Cardiac Hot Spot Imaging With 18FDG Diwakar Jain, MD, FACC, FRCP, FASNC,* Zuo-Xiang He, MD,† and Vikram Lele, MD‡ Myocardial perfusion imaging is the mainstay of nuclear cardiovascular imaging. It has been in extensive clinical use for well over 35 years for diagnosing, risk-stratification, and long-term follow-up of patients with suspected or known coronary artery disease. A unique strength of nuclear imaging is its ability to provide a repertoire of tools for imaging metabolic and biochemical processes, receptor and transporter function, inflammation, and gene expression at molecular and cellular levels in intact organisms, under a wide variety of physiological conditions. With this approach, only selective myocardium with targeted abnormality can be visualized (hot spot imaging). This provides an opportunity for imaging complex biochemical, metabolic, and inflammatory processes of the cardiovascular system. 18F-labeled 18FDG, a radiolabeled glucose analogue, tracks cellular uptake and metabolism of glucose in the tissue and organs. Profound changes in regional glucose metabolism accompany several cardiovascular disease processes, which can be imaged using 18FDG. However, caution is required while performing and interpreting these images. Because myocardial glucose uptake can vary widely under different metabolic and physiological states and this variation can overlap with the changes in myocardial glucose uptake under pathologic conditions, a strict and careful regulation of metabolic milieu is required while performing 18FDG imaging. Cardiac 18FDG imaging can be used for imaging myocardial ischemia, viability, and sarcoidosis. These techniques can overcome many of the limitations of current imaging techniques. In this article, we describe recent studies using 18FDG for imaging myocardial ischemia and cardiac sarcoidosis. Semin Nucl Med 44:375-385 C 2014 Elsevier Inc. All rights reserved.
Introduction
N
uclear cardiovascular imaging using SPECT or PET tracers is used extensively for myocardial perfusion imaging (MPI) and cardiac function assessment. MPI provides very powerful diagnostic and prognostic information in patients with known or suspected coronary artery disease (CAD).1-4 Development of new perfusion tracers, pharmacologic stress agents, and innovations and improvement in imaging equipment and software for quantitative analysis and interpretation has resulted in a wide acceptance of this
*Cardiovascular Nuclear Imaging Laboratory, Department of Medicine, New York Medical College, Westchester Medical Center, Valhalla, NY. †Department of Nuclear Medicine, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. ‡Department of Nuclear Medicine, Jaslok Hospital & Research Centre, Mumbai, Maharashtra, India. Address reprint requests to Diwakar Jain, MD, FACC, FRCP, FASNC, New York Medical College, Macy Pavilion 111, Westchester Medical Center, 100 Woods Rd, Valhalla, NY 10595. E-mail: [email protected]
http://dx.doi.org/10.1053/j.semnuclmed.2014.06.010 0001-2998/& 2014 Elsevier Inc. All rights reserved.
technique in routine clinical practice.4-8 Nuclear imaging also provides a unique and unrivaled opportunity to image biochemical and metabolic processes, cell membrane receptor and transporter function, inflammation, and gene expression by identifying and developing a repertoire of suitable ligands, and radiolabeling them with various SPECT and PET radiotracers. Thus, radionuclide imaging techniques can be developed for imaging myocardial metabolism, ischemia, viability, inflammation, angiogenesis, apoptosis, necrosis, and adrenergic neuronal activity at molecular and cellular levels. These novel molecular imaging techniques provide us with an unforeseen insight into the arena of cardiovascular pathophysiology, which can transform the field of therapy. Deoxyglucose is a glucose analogue, which tracks the initial steps of glucose uptake and phosphorylation by the tissues or organs. Once inside the cells, it enters glycolytic pathway similar to glucose. Glucose is phosphorylated to glucose-6phoshpate by enzyme hexokinase. Glucose-6-phosphate is further phosphorylated and converted to 2 molecules of glycerol phosphate. Deoxyglucose also is phosphorylated to deoxyglucose-6-phosphate by hexokinase, but its metabolism 375
376 stops here with no further phosphorylation. Deoxyglucose-6phosphate is trapped intracellularly.9 Deoxyglucose can be radiolabeled9 with F-18 (18FDG). 18FDG is used for imaging initial steps of glucose metabolism in various organs and tissues in the body.9 This technique is used extensively for imaging malignant tumors,9-11 as malignant tumors show increased glucose uptake. 18FDG is also used for imaging viable myocardium.12,13 Management of patients with CAD and impaired left ventricular function requires a precise differentiation of irreversibly damaged or scarred myocardium that is unlikely to improve after revascularization from myocardium that is dysfunctional but viable and is likely to improve after revascularization. Several different imaging techniques such as thallium-201 perfusion imaging after a long redistribution phase, low-dose dobutamine echocardiography, and MRI can be used to draw this distinction. 18FDG imaging detects preserved or enhanced glucose uptake relative to its perfusion in the viable myocardium. Apart from viability detection, myocardial 18FDG imaging can also be used for imaging myocardial ischemia and cardiac sarcoidosis. This article is focused on these newly emerging “hot spot” cardiac imaging techniques using 18FDG. 18
FDG for Myocardial Ischemia Imaging Although in extensive clinical use, MPI has several limitations. The sensitivity and specificity are far from ideal.14-16 The sensitivity of stress-rest MPI for the detection of individual vascular territories with significant obstructive disease is relatively low. Perfusion abnormalities can sometimes be relatively unimpressive or rarely even absent in patients with severe triple-vessel CAD. Artifacts due to soft tissue attenuation, extracardiac tracer activity, partial volume effect, scatter, relatively poor spatial resolution, and other technical reasons are common and may not be entirely corrected or eliminated using existing technologies. Some of these drawbacks are inherent to “cold spot” imaging. A technique for “hot spot” imaging of myocardial ischemia can potentially eliminate some of the drawbacks of MPI.17
Metabolic Changes in Myocardial Ischemia Myocardial ischemia imaging can be accomplished by targeting metabolic changes, which accompany myocardial ischemia. Several unique features of myocardial metabolism and their alteration with myocardial ischemia make them potential targets for direct imaging of myocardial ischemia.18-26 Myocardium has an extremely high metabolism to meet energy requirements for its pumping function. Nearly 90% of the myocardial energy demand is for its contractile function. Myocardium consumes 8-15 mL of oxygen/min/100 g of tissue at rest, which increases up to 70 mL/min/100 g at maximum workload.27 Myocardium needs a constant supply of oxygen as well as substrates for energy production. Normal myocardium is capable of extracting a wide variety of substrates for energy production: glucose, free fatty acids,
D. Jain et al. pyruvate, lactate, amino acids, and ketone bodies. Of these, free fatty acids and glucose are the predominant sources of energy production. However, the proportion of their relative uptake and percent contribution to energy production is highly variable and dependent on several factors: fasting or fed state, insulin levels, oxygen supply, circulating catecholamines, and the relative plasma concentration of these substrates. Under fasting conditions, free fatty acid levels are high and glucose and insulin levels are low; therefore, free fatty acids constitute the major source of energy production, with a relatively low glucose uptake. After a carbohydrate-rich meal, the blood glucose and insulin levels are high; therefore, myocardial glucose uptake is high and glucose contributes a higher fraction of energy production. Exercise results in an increase in catecholamines and free fatty acid levels, and a higher proportion of energy is derived from free fatty acid metabolism. However, profound changes in substrate use occur with the onset of myocardial ischemia. Free fatty acid oxidation being an obligatory aerobic process is very sensitive to reduced oxygen availability. Myocardial ischemia results in an impaired uptake and oxidation of free fatty acids. Interestingly, impaired free fatty acid uptake and oxidation persists much longer than the duration of ischemia, providing a signature or memory of myocardial ischemia. Glucose metabolism is a 2-step process: the initial glycolysis is an anerobic process, which occurs in cytosol and results in conversion of glucose to pyruvate. Pyruvate is converted to lactate under anerobic conditions. But in the presence of oxygen, pyruvate enters the Krebs cycle in the mitochondria after conversion to acetyl co-enzyme A, an obligatory aerobic process, and through a chain of oxidative reactions undergoes conversion to carbon dioxide and water. With the onset of ischemia, glycolysis becomes the predominant source of energy production for the sustenance of the ischemic myocardium. However, glycolysis is inefficient in energy production. One molecule of glucose provides only 2 molecules of adenosine triphosphate by anerobic glycolysis, whereas oxidative metabolism yields 38 molecules of adenosine triphosphate. Therefore, ischemic myocardium requires a very large supply of glucose for its sustenance during ischemia. This is brought about by an immediate translocation of specialized transporters (glucose transporters GLUT-4 and GLUT-1) from cytosol to the sarcolemma with the onset of myocardial ischemia. These transporters are highly efficient in glucose transport across the cell membrane and are insulin independent. Another interesting feature of this process is that once GLUT transports are translocated to the sarcolemma, they remain there for a much longer period even after the resolution of myocardial ischemia. The exact reason or biological advantage of this prolonged overexpression of GLUT receptors even after the resolution of ischemia is not known. Perhaps, further research on the kinetics and recycling of cell membrane proteins, receptors, and transporters may be able to explain this phenomenon. However, from a practical standpoint, it indicates that this metabolic signature of myocardial ischemia lasts much longer than the exact duration of myocardial ischemia, which can be exploited to our advantage for imaging myocardial ischemia in the clinical context.
Myocardial 18FDG imaging
377
Myocardial ischemia results in a dramatic and sustained increase in glucose uptake compared with the normal myocardium.19-23 However, normal myocardium would have a much lower glucose extraction on exercise under fasting conditions, as free fatty acids uptake is the predominant source of energy production. Thus, a profound metabolic differential exists between the normal and ischemic myocardium on exercise. 18 FDG imaging can thus be used for imaging myocardial ischemia.
