138 Effects of exogenous ketone supplementation on cardiac energetics, steatosis, function, and perfusion in type 2 diabetes, heart failure, and healthy participants- a single center, open labelled clinical study

Background Type 2 diabetes (T2D) confers loss of cardiac metabolic flexibility in fuel selection and impaired mitochondrial function. Enhanced ketone metabolism observed in T2D may represent a compensatory adaptive mechanism. This is because ketones are a more efficient energy resources than carbohydrates or free fatty acids. Favorable energetic properties of ketones may potentially mitigate the energy starved state in T2D and heart failure. Purpose To test the hypothesis that exogenous oral ketone supplementation with ketone ester drinks would reverse cardiac energetic deficit and reduce myocardial lipid accumulation, as well as improving cardiac function and perfusion in patients with T2D and in patients with heart failure with reduced ejection fraction (HFrEF) and in healthy volunteers (HV). Methods In this single center, open labelled, cohort study we have recruited 3 groups of participants including patients withT2D (n=33); patients with HFrEF (n=29, 14 with T2D); and HVs (n=25). All participants underwent baseline blood tests, cardiovascular magnetic resonance imaging (MRI) and spectroscopy scans to assess left ventricular (LV) function, rest and dobutamine stress perfusion and energetics (phosphocreatine/adenosine triphosphate ratio PCr/ATP) and intramyocardial lipid content. After the initial scans following a 2 weeks of oral ketone ester supplementation (30 g daily) all participants were invited for an identical second research scan visit. Results Participants were matched in age and sex distribution, systolic and diastolic blood pressures (table-1). Resting heart rates were significantly lower in HV compared to the other two groups. At baseline, both compared to controls and compared to patients with T2D, the HFrEF group showed significantly lower LV ejection (LVEF); while there was no significant difference in LVEF between patients with T2D and controls. However, both the T2D group and the HFrEF group showed significant reductions in PCr/ATP ratio and the rest and dobutamine stress GLS compared to the HV (table 1). The numeric differences in myocardial lipid content did not reach statistical significance between the three groups. The resting and dobutamine-stress myocardial blood flow were only significantly reduced in patients with HFrEF compared to both the T2D and the HV groups. In parallel, the myocardial scar percentage was highest in the HFrEF group 22 (76%) had myocardial scar, all of which was non-ischemic. Subgroup analyses of the HfrEF patients with and without T2D showed no significant differences in energetics, perfusion, or functional assessments. A significant increase in PCr/ATP ratio was seen only in T2D group from baseline after 2 weeks of ketone ester supplementation Visit-1:1.6(1.5,1.8) vs Visit-2:1.9(1.7,2.1); P=0.01. This significant increment was not observed in HFrEF or control groups. Two weeks of ketone ester supplementation were not associated with any significant changes in LVEF, GLS, rest or dobutamine-stress myocardial blood flow, or in myocardial lipid content (table 2). Conclusions Short-term exogenous ketone supplementation is associated with isolated significant improvements in resting cardiac energetics in patients with T2D, without accompanying changes in rest or stress cardiac function, perfusion, or myocardial lipid content. In contrast to patients with T2D and preserved LVEF, short-term exogenous ketone supplementation does not lead to any significant improvements in rest or dobutamine stress energetics in patients with HFrEF suggesting loss of mitochondrial plasticity with transition to HFrEF. Moreover, healthy volunteers experience no further increments of myocardial energetics from the normal range values at baseline with ketone supplementation. Conflict of Interest None