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Overview: Myocardial Perfusion and Metabolism—Now and at the Beginning
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Low coronary blood flow may cause acute coronary syndromes, angina pectoris, heart failure, arrhythmias, and even death, as reviewed in detail in Chapter 34. The capacity for increased coronary blood flow is associated with cardiovascular health, and its variations may reflect our emotional states and lifestyles, including the foods we eat—even our most recent meal. Intense risk factor treatment prevents or stabilizes atherosclerosis, thereby preserving coronary blood flow, which is the most basic vital sign of life on which blood pressure, heart rate, and respiration depend. Assessing, maintaining, or restoring coronary blood flow are the objectives of all coronary procedures and most cardiac diagnostic testing. Next to “heart,” the commonest critical word in cardiovascular practice is “ischemia,” implicitly referring to low myocardial perfusion.
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Coronary blood flow is a personalized, vital sign of individual status. When severely depressed, similar to blood pressure, it heralds imminent adverse events in an individual, not just a statistical probability of adverse outcome as do risk factors or the diagnosis of coronary artery disease (CAD). Advanced imaging technology and an extensive research literature document its measurement and relevance. Yet quantitative assessment of myocardial perfusion or coronary blood flow remains largely unused and unmeasured in clinical practice; its use is restricted to a research tool in a small number of academic centers where it usually has limited impact on clinical decisions. However, in view of revascularization trials failing to improve event-free survival in patients with CAD or reduced left ventricular function, quantitative perfusion and metabolic imaging should play a larger role in selecting patients optimally benefiting from revascularization.
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How does the “now” of coronary blood flow in acute coronary syndromes relate to “the beginning” of the four-chambered mammalian heart that had already evolved 200 million years ago? A stem mammal (eg, Morganucodon watsoni) was a 1-inch long weasel-like animal during dinosaurs' domination for 250 million years.1 The Chicxulub asteroid impact2 and associated Deccan volcanism blocked the sun, causing the end-Cretaceous mass extinction of most life.3,4 However, small mammals survived,5 radiating into multiple open niches and large sizes, reflecting adaptability to extreme demands and environments that required an extraordinary heart and cardiovascular system before large brains and facile limbs evolved. As documented in humans,6 canines,7 and swine,8 the branching coronary artery tree of mammals is structured in mathematically exact arterial size and length for myocardial mass.6,7
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This arterial size-length-mass relationship and the branching structure of the coronary arterial tree are precisely related to coronary blood flow by a power equation for minimum energy loss. This relationship is mediated by normalized wall shear force to distribute efficiently the oxygenated coronary blood to myocardium6 while preserving capacity for high demands of coronary blood flow or coronary flow reserve (CFR).9,10 The same equation characterizes the observed mother-daughter relationship of coronary arterial branch diameters.6 This power equation may even explain some of the different manifestation of CAD in women compared to men, as addressed in Chapter 34. The heart’s phasic contraction and relaxation is the oldest, most developed mechanism for pumping its own fuel supply and systemic needs. Evolutionary functional demands drove coronary physiology, thence anatomy, to its current essential role for understanding and managing CAD addressed in this chapter on clinical quantitative myocardial perfusion by positron emission tomography (PET).
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Cellular metabolism and contractile proteins evolved for survival even earlier than physiology or coronary blood flow.11,12 One of many such mechanisms is myocardial metabolism that switches from aerobic metabolism of fatty acids when there is adequate supply of oxygenated coronary blood to anaerobic metabolism of glucose when coronary blood flow is impaired or hypoxic.13 Under such adverse circumstances, the flow-deprived myocardium “hibernates” or stops contracting but remains “alive or viable” for potential return of normal contractile function when coronary blood flow is restored. Transient severely impaired coronary blood flow may temporarily stop or “stun” myocardial contraction after the low-flow episode is over, with slow contractile recovery over hours to days after normal blood flow is restored. PET metabolic or viability imaging drives optimal personalized management of patients with advanced coronary artery disease and impaired left ventricular function as addressed in this chapter.