Hot Spot Imaging of Myocardial Ischemia The differential uptake of glucose between normal and ischemic myocardium permits the use of exercise 18FDG as a “hot spot” imaging agent28-37 for imaging exercise-induced myocardial ischemia. 18FDG is ordinarily imaged using PET cameras; however, SPECT cameras equipped with thicker sodium iodide crystals and ultra-high energy collimators have also been used with varying success for its imaging.38,39 Several studies have investigated the potential of 18FDG as an ischemic marker by injecting it during stress testing followed by imaging. Camici et al30 observed 18FDG uptake in 9 of 10 patients in regions with reduced rubidium-82 uptake during exercise. Abramson et al29 observed increased 18FDG uptake in 8 of 9 women in myocardial segments with reversible perfusion abnormalities. Araujo et al studied myocardial blood flow using 15O-water and 18FDG uptake at rest and after dipyridamole infusion using PET imaging in 11 patients with single-vessel disease and no prior myocardial infarction. They observed significantly increased myocardial 18FDG uptake after dipyridamole administration in vascular territories with blunted coronary vasodilatory capacity with dipyridamole.31 Abbott et al33 examined the feasibility of 18FDG imaging as a memory marker of myocardial ischemia. They injected 18FDG 60-90 minutes after exercise in a group of patients with CAD. They observed increased 18FDG uptake in only one-third of the vascular territories with perfusion abnormalities. The relatively low sensitivity of 18FDG imaging for the detection of myocardial ischemia in this study may be related to a delay of 1-1.5 hours between exercise and injection of 18FDG. These studies were carried out using PET imaging. He et al32 studied 26 patients with known or suspected CAD and no prior myocardial infarction. These patients underwent simultaneous MPI and ischemia imaging following the intravenous injection of 99mTc-sestamibi and 18FDG at peak exercise. They used
SPECT camera equipped with thicker sodium iodide crystal and ultra-high energy collimators to permit simultaneous perfusion and ischemia imaging. Rest perfusion imaging was carried out separately. All patients underwent coronary angiography. They compared exercise 18FDG myocardial images with exercise-rest 99mTc-sestamibi images and coronary angiography. Of 22 patients with Z50% narrowing of Z1 coronary arteries, 18 had perfusion abnormalities (sensitivity 82%), whereas 20 had abnormal myocardial 18FDG uptake (sensitivity 91%, P ¼ not significant). Perfusion abnormalities were seen in myocardial segments corresponding to 25 vascular territories of 51 vessels with Z50% luminal narrowing in 22 patients (sensitivity 49%), whereas increased 18FDG uptake was seen in 34 vascular territories (sensitivity 67%, P ¼ 0.008) (Table). 18FDG images were of high quality and easy to interpret but required simultaneous perfusion images for localizing abnormal myocardial 18FDG uptake. This study provided a proof that exercise-induced myocardial ischemia can be imaged directly with 18FDG (Figs. 1-5). Combined exercise 18FDG-99mTc-sestamibi imaging provides a better assessment of exercise-induced myocardial ischemia compared with exercise-rest perfusion imaging. This study not only evaluated the role of 18FDG as a “hot spot” imaging agent for exercise-induced myocardial ischemia using SPECT imaging cameras but also addressed the issues of 18FDG image quality, need for a roadmap for an accurate myocardial localization of 18 FDG, and an imaging protocol suitable for routine clinical use and potential advantages of ischemia imaging over standard stress-rest MPI. These results have been confirmed by several investigators. Although based on a relatively small sample size, the potential advantages of direct ischemia imaging are obvious from the aforementioned results. Direct ischemia imaging has a trend toward higher sensitivity compared with stress-rest perfusion imaging for the detection of patients with CAD. However, it does have significantly higher sensitivity for the detection of individual vascular territories perfused by significantly narrowed coronary arteries. This is particularly obvious in patients with triple-vessel CAD, where increased 18FDG may be observed in all vascular territories (Fig. 3). A particular limitation of standard exercise-rest MPI is the underestimation of myocardial ischemia or viability or overestimation of scar with this technique.13 A small but significant percentage of myocardial segments may show a fixed or only partially reversible perfusion abnormality despite the presence of
Table Comparison of Abnormalities in Patients With Z50% Narrowing of Z1 Coronary Vessels. (Reproduced With Permission From He et al.32) Ischemia 99m
Tc-sestamibi 18 FDG
99m
Tc-sestamibi FDG
18
Ischemia and Scar
Patients (n ¼ 22) 12 (55%) 4 (18%) 20 (91%) 0 P ¼ 0.04 Vascular territories with Z50% narrowing (n ¼ 51) 16 (31%) 6 (12%) 34 (67%) 0 P o 0.001
Scar
No Abnormality
2 (9%) 0
4 (18%) 2 (9%)
3 (6%) 0
26 (51%) 17 (33%)
D. Jain et al.
378
Figure 1 Exercise (Ex) and rest (R) 99mTc-sestamibi and exercise 18FDG images of a 67-year-old man with angina and no prior myocardial infarction. There is a large area of partially reversible perfusion abnormality involving the septum, anterior wall, and apex (small arrows). Intense 18FDG uptake is present in these areas (solid arrowheads). Coronary angiography showed 90% stenosis of the left anterior descending coronary artery and 60% stenosis of the left circumflex artery. (Reproduced with permission from He et al.32)
myocardial viability. This observation has led to the recommendation for the use of additional imaging studies in patients with fixed perfusion abnormality on standard stress-rest perfusion imaging finding if one suspects the presence of viability in segments with fixed perfusion abnormality.13 In the aforementioned study, a small percentage of patients with CAD (9%) exhibited fixed perfusion abnormality despite no
evidence of prior myocardial infarction. All of these patients showed intense regional 18FDG uptake in the areas of fixed perfusion abnormality similar to the one seen in myocardial segments with reversible perfusion abnormality, indicating that exercise 18FDG is more sensitive for the detection of exerciseinduced myocardial ischemia compared with exercise-rest perfusion imaging. Figure 5 shows a patient with a
Figure 2 Exercise (Ex) and rest (R) 99mTc-sestamibi and exercise 18FDG ischemia images of a 57-year-old man with angina and no prior myocardial infarction. There is a large area of reversible perfusion abnormality involving the septum and inferior wall. Intense 18FDG uptake is present in these areas. Coronary angiography showed 70% stenosis of the left anterior descending coronary artery and 80% stenosis of the right coronary artery. (Reproduced with permission from Jain et al.37)
Myocardial 18FDG imaging
379
Figure 3 Exercise-rest 99mTc-sestamibi and exercise 18FDG ischemia (Is) images of a 40-year-old man with angina and no prior myocardial infarction. There is no perfusion abnormality on stress and rest 99mTc-sestamibi images. There is intense global uptake of 18FDG in all 3 vascular territories (solid arrowheads). Coronary angiography revealed 3-vessel disease (70% stenosis of the left anterior descending, 60% stenosis of the left circumflex, and 60% narrowing of the right coronary arteries). (Reproduced with permission from He et al.32)
predominantly fixed inferolateral perfusion abnormality on exercise-rest MPI, but very intense 18FDG uptake on exercise 18 FDG images in the corresponding segments. Perfusion abnormalities in inferior walls are sometimes hard to differentiate from attenuation artifacts. However, abnormally increased 18FDG uptake in inferior wall is not affected by any kind of artifacts and is indicative of inferior wall ischemia. Exercise perfusion and 18FDG imaging can substantially cut down the imaging time by avoiding the need for separate rest perfusion imaging. However, these highly encouraging preliminary results also raise several important questions about exercise 18FDG imaging. What about diabetic patients? What about glucose loading
for patients similar to what is done in 18FDG viability studies? What is the optimal time for the injection of 18FDG during or after exercise? How long after an episode of exercise-induced myocardial ischemia, increased regional myocardial 18FDG uptake can be observed? What is the optimal time for imaging after injection of 18FDG? What happens to the increased myocardial FDG uptake after coronary revascularization? Can exercise 18FDG imaging alone provide enough information, without any perfusion imaging? What is the optimal imaging modality for exercise 18FDG: PET or SPECT? A significant heterogeneity exists in regional myocardial 18FDG uptake on resting 18FDG studies, how can exercise 18FDG work with that? How critical is quantitative analysis for the interpretation
Figure 4 Exercise 99mTc-sestamibi and exercise 18FDG ischemia images of a 57-year-old woman with chest pain but no CAD. Exercise perfusion images show normal results. There is no myocardial 18FDG uptake. Only minimal background activity in the regions of left and right ventricular blood pools is seen. Coronary angiography show normal finding. (Reproduced with permission from He et al.32)
D. Jain et al.
380
Figure 5 Exercise-rest 99mTc-sestamibi and Ex 18FDG ischemia (Is) images in short axis, vertical, and horizontal long axes of a 65-year-old man showing a large area of fixed perfusion abnormality in the inferolateral wall. The patient had no prior myocardial infarction. There is intense 18FDG uptake in the inferolateral wall indicating the presence of ischemia rather than scar in this area. Coronary angiography showed 50% narrowing of the left main stem and left anterior coronary arteries and 100% occlusion of the right and left circumflex coronary arteries. (Reproduced with permission from Jain and He.36)
of exercise 18FDG imaging? These issues are discussed in the following paragraphs. It is well known that resting myocardial glucose uptake is insulin dependent. Diabetic patients show low 18FDG uptake at rest, and this abnormality may persist despite the use of insulin-glucose clamp. Whether this factor plays a role in ischemia-induced increase in myocardial 18FDG uptake is not adequately known. Ischemia-induced translocation of GLUT receptors may not be dependent on insulin and one may still be able to successfully use exercise 18FDG imaging in diabetic patients. However, the issue of exercise ischemia imaging in diabetic subjects requires further studies. Unlike rest 18FDG imaging for conventional viability studies, the goal of exercise 18FDG study is to suppress myocardial glucose uptake by the normal myocardium to maximize the difference in glucose uptake between nonischemic and ischemic myocardium, so that only ischemic myocardium is visualized. This requires fasting for at least 12 hours (or perhaps longer, if possible). It has been proposed that perhaps a low carbohydrate meal before fasting may be further helpful in this regard. But, this has not been evaluated so far. 18 FDG was injected at peak exercise in the study by He et al.32 Whether similar results can be obtained if 18FDG were injected hours or even days after an episode of exerciseinduced myocardial ischemia is highly relevant clinically. This may permit the use of 18FDG as a memory marker for ischemia similar to 123I-beta-methyliodophenyl-pentadecanoic acid, a radiolabeled fatty acid analogue. Data from animal studies suggest that increased glucose uptake may persist for days in the myocardial segments following experimental occlusion of a coronary artery for a few minutes.25 Whether intensity of this
experimental ischemia is similar to that observed with clinically induced myocardial ischemia with treadmill exercise is unclear. Abbott et al injected 18FDG 60-90 minutes after treadmill exercise in patients with CAD who underwent separate exercise-rest SPECT imaging. Increased 18FDG uptake was still observed but only in one-third of vascular territories with reversible perfusion abnormalities.33 To explore this phenomenon further, Dou et el40 performed exercise and rest 99mTcsestamibi and 18FDG imaging 24 hours apart in 18 patients with Z70% luminal narrowing of Z1 coronary vessel(s). A total of 15 patients showed increased regional 18FDG uptake on exercise imaging. Of these 15 patients, 8 (53%) had no discernible 18FDG uptake, 5 (33%) had decreased 18FDG uptake, and only 2 (13%) had persistent 18FDG uptake on rest 18 FDG images (Fig. 6). The summed 18FDG uptake score significantly decreased from 14.4 ⫾ 10.3 at exercise to 6.7 ⫾ 9.2 at rest (P ¼ 0.01). Patients with persistent 18FDG uptake at rest had more extensive 18FDG uptake and lower peak rate pressure product (double product) at exercise in comparison with patients with no residual 18FDG uptake at rest. This study shows that increased exercise-induced regional myocardial 18 FDG uptake is a specific marker of myocardial ischemia and is not seen 24 hours after an episode of myocardial ischemia in most patients with CAD. Persistent regional myocardial 18FDG uptake can still be seen, but only in a small proportion of patients and is probably a marker of more severe CAD and more severe myocardial ischemia on exercise. Therefore, for routine clinical diagnostic studies, 18FDG should be injected at peak exercise. Unlike perfusion tracers, 18FDG is cleared slowly from the blood pool, and on standard resting 18FDG studies, a delay of 45-60 minutes is required following the
Myocardial 18FDG imaging
381
Figure 6 Exercise (Ex) and rest (R) 99mTc-sestamibi perfusion (Perf) and 18FDG images of a 49-year-old male with exertional angina in short axis and vertical and horizontal long axes. There is exercise-induced perfusion abnormality in the posterior septum and inferior wall, which is reversible on the rest images. There is intense 18FDG uptake on the exercise images (yellow arrows) in the corresponding segments, which is not present in the rest images. This patient had 85% stenosis of the right coronary artery. (This research was originally published in JNM, Dou et al.40 © by the Society of Nuclear Medicine and Molecular Imaging, Inc.)
