Hi, I'm Jamie Bork, a professor of medicine and radiology at the University of Virginia, where I'm medical director of nuclear cardiology, echocardiography, and the stress laboratory. And I will be speaking today on technical advantages of CardiacPET, Radio Tracers, Hardware, and PET Physics 101. Here are my disclosures. There are numerous applications of CardiacPET, including myocardial perfusion, the ability to assess myocardial function, including at peak stress, assessment of absolute myocardial blood flow, the ability when combined with CT to assess coronary calcium, unique ability to assess metabolism and therefore assess myocardial viability, as well as inflammation imaging to assess infection, inflammatory diseases, and numerous applications of hybrid PET-CT approaches. And a lot of these advantages of CardiacPET stem from some of the hardware and radionuclide advantages that are present. So CardiacPET has superior spatial resolution that is depth independent. It's four to eight millimeters. And if you look at the top figure on the right here, you can see that if we look at our typical SPECT photomultiplier tubes and we look at the bismuth germinate sort of blocks that are present sort of next to them, you can see why there would be superior spatial resolution. There's also advantages from the radio tracers that we'll talk about in a minute. There's increased sensitivity of CardiacPET. So if you look down here at this figure, you can see that the way the imaging works is you have a radio tracer that gives off a positron. That positron annihilates with an electron and gives off two high energy photons that are 511 kiloelectron volt. And those photons then interact with a ring detector that's all the way around the patient. And the fact that the two photons come at the same time diametrically opposite each other is called coincidence imaging. And that process allows us to both have intrinsic attenuation correction. There's the ability to have a better resolution. You are taking out a lot of the scattered photons that we get with SPECT imaging. And then there's increased sensitivity because those photons are very high energy. Because the ring detector is all the way around the patient, you also have high temporal resolution. And this high temporal resolution allows quantitation of absolute myocardial blood flow. Because we are looking at the heart over the entire time that the tracer is injected at the time of vasodilator administration rather than multiple minutes later, we get a peak stress lenticular ejection fraction. The radio tracers have a lower radiation burden compared with our SPECT tracers. And there are unique radio tracers used for PET that have the ability to assess metabolism. And we'll talk about that in a second. So when we add CT to PET, this provides improved accuracy. And therefore, the specificity goes up. One reason for that is that we can do attenuation correction. And if you look here, if we can use the CT images to correct for the soft tissue that the counts are having to get through to get to the ring detector, this allows us to adjust for those. And you can see here, if we have no attenuation correction in these images up top, and then we add attenuation correction, you can see there's really robust fill-in of some of these areas and allows for perfusion defects to be more likely to represent disease rather than just attenuation. The ability that we can do coronary calcium allows us to make a determination of the presence of coronary plaque. And in particular, if there's a high level of coronary plaque, but normal perfusion, there's maybe a higher suspicion for more extensive disease. So the coronary calcium allows us to modulate our read. And then when we add a full coronary CT, we can actually assess both anatomy and function. And in particular, if someone has multiple lesions, we could determine which area is actually having reduced perfusion. And this allows us to improve our concomitant assessment of both anatomy and function. Our PET radiotracers provide information on perfusion metabolism. And there are also novel radiotracers that look at inflammation and other markers. There are multiple perfusion radiotracers commercially available. Rubidium-82 and N13 ammonia have been available for a while. And I actually had to just edit this slide because F18 flipuridaz was just approved by the FDA and will be commercially available soon. And then there are perfusion radiotracers in development, including O15 water. There are key production and administration characteristics that help determine the sort of advantages of different tracers. And those advantages may be depending on the individual lab situation or the specific patient and the clinical need. So you can see that rubidium-82, if you look at the table on the upper right, is produced in a generator. You can see that generator down here, the image on the bottom left. And the half-life is 75 seconds. So literally, this generator is right next to the patient, and the tracer is injected into the patient at the appropriate time. The other three use cyclotrons, but the cyclotrons can be in various locations. For O15 water with a half-life of two minutes and the production from the cyclotron is actually the gas, the cyclotron has to be in the same location as the PET camera, at least within a couple of rooms or, at the very least, a short distance away in a building or an adjacent building, whereas N13 pneumonia, you could have a cyclotron that's just nearby because the half-life is 10 minutes. And then F18 flipiridaz has the advantage of being able to be produced in a cyclotron that is more remote, as there is a 110-minute half-life. So this would allow PET imaging with perfusion to be performed at places that were otherwise not able to do cyclotron administration previously. And you can see that the radiation doses vary for the different tracers. Another key technical consideration is spatial resolution, which is partially determined from positron