The Heart has Intrinsic Ketogenic Capacity that is Facultatively Upregulated in Heart Failure with Preserved Ejection Fraction

ABSTRACT: Heart Failure with preserved Ejection Fraction or ‘HFpEF’ is now the most common type of heart failure worldwide, with considerable morbidity and mortality, and with no effective pharmacotherapies1. For the first time, we show that the human and murine HFpEF heart have impaired uptake of ketone bodies, and reveal an intrinsic capability of human and murine hearts to generate their own ketones via the canonical rate-limiting ketogenic enzyme, 3-hydroxy-3-methylglutaryl CoA synthase 2 (HMGCS2). We demonstrate that protein levels of HMGCS2 are dramatically elevated in HFpEF myocardium that does not overcome reduced specific activity of this enzyme, due to hyperacetylation caused by depletion of the de-acetylating enzyme sirtuin 3 and decreased oxidized/reduced nicotinamide adenine dinucleotide (NAD+/NADH) ratio, upon which the deacetylation activity of sirtuins is dependent. For the first time, we show that the canonical stimuli that serve to turn on ketogenesis in the liver are also present locally in the HFpEF heart, enhanced by a profound energy deficiency as determined by depleted phosphocreatine/ adenosine triphosphate (PCr/ATP) ratio. Thus, metabolically inflexible HFpEF hearts try to auto-regulate their energy supply by upregulating ketogenesis as an apparent “rescue strategy”. These results serve to reframe our understanding of cardiac ketone metabolism and open opportunities for novel therapeutic strategies for HFpEF, which are urgently needed.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Travis Ruan  

LAB HEAD: Mark Larance

PROVIDER: PXD026582 | Pride | 2025-05-26

REPOSITORIES: Pride