Nicotinamide riboside supplementation improved mitochondrial function and reversed the HFpEF phenotype in mice, demonstrated by enhanced palmitoylcarnitine-mediated OCR and ameliorated diastolic dysfunction.
Does NAD+ repletion improve mitochondrial function and ameliorate the HFpEF phenotype in a preclinical mouse model?
NAD+ repletion improves mitochondrial function and ameliorates the HFpEF phenotype in a preclinical model, suggesting a potential novel therapeutic approach for HFpEF.
Effect estimate: OCR increase
Rationale: Heart failure with preserved ejection fraction (HFpEF) is a mortal clinical syndrome without effective therapies. We recently demonstrated in mice that a combination of metabolic and hypertensive stress recapitulates key features of human HFpEF. Objective: Using this novel preclinical HFpEF model, we set out to define and manipulate metabolic dysregulations occurring in HFpEF myocardium. Methods and Results: We observed impairment in mitochondrial fatty acid oxidation associated with hyperacetylation of key enzymes in the pathway. Downregulation of sirtuin 3 and deficiency of NAD + secondary to an impaired NAD + salvage pathway contribute to this mitochondrial protein hyperacetylation. Impaired expression of genes involved in NAD + biosynthesis was confirmed in cardiac tissue from patients with HFpEF. Supplementing HFpEF mice with nicotinamide riboside or a direct activator of NAD + biosynthesis led to improvement in mitochondrial function and amelioration of the HFpEF phenotype. Conclusions: Collectively, these studies demonstrate that HFpEF is associated with myocardial mitochondrial dysfunction and unveil NAD + repletion as a promising therapeutic approach in the syndrome.
Tong et al. (Thu,) conducted a other in Heart failure with preserved ejection fraction (HFpEF). Nicotinamide riboside (NR) vs. Placebo (untreated HFpEF mice) was evaluated on Improvement in palmitoylcarnitine-mediated oxygen consumption rates (OCR) in isolated mitochondria (OCR increase). Nicotinamide riboside supplementation improved mitochondrial function and reversed the HFpEF phenotype in mice, demonstrated by enhanced palmitoylcarnitine-mediated OCR and ameliorated diastolic dysfunction.