tracer injection before images can be acquired. Blood pool clearance kinetics of 18FDG have not been studied following its administration at peak exercise. It is likely that blood pool clearance of 18FDG may be faster compared with its clearance on resting 18FDG studies. However, till exact data are available, it is prudent to start image acquisition 40-60 minutes after injection on exercise 18FDG studies. Hot spot cardiac imaging does require a roadmap for proper processing and interpretation of the images. Spatial orientation of the left ventricle may be extremely difficult if there is no tracer uptake or only localized tracer uptake in the heart. Getting adequate orientation of the heart is rarely a problem with MPI even in the presence of large areas of perfusion abnormalities; however, this can be a major challenge with “hot spot” imaging. In the absence of a proper roadmap, extracardiac tracer uptake or even cardiac blood activity may be misinterpreted as myocardial uptake or a true cardiac uptake may be incorrectly localized to a different myocardial segment. Simultaneous 18FDG and perfusion imaging can overcome this difficulty apart from providing information about myocardial perfusion. PET/CT imaging can provide a good roadmap of the myocardium, which may obviate the need for a perfusion map. There is a significant degree of regional variability in 18FDG uptake by the left ventricular myocardium on resting studies.41 It has been speculated that given this variability, it may be difficult to use 18FDG for imaging exercise-induced myocardial ischemia. However, ischemia-induced increase in myocardial glucose or 18FDG appears to be 10-fold or even more, several times higher than the regional variability in glucose uptake at rest. This results in a very high contrast between the ischemic
and nonischemic myocardium, irrespective of regional heterogeneity in 18FDG uptake at rest by the nonischemic myocardium. Quantitative analysis is always helpful in determining subtle differences in tracer uptake and in determining whether these differences are within normal or outside the range of normal variability. Whereas, quantitative analyses are well standardized for perfusion imaging, quantitative programs for hot spot imaging are not yet adequately developed. PET images lend themselves more readily to quantitative analysis than SPECT images. Quantitative programs are yet to be developed for 18 FDG ischemia imaging. Nevertheless, qualitative analysis can still be used quite effectively for interpreting exercise 18FDG images till quantitative programs are developed. 18 FDG is a promising agent for direct imaging of exerciseinduced myocardial ischemia, which can potentially result in the single largest indication for use of 18FDG in clinical practice. 18
FDG for Cardiac Sarcoidosis Imaging Cardiac sarcoidosis is a systemic inflammatory disorder of unclear etiology characterized by noncaseating granulomas in multiple organs.42,43 The incidence of this disease varies according to ethnicity, sex, and geographic region and ranges from 3-80/100,000. The incidence is higher in African Americans, women, and Scandinavian countries. The disease is associated with a long course of remissions and
382 exacerbations and has a low mortality rate. Lymph nodes and lungs are the most frequently affected organs, but any other organ system can be involved. Cardiac involvement occurs in a variable proportion of cases and has been described to occur in 20%-40% of the cases. Although cardiac involvement is less common, it is associated with a worse prognosis and high mortality from arrhythmias and congestive heart failure and warrants a more aggressive therapy.43 However, detection of cardiac involvement is often challenging and cumbersome and may require multiple diagnostic tests.44 Several different imaging and nonimaging tests such as echocardiography, MPI, gallium-67 scintigraphy, MRI, and endomyocardial biopsy are used. However, all of these tests suffer from low sensitivity and low specificity and are not suitable for serial follow-up and for evaluation of efficacy of therapy. It is likely that cardiac involvement in sarcoidosis remains underdiagnosed owing to a lack of readily available and reliable tests for its diagnosis. In the absence of a diagnostic gold standard, cardiac sarcoidosis is often missed in its early stages, when treatment is most likely to be effective. Currently, Guidelines of the Japanese Ministry of Health and Welfare, as revised by the Japanese Society of Sarcoidosis and Other Granulomatous Disorders in 2006, remain the worldwide standard for clinical diagnosis of cardiac sarcoidosis.45 According to these criteria, diagnosis of cardiac sarcoidosis is established with the histologic evidence of noncaseating epithelioid granulomas on endomyocardial biopsy or in the presence of at least 2 major criteria (advanced atrioventricular block, thinning or scarring of the basal interventricular septum, positive gallium-67 scintigraphy, or depressed left ventricular ejection fraction) or 1 major and 2 or more minor criteria (abnormal electrocardiogram showing multifocal or frequent ventricular ectopics, right bundle branch block; abnormal echocardiogram showing regional wall motion abnormalities or ventricular aneurysm; perfusion defects on MPI; or unexplained interstitial fibrosis or significant monocyte infiltration on endomyocardial biopsy) in patients with systemic sarcoidosis. Development of a reliable noninvasive test for diagnosing cardiac sarcoidosis remains an important unmet need in diagnostic imaging. Recent studies have indicated a potential role of hot spot imaging with 18FDG for the detection of inflammatory response that accompanies cardiac sarcoidosis. Inflammatory cells have a very high glucose uptake, and 18FDG has been used for imaging infection and inflammation46,47 in various organ systems. 18FDG imaging shows increased focal or diffuse myocardial 18FDG uptake in patients with active cardiac sarcoidosis. Focal or regional myocardial 18FDG uptake is more specific for cardiac sarcoidosis than a diffuse or global myocardial 18FDG uptake, as the later could also be due to a normal variant such as incomplete suppression or normal physiological myocardial 18FDG uptake (Fig. 7). As normal myocardium may also show variable degrees of 18FDG uptake, particularly after carbohydrate-rich meal, a strict physiological milieu is required to suppress normal myocardial 18FDG uptake. This can be achieved by prolonged fasting, feeding a diet rich in fats and proteins and low on carbohydrates for 2448 hours, or by administration of heparin before 18FDG.44
D. Jain et al. Heparin administration increases the plasma levels of free fatty acids, which helps to decrease myocardial 18FDG uptake. Currently, there is no consensus on the optimal patient preparation for myocardial 18FDG imaging for cardiac sarcoidosis. Perhaps a combination of prolonged fasting, low carbohydrate diet, and heparin administration may be the best approach. Yamagishi et al48 performed cardiac N-13 ammonia perfusion imaging, fasting 18FDG imaging, 201Tl perfusion imaging, and 67Ga imaging in 17 patients with cardiac sarcoidosis. 201Tl perfusion defects were seen only in 35%, abnormal cardiac 67 Ga uptake was seen only in 18%, 13N-ammonia perfusion defects were present in 76%, and abnormal 18FDG uptake was present in 82%. 18FDG uptake was seen most frequently in the basal and midanteroseptal walls of the left ventricle. On followup after steroid therapy, there was marked reduction in 18FDG uptake, whereas there was no change in 13N-ammonia perfusion defects. Okumura et al49 performed 99mTc-sestamibi SPECT MPI, 67 Ga scintigraphy, and 18FDG imaging in 22 patients with sarcoidosis, of whom 11 had evidence of cardiac involvement and 11 did not have cardiac involvement. The sensitivities of 18 FDG, MPI, and gallium-67 were 100%, 64%, and 36%, respectively. They also compared myocardial standardized uptake values (SUVs) of the 18FDG in patients with and without cardiac sarcoidosis, and with a group of healthy controls. SUVs ranged from 1.85-1.94 in normal healthy subjects, from 1.74-3.3 in patients with no sarcoidosis, and from 2.84-14.13 in patients with cardiac sarcoidosis. This study indicates a superiority of fasting cardiac 18FDG imaging over other nuclear imaging modalities for the detection of cardiac involvement in patients with sarcoidosis. However, simultaneous cardiac 18FDG and perfusion imaging may have a complimentary role. Increased 18FDG uptake may be more indicative of active inflammation, and perfusion abnormalities may be more indicative of fibrosis and scar formation. From a therapeutic standpoint, presence of active inflammation would require treatment with steroids and other anti-inflammatory agents, whereas the presence of scar would warrant consideration for antiarrhythmic therapy. Detection and treatment of inflammation at early stages could prevent fibrosis and scar formation and their complications. Osborne et al50 performed serial 18FDG imaging and gated 82Rb perfusion imaging in 23 patients with cardiac sarcoidosis. The median interval between the first and last imaging studies was 2 years. The patients were treated with steroids, angiotensin converting enzyme inhibitors or angiotensin receptor blockers, and beta-blockers in the interim. The investigators observed an inverse relationship between reduction in myocardial 18FDG uptake and improvement in left ventricular ejection fraction. The patients were classified as responders or nonresponders to treatment based on reduction in myocardial 18FDG uptake on follow-up imaging studies. The responders showed a progressive improvement in left ventricular ejection fraction, whereas nonresponders showed no change or a deterioration in left ventricular ejection fraction. This study shows the powerful role that 18FDG imaging can play in the initial evaluation, titration of
Myocardial 18FDG imaging
383
Figure 7 PET/CT study in a subject with sarcoidosis involving the heart. (A) Stress (dipyridamole) and rest 82Rb perfusion images show normal perfusion. 18FDG uptake is focally increased in basal inferior wall, consistent with active cardiac sarcoidosis (arrows). (B) Whole-body imaging shows multiple extracardiac foci of 18FDG uptake in chest, liver, bone, and lymph nodes, consistent with extensive systemic sarcoidosis. HLA, horizontal long axis; MIP, maximum intensity projection; SA, short axis; VLA, vertical long axis (This research was originally published in JNM, Schatka and Bengel.44 © by the Society of Nuclear Medicine and Molecular Imaging, Inc.)
therapy, and subsequent follow-up of patients with known or suspected cardiac sarcoidosis. Ahmadian and colleagues have proposed cardiac metabolic activity (CMA), a new quantitative measure of cardiac involvement by sarcoidosis on cardiac 18FDG-PET imaging.51 CMA is a numerical score that takes into account the volume and intensity of abnormal myocardial 18FDG uptake. CMA
calculates the voxels in the myocardium with 18FDG activity above a predefined threshold and multiplies it by the mean SUVs in these voxels. This measurement of volume and volume intensity is similar to what is referred to as metabolic tumor volume and total lesion glycolysis in oncologic 18FDG imaging for solid tumors. The investigators compared CMA with traditional indices of quantitative analysis of cardiac
384 18
FDG-PET images in 24 patients with cardiac sarcoidosis and 7 normal controls. SUVs provide a good measure of the intensity of myocardial 18FDG uptake but do not take into consideration the extent of this uptake. However, any potential advantages of this new index over the currently used indices of SUVs and number of myocardial segments with increased uptake need to be evaluated in prospective studies. Hot spot cardiac imaging with 18FDG remains a highly exciting new imaging modality with profound diagnostic and therapeutic implications for cardiac sarcoidosis. It can provide a very useful insight into the pathophysiology of cardiac sarcoidosis and can potentially redefine the extent and frequency of cardiac involvement in patients with sarcoidosis. This technique may also enable detection of cardiac involvement early in the course of sarcoidosis, when suitable treatment can prevent further cardiac damage and prevent fibrosis and scar that are responsible for much of the cardiac morbidity and mortality in these patients.
