NAD+ Repletion Reverses Heart Failure with Preserved Ejection Fraction

Dan Tong, Gabriele G Schiattarella, Nan Jiang, Francisco Altamirano, Pamela A Szweda, Abdallah Elnwasany, Dong I Lee, Heesoo Yoo, David A Kass, Luke I Szweda, Sergio Lavandero, Eric Verdin, Thomas G Gillette, Joseph A Hill

Research output: Contribution to journalArticle

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. 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.

Original languageEnglish (US)
JournalCirculation Research
DOIs
StateE-pub ahead of print - Apr 22 2021

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