Endothelial dysfunction in heart failure with preserved ejection fraction – ED-HFpEF
Context: By 2020, the prevalence of heart failure with preserved ejection fraction (HFpEF) will turn into the most common heart failure phenotype with a mortality rate similar to the one of heart failure with reduced ejection fraction (HFrEF). Nevertheless, in contrast to HFrEF, there is a lack of consensus on the basic pathophysiology and definition of HFpEF. As a result, to date, there are no approved therapies available to reduce mortality or hospitalization for these patients. There is, then, an urgent need to understand HFpEF pathophysiology in order to develop new drugs. A unifying, but untested, theory suggests that the high prevalence of cardiovascular comorbidities (obesity, type 2 diabetes, hypertension etc...) lead to a systemic inflammation, which triggers heart endothelial microvascular dysfunction and subsequently HFpEF. Nevertheless the role of endothelial cell (EC) dysfunction in the pathophysiology of HFpEF has never been demonstrated.
The present project has been designed to explore the role of EC dysfunction in the pathophysiology of HFpEF.
Objectives/Tasks: In task 1, we will investigate phenotypic changes in cardiac microvasculature associated with diastolic dysfunction. To do so, we will use Leprdb/db female mice which recapitulate most features of human HFpEF. Task 2 will use a combination of genetic approaches in attempt to significantly increase our knowledge of the role of endothelial dysfunction in the pathogenesis of HFpEF in the absence of any risk factors and co-morbidities. Task 3‘s objective is to get insights regarding the molecular mechanisms by which EC may regulate cardiomyocyte function. Task 4 aims to confirm the role of endothelial dysfunction in the pathophysiology of HFpEF by testing the therapeutic potential of the Hh signalling agonist, SAG, though its ability to ameliorate EC function. Finally, in Task 5 we expect to identify new circulating markers of HFpEF.
Strategy: The achievement of this project is made possible thanks to collaboration between M.A. Renault (Inserm UMR 1034), J.S. Hulot (Inserm U970-PARCC) and B. Lauizer (Inserm UMR 1087). M.A. Renault, the leader of the project is an expert in both vascular biology and Hedgehog (Hh) signaling. M.A. Renault‘s laboratory recently developed 2 mouse models of genetically-induced EC dysfunction based on alteration of Hedgehog and Wnt signaling. J.S. Hulot is a cardiologist and an expert in cardiomyocyte biology and heart failure pathophysiology. In addition, J.S. Hulot has access to plasma biobanks of patients with HFpEF. B. Lauzier, in an expert on cardiac function evaluation. He recently developed a rat model with ED dysfunction displaying altered vasoreactivity.
Expected outcomes: The present study will have direct significant scientific impacts: the present project will result in (1) describing the specific consequences of cardiac microvascular dysfunction on heart structure and function, (2) identifying novel molecular mechanisms by which EC dysfunction may induce heart failure and contribute to the development of HFpEF and (3) identifying new circulating markers of HFpEF and (4) testing the therapeutic potential role of a candidate molecule ameliorating EC function in mice with HFpEF. This study will be the first one, to our knowledge, to demonstrate the specific contribution of EC dysfunction in the pathophysiology of heart failure and per se represent a big step toward the understanding of HFpEF pathophysiology and the development of active drugs for this pathology.
Madame Marie-Ange Renault (Institut National de la Santé et de la Recherche Médicale)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
INSERM UMR1034 Biologie des maladies cardiovasculaires Institut National de la Santé et de la Recherche Médicale
PARCC PARIS CENTRE DE RECHERCHE CARDIOVASCULAIRE
L'unité de recherche de l'institut du thorax
Help of the ANR 470,151 euros
Beginning and duration of the scientific project: March 2020 - 42 Months