Hello, my name is Gary Small and I'm a nuclear and clinical cardiologist at the University of Ottawa Heart Institute in Canada. Hello, I am Dr. Christian Vifols and I am a nuclear medicine physician at the Ottawa Heart Institute and Ottawa Hospital. Today we are pleased to present how to perform an FTG viability study as part of the PET curriculum produced by ASNIC. The following slide presentation is based upon the 2016 ASNIC imaging guidelines as an MMI procedure standard for PETs and published online and in the Journal of Nuclear Cardiology. This is our disclosure slide. These are the learning objectives from today's talk. The goal of the presentation is to learn how to perform FTG viability studies. There are five learning objectives, firstly to describe how to prepare patients for FTG viability imaging, secondly to learn procedures to optimise FTG administration, thirdly to describe how to acquire and process FTG cardiac viability images, fourthly to interpret image patterns and findings, and then lastly to explain the components in a concise viability study report. So identification of viable myocardium has a key role in the management of patients with left ventricular dysfunction due to coronary artery disease. The premise of viability imaging is that LV systolic impairment may be reversible, attributable to myocardial hibernation or stunning, and not necessarily due to irreparable myocardium scarring. Typical patients are those with LVEF less than or equal to 35% with potential coronary artery targets for revascularisation in whom surgical risk is elevated, like elderly patients with multiple comorbidities, with prior CABG, no evidence of ischemia, and with persistent perfusion defects suggesting scar or hibernation. Myocardial viability imaging with PET uses preservation of myocardial glucose metabolism, particularly in the presence of resting hyperperfusion, as a syntagraphy marker of viable myocardium, and it's accomplished by using FTG as a tracer of exogenous glucose utilisation. So the cardiomyocytes can consume either metabolic fuel with using long-chain fatty acids or glucose, and under fasting and aerobic conditions, long-chain fatty acids are the preferred fuel in the heart. When myocardial perfusion is reduced, leading to ischemia, or if persistently reduced, associated with hibernating myocardium, glucose becomes a preferred energy substrate. So in ischemic or hibernating myocardium, there is an over-dependence on glucose metabolism by the cardiomyocyte. FTG makes use of this and competes with glucose for transport and then phosphorylation by hexose kinase. From physiological glucose, the phosphorylated radio tracer, FTG6-phosphate, does not proceed into glycolysis or glycogen synthesis with only minimal dephosphorylation and return of tracer to the blood. Thus, it's metabolically tramped in cardiomyocytes, consequently its uptake is reflective of overall glucose uptake. In viability imaging, the regional myocardial concentrations of FTG are compared with the regional distribution of myocardial perfusion. PET utilizes radionuclide tracer techniques to produce images of radionuclide distribution using an external detector camera. PET radionuclides reach a more stable configuration by the emission of a positron. When a positron collides with an electron, the two annihilate, and in their place, two 511 KeV gamma rays are emitted. Because the gamma rays are nearly collinear, they charge 180 degrees to each other and traveling in opposite directions, the PET detectors can be programmed to register only events with temporal coincidence of photons that strike directly at opposing detectors. The PET detectors are placed in a ring surrounding the patient and are configured to register only photon pairs that strike opposing detectors at approximately the same time, and this is termed coincidence detection. Over the course of a typical scan, millions of coincident events are recorded, and projections of the activity distribution are measured at all angles around the patient. Coincidences between detectors in a single ring produce one tomographic slice of data. Usually, one or more adjacent rings may also contribute to counts in that slice. So in a two-dimensional, or SEPTA-in PET scanner, there is a septum, generally made of lead or tungsten, between adjacent rings. So this septum partially shields coincidences from occurring between detectors in one ring and detectors in a non-adjacent or more distant ring. By minimizing coincidences between a ring and its more distant neighboring rings, SEPTA greatly reduces scattered events. A scanner with no SEPTA in place is referred to as a three-dimensional, or 3D, or SEPTA-out scanner. So the SEPTA-out 3D mode, however, permits coincidences between all possible rings, greatly increasing sensitivity, but also greatly increasing scatter, as well as the count rate for each individual detector. So this increase in count rate can increase dead time and random events. Some scanners have retractable SEPTA, permitting the user to choose between 2D and 3D operation. So there is also three different crystal types that are commonly employed in PET detectors, including BGO, GSO, and lutetium-based crystals, such as LSO and LISO. So