Ribose supplementation alone or with elevated creatine does not preserve high energy nucleotides or cardiac function in the failing mouse heart

Background: Reduced levels of creatine and total adenine nucleotides (sum of ATP, ADP and AMP) are hallmarks of chronic heart failure and restoring these pools is predicted to be beneficial by maintaining the diseased heart in a more favourable energy state. Ribose supplementation is thought to support both salvage and re-synthesis of adenine nucleotides by bypassing the rate-limiting step. We therefore tested whether ribose would be beneficial in chronic heart failure in control mice and in mice with elevated myocardial creatine due to overexpression of the creatine transporter (CrT-OE). Methods and Results: Four groups were studied: sham; myocardial infarction (MI); MI+ribose; MI+CrT-OE+ribose. In a pilot study, ribose given in drinking water was bioavailable, resulting in a two-fold increase in myocardial ribose-5-phosphate levels. However, 8 weeks post-surgery, total adenine nucleotide (TAN) pool was decreased to a similar amount (8–14%) in all infarcted groups irrespective of the treatment received. All infarcted groups also presented with a similar and substantial degree of left ventricular (LV) dysfunction (3-fold reduction in ejection fraction) and LV hypertrophy (32–47% increased mass). Ejection fraction closely correlated with infarct size independently of treatment (r2 = 0.63, p<0.0001), but did not correlate with myocardial creatine or TAN levels. Conclusion: Elevating myocardial ribose and creatine levels failed to maintain TAN pool or improve post-infarction LV remodeling and function. This suggests that ribose is not rate-limiting for purine nucleotide biosynthesis in the chronically failing mouse heart and that alternative strategies to preserve TAN pool should be investigated

Improved method for quantification of regional cardiac function in mice using phase-contrast MRI

Phase-contrast magnetic resonance imaging is a technique that allows for characterization of regional cardiac function and for measuring transmural myocardial velocities in human hearts with high temporal and spatial resolution. The application of this technique (also known as tissue phase mapping) to murine hearts has been very limited so far. The aim of our study was to implement and to optimize tissue phase mapping for a comprehensive assessment of murine transmural wall motion. Baseline values for regional motion patterns in mouse hearts, based on the clinically used American Heart Association's 17-segment model, were established, and a detailed motion analysis of mouse heart for the entire cardiac cycle (including epicardial and endocardial motion patterns) is provided. Black-blood contrast was found to be essential to obtain reproducible velocity encoding. Tissue phase mapping of the mouse heart permits the detailed assessment of regional myocardial velocities. While a proof-of-principle application in a murine ischemia–reperfusion model was performed, future studies are warranted to assess its potential for the investigation of systolic and diastolic functions in genetically and surgically manipulated mouse models of human heart disease. Magn Reson Med, 2012. © 2011 Wiley Periodicals, Inc

Semi-Automatic segmentation of multiple mouse embryos in MR images

<p>Abstract</p> <p>Background</p> <p>The motivation behind this paper is to aid the automatic phenotyping of mouse embryos, wherein multiple embryos embedded within a single tube were scanned using Magnetic Resonance Imaging (MRI).</p> <p>Results</p> <p>Our algorithm, a modified version of the simplex deformable model of Delingette, addresses various issues with deformable models including initialization and inability to adapt to boundary concavities. In addition, it proposes a novel technique for automatic collision detection of multiple objects which are being segmented simultaneously, hence avoiding major leaks into adjacent neighbouring structures. We address the initialization problem by introducing balloon forces which expand the initial spherical models close to the true boundaries of the embryos. This results in models which are less sensitive to initial minimum of two fold after each stage of deformation. To determine collision during segmentation, our unique collision detection algorithm finds the intersection between binary masks created from the deformed models after every few iterations of the deformation and modifies the segmentation parameters accordingly hence avoiding collision.</p> <p>We have segmented six tubes of three dimensional MR images of multiple mouse embryos using our modified deformable model algorithm. We have then validated the results of the our semi-automatic segmentation versus manual segmentation of the same embryos. Our Validation shows that except paws and tails we have been able to segment the mouse embryos with minor error.</p> <p>Conclusions</p> <p>This paper describes our novel multiple object segmentation technique with collision detection using a modified deformable model algorithm. Further, it presents the results of segmenting magnetic resonance images of up to 32 mouse embryos stacked in one gel filled test tube and creating 32 individual masks.</p