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Although current literature provides many excellent supporting papers and reviews,14–42 quantitative myocardial perfusion and metabolism remain at the edges of mainstream cardiology despite their value in relation to myocardial ischemia (see Chap. 34). Consequently, this chapter on PET takes a different approach. Rather than providing a detailed summary of the literature on the current “average” use of cardiac PET perfusion imaging, this chapter emphasizes two major themes developed in the two leading centers prominent in developing clinical cardiac PET—the David Geffen School of Medicine at the University of California at Los Angeles and the McGovern Medical School, University of Texas–Houston.
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First, we use quantitative PET to elucidate complex, but clinically relevant, coronary pathophysiology and integrate its complexity into comprehensive decisional “smart” analytical displays to guide binary clinical decisions personalized for individuals. Second, we demonstrate, by case examples, how quantifying myocardial perfusion and metabolism drives personalized assessment of CAD, its severity, and its management, including invasive procedures and revascularization for individuals or for optimally determining average group treatment outcomes. For conceptual simplicity, the term coronary blood flow is used interchangeably with myocardial perfusion because of their physiologic interchangeability of mechanisms and consequences while having slightly different units of cc/min versus cc/min/g due to different measurement methodology.
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Each case illustrates a major class of clinical conditions uniquely addressed by PET, providing personalized insight so that clinical readers and patients can see its value in the delivery of individually tailored cardiovascular practice, and not just as a remote research tool capable of generating bulk data without personalized relevance. Although somewhat unconventional, our approach provides the vision for readers, cardiologists, and patients to see what can and should be the optimal, objective, and personalized mechanism for establishing and managing CAD. The quantitative, personalized data from PET allows for individualized decisions about the intensity of therapy recommended—lifestyle changes alone or combined with medical therapy with or without revascularization. In essence, PET provides quantitative data highly specific for each individual’s personalized coronary care, with a scientific and technically valid basis, that physicians and patients themselves visually readily understand, with a corresponding powerful influence on their management.
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Why Cardiac Positron Emission Tomography for Myocardial Perfusion?
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Diagnostic Sensitivity and Specificity
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The diagnostic sensitivity and specificity of PET for the diagnosis of CAD are 90% to 95% and 88% to 95%, respectively, and are higher than those for single-photon emission computed tomography (SPECT) at 85% and 85%, respectively.24,25,43,44 The area under the receiver-operating characteristic for PET was 0.95 compared to 0.90 for SPECT, a significant difference (P < .0001).24 This greater diagnostic accuracy of PET versus SPECT results from better resolution and attenuation correction of PET.
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However significant, these comparisons fail to demonstrate the enormous differences between these two technologies for several reasons. In these studies, the reference gold standard for defining CAD to which PET and SPECT were compared was visually interpreted angiographic percent diameter stenosis. The variability of visually estimated percent diameter stenosis; its poor correlation with coronary blood flow or myocardial perfusion; and failure to account for diffuse narrowing, complex anatomy, or arterial remodeling contravene the validity of the angiogram as a reference for identifying or assessing either anatomic or physiologic severity of stenosis or diffuse disease.16,31,37,38,39,40,41 When compared to objective automated quantitative coronary analysis (QCA) of angiographic severity of discrete coronary artery stenosis, diagnostic sensitivity and specificity of PET perfusion images approaches 95%.34
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However, even QCA remains limited as a gold standard of severity of CAD,16,31,37,38,39,40,41 for several reasons. The coronary angiogram fails to quantify the essential and more basic physiologic function of the coronary arteries now shown to define severity for guiding management.16,31,39 Diffuse epicardial atherosclerosis cannot be measured. Epicardial endothelial function or small-vessel disease may profoundly affect coronary blood flow but is not accounted for on an angiogram. Moreover, coronary blood flow relates to the arterial diameter raised to the fourth power so that small changes in arterial size that cannot be measured accurately on an arteriogram markedly alters coronary blood flow. Finally, the varying diameters and irregularities over different lengths, angles, and shapes affect coronary blood flow but are not reliably accounted for on anatomic images. The computed tomography (CT) angiogram, with best resolution of 0.5 mm, has a large uncertainty at each arterial border that precludes projecting or calculating blood flow capacity in 3- to 5-mm diameter coronary arteries because the flow-diameter to the fourth power relation magnifies the uncertainty of arterial dimensions.39 Coronary anatomic-functional relationships are detailed further in Chapter 34 on coronary blood flow and myocardial ischemia.