each type of crystal has been used successfully for cardiac imaging. BGO has the highest stopping power, relatively poor energy resolution, which limits energy-based scatter reduction, and poor timing resolution, limiting its ability to reduce randoms at high count rates. GSO, LSO, and LISO all have better timing resolution, and in theory, better energy resolution. So the main advantage of GSO and lutetium-based crystals is reduced dead time, which enables them to acquire data at higher count rates associated with operating in 3D mode, and to better minimize the effect of randoms. So for many years, most PET scanners have been sold combined with a CT scan. These combined systems, in practice, demonstrate a range of integration. The CT component of the hybrid PET-CT camera was originally developed for attenuation correction and anatomical co-localization purposes. CT-based attenuation correction generates Hounsfield units that can be adequately converted into PET attenuation values. For dedicated PET scanners without CT, rotating rod sources or rings of germanium-68 or cesium-137 are used to acquire the transmission scan for attenuation correction. There are no widely acceptable published quality control procedures for PET. Each day, the PET detector should be evaluated to ensure proper operation before commencing with patient injections or scans. The daily quality procedure varies according to the design of the scanner and recommendations of the vendor. Typically, a blank point source transmission scan is performed to evaluate detector consistency, signals sensitivity, dead time, count timing, and energy calibration. Following QC of the PET detectors, QC of the attenuation correction methods is also performed. So for a dedicated PET scanner, as I said, without CT, rotating resources or rings of germanium-68 or gallium-68 or cesium-137 are used to acquire transmission scan for attenuation correction. And attenuation correction should be assessed using the IEC phantom or similar. Overall, proper basic operation of CT scanner is checked daily. CT system calibration is performed to ensure absolute accurate CT numbers in household units are obtained. Any errors in CT numbers will be propagated as errors in estimating PET attenuation coefficients at 511 KeV. CT system calibration is performed with a special calibration phantom that includes inserts of known CT numbers as well as the CT calibration using the phantom. The technologist will also perform air calibration. Field uniformity is also assessed. The reconstructed CT image must exhibit uniform response throughout the field of view. This means a reconstructed image for a uniform water filled cylinder must demonstrate low variation in CT number throughout this image. The PET and CT portion of the combined system should be assessed as described for dedicated PET and CT imaging devices. In addition to the independent QC tests for the PET and CT portion of the combined system, it is necessary to perform additional tests that assess the combined use of PET and CT. So for registration, the reconstructed PET and CT images must accurately reflect the same 3D locations, so the two images must be in registration. Such registration is often difficult because the PET and CT portions of all commercial combined PET-CT systems are not coincident. In practice, this means that the PET and CT acquisitions do not simultaneously image the same slice. In addition, electronic drift can influence the position of each image, so that calibration for mechanical registration can become inaccurate over time. Thus, it is imperative to check PET-to-CT registration on an ongoing basis. This is usually performed with a specific phantom containing an array of point sources visible in both PET and CT. For attenuation correction accuracy, the use of the CT image for PET attenuation correction requires a transformation of the observed CT numbers in Hansel units to attenuation coefficients. At a minimum, it is important to image a water-filled cylinder to assess PET field uniformity in PET activity concentration after CT-based PET attenuation correction. Errors in CT-to-PET attenuation translations are usually manifest as a corrected PET image without a flat profile from a center. So the activity at the edge is either too high or too low relative to that at the center of the phantom. And with resulting attenuation corrected, absolute PET values that are incorrect. We're going to spend some time looking at patient preparation. As a result of the marked flexibility in substrate used by a myocardium, the standardization of the substrate environment is of critical importance when performing cardiac FDG imaging. For the evaluation of myocardial viability with FDG, the substrate and hormonal levels in the blood need to favor metabolism of glucose over fatty acids by the myocardium. This maximizes the FDG uptake in the myocardium, resulting in superior image quality and reduces the regional variations in FDG uptake that can occur when imaging under fasting conditions. Examples to standardize the substrate environment for viability imaging are shown in the tables. Standardization is usually accomplished by loading the patient with glucose after fasting for at