Myocardial substrate metabolism imaged by PET

Professor Juhani Knuuti, MD
Director, Turku PET Centre, Turku University Central Hospital, Turku, Finland

Introduction
Recent methodological developments have provided us with the possibility for quantitative characterization of physiological and pathophysiological processes in vivo in humans. Positron emission tomography (PET), single photon emission tomography (SPET) and nuclear magnetic resonance (NMR) can be used to study myocardial energy metabolism non-invasively. The energy metabolism in the myocardium represents a link between oxygen delivery and functional performance. The quantitation of myocardial glucose utilization, fatty acid uptake and oxidation, perfusion, oxygen consumption, contractile function as well as characterization of cardiac presynaptic and postsynaptic neuronal activity are now possible. This allows study of the effects of nutritional interventions, medication, hormonal and neural activity as well as disease processes on the metabolism and function of the human heart.

Myocardial energy metabolism
Free fatty acids (FFA), glucose and lactate are the main fuels of the heart.[1,2] Ketone bodies and amino acids are used to a lesser extent. Several factors affect the use of an individual substrate. These include the plasma concentration of the substrate and alternate substrates, myocardial blood flow and oxygen supply, hormone levels and regulatory effects of metabolites arising during degradation of substrates.[1]
In the fed state, after a high-carbohydrate meal when insulin concentrations are increased, the use of glucose accounts for ~70% and lactate for ~30% of the oxygen uptake of the heart.[1] Conversely, in the fasted state the use of glucose accounts for ~30%, lactate for ~10% and FFA for ~60–70% of the oxygen uptake of the heart.[1] The uptake of ketone bodies is concentration-dependent and their use is increased in uncontrolled diabetes and starvation.[2] Amino acid oxidation is enhanced after a protein-rich meal, but their use accounts for a small fraction of total oxygen consumption.[2]
Myocardial blood flow and oxygen consumption are tightly coupled, and changes in the coronary flow rate control the delivery of oxygen. Myocardial oxygen consumption reflects almost totally the overall energy demand of the heart and is determined by heart rate, systolic wall stress, contractility, myofibre shortening and the oxygen demand necessary to maintain basal myocardial metabolism.[3] At rest, human myocardium is characterized usually by a blood flow of 80–100 ml 100 g–1 min–1 and oxygen consumption of ~10 ml 100 g–1 min–1. [1,4]
Striking changes occur in substrate utilization during myocardial ischaemia. With the decline in oxygen delivery, oxidative metabolism decreases markedly but still remains the predominant (over 90%) source of residual adenosine triphosphate (ATP) production.[1] Since b-oxidation of FFA is very sensitive to ischaemia, the principal fuel-contributing substrate for the citric acid cycle during ischaemia is glucose. During mild ischaemia, lactate and other products are washed out from the cell and glycolysis can be maintained. However, during severe ischaemia, lactate and protons will accumulate in the myocardium and glycolysis is inhibited, which may contribute to lethal injury.[1]

Imaging techniques to study myocardial energy metabolism in vivo
Imaging techniques are based on radioactive tracers or nuclear magnetic resonance. With the isotope techniques, the labelled compounds are administered to the subjects, and their kinetics can be studied using PET or SPET.

Positron emission tomography (PET)
PET enables us to study regional myocardial blood flow, glucose and fatty acid metabolism and oxygen consumption non-invasively in research as well as in clinical practice. In principle, an unlimited amount of compounds can be labelled with positron emitters. Based on the distribution and kinetics of the compounds studied by PET, quantitative metabolic parameters can be derived. The advantages of PET are non-invasive quantitation of regional metabolic rates in tissues with high resolution and sensitivity.[5,6] At present, PET is the only technique that permits non-invasive measurement of regional myocardial energy substrate utilization in absolute terms.

Glucose metabolism
[18F]-2-fluoro-2-deoxy-D-glucose ([18F]FDG) is a fluorine-18-labelled glucose analogue, which is transported to heart cell and phosphorylated. In contrast to glucose, it cannot be further metabolized and it remains trapped in the cytosol.[7,8] Using [18F]FDG it is possible to study glucose transport and phosphorylation but not further metabolism.[9] By using simple graphical analysis10 the glucose uptake rates in the myocardium can be calculated.
The method has been widely used to study myocardial glucose metabolism in various conditions such as coronary heart disease, diabetes, hypertension and cardiac failure. An example of the potential of the method is given in a recent study about the regulation of glucose metabolism in the hibernating myocardium in humans (Figure 1).