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Fractional flow reserve (FFR), measured by trans-stenotic invasive pressure wire during cardiac catheterization, was originally validated and compared to CFR by quantitative PET perfusion imaging.45 Although FFR has advanced cardiovascular science from anatomic characterization to one based on the physiologic severity of stenosis to guide percutaneous coronary intervention (PCI),46,47 FFR is also an inadequate reference standard because of the substantial discordance between FFR and CFR by invasive technologies and also by quantitative and relative myocardial perfusion by PET.48,49 Moreover, FFR was low or discordant with the absence of visually significant stenosis when all arteries were interrogated as opposed to measuring FFR in only arteries with stenosis visually severe enough to be considered for PCI.50
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While offering a major advantage over SPECT imaging, relative PET perfusion images fail to utilize PET capacity for absolute quantification of perfusion in cc/min/g and absolute CFR. Such quantitative measurements move PET into the highest level of assessing CAD in order to personalize the physiologic severity of CAD that is unmatched by any other technology. To date, all trials of elective revascularization fail to reduce myocardial infarction (MI) or cardiovascular death, despite relief of angina.51,52,53,54 Consequently, simply diagnosing CAD should no longer be considered the primary, or even an adequate goal of diagnostic testing, because establishing evidence-driven physiologic severity is now the optimal scientific basis for revascularization versus medical management alone.
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The evidence-driven goal of diagnostic testing now requires objectively identifying those patients with quantitative physiologically severe CAD of sufficiently high risk in whom revascularization would reduce the risk for MI or mortality, while also relieving angina.35,36,37,38,39 Quantitative assessment of perfusion provides comprehensive personalized quantification of physiologic severity of CAD, integrating information from each individual coronary artery and its secondary and tertiary branches to delivery an integrated gold standard. Within the confines of biologic and methodological variability, quantitative perfusion defines the flow through a coronary artery as a vital sign essential for survival, just like blood pressure, where a defined low range may bode illness.
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As addressed in Chapter 34, randomized trials are needed to determine the threshold at which coronary perfusion or pressure is so low that the risk of adverse events is high enough to justify revascularization as a means to improve outcomes. However, a deep truth resides in individual cases, representative of the variations of CAD, where quantitative PET provides unique insights and management guidance as the basis for its current clinical use. The cases also illustrate the need for more advanced interventional trials; those completed to date lack adequate low flow thresholds high enough risk for optimal benefit from revascularization.
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The Coronary Flow Capacity Map: Complexity Made Simple for Personalized Patient Decisions
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Three measures of coronary blood flow, or myocardial perfusion, quantify its profound effects in all manifestations of CAD. Rest and stress myocardial perfusion in cc/min/g and CFR as the ratio of stress perfusion to rest perfusion on a regional pixel basis are the final common pathways of coronary anatomy and physiology on patient outcomes. Myocardial perfusion is commonly heterogeneous regionally and temporally associated with multiple, interacting mechanisms that may contravene some providers' preference for a simple, binary, positive or negative, one-result-fits-all test to guide management. Rather than a diagnostic limitation of methodology or biological variability, these three perfusion measurements provide rich insights into the reality of heterogeneous coronary pathophysiology essential for individualized management when integrated to provide a valid binary directive—“complexity made knowledgeably simple.” These insights for individual personalized management provide an equally rational basis for randomized trials of “group” management or revascularization based on quantitative physiologic severity of CAD.