Conclusion Cardiac imaging is at an important crossroads. Technological advances permit ultrafast noninvasive imaging of coronary arteries, coronary calcium, and atheroma. These techniques are being proposed to replace standard nuclear MPI techniques. Nuclear imaging may not be able to match the speed and resolution of these techniques. However, nuclear imaging has unrivaled ability to noninvasively image biochemical, molecular, and metabolic processes and receptor and transporter function under different physiological conditions. These techniques have a potential to be used as very powerful diagnostic tools in routine clinical practice and also serve as sophisticated experimental tools for studying difficult-tounderstand phenomena related to cardiac pathophysiology under various disease conditions, and for studying the effect of therapeutic interventions in these conditions. Hot spot imaging of the heart using 18FDG provides unique diagnostic tools for studying myocardial ischemia and cardiac sarcoidosis. Exercise 18 FDG imaging seems to be ideally suited for direct imaging of exercise-induced myocardial ischemia and for the routine detection of CAD. These new developments can greatly advance the field of nuclear cardiology but further large-scale and carefully planned studies are needed before they can find an appropriate clinical niche.
References 1. Zaret BL, Strauss HW, Martin ND, et al: Noninvasive evaluation of regional myocardial perfusion with radioactive potassium: Study of patients at rest, exercise, and during anginal pectoris. N Engl J Med 1973;288:809-812 2. Iskandrian AE, Hage FG, Shaw LJ, et al: Serial myocardial perfusion imaging: Defining a significant change and targeting management decisions. JACC Cardiovasc Imaging 2014;7:79-96. http://dx.doi.org/ 10.1016/j.jcmg.2013.05.022 3. Beller GA, Zaret BL: Contributions of nuclear cardiology to diagnosis and prognosis of patients with coronary artery disease. Circulation 2000;101:1465-1478 4. Jain D, Zaret BL: Nuclear imaging in cardiovascular medicine. In: Rosendorf C, (ed): Chapter in Essential Cardiology. ed 3. Springer; 2013, pp. 195-220. 978-1-4614-6705-2
D. Jain et al. 5. Jain D: 99mTechnetium labeled myocardial perfusion imaging agents. Semi Nucl Med 1999;29:221-236 6. Travin MI: Cardiac cameras. Semin Nucl Med 2011;41:182-201. http://dx.doi.org/10.1053/j.semnuclmed.2010.12.007. [review] 7. Ghimire G, Hage FG, Heo J, et al: Regadenoson: A focused update. J Nucl Cardiol 2013;20:284-288. http://dx.doi.org/10.1007/s12350-012-96613. [review] 8. Boden W: Management of chronic coronary disease: Is the pendulum returning to equipoise? Am J Cardiol 2008;101:S69-S74 9. Lapi SE, Voller TF, Welch MJ: Positron emission tomography imaging of hypoxia. PET Clin 2009;4:39-47 10. Krohn KA, Link JM, Mason RP: Molecular imaging of hypoxia. J Nucl Med 2008;49(suppl 2):129S-148S 11. Buerkle A, Weber WA: Imaging of tumor glucose utilization with positron emission tomography. Cancer Metastasis Rev 2008;27:545-554 12. Di Carli MF: Assessment of myocardial viability after myocardial infarction. J Nucl Cardiol 2002;9:229-235 13. Dilsizian V, Arrighi JA, Diodati JG, et al: Myocardial viability in patients with chronic coronary artery disease. Comparison of 99mTc-sestamibi with thallium reinjection and 18F-fluorodeoxyglucose. Circulation 1994;89:578-587 14. Llaurado JG: The quest of the perfect myocardial perfusion indicator…still a long way to go. J Nucl Med 2001;42:282-284 15. Zaret BL: Pursuit of the ideal perfusion agent. J Nucl Cardiol 2002;9:149-150 [editorial] 16. Beller GA: Will cardiac positron emission tomography ultimately replace SPECT for myocardial perfusion imaging? J Nucl Cardiol 2009;16:841-843 [editorial] 17. Jain D, McNulty PH: Exercise-induced myocardial ischemia: Can this be imaged with F-18-fluorodeoxyglucose? J Nucl Cardiol 2000;7:286-288 [editorial] 18. Neely JR, Rovetto MJ, Oram JF: Myocardial utilization of carbohydrates and lipids. Prog Cardiovasc Dis 1972;15:289-329 19. Liedtke AJ: Alterations of carbohydrate and lipid metabolism in the acutely ischemic heart. Prog Cardiovasc Dis 1981;23:321-336 20. Schwaiger M, Schelbert HR, Ellison D, et al: Sustained regional abnormalities in cardiac metabolism after transient ischemia in the chronic dog model. J Am Coll Cardiol 1985;6:336-347 21. Schwaiger M, Neese RA, Araujo L, et al: Sustained nonoxidative glucose utilization and depletion of glycogen in reperfused canine myocardium. J Am Coll Cardiol 1989;13:745-754 22. McNulty PH, Sinusas AJ, Shi CQ, et al: Glucose metabolism distal to a critical coronary stenosis in a canine model of low-flow myocardial ischemia. J Clin Invest 1996;98:62-69 23. McNulty PH, Jagasia D, Cline GW, et al: Persistent changes in myocardial glucose metabolism in vivo during reperfusion of a limited-duration coronary occlusion. Circulation 2000;101:917-922 24. Herraro P, Weinhemer CJ, Dence C, et al: Quantification of myocardial glucose utilization by PET and 1-carbon-11-glucose. J Nucl Cardiol 2002;9:5-14 25. McNulty PH, Jagasia D, Cline G, et al: Persistent changes in myocardial glucose metabolism in vivo during reperfusion of a limited-duration coronary occlusion. Circulation 2000;101:917-923 26. Sun D, Nguyen N, Degrado T, et al: Ischemia induces translocation of the insulin-responsive glucose transporter GLUT 4 to the plasma membrane of cardiac myocytes. Circulation 1994;89:793-798 27. Giordano FJ: Oxygen, oxidative stress, hypoxia, and heart failure. J Clin Invest 2005;115:500-508 28. Jain D, He ZX, Lele V, et al : Direct myocardial ischemia imaging: A new paradigm in cardiovascular nuclear imaging. Clin Cardiol 2014 (in press) 29. Abramson BL, Ruddy TD, de Kemp RA, et al: Stress perfusion/metabolic imaging: A pilot study for a potential new approach to the diagnosis of coronary artery disease in women. J Nucl Cardiol 2000;7:205-212 30. Camici P, Araujo LI, Spinks T, et al: Increased uptake of 18Ffluorodeoxyglucose in postischemic myocardium of patients with exercise-induced angina. Circulation 1986;74:81-88 31. Araujo LI, McFalls EO, Lammertsma AA, et al: Dipyridamole-induced increased glucose uptake in patients with single-vessel coronary artery disease assessed with PET. J Nucl Cardiol 2001;8:339-346
Myocardial 18FDG imaging 32. He ZX, Shi RF, Wu YJ, et al: Direct imaging of exercise-induced myocardial ischemia with fluorine-18-labeled deoxyglucose and Tc-99m-sestamibi in coronary artery disease. Circulation 2003;108: 1208-1213 33. Abbott BG, Liu YH, Arrighi JA: [18F]Fluorodeoxyglucose as a memory marker of transient myocardial ischaemia. Nucl Med Commun 2007;28:89-94 34. Arrighi JA: F-18 fluorodeoxyglucose imaging in myocardial ischemia: Beyond myocardial viability. J Nucl Cardiol 2001;8:417-420 35. He ZX, Shi RF, Wu YJ, et al: Myocardial ischemia, fluorodeoxyglucose, and severity of coronary artery stenosis: The complexities of metabolic remodeling in hibernating myocardium. Circulation 2004;109: e167-e170 [authors' reply to letter to the editor] 36. Jain D, He ZX: Direct imaging of myocardial ischemia: A potential new paradigm in nuclear cardiovascular imaging. J Nucl Cardiol 2008; 15:617-630 [editorial point of view] 37. Jain D, He ZX, Ghanbarinia A: Direct imaging of myocardial ischemia with 18FDG: A new potentially paradigm-shifting molecular cardiovascular imaging technique. Curr Cardiovasc Imag Rep 2010;3:134-150 38. Sandler MP, Patton JA: Fluorine-18 labeled fluorodeoxyglucose myocardial single-photon emission computed tomography: An alternative for determining myocardial viability. J Nucl Cardiol 1996;3:342-349 39. Slatt RH, Bax JJ, van Veldhuisen DJ, et al: Prediction of functional recovery after revascularization in patients with chronic left ventricular dysfunction: Head to head comparison between 99mTc-sestamibi/18F-FDG DISA SPECT and 13N-ammonia/18F-FDG PET. Eur J Nucl Med Mol Imaging 2006;33:716-723 40. Dou KF, Yang MF, Yang YJ, et al: Direct myocardial ischemia imaging: 18 FDG uptake during exercise and at rest in patients with coronary artery disease. J Nucl Med 2008;49:1986-1991
385 41. Herrero P, Gropler RJ: Imaging of myocardial metabolism. J Nucl Cardiol 2005;12:345-358 [review] 42. Doughman AR, Williams BR: Cardiac sarcoidosis. Heart 2006;92: 282-288 43. Mehta D, Lubitz SA, Frankle Z, et al: Cardiac involvement in patients with sarcoidosis: Diagnostic and prognostic value of outpatient testing. Chest 2008;133:1426-1435 44. Schatka I, Bengel FM: Advanced imaging of cardiac sarcoidosis. J Nucl Med 2014;55:99-106 45. Soejima K, Yada H: The workup and management of patients of patients with apparent or subclinical cardiac sarcoidosis: With emphasis of the associated heart rhythm abnormalities. J Cardiovasc Electrophysiol 2009;20:578-583 46. Meller J, Sahlmann C, Scheel AK: 18F-FDG PET and PET-CT in fever of unknown origin. J Nucl Med 2007;48:35-45 47. Keidar Z., Nitecki S. FDG-PET in prosthetic graft infections. Semin Nucl Med 2013;43:396-402 [review]. 10.1053/j.semnuclmed.2013.04.004 48. Yamagishi H, Shirai N, Takagi M, et al: Identification of cardiac sarcoidosis with 13N-NH3/18F-FDG PET. J Nucl Med 2003;44:1030-1036 49. Okumura W, Iwasaki T, Toyama T, et al: Usefulness of fasting 18F-FDG PET in identification of cardiac sarcoidosis. J Nucl Med 2004;45: 1989-1998 50. Osborne MT, Hulten EA, Singh A, et al: Reduction in (18)F-fluorodeoxyglucose uptake on serial cardiac positron emission tomography is associated with improved left ventricular ejection fraction in patients with cardiac sarcoidosis. J Nucl Cardiol 2014;21:166-174 51. Ahmadian A, Brogan A, Berman J, et al: Quantitative interpretation of FDG PET/CT with myocardial perfusion imaging increases diagnostic information in the evaluation of cardiac sarcoidosis. J Nucl Cardiol 2014;20:9901-9909 10-1007/s12350-014
Introduction
N
uclear cardiovascular imaging using SPECT or PET tracers is used extensively for myocardial perfusion imaging (MPI) and cardiac function assessment. MPI provides very powerful diagnostic and prognostic information in patients with known or suspected coronary artery disease (CAD).1-4 Development of new perfusion tracers, pharmacologic stress agents, and innovations and improvement in imaging equipment and software for quantitative analysis and interpretation has resulted in a wide acceptance of this
*Cardiovascular Nuclear Imaging Laboratory, Department of Medicine, New York Medical College, Westchester Medical Center, Valhalla, NY. †Department of Nuclear Medicine, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. ‡Department of Nuclear Medicine, Jaslok Hospital & Research Centre, Mumbai, Maharashtra, India. Address reprint requests to Diwakar Jain, MD, FACC, FRCP, FASNC, New York Medical College, Macy Pavilion 111, Westchester Medical Center, 100 Woods Rd, Valhalla, NY 10595. E-mail: [email protected]
http://dx.doi.org/10.1053/j.semnuclmed.2014.06.010 0001-2998/& 2014 Elsevier Inc. All rights reserved.
