 60% HFD for 8 wk, with or without intermittent restraint stress (3 h) conducted three times a week. HFD administration increased fat accumulation in liver tissues. Unlike the stressed standard diet group, the levels of hepatic total cholesterol and triglycerides were significantly ameliorated in the HFD with stress group compared with the HFD alone group. These beneficial results were in accordance with serum levels of liver enzymes (aspartate transaminase, alanine transaminase) and hepatic levels of TNF-α and oxidative stress parameters (reactive oxygen species, nitric oxide, and malondialdehyde). The intermittent restraint stress significantly attenuated the HFD-derived alterations in serum insulin levels, hepatic protein kinase B activity, and gene expression, especially related to lipogenesis. This intermittent restraint stress also elevated the serum epinephrine concentration and activated the adrenergic receptor ß2 or ß3 in livers or white adipose tissue (WAT). Activation of energy expenditure markers (uncoupling protein 1, peroxisome proliferator-activated receptor-γ coactivator-1α) in brown adipose tissue and the browning of WAT were also observed in the HFD with stress group. Taken together, our findings showed the beneficial effects of sympathetic activation by intermittent restraint stress on HFD-induced hepatic steatosis and partial inflammation.NEW & NOTEWORTHY In modern society, stress is a part of daily life, and a certain level of stress is inevitable to most of the general population. Uncontrolled severe stress is obviously harmful; however, certain kind/level of stress could be beneficial on lipid metabolism via sympathetic activation. Our data suggest that a sympathetic activation by intermittent restraint stress could play a positive role in maintaining the balance of hepatic lipid metabolism, especially under high-fat diet conditions.

Hyperpolarized [1-13 C]pyruvate MRI can image the metabolic shift in cardiac metabolism between the fasted and fed state in a porcine model.

PURPOSE: Owing to its noninvasive nature, hyperpolarized MRI may improve delineation of myocardial metabolic derangement in heart disease. However, consistency may depend on the changeable nature of cardiac metabolism in relation to whole-body metabolic state. This study investigates the impact of feeding status on cardiac hyperpolarized MRI in a large animal model resembling human physiology. METHODS: Thirteen 30-kg pigs were subjected to an overnight fast, and 5 pigs were fed a carbohydrate-rich meal on the morning of the experiments. Vital parameters and blood samples were registered. All pigs were then scanned by hyperpolarized [1-13 C]pyruvate cardiac MRI, and results were compared between the 2 groups and correlated with circulating substrates and hormones. RESULTS: The fed group had higher blood glucose concentration and mean arterial pressure than the fasted group. Plasma concentrations of free fatty acids (FFAs) were decreased in the fed group, whereas plasma insulin concentrations were similar between groups. Hyperpolarized MRI showed that fed animals had increased lactate/pyruvate, alanine/pyruvate, and bicarbonate/pyruvate ratios. Metabolic ratios correlated negatively with FFA levels. CONCLUSION: Hyperpolarized MR can identify the effects of different metabolic states on cardiac metabolism in a large animal model. Unlike previous rodent studies, all metabolic derivatives of pyruvate increased in the myocardium of fed pigs. Carbohydrate-rich feeding seems to be a feasible model for standardized, large animal hyperpolarized MRI studies of myocardial carbohydrate metabolism.

Acute hypertensive stress imaged by cardiac hyperpolarized [1-13 C]pyruvate magnetic resonance.

