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Objective: Cell therapy may be a promising alternative or adjunct to current treatment modalities for ischemic heart failure. But little is known on the impact of myogenic cell transplantation in large animal models of non-ischemic cardiomyopathy. The aim of the present study was to explore whether an ovine model of toxin-induced heart disease could benefit from non-cultured skeletal muscle cell transplantation., Methods: Sequential intracoronary injections of doxorubicin (0.75 mg/kg) were carried out every 2 weeks until echocardiographic detection of myocardial dysfunction. Sheep were then randomly assigned to either non-cultured cell transplantation (n=8) or placebo injection (n=5). For the cell therapy group, a skeletal muscle biopsy (about 10 g) was explanted from each animal approximately 3h before grafting. After thoracotomy, 20 epicardial injections were carried out. The animals were assessed one last time before sacrifice, 2 months after the thoracotomy. Cells were tracked with cmDiI (red fluorescence) and characterized with immunohistochemistry with monoclonal antibodies to a fast skeletal isoform of myosin heavy chain., Results: Two months after intramyocardial grafting, tissue Doppler imaging and conventional echocardiographic assessment of the groups showed a marked improvement in the non-cultured cell therapy group. Ejection fraction (EF) (p<0.05) as well as systolic endocardial velocities (p<0.01) improved versus the placebo group. CmDiI and skeletal myosin heavy chain expression was detected in all animals at 2 months after implantation confirming engraftment of skeletal muscle cells., Conclusions: In conclusion, our data indicate that non-cultured muscle cell transplantation is feasible and may translate into a functional benefit in an ovine model of dilated heart failure.

Aims: The aim of the present study was to evaluate whether off-pump mini-invasive mitral valve replacement is possible after prior bioprosthetic mitral valve replacement in animals., Methods and Results: To validate this concept for off-pump redo mitral valve insertion, we first replaced surgically mitral valves of six sheep under extracorporeal circulation using a Mosaïc valve. Prior to its insertion, we added a radio-opaque ring on its base to enhance its visualization under fluoroscopy. A bovine jugular valve mounted into a stent was then inserted off-pump through an opening of the atrial wall. Mitral valves were replaced successfully in all animals. Following the surgical valve insertion, mean left atrium and left ventricular end-diastolic pressures were 38 (22-42) and 18.8 mmHg (13-22), respectively. Angiography showed perfectly functioning valves, no subaortic valve obstruction, and a mild paravalvular leak in one animal. In one animal, we were unable to control the bleeding from the atrial opening. In this case, trans-atrial valvulation was not attempted. The off-pump valvular implantation was successful in the other five sheep. Haemodynamic data did not change after the insertion of valved stents. Implanted valves were all competent. The animal with the better haemodynamics was kept alive and is still alive 3 months after implantation., Conclusion: Surgically implanted bioprosthetic valves provide excellent support for off-pump insertion of a valved stent. Further experiments are necessary, in particular with appropriate valve size, before considering this approach for percutaneous mitral valvular replacement in patients with a dysfunctional bioprosthesis.

The intestinal tumor multiplicity in mice heterozygous for ApcMin is strongly modulated by genetic background. On the sensitive C57BL/6J (B6) background, mice develop large numbers of intestinal adenomas. The AKR/J (AKR) strain carries alleles that correlate with a strong reduction in tumor multiplicity. To study the effect of one of these modifiers, Mom1, we have generated a mouse line in which the AKR allele of Mom1 is carried on the sensitive B6 genetic background. This strain was produced by using a marker-assisted selection method to eliminate unlinked AKR alleles more rapidly. The application and efficiency of this method are discussed. We used this strain to determine that Mom1 affects both tumor multiplicity and tumor size in a semi-dominant fashion.

As genetic mapping of quantitative trait loci (QTL) becomes routine, the challenge is to identify the underlying genes. This paper develops rigorous genetic tests for evaluation of candidate genes for a QTL, involving determination of allelic status in inbred strains and fine-structure genetic mapping. For the Mom1 modifier of intestinal adenomas caused by ApcMin, these tests are used to evaluate two candidate genes: Pla2g2a, a secretory phospholipase, and Rap1GAP, a GTPase activating protein. Rap1GAP passes the first test but is excluded by a single fine-structure recombinant. Pla2g2a passes both tests and is a strong candidate for Mom1. Significantly, we also find that ApcMin-induced adenomas remain heterozygous for the Mom1 region, consistent with Mom1 acting outside the tumor lineage and encoding a secreted product.