Résumé :
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Purpose: Advances in cardiac surgery have improved short-term prognoses of patients with congenital heart diseases but, at long-term, right ventricular (RV) failure may occur, leading to morbidity and mortality. As conventional therapy gives poor results, cell therapy may be a therapeutic option for cardiac repair. The ability of embryonic stem cells (ESC) differentiation towards a cardiomyogenic phenotype makes them attractive candidates. Our aim was to evaluate, in a large animal model, effects of human cardiac progenitors' transplantation on the RV function.Methods: RV dysfunction was created in 6 piglets mimicking RV tract sequellae of repaired tetralogy of Fallot leading, after 4 months, to a chronic combined, volumetric and barometric, RV overload. 3 pigs received vehicle and 3 others received HUES-24 derived human cardiac progenitors cells injected at multiple sites into the free wall of RV myocardium. All pigs were immunosuppressed using tacrolimus (0.2mg/kg/d). Myocardial function was measured 3 months after cell transplantation by conductance catheter technique using maximal elastance (Emax) slope and ventricular energetics (stroke work, pression-volume area). The risk of ventricular arrhythmia was evaluated by programmed ventricular stimulation at the end of the follow-up. Structural remodelling was assessed by histological examination.Results: All pigs survived and no complication (inflammation, teratoma, infection) occurred related to either myocardial injections or immunosuppression. No ventricular arrhythmia was induced. In all treated pigs, myocardial contractility was improved as assessed by an increasing Emax slope relative to baseline (mean values: 0.61±0.02 vs 0.40±0.01, p<0.001) and to controls at the follow-up end (0.32±0.02, p<0.05). For a same level of RV overload, stroke work was similar in both groups whereas pression-volume area tended to decrease in the treated group (6813±1773 vs 9614±1836 mmHg.mL). This last result reflecting a decrease of the total myocardial oxygen consumption suggested that the RV myocardium was more efficient in the treated group. In this group, myocardial fibrosis appeared less extensive with a predominant peritrabecular localisation.Conclusion: Cell therapy by multiple trans-epicardial injections of ESC derived human cardiac progenitor cells in failed RV secondary to chronic overload is feasible, improves RV myocardial contractility and allows a better adaptation to chronic overload.
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