Lipid emulsion interfacial design modulates human in vivo digestion and satiation hormone response.

Lipid emulsions (LEs) with tailored digestibility have the potential to modulate satiation or act as delivery systems for lipophilic nutrients and drugs. The digestion of LEs is governed by their interfacial emulsifier layer which determines their gastric structuring and accessibility for lipases. A plethora of LEs that potentially modulate digestion have been proposed in recent years, however, in vivo validations of altered LE digestion remain scarce. Here, we report on the in vivo digestion and satiation of three novel LEs stabilized by whey protein isolate (WPI), thermo-gelling methylcellulose (MC), or cellulose nanocrystals (CNCs) in comparison to an extensively studied surfactant-stabilized LE. LE digestion and satiation were determined in terms of gastric emptying, postprandial plasma hormone and metabolite levels characteristic for lipid digestion, perceived hunger/fullness sensations, and postprandial food intake. No major variations in gastric fat emptying were observed despite distinct gastric structuring of the LEs. The plasma satiation hormone and metabolite response was fastest and highest for WPI-stabilized LEs, indicating a limited capability of proteins to prevent lipolysis due to fast hydrolysis under gastric conditions and displacement by lipases. MC-stabilized LEs show a similar gastric structuring as surfactant-stabilized LEs but slightly reduced hormone and metabolite responses, suggesting that thermo-gelling MC prevents lipase adsorption more effectively. Ultimately, CNC-stabilized LEs showed a drastic reduction (>70%) in plasma hormone and metabolite responses. This confirms the efficiency of particle (Pickering) stabilized LEs to prevent lipolysis proposed in literature based on in vitro experiments. Subjects reported more hunger and less fullness after consumption of LEs stabilized with MC and CNCs which were able to limit satiation responses. We do not find evidence for the widely postulated ileal brake, i.e. that delivery of undigested nutrients to the ileum triggers increased satiation. On the contrary, we find decreased satiation for LEs that are able to delay lipolysis. No differences in food intake were observed 5 h after LE consumption. In conclusion, LE interfacial design modulates in vivo digestion and satiation response in humans. In particular, Pickering LEs show extraordinary capability to prevent lipolysis and qualify as oral delivery systems for lipophilic nutrients and drugs.

A Rat Model of Human Lipid Emulsion Digestion.

A better understanding of how dietary lipids are processed by the human body is necessary to allow for the control of satiation and energy intake by tailored lipid systems. To examine whether rats are a valid model of human dietary lipid processing and therefore useful for further mechanistic studies in this context, we tested in rats three lipid emulsions of different stability, which alter satiety responses in humans. Different sets of 15 adult male Sprague Dawley rats, equipped with gastric catheters alone or combined with hepatic portal vein (HPV) and vena cava (VC) catheters were maintained on a medium-fat diet and adapted to an 8 h deprivation/16 h feeding schedule. Experiments were performed in a randomized cross-over study design. After gastric infusion of the lipid emulsions, we assessed gastric emptying by the paracetamol absorption test and recorded in separate experiments food intake and plasma levels of gastrointestinal hormones and metabolites in the HPV. For an acid stable emulsion, slower gastric emptying and an enhanced release of satiating gastrointestinal (GI) hormones were observed and were associated with lower short-term energy intake in rats and less hunger in humans, respectively. The magnitude of hormonal responses was related to the acid stability and redispersibility of the emulsions and thus seems to depend on the availability of lipids for digestion. Plasma metabolite levels were unaffected by the emulsion induced changes in lipolysis. The results support that structured lipid systems are digested similarly in rats and humans. Thus unstable emulsions undergo the same intragastric destabilization in both species, i.e., increased droplet size and creaming. This work establishes the rat as a viable animal model for in vivo studies on the control of satiation and energy intake by tailored lipid systems.

Tailoring Emulsions for Controlled Lipid Release: Establishing in vitro-in Vivo Correlation for Digestion of Lipids.

The use of oil-in-water emulsions for controlled lipid release is of interest to the pharmaceutical industry in the development of poorly water soluble drugs and also has gained major interest in the treatment of obesity. In this study, we focus on the relevant in vitro parameters reflecting gastric and intestinal digestion steps to reach a reliable in vitro-in vivo correlation for lipid delivery systems. We found that (i) gastric lipolysis determines early lipid release and sensing. This was mainly influenced by the emulsion stabilization mechanism. (ii) Gastric mucin influences the structure of charge-stabilized emulsion systems in the stomach, leading to destabilization or gel formation, which is supported by in vivo magnetic resonance imaging in healthy volunteers. (iii) The precursor structures of these emulsions modulate intestinal lipolysis kinetics in vitro, which is reflected in plasma triglyceride and cholecystokinin concentrations in vivo.

