ERA-CVD_JTC2019-055

HF-MetaB – Metabolic therapy of heart failure: which role for B vitamins

Principal Investigator: Alexandra Zahradníková jr.

Duration: April 2020 – March 2024
Coordinating Organization: INSERM, Paris Sud University, Laboratory of signalling and cardiovascular pathophysiology

Annotation:

Heart failure (HF) is a major cause of death worldwide. It is clear that profound modulations of energy metabolism are involved in the development of HF. This includes a drop in the cardiac levels of energy carrier compounds, ATP, Phosphocreatine, and nicotinamide adenine dinucleotide (NAD+), a major coenzyme in glycolysis and mitochondrial ATP generation. In this respect we previously showed, in a mouse model of cardiac pressure overload, the protective effect of diet supplementation with two vitamins (B12/B9) stimulating the mitochondrial biogenesis pathways, or with nicotinamide riboside (NR), a recently characterized vitamin B3 which is a NAD+ precursor. Inasmuch as these treatments were given before the appearance of the first symptoms of HF in these studies, we propose here to test the efficiency of a treatment with a cocktail of these 3 B vitamins in symptomatic HF in mice to propose an eventual curative use of these vitamins. Our primary aim will be to assess the impact of treatment on survival, exercise capacities, cardiac function, mitochondrial respiration and dynamics, calcium metabolism and metabolic fluxes. In a translational perspective toward clinics, we will also assess the impact of this vitamins B cocktail in the context of standard of care of HF (β-blocker, ACE inhibitor). Finally, it is critically important to consider the sex differences in treatment of HF. Therefore the second aim of the presented project is to compare the effect of the treatment in males and females that differ as regards alteration in mitochondrial and calcium metabolism in HF.

Keywords:

heart failure, energy metabolism, mitochondria, calcium signalling, metabolic therapy, B vitamins

Objectives:

The overall aim of the project is to assess the effect of metabolic therapy in mice with clinical signs of heart failure:

Effect of metabolic treatment alone on survival, exercise capacity, heart function and mitochondrial state.
Effect of metabolic treatment together with standard therapy of HF (β-blocker, ACE inhibitor).
Difference in the effect between the sexes.

Publications:

Baglaeva I, Iaparov B, Zahradnik I, Zahradnikova A (2023). Analysis of noisy transient signals based on Gaussian process regression. Biophys J 122: 451–459. doi: 10.1016/j.bpj.2023.01.003.