PURPOSE: Deranged metabolism is now recognized as a key causal factor in a variety of heart diseases, and is being studied extensively. However, invasive methods may alter metabolism, and conventional imaging techniques measure tracer uptake but not downstream metabolism. These challenges may be overcome by hyperpolarized MR, a noninvasive technique currently crossing the threshold into human trials. The aim of this study was to image metabolic changes in the heart in response to endogastric glucose bolus and to acute hypertension. METHODS: Five postprandial pigs were scanned with hyperpolarized [1-13 C]pyruvate cardiac MR at baseline, after oral glucose bolus, and after infusion of angiotensin-II. RESULTS: No effect of glucose bolus was seen using hyperpolarized [1-13 C]pyruvate MR despite changes in circulating substrates. During angiotensin-II infusion, blood pressure increased 179% (P = 0.008) and ejection fraction decreased from 54 ± 2% to 47 ± 6% (P = 0.03) The hemodynamic changes were accompanied by increases in the hyperpolarized [1-13 C]pyruvate MR derived ratios of lactate/alanine (from 0.58 ± 0.13 to 0.78 ± 0.06, P = 0.03) and bicarbonate/alanine (from 0.55 ± 0.12 to 0.91 ± 0.14, P = 0.007). CONCLUSION: Glucose loading did not alter cardiac metabolism, but during acute hypertensive stress, cardiac aerobic, carbohydrate metabolism, and pyruvate-lactate exchange was altered. Hyperpolarized MR allows noninvasive evaluation of acute changes in cardiac metabolism. However, hemodynamics must be taken into account when interpreting the results.

Test-retest repeatability of myocardial oxidative metabolism and efficiency using standalone dynamic 11C-acetate PET and multimodality approaches in healthy controls.

BACKGROUND: Myocardial efficiency measured by 11C-acetate positron emission tomography (PET) has successfully been used in clinical research to quantify mechanoenergetic coupling. The objective of this study was to establish the repeatability of myocardial external efficiency (MEE) and work metabolic index (WMI) by non-invasive concepts. METHODS AND RESULTS: Ten healthy volunteers (63 ± 4 years) were examined twice, one week apart, using 11C-acetate PET, cardiovascular magnetic resonance (CMR), and echocardiography. Myocardial oxygen consumption from PET was combined with stroke work data from CMR, echocardiography, or PET to obtain MEE and WMI for each modality. Repeatability was estimated as the coefficient of variation (CV) between test and retest. MEECMR, MEEEcho, and MEEPET values were 21.9 ± 2.7%, 16.4 ± 3.7%, and 23.8 ± 4.9%, respectively, P < .001. WMICMR, WMIEcho, and WMIPET values were 4.42 ± 0.90, 4.07 ± 0.63, and 4.58 ± 1.13 mmHg × mL/m2 × 106, respectively, P = .45. Repeatability for MEECMR was superior compared with MEEEcho but did not differ significantly compared with MEEPET (6.3% vs 12.9% and 9.4%, P = .04 and .25). CV values for WMICMR, WMIEcho, and WMIPET were 10.0%, 14.8%, and 12.0%, respectively, (P = .53). CONCLUSIONS: Non-invasive measurements of MEE using 11C-acetate PET are highly repeatable. A PET-only approach did not differ significantly from CMR/PET and might facilitate further clinical research due to lower costs and broader applicability.

Effect of long-term remote ischemic conditioning in patients with chronic ischemic heart failure.

Remote ischemic conditioning (RIC) protects against acute ischemia-reperfusion injury and may also have beneficial effects in patients with stable cardiovascular disease. We investigated the effect of long-term RIC treatment in patients with chronic ischaemic heart failure (CIHF). In a parallel group study, 22 patients with compensated CIHF and 21 matched control subjects without heart failure or ischemic heart disease were evaluated by cardiac magnetic resonance imaging, cardiopulmonary exercise testing, skeletal muscle function testing, blood pressure measurement and blood sampling before and after 28 ± 4 days of once daily RIC treatment. RIC was conducted as four cycles of 5 min upper arm ischemia followed by 5 min of reperfusion. RIC did not affect left ventricular ejection fraction (LVEF) or global longitudinal strain (GLS) in patients with CIHF (p = 0.63 and p = 0.11) or matched controls (p = 0.32 and p = 0.20). RIC improved GLS in the subgroup of patients with CIHF and with NT-proBNP plasma levels above the geometric mean of 372 ng/l (p = 0.04). RIC did not affect peak workload or oxygen uptake in either patients with CIHF (p = 0.26 and p = 0.59) or matched controls (p = 0.61 and p = 0.10). However, RIC improved skeletal muscle power in both groups (p = 0.02 for both). In patients with CIHF, RIC lowered systolic blood pressure (p < 0.01) and reduced NT-proBNP plasma levels (p = 0.02). Our findings suggest that long-term RIC treatment does not improve LVEF but increases skeletal muscle function and reduces blood pressure and NT-proBNP in patients with compensated CIHF. This should be investigated in a randomized sham-controlled trial.