Exploiting multicompartment effects in triple-echo steady-state T2 mapping for fat fraction quantification.

PURPOSE: To investigate and exploit the effect of intravoxel off-resonance compartments in the triple-echo steady-state (TESS) sequence without fat suppression for T2 mapping and to leverage the results for fat fraction quantification. METHODS: In multicompartment tissue, where at least one compartment is excited off-resonance, the total signal exhibits periodic modulations as a function of echo time (TE). Simulated multicompartment TESS signals were synthesized at various TEs. Fat emulsion phantoms were prepared and scanned at the same TE combinations using TESS. In vivo knee data were obtained with TESS to validate the simulations. The multicompartment effect was exploited for fat fraction quantification in the stomach by acquiring TESS signals at two TE combinations. RESULTS: Simulated and measured multicompartment signal intensities were in good agreement. Multicompartment effects caused erroneous T2 offsets, even at low water-fat ratios. The choice of TE caused T2 variations of as much as 28% in cartilage. The feasibility of fat fraction quantification to monitor the decrease of fat content in the stomach during digestion is demonstrated. CONCLUSIONS: Intravoxel off-resonance compartments are a confounding factor for T2 quantification using TESS, causing errors that are dependent on the TE. At the same time, off-resonance effects may allow for efficient fat fraction mapping using steady-state imaging. Magn Reson Med 79:423-429, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Gastric and Postgastric Processing of 13C Markers Renders the 13C Breath Test an Inappropriate Measurement Method for the Gastric Emptying of Lipid Emulsions in Healthy Adults.

Background: Breath tests (BTs) present an alternative gastric-emptying (GE) measure. However, their efficacy in the measurement of the GE rate of lipid emulsions (LEs) is unknown.Objective: The objective of this work was to investigate the validity of 13C BTs as a measure of fat GE rate in LEs.Methods: The lipophilic 13C octanoate (OCC) BT marker was investigated for fat GE with the hydrophilic 13C sodium acetate (ACC) and the triglyceride 13C trioctanoin (TCC) markers as comparators. Data from 2 randomized studies were combined [50 healthy participants; 25 men, mean ± SD age: 23 ± 2.8 y; mean ± SD body mass index (in kg/m2): 22.4 ± 1.7]. Each participant was given either an acid-stable LE (LE1) or an acid-unstable LE (LE4) at each visit. Twenty-three participants underwent simultaneous MRI. The effect of LEs on 13CO2 excretion profiles was determined. The BT half-emptying times (BT T50) were validated with the MRI half-emptying time of the ingested fat volume (MRI T50).Results: The effect of LEs on 13CO2 excretion depended on the properties of the 13C marker. T50 for OCC was shorter by 98 min for LE1 than for LE4 (P < 0.001). Other markers showed either no LE dependency or a longer T50 for LE1 than for LE4. No difference in T50 between OCC and ACC was detected in LE1. In LE4, the T50 was longer by 154 min (P < 0.0001). There was some concordance between MRI T50 and OCC BT T50 for LE1 (rc = 0.7). No other marker showed any concordance with fat GE. 13C-Nuclear magnetic resonance in vitro findings were compatible with changes in the kinetics of phase transfer of OCC dependent on its protonation state.Conclusions: The structure of fat present in the stomach affects 13CO2 excretion. The chemical properties of the 13C marker and their gastric and postgastric interaction with fat renders 13CO2 excretion an inappropriate measure of LE emptying in healthy adults. This trial was registered at clinicaltrials.gov as NCT02226029 and NCT02602158.

The Dynamics of Gastric Emptying and Self-Reported Feelings of Satiation Are Better Predictors Than Gastrointestinal Hormones of the Effects of Lipid Emulsion Structure on Fat Digestion in Healthy Adults-A Bayesian Inference Approach.

