ABSTRACTAlterations in cardiac fuel metabolism underpin the development of heart failure with preserved ejection fraction (HFpEF). Mouse models of HFpEF, in addition to changes in fuel choice, display elevated levels of mitochondrial protein acetylation. Reversal of mitochondrial hyperacetylation restores cardiac bioenergetics and function. In this study, we examined the metabolic mechanisms of diastolic dysfunction in diet-induced failing hearts, using a model of constitutively-reduced mitochondrial protein acetylation.
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.
For many with heart failure, including the elderly and those with a preserved ejection fraction, both risk stratification and treatment are challenging. For these large populations and others there is increasing recognition of the role of cardiac fibrosis in the pathophysiology of heart failure. Galectin-3 is a novel biomarker of fibrosis and cardiac remodelling that represents an intriguing link between inflammation and fibrosis. In this article we review the biology of galectin-3, recent clinical research and its application in the management of heart failure patients.
Inhibitory Acetylation of Pyruvate Dehydrogenase Promotes Diastolic Dysfunction in Mice