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Accordingly, at the outset, we account for and incorporate these three measures into a coronary flow capacity map color-coded for severity from healthy young volunteers to patients having angina and significant electrocardiogram (ECG) changes during dipyridamole stress PET imaging.55,56,57 After we demonstrate its clinical utility, we then address the technical details of quantifying myocardial perfusion. Figure 19–1 orients topographic PET images derived from tomographic views, as previously described.16,31,37,40,48,55,56,57
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Stress flow and CFR require integrated interpretation caused by frequent discordance of rest and stress flow, as seen in Fig. 19–2. High rest flow (A, white) caused by a high pressure-rate product, anxiety, medications, or female sex,41 either separately or cumulatively (proportionately higher than stress flow) may cause low CFR (A, blue) that alone erroneously implies flow-limiting stenosis. Alternatively, CFR may be high (B, white or red) with no ischemia despite low flow at rest and stress (B, blue) because of beta-blockers, physical conditioning, increased vagal tone, or CAD with low stress flow erroneously suggesting ischemia if it is considered alone without CFR. By plotting values for each pixel of stress flow in cc/min/g on the horizontal axis and CFR on the vertical axis (C), all three perfusion measures for each pixel are accounted for in the coronary flow capacity map panel (D, red) because CFR is the ratio of stress to rest flow. Caffeine, beta-blockers, inadequate vasodilator stress, and diffuse or small-vessel disease may lower stress perfusion in cc/min/g to apparently low ischemic levels; therefore, measuring rest flow and CFR commonly provides essential diagnostic information for correct clinical interpretation from the coronary flow capacity map.
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The coronary flow capacity map plot is color-coded red for stress flow and CFR in 241 young healthy volunteers with no risk factors, no medical conditions, no measurable blood caffeine, and no measurable urinary cotinine as an objective test for smoking, as previously reported.40,45,56,57 The lower limit of red is the mean minus one standard deviation (SD) of CFR and stress flow for this group. Blue indicates the optimal stress flow and CFR thresholds for patients with angina, ECG changes, and/or a regional stress defect during dipyridamole stress PET imaging. Green indicates patients with either angina or ECG, changes but not both, during stress imaging with a regional stress defect. Orange indicates patients with CFR and stress flow at the lower one SD of the healthy volunteers. Yellow indicates the upper one SD above the patients with angina or ST-segment changes during stress imaging. The orange-to-yellow transition is halfway between these SD limits.
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Each color-coded pixel is then mapped to its original position and displayed as the coronary flow capacity map in four projections (lateral, inferior, septal, and anterior views) showing coronary flow capacity comparable to that in young healthy volunteers within the distribution of the coronary arteries (D). The specific ranges of stress perfusion in cc/min/g and CFR for each color used for all PET perfusion images in this chapter are detailed in Fig. 19–3.
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Complete relevant perfusion information in a single clinical case involve, five sets of different data in four views involving 6720 pixels spatially distributed over a total of 20 different image views. Each of these views has 5 continuous variables (rest-stress uptake, rest-stress flow and CFR) color coded into 7 ranges from healthy young volunteers to patients with overt ischemia during dipyridamole stress as in Figs. 19-3 and 19-4. The rest and stress relative images (A) are abnormal with subtle differences between the distal anterior region (green) and the distal septum (yellow) that are difficult to interpret, inconsistent with a single left anterior descending coronary artery (LAD) territory and providing little insight into the detailed regional severity and size of abnormal stress perfusion.57 Rest perfusion and stress perfusion images (B) are proportionately larger and more severe than the relative perfusion defects, but are complicated by spatial heterogeneity of both rest and stress perfusion. The CFR display (B) reflects the rest-stress perfusion heterogeneity into better defined normal or abnormal regions but still fails to define the subtle differences between the distal septum and the distal anterior regions on the relative images. Visually interpreting or simply quantifying the 6720 pixels spatially distributed in the 20 different views is difficult or limited for even an experienced reader.
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However, based on the color-coded pixel graph (C), the coronary flow capacity map (D) integrates all these data into a single four-view color-coded image for the entire range of flows from active ischemia (blue) to flow in healthy young volunteers (red), accounting for all the flow data in a particular patient.57 The map demonstrates preserved flow capacity (red) in left circumflex coronary artery (LCX) and right coronary artery (RCA) distributions, minimally reduced flow capacity on the proximal LAD distribution tapering to mild (yellow) diffuse narrowing in the distal LAD and thence to the moderate (green) border zones around a small severe stress defect (blue) in the distribution of a small distal diagonal branch off the patent but diffusely narrowed distal LAD. The small apical defect shows myocardial steal, indicating an occluded collateralized distal diagonal branch. The PET findings are confirmed by the angiogram inset done as part of a research protocol because the defect is too small and distal to warrant PCI.