Background: Limited information exists on the relation between fat emulsion structure and its effect on the release of gastrointestinal hormones and feelings of satiation.Objective: We investigated the impact of fat emulsion droplet size, gravitational and acid stability, and redispersibility on gastrointestinal responses and sought to deduce the relative importance of the hormones ghrelin, cholecystokinin, glucagon-like peptide-1, and peptide YY (PYY) in controlling fat emptying and related satiation.Methods: Within a randomized, double-blind, 4-armed crossover study, an extensive data set was generated by MRI of gastric function, analysis of hormone profiles, and ratings of satiation in healthy participants [10 women and 7 men with a mean ± SD age of 25 ± 7 y and body mass index (in kg/m2) of 22 ± 1] after intake of 4 different fat emulsions. Iterative Bayesian model averaging variable selection was used to investigate the influence of hormone profiles in controlling fat emulsion emptying and satiation.Results: The emulsion structure had a distinct effect on the gastric emptying (primary outcome), gastrointestinal hormone profiles, and ratings of satiation (secondary outcomes). Gravitational and acid stability were stronger modulators of fat emptying and hormone profiles than were emulsion droplet size or redispersibility. Cholecystokinin and PYY were most strongly affected by fat emulsion instability and droplet size. Although both hormones were relevant predictors of gastric emptying, only PYY was identified as a relevant predictor of satiation.Conclusions: This work indicates that evenly dispersed, stable, small-emulsion droplets within the stomach lead to prolonged gastric distension, longer ghrelin suppression, and accelerated fat sensing (cholecystokinin and PPY), triggering prolonged feelings of satiation. It suggests that the effects of emulsion instability and droplet size on energy consumption are best studied by assessing changes in gastric emptying and ratings of satiation rather than changes in venous hormone profiles. This trial was registered at clinicaltrials.gov as NCT01253005.

Relationship of body weight with gastrointestinal motor and sensory function: studies in anorexia nervosa and obesity.

BACKGROUND: Whether gastrointestinal motor and sensory function is primary cause or secondary effect of abnormal body weight is uncertain. Moreover, studies relating continuous postprandial sensations of satiation to measurable pathology are scarce. This work assessed postprandial gastrointestinal function and concurrent sensations of satiation across a wide range of body weight and after weight change. METHODS: Patients with anorexia nervosa (AN) and obesity (OB) were investigated in reference to normal weight controls (HC). AN were additionally investigated longitudinally. Gastric emptying, antral contractions and oro-cecal transit after ingestion of a solid meal were investigated by MRI and 13C-lactose-ureide breath test. The dependency of self-reported sensations of satiation on the varying degree of stomach filling during gastric emptying was compared between groups. RESULTS: 24 AN (BMI 14.4 (11.9-16.0) kg/m2), 16 OB (34.9 (29.6-41.5) kg/m2) and 20 HC (21.9 (18.9-24.9) kg/m2) were studied. Gastric half-emptying time (t50) was slower in AN than HC (p = 0.016) and OB (p = 0.007), and a negative association between t50 and BMI was observed between BMI 12 and 25 kg/m2 (p = 0.007). Antral contractions and oro-cecal transit were not different. For any given gastric content volume, self-reported postprandial fullness was greater in AN than in HC or OB (p < 0.001). After weight rehabilitation, t50 in AN tended to become shorter (p = 0.09) and postprandial fullness was less marked (p < 0.01). CONCLUSIONS: A relationship between body weight and gastric emptying as well as self-reported feelings of satiation is present. AN have slower gastric emptying and heightened visceral perception compared to HC and OB. Longitudinal follow-up after weight rehabilitation in AN suggests these abnormalities are not a primary feature, but secondary to other factors that determine abnormal body weight. TRIAL REGISTRATION: Registered July 20, 2009 at ClinicalTrials.gov ( NCT00946816 ).

Accelerating MRI fat quantification using a signal model-based dictionary to assess gastric fat volume and distribution of fat fraction.

To quantify intragastric fat volume and distribution with accelerated magnetic resonance (MR) imaging using signal model-based dictionaries (DICT) in comparison to conventional parallel imaging (CG-SENSE). This study was approved by the local ethics committee and written informed consent was obtained. Seven healthy subjects were imaged after intake of a lipid emulsion and data at three different time points during the gastric emptying process was acquired in order to cover a range of fat fractions. Fully sampled and prospectively undersampled image data at a reduction factor of 4 were acquired using a multi gradient echo sequence at 1.5T. Retrospectively and prospectively undersampled data were reconstructed with DICT and CG-SENSE. Image quality of the retrospectively undersampled data was assessed relative to the fully sampled reference using the root mean square error (RMSE). In order to assess the agreement of fat volumes and intragastric fat distribution, Bland-Altman analysis and linear regression were performed on the data. The RMSE in intragastric content (ΔRMSE=0.10±0.01, P<0.001) decreased significantly with DICT relative to CG-SENSE. CG-SENSE overestimated fat volumes (bias 2.1±1.3mL; confidence limits 5.4 and -1.1mL) in comparison to the prospective DICT reconstruction (bias -0.1±0.7mL; confidence limits 1.8 and -2.0mL). There was a good agreement in fat distribution between the images reconstructed by retrospective DICT and the reference images (regression slope: 1.01, R2=0.961). Accelerating gastric MRI by integrating a dictionary-based signal model allows for improved image quality and increases accuracy of fat quantification during breathholds.