Prevalence rate and clinical characteristics of esophageal ectopic sebaceous glands in asymptomatic health screen examinees.

Ectopic sebaceous glands in the esophagus have rarely been reported and, thus, represent an obscure medical condition. The aim of this study is to identify the prevalence rate and clinical characteristics of this lesion in an asymptomatic population. We prospectively enrolled health screen examinees who underwent esophagogastroduodenoscopy for gastric cancer screening. An esophageal biopsy was performed in the cases in which esophageal ectopic sebaceous glands were suspected. The general characteristics of the examinees were analyzed based on their medical records. A total of 9989 examinees were enrolled, and five examinees were diagnosed with esophageal ectopic sebaceous glands between December 2012 and June 2014. The endoscopic findings of the esophageal ectopic sebaceous glands indicated multiple yellowish patches or papules, which varied in size. The histopathological findings indicated several lobulated sebaceous glands in the squamous epithelium with inflammatory infiltration. The follow-up endoscopic findings indicated that there was no grossly discernible change. In conclusion, esophageal ectopic sebaceous glands are present in 0.05% of asymptomatic subjects. This lesion is thought to be benign and is not related to clinical symptoms. Therefore, esophageal ectopic sebaceous glands do not require further treatment or follow-up, which makes endoscopists free from active efforts for differential diagnosis with other malignant diseases.

The ethanol extract of Aquilariae Lignum ameliorates hippocampal oxidative stress in a repeated restraint stress mouse model.

BACKGROUND: Chronic stress contributes to the development of brain disorders, such as neurodegenerative and psychiatric diseases. Oxidative damage is well known as a causative factor for pathogenic process in brain tissues. The aim of this study is to evaluate the neuroprotective effect of a 30% ethanol extract of Aquilariae Lignum (ALE) in repeated stress-induced hippocampal oxidative injury. METHODS: Fifty BALB/c male mice (12 weeks old) were randomly divided into five groups (n = 10). For 11 consecutive days, each group was orally administered with distilled water, ALE (20 or 80 mg/kg) or N-acetylcysteine (NAC; 100 mg/kg), and then all mice (except unstressed group) were subjected to restraint stress for 6 h. On the final day, brain tissues and sera were isolated, and stress hormones and hippocampal oxidative alterations were examined. We also treated lipopolysaccharide (LPS, 1 µg/mL)-stimulated BV2 microglial cells with ALE (1 and 5 µg/mL) or NAC (10 µM) to investigate the pharmacological mechanism. RESULTS: Restraint stress considerably increased the serum levels of corticosterone and adrenaline and the hippocampal levels of reactive oxygen species (ROS), nitric oxide (NO), and malondialdehyde (MDA). ALE administration significantly attenuated the above abnormalities. ALE also significantly normalized the stress-induced activation of astrocytes and microglial cells in the hippocampus as well as the elevation of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß). The in vitro assay outcome supplemented ALE could dramatically block NF-κB activation in microglia. The anti-oxidative stress effects of ALE were supported by the results of antioxidant components, 4-hydroxynonenal (4-HNE), NADPH oxidase 2 (NOX2), inducible nitric oxide synthase (iNOS) and NFE2L2 (Nrf2) in the hippocampal tissues. CONCLUSIONS: We firstly demonstrated the neuroprotective potentials of A. Lignum against hippocampal oxidative injury in repeated restraint stress. The corresponding mechanisms might involve modulations in the release of ROS, pro-inflammatory cytokines and stress hormones.

Evaluation of ECG-gated [(11)C]acetate PET for measuring left ventricular volumes, mass, and myocardial external efficiency.

BACKGROUND: Noninvasive estimation of myocardial external efficiency (MEE) requires measurements of left ventricular (LV) oxygen consumption with [(11)C]acetate PET in addition to LV stroke volume and mass with cardiovascular magnetic resonance (CMR). Measuring LV geometry directly from ECG-gated [(11)C]acetate PET might enable MEE evaluation from a single PET scan. Therefore, we sought to establish the accuracy of measuring LV volumes, mass, and MEE directly from ECG-gated [(11)C]acetate PET. METHODS: Thirty-five subjects with aortic valve stenosis underwent ECG-gated [(11)C]acetate PET and CMR. List mode PET data were rebinned into 16-bin ECG-gated uptake images before measuring LV volumes and mass using commercial software and compared to CMR. Dynamic datasets were used for calculation of mean LV oxygen consumption and MEE. RESULTS: LV mass, volumes, and ejection fraction measured by CMR and PET correlated strongly (r = 0.86-0.92, P < .001 for all), but were underestimated by PET (P < .001 for all except ESV P = .79). PET-based MEE, corrected for bias, correlated fairly with PET/CMR-based MEE (r = 0.60, P < .001, bias -3 ± 21%, P = .56). PET-based MEE bias was strongly associated with LV wall thickness. CONCLUSIONS: Although analysis-related improvements in accuracy are recommended, LV geometry estimated from ECG-gated [(11)C]acetate PET correlate excellently with CMR and can indeed be used to evaluate MEE.

Cardiac abnormalities assessed by non-invasive techniques in patients with newly diagnosed idiopathic inflammatory myopathies.

OBJECTIVES: Knowledge of cardiac involvement in idiopathic inflammatory myopathies (IIM) is limited, especially in the early stage of disease. The objective of the present study was to perform a controlled evaluation of cardiac abnormalities in newly diagnosed, untreated patients with idiopathic inflammatory myopathies (IIM) by means of non-invasive techniques. METHODS: Fourteen patients with IIM (8 polymyositis, 4 dermatomyositis, 2 cancer-associated dermatomyositis) and 14 gender- and age- matched healthy control subjects were investigated. Participant assessments included a cardiac questionnaire, cardiac troponin-I (TnI), electrocardiogram (standard 12-lead and 48-h Holter monitoring), echocardiography with tissue Doppler measures, cardiac magnetic resonance (CMR) imaging with T2 mapping and semi-quantitative (99m)technetium pyrophosphate ((99m)Tc-PYP) scintigraphy. RESULTS: Dyspnoea was present in 8 (57%) of the patients compared to none of the controls (p<0.01). Median levels of TnI in patients and controls were 20 ng/L and 6 ng/L, respectively (p=0.06). QTc intervals were prolonged in the patient group (p=0.01). Two patients had systolic dysfunction, and one diastolic dysfunction. The myocardial (99m)Tc-PYP uptake and CMR results differed between patients and controls, albeit not with statistical significance. Overall, cardiac abnormalities were demonstrated in 9 (64%) of the patients versus 2 (14%) of the controls (p=0.02). CONCLUSIONS: Cardiac abnormalities assessed by TnI, ECG or imaging modalities were significantly more common in newly diagnosed, treatment naïve patients with IIM compared to healthy control subjects. These abnormalities, although subclinical, may indicate that myocardial involvement is common in patients and calls for larger controlled studies and further investigations of the prognostic implications of this finding.

A Herbal Formula, Atofreellage, Ameliorates Atopic Dermatitis-Like Skin Lesions in an NC/Nga Mouse Model.

