NAD+ precursor supplementation for metabolic therapy of heart failure – NAD-HEART

Context
Chronic heart failure (HF) is characterized by the inability of the cardiac pump to deliver enough oxygen and nutriments to the peripheral organs. Current therapy mainly targets the neurohormonal overdrive that is associated with this syndrome. Even with optimal treatment, mortality rates remain high, over 40% at 5 years. There is thus an urgent need for innovative approaches to halt or reverse the course of ventricular dysfunction leading to terminal HF.
One system, for which there is a major perturbation in the failing heart but few dedicated therapies, is the alteration of the bioenergetics systems. This defect is associated with mitochondrial dysfunction and altered energy transfer systems in the heart and ultimately in peripheral organs as well.
Several groups worldwide including partners in this consortium observed a loss of the nicotinamide adenine dinucleotide (NAD) in the failing heart of preclinical rodent models of HF. NAD is a major coenzyme in energy metabolism and an essential co-substrate of sirtuins and PARP enzymes that cleave NAD+ into nicotinamide (NAM) and ADPribose to regulate energy metabolism and oxidative stress response.

Preliminary results leading to this project
This consortium gathers scientists and clinicians with strong experience in cardiovascular research. We found that the NAM recycling pathway mediated by the NAMPT enzyme, which is important to maintain cellular NAD+ levels, is depressed in the failing heart. In contrast, we observed in murine and human failing hearts, an induction of the NMRK2 kinase that uses the alternative NAD+ precursor nicotinamide riboside (NR). NR is a vitamin B3, present in trace amounts in some foods, with superior bioavailability compared to other precursors. Our preclinical data show that NR treatment efficiently limits the drop in left ventricle (LV) ejection fraction and blocks cardiac dilatation in mouse models of dilated cardiomyopathy. Moreover, metabolomics analyses on HF patients’ sera show alterations of circulating levels of NAM compared to healthy age-matched controls.

Objectives
In this translational research project, we aim to characterize the alterations of NAD metabolism in human failing heart and to optimize the use of NR as a specific precursor of NAD to treat HF.
We will:
i) characterize perturbations of NAD metabolism and signalling in human HF at the cardiac level. We will analyse different markers in LV tissues from HF patients (with different origins of HF) and control donors who died from non-cardiovascular causes (expression level of enzymes from the NAD biosynthetic and signalling pathways, NAD-dependent post-translational modifications of proteins, NAD+ and NADH levels).

ii) validate the impact of NR treatment on preclinical models of HF using two types of models: Rodent models of HF (DCM and myocardial infarction) and human induced pluripotent cells from control and DCM patients differentiated into cardiomyocytes (impact on NAD levels, energetic substrate use and oxidative metabolism and NAD signalling).

iii) use targeted metabolomics assays for the detection of NAD metabolome alterations (precursors, and waste products coming from NAD+ catabolism) to identify surrogate markers of NR treatment efficiency for future clinical trials

iv) prepare the clinical protocol and initial review application for a phase II clinical trial assessing the efficiency of NR for the treatment of HF.

Expected results- 12 clinical trials with NR are already on going in different field of research including metabolic syndrome and skeletal muscle ageing but none yet in HF. In the first phase I trial published, the NR vitamin was shown to be highly bioavailable in humans and well tolerated. Our project will lay robust bases to identify patients more likely to benefit from NR supplementation and to design a phase II clinical within the next 3 years that will be the next step at the completion of this translational project.