technique in routine clinical practice.4-8 Nuclear imaging also provides a unique and unrivaled opportunity to image biochemical and metabolic processes, cell membrane receptor and transporter function, inflammation, and gene expression by identifying and developing a repertoire of suitable ligands, and radiolabeling them with various SPECT and PET radiotracers. Thus, radionuclide imaging techniques can be developed for imaging myocardial metabolism, ischemia, viability, inflammation, angiogenesis, apoptosis, necrosis, and adrenergic neuronal activity at molecular and cellular levels. These novel molecular imaging techniques provide us with an unforeseen insight into the arena of cardiovascular pathophysiology, which can transform the field of therapy. Deoxyglucose is a glucose analogue, which tracks the initial steps of glucose uptake and phosphorylation by the tissues or organs. Once inside the cells, it enters glycolytic pathway similar to glucose. Glucose is phosphorylated to glucose-6phoshpate by enzyme hexokinase. Glucose-6-phosphate is further phosphorylated and converted to 2 molecules of glycerol phosphate. Deoxyglucose also is phosphorylated to deoxyglucose-6-phosphate by hexokinase, but its metabolism 375
376 stops here with no further phosphorylation. Deoxyglucose-6phosphate is trapped intracellularly.9 Deoxyglucose can be radiolabeled9 with F-18 (18FDG). 18FDG is used for imaging initial steps of glucose metabolism in various organs and tissues in the body.9 This technique is used extensively for imaging malignant tumors,9-11 as malignant tumors show increased glucose uptake. 18FDG is also used for imaging viable myocardium.12,13 Management of patients with CAD and impaired left ventricular function requires a precise differentiation of irreversibly damaged or scarred myocardium that is unlikely to improve after revascularization from myocardium that is dysfunctional but viable and is likely to improve after revascularization. Several different imaging techniques such as thallium-201 perfusion imaging after a long redistribution phase, low-dose dobutamine echocardiography, and MRI can be used to draw this distinction. 18FDG imaging detects preserved or enhanced glucose uptake relative to its perfusion in the viable myocardium. Apart from viability detection, myocardial 18FDG imaging can also be used for imaging myocardial ischemia and cardiac sarcoidosis. This article is focused on these newly emerging “hot spot” cardiac imaging techniques using 18FDG. 18
FDG for Myocardial Ischemia Imaging Although in extensive clinical use, MPI has several limitations. The sensitivity and specificity are far from ideal.14-16 The sensitivity of stress-rest MPI for the detection of individual vascular territories with significant obstructive disease is relatively low. Perfusion abnormalities can sometimes be relatively unimpressive or rarely even absent in patients with severe triple-vessel CAD. Artifacts due to soft tissue attenuation, extracardiac tracer activity, partial volume effect, scatter, relatively poor spatial resolution, and other technical reasons are common and may not be entirely corrected or eliminated using existing technologies. Some of these drawbacks are inherent to “cold spot” imaging. A technique for “hot spot” imaging of myocardial ischemia can potentially eliminate some of the drawbacks of MPI.17
Metabolic Changes in Myocardial Ischemia Myocardial ischemia imaging can be accomplished by targeting metabolic changes, which accompany myocardial ischemia. Several unique features of myocardial metabolism and their alteration with myocardial ischemia make them potential targets for direct imaging of myocardial ischemia.18-26 Myocardium has an extremely high metabolism to meet energy requirements for its pumping function. Nearly 90% of the myocardial energy demand is for its contractile function. Myocardium consumes 8-15 mL of oxygen/min/100 g of tissue at rest, which increases up to 70 mL/min/100 g at maximum workload.27 Myocardium needs a constant supply of oxygen as well as substrates for energy production. Normal myocardium is capable of extracting a wide variety of substrates for energy production: glucose, free fatty acids,
D. Jain et al. pyruvate, lactate, amino acids, and ketone bodies. Of these, free fatty acids and glucose are the predominant sources of energy production. However, the proportion of their relative uptake and percent contribution to energy production is highly variable and dependent on several factors: fasting or fed state, insulin levels, oxygen supply, circulating catecholamines, and the relative plasma concentration of these substrates. Under fasting conditions, free fatty acid levels are high and glucose and insulin levels are low; therefore, free fatty acids constitute the major source of energy production, with a relatively low glucose uptake. After a carbohydrate-rich meal, the blood glucose and insulin levels are high; therefore, myocardial glucose uptake is high and glucose contributes a higher fraction of energy production. Exercise results in an increase in catecholamines and free fatty acid levels, and a higher proportion of energy is derived from free fatty acid metabolism. However, profound changes in substrate use occur with the onset of myocardial ischemia. Free fatty acid oxidation being an obligatory aerobic process is very sensitive to reduced oxygen availability. Myocardial ischemia results in an impaired uptake and oxidation of free fatty acids. Interestingly, impaired free fatty acid uptake and oxidation persists much longer than the duration of ischemia, providing a signature or memory of myocardial ischemia. Glucose metabolism is a 2-step process: the initial glycolysis is an anerobic process, which occurs in cytosol and results in conversion of glucose to pyruvate. Pyruvate is converted to lactate under anerobic conditions. But in the presence of oxygen, pyruvate enters the Krebs cycle in the mitochondria after conversion to acetyl co-enzyme A, an obligatory aerobic process, and through a chain of oxidative reactions undergoes conversion to carbon dioxide and water. With the onset of ischemia, glycolysis becomes the predominant source of energy production for the sustenance of the ischemic myocardium. However, glycolysis is inefficient in energy production. One molecule of glucose provides only 2 molecules of adenosine triphosphate by anerobic glycolysis, whereas oxidative metabolism yields 38 molecules of adenosine triphosphate. Therefore, ischemic myocardium requires a very large supply of glucose for its sustenance during ischemia. This is brought about by an immediate translocation of specialized transporters (glucose transporters GLUT-4 and GLUT-1) from cytosol to the sarcolemma with the onset of myocardial ischemia. These transporters are highly efficient in glucose transport across the cell membrane and are insulin independent. Another interesting feature of this process is that once GLUT transports are translocated to the sarcolemma, they remain there for a much longer period even after the resolution of myocardial ischemia. The exact reason or biological advantage of this prolonged overexpression of GLUT receptors even after the resolution of ischemia is not known. Perhaps, further research on the kinetics and recycling of cell membrane proteins, receptors, and transporters may be able to explain this phenomenon. However, from a practical standpoint, it indicates that this metabolic signature of myocardial ischemia lasts much longer than the exact duration of myocardial ischemia, which can be exploited to our advantage for imaging myocardial ischemia in the clinical context.
Myocardial 18FDG imaging
377
Myocardial ischemia results in a dramatic and sustained increase in glucose uptake compared with the normal myocardium.19-23 However, normal myocardium would have a much lower glucose extraction on exercise under fasting conditions, as free fatty acids uptake is the predominant source of energy production. Thus, a profound metabolic differential exists between the normal and ischemic myocardium on exercise. 18 FDG imaging can thus be used for imaging myocardial ischemia.