We evaluated the anti-atopic dermatitis (AD) effect of Atofreellage (AF), a herbal formula composed of 10 medicinal plants. AD was induced on the dorsal skin areas of NC/Nga mice (male, seven weeks old) by daily application of 2,4-dinitrochlorobenzene (DNCB) for five weeks. After three weeks of DNCB application, 200 µL of AF (0, 25, 50 or 100 mg/mL) was applied to the skin lesions. Histological findings, blood cell populations, serum levels of immunoglobulin E (IgE), histamine, pro-inflammatory cytokines, and inflammatory signaling in the skin tissue, and T-helper cell type 2 (Th2)-related cytokines in splenocytes were analyzed. Histopathological findings showed AF treatment notably attenuated the thickness of dorsal skin, and eosinophil infiltration. AF treatment (especially 100 mg/mL) also demonstrably ameliorated the blood cell population abnormalities, as the notable elevation of serum concentrations of IgE, histamine, TNF-α, IL-6 and IL-1ß were remarkably normalized by AF treatment. Western blot analysis evidenced the apparent normalization of inflammatory signals (ERK, p38 MAP kinase, JNK, and NF-κB) in the skin tissue. Additionally, AF treatment notably attenuated the activation of Th2-dominant cytokines (IL-13, IL-4, and IL-5) in Con A-treated splenocytes in an ex vivo assay. In conclusion, this study provides experimental evidence for the clinical relevance of Atofreellage.

Imaging of carotid artery vessel wall edema using T2-weighted cardiovascular magnetic resonance.

BACKGROUND: Atherothrombosis remains a major health problem in the western world, and carotid atherosclerosis is an important contributor to embolic ischemic strokes. It remains a clinical challenge to identify rupture-prone atherosclerotic plaques before clinical events occur. Inflammation, endothelial injury and angiogenesis are features of vulnerable plaques and may all be associated with plaque edema. Therefore, vessel wall edema, which can be detected by 2D T2-weighted cardiovascular magnetic resonance (CMR), may be used as a dynamic marker of disease activity in the atherosclerotic plaque. However, 2D imaging is limited by low spatial resolution in the slice-select direction compared to 3D imaging techniques. We sought to investigate the ability of novel 3D techniques to detect edema induced in porcine carotid arteries by acute balloon injury compared to conventional 2D T2-weighted black-blood CMR. METHODS: Edema was induced unilaterally by balloon overstretch injury in the carotid artery of nine pigs. Between one to seven hours (average four hours) post injury, CMR was performed using 2D T2-weighted short-tau inversion recovery (T2-STIR), 3D volumetric isotropic turbo spin echo acquisition (VISTA) and 3D T2 prepared gradient-echo (T2prep-GE). The CMR images were compared in terms of signal-to-noise ratio (SNR) and contrast-to-noise (CNR) ratio. Furthermore, the presence of vessel wall injury was validated macroscopically by means of Evans Blue dye that only enters the injured vessel wall. RESULTS: All three imaging sequences classified the carotid arteries correctly compared to Evans Blue and all sequences demonstrated a significant increase in SNR of the injured compared to the non-injured carotid vessel wall (T2-STIR, p = 0.002; VISTA, p = 0.004; and T2prep-GE, p = 0.003). There was no significant difference between sequences regarding SNR and CNR. CONCLUSION: The novel 3D imaging sequences VISTA and T2prep-GE perform comparably to conventional 2D T2-STIR in terms of detecting vessel wall edema. The improved spatial coverage of these 3D sequences may facilitate visualization of vessel wall edema to enable detection and monitoring of vulnerable carotid atherosclerotic plaques.

Isomorphic Ti substitution into SBA-15 without Ti loss and with lower TiO2 segregation.

A convenient method has been discovered to incorporate Ti atoms isomorphically into a SBA-15 lattice without Ti loss. By hydrolysis of a Ti precursor near neutral pH instead of conventional acidic conditions, Ti loss was almost eliminated and its segregation to form TiO2 particles was suppressed while the mesoporous structure remained intact.