Heart failure with preserved ejection fraction: development of animal model to identify therapeutic targets – HFpEF-Beta3

Heart failure (HF) represents a major and growing public health burden. Patients with HF are classically divided into two groups: those with HF with preserved ejection fraction (HFpEF), and those with HF and reduced ejection fraction (HFrEF). In the last two decades, the proportion of patients with HFpEF over HFrEF has increased from 38% to 54% out of cases of HF, a proportion that will continue to rise due to the progressive aging of population and expected increase in the prevalence of hypertension, obesity and diabetes. This pathology is most prevalent among elderly women. Diastolic dysfunction plays a crucial role in HFpEF. This alteration is present at rest and trend to increase during exercise, stress test or cardiac pacing and are associated to abnormal increase in LV filling pressure. In contrast to HFrEF, no efficient specific drug therapy exists for HFpEF. Today, only few animal models of HFpEF have been proposed. Most of them consist in hypertension models that further develop LV hypertrophy and diastolic dysfunction, but none presents all hemodynamic characteristics of human HFpEF, and none has been used to test potential therapeutic tools.
Based on our previous results showing an increase in ß3-adrenergic receptor (ß3-AR) in human HF heart, we developed a new animal model of HFpEF. These rats overexpress ß3-AR in the endothelial cells. In normal conditions, ß3-AR is located both in heart and vessels where they induce a negative inotropic effect and a vasodilation, respectively, through activation of the NO pathway. The hemodynamic characterization of our transgenic 30 weeks-old rats both by echocardiography and pressure-volume loops has shown a cardiovascular phenotype close to human HFpEF and its analysis should lead to determine the pathophysiological mechanisms involved in the HFpEF disease. Our scientific program will be to complete the characterization of the animal model of HFpEF that we have developed and to identify specific molecular targets involved in the progression of the disease in order to develop new therapies in the future. To conduct this project, we have identified three tasks.
- Task 1. Characterization of the HFpEF phenotype of Tgß3 rats. We will evaluate if the severity of the pathology is correlated with gender and aging as in human disease. As the characteristics of the pathology are increased by stress in human, we will also determine if various stress conditions will enhance HFpEF disorders in our model.
- Task 2. Identification of molecular targets potentially involved in HFpEF. In function of the results of the first part of Task 1, this study will be performed only in males or in females at the most suitable age. This task will identify the genes up or downregulated in HFpEF by a transcriptomic approach and determine the involvement of ß-adrenergic, renin-angiotensin and endothelin systems as well as phosphodiesterases and cardiac metabolism abnormalities.
- Task 3. Identification of the roles of endothelium in HFpEF. Finally, as the animal model of HFpEF is based on the overexpression of ß3-AR specifically in the endothelium and ß3-AR are linked to the NO pathway, the aim of the third task will be to evaluate whether an alteration of the endocardial endothelium could be responsible for a cardiac dysfunction leading to HFpEF. This hypothesis is corroborated by recent data showing that the administration of arginine and/or citrulline in patients in HFpEF improves endothelial function by increasing NO liberation
This project, which combines basic research in cell, papillary muscle, isolated heart and rat models, molecular, biochemical and functional analyses ex vivo and in vivo, as well as complementary competences in hemodynamic, contractile activity, and electrophysiology should lead to rapid clinical applications. We expect to identify at least one putative target for developing a specific therapy for human HFpEF.