Abstract

--- - "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.