Emulsion Stability Modulates Gastric Secretion and Its Mixing with Emulsified Fat in Healthy Adults in a Randomized Magnetic Resonance Imaging Study.

BACKGROUND: Oil-in-water emulsions have recently become of interest to nutritional sciences because of their ability to influence gastrointestinal digestive processes and ultimately benefit human health. MRI offers the potential to noninvasively characterize the interaction between emulsified lipids and gastric secretion within the stomach. OBJECTIVES: We determined noninvasively how emulsion stability modulates volumes of fat and secretion, layering of fat, and the mixing of emulsified fat with secretion within the stomach. This required the development of MRI technology for quantifying fat and secretion concentrations inside the stomach. METHODS: Twenty-one healthy adults [13 men, mean ± SD age: 22.5 ± 2.5 y, mean ± SD body mass index (in kg/m2): 22.7 ± 1.8] were analyzed in a single-blind, randomized, parallel design. MRI was used to acquire the distributions of fat and secretion in the stomach after ingestion of 2 emulsions: a stable emulsion (E1) or an unstable emulsion (E4) with 20% fat fraction and ∼0.3 mm droplet sizes. Layer, volume, and mixing variables were fitted to the data and compared between the 2 emulsions. RESULTS: The intragastric mixing between fat and secretion was better with the E4 than the E1 [increase in content heterogeneity of 17.1% (95% CI: 12.3%, 21.9%)]. The E4 demonstrated a linear relation [slope 1.57 (95% CI: 0.86, 2.29)] between the degree of layering and mixing. In contrast, no such relation was detected for the E1. Accumulated secretion volume in the stomach was lower with the E4 [decrease in volume variable ks of 2.3 (95% CI: -3.9, -0.7)] and correlated with the degree of layering (r = 0.62, P < 0.001). CONCLUSIONS: In healthy adults, intragastric fat layering was influenced mainly by the degree of intragastric mixing, rather than the overall dominance of secretion. The E1 triggered a higher accumulation of gastric secretion, which in turn facilitated homogenization of intragastric content in comparison with its unstable counterpart. This trial was registered at clinicaltrials.gov as NCT02602158.

The visualisation and quantification of human gastrointestinal fat distribution with MRI: a randomised study in healthy subjects.

We aimed to study the fate of fat during digestion. For this purpose, we validated and investigated the non-invasive quantification of gastric and duodenal fat emptying and emulsion processing (creaming and phase separation) using the MRI method iterative decomposition with echo asymmetry and least squares estimation (IDEAL). In total, twelve healthy subjects were studied on two separate visits in a single-blind, randomised, cross-over design study. IDEAL was utilised to repeatedly acquire quantitative fat fraction maps of the gastrointestinal tract after infusion of one of two fat emulsions: E1 (acid stable, droplet size 0·33 mm) and E4 (acid unstable, 0·38 mm). In vitro and in vivo validation was carried out using diluted emulsion and gastric content samples, respectively, and resulted in Lin's concordance correlation coefficients of 1·00 (95% CI 0·98, 1·00) and 0·91 (95% CI 0·87, 0·94), respectively. Fat fraction maps and intragastric emulsion profiles enabled the identification of features of intraluminal phase separation and creaming that were not visible in conventional MRI. Gastric fat emptying was faster for E4 compared with E1 with a difference of 2·5 (95% CI 1·9, 3·1) ml/h. Duodenal content volumes were larger for E1 than for E4 with a difference of 4·9 (95% CI 3·9, 8·5) ml. This study demonstrated that with IDEAL it was possible (1) to visualise the intragastric and duodenal fat distribution and (2) to quantify the differences in emptying, phase separation and creaming of an acid-stable and an acid-unstable emulsion. This method has potential to bridge the gap between current in vitro digestive models and in vivo behaviour and to be applied in the development of effective functional foods.

