Linking Ketone Metabolism and Signaling in Heart Failure with Preserved Ejection Fraction

Introduction

Heart failure with preserved ejection fraction (HFpEF) is a burgeoning public health problem for which there are little to no evidence-based therapies. This syndrome has proven particularly challenging because of the limited insight into its underlying molecular mechanisms.

Metabolic Adaptations

Metabolic adaptations are critical for cardiomyocyte response to stress. Ketones are metabolites actively produced in heart failure, and their role as a metabolic rheostat capable of modulating cardiac metabolism and cardiomyocyte signaling pathways has been postulated.

Research Gap

However, there is a fundamental, open gap in understanding how ketones are utilized as a source of energy in HFpEF and how β-hydroxybutyrate (β-OHB) – the most abundant ketone – plays a role as a non-energy carrier governing cardiomyocyte function.

Hypothesis

In this project proposal, I hypothesize that:

1. Ketones are major regulators of cardiomyocyte biology, representing an alternative source of fuel in HFpEF (“energy” role).
2. Ketones act as protein modifiers through β-hydroxybutyrylation – a lysine-based post-translational modification (PTM) – thereby regulating chromatin architecture, gene transcription, and metabolic signaling in cardiomyocytes (“non-energy” role).

Project Aim

The overall aim of KetoCardio is to define mechanisms integrating ketone metabolic adaptation with signaling pathways and epigenetic changes in HFpEF-stressed cardiomyocytes.

Methodology

Coupling proteomics, transcriptomics, and genomics approaches together with cardiac and systemic metabolic evaluation and rigorous preclinical experimental modeling of HFpEF, I will be able to define the previously unrecognized role(s) of ketones as energy substrates in HFpEF and as substrates for protein PTM impacting cardiomyocyte function.

Conclusion

In summary, focusing on metabolic pathways that govern cardiomyocyte abnormalities in preclinical HFpEF, this project will provide a transformative molecular understanding of ketone biology in cardiomyocytes, fostering innovation in the field and beyond.