least six hours to produce an endogenous insulin response. The temporary increase in plasma glucose levels stimulates pancreatic insulin production, which in turn reduces fatty acid levels through its lipogenic effects on adipocytes and also normalizes plasma glucose levels. The most common method of glucose loading is with an oral load of 25 to 50 grams, but IV loading can be used. The IV route avoids potential problems due to variable gastrointestinal absorption or an inability to tolerate oral dosage. As a result of its simplicity, however, most laboratories utilize the oral glucose loading approach with supplemental insulin administered as needed. The physician should take into account whether or not the patient is taking medications that may either antagonize or potentiate the effects of insulin. So patients with diabetes pose a challenge either because they have limited ability to produce endogenous insulin or because the cells are less able to respond to insulin stimulation or both. So for this reason, the simple fasting oral glucose loading paradigms are often not as effective in diabetic patients. Use of insulin along with close monitoring of blood glucose yields satisfactory results. Improved FTG images can also be seen when image acquisition is delayed two to three hours after injection of the FTG dose. Of course, the latter comes at the expense of increased decay of the radiopharmaceutical. So an alternative technique is the euglycemic hyperinsulinemic plan. So an example of the euglycemic hyperinsulinemic plan is shown in this slide from the protocol that we use locally in patients with diabetes. The protocol, as noted, is rigorous and time-consuming. However, it enables close titration of the metabolic substances and insulin levels, which result in excellent image quality in most patients. And if combined with dynamic imaging, enables absolute quantification of myocardial glucose utilization. To determine myocardial viability, myocardial perfusion and metabolic imaging are compared. PET or SPECT perfusion data can be used for this comparison. FDA-approved PET perfusion traces include rubidium-82 and N13 ammonia. The specific differences in acquisition protocols for rubidium and ammonia imaging are related to the duration of uptake and clearance of these radiopharmaceuticals and their physical half-lives. Rubidium-82 is a well-established and highly accurate technique for the assessment of myocardial perfusion. Rubidium-82 is a monovalent cation analog of potassium. It's extracted from plasma with high efficiency by myocardial cells using a sodium-potassium ATP pump. N13 ammonia is also a valuable agent for measuring myocardial perfusion. Myocardial uptake of N13 ammonia depends on flow extractions and retention. Following initial extraction across the capillary membrane, N13 ammonia may cross myocardial cell membranes by passive diffusion or as an ammonium ion by the active sodium-potassium transport mechanism. Once in the cardiomyocyte, N13 ammonia is either incorporated into the amino acid pool as N13 glutamine or diffuses back into the blood. Myocardial tissue retention of N13 ammonia as N13 glutamine is mediated by the ATP glutamine synthase. Thus, uptake and retention can both be altered by changes in the metabolic state of the myocardium. In current clinical practice, F18 FDG PET images are best read in combination with PET perfusion imaging, but SPECT myocardial perfusion images can also be used. Full-rest protocols for technetium or thallium radiotracers can be used to acquire this data. So typically, 5 to 15 millicuries of FDG is injected into a peripheral vein. The effective dose for a 10-millicury dose of F18 FDG administered intravenously is 7 millisieverts. The critical organ is the urinary bladder wall, which receives an effective dose of 48 millisieverts. To reduce patient dose, the patient should be encouraged to void frequently for three to four hours after the study period. Acquisition parameters for F18 FDG PET cardiac imaging are shown in the table. Typically, measurements of myocardial perfusion are performed with either rubidium-82 or N13 ammonia using procedures described in the PET myocardial perfusion imaging, as we've discussed. Alternatively, perfusion can be determined using technetium or thallium-based SPECT tracers. Ideally, measurements of perfusion should be obtained in the same imaging session as measurements of myocardial glucose metabolism. If, however, perfusion metabolism data has to be acquired on separate days, this should be done less than two weeks apart, and it's important to verify that the patient has been stable during that time interval and there's been no change in symptoms or medications. Combining the information from the glucose metabolism and blood flow studies generates metabolism perfusion patterns indicative of viable and non-viable myocardium. During patient preparation and dosing with F18 FDG, it's suggested to allow 45 minutes before starting the static FDG scan acquisition. While waiting for 90 minutes after the injection of FDG may give better blood clearance and myocardial uptake, especially in diabetics or subjects with high blood glucose levels. This comes at an expense of reduced count rate. If