Volume, distribution and acidity of gastric secretion on and off proton pump inhibitor treatment: a randomized double-blind controlled study in patients with gastro-esophageal reflux disease (GERD) and healthy subjects.

BACKGROUND: Postprandial accumulation of gastric secretions in the proximal stomach above the meal adjacent to the esophagogastric junction (EGJ), referred to as the 'acid pocket', has been proposed as a pathophysiological factor in gastro-esophageal reflux disease (GERD) and as a target for GERD treatment. This study assessed the effect of proton pump inhibitor (PPI) therapy on the volume, distribution and acidity of gastric secretions in GERD and healthy subjects (HS). METHODS: A randomized, double blind, cross-over study in 12 HS and 12 GERD patients pre-treated with 40 mg pantoprazole (PPI) or placebo b.i.d. was performed. Postprandial secretion volume (SV), formation of a secretion layer and contact between the layer and the EGJ were quantified by Magnetic Resonance Imaging (MRI). Multi-channel pH-monitoring assessed intragastric pH. RESULTS: A distinct layer of undiluted acid secretion was present on top of gastric contents in almost all participants on and off high-dose acid suppression. PPI reduced SV (193 ml to 100 ml, in HS, 227 ml to 94 ml in GERD; p < 0.01) and thickness of the acid layer (26 mm to 7 mm, 36 mm to 9 mm respectively, p < 0.01). No differences in secretion volume or layer thickness were observed between groups; however, off treatment, contact time between the secretion layer and EGJ was 2.6 times longer in GERD compared to HS (p = 0.012). This was not the case on PPI. CONCLUSIONS: MRI can visualize and quantify the volume and distribution dynamics of gastric secretions that form a layer in the proximal stomach after ingestion of a liquid meal. The secretion volume and the secretion layer on top of gastric contents is similar in GERD patients and HS; however contact between the layer of undiluted secretion and the EGJ is prolonged in patients. High dose PPI reduced secretion volume by about 50% and reduced contact time between secretion and EGJ towards normal levels. TRIAL REGISTRATION: NCT01212614.

Imaging gastric structuring of lipid emulsions and its effect on gastrointestinal function: a randomized trial in healthy subjects.

BACKGROUND: Efficient fat digestion requires fat processing within the stomach and fat sensing in the intestine. Both processes also control gastric emptying and gastrointestinal secretions. OBJECTIVE: We aimed to visualize the influence of the intragastric stability of fat emulsions on their dynamics of gastric processing and structuring and to assess the effect this has on gastrointestinal motor and secretory functions. DESIGN: Eighteen healthy subjects with normal body mass index (BMI) were studied on 4 separate occasions in a double-blind, randomized, crossover design. Magnetic resonance imaging (MRI) data of the gastrointestinal tract and blood triglycerides were recorded before and for 240 min after the consumption of the following 4 different fat emulsions: lipid emulsion 1 (LE1; acid stable, 0.33 µm), lipid emulsion 2 (LE2; acid stable, 52 µm), lipid emulsion 3 (LE3; acid unstable, solid fat, 0.32 µm), and lipid emulsion 4 (LE4; acid unstable, liquid fat, 0.38 µm). RESULTS: Intragastric emulsion instability was associated with a change in gastric emptying. Acid-unstable emulsions exhibited biphasic and faster emptying profiles than did the 2 acid-stable emulsions (P ≤ 0.0001). When combined with solid fat (LE3), different dynamics of postprandial gallbladder volume were induced (P ≤ 0.001). For acid-stable emulsions, a reduction of droplet size by 2 orders of magnitude [LE1 (0.33 µm) compared with LE2 (52 µm)] delayed gastric emptying by 38 min. Although acid-stable (LE1 and LE2) and redispersible (LE4) emulsions caused a constant increase in blood triglycerides, no increase was detectable for LE3 (P < 0.0001). For LE3, MRI confirmed the generation of large fat particles during gastric processing, which emptied into and progressed through the small intestine. CONCLUSIONS: MRI allows the detailed characterization of the in vivo fate of lipid emulsions. The acute effects of lipid emulsions on gastric emptying, gallbladder volume, and triglyceride absorption are dependent on microstructural changes undergone during consumption. Gastric peristalsis and secretion were effective at redispersing pools of liquid fat in the stomach. This trial was registered at clinicaltrials.gov as NCT01253005.

Noncoagulating Enteral Formula Can Empty Faster From the Stomach: A Double-Blind, Randomized Crossover Trial Using Magnetic Resonance Imaging.

