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 journalArticlepeer-review

50 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1629-1641
Number of pages13
JournalCirculation Research
Issue number11
StatePublished - May 28 2021


  • NAD
  • acetylation
  • cardiomyopathy
  • heart failure
  • mitochondria

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


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