Imaging Myocardium Enzymatic Pathways with Carbon-11 Radiotracers

Publisher Summary

This chapter elaborates the imaging of myocardium enzymatic pathways with carbon-11 radiotracers. Under normal conditions, the heart utilizes a variety of metabolic pathways, such as the oxidation of carbohydrates, fatty acids, lactate, and pyruvate, to meet the high-energy demands of contraction and maintenance of cellular function. Carbon-11 is produced by the ¹⁴N(p, α) ¹¹C reaction using a gas target system of 0.5% oxygen in nitrogen with typical bombardments of 20 –40 min at 40 μA beam power. The product obtained from the target is [¹¹C]CO₂, which is then trapped under vacuum in a specially designed stainless steel coil cooled to −196° with liquid nitrogen. It is found that as blood contains radiolabeled metabolites in addition to 1-[¹¹C]palmitate, the PET-derived ¹¹C blood activity must be corrected for the presence of ¹¹CO₂ in order to derive the true input function. It is found that data analyses require minimum manual data entry and, on average, are completed within 2 h from the time the myocardial positron emission tomography (PET) images are reconstructed, making these types of complex studies feasible to implement in a clinical PET environment.

Introduction

Under normal conditions, the heart utilizes a variety of metabolic pathways, such as the oxidation of carbohydrates, fatty acids, lactate, and pyruvate, to meet the high-energy demands of contraction and maintenance of cellular function. The metabolic flux through each pathway is determined by the availability of substrates for each metabolic pathway in plasma, as well as hormonal status and myocardial oxygen supply. For example, the high blood levels of fatty acids during fasting result in the oxidation of fatty acids as the principal form of energy production and account for approximately 70% of the cardiac energy requirements. Consumption of a high carbohydrate meal results in an elevation of plasma glucose levels, an increase in insulin production, and an activation of glycolysis. Exercise results in the release of lactate by skeletal muscle, which is taken up rapidly by the heart, converted to acetyl-CoA, and oxidized through the tricarboxylic acid cycle (TCA) cycle. The extraordinary ability of the heart to utilize a number of different metabolic pathways and to change its metabolic preference rapidly is necessary for the maintenance of proper mechanical function under a variety of physiological conditions. Therefore, a derangement in the balance of myocardial metabolism is expected to play a key role in a number of pathological conditions leading to abnormal cardiac function.

Much of the work that resulted in the characterization of the different enzymes involved in intermediary metabolism was carried out in vitro. Although this seminal research provided the foundation for the fields of biochemistry and enzymology, the techniques used in the mapping of intermediary metabolism are inadequate for studying the change in metabolic processes that underlie myocardial dysfunction in human disease. While the elucidation of the different metabolic pathways was complete by the middle of the 20th century, the study of the change in myocardial metabolism as a consequence of disease was not possible until the advent of noninvasive imaging techniques such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) in the 1970s.

Positron emission tomography is an imaging technique developed for the in vivo study of metabolic functions in both healthy and diseased stages. The goal of the technique was best expressed in 1975 by Dr. Michel Ter-Pogossian,¹ one of the pioneers of this modality at Washington University: “Our ultimate goal is to measure in vivo regionally and as noninvasively as possible metabolic processes. Perhaps a term for this approach could be either in vivo biochemistry or functional [imaging]. The reason for seeking this goal, of course, is the application of this approach to medicine using the premise that any form of pathology either results from or is accompanied by an alteration of some metabolic pathway. Our approach to achieve the above goal consists in labeling with cyclotron-produced radionuclides, more specifically, oxygen-15, carbon-11, nitrogen-13 and fluorine-18, certain metabolic substrates, the fate of which is studied in vivo subsequent to their administration, by some radiation detector or imaging device, with the hope, after suitable unraveling of the metabolic model used, of measuring in vivo a particular pathway.”

Since the early 1980s and more extensively in the mid 1990s, investigators at the Washington University School of Medicine have used PET to study the change in metabolic substrate utilization that occurs under a variety of experimental conditions, including normal aging, obesity, dilated cardiomyopathy, type 1 diabetes mellitus, and hypertension-induced left ventricular hypertrophy. This is accomplished by measuring the dynamics (i.e., uptake and washout kinetics) of radiolabeled substrates for each metabolic pathway. These studies, which utilize the radiotracers 1-[¹¹C]d-glucose, 1-[¹¹C]acetate, and 1-[¹¹C]palmitate, are collectively termed the GAP studies. This Chapter provides details of the radiosynthesis, dosimetry, quality control, data acquisition, and kinetic modeling that are needed to conduct this experimental paradigm successfully. These issues are discussed to help the reader new to the field gain a broad understanding of the problems faced by the PET researchers that work with short-lived isotopes and to learn some of the approaches used to solve these problems. This Chapter does not include a discussion of the basic principles of PET. The reader interested in a general survey on the synthesis of ¹¹C-labeled compounds and of radiopharmaceuticals used for studying the heart is referred to Antoni et al.² and Hwang and Bergmann,³ respectively.