BACKGROUND: The gastric accumulation of enteral formulas in tube-fed patients leads to an increased risk of vomiting and regurgitation. Gastric secretion-induced coagulation of proteins in enteral formulas might lead to gastric accumulation of solid protein particles that further increase the risk of upper digestive intolerance. This study used magnetic resonance imaging to noninvasively assess the half-emptying time (t50) of enteral formulas differing in protein composition. METHODS: Three isocaloric (450 kcal) and isovolumetric (300 mL) enteral formulas, 1 with a noncoagulating P4 protein blend and 2 with coagulating casein-dominant protein blends, were compared in a double-blind, randomized, 3-way crossover study in 21 healthy volunteers. Gastric content emptying curves were fitted with the LinExp model to compute t50 and the parameter κ with κ > 1 reflecting the accumulation of gastric secretion. t50 and κ were compared between all 3 enteral formulas. The formula that emptied fastest was identified by an ordinal mixed model using the ranks of t50. RESULTS: As indicated by values for κ > 1, all enteral formulas induced gastric secretion. No differences were detected for t50. However, the noncoagulating formula emptied fastest in 74% of all participants (P = .004). CONCLUSION: This study demonstrates that a noncoagulating enteral formula can empty faster from the stomach compared with coagulating formulas in a large cohort of healthy volunteers. Investigations on the efficiency of the noncoagulating P4 protein blend in patients requiring tube feeding will further elucidate its potential for reducing upper digestive intolerance during enteral nutrition. Trial NTR2979.

Validation of a golden angle radial sequence (GOLD) for abdominal T1 mapping during free breathing: demonstrating clinical feasibility for quantifying gastric secretion and emptying.

PURPOSE: To validate a magnetic resonance imaging sequence suitable for quantitative assessment of acid suppression by a proton pump inhibitor (PPI) on gastric secretion and emptying in clinical practice. METHODS: A golden angle radial sequence (GOLD) was validated in a series of in vitro and in vivo experiments and clinical feasibility was shown in two studies. The impact of free breathing and image plane orientation on T1 values was evaluated in a controlled in vivo experiment. The free-breathing GOLD sequence was compared against a standard breath-hold gradient echo sequence for gastric half emptying time in 23 subjects during a gastric emptying study. Pilot data from five subjects assessed the sensitivity of the GOLD sequence to detect changes in acid secretion volume produced by PPI treatment. RESULTS: The coronal free-breathing GOLD sequence and the axial breath-hold standard gradient echo sequence showed good agreement of the gastric half emptying time (6 ± 3 min, P = 0.053). The GOLD sequence demonstrated sensitivity to reduction of gastric secretion volumes induced by PPI treatment (55 ± 5 mL, P < 0.001). CONCLUSION: The GOLD sequence allowed for free breathing, multislice, combined imaging and T1 mapping of the stomach content. GOLD presents a promising multipurpose, noninvasive imaging tool for monitoring gastric function in clinical studies.

Abnormal structure and function of the esophagogastric junction and proximal stomach in gastroesophageal reflux disease.

OBJECTIVES: This study applies concurrent magnetic resonance imaging (MRI) and high-resolution manometry (HRM) to test the hypothesis that structural factors involved in reflux protection, in particular, the acute insertion angle of the esophagus into the stomach, are impaired in gastroesophageal reflux disease (GERD) patients. METHODS: A total of 24 healthy volunteers and 24 patients with mild-moderate GERD ingested a test meal. Three-dimensional models of the esophagogastric junction (EGJ) were reconstructed from MRI images. Measurements of the esophagogastric insertion angle, gastric orientation, and volume change were obtained. Esophageal function was assessed by HRM. Number of reflux events and EGJ opening during reflux events were assessed by HRM and cine-MRI. Statistical analysis applied mixed-effects modeling. RESULTS: The esophagogastric insertion angle was wider in GERD patients than in healthy subjects (+7° ± 3°; P=0.03). EGJ opening during reflux events was greater in GERD patients than in healthy subjects (19.3 mm vs. 16.8 mm; P=0.04). The position of insertion and gastric orientation within the abdomen were also altered (both P<0.05). Median number of reflux events was 3 (95% CI: 2.5-4.6) in GERD and 2 (95% CI: 1.8-3.3) in healthy subjects (P=0.09). Lower esophageal sphincter (LES) pressure was lower (-11 ± 2 mm Hg; P<0.0001) and intra-abdominal LES length was shorter (-1.0 ± 0.3 cm, P<0.0006) in GERD patients. CONCLUSIONS: GERD patients have a wider esophagogastric insertion angle and have altered gastric morphology; structural changes that could compromise reflux protection by the "flap valve" mechanism. In addition, the EGJ opens wider during reflux in GERD patients than in healthy volunteers: an effect that facilitates volume reflux of gastric contents.

