General context Acute Decompensation of Heart Failure (ADHF) is a growing medical problem, remaining associated, despite current treatments, with a high morbimortality. Recently, metabolic remodeling, has been shown to play a crucial role in the chronic heart failure contributing to the imbalance between oxygen demand and supply. However, the role of metabolic remodeling in ADHF has been mostly overlooked. Thus, the goal of the project is to elucidate the temporal evolution of the metabolic remodeling during ADHF in order to identify new therapeutic targets. Methods and Material Experimental model ADHF will be induced by NaCl loading to rats with heart failure. Temporal evaluation of cardiac metabolic remodeling during ADHF.
(first year) The effects of ADHF will be confirmed by echocardiographic, hemodynamics and MRI assessment. The plasma and hearts of the animals will be collected for evaluations of cardiac energy metabolism (Seahorse FX metabolic imager. The bioavailability of energy substrates will be assessed using ELISA kits, while the 4/10 expression and / or activity of enzymes involved in the metabolic remodeling will be studied using the MALDI-TOF MSI. Impact of metabolic modulation on cardiovascular dysfunction induced by ADHF.
(second year) Heart rate reduction by the If current inhibitor S38844 opposes the ADHF. However, the role of the metabolism in these beneficial effects is unknown. Thus, we will evaluate modifications of metabolic remodeling induced by S38844 in relation with the cardiovascular effects. Moreover, the coronary and mesenteric resistance arteries will be removed to assess the impact on the endothelial vascular function, while cardiac metabolic assays will be performed as indicated above. Investigations of direct effects of treatments on cardiac cells
(third year) In order to evaluate whether the cardiac functional effects result from direct metabolic effects on cardiomyocytes, or depend on indirect effects including vascular changes influencing myocardial perfusion, the impact of S38844 will also be assessed by ex vivo and in vitro incubation with S38844 of isolated myocytes and coronary vessels obtained from animals 24 hours or 6 and 14 days after ADHF
The candidate will have knowledge of the physiology and pathophysiology of heart failure. He/she should have notions in the field of metabolic energy adaptation of the myocardium during heart failure. Moreover, the following skills are required: 1) in vivo functional analyzes by echocardiography and plethysmography, 2) in vivo and in vitro metabolic assessment, 3) evaluation of vascular function in vitro, 4) stress test on a treadmill, 5) monitoring of animals in long-term protocols (authorization for animal experimentation level2), 6) immuno-histology and image analysis.