SAMβA: a novel therapeutic strategy for heart failure with preserved ejection fraction (HFpEF).

Author(s)

Lisley Santos Ramalho

• Document type: Master's Dissertation
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2022-08-01

Examining board members

Julio Cesar Batista Ferreira; Maria Luiza de Morais Barreto de Chaves; Fabiana de Sant'Anna Evangelista; Silvia Carolina Guatimosim Fonseca

• Advisor: Julio Cesar Batista Ferreira

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a multifactorial syndrome associated with high morbidity and mortality. Unfortunately, there are no effective therapies capable of improving HFpEF outcome. HFpEF patients display cardiac accumulation of fragmented and dysfunctional mitochondria. These findings raise the question whether cardiac mitochondrial fragmentation contributes to the pathophysiology of HFpEF, and whether selective therapies capable of inhibiting this excessive mitochondrial fragmentation have a positive impact on cardiac bioenergetics and the prognosis of HFpEF. We recently developed a peptide, termed SAMβA, capable of blocking the accumulation of fragmented mitochondria and improving, mitochondrial function and cardiac performance in an experimental model of heart failure with reduced ejection fraction. Thus, the objective of this dissertation is to develop a HFpEF preclinical model (combination of metabolic stress and hypertension) recapitulating the main clinical features of HFpEF, including impaired cardiac mitochondria connectiveness and metabolism. If confirmed the mitochondrial phenotype in HFpEF, we intend to test the long-term therapeutic effects of SAMβA. Our results demonstrate that a combination of high-fat diet and sustained L-NAME administration was effective in recapitulating many characteristics of HFpEF in rats, including elevated body weight, hypertension, dyslipidemia, cardiac hypertrophy, increased left ventricular mass, elevated B-type N-terminal natriuretic peptide (NT-proBNP) levels, mild diastolic dysfunction, exercise intolerance, and impaired skeletal muscle morphological and contractile properties. Cardiac mitochondria isolated from HFpEF rats displayed mild bioenergetics dysfunction without major changes in the size and number of mitochondria when compared with sham animals. Interestingly, we observed a significant impairment of cardiac mitochondrial calcium uptake and retention HFpEF rats. In conclusion, the experimental model of HFpEF described here did not recapitulate the phenotype of accumulation of fragmented mitochondria observed in HFpEF patients. We also described for the first time that cardiac mitochondrial calcium handling is impaired in this experimental model of HFpEF. These results open new perspectives for a better understanding of the role of mitochondria in controlling the cardiac calcium handling in HFpEF. (AU)

• FAPESP's process: 20/04006-7 - SAMbA: a novel therapeutic strategy for heart failure with preserved ejection fraction (HFpEF)
• Grantee: Lisley Santos Ramalho
• Support Opportunities: Scholarships in Brazil - Master