the background ratio is poor at 45 to 60 minutes, injecting an additional one to three units of insulin, depending on the blood glucose level, and then waiting for an additional 45 to 60 minutes may improve the image quality substantially. Scan generation is typically 10 to 30 minutes. the comparison of perfusion and metabolism images obtained with PET is relatively straightforward because both image sets are attenuation corrected. FTG-PET images are however often read in combination with SPECT myocardial perfusion images. Both non-attenuation correction and attenuation correction images should be viewed. When this occurs, the interpreting physician should be careful and pay attention when comparing the non-attenuation corrected SPECT images with the attenuation corrected FTG-PET images. Myocardial lesions showing an excessive reduction in intrinsic concentration as a result of attenuation artifacts such as the inferior wall in men or the anterior wall in females may be interpreted as perfusion metabolism mismatches resulting in false positive study. Differences may also be present between PET metabolism images and SPECT perfusion data with regard to image resolution and registration. It should be noted that if a thallium or technetium labeled perfusion tracer is used to assess myocardial perfusion when a 2D PET camera is used, FTG-PET images can be obtained on the same day. With a 2D PET having SEPTA, lower KeV thallium or technetium photons will not interfere with the higher energy F18 photons. However, with a 3D PET imaging, the technetium photons can increase the dead time and thus decrease the true counts from F18 FTG. Thus, when 3D PET imaging is planned, a two-day protocol should be considered. If FTG-PET images are acquired first, then it is necessary to wait at least 5 half-lives, depending on the dose of F18 administered, before a low-energy, like thallium or technetium SPECT study is performed. This is because a 511 KeV photons from the PET tracer penetrate the collimators that are commonly used for thallium or technetium imaging. And iterative reconstruction is a recommended method of image reconstruction. A summary table of the FTG-PET imaging acquisition guidelines is demonstrated here. This is published in the ASNIC SMMMI document. The combined evaluation of regional myocardial perfusion and FTG metabolism images enables identification of specific flow metabolism patterns that are useful to differentiate viable from non-viable myocardium. So it is important to look at the functional assessment, ideally from gated PET or SPECT imaging, identifying dysfunctional segments as those suitable for evaluation of myocardial viability. If stress and respiration fusion imaging information is available, it is also useful to also consider an estimate of the extent of stress-inducible ischemia. Differences in blood pool concentration of tracers can impact the apparent match or mismatch of perfusion FTG images. The separate adjustment of threshold and contrast settings can help compensate for these discrepancies. A standard display would be like that seen here on the right-hand side. That would include relative tracer uptake, resting perfusion, and metabolism images in short axis, horizontal long axis, and vertical long axis slices. The resting perfusion tracer uptake is then compared to the F18 FTG images, which are below in this particular example, in each of the views. The image description should include a location, extent, and severity of perfusion defects. F18 uptake should also be described in terms of its relation to the regions of normal and hypoperfused myocardium. Finally, it's important that the success of glucose loading should be noted as evidenced by glucose uptake in normally perfused myocardium and also in terms of the blood pool activity. So when comparing F18 FTG metabolism with perfusion images, it is important to first identify a normal reference region. So this means the region with the highest perfusion tracer uptake. The extent of mismatched or matched defect may be small, so 0-10% of DLV, moderate, 10-20% of DLV, or large, greater than 20% of DLV. The severity of a matched defect can be expressed as mild, moderate, or severe in order to differentiate between non-transmural or transmural myocardial infarction. If available, coronary angiographic information should be referred to during image interpretation. And similarly, interpretation should refer to regional wall motion abnormalities from functional assessment of gated images. It is important to recognize that the presence of relatively well-preserved F18 FTG uptake in dysfunctional myocardium does not differentiate ischemic from non-ischemic cardiomyopathy. The degree of FTG accumulation over and above regional perfusion helps assess the relative amount of scar and a metabolically viable myocardium. The latter information may significantly influence the power of the test for predicting functional recovery. Broadly, there are four patterns of perfusion FTG metabolism comparison that are recognized. Firstly, you have normal blood flow and normal FTG uptake, and this represents normal myocardium. Secondly, there can be reduced myocardial perfusion with preserved or enhanced FTG uptake. This