Real-time multipoint gastrointestinal 19-fluorine catheter tracking.

PURPOSE: To develop MR based real-time gastrointestinal 19-Fluorine (19F) catheter tracking and visualization allowing for real-time detection and feedback of 3D catheter shape and movement as well as catheter-driven adjustments of 1H imaging geometry parameters. METHODS: Data were acquired on a 3T clinical system using 3D Golden Angle radial sampling. Two gastrointestinal catheters incorporating four fiducial 19F markers (65 or 50 µL marker volume) were tracked while being pulled through a gel phantom by an operator inside the MR room with velocities of 2-18 mm/s. During continuous acquisition, k-space profiles were transferred in real-time to an external computer for concurrent reconstruction of 3D 19F images and detection and visualization of marker positions. Based on αthe marker positions, automatic adjustments of 1H imaging planes to facilitate targeted anatomical scanning was implemented. RESULTS: Mean tracking reliabilities were 94.5 and 83.6% (catheters 1 and 2) for temporal resolutions 185-740 ms. Reconstruction times of 196 ms were achieved. Real-time visual feedback allowed the operator to accurately control the catheter movement. Catheter-guidance for 1H imaging was reliable. CONCLUSION: The presented real-time 19F MR based framework for the tracking of 19F labeled devices is applicable to combined 19F and 1H MRI guidance of gastrointestinal devices in vivo.

19F MR imaging golden angle-based capsule tracking for intestinal transit and catheter tracking: initial in vivo experience.

PURPOSE: To combine fluorine 19 ((19)F) magnetic resonance (MR) imaging and golden angle radial acquisition and to assess the feasibility of (19)F MR imaging golden angle-based tracking for catheter tracking applications and simultaneous three-dimensional (3D) intestinal tracking of ingested (19)F-labeled capsules in vivo. MATERIALS AND METHODS: Approval from the local ethical committee and informed consent from the subject were obtained. In vitro studies were performed to assess (19)F MR imaging golden angle-based tracking reliability with regard to temporal resolution and different tracking strategies (boundary condition-free tracking, composite image-based tracking, and model-based tracking). In vivo performance of the method was investigated in one healthy volunteer on 2 days. On study day 1, a duodenal catheter incorporating five (19)F-labeled capsules was administered nasally, and its 3D movement was tracked inside the stomach and esophagus. On study day 2, three (19)F-labeled capsules were swallowed, and intestinal movement was tracked. RESULTS: Simultaneous in vivo 3D tracking of multiple (19)F-labeled capsules was successfully performed without incorporation of boundary conditions at a temporal resolution of 252 msec. Incorporation of boundary conditions with composite image-based tracking and model-based tracking increased tracking reliability and enabled temporal resolution as high as 108 msec. CONCLUSION: Use of (19)F MR imaging golden angle-based capsule tracking enables in vivo tracking of (19)F-labeled capsules and catheters at high temporal resolution. The presented method is applicable to physioanatomic studies of the gastrointestinal tract and shows potential for real-time tracking in interventional radiology.

Assessing antiangiogenic therapy response by DCE-MRI: development of a physiology driven multi-compartment model using population pharmacometrics.

Dynamic contrast enhanced (DCE-) MRI is commonly applied for the monitoring of antiangiogenic therapy in oncology. Established pharmacokinetic (PK) analysis methods of DCE-MRI data do not sufficiently reflect the complex anatomical and physiological constituents of the analyzed tissue. Hence, accepted endpoints such as Ktrans reflect an unknown multitude of local and global physiological effects often rendering an understanding of specific local drug effects impossible. In this work a novel multi-compartment PK model is presented, which for the first time allows the separation of local and systemic physiological effects. DCE-MRI data sets from multiple, simultaneously acquired tissues, i.e. spinal muscle, liver and tumor tissue, of hepatocellular carcinoma (HCC) bearing rats were applied for model development. The full Markov chain Monte Carlo (MCMC) Bayesian analysis method was applied for model parameter estimation and model selection was based on histological and anatomical considerations and numerical criteria. A population PK model (MTL3 model) consisting of 3 measured and 6 latent (unobserved) compartments was selected based on Bayesian chain plots, conditional weighted residuals, objective function values, standard errors of model parameters and the deviance information criterion. Covariate model building, which was based on the histology of tumor tissue, demonstrated that the MTL3 model was able to identify and separate tumor specific, i.e. local, and systemic, i.e. global, effects in the DCE-MRI data. The findings confirm the feasibility to develop physiology driven multi-compartment PK models from DCE-MRI data. The presented MTL3 model allowed the separation of a local, tumor specific therapy effect and thus has the potential for identification and specification of effectors of vascular and tissue physiology in antiangiogenic therapy monitoring.

