Heart failure (HF) is the end stage of major cardiovascular diseases and a common cause of death and disability worldwide. Several pathogenetic mechanisms contribute to HF development and progression. Among them, recent evidence undercores the mitochondrial dysfunction as one of the most relevant by its ability to increase oxidative stress, reduce ATP production and ultimately accelerate cell damage and death. Mitophagy, an autophagic process devoted to the removal of dysfunctional and damaged mitochondria to allow an adequate cell response to stress stimuli, is reduced in HF.
Natriuretic peptides (NPs) are cardiac hormones that play several beneficial hemodynamic and cellular functions in the cardiovascular system. Among their cellular effects, they stimulate the process of autophagy, in order to remove damaged cells, at both cardiac and vascular level. NPs increase in HF and they help maintain the hemodynamic homeostasis in this condition. It is likely that an enhancement of the cellular effects contributes to explain the protective role of NPs in HF.
A novel class of drug, Angiotensin Receptor Neprilysin inhibitor (ARNi), has been introduced for the treatment of HF patients with reduced systolic function. This drug increases NPs level by reducing their catabolism, therefore enhancing the cardiovascular beneficial properties of these hormones in HF.
Our study will explore the relationship between NPs and preservation of mitochondrial function. In particular, we will analyze: 1) in vitro, the impact of atrial natriuretic peptide on mitochondrial function and mitophagy in circulating leucocytes (PBMCs) of HF patients; 2) in vivo, the impact of increased NPs level upon ARNi treatment on parameters of mitochondrial function and dynamics in HF patients.
Our investigation will reveal novel aspects of the protective function of NPs in HF, and it will provide detailed mechanistic information to explain the beneficial effects of ARNi treatment in HF patients.
The role of mitochondrial dysfunction in the context of CVDs, including HF, is a current matter of research. We are progressively becoming aware of the implications that this mechanism exerts in the pathogenesis of HF and of the need to focus on mitochondria as a therapeutic target. Of note, an additional disease mechanism involved in the pathogenesis of CVDs has been recently discovered, that is the process of autophagy and, when referred to mitochondria, of mitophagy. It allows the removal of damaged cells/organelles to protect cells from stress stimuli. A defective auto/mitophagic mechanism contributes to CVDs pathogenesis and progression.
A known mechanism strictly related to the development of HF is the activation of the cardiac NPs. These cardiac hormones play beneficial systemic and cellular effects within the cardiovascular system. Among the cellular effects, based on ongoing research of our laboratory, they are able to stimulate authophagy at both cardiac and vascular level as a defensive response toward stress stimuli.
Nowadays, a novel compound, sacubitril/valsartan, defined as Angiotensin Receptor Neprilysin inhibitor (ARNi), in view of its ability to block the renin-angiotensin system downstream and to enhance NPs activation, has been introduced in the clinical practice for the treatment of HF with reduced ejection fraction. In spite of reasonable but still hypothetical mechanisms through which ARNi improves cardiovascular outcome in HF, there are several areas of uncertainties such as the modest rise of NPs in blood upon ARNi treatment. This observation points to the need to explore further the basis of the protective role of NPs in HF. In this regard, our study will explore for the first time whether ARNi, through the consequent increase of NPs, particularly of ANP, promotes autophagy and mitophagy and improves mitochondrial function in HF patients. Along with the known NPs hemodynamic properties, this effect would contribute to ameliorate the cardiovascular health and the clinical disease manifestations.
The results of our study may provide novel original and clinically relevant information on the impact of NPs on mitochondrial health in HF and may illustrate potential new therapeutic avenues for the management of HF patients.