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Ketones: a new hope for heart failure with preserved ejection fraction (HFpEF)
Session:
Sessão de Comunicações Orais 02 – Perspectivas translacionais na Insuficiência Cardíaca: dos modelos experimentais ao prognóstico clínico
Speaker:
Alexandre Gonçalves
Congress:
CPC 2026
Topic:
D. Heart Failure
Theme:
36. Basic Science
Subtheme:
36.3 Basic Science - Cardiac Diseases
Session Type:
Comunicações Orais
FP Number:
---
Authors:
Alexandre Gonçalves; Inês N Alves; Cláudia Mendes; Daniela Miranda; João Almeida-Coelho; Diana Martins; Sandra Marisa Oliveira; José Sereno; Maria João Ferreira; Adelino F. Leite-Moreira; Vasco Sequeira; Inês Falcão-Pires
Abstract
<p style="text-align:justify"><strong>Introduction</strong><br /> Heart failure with preserved ejection fraction (HFpEF) presents a major therapeutic challenge that remains with limited therapeutic options. While ketones have shown beneficial effects on myocardial function in other cardiac pathologies, their impact on HFpEF pathophysiology remains to be elucidated. Beyond their metabolic role, ketones act as signalling molecules, capable of modulating inflammation, cardiac hypertrophy, and fibrosis. This study seeks to assess the efficacy of ketone elevation as a strategy for the management of HFpEF.<br /> <strong>Methods</strong><br /> At 16-week-old, when ZSF1 Obese rats already exhibit clear signs of HFpEF, we randomly assigned them to three subgroups: (1) control diet (CT), (2) ketogenic diet (KD), or (3) control diet with added exogenous ketone salts (KS) in their drinking water for 10 weeks (<strong>Figure 1A</strong>). During the weeks leading to the terminal procedures, the groups were subjected to echocardiography, PET/CT imaging for [11C]-Acetoacetate and [18F]-Fluorodeoxyglucose (FDG) and blood collection. At the terminal procedures, tissue samples were collected for biochemical work and histology. Hearts were perfused in order to isolate left ventricular cardiomyocytes for intact studies, while frozen left ventricular samples were used for permeabilized cardiomyocyte analysis.<br /> <strong>Results</strong><br /> We found that both KD and KS ameliorated the HFpEF phenotype by lowering glycaemia and lipid profiles (<strong>Figure 1B</strong>), modulating energy metabolism (<strong>Figure 1C</strong>), improving structural echocardiographic parameters, cardiac stress biomarkers, and reducing HFpEF-related fibrosis and hypertrophy, without impacting <em>in vivo</em> diastolic function (<strong>Figure 1D</strong>). Nevertheless, <em>ex vivo</em> cardiomyocyte preparations shown improved Ca<sup>2+</sup> handling and myofilament relaxation, suggesting benefits at the cellular level (<strong>Figure 1E</strong>). Both groups decreased myofilament Ca<sup>2+</sup>-sensitivity and normalized active and passive tension, especially KS (<strong>Figure 1F</strong>), in line with the reversed resting sarcomere length from intact unloaded tests (<strong>Figure 1E</strong>). Acute organotypic experiments suggested that these effects are driven by epigenetic modulation rather than solely by enhanced energetics.<br /> <strong>Conclusions</strong><br /> These results suggest that providing ketone through diet or supplements could be a valuable strategy to complement HFpEF treatment. Given the well-known challenges of implementing dietary changes, exogenous ketone salts offer a more practical and effective alternative to achieve these benefits.</p>
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