Étude de l’effet d’un mimétique de l’apoA-I sur la dysfonction diastolique du ventricule gauche
Left ventricular diastolic dysfunction (LVDD), a precursor form of heart failure, is a condition that affects compliance and relaxation of the myocardium. Unlike systolic heart failure, there is no clinically approved treatment yet for LVDD. Complexity of the pathways behind this disease as well as the small number of adequate animal models reflecting its physiopathology are the main causes of this lack of treatment. In our laboratory, we previously showed that mimetic of apolipoprotein A-I (apoA-I), a major component of high-density lipoproteins (HDL), improves LVDD in a rabbit model of aortic valve stenosis (AVS). AVS is one of the main risk factors which can cause LVDD. The first objective of this thesis is to develop a valid animal model of LVDD without AVS. The second objective is to test the potential effects of apoA-I on this pathology and to elucidate the mechanisms of action behind these effects. To do so, we used two different models of rabbits. The first, was based on the exposure of rabbits to a high-cholesterol diet for an average period of 16 weeks (without excess of vitamin D2 to prevent development of AVS). The second, is a surgical model of transaortic constriction (TAC). With this model, rabbits develop LVDD within 12 weeks after surgery, without involvement of AVS. Once LVDD was established, rabbits were treated with 3 injections of 25 mg/kg of apoA-I mimetic peptide weekly for 4 consecutive weeks. Echocardiography sessions were performed throughout the study to assess the stage of the disease at different time points. Molecular effects of the treatment were evaluated by qPCR and by immunohistochemistry experiments. In our two rabbit models, LVDD was established without the presence of AVS. At the end of the treatment period, our drug did not significantly improve diastolic dysfunction in rabbits. Only a few positive effects of treatment involved in the anti-inflammatory pathway have been noticed. In conclusion, these results allowed us to confirm that the positive effects of apoA-I mimetic peptide that we have previously reported on LVDD in another study were mediated by the improvement of AVS but not by a direct effect on the myocardium.
apoA-I Diastolic  Dysfunction Aortic valve stenosis Animal model