A9 - High-resolution Respirometry Reveals Enhanced Myocardial Mitochondrial Ketone Oxidation after Ventricular Unloading

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Support:The development of this supplement was funded by Abiomed.

Correspondence Details:Erik Zweck,

Open Access:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

Background: Myocardial mitochondrial function is impaired in heart failure. Both ventricular unloading and enhanced ketone body oxidation potentially exert protective effects on myocardial function and mitochondria but have not been linked to each other yet. The gold standard high-resolution respirometry (HRR) has not been used to determine myocardial mitochondrial ketone oxidation as yet.

Hypothesis: We hypothesised that quantification of myocardial ketone-supported oxidative capacity (OC) utilising ex vivo HRR is feasible; and that ketone-associated OC is elevated under conditions of chronic mechanical ventricular unloading.

Methods: We developed new HRR (Oxygraph-2k) protocols, measuring oxygen flux generated by oxidation of the ketone substrates beta-hydroxybutyrate (HBA) and acetoacetate (ACA). Ketone protocols were then applied to the left ventricular tissue of 10 C57BL/6 mice and 21 terminal heart failure patients, harvested at heart transplantation. Heart transplant recipients were subdivided into patients with left ventricular assist device prior to transplantation (UNLOAD group, n=9) or no unloading prior to transplantation (CON group, n=12).

Results: In rodent hearts, HBA alone yielded an OC of 25 ± 4 pmol/(s*mg wet tissue) above basal respiration (p<0.0001). When titrated after succinate, ACA increased OC by 93 ± 25 pmol/(s*mg) (p=0.0003). Study participants in UNLOAD and CON had comparable age and sex, while UNLOAD patients tended to have higher BMI (p=0.30, 0.34 and 0.10, respectively). There was no significant group difference in complex I-related or ACA-supported OC (p=0.09 and p=0.53), HBA-supported OC was 41% higher in UNLOAD compared to CON (34 ± 10 versus 48 ± 15 pmol/(s*mg), p=0.03). Overall, mitochondrial coupling efficiency was higher in UNLOAD (1.8 ± 0.6 versus 2.4 ± 0.5, p=0.02).

Conclusion: Quantification of ketone body OC with our novel method revealed increased HBA-supported myocardial mitochondrial respiration in chronically unloaded hearts. Our findings support a concept of cardioprotective effects of ventricular unloading via enhanced ketone oxidation in myocardial mitochondria, thus providing the failing heart an additional substrate as a fuel.