NAD ⁺ Repletion Reverses Heart Failure With Preserved Ejection Fraction

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.

Modulating Sirtuin Biology and Nicotinamide Adenine Diphosphate Metabolism in Cardiovascular Disease—From Bench to Bedside

“…Another promising NAD + booster candidate is NR. NR fueled the NAD + pool and exerted protective effects in experimental mouse models of HFrEF and HFpEF (Diguet et al, 2018;Tong et al, 2021). NR, whether given in a preventive or in a treatment context, conferred beneficial effects on liver steatosis by upregulating Sirt1 expression and replenishing NAD + concentration (Gariani et al, 2016).…”

GCN5L1 promotes diastolic dysfunction by inhibiting cardiac pyruvate oxidation

“…We found that PDH activity was significantly increased in mitochondria from KO mice on a HFD relative to both WT diet groups ( Figure C ). Elevated PDH enzyme activity is typically associated with decreased inhibitory phosphorylation at Ser-293 [2] , however we detected no difference in PDH phosphorylation between WT and KO mice on either diet ( Figure C ). Instead, we found a significant increase in PDH hyperacetylation in HFD-fed WT mice relative to LFD controls, and a significant decrease in PDH acetylation in both KO diet groups ( Figure C ).…”

“…Deleterious changes in energy metabolism underpin the development of heart failure with preserved ejection fraction (HFpEF) [1] . Studies on two recently developed murine models of HFpEF have reported altered cardiac fuel substrate utilization, culminating in changes to the relative oxidation rates of fatty acids, ketone bodies, and glucose in failing hearts [2,3] . These two distinct murine HFpEF models are also characterized by increased mitochondrial protein acetylation, a reversible posttranslational modification that is commonly linked to reduced metabolic enzyme activity [2,3] .…”

“…No changes were observed between WT and KO mice in either morphological parameters (LVEDV and LVEDPW) or systolic function (LVEF) on either diet ( Figure A ). In contrast, WT mice displayed a significant increase in E/e’ ratio (a marker of HFpEF-related diastolic dysfunction [2] ) on a HFD, which was absent in acetylation-deficient GCN5L1 KO mice ( Figure A ).…”

“…To understand which fuel metabolism pathways may be disrupted in mice with diastolic dysfunction, we performed Oroboros respirometry in mitochondrial-enriched cardiac tissue preparations from HFD-fed WT and KO mice. Previous reports have shown that fatty acid oxidation is significantly modified in hyperacetylated mitochondria from HFpEF mice [2,3] . Surprisingly, ADP-stimulated state 3 respiration was not different between WT (hyperacetylated) and KO (hypoacetylated) samples provided with palmitate as a fuel substrate ( Figure B ).…”