NAD(+) repletion reverses heart failure with preserved ejection fraction

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. Down-regulation 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 HFpEF patients. 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.