Oral Abstract Session
SCMR 22nd Annual Scientific Sessions
Heart failure is characterised by reduced fatty acid and glucose oxidation, energetic impairment and reduced systolic function. In this work, we first sought to use multiparametric CMR to (a) determine if altering glucose and free fatty acid (FFA) delivery to the normal human heart could alter myocardial energetics and reduce systolic function, and (b) if changes occurred, determine the underlying mechanisms by back translation into rodents.
Elevation of circulating FFA was associated with an increase in LVEF, (+5% p<0.001), but no change in myocardial energetics (PCr/ATP 2.16±0.33 vs. 2.09±0.35). In contrast, a decreased FFA was associated with decreased LVEF (-4%, p = 0.03), and lower PCr/ATP (2.16±0.40 vs. 1.78±0.14, p=0.04).
As in humans, low FFA in fasted rodents resulted in reduced LVEF (60±4 vs. 67±3, p=0.009) and cardiac index by 20% (p <0.001) compared to saline injection in fasted animals. Although glucose oxidation rate was four-fold higher in the acipimox group than the saline group (p=0.005), it was 40% lower than in the fed group (p=0.003, Figure 1) and, in the fasted animals, showed an inverse correlation with ejection fraction and cardiac index (R2=0.73, p=0.002).
We have shown that 1) in the fasted human heart, nicotinic acid receptor agonism impaired myocardial energetics and reduced systolic function, and 2) the mechanism of this fall appears to be insufficient upregulation of pyruvate dehydrogenase activity and glucose oxidation to prevent energetic impairment during fatty acid depletion. This proves the concept that substrate manipulation is related to function, provides a novel model for the energetically starved heart failure state, and provides evidence that PDH flux is a potential therapeutic target for heart failure.