range. So if you look at the figure in the upper right, you can see that we have our molecule. And so let's say this is N13 ammonia, and the proton decays into a neutron emitting a positron and a neutrino. The neutrino goes off. The positron is high energy, and so it goes around bouncing off of electrons, losing energy each time it interacts with an electron. And eventually, it's low enough energy that when it interacts with an electron, it's annihilated, and that annihilation event creates two high-energy photons, 511 kiloelectron volt, that go off at 180 degrees, as we had talked previously. And our different perfusion tracers have different positron ranges. In particular, you can see that the positron range is particularly low for O15 water and N13 ammonia, and is much higher for rubidium-82. So the higher the positron range, the further away from where the tracer actually was that the annihilation event happens, and so this decreases our spatial resolution. So if you look at our image examples on the left, you can see that N13 ammonia and F18 fluorpyridaz have a better spatial resolution compared with our rubidium images. All of these have been shown to be effective and to have superior diagnostic accuracy compared with SPECT, including rubidium-82, but the spatial resolution is even better with N13 ammonia and F18 fluorpyridaz. Another key technical consideration is the accuracy of myocardial blood flow quantitation. So an ideal radio tracer has no roll-off as blood pressure increases. And what you can see here, if you look at the figure on the right, is that for our typical SPECT imaging agents, there's a fair amount of roll-off as the absolute myocardial blood flow increases. You can see that the myocardial uptake is less than what the absolute myocardial blood flow is. A perfect tracer would be right along the 45-degree line here. And you can see that the PET agents are all better than the SPECT agent with regard to But in particular, our N13 ammonia fluorpyridaz and most prominently O15 water, and O15 water tends to approach microsphere accuracy. And excuse me, this allows for us to see perfusion defects more prominently and also more accurately assess macro and microvascular function. We can use F18 fluorodeoxyglucose to do metabolic imaging. One example of that or one application is in inflammation. So you can see, if you look at the figure on the top right, that neutrophils exclusively use glucose for their fuel. And if you inject F18 fluorodeoxyglucose, you can see that that is taken up in the blood vessels just like glucose. And the glucose undergoes the glycolysis process. And when the F18 FDG goes through that process and is converted into F18 FDG 6P by hexokinase, you can see that it then accumulates. And so we can assess the presence of the neutrophils of the inflammatory agents. And so if you look at the bottom middle image, you can see that there is uptake in the subclavian and axillary arteries as well as in the wall of the aorta. If you look at the bottom right, you can see there's heterogeneous focal on diffuse uptake around this mechanical valve in a patient with aortic valve infection. In particular, the dietary prep used for inflammation imaging involves the use of a high-fat diet with absolutely no carbohydrates followed by a prolonged fast. And this allows us to assess inflammation for diseases such as sarcoidosis, myocarditis, as well as an infection or infective endocarditis or device infection, VAD device infection. And then in another application, we can use F18 FDG to actually assess metabolically active tissue, aka tissue that is alive. And we can use this for viability imaging. For this application, we have to use a prep that encourages the myocardium to take up glucose. And normally, the myocardium uses fatty acids for its fuel. And so in order to encourage myocardial uptake, we have to use a hyperinsulinemic euglycemic clamp. And so what we do is we administer glucose to the patient and then insulin. And in doing so, we try to get to a steady state of blood glucose with the insulin encouraging the myocardium to take up the glucose. And if you look at the imaging on the right, you can see that we can do perfusion imaging with one of our perfusion tracers, identify an area that has decreased perfusion. And then we can look at metabolism, metabolically alive tissue by F18 FDG using this prep. And you can see a mismatch pattern where there's a perfusion defect and FDG uptake in the same area. And this is suggestive of viable myocardium, whereas areas that have reduced perfusion and also do not have uptake of FDG, that's a match pattern. And that would be thought to be non-viable myocardium. Other novel radiotracers can be used, such as in cardiac amyloidosis, where PET amyloid tracers allow superior quantitation and are actually able to assess AL as well as ATTR cardiac amyloidosis. Image on the bottom left shows F18 for beta-PIR. You can see that there's uptake with both ATTR and AL cardiac amyloidosis. There are also multiple other radiotracers that are in preclinical stages using molecular imaging approaches for inflammation. You can see multiple agents used for apoptosis and necrosis for matrix metalloproteinase activation, neoangiogenesis, fibroblast activation. Multiple tracers are available. So in summary, cardiac PET has numerous and growing applications in cardiovascular disease and in systemic diseases with cardiovascular manifestations. The mechanisms of PET image creation, both the radionuclide tracers and hardware advantages, create superior characteristics for cardiovascular imaging versus SPECT approaches. Novel targets for radiotracers and the favorable radiotracer characteristics allow us to extend PET cardiovascular imaging capabilities from perfusion, both to enhance the ability to assess perfusion as well as to examine for inflammation and in other disease processes. Thank you very much.

Cardiac PET

radiotracers

myocardial perfusion

coronary artery disease

metabolic imaging