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Clinical PET Cases: Personalized to Quantify Severity for Guiding Management
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The following fourteen cases visually demonstrate the principles and personalized management for the wide range of manifestations of CAD for which PET uniquely drives patient management as examples seen daily at the Weatherhead PET Imaging Center for Preventing and Reversing Atherosclerosis. The clinical power of cardiac PET illustrated in these cases requires knowledge of coronary physiology and myocardial ischemia addressed in the chapter on coronary blood flow and myocardial ischemia (Chap. 34). Here, to begin, quantitative PET is integrated with coronary physiology as comprehensive analytical displays of complex perfusion data made knowledgeably “simple” for clinical use in both physician and patient understanding. Later sections address technical aspects of measuring myocardial perfusion by PET.
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Case 1: Coronary Flow Capacity in Multivessel Complex CAD
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A 63-year-old man with 6 months of mild stable angina (Fig. 19–5)47 illustrates the complex data inherent in all quantitative perfusion imaging that is integrated into a “simple,” easily understood image for clinical decisions by validated directive software based on a large patient database detailed in a later section. Figure 19–5 displays relative myocardial perfusion images of rubidium (Rb)-82 at rest (A) and during dipyridamole stress (B). With the arterial input function as detailed later, stress perfusion in cc/min/g (C) and CFR (D) for every pixel in every topographic image in each of four topographic views are plotted (E), color-coded and back-projected to the coronary flow capacity map (F).
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For the patient whose images are depicted in Fig. 19–5, the coronary flow capacity map (F) shows occlusion or subtotal stenosis of the mid LAD, of the RCA, and of the distal LCX. Coronary flow capacity is severely reduced in 47% of the left ventricle (LV), of which 28% of the LV shows myocardial steal in the central area of the stress defect, a typical pattern indicating collaterals beyond occlusions or subtotal stenosis. There is a more proximal moderate or “intermediate” LAD stenosis involving the first septal perforator (yellow, 22% of the LV) with further reduced border zones (green, 10% of the LV). The diagonals and ramus intermedius distributions have only minimally reduced (orange, 17% of the LV) or good (red, 4% of the LV) coronary flow capacity. Because of the definitive images of complex multivessel disease, the patient was scheduled for coronary artery bypass graft (CABG) surgery with preoperative coronary angiography confirming the PET findings. He has done well over the following 3 years with a good flow capacity on follow-up PET.
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Case 2: Saved from Unnecessary CABG Surgery
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A 76-year-old asymptomatic man with preserved left ventricular ejection fraction (LVEF) had PET for a second opinion after CABG surgery was recommended following abnormal SPECT imaging and angiography reported to show the following stenoses: 70% left main; 80% LAD; 80% first diagonal; 70% first obtuse marginal; and 70% and 80% serial stenoses in the RCA. In Fig. 19–6, his rest-stress relative uptake images show no stress defect but only a small inferoapical motion artifact from the inferior apex recoiling briefly into the most inferior image plane during systole. The inferior apex is outside this lowest imaging plane during diastole, lasting two-thirds of the contraction cycle, thereby acquiring less activity. It normalized on ECG-gated systolic images. As the coronary flow capacity map shows, 69% of the LV has flow capacity comparable to that of healthy young volunteers, with 21% of the LV having minimal reduction (orange) and 10% with mildly reduced flow capacity consistent with age and mild, diffuse, nonobstructive, calcific CAD with coronary flow capacity well above the low ischemic flows that would be coded green or blue if present. The patient was advised against CABG surgery and did not have it performed. After the PET, the prior angiogram on which the recommendation for CABG surgery was based was obtained for review by the author K. Lance Gould (KLG). It showed luminal irregularities, mild nonobstructive CAD, and arterial lip dividers at branch points with no significant stenosis that were overinterpreted by the prior cardiologist. The SPECT images were false positives.
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Case 3: Missed Severe CAD with Normal Treadmill Test
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A 62-year-old asymptomatic man with risk factors but no known CAD recently had a normal ECG exercise stress test, and he underwent PET in a research protocol. He had a history of back pain related to activity thought to be the result of degenerative disc disease that he experienced during his normal treadmill stress test. His relative myocardial uptake images in Fig. 19–7 show a large, severe, anterior, septal and apical stress-induced defect involving 55% of the LV in the distribution of the LAD proximal to the first septal perforator and wrapping around the apex and up the distal inferior wall.