Hot Spot Imaging of Myocardial Ischemia The differential uptake of glucose between normal and ischemic myocardium permits the use of exercise 18FDG as a “hot spot” imaging agent28-37 for imaging exercise-induced myocardial ischemia. 18FDG is ordinarily imaged using PET cameras; however, SPECT cameras equipped with thicker sodium iodide crystals and ultra-high energy collimators have also been used with varying success for its imaging.38,39 Several studies have investigated the potential of 18FDG as an ischemic marker by injecting it during stress testing followed by imaging. Camici et al30 observed 18FDG uptake in 9 of 10 patients in regions with reduced rubidium-82 uptake during exercise. Abramson et al29 observed increased 18FDG uptake in 8 of 9 women in myocardial segments with reversible perfusion abnormalities. Araujo et al studied myocardial blood flow using 15O-water and 18FDG uptake at rest and after dipyridamole infusion using PET imaging in 11 patients with single-vessel disease and no prior myocardial infarction. They observed significantly increased myocardial 18FDG uptake after dipyridamole administration in vascular territories with blunted coronary vasodilatory capacity with dipyridamole.31 Abbott et al33 examined the feasibility of 18FDG imaging as a memory marker of myocardial ischemia. They injected 18FDG 60-90 minutes after exercise in a group of patients with CAD. They observed increased 18FDG uptake in only one-third of the vascular territories with perfusion abnormalities. The relatively low sensitivity of 18FDG imaging for the detection of myocardial ischemia in this study may be related to a delay of 1-1.5 hours between exercise and injection of 18FDG. These studies were carried out using PET imaging. He et al32 studied 26 patients with known or suspected CAD and no prior myocardial infarction. These patients underwent simultaneous MPI and ischemia imaging following the intravenous injection of 99mTc-sestamibi and 18FDG at peak exercise. They used
SPECT camera equipped with thicker sodium iodide crystal and ultra-high energy collimators to permit simultaneous perfusion and ischemia imaging. Rest perfusion imaging was carried out separately. All patients underwent coronary angiography. They compared exercise 18FDG myocardial images with exercise-rest 99mTc-sestamibi images and coronary angiography. Of 22 patients with Z50% narrowing of Z1 coronary arteries, 18 had perfusion abnormalities (sensitivity 82%), whereas 20 had abnormal myocardial 18FDG uptake (sensitivity 91%, P ¼ not significant). Perfusion abnormalities were seen in myocardial segments corresponding to 25 vascular territories of 51 vessels with Z50% luminal narrowing in 22 patients (sensitivity 49%), whereas increased 18FDG uptake was seen in 34 vascular territories (sensitivity 67%, P ¼ 0.008) (Table). 18FDG images were of high quality and easy to interpret but required simultaneous perfusion images for localizing abnormal myocardial 18FDG uptake. This study provided a proof that exercise-induced myocardial ischemia can be imaged directly with 18FDG (Figs. 1-5). Combined exercise 18FDG-99mTc-sestamibi imaging provides a better assessment of exercise-induced myocardial ischemia compared with exercise-rest perfusion imaging. This study not only evaluated the role of 18FDG as a “hot spot” imaging agent for exercise-induced myocardial ischemia using SPECT imaging cameras but also addressed the issues of 18FDG image quality, need for a roadmap for an accurate myocardial localization of 18 FDG, and an imaging protocol suitable for routine clinical use and potential advantages of ischemia imaging over standard stress-rest MPI. These results have been confirmed by several investigators. Although based on a relatively small sample size, the potential advantages of direct ischemia imaging are obvious from the aforementioned results. Direct ischemia imaging has a trend toward higher sensitivity compared with stress-rest perfusion imaging for the detection of patients with CAD. However, it does have significantly higher sensitivity for the detection of individual vascular territories perfused by significantly narrowed coronary arteries. This is particularly obvious in patients with triple-vessel CAD, where increased 18FDG may be observed in all vascular territories (Fig. 3). A particular limitation of standard exercise-rest MPI is the underestimation of myocardial ischemia or viability or overestimation of scar with this technique.13 A small but significant percentage of myocardial segments may show a fixed or only partially reversible perfusion abnormality despite the presence of
Table Comparison of Abnormalities in Patients With Z50% Narrowing of Z1 Coronary Vessels. (Reproduced With Permission From He et al.32) Ischemia 99m
Tc-sestamibi 18 FDG
99m
Tc-sestamibi FDG
18
Ischemia and Scar
Patients (n ¼ 22) 12 (55%) 4 (18%) 20 (91%) 0 P ¼ 0.04 Vascular territories with Z50% narrowing (n ¼ 51) 16 (31%) 6 (12%) 34 (67%) 0 P o 0.001
Scar
No Abnormality
2 (9%) 0
4 (18%) 2 (9%)
3 (6%) 0
26 (51%) 17 (33%)
D. Jain et al.
378
Figure 1 Exercise (Ex) and rest (R) 99mTc-sestamibi and exercise 18FDG images of a 67-year-old man with angina and no prior myocardial infarction. There is a large area of partially reversible perfusion abnormality involving the septum, anterior wall, and apex (small arrows). Intense 18FDG uptake is present in these areas (solid arrowheads). Coronary angiography showed 90% stenosis of the left anterior descending coronary artery and 60% stenosis of the left circumflex artery. (Reproduced with permission from He et al.32)
myocardial viability. This observation has led to the recommendation for the use of additional imaging studies in patients with fixed perfusion abnormality on standard stress-rest perfusion imaging finding if one suspects the presence of viability in segments with fixed perfusion abnormality.13 In the aforementioned study, a small percentage of patients with CAD (9%) exhibited fixed perfusion abnormality despite no
evidence of prior myocardial infarction. All of these patients showed intense regional 18FDG uptake in the areas of fixed perfusion abnormality similar to the one seen in myocardial segments with reversible perfusion abnormality, indicating that exercise 18FDG is more sensitive for the detection of exerciseinduced myocardial ischemia compared with exercise-rest perfusion imaging. Figure 5 shows a patient with a
Figure 2 Exercise (Ex) and rest (R) 99mTc-sestamibi and exercise 18FDG ischemia images of a 57-year-old man with angina and no prior myocardial infarction. There is a large area of reversible perfusion abnormality involving the septum and inferior wall. Intense 18FDG uptake is present in these areas. Coronary angiography showed 70% stenosis of the left anterior descending coronary artery and 80% stenosis of the right coronary artery. (Reproduced with permission from Jain et al.37)
Myocardial 18FDG imaging
379
Figure 3 Exercise-rest 99mTc-sestamibi and exercise 18FDG ischemia (Is) images of a 40-year-old man with angina and no prior myocardial infarction. There is no perfusion abnormality on stress and rest 99mTc-sestamibi images. There is intense global uptake of 18FDG in all 3 vascular territories (solid arrowheads). Coronary angiography revealed 3-vessel disease (70% stenosis of the left anterior descending, 60% stenosis of the left circumflex, and 60% narrowing of the right coronary arteries). (Reproduced with permission from He et al.32)
predominantly fixed inferolateral perfusion abnormality on exercise-rest MPI, but very intense 18FDG uptake on exercise 18 FDG images in the corresponding segments. Perfusion abnormalities in inferior walls are sometimes hard to differentiate from attenuation artifacts. However, abnormally increased 18FDG uptake in inferior wall is not affected by any kind of artifacts and is indicative of inferior wall ischemia. Exercise perfusion and 18FDG imaging can substantially cut down the imaging time by avoiding the need for separate rest perfusion imaging. However, these highly encouraging preliminary results also raise several important questions about exercise 18FDG imaging. What about diabetic patients? What about glucose loading
for patients similar to what is done in 18FDG viability studies? What is the optimal time for the injection of 18FDG during or after exercise? How long after an episode of exercise-induced myocardial ischemia, increased regional myocardial 18FDG uptake can be observed? What is the optimal time for imaging after injection of 18FDG? What happens to the increased myocardial FDG uptake after coronary revascularization? Can exercise 18FDG imaging alone provide enough information, without any perfusion imaging? What is the optimal imaging modality for exercise 18FDG: PET or SPECT? A significant heterogeneity exists in regional myocardial 18FDG uptake on resting 18FDG studies, how can exercise 18FDG work with that? How critical is quantitative analysis for the interpretation
Figure 4 Exercise 99mTc-sestamibi and exercise 18FDG ischemia images of a 57-year-old woman with chest pain but no CAD. Exercise perfusion images show normal results. There is no myocardial 18FDG uptake. Only minimal background activity in the regions of left and right ventricular blood pools is seen. Coronary angiography show normal finding. (Reproduced with permission from He et al.32)
D. Jain et al.
380
Figure 5 Exercise-rest 99mTc-sestamibi and Ex 18FDG ischemia (Is) images in short axis, vertical, and horizontal long axes of a 65-year-old man showing a large area of fixed perfusion abnormality in the inferolateral wall. The patient had no prior myocardial infarction. There is intense 18FDG uptake in the inferolateral wall indicating the presence of ischemia rather than scar in this area. Coronary angiography showed 50% narrowing of the left main stem and left anterior coronary arteries and 100% occlusion of the right and left circumflex coronary arteries. (Reproduced with permission from Jain and He.36)
of exercise 18FDG imaging? These issues are discussed in the following paragraphs. It is well known that resting myocardial glucose uptake is insulin dependent. Diabetic patients show low 18FDG uptake at rest, and this abnormality may persist despite the use of insulin-glucose clamp. Whether this factor plays a role in ischemia-induced increase in myocardial 18FDG uptake is not adequately known. Ischemia-induced translocation of GLUT receptors may not be dependent on insulin and one may still be able to successfully use exercise 18FDG imaging in diabetic patients. However, the issue of exercise ischemia imaging in diabetic subjects requires further studies. Unlike rest 18FDG imaging for conventional viability studies, the goal of exercise 18FDG study is to suppress myocardial glucose uptake by the normal myocardium to maximize the difference in glucose uptake between nonischemic and ischemic myocardium, so that only ischemic myocardium is visualized. This requires fasting for at least 12 hours (or perhaps longer, if possible). It has been proposed that perhaps a low carbohydrate meal before fasting may be further helpful in this regard. But, this has not been evaluated so far. 18 FDG was injected at peak exercise in the study by He et al.32 Whether similar results can be obtained if 18FDG were injected hours or even days after an episode of exerciseinduced myocardial ischemia is highly relevant clinically. This may permit the use of 18FDG as a memory marker for ischemia similar to 123I-beta-methyliodophenyl-pentadecanoic acid, a radiolabeled fatty acid analogue. Data from animal studies suggest that increased glucose uptake may persist for days in the myocardial segments following experimental occlusion of a coronary artery for a few minutes.25 Whether intensity of this
experimental ischemia is similar to that observed with clinically induced myocardial ischemia with treadmill exercise is unclear. Abbott et al injected 18FDG 60-90 minutes after treadmill exercise in patients with CAD who underwent separate exercise-rest SPECT imaging. Increased 18FDG uptake was still observed but only in one-third of vascular territories with reversible perfusion abnormalities.33 To explore this phenomenon further, Dou et el40 performed exercise and rest 99mTcsestamibi and 18FDG imaging 24 hours apart in 18 patients with Z70% luminal narrowing of Z1 coronary vessel(s). A total of 15 patients showed increased regional 18FDG uptake on exercise imaging. Of these 15 patients, 8 (53%) had no discernible 18FDG uptake, 5 (33%) had decreased 18FDG uptake, and only 2 (13%) had persistent 18FDG uptake on rest 18 FDG images (Fig. 6). The summed 18FDG uptake score significantly decreased from 14.4 ⫾ 10.3 at exercise to 6.7 ⫾ 9.2 at rest (P ¼ 0.01). Patients with persistent 18FDG uptake at rest had more extensive 18FDG uptake and lower peak rate pressure product (double product) at exercise in comparison with patients with no residual 18FDG uptake at rest. This study shows that increased exercise-induced regional myocardial 18 FDG uptake is a specific marker of myocardial ischemia and is not seen 24 hours after an episode of myocardial ischemia in most patients with CAD. Persistent regional myocardial 18FDG uptake can still be seen, but only in a small proportion of patients and is probably a marker of more severe CAD and more severe myocardial ischemia on exercise. Therefore, for routine clinical diagnostic studies, 18FDG should be injected at peak exercise. Unlike perfusion tracers, 18FDG is cleared slowly from the blood pool, and on standard resting 18FDG studies, a delay of 45-60 minutes is required following the
Myocardial 18FDG imaging
381
Figure 6 Exercise (Ex) and rest (R) 99mTc-sestamibi perfusion (Perf) and 18FDG images of a 49-year-old male with exertional angina in short axis and vertical and horizontal long axes. There is exercise-induced perfusion abnormality in the posterior septum and inferior wall, which is reversible on the rest images. There is intense 18FDG uptake on the exercise images (yellow arrows) in the corresponding segments, which is not present in the rest images. This patient had 85% stenosis of the right coronary artery. (This research was originally published in JNM, Dou et al.40 © by the Society of Nuclear Medicine and Molecular Imaging, Inc.)
