81 Increased myocardial fat supply enhances cardiac function in normal hearts and in heart failure

Abstract

Introduction The failing heart is starved of energy, in part accounting for its contractile dysfunction. Energy supply is dependent upon metabolism of fat and glucose, hence altering metabolism of glucose and/or fat within the myocardium is therefore attractive as a therapeutic strategy for heart failure. We hypothesized that increasing supply of glucose in the failing heart would be beneficial over increasing fat supply and designed a multiparametric assessment to compare the two interventions in a heart failure group. Methods 10 healthy volunteers were recruited as a control group: mean age 41 (range 24-79), mean BMI 23.4 (range 20.6-27.1), F:M 7:3. 8 patients with clinical diagnosis of heart failure and nonischaemic cardiomyopathy were recruited, mean age 65 (range 49-79), mean BMI 26.5 (range 21.3-37.5), F:M 3:5. On the first visit, participants had a baseline cardiac magnetic resonance (CMR), collecting cardiac volumes and function, then were randomised to receive either a 60ml/H intralipid infusion or a hyperinsulinaemic euglycaemic clamp (40mU/kg/min). Following an hour of infusion, CMR was repeated followed by 31P cardiac magnetic resonance spectroscopy (MRS) for PCr/ATP ratio and creatine kinase flux, then a dobutamine stress sequence targeting 65% of maximum heart rate. Results Data was normally distributed. See tables 1 and 2. In the control group, ejection fraction was significantly higher in those receiving intralipid infusion. PCr/ATP was not significantly different, however there was a rise in creatine kinase first order rate constant and creatine kinase flux. The mean baseline ejection fraction in the heart failure group was 37 ± 9 %. Intralipid elevated ejection fraction over the baseline by 6.2 ± 6 % compared to euglycaemic clamp in which there was no significant difference (+0.1 ± 3.6 %, p = 0.004 vs change in intralipid group). With intralipid, left ventricular end diastolic volume fell below baseline (-14 ± 13 ml, compared to + 9.5 ± 18.8 ml with euglycaemic clamp, p = 0.003), as did left ventricular end systolic volume (- 22.9 ± 23.4 ml compared to + 6.86 ± 17.8 ml, p = 0.001), suggesting increased contractility. Unlike the normal heart group, PCr/ATP was elevated with intralipid compared to euglycaemic clamp. There was no significant difference in creatine kinase rate constant nor flux. Conclusions Increased supply of fat to the myocardium brought about improved contractility in these heart failure patients over their baseline measurements, unlike a euglycaemic clamp which did not cause any significant changes, mirroring the pattern seen in the control group where patients infused with intralipid had higher contractility. Cardiac energetics were relatively improved with the intralipid compared to euglycaemic clamp in the heart failure group, but not in the normal heart controls. The higher PCr/ATP ratio in the heart failure group would imply (given myocardial ATP concentration remains relatively constant) that there is a greater availability of phosphocreatine, suggesting improved mitochondrial ATP synthesis. This did not occur in the normal heart control group, perhaps as their metabolism was already optimal. These results were unexpected as it has traditionally been thought increased glucose metabolism would yield greater cardiac function in the failing heart. These data suggest targeting myocardial fat metabolism may provide novel treatments for cardiac dysfunction. Conflict of Interest None