Assessment of myocardial triglyceride oxidation with PET and 11C-palmitate

Abstract

Background The goal of this study was to test whether myocardial triglyceride (TG) turnover including oxidation of TG-derived fatty acids could be assessed with PET and 11C-palmitate. Methods and Results 26 dogs were studied fasted (FAST), during Intralipid infusion (IL), during a hyperinsulinemic-euglycemic clamp without (HIEG) or with Intralipid infusion (HIEG+IL). 11C-palmitate was injected, and 45 min were allowed for labeling of myocardial TG pool. 3-D PET data were then acquired for 60 min, with first 15 min at baseline followed by 45 min during cardiac work stimulated with constant infusion of either phenylephrine (FAST, n=6; IL, n=6; HIEG+IL, n=6) or dobutamine (FAST, n=4; HIEG, n=4). Myocardial 11C washout during adrenergic stimulation (AS) was fitted to a mono-exponential function (Km(PET)). To determine the source of this 11C clearance, Km(PET) was compared to direct coronary sinus-arterial measurements of total 11C activity, 11C-palmitate, and 11CO2. Before AS, PET curves in all groups were flat indicating absence of net clearance of 11C activity from heart. In both FAST groups, AS resulted in negligible net 11C activity and 11CO2 production higher than net 11C-palmitate uptake. AS with phenylephrine resulted in net myocardial uptake of total 11C activity and 11C-palmitate in IL and HIEG+IL, and 11CO2 production lower than 11C-palmitate uptake. In contrast, AS with dobutamine in HIEG resulted in net clearance of all 11C metabolites (total 11C activity, 11C-palmitate and 11CO2) with 11CO2 contributing 66% to endogenous FA oxidation. AS resulted in significant Km(PET) in all groups, except HIEG+IL. However, positive correlation between Km(PET) and 11CO2 was observed only in HIEG (R2=0.83, P=0.09). Conclusions This is the first study to demonstrate that using PET and pre-labeling of intracardiac TG pool with 11C-palmitate, noninvasive assessment of myocardial TG use is feasible under metabolic conditions that favor endogenous TG use such as increased metabolic demand (β-adrenergic stimulation of cardiac work) with limited availability of exogenous substrate (HIEG).

Fatty Acid Imaging of the Heart

“…Adrenergic stimulation of dogs in the fasting state with both phenylephrine and dobutamine resulted in negligible net 11 C activity, and 11 Cpalmitate uptake was lower than 11 CO 2 production, suggesting oxidation of FAs from both exogenous and endogenous sources. Of note, phenylephrine inhibits lipolysis, whereas dobutamine has a direct lipolytic effect [21]. The Km was very low in the phenylephrine-treated group, whereas it was threefold higher in the dobutamine-treated group.…”

“…Although lipolysis of intracardiac triglyceride may help protect the heart from such deleterious effects, little is known about myocardial triglyceride metabolism in humans. Compartmental modeling of the PET kinetics of 11 C-palmitate allows noninvasive measurement of metabolism of exogenous FAs, but does not account for the contribution from the intracardiac triglyceride pool [21].…”

“…Researchers at Washington University School of Medicine in St. Louis, Missouri, demonstrated that noninvasive assessment of myocardial triglyceride degradation and oxidation under conditions favoring endogenous triglyceride use is feasible using 11 C-palmitate [21]. Using a canine model, myocardial triglyceride turnover was assessed using PET and 1-11 C-palmitate.…”

“…Cardiac work was then increased with a continuous infusion of phenylephrine or dobutamine, and data were acquired over 60 min. Estimated rate constants for each intervention were averaged to generate a mean rate constant per study, which constants were compared with the direct arterial-coronary sinus 11 C measurements [21].…”

“…The Km was very low in the phenylephrine-treated group, whereas it was threefold higher in the dobutamine-treated group. When dogs treated with a hyperinsulinemic-euglycemic clamp to switch myocardial substrate use from FAs to glucose were given a continuous dobutamine infusion, there was a net clearance of all directly measured 11 C metabolites, with 11 CO 2 comprising two thirds of the total 11 C washout, suggesting that 11 CO 2 production was due solely to oxidation of endogenous FAs [21]. Although the rate-pressure products obtained in the phenylephrine-treated dogs were lower than the products achieved in dogs treated with dobutamine, raising the possibility that the higher Km rates in the latter group could be due to the higher workload attained, the mean Km was still significantly higher in the dobutamine group, compared with the phenylephrine group, when analysis was restricted to dogs with comparable rate-pressure products.…”