Ketone body supplementation attenuates myocardial fibrosis in an experimental model of sepsis

Abstract Background Cardiac dysfunction associated with sepsis, known as septic cardiomyopathy, involves multiple pathways of myocardial injury, culminating in structural and functional changes to the heart, called cardiac remodeling (CR). In this context, the availability of energy substrates plays a fundamental role. Ketone bodies, especially β-hydroxybutyrate (BHB), stand out as an alternative source of energy for the myocardium, especially when the use of fatty acids and glucose becomes insufficient, as occurs in CR. Thus, supplementation with ketone bodies appears as a potential therapeutic strategy to reduce the effects of cardiac dysfunction in sepsis. Purpose To evaluate the effect of ketone body supplementation on CR and mortality in the sepsis model induced by cecal ligation and puncture (CLP) in rats. Methods Wistar rats were subjected to sepsis using the CLP method, and subsequently allocated into 4 groups: sham (C), sham with ketone body supplementation (CBHB), control sepsis (S), and sepsis with ketone body supplementation (SBHB). ketone bodies were administered via gavage, daily after sepsis induction, at a dose of 10g/kg/day, applied at two times of the day. After 7 days, the animals underwent echocardiography, heart isolation study, euthanasia, and subsequently morphometric, and biochemical studies. Statistical analyses: Generalized linear model (GLM) (p0.05). Results The mortality of animals subjected to sepsis was 88.6%. Animals treated with ketone bodies showed an increase in ketosis compared to those without supplementation C= 0.7±0.1 vs. CBHB= 2.0±0.7 vs. S= 0.7±0.2 vs. SBHB= 1.7±0.9 p0.001, demonstrating effectiveness of the dose. Regarding echocardiographic variables, sepsis resulted in an enlargement of the left atrium C= 16.4±1.5 vs. CBHB= 18.7±2.5 vs. S= 19.0±2.8 vs. SBHB= 17.1±3.2 p=0.002 and mean S C= 4.0±0.3 vs. CBHB= 3.9±0.3 vs. S= 3.8±0.2 vs. SBHB= 3.7±0.3 p= 0.022. In the in vivo study with isolated heart, a reduction in the positive derivative was observed in the septic condition C= 5417±1697 vs. CBHB= 5417±1872 vs. S= 4125±177 vs. SBHB= 3438±884 p=0.043. Furthermore, the protein expression of ASC, a component of the inflammasome pathway, was increased in septic animals C=1.5±0.8 vs. CBHB= 1.3±0.9 vs. S=1.9±1.6 vs. SBHB= 2.8±1.2 p=0.039. In the morphometric study, myocytes showed a tendency to reduce in size C= 256±35.7 vs. CBHB= 243±27.9 vs. 400±78.8 vs. 324±56.3 p=0.050, in SBHB group compared with S group, while the percentage of collagen decreased in animals treated with ketone bodies C= 2.8±0.4 vs. CBHB= 2.7±0.5 vs. S= 4.4±0.7 vs. SBHB= 2.5±0.5 p0.001. Conclusion Ketone body supplementation attenuated myocardial fibrosis in sepsis. The mechanisms related to these features were not yet determined.Figure 1.Representative