is called perfusion metabolism mismatch and is characteristic of hyphenated myocardium. The third demonstrates normal or near-normal myocardial perfusion with reduced FTG uptake, and this is termed reverse perfusion metabolism mismatch. And this may be seen in the septum of patients with left bundle branch block or in patients with diabetes and impaired myocardial glucose utilization. Fourthly, we can see proportionally reduced myocardial perfusion trace uptake and reduced FTG metabolism trace uptake, and this is characteristic of a perfusion metabolism match and is indicative of scar. So, the first three of the above patterns in the table represent viable myocardium, and only the last pattern, where both perfusion and metabolism defects are matched, represents non-viable or scar tissue. Okay, so far we have reviewed physics, protocols, and interpretation of a viability study. We will now show you three case examples to put our knowledge into practice. In our first example, we see images from a 75-year-old male. His angiogram demonstrated an occluded mid-LED with a dominant circumflex anatomy and moderate 60 to 70 percent mid-circumflex diffused disease. His non-dominant right was occluded. His left ventricle ejection fraction was 25 percent and demonstrated global hypokinesis with severe hypotoakinesis in the distal anterior wall in apex. Resting perfusion images with N13 ammonia are demonstrated on the first row in short axis slices with corresponding horizontal long axis and vertical long axis perfusion images as labels. F18-FDG metabolism images is demonstrated beneath the corresponding perfusion images. On rest perfusion imaging, there is a severe reduction in tracer uptake in the mid to distal anterior wall, mid-anteroseptum, septum, and apex. On FDG imaging, there is a severe reduction in tracer uptake in the mid to distal anterior wall, mid-anteroseptum, septum, and apex. So therefore, on the relative perfusion metabolism images, there appears to be a large matched perfusion metabolism reduction in tracer uptake. There does not appear to be any significant mismatched areas or hibernating myocardium. When you look on the right, the quantitative analysis, this confirms this impression. So in this model of quantitative analysis, the lab ventricle is divided into 460 sectors. Areas of reduced perfusion tracer uptake less than 80% are demonstrated in the rest ammonia labeled bullseye plots. In this case, there is normal perfusion in 58% of the LV. In the second level of images areas with normal perfusion greater than or equal to 80% are demonstrated in blue. This focuses the attention on the perfusion defect, which is 42%. Next to the perfusion bullseye image, the FDG bullseye representations are seen. In the areas of reduced perfusion, there is a similarly sized, similarly reduced, and similarly distributed reduction in FDG uptake. The quantification process in the areas of reduced perfusion consider the extent and severity of FDG reduction to ensure accurate assessment of matched, proportionally similar, versus mismatched defects. So the total matched defects were 37%, indicating a large LV scar. So the patient is unlikely to benefit from revascularization of the LAD in terms of LV ejection fraction improvement. Our second example is a 62-year-old male with severe LV ejection fraction impairment, approximately 28%, and global LV hypokinesis. Coriandrography revealed an occluded mid-dominant right coronary artery, occluded mid-LAD, and severe distal circumflex disease. The relative perfusion images demonstrate a shown obesity in short axis, horizontal long axis, and vertical long axis, and beneath them are the FDG metabolism images as labeled. On rest perfusion images, there is a severe reduction in tracer uptake in the mid-to-distal anterior wall, mid-anteroceptome, all apical segments, and apex. This would be consistent with reduced resting flow in the LAD. In addition, there is a mild reduction in the mid-to-distal inferior wall, and this would be consistent with reduced resting perfusion in the RCA. In the areas of reduced perfusion, FDG uptake is only mildly reduced in the anterior wall distal segments and apex, consistent with a large area of perfusion metabolism mismatch or hibernation in the LAD territory. In the mid-inferior and mid-anteroceptal walls, there is normal FDG uptake, consistent with a large area of perfusion metabolism mismatch or hibernation in the RCA territory. If we look on the right-hand side of the slide at the semi-quantitative analysis using the model of 460 sectors, you notice that there is normal perfusion in approximately 71 percent of the left ventricle. And the converse of that shown below is that there's reduced perfusion in 29 percent of the LV. In comparison, if we look at the FDG images, we see that there is normal FDG uptake in 91 percent, but only reduced FDG uptake in 8.6 percent. So what we see is that consistent with the relative perfusion metabolism images, there is a large area of perfusion metabolism mismatch in the LAD and RCA territories, accounting for 21 percent of the LV. So this patient was expected to have improved LV function and improved benefit from revascularization. In fact, the patient did undergo bypass