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

Abstract

Abstract 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 as ketones are a more energy efficient resource than carbohydrates or fatty acids. Favorable energetic properties of ketones may potentially mitigate the energy starved state in T2D and heart failure (HF). Purpose To test whether exogenous oral ketone supplementation would reverse cardiac energetic deficit, as well as improve cardiac function and perfusion in patients with T2D, with HF with reduced ejection fraction (HFrEF), and healthy volunteers (HV). Methods Three groups of patients were recruited: patients with T2D (n=33); patients with HFrEF (n=29, 14 with T2D); and HVs(n=25). Participants underwent cardiovascular magnetic resonance and spectroscopy to assess left ventricular (LV) function, rest and dobutamine stress perfusion and energetics (phosphocreatine/adenosine triphosphate ratio[PCr/ATP]). After the initial visit, participants had an identical second visit following 2 weeks of oral ketone supplementation (30g daily). Results Participants were matched in age and sex distribution. There were no significant differences in LV ejection fraction (LVEF) between T2D and HV groups with significantly lower LVEF in HFrEF group. Both the T2D group and the HFrEF group showed significant reductions in PCr/ATP ratio and the rest and stress GLS compared to the HV. The resting and dobutamine-stress myocardial blood flow (MBF) were only significantly reduced in patients with HFrEF compared to T2D and HV groups. Subgroup analyses of HFrEF group with and without T2D showed no significant differences in energetics, perfusion, or functional assessments. Significant increase in PCr/ATP ratio was seen only in T2D group from baseline after 2 weeks of ketone 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 HV groups. Two weeks of ketone supplementation was not associated with any significant changes in LVEF, GLS, rest or dobutamine-stress myocardial blood flow, or in myocardial lipid content (Table-1). Conclusions Short-term ketone supplementation is associated with isolated significant improvements in resting cardiac energetics in patients with T2D and preserved LVEF, without changes cardiac function or perfusion. In contrast to patients with T2D and preserved LVEF, short-term ketone supplementation does not lead to any significant improvements in 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.