tracer injection before images can be acquired. Blood pool clearance kinetics of 18FDG have not been studied following its administration at peak exercise. It is likely that blood pool clearance of 18FDG may be faster compared with its clearance on resting 18FDG studies. However, till exact data are available, it is prudent to start image acquisition 40-60 minutes after injection on exercise 18FDG studies. Hot spot cardiac imaging does require a roadmap for proper processing and interpretation of the images. Spatial orientation of the left ventricle may be extremely difficult if there is no tracer uptake or only localized tracer uptake in the heart. Getting adequate orientation of the heart is rarely a problem with MPI even in the presence of large areas of perfusion abnormalities; however, this can be a major challenge with “hot spot” imaging. In the absence of a proper roadmap, extracardiac tracer uptake or even cardiac blood activity may be misinterpreted as myocardial uptake or a true cardiac uptake may be incorrectly localized to a different myocardial segment. Simultaneous 18FDG and perfusion imaging can overcome this difficulty apart from providing information about myocardial perfusion. PET/CT imaging can provide a good roadmap of the myocardium, which may obviate the need for a perfusion map. There is a significant degree of regional variability in 18FDG uptake by the left ventricular myocardium on resting studies.41 It has been speculated that given this variability, it may be difficult to use 18FDG for imaging exercise-induced myocardial ischemia. However, ischemia-induced increase in myocardial glucose or 18FDG appears to be 10-fold or even more, several times higher than the regional variability in glucose uptake at rest. This results in a very high contrast between the ischemic
and nonischemic myocardium, irrespective of regional heterogeneity in 18FDG uptake at rest by the nonischemic myocardium. Quantitative analysis is always helpful in determining subtle differences in tracer uptake and in determining whether these differences are within normal or outside the range of normal variability. Whereas, quantitative analyses are well standardized for perfusion imaging, quantitative programs for hot spot imaging are not yet adequately developed. PET images lend themselves more readily to quantitative analysis than SPECT images. Quantitative programs are yet to be developed for 18 FDG ischemia imaging. Nevertheless, qualitative analysis can still be used quite effectively for interpreting exercise 18FDG images till quantitative programs are developed. 18 FDG is a promising agent for direct imaging of exerciseinduced myocardial ischemia, which can potentially result in the single largest indication for use of 18FDG in clinical practice. 18
FDG for Cardiac Sarcoidosis Imaging Cardiac sarcoidosis is a systemic inflammatory disorder of unclear etiology characterized by noncaseating granulomas in multiple organs.42,43 The incidence of this disease varies according to ethnicity, sex, and geographic region and ranges from 3-80/100,000. The incidence is higher in African Americans, women, and Scandinavian countries. The disease is associated with a long course of remissions and
382 exacerbations and has a low mortality rate. Lymph nodes and lungs are the most frequently affected organs, but any other organ system can be involved. Cardiac involvement occurs in a variable proportion of cases and has been described to occur in 20%-40% of the cases. Although cardiac involvement is less common, it is associated with a worse prognosis and high mortality from arrhythmias and congestive heart failure and warrants a more aggressive therapy.43 However, detection of cardiac involvement is often challenging and cumbersome and may require multiple diagnostic tests.44 Several different imaging and nonimaging tests such as echocardiography, MPI, gallium-67 scintigraphy, MRI, and endomyocardial biopsy are used. However, all of these tests suffer from low sensitivity and low specificity and are not suitable for serial follow-up and for evaluation of efficacy of therapy. It is likely that cardiac involvement in sarcoidosis remains underdiagnosed owing to a lack of readily available and reliable tests for its diagnosis. In the absence of a diagnostic gold standard, cardiac sarcoidosis is often missed in its early stages, when treatment is most likely to be effective. Currently, Guidelines of the Japanese Ministry of Health and Welfare, as revised by the Japanese Society of Sarcoidosis and Other Granulomatous Disorders in 2006, remain the worldwide standard for clinical diagnosis of cardiac sarcoidosis.45 According to these criteria, diagnosis of cardiac sarcoidosis is established with the histologic evidence of noncaseating epithelioid granulomas on endomyocardial biopsy or in the presence of at least 2 major criteria (advanced atrioventricular block, thinning or scarring of the basal interventricular septum, positive gallium-67 scintigraphy, or depressed left ventricular ejection fraction) or 1 major and 2 or more minor criteria (abnormal electrocardiogram showing multifocal or frequent ventricular ectopics, right bundle branch block; abnormal echocardiogram showing regional wall motion abnormalities or ventricular aneurysm; perfusion defects on MPI; or unexplained interstitial fibrosis or significant monocyte infiltration on endomyocardial biopsy) in patients with systemic sarcoidosis. Development of a reliable noninvasive test for diagnosing cardiac sarcoidosis remains an important unmet need in diagnostic imaging. Recent studies have indicated a potential role of hot spot imaging with 18FDG for the detection of inflammatory response that accompanies cardiac sarcoidosis. Inflammatory cells have a very high glucose uptake, and 18FDG has been used for imaging infection and inflammation46,47 in various organ systems. 18FDG imaging shows increased focal or diffuse myocardial 18FDG uptake in patients with active cardiac sarcoidosis. Focal or regional myocardial 18FDG uptake is more specific for cardiac sarcoidosis than a diffuse or global myocardial 18FDG uptake, as the later could also be due to a normal variant such as incomplete suppression or normal physiological myocardial 18FDG uptake (Fig. 7). As normal myocardium may also show variable degrees of 18FDG uptake, particularly after carbohydrate-rich meal, a strict physiological milieu is required to suppress normal myocardial 18FDG uptake. This can be achieved by prolonged fasting, feeding a diet rich in fats and proteins and low on carbohydrates for 2448 hours, or by administration of heparin before 18FDG.44
D. Jain et al. Heparin administration increases the plasma levels of free fatty acids, which helps to decrease myocardial 18FDG uptake. Currently, there is no consensus on the optimal patient preparation for myocardial 18FDG imaging for cardiac sarcoidosis. Perhaps a combination of prolonged fasting, low carbohydrate diet, and heparin administration may be the best approach. Yamagishi et al48 performed cardiac N-13 ammonia perfusion imaging, fasting 18FDG imaging, 201Tl perfusion imaging, and 67Ga imaging in 17 patients with cardiac sarcoidosis. 201Tl perfusion defects were seen only in 35%, abnormal cardiac 67 Ga uptake was seen only in 18%, 13N-ammonia perfusion defects were present in 76%, and abnormal 18FDG uptake was present in 82%. 18FDG uptake was seen most frequently in the basal and midanteroseptal walls of the left ventricle. On followup after steroid therapy, there was marked reduction in 18FDG uptake, whereas there was no change in 13N-ammonia perfusion defects. Okumura et al49 performed 99mTc-sestamibi SPECT MPI, 67 Ga scintigraphy, and 18FDG imaging in 22 patients with sarcoidosis, of whom 11 had evidence of cardiac involvement and 11 did not have cardiac involvement. The sensitivities of 18 FDG, MPI, and gallium-67 were 100%, 64%, and 36%, respectively. They also compared myocardial standardized uptake values (SUVs) of the 18FDG in patients with and without cardiac sarcoidosis, and with a group of healthy controls. SUVs ranged from 1.85-1.94 in normal healthy subjects, from 1.74-3.3 in patients with no sarcoidosis, and from 2.84-14.13 in patients with cardiac sarcoidosis. This study indicates a superiority of fasting cardiac 18FDG imaging over other nuclear imaging modalities for the detection of cardiac involvement in patients with sarcoidosis. However, simultaneous cardiac 18FDG and perfusion imaging may have a complimentary role. Increased 18FDG uptake may be more indicative of active inflammation, and perfusion abnormalities may be more indicative of fibrosis and scar formation. From a therapeutic standpoint, presence of active inflammation would require treatment with steroids and other anti-inflammatory agents, whereas the presence of scar would warrant consideration for antiarrhythmic therapy. Detection and treatment of inflammation at early stages could prevent fibrosis and scar formation and their complications. Osborne et al50 performed serial 18FDG imaging and gated 82Rb perfusion imaging in 23 patients with cardiac sarcoidosis. The median interval between the first and last imaging studies was 2 years. The patients were treated with steroids, angiotensin converting enzyme inhibitors or angiotensin receptor blockers, and beta-blockers in the interim. The investigators observed an inverse relationship between reduction in myocardial 18FDG uptake and improvement in left ventricular ejection fraction. The patients were classified as responders or nonresponders to treatment based on reduction in myocardial 18FDG uptake on follow-up imaging studies. The responders showed a progressive improvement in left ventricular ejection fraction, whereas nonresponders showed no change or a deterioration in left ventricular ejection fraction. This study shows the powerful role that 18FDG imaging can play in the initial evaluation, titration of
Myocardial 18FDG imaging
383
Figure 7 PET/CT study in a subject with sarcoidosis involving the heart. (A) Stress (dipyridamole) and rest 82Rb perfusion images show normal perfusion. 18FDG uptake is focally increased in basal inferior wall, consistent with active cardiac sarcoidosis (arrows). (B) Whole-body imaging shows multiple extracardiac foci of 18FDG uptake in chest, liver, bone, and lymph nodes, consistent with extensive systemic sarcoidosis. HLA, horizontal long axis; MIP, maximum intensity projection; SA, short axis; VLA, vertical long axis (This research was originally published in JNM, Schatka and Bengel.44 © by the Society of Nuclear Medicine and Molecular Imaging, Inc.)
therapy, and subsequent follow-up of patients with known or suspected cardiac sarcoidosis. Ahmadian and colleagues have proposed cardiac metabolic activity (CMA), a new quantitative measure of cardiac involvement by sarcoidosis on cardiac 18FDG-PET imaging.51 CMA is a numerical score that takes into account the volume and intensity of abnormal myocardial 18FDG uptake. CMA
calculates the voxels in the myocardium with 18FDG activity above a predefined threshold and multiplies it by the mean SUVs in these voxels. This measurement of volume and volume intensity is similar to what is referred to as metabolic tumor volume and total lesion glycolysis in oncologic 18FDG imaging for solid tumors. The investigators compared CMA with traditional indices of quantitative analysis of cardiac
384 18
FDG-PET images in 24 patients with cardiac sarcoidosis and 7 normal controls. SUVs provide a good measure of the intensity of myocardial 18FDG uptake but do not take into consideration the extent of this uptake. However, any potential advantages of this new index over the currently used indices of SUVs and number of myocardial segments with increased uptake need to be evaluated in prospective studies. Hot spot cardiac imaging with 18FDG remains a highly exciting new imaging modality with profound diagnostic and therapeutic implications for cardiac sarcoidosis. It can provide a very useful insight into the pathophysiology of cardiac sarcoidosis and can potentially redefine the extent and frequency of cardiac involvement in patients with sarcoidosis. This technique may also enable detection of cardiac involvement early in the course of sarcoidosis, when suitable treatment can prevent further cardiac damage and prevent fibrosis and scar that are responsible for much of the cardiac morbidity and mortality in these patients.