surgery, which was successful, and his LV improved up to 44 percent. Okay, so those images are from a 73-year-old female patient with congestive heart failure and an LVAF of 19 percent with severe global hypokinesis. Coronary angiography demonstrated approximately occluded co-dominant right coronary artery, 99 percent stenosed mid-LAD, and 90 percent distal LCX with an occluded large OM1 and severely diseased D1. So N13 ammonia RAS perfusion images demonstrate a moderate to severe reduction in tracer uptake in the apex septum, distal anterior wall, and mid-anterior septum. So this is consistent with reduced perfusion in the mid-to-distal LAD territory. In addition, there is moderate to severe reduced RAS and perfusion tracer uptake in the mid- distal inferior and inferior septum consistent with reduced resting perfusion in the RCA territory. So in the areas of reduced perfusion, there is a moderate reduction FDG uptake in the apex septum and distal anterior segments with a mild reduction in the mid-anterior septum. So this is consistent with a mixture of hibernating myocardium and non-transmural scar in the LAD territory. In addition, there is a moderate reduction in FDG uptake in the mid-to-apical inferior segments and mid-inferior septum. And this is consistent with a mixture of non-transmural scar and a small area of hibernating myocardium in the RCA territory. Semi-quantitative analysis demonstrate normal resting perfusion in 74 percent of the LV, as you can see on the right. And the areas of reduced perfusion are in the LAD and RCA territories, as noted in relative perfusion imaging. FDG uptake is reduced in the areas of reduced perfusion. Proportionally reduced perfusion and metabolism was noted in 17 percent of the LV, consistent with a moderate to large area of non-transmural and transmural scar in the LAD and RCA territories. There are some areas with preserved FDG uptake within this area, with 8.5 percent of the LV noted to have mismatched or hibernating myocardium. So this is consistent with a mild to moderate area of hibernating myocardium within the LAD and RCA territories. The most cases for which viability imaging is performed usually will have some scar and some hibernating myocardium, as in this case. We and others have previously demonstrated that revascularization in the presence of 7.5 to 10 percent of hibernating myocardium is associated with improved outcomes. In contrast, revascularization in the presence of a large scar, so above 25 percent, was not associated with improved LV function. These percentages can provide some guidance as the potential benefit versus risk in challenging cases. In all such patients, careful consideration is required to determine the potential for harm versus efficacy in view of the high surgical risk that ischemic heart failure patients operate under. It is recommended that the FDG perfusion report will contain some guidance as to the potential benefit or otherwise if successful revascularization can be achieved. In this case, with mild to moderate hibernation and moderate but not severe extent of scar, revascularization may be considered to have benefit in terms of LV recovery and possibly outcome. In this case, the patient underwent successful revascularization with coronary artery bypass surgery and postoperatively her LV improved from 19 percent to 37 percent. So here I will talk about the elements of a comprehensive FDG-PET viability report. These recommendations are from the ASNIC practice point for FDG-PET. The essential information is similar to that recommended in perfusion imaging. Documentation should include patient information, study indication, and study techniques. Findings are described with respect to coronary artery territories. FDG images should reference those areas of reduced perfusion imaging. Functional gated images should be reported. And the summary should include a concise description of the proportional FDG and perfusion findings and determine whether these are matched or mismatched and representative of scar or hibernation, respectively. And finally, it is recommended, as I mentioned, that guidance is provided as the likely utility of revascularization with the caveat of if revascularization can be successfully achieved. For it is possible that the coronary anatomy, absence of chondrites, or suitable targets may prohibit complete revascularization. We would recommend the following articles for further reading. Much of this slide presentation is based upon these documents, both of which can be accessed through the ASNIC website. The ASNIC imaging guidelines document produced in conjunction with SMMMI is an excellent reference guide. The practice points are similarly excellent with succinct pointers to ensure successful viability imaging. I'd like to take this opportunity to thank ASNIC for allowing us to present this teaching aid and thank Christiane for her help in preparation and for presentation. We thank you for your attention and we trust you found this presentation helpful and informative. Thank you very much for your attention.

FDG viability study

PET curriculum

learning objectives

cardiac viability images

viability imaging

myocardial glucose metabolism

PET imaging protocols