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Absolute myocardial perfusion capacity was severely reduced, with myocardial steal in 37% of the LV indicating occlusion just distal to the first septal perforator. The proximal LAD had additional proximal moderately severe stenosis involving the first septal perforator (green, 10% of LV) with small-vessel or diffuse disease of distal the RCA supplying posterior perforators (yellow, 23%). The LCX had preserved coronary flow capacity (red, 14% of LV) with mild diffuse disease tapering to yellow distally (orange, 17% of LV). The CT scan done for attenuation of PET data shows moderate coronary calcification in the LAD and RCA. Gated PET perfusion images showed normal left ventricular contraction with an LVEF of 73% at stress. Based on the PET scan, medical therapy and coronary angiography with revascularization were recommended due to the size and severity of the rest-stress PET abnormalities. An angiogram confirmed the PET findings, for which his cardiologist had CABG carried out.
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Case 4: Complex Post PCI Perfusion—Septal Perforator Caged by LAD Stent
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A 58-year-old man with atypical chest discomfort, separate episodes of dyspnea—at night or inconsistently while walking—had PET as part of a research protocol. His baseline coronary flow capacity map in Fig. 19–8A shows a severe stress defect typical of a severe stenosis of the LAD proximal to the first septal perforator and wrapping around the apex. An angiogram confirmed these findings, and PCI was done with a proximal stent. The post-PCI PET showed a residual small, severe, basal septal, stress defect comprising 4% of the LV in the distribution of the first septal perforator caged by the LAD stent. In our experience, most coronary branches caged by stents have reduced coronary flow capacity even when open on post-PCI angiogram.
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Case 5: Normal Relative Myocardial Uptake Images Miss Severe Diffuse CAD
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A 56-year-old man with mild stable angina had a PET scan as part of a research protocol. During dipyridamole stress he had angina with 1 mm ST-segment depression with normal relative uptake images in Fig. 19–9. Despite completely normal relative stress images (A), stress perfusion in cc/min/g (B) and CFR (C) were severely reduced to low flow ischemic levels caused by severe diffuse CAD. The histogram color bars to right of each image show color-coded severity and percent of the LV in each range of severity. He developed angina and greater than 1 mm ST-segment depression at 5 minutes (early stage 2) of the Bruce protocol. An angiogram confirmed severe diffuse disease with superimposed visually estimated 70% stenosis in all three epicardial arteries. He underwent CABG surgery, after which his symptoms resolved and treadmill duration increased to 7 minutes without angina but with still with greater than 1 mm ST-segment depression. At follow up PET, global stress flow increased from 1.25 to 2.0 cc/min/g reflecting improved coronary flow capacity but still limited by residual diffuse CAD at the borderline threshold for ischemia.
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Case 6: Complex Post-PCI Angiogram with Question of Left Main
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A 52-year-old physically active asymptomatic man had PET for a second opinion for CABG surgery. He had a prior PCI with two stents to the LAD, with a moderate estimated 50% to 55% diameter left main stenosis that was not stented. Treadmill exercise stress testing and myocardial perfusion imaging were reported as normal; however, the patient developed nonsustained supraventricular tachycardia in recovery from exercise, leading his cardiologist to recommend CABG surgery (given the moderate left main disease on angiography). In Fig. 19–10, rest relative uptake is normal (A). Stress relative uptake (B) and the coronary flow capacity map (C) show the following:
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A severe stress defect in the distribution of LCX proximal to its the first obtuse marginal branch (blue on the flow capacity map)
A severe stress defect in the distribution of the first diagonal branch off the LAD (blue on the flow capacity map)
Mildly reduced but adequate coronary flow capacity of the proximal LAD and first septal perforator above low flow ischemic levels (yellow on the flow capacity map) tapering to more severely reduced flow at the apex (green on the flow capacity map) consistent with severe diffuse narrowing
Mildly reduced but adequate flow capacity above ischemic levels in the ramus intermedius distribution anterior to the lateral stress defect caused by the first obtuse marginal branch stenosis
Excellent high flow capacity in the RCA distribution
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Objective computer analysis and review of the angiogram by KLG measured the left main as a 52% diameter stenosis with diffuse LAD narrowing with moderate stenosis of the first obtuse marginal branch of the LCX and first diagonal branch. The left main stenosis alone did not severely limit flow capacity. However, the cumulative effects of the left main in sequence with diffuse disease and downstream moderate anatomic stenosis severely reduced flow capacity heterogeneously. The PET results suggested that CABG surgery was appropriate and also helped elucidate appropriate bypass targets (LAD with its diffuse narrowing, the large first diagonal branch, and first obtuse marginal branch with branches on either side of the ramus). In the absence of symptoms, the patient was reluctant to have CABG surgery but after reviewing the PET with him and his cardiologist with the high risk of cumulatively severe CAD, CABG surgery was performed with the patient doing well at follow-up 9 years later.