Figure 1. Transaxial 10 min PET images obtained 50 min after FDG injection during fasting (left) and during an insulin clamp (right). Increased FDG uptake is seen in the hibernating anterior wall during fasting but not during insulin stimulation. However, in a quantitative analysis, the hibernating anterior myocardium also responded strikingly to insulin (sixfold increase in glucose uptake). Reproduced from Mäki et al.[11]

Free fatty acid (FFA) metabolism
[1-11C]-palmitic acid has been traditionally used as a natural tracer of FFA metabolism by PET. The rapid washout of the tracer is assumed to be associated with the oxidative metabolism of fatty acids and the slower washout with the incorporation to the myocardial triglyceride pool.[2,12] However, [1-11C]-palmitic acid is distributed between several tissue pools with variable turnover rates, which makes it mainly useful as a qualitative tracer in PET studies.[12] Recently, Bergmann et al.[13] introduced a model to quantitate [1-11C]-palmitic acid utilization with PET. This model is still complicated and requires simultaneous measurement of myocardial blood flow, which limits its use.
18F-labelled 6-thia-hepta-decanoic acid ([18F]FTHA) has recently been used to study fatty acid metabolism in the human heart.[14–18] [18F]FTHA is a false long-chain fatty acid substrate and inhibitor of fatty acid metabolism.[19] After transport into the mitochondria, it undergoes initial steps of b-oxidation and is thereafter trapped in the cell because further b-oxidation is blocked by sulphur heteroatom. Accumulation of [18F]FTHA has been suggested to be mainly tracing FFA oxidation in the heart.[19,20] A similar graphical analysis such as is used with [18F]FDG has been successfully applied in quantitation of [18F]FTHA uptake in the heart14,17,18 (Figure 2).

Figure 2. Examples of FFA uptake quantitative images measured using [18F]FTHA. The myocardial mid-ventricular transaxial slice and cross-section of the femoral region measured in the fasting state (A, C) and during an insulin clamp (B, D) in the same subject. Reproduced from Mäki et al.18

Oxidative metabolism
The tracers [1-11C]acetate and [15O]O2 have been used for measuring myocardial oxygen consumption with PET in humans.4,21 [1-11C]acetate has been widely used, but until recently this tracer has provided only an index of oxidative metabolism rather than absolute quantification. A new model for [1-11C]acetate as a tracer of myocardial oxygen consumption has been introduced. This model allows quantification and has been applied in humans.21 The most substantial drawback of the method is the lack of information on pool sizes of metabolites.
The model employed using [15O]O2 also requires measurements of myocardial blood volume and flow, which are needed for corrections of spillover of the cardiac chamber, and corrections of wall motion and wall thickness.[4] The model provides absolute values of myocardial regional oxygen consumption and extraction fraction. This model has been successfully applied in healthy humans[4] and recently in patients with hypertension-induced left ventricular hypertrophy[.22]

Single photon emission tomography (SPET)
SPET provides an alternative to PET at a lower cost. With SPET it is possible to detect radiation emitted by gamma-emitting isotopes, such as 99mTc, 201Tl and 123I, which have longer half-lives (6–72 h) than those used with PET. However, the sensitivity and resolution of SPET are not as high as those of PET. Moreover, attenuation and scatter corrections are difficult with SPET and thus absolute quantitation is not currently possible.[23]
SPET has been successfully used to study myocardial FFA metabolism. Various FFA ligands have been applied and semi-quantitative analysis of FFA uptake and oxidation has been performed.[24]
Nuclear magnetic resonance (NMR)
Use of 31P NMR to measure energy metabolism can provide information on ATP, creatine phosphate, inorganic phosphates, sugar phosphates and intracellular pH. As for its limitations, it provides information only about ATP levels and not about the rates of production or utilization of ATP. In addition, with 31P NMR measurement no data are obtained about which metabolic pathway produces the high-energy phosphates.6 NMR and 13Clabelled substrates can be used in measurements of tricarboxylic acid cycle activity (mainly glutamate pool), glucose uptake and glycogen turnover. NMR can be also used in in vivo studies but the high costs and complexity of quantitative analysis currently limit its use in this area.[6]

Clinical applications of metabolic imaging
The assessment of myocardial viability is a clinically important issue for the management of patients with post-ischaemic left ventricular dysfunction and particularly for those with severe impairment of left ventricular function.
Clinical investigations have demonstrated the utility of [18F]FDG PET for detection of myocardial viability.[25–29] In addition, [18F]FDG imaging is able to identify patients at increased risk of having an adverse cardiac event or death.[30] The detection of viable myocardium by PET is based on the demonstration of preserved metabolic activity in regions of severely underperfused and dysfunctional myocardium. SPET imaging with FFA tracers has also been used as a clinical tool in the detection of myocardial viability.[24]
At present, increased [18F]FDG uptake relative to flow is regarded as the gold standard to predict viability and functional recovery and is superior to dobutamine echocardiography or SPET imaging in patients with severe left ventricular dysfunction.[29]

In Short
There are currently several imaging methods that can be successfully used to study myocardial energy metabolism. PET, SPET and NMR can all be used to study certain areas of this topic. The methods provide a powerful way to increase our understanding of cardiac physiology and the mechanisms of disease. Due to the unique features and large number of existing tracers, PET appears to provide the most complete insight into myocardial energy metabolism in vivo. In the detection of myocardial viability, PET is regarded as the gold standard. The future role of these methods in clinical cardiology remains unclear and further studies are needed. Novel applications also depend on improved instrumentation and development of new tracers. 

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