Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
Imaging of myocardial fatty acid oxidation☆
Introduction
Although the heart is a metabolic omnivore, fatty acids are the dominant myocardial fuel under usual circumstances in health and disease [1]. The balance between fuel types can be shifted as an externally imposed change that affects myocardial fuel selection, or as intrinsic changes that are the result of myocardial disease.
Primary sites of regulation of fuel selection and MFAO include transmembrane transport, oxidative and non-oxidative fatty acid metabolic processes, levels of regulatory intermediates, and external regulators like insulin or catecholamines. The importance of these sites as targets of regulation or sites of disease-related imbalance is beginning to be explored.
Fuel selection impacts oxidative efficiency, i.e. efficiency of energy generation per unit O2 used. This also impacts work efficiency (work produced per unit O2 used) but the importance of shifts in oxidative efficiency on MFAO, contractile function, or other outcomes of importance has not yet been well explored.
Measurement of fuel selection in the heart is challenging. Ex vivo experiments on isolated hearts are extremely useful but incompletely informative, and ultimately measurements in vivo in circumstances of health and disease are needed. The traditional methods of “organ balance” measurements of fuel metabolism require measurements of rates and amounts of fuel delivery and uptake, using invasive tools to make samples and measurements of analyte blood concentrations. Imaging tools provide a major advantage in animal and human studies, because a set of in vivo measurements can be made with only modest needs for blood sampling to assess metabolite concentrations. Particularly, for evaluations of myocardial metabolism, tracer-based methods have been advanced that provide arterial measurements of imaging tracers, obviating the need for peripheral arterial sampling. Together with progressive advances in the design and production of radiolabeled fatty acid probes, and in the modeling approaches to extracting relevant kinetic parameters from the time-activity curves, imaging studies can provide accessible, accurate, and quantitative measurements of MFAO safely and non-invasively. These tools have already provided major advances in our understanding of myocardial fatty acid metabolism, and of fuel metabolism more generally, in health and disease. In the following sections, we will review the state of the art in radiopharmaceutical tracers that allow non-invasive measurement of MFAO, followed by a review of the knowledge that these approaches have provided for us in realms of human health and disease.
Section snippets
Metabolically cleared MFAO probes
The central role of fatty acids in energy provision to the myocardium motivated efforts to develop radiolabeled long-chain fatty acids (LCFAs) that could be imaged by PET or SPECT. As early as 1976, the synthesis of 1-11C-palmitate (CPA, T1/2 = 20 min, Fig. 1) had been achieved and this radiotracer was evaluated in isolated perfused rabbit hearts and in living dogs [2]. CPA has been used extensively in cardiovascular PET research studies to monitor changes in palmitate uptake and metabolism in
MFAO imaging in ischemic heart disease
The application of fatty acid oxidation imaging to myocardial ischemia has been in two overall areas of interest. First is the pathophysiologic question of the shifts in fuel selection in ischemic myocardium. Second is the more clinically approachable application of using fatty acid imaging to identify and quantify regions of ischemia. We will further explore each of these topics.
The heart does not maintain a significant depot of stored fuel substrate, and in the absence of ongoing supply of
Conclusions
Quantitative imaging of myocardial fatty acid uptake and oxidation provides a uniquely valuable set of tools for clinical and research applications. The optimal fatty acid probe has not yet been defined, and work is ongoing attempting to optimize these probes by designing probes with specific metabolic fates or mitochondrial targeting, for example. Application of the probes available to date has defined abnormalities in myocardial fuel selection as a key feature of many cardiac and
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Acknowledgments
The authors would like to acknowledge funding support from the National Institutes for Health grants HL63371 (TD), DK071142 (KM), M01-RR00750 (KM) and TR000006 (KM).
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This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk.