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Ketones’ impact on a dysmetabolic rat model of heart failure with preserved ejection fraction
Session:
Comunicações Orais - Sessão 16 - Ciência Básica
Speaker:
Alexandre Gonçalves
Congress:
CPC 2023
Topic:
O. Basic Science
Theme:
36. Basic Science
Subtheme:
36.6 Basic Science - Other
Session Type:
Comunicações Orais
FP Number:
---
Authors:
Alexandre Gonçalves; Daniela Miranda; Cláudia Mendes; Carolina Silva; Inês Alves; Panagiotis Peppas; Mónica Zuzarte; Alexandre Rodrigues; Liliana Leite; José Sereno; Maria Vidigal; Adelino Leite-Moreira; Henrique Girão; Vasco Sequeira; Inês Falcão-Pires
Abstract
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Heart Failure with Preserved Ejection Fraction (HFpEF) affects 1.1-5.5% of the general population whilst being associated with poor prognosis and hospitalization. This is particularly concerning given that, until very recently, pharmacological options were extremely limited. While the specific mechanisms through which these drugs reduce all-cause mortality remains unknown, data from the recent EMPEROR-Preserved trial has shown associations with increased ketone levels that may be key to the effects observed. </span></span><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Previous studies have shown that increasing ketone levels may have beneficial effects on cardiovascular field, but their potential impact on HFpEF remains unknown. In this study, we explore ketone increase as a potential therapeutical option for HFpEF.</span></span></p> <p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">To this end, at 16 weeks of age, 30 ZSF1 Lean (Controls) and 30 ZSF1 Obese rats (a well characterized dysmetabolic HFpEF animal model), were randomly assigned to remain on control diet, change to a ketogenic diet (KD) or keep the regular chow whilst having ketone salts (KS) delivered through drinking water. Glucose and B-hydroxybutyrate levels were monitored throughout the study. Metabolic and functional assessments including oral glucose tolerance test, VO2max, echocardiography and PET/CT were conducted throughout the protocol, culminating with terminal procedures at 23-30 weeks of age. Fresh samples were used to study mitochondrial respiration and assess isolated cardiomyocyte function. </span></span></p> <p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">By 23 weeks of age, baseline hyperglycaemia was reduced by up to 48% with KD and KS on these diabetic HFpEF rats, while glycaemic tolerance was improved only under the KD. By itself, HFpEF appears to promote 11-Acetoacetate uptake similarly to both treatments under control conditions, hinting at the metabolic shift that must be occurring on the starving HFpEF hearts. Importantly, both KD and KS were shown to significantly reduce HFpEF-associated cardiac fibrosis and hypertrophy. The extent of these changes was further studied on isolated cardiomyocytes, where we observed improvements in calcium handling with KS (peak Ca2+ to 90% baseline) and contractile function with both therapies (time to peak, peak height, baseline sarcomere length and Tau). Lastly, these changes seemed to be accompanied by a significant reduction in cardiac complex II mitochondrial respiration on HFpEF with KS, which might constitute a defence mechanism against oxidative stress.</span></span></p> <p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Taken together, our data seem to suggest that increased ketone levels may alleviate or even reverse some of the cardiometabolic impairments associated with the HFpEF phenotype in this rat model and our follow-up studies may shed further light on this potential.</span></span></p>
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