Liver X Receptor Agonist AZ876 Induces Beneficial Endogenous Cardiac Lipid Reprogramming and Protects Against Isoproterenol-Induced Cardiac Damage.

Background It is known that dietary intake of polyunsaturated fatty acids may improve cardiac function. However, relatively high daily doses are required to achieve sufficient cardiac concentrations of beneficial omega-3 fatty acids. The liver X receptor (LXR) is a nuclear hormone receptor and a crucial regulator of lipid homeostasis in mammals. LXR activation has been shown to endogenously reprogram cellular lipid profiles toward increased polyunsaturated fatty acids levels. Here we studied whether LXR lipid reprogramming occurs in cardiac tissue and exerts cardioprotective actions. Methods and Results Male 129SV mice were treated with the LXR agonist AZ876 (20 µmol/kg per day) for 11 days. From day 6, the mice were injected with the nonselective ß-agonist isoproterenol for 4 consecutive days to induce diastolic dysfunction and subendocardial fibrosis while maintaining systolic function. Treatment with isoproterenol led to a marked impairment of global longitudinal strain and the E/e' ratio of transmitral flow to mitral annular velocity, which were both significantly improved by the LXR agonist. Histological examination showed a significant reduction in isoproterenol-induced subendocardial fibrosis by AZ876. Analysis of the cardiac lipid composition by liquid chromatography-high resolution mass spectrometry revealed a significant increase in cardiac polyunsaturated fatty acids levels and a significant reduction in saturated fatty acids by AZ876. Conclusions The present study provides evidence that the LXR agonist AZ876 prevents subendocardial damage, improves global longitudinal strain and E/e' in a mouse model of isoproterenol-induced cardiac damage, accompanied by an upregulation of cardiac polyunsaturated fatty acids levels. Cardiac LXR activation and beneficial endogenous cardiac lipid reprogramming may provide a new therapeutic strategy in cardiac disease with diastolic dysfunction.

Treatment of Active Crohn's Disease With an Ordinary Food-based Diet That Replicates Exclusive Enteral Nutrition.

BACKGROUND & AIMS: Exclusive enteral nutrition (EEN) is the only established dietary treatment for Crohn's disease (CD), but its acceptability is limited. There is a need for novel dietary treatments for CD. METHODS: We evaluated the effects of an individualized food-based diet (CD-TREAT), with similar composition to EEN, on the gut microbiome, inflammation, and clinical response in a rat model, healthy adults, and children with relapsing CD. Twenty-five healthy adults randomly received EEN or CD-TREAT for 7 days, followed by a 14-day washout period, followed by the alternate diet. Fecal microbiome and metabolome were assessed before and after each diet. HLA-B7 and HLA-B27 transgenic rats with gut inflammation received EEN, CD-TREAT, or standard chow for 4 weeks. Fecal, luminal, and tissue microbiome, fecal metabolites, and gut inflammation were assessed. Five children with active CD activity received CD-TREAT and their clinical activity and calprotectin were evaluated after 8 weeks of treatment. RESULTS: For healthy adults, CD-TREAT was easier to comply with and more acceptable than EEN. CD-TREAT induced similar effects to EEN (EEN vs CD-TREAT) on fecal microbiome composition, metabolome, mean total sulfide (increase 133.0 ± 80.5 vs 54.3 ± 47.0 nmol/g), pH (increase 1.3 ± 0.5 vs 0.9 ± 0.6), and the short-chain fatty acids (µmol/g) acetate (decrease 27.4 ± 22.6 vs 21.6 ± 20.4), propionate (decrease 5.7 ± 7.8 vs 5.2 ± 7.9), and butyrate (decrease 7.0 ± 7.4 vs 10.2 ± 8.5). In the rat model, CD-TREAT and EEN produced similar changes in bacterial load (decrease 0.3 ± 0.3 log10 16S rRNA gene copies per gram), short-chain fatty acids, microbiome, and ileitis severity (mean histopathology score decreases of 1.25 for EEN [P = .015] and 1.0 for CD-TREAT [P = .044] vs chow). In children receiving CD-TREAT, 4 (80%) had a clinical response and 3 (60%) entered remission, with significant concurrent decreases in fecal calprotectin (mean decrease 918 ± 555 mg/kg; P = .002). CONCLUSION: CD-TREAT replicates EEN changes in the microbiome, decreases gut inflammation, is well tolerated, and is potentially effective in patients with active CD. ClinicalTrials.gov, numbers NCT02426567 and NCT03171246.

Experimental investigation and histopathological identification of acute thermal damage in skeletal porcine muscle in relation to whole-body SAR, maximum temperature, and CEM43 °C due to RF irradiation in an MR body coil of birdcage type at 123 MHz.

PURPOSE: This study is an investigation of the relationship between several characteristic parameters and acute thermal damage in porcine skeletal muscle. MATERIAL AND METHODS: Fourteen pigs under injection anaesthesia were placed into a magnetic resonance body coil and exposed for different time durations to different specific energy absorption rate (SAR) levels at 123 MHz. Local temperatures were measured using four temperature sensors. Sensors 1-3 were placed in skeletal muscle and one sensor was placed in the rectum. Sensors 1 and 2 were placed in hot-spot areas and sensor 3 was placed at the periphery of the animals. The pigs were exposed to whole-body SAR (SAR-wb) between 2.5 W/kg and 5.2 W/kg for 30 or 60 min. Three animals received no SAR. After each experiment, muscle samples adjacent to the positions of sensors 1-3 were taken for frozen section analysis. Three characteristic parameters were chosen for investigation: SAR-wb, maximum sensor temperature (T-max), and cumulative equivalent minutes at 43 °C (CEM43 °C). RESULTS: Histopathological criteria were established to detect acute thermal tissue damage in frozen sections such as widening of intercellular space between the muscle fibres and loss of glycogen. Clear tissue damage thresholds were found for T-max and CEM43 °C, though not for SAR-wb. For all animals with high thermal exposure, damage was also found for muscle samples adjacent to the peripheral sensor 3. CONCLUSIONS: Both T-max and CEM43, are able to predict thermal damage in porcine muscle. However, CEM43 is the less ambiguous parameter. The reasons for the occurrence of the aforementioned damage at low local temperatures at the animals' periphery remain unclear and further investigations are needed.