Increasing substrate supply to the heart as a therapeutic strategy in heart failure

Based on the dogma that that the heart is metabolically inflexible and oxygen starved in heart failure with reduced ejection fraction (HFrEF), drugs have aimed to increase glucose oxidation.

In pilot data, in severe HFrEF I show that the human heart retains flexibility, with fatty acid uptake and oxidation increased during Intralipid and glucose uptake and oxidation increased during glucose/insulin (G+I) infusion.

We also show that during Intralipid, contractility (LVEF by 6%, LV developed pressure by 8mmHg), ATP delivery (by 44%) and MVO2 (by 27%) are all higher than during G+I, where LV contractility was unchanged. Despite this, lactate was consumed, and PCr/ATP not reduced, showing oxygen supply was sufficient.

This suggests a second approach may be beneficial, i.e. increasing fatty acid oxidation.

As a result, I propose 1) an RCT of PPARa agonists in HFrEF, 2) a study of substrate flexibility in HFpEF and 3) to investigate the role of ketone supplementation in both HFrEF and HFpEF. If successful, this would provide evidence for a new, cost effective treatment in HFrEF.

This would also further our understanding of substrate flexibility in HFpEF, and the potential for clinical application of ketone supplementation, both of which may guide future drug development.