Oral Abstract Session

SCMR 22nd Annual Scientific Sessions

3 - In the Fasted State and Following Nicotinic Receptor Agonism, Inadequate Glucose Oxidation Decreases Left Ventricular Energetics and Reduces Systolic Function

Presenter(s)

• 

  William Watson, BSc

  Clinical Research Fellow
  University of Oxford

Author Only(s)

• KT

  Kerstin Timm, PhD

  BHF Immediate Postdoctoral Basic Science Research Fellow
  University of Oxford
• KC

  Kieran Clarke, PhD

  Professor of Physiological Biochemistry
  University of Oxford
• 

  Stefan Neubauer, MD

  Director, Oxford Centre for Clinical Magnetic Resonance Research
  University of Oxford
• DT

  Damian Tyler, PhD

  Professor
  University of Oxford
• OR

  Oliver Rider, PhD

  Associate Professor of Cardiovascular Medicine
  University of Oxford

Background:

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.

Methods:

Human Study

Fasted participants (average age 24±2yrs, m/f=7/4) with no cardiac risk factors underwent CMR imaging (1.5T) before and 4 h after substrate manipulation.  Circulating FFA levels were elevated using a triglyceride infusion (60 mL/hr, 20% Intralipid™/ heparin 0.4 U/kg per min) or lowered using nicotinic acid (400mg).  

Animal Studies

Male Wistar rats (n=16) were randomised to fasting and injections of saline or acipimox (to reduce FFA) or fed chow then underwent hyperpolarized [1-¹³C]pyruvate MRS to measure glucose oxidation.  

Results:

Human Study

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).

Animal Studies

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).

Conclusion:

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.