Cardiac rest and stress metabolism in type 2 diabetes (T2D): can the diabetic heart flex under stress?

Abstract

Abstract Background Efficient matching of energy supply to demand is essential for maintaining normal cardiac function. Altered cardiac metabolism may contribute to the development of cardiac dysfunction by impairing metabolic flexibility in type 2 diabetes (T2D). Purpose We aimed to evaluate the effect of T2D on myocardial substrate preferences in response to acute increases in cardiac workload and the effects on contractile function utilising simultaneous coronary sinus (CS) and aorta blood sampling and cardiac magnetic resonance (CMR) imaging Methods Eligible participants without obstructive coronary artery disease (>50% luminal coronary artery stenosis on coronary angiography) underwent transmyocardial arteriovenous blood sampling. Metabolites in paired coronary sinus and arterial samples were quantified to determine myocardial fuel selection at rest and during a stress protocol with intravenous dobutamine. Free fatty acid (FFA), glucose, 3-hydroxybutyric acid (3HBA) and lactate utilisation at rest and haemodynamic stress was calculated as an extraction fraction % (EF). Participants underwent dobutamine stress multiparametric CMR imaging at 3.0 Tesla (Skyra, Siemens, Germany) on a separate visit within 21 days to quantify cardiac volumes, function and perfusion. Results Two thousand and sixty-one participants were screened and due to stringent inclusion and exclusion criteria for this mechanistic study, three T2D patients and five matching controls were enrolled. Baseline demographics and metabolic and CMR results are documented in Table 1. At peak stress levels there was a significant increase in FFA use from rest to stress in controls only (p=0.002). There were no significant differences in FA or glucose uptake between T2D patients and controls at rest or stress. 3HBA EF was significantly increased in T2D during stress (25.04% vs 5.31%, p=0.007). Mean FFA and 3-HBA changes calculated as extraction fraction at stress and rest are illustrated in Figure 1. Conclusions We demonstrate for the first time in vivo that the diabetic heart switches to ketone bodies during increased workloads as a significant fuel source. At present, it is unknown whether enhanced ketone body metabolism in T2D is beneficial, maladaptive, or a bystander. As the energetic properties of ketones are favourable, increased myocardial ketone oxidation could be an adaptive change designed to compensate for defects in myocardial energy metabolism in diabetes. Further, larger studies are warranted. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): British Heart Foundation - Clinical Research Training FellowshipWellcome Trust Seed Grant Table 1Figure 1