Effect of beta-hydroxybutyrate on isolated myocardium contractility in rat models

Background

In patients with heart failure, there has been observed an increase in utilisation of beta-hydroxybutyrate (3-OHB), which is known to increase cardiac output, but the underlying mechanism of this effect remains unclear. The observed hemodynamic benefit may result from decreased systemic vascular resistance and/or increased myocardial contractility. The authors' focus was on the possible positive inotropic effect. We investigate this effect using isolated myocardial trabeculae mounted in the Mayflower horizontal tissue bath system for isometric contraction force measurement.

Objectives

This study aimed to investigate the inotropic effect of 3-OHB on the contractility of isolated myocardial trabeculae from healthy rats and rats with established myocardial infarction. Furthermore, we compared both baseline contractility and the magnitude of the 3-OHB-induced response between studied groups.

Methods

Normotensive male HanSD rats were divided into two groups: a healthy control group (n=8) and a group with established myocardial infarction (n=8) induced by permanent ligation of the left anterior descending (LAD) coronary artery at 13 weeks of age. At 20 weeks, left ventricular trabeculae were isolated and mounted in an organ bath containing a perfusion solution maintained at 37 °C, with electrical stimulation applied at 1 Hz and subsequently across a frequency range of 0.5–5 Hz. Twitch force was recorded under baseline conditions (without any added substrates) and after the application of 1 mM 3-OHB.

Results

In controls stimulated at 1 Hz, 3-OHB increased twitch force from 0.86 ± 0.07 to 1.34 ± 0.10 cN (+55.8%; p <0.0001). In infarcted rats, twitch force rose from 0.59 ± 0.11 to 0.80 ± 0.14 cN (+35.6%; p = 0.0004). Baseline twitch force was higher in controls than in infarcted rats (+45.8%; p = 0.002), and the 3-OHB-induced effect was also more significant in controls (+67.5%; p <0.0001).

Conclusion

Beta-hydroxybutyrate significantly increased contractile force in both groups, however the effect is greater in the control group. Based on these results, 3-OHB could potentially present as a novel treatment option in conditions associated with decreased myocardial contractility and serve as an alternative to traditional inotropic drugs.

In addition to these results, we aim to explore the underlying mechanism of the observed inotropic effect of 3-OHB. We investigated whether the increase in contractility is mediated by enhanced myocardial bioenergetics or by activation of G-protein–coupled receptor signaling with subsequent cAMP production. The inotropic effect of 3-OHB persisted despite pharmacological inhibition of cAMP signaling using 2,5-dideoxyadenosine. This suggests a predominantly metabolic mechanism, although further studies are required.Control group twitch forceFor image description, please refer to the figure legend and surrounding text.MI group twitch forceFor image description, please refer to the figure legend and surrounding text.