Mitochondrial Dynamics in Heart Failure with Preserved Ejection Fraction

• Grant number: 22/10579-5
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: December 01, 2022
• End date: November 30, 2024
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Itamar Couto Guedes de Jesus
• Grantee: Raphael Prando D'Elia
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Heart failure (HF) is the leading cause of morbidity and mortality worldwide. Patients with HF are classified into two subgroups, those with HF with reduced ejection fraction (HFrEF) and those with HF with preserved ejection fraction (HFpEF). For decades, practically all clinical and academic attention has been focused on understanding HFrEF due to the ease of diagnosis and high degree of morbidity and mortality among patients, thus, there has been little progress in understanding the pathophysiology of HFpEF. Recently, epidemiological studies have shown that mortality and hospitalization rates, as well as the quality of life of patients with HFpEF are similar to those with HFrEF. In fact, HFpEF is responsible for 50% of HF cases, being more prevalent in women and the elderly. In general, the onset of HFpEF is associated with the presence of some comorbidities such as arterial hypertension, diabetes, chronic kidney disease and obesity, which seems to favor structural and functional changes characteristic of the syndrome such as ventricular remodeling, cardiac diastolic dysfunction, exercise intolerance, retention of fluid and reduced longevity. However, little is understood about the molecular mechanisms involved in the establishment and progression of HFpEF, making it difficult to develop effective and specific therapeutic strategies to combat this syndrome. Recently, knowledge about the pathophysiology of HFpEF has established that in addition to the cardiac hemodynamic and morphological disorders associated with the disease, mitochondrial alterations are present in the heart of patients with HFpEF. However, little is known about the process of mitochondrial dynamics, characterized by the process of mitochondrial fusion and fission, in the heart in a model of HFpEF. Therefore, in order to better understand the mitochondrial biology in HFpEF, we propose in this research project to characterize cardiac mitochondrial dynamics and bioenergetics in an experimental model of HFpEF. In this study, HFpEF will be induced in C57BL6 female mice through the combination of a high-fat diet (60%) and chronic infusion of Angiotensin II (2mg/kg/day) for 12 weeks, as previously standardized in our laboratory. To characterize mitochondrial dynamics and bioenergetics, we will evaluate the protein expression profile of enzymes involved in mitochondrial dynamics in the heart of animals. We will also evaluate oxygen consumption and hydrogen peroxide release from mitochondria isolated from the heart of mice with HFpEF and their respective controls. This study becomes important since a more detailed understanding of mitochondrial dynamics in HFpEF may contribute to the clarification of the pathophysiology of HFpEF and, thus, direct future therapeutic targets that act on key mechanisms involved in the pathophysiology of HFpEF. Finally, this work will have the collaboration of Prof. Dr. Julio Cesar Batista Ferreira (ICB-USP) and Dr. Luiz Roberto Grassmann Bechara (ICB-USP). It is worth mentioning that most of the aforementioned experimental procedures are already standardized by the research group involved in this proposal, favoring the feasibility of the project within the proposed period for the scientific initiation grant.