Free-breathing quantitative dynamic contrast-enhanced magnetic resonance imaging in a rat liver tumor model using dynamic radial T(1) mapping.

OBJECTIVES: : The high sensitivity to motion artifacts is a major limiting factor for applying the dynamic 3D T1-weighted gradient-echo (3D T1w GRE) technique for dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) experiments in small rodents. Dynamic quantification of the relaxation rate R1 (1/T1) presents an alternative approach to reduce these motion artifacts. In this work, an optimized 2D single-shot Look-Locker based T1 mapping technique, named GOLD, applying radial sampling in the golden-angle view order and contrast-enhancing k-space filter was evaluated for its use in free-breathing quantitative DCE-MRI of rat liver on a clinical 1.5 T MRI system. MATERIALS AND METHODS: : In vitro measurements and initial in vivo experiments in healthy rats were performed to evaluate the accuracy and resilience of the GOLD technique to motion artifacts. Unifocal hepatocellular carcinoma (HCC) was established in 20 male Buffalo rats. Twelve days after tumor cell implantation, animals were screened for intrahepatic tumor nodules by high-resolution T2-weighted MRI. Quantitative DCE-MRI experiments applying bolus injected gadopentetate dimeglumine were performed in 11 HCC-bearing rats using the GOLD technique. For comparison, a standard 3D T1w GRE sequence was applied in 6 additional rats. RESULTS: : Phantom experiments showed good agreement for T1 values measured by the GOLD method and an inversion recovery spectroscopy measurement. The in vivo experiments in healthy rats confirmed the robustness of the GOLD method in T1 value determination and its resilience to motion artifacts. Gadopentetate dimeglumine concentration (CGd) time curves determined from free-breathing GOLD-based DCE-MRI experiments of HCC-bearing rats allowed reliable and robust pharmacokinetic modeling (K, ve, lag time Td, and slow washout rate rwo) of tumor, liver, and spinal muscle. In comparison to the dynamic 3D T1w GRE, the GOLD method showed less variation and jitter in the CGd time curves and significantly increased accuracy (in terms of the goodness of fit) in the pharmacokinetic modeling. Significant differences were detected for K and ve with the 3D T1w GRE method apparently underestimating those parameters. CONCLUSIONS: : The GOLD technique allowed dynamic sampling of 2D axial T1 maps of the rat abdomen with 6-second temporal resolution enabling simultaneous and robust pharmacokinetic modeling of HCC, normal liver, and spinal muscle.

Visualization and quantification of intestinal transit and motor function by real-time tracking of 19F labeled capsules in humans.

A combined (19)F and (1)H MRI framework for the assessment of human intestinal transit and motor function is presented. This framework consists of silicone coated polychlorotrifluoroethylene capsules filled with perfluoro-[15]-crown-5-ether as (19)F marker, a flexible (19)F surface coil and a (19)F projection imaging sequence, allowing for real-time tracking of a single or multiple capsules. The capsules (length 11.5 mm, Ø 7.2 mm) contain 140 µL perfluoro-[15]-crown-5-ether and were tested for cytotoxicity and leakage prior to oral administration. A balanced SSFP projection sequence was implemented, yielding a temporal resolution of 133 ms. Optional multi-frequency excitation, allowing for interleaved tracking of differently labeled (19)F capsules, was incorporated. The passage of the (19)F capsules through intestinal sections was monitored in two healthy volunteers. Capsule coordinates were successfully coregistered with anatomical reference scans. Intestinal motility, residence times, lengths and forward velocities were determined. Simultaneous tracking of two capsules allowed for the assessment of peristaltic patterns with correction for respiratory motion. By providing the means for real-time multiple capsule tracking and high resolution anatomical imaging, the presented multinuclear imaging framework has the potential to provide important supplemental information for physiological and pharmaceutical research.