Accelerating cine-MR Imaging in Mouse Hearts Using Compressed Sensing

PURPOSE: To combine global cardiac function imaging with compressed sensing (CS) in order to reduce scan time and to validate this technique in normal mouse hearts and in a murine model of chronic myocardial infarction. MATERIALS AND METHODS: To determine the maximally achievable acceleration factor, fully acquired cine data, obtained in sham and chronically infarcted (MI) mouse hearts were 2-4-fold undersampled retrospectively, followed by CS reconstruction and blinded image segmentation. Subsequently, dedicated CS sampling schemes were implemented at a preclinical 9.4 T magnetic resonance imaging (MRI) system, and 2- and 3-fold undersampled cine data were acquired in normal mouse hearts with high temporal and spatial resolution. RESULTS: The retrospective analysis demonstrated that an undersampling factor of three is feasible without impairing accuracy of cardiac functional parameters. Dedicated CS sampling schemes applied prospectively to normal mouse hearts yielded comparable left-ventricular functional parameters, and intra- and interobserver variability between fully and 3-fold undersampled data. CONCLUSION: This study introduces and validates an alternative means to speed up experimental cine-MRI without the need for expensive hardware

Dietary Supplementation with Homoarginine Preserves Cardiac Function in a Murine Model of Post-Myocardial Infarction Heart Failure

Low plasma homoarginine (HA) is an emerging biomarker for cardiovascular disease and an independent predictor of mortality in patients with heart failure. Plasma levels appear to reflect cardiac dysfunction, positively correlating with ejection fraction and inversely with circulating brain natriuretic peptide. However, whether this outcome is a bystander or cause-and-effect has yet to be established. Within the context of stroke, a direct causal relationship has been inferred because normal mice pretreated with 14 mg/L HA had a smaller stroke size. In the present study, we show for the first time that dietary supplementation with HA improves cardiac function in the setting of chronic heart failure, suggesting a novel preventive strategy and inferring that low HA levels may be inherently detrimental because of a loss of this effect

Identification of cardiac malformations in mice lacking Ptdsr using a novel high-throughput magnetic resonance imaging technique

BACKGROUND: Congenital heart defects are the leading non-infectious cause of death in children. Genetic studies in the mouse have been crucial to uncover new genes and signaling pathways associated with heart development and congenital heart disease. The identification of murine models of congenital cardiac malformations in high-throughput mutagenesis screens and in gene-targeted models is hindered by the opacity of the mouse embryo. RESULTS: We developed and optimized a novel method for high-throughput multi-embryo magnetic resonance imaging (MRI). Using this approach we identified cardiac malformations in phosphatidylserine receptor (Ptdsr) deficient embryos. These included ventricular septal defects, double-outlet right ventricle, and hypoplasia of the pulmonary artery and thymus. These results indicate that Ptdsr plays a key role in cardiac development. CONCLUSIONS: Our novel multi-embryo MRI technique enables high-throughput identification of murine models for human congenital cardiopulmonary malformations at high spatial resolution. The technique can be easily adapted for mouse mutagenesis screens and, thus provides an important new tool for identifying new mouse models for human congenital heart diseases

A TNF-α Promoter Polymorphism Is Associated with Juvenile Onset Psoriasis and Psoriatic Arthritis

Tumor necrosis factor-α is considered to be one of the important mediators in the pathogenesis of psoriasis. A strong association of juvenile onset psoriasis with the major histocompatibility complex encoded HLA-Cw6 antigen has been reported but it is unclear whether Cw6 itself or a closely linked gene is involved in the pathogenesis. This study has focused on the association of promoter polymorphisms of the major histocompatibility complex encoded tumor necrosis factor-α gene with psoriasis and psoriatic arthritis. Tumor necrosis factor-α promoter polymorphisms were sought by sequence-specific oligonucleotide hybridization and by direct sequencing in Caucasian patients with juvenile onset psoriasis and with psoriatic arthritis and in healthy controls. A mutation at position −238 of the tumor necrosis factor-α promoter was present in 23 of 60 patients (38%; p < 0.0001; Pcorr < 0.008) with juvenile onset psoriasis and in 20 of 62 patients (32%; p < 0.0003; Pcorr < 0.03) with psoriatic arthritis, compared with seven of 99 (7%) Caucasian controls. There was a marked increase of homozygotes for this mutation in the psoriasis group. Another mutation at position −308 was found in similar proportions of patients and controls. Our study shows a strong association of the tumor necrosis factor-α promoter polymorphism at position −238 with psoriasis and psoriatic arthritis. Our findings suggest that this promoter polymorphism itself or a gene in linkage disequilibrium with tumor necrosis factor-α predispose to the development of psoriasis