Conclusion Cardiac imaging is at an important crossroads. Technological advances permit ultrafast noninvasive imaging of coronary arteries, coronary calcium, and atheroma. These techniques are being proposed to replace standard nuclear MPI techniques. Nuclear imaging may not be able to match the speed and resolution of these techniques. However, nuclear imaging has unrivaled ability to noninvasively image biochemical, molecular, and metabolic processes and receptor and transporter function under different physiological conditions. These techniques have a potential to be used as very powerful diagnostic tools in routine clinical practice and also serve as sophisticated experimental tools for studying difficult-tounderstand phenomena related to cardiac pathophysiology under various disease conditions, and for studying the effect of therapeutic interventions in these conditions. Hot spot imaging of the heart using 18FDG provides unique diagnostic tools for studying myocardial ischemia and cardiac sarcoidosis. Exercise 18 FDG imaging seems to be ideally suited for direct imaging of exercise-induced myocardial ischemia and for the routine detection of CAD. These new developments can greatly advance the field of nuclear cardiology but further large-scale and carefully planned studies are needed before they can find an appropriate clinical niche.
References 1. Zaret BL, Strauss HW, Martin ND, et al: Noninvasive evaluation of regional myocardial perfusion with radioactive potassium: Study of patients at rest, exercise, and during anginal pectoris. N Engl J Med 1973;288:809-812 2. Iskandrian AE, Hage FG, Shaw LJ, et al: Serial myocardial perfusion imaging: Defining a significant change and targeting management decisions. JACC Cardiovasc Imaging 2014;7:79-96. http://dx.doi.org/ 10.1016/j.jcmg.2013.05.022 3. Beller GA, Zaret BL: Contributions of nuclear cardiology to diagnosis and prognosis of patients with coronary artery disease. Circulation 2000;101:1465-1478 4. Jain D, Zaret BL: Nuclear imaging in cardiovascular medicine. In: Rosendorf C, (ed): Chapter in Essential Cardiology. ed 3. Springer; 2013, pp. 195-220. 978-1-4614-6705-2
D. Jain et al. 5. Jain D: 99mTechnetium labeled myocardial perfusion imaging agents. Semi Nucl Med 1999;29:221-236 6. Travin MI: Cardiac cameras. Semin Nucl Med 2011;41:182-201. http://dx.doi.org/10.1053/j.semnuclmed.2010.12.007. [review] 7. Ghimire G, Hage FG, Heo J, et al: Regadenoson: A focused update. J Nucl Cardiol 2013;20:284-288. http://dx.doi.org/10.1007/s12350-012-96613. [review] 8. Boden W: Management of chronic coronary disease: Is the pendulum returning to equipoise? Am J Cardiol 2008;101:S69-S74 9. Lapi SE, Voller TF, Welch MJ: Positron emission tomography imaging of hypoxia. PET Clin 2009;4:39-47 10. Krohn KA, Link JM, Mason RP: Molecular imaging of hypoxia. J Nucl Med 2008;49(suppl 2):129S-148S 11. Buerkle A, Weber WA: Imaging of tumor glucose utilization with positron emission tomography. Cancer Metastasis Rev 2008;27:545-554 12. Di Carli MF: Assessment of myocardial viability after myocardial infarction. J Nucl Cardiol 2002;9:229-235 13. Dilsizian V, Arrighi JA, Diodati JG, et al: Myocardial viability in patients with chronic coronary artery disease. Comparison of 99mTc-sestamibi with thallium reinjection and 18F-fluorodeoxyglucose. Circulation 1994;89:578-587 14. Llaurado JG: The quest of the perfect myocardial perfusion indicator…still a long way to go. J Nucl Med 2001;42:282-284 15. Zaret BL: Pursuit of the ideal perfusion agent. J Nucl Cardiol 2002;9:149-150 [editorial] 16. Beller GA: Will cardiac positron emission tomography ultimately replace SPECT for myocardial perfusion imaging? J Nucl Cardiol 2009;16:841-843 [editorial] 17. Jain D, McNulty PH: Exercise-induced myocardial ischemia: Can this be imaged with F-18-fluorodeoxyglucose? J Nucl Cardiol 2000;7:286-288 [editorial] 18. Neely JR, Rovetto MJ, Oram JF: Myocardial utilization of carbohydrates and lipids. Prog Cardiovasc Dis 1972;15:289-329 19. Liedtke AJ: Alterations of carbohydrate and lipid metabolism in the acutely ischemic heart. Prog Cardiovasc Dis 1981;23:321-336 20. Schwaiger M, Schelbert HR, Ellison D, et al: Sustained regional abnormalities in cardiac metabolism after transient ischemia in the chronic dog model. J Am Coll Cardiol 1985;6:336-347 21. Schwaiger M, Neese RA, Araujo L, et al: Sustained nonoxidative glucose utilization and depletion of glycogen in reperfused canine myocardium. J Am Coll Cardiol 1989;13:745-754 22. McNulty PH, Sinusas AJ, Shi CQ, et al: Glucose metabolism distal to a critical coronary stenosis in a canine model of low-flow myocardial ischemia. J Clin Invest 1996;98:62-69 23. McNulty PH, Jagasia D, Cline GW, et al: Persistent changes in myocardial glucose metabolism in vivo during reperfusion of a limited-duration coronary occlusion. Circulation 2000;101:917-922 24. Herraro P, Weinhemer CJ, Dence C, et al: Quantification of myocardial glucose utilization by PET and 1-carbon-11-glucose. J Nucl Cardiol 2002;9:5-14 25. McNulty PH, Jagasia D, Cline G, et al: Persistent changes in myocardial glucose metabolism in vivo during reperfusion of a limited-duration coronary occlusion. Circulation 2000;101:917-923 26. Sun D, Nguyen N, Degrado T, et al: Ischemia induces translocation of the insulin-responsive glucose transporter GLUT 4 to the plasma membrane of cardiac myocytes. Circulation 1994;89:793-798 27. Giordano FJ: Oxygen, oxidative stress, hypoxia, and heart failure. J Clin Invest 2005;115:500-508 28. Jain D, He ZX, Lele V, et al : Direct myocardial ischemia imaging: A new paradigm in cardiovascular nuclear imaging. Clin Cardiol 2014 (in press) 29. Abramson BL, Ruddy TD, de Kemp RA, et al: Stress perfusion/metabolic imaging: A pilot study for a potential new approach to the diagnosis of coronary artery disease in women. J Nucl Cardiol 2000;7:205-212 30. Camici P, Araujo LI, Spinks T, et al: Increased uptake of 18Ffluorodeoxyglucose in postischemic myocardium of patients with exercise-induced angina. Circulation 1986;74:81-88 31. Araujo LI, McFalls EO, Lammertsma AA, et al: Dipyridamole-induced increased glucose uptake in patients with single-vessel coronary artery disease assessed with PET. J Nucl Cardiol 2001;8:339-346
Myocardial 18FDG imaging 32. He ZX, Shi RF, Wu YJ, et al: Direct imaging of exercise-induced myocardial ischemia with fluorine-18-labeled deoxyglucose and Tc-99m-sestamibi in coronary artery disease. Circulation 2003;108: 1208-1213 33. Abbott BG, Liu YH, Arrighi JA: [18F]Fluorodeoxyglucose as a memory marker of transient myocardial ischaemia. Nucl Med Commun 2007;28:89-94 34. Arrighi JA: F-18 fluorodeoxyglucose imaging in myocardial ischemia: Beyond myocardial viability. J Nucl Cardiol 2001;8:417-420 35. He ZX, Shi RF, Wu YJ, et al: Myocardial ischemia, fluorodeoxyglucose, and severity of coronary artery stenosis: The complexities of metabolic remodeling in hibernating myocardium. Circulation 2004;109: e167-e170 [authors' reply to letter to the editor] 36. Jain D, He ZX: Direct imaging of myocardial ischemia: A potential new paradigm in nuclear cardiovascular imaging. J Nucl Cardiol 2008; 15:617-630 [editorial point of view] 37. Jain D, He ZX, Ghanbarinia A: Direct imaging of myocardial ischemia with 18FDG: A new potentially paradigm-shifting molecular cardiovascular imaging technique. Curr Cardiovasc Imag Rep 2010;3:134-150 38. Sandler MP, Patton JA: Fluorine-18 labeled fluorodeoxyglucose myocardial single-photon emission computed tomography: An alternative for determining myocardial viability. J Nucl Cardiol 1996;3:342-349 39. Slatt RH, Bax JJ, van Veldhuisen DJ, et al: Prediction of functional recovery after revascularization in patients with chronic left ventricular dysfunction: Head to head comparison between 99mTc-sestamibi/18F-FDG DISA SPECT and 13N-ammonia/18F-FDG PET. Eur J Nucl Med Mol Imaging 2006;33:716-723 40. Dou KF, Yang MF, Yang YJ, et al: Direct myocardial ischemia imaging: 18 FDG uptake during exercise and at rest in patients with coronary artery disease. J Nucl Med 2008;49:1986-1991
385 41. Herrero P, Gropler RJ: Imaging of myocardial metabolism. J Nucl Cardiol 2005;12:345-358 [review] 42. Doughman AR, Williams BR: Cardiac sarcoidosis. Heart 2006;92: 282-288 43. Mehta D, Lubitz SA, Frankle Z, et al: Cardiac involvement in patients with sarcoidosis: Diagnostic and prognostic value of outpatient testing. Chest 2008;133:1426-1435 44. Schatka I, Bengel FM: Advanced imaging of cardiac sarcoidosis. J Nucl Med 2014;55:99-106 45. Soejima K, Yada H: The workup and management of patients of patients with apparent or subclinical cardiac sarcoidosis: With emphasis of the associated heart rhythm abnormalities. J Cardiovasc Electrophysiol 2009;20:578-583 46. Meller J, Sahlmann C, Scheel AK: 18F-FDG PET and PET-CT in fever of unknown origin. J Nucl Med 2007;48:35-45 47. Keidar Z., Nitecki S. FDG-PET in prosthetic graft infections. Semin Nucl Med 2013;43:396-402 [review]. 10.1053/j.semnuclmed.2013.04.004 48. Yamagishi H, Shirai N, Takagi M, et al: Identification of cardiac sarcoidosis with 13N-NH3/18F-FDG PET. J Nucl Med 2003;44:1030-1036 49. Okumura W, Iwasaki T, Toyama T, et al: Usefulness of fasting 18F-FDG PET in identification of cardiac sarcoidosis. J Nucl Med 2004;45: 1989-1998 50. Osborne MT, Hulten EA, Singh A, et al: Reduction in (18)F-fluorodeoxyglucose uptake on serial cardiac positron emission tomography is associated with improved left ventricular ejection fraction in patients with cardiac sarcoidosis. J Nucl Cardiol 2014;21:166-174 51. Ahmadian A, Brogan A, Berman J, et al: Quantitative interpretation of FDG PET/CT with myocardial perfusion imaging increases diagnostic information in the evaluation of cardiac sarcoidosis. J Nucl Cardiol 2014;20:9901-9909 10-1007/s12350-014
