NAD+ Repletion Reverses Heart Failure With Preserved Ejection Fraction. Issue 11 (22nd April 2021)

• Record Type: Journal Article
• Authors: Tong, Dan; Schiattarella, Gabriele G.; Jiang, Nan; Altamirano, Francisco; Szweda, Pamela A.; Elnwasany, Abdallah; Lee, Dong I.; Yoo, Heesoo; Kass, David A.; Szweda, Luke I.; Lavandero, Sergio; Verdin, Eric; Gillette, Thomas G.; Hill, Joseph A.
• Is Part Of: Circulation research. Volume 128:Issue 11(2021)
• Page Start: 1629
• Page End: 1641
• Publication Date: 2021-04-22
• Subjects: acetylation -- cardiomyopathy -- heart failure -- mitochondria -- NAD; Cardiovascular system -- Periodicals; Blood -- Circulation -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; Sang -- Circulation -- Périodiques; Appareil cardiovasculaire -- Périodiques; 612.1
• DOI: 10.1161/CIRCRESAHA.120.317046
• Languages: English
• ISSNs: 0009-7330

Abstract

Abstract : Supplemental Digital Content is available in the text. 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.