Increased myocardial fat supply improves cardiac energetics and function in heart failure

Introduction The failing heart is starved of energy, in part accounting for its contractile dysfunction. Reduced uptake of fat and sugar required for energy production has frequently been demonstrated in heart failure, therefore altering metabolism of glucose and/or fat is therefore attractive as a therapy. We hypothesized increasing glucose supply would be beneficial over increasing fat supply so measured ATP usage (via PCr/ATP ratio and flux through creatine kinase) and cardiac function during fat emulsion infusion or euglycaemic hyperinsulinaemic clamp. Methods 11 patients with a diagnosis of heart failure and nonischaemic cardiomyopathy were recruited, mean age 66 (range 49–80), mean BMI 27.7 (range 21.3–37.5), F:M 3:8, 3 diabetic and 8 non-diabetic. On the first visit they had a baseline cardiac magnetic resonance (CMR), collecting cardiac volumes and function, then were randomised to receive either fat infusion or euglycaemic clamp. Following an hour of infusion, CMR was repeated followed by 31P cardiac magnetic resonance spectroscopy, then a dobutamine stress sequence at 65% maximum heart rate. They received the alternate infusion at the next visit. Results Data was normally distributed. Baseline ejection fraction was 37±9%. PCr/ATP ratio was greater with the fat infusion compared to euglycaemic clamp (1.82±0.26 vs 1.68±0.24, p=0.04). Fat emulsion infusion also brought about a greater ejection fraction increase over the baseline, compared to the euglycaemic clamp in which there was little difference (+5.3±5.3% vs −0.6±3.1%, p=0.004). Calculated cardiac work was greater in the fat infusion group than the Insulin/glucose group (682±156 L.mmHg/min vs 581±85 L.mmHg/min, p=0.009). There was no significant difference in creatine kinase first order rate constant (fat infusion 0.2±0.09/s vs euglycaemic clamp 0.16±0.07/s, p=0.32) nor creatine kinase flux (fat infusion 1.85±0.92 μmol/g/s vs euglycaemic clamp 1.46±0.58 μmol/g/s, p=0.22). The increment in cardiac output on stress over baseline was not significantly different between arms (fat infusion +3.39±3.07 L/min vs euglycaemic clamp +3.08±2.57 L/min, p=0.42). The PCr/ATP ratio showed positive correlation with the stress ejection fraction (R2=0.656, p=0.001), but not with resting ejection fraction. Conclusions Increased supply of fat to the myocardium brought about improved contractility and cardiac energetics compared to an increased glucose supply. The increase in PCr/ATP ratio would imply (given ATP concentrations are kept constant in the myocardium) there is a greater availability of phosphocreatine, suggesting increased mitochondrial ATP synthesis. These results were unexpected as it has traditionally been thought that 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. Figure 1 Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation

Effects of dipeptidyl peptidase IV inhibition on glycemic, gut hormone, triglyceride, energy expenditure, and energy intake responses to fat in healthy males

Fat is the most potent stimulus for glucagon-like peptide-1 (GLP-1) secretion. The aims of this study were to determine whether dipeptidyl peptidase IV (DPP-IV) inhibition would enhance plasma active incretin [glucose-dependent insulinotropic polypeptide (GIP), GLP-1] concentrations and modulate the glycemic, gut hormone, triglyceride, energy expenditure, and energy intake responses to intraduodenal fat infusion. In a double-blind, randomized, placebo-controlled crossover design, 16 healthy lean males received 50 mg vildagliptin (V), or matched placebo (P), before intraduodenal fat infusion (2 kcal/min, 120 min). Blood glucose, plasma insulin, glucagon, active GLP-1, and GIP and peptide YY (PYY)-(3–36) concentrations; resting energy expenditure; and energy intake at a subsequent buffet meal (time = 120–150 min) were quantified. Data are presented as areas under the curve (0–120 min, means ± SE). Vildagliptin decreased glycemia (P: 598 ± 8 vs. V: 573 ± 9 mmol·l−1·min−1, P < 0.05) during intraduodenal lipid. This was associated with increased insulin (P: 15,964 ± 1,193 vs. V: 18,243 ± 1,257 pmol·l−1·min−1, P < 0.05), reduced glucagon (P: 1,008 ± 52 vs. V: 902 ± 46 pmol·l−1·min−1, P < 0.05), enhanced active GLP-1 (P: 294 ± 40 vs. V: 694 ± 78 pmol·l−1·min−1) and GIP (P: 2,748 ± 77 vs. V: 4,256 ± 157 pmol·l−1·min−1), and reduced PYY-(3–36) (P: 9,527 ± 754 vs. V: 4,469 ± 431 pM/min) concentrations compared with placebo ( P < 0.05, for all). Vildagliptin increased resting energy expenditure (P: 1,821 ± 54 vs. V: 1,896 ± 65 kcal/day, P < 0.05) without effecting energy intake. Vildagliptin 1) modulates the effects of intraduodenal fat to enhance active GLP-1 and GIP, stimulate insulin, and suppress glucagon, thereby reducing glycemia and 2) increases energy expenditure. These observations suggest that the fat content of a meal, by enhancing GLP-1 and GIP secretion, may contribute to the response to DPP-IV inhibition.