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Case 7: Left Main Stenosis with Patent RCA
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A 49-year-old man had PET as part of a research protocol. Nine years previously, he had a prior ascending aorta graft for type A aortic dissection complicated by severe aortic regurgitation. The left main coronary artery had been reattached to the graft. He followed an intense exercise regimen consisting of 1 hour on the elliptical and 30 minutes on the bicycle five times weekly without symptoms or limitation of exercise, except over the prior week when he felt that “something was not quite right.” After rest and dipyridamole stress images were completed (Fig. 19–11), he developed hypotension, deep ST-segment depression, and cardiac arrest. He was supported by advanced cardiac life support to the catheterization laboratory, with subsequent extracorporeal membrane oxygenation. An angiogram showed a severe stenosis at the anastomosis of the left main to the aortic graft that was stented open. He recovered fully with normal brain function and normal LVEF.
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Case 8: Left Main Stenosis with Occluded RCA
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A 69-year-old man with poorly controlled risk factors, right bundle branch block, and past angiogram showing an occluded RCA had mild exertional angina for 3 years. Although his angina was variable, he thought that perhaps it had slightly worsened over the prior 3 weeks; however, he was reluctant to have an angiogram. Dipyridamole stress led to severe angina, 3-mm ST-segment depressions, and blood pressure falling from 126/78 to 90/56 mm Hg, requiring early imaging and termination of stress with intravenous aminophylline, metoprolol, and nitroglycerin resolving these stress effects. The relative images in Fig. 19–12 show mild perfusion heterogeneity or small mild separate stress defect with no severe large regional perfusion defect. However, the stress flow, CFR, and coronary flow capacity map show severely reduced stress perfusion to low ischemic flow levels. Angiogram confirmed a severe stenosis of the left main coronary artery and an occluded RCA; he underwent successful CABG surgery.
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Case 9: Abnormal Relative Stress Image But Adequate Absolute Perfusion
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A 60-year-old man had known angiographic occlusion of the LCX with extensive collaterals and variable angina over the prior 10 years, depending on adherence to exercise and healthy living. After a half year of unhealthy high-stress living, his exertional angina worsened, leading to a follow-up PET scan (Fig. 19–13). While there is stress perfusion abnormality on the relative perfusion images, the flow capacity map shows only mildly to moderately reduced flow capacity in a small lateral region with good flow capacity in the remaining myocardium. The collaterals supplying collaterals to the LCX distribution were sufficiently well developed to prevent myocardial steal. Collateral perfusion improves with regular exercise, as well as low-fat and low-carbohydrate foods by complex mechanisms, including lowering the postprandial lipid surge that inhibits endothelial function.58,59,60,61,62,63 Accordingly, an angiogram was avoided, and return to healthy habits resolved his angina.
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Case 10: Progression of Diffuse CAD, Compromising Collateral Supply
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A 69-year-old asymptomatic man with total occlusion of the RCA by angiogram and poor risk-factor control had a baseline PET as part of a research protocol (Fig. 19–14A). The baseline coronary capacity map showed a severe perfusion defect comprising 13% of the LV (blue) with the central 7% revealing myocardial steal (dark blue) associated with collateral perfusion. Although he was still asymptomatic 6 years later, protocol follow-up PET in Fig. 19–14B showed a larger, severe defect comprising 23% of the LV (blue) with an additional 9% border zones (green) and 13% central steal (dark blue). In the rest of the myocardium outside the severe stress defect, the best coronary flow capacity (red) had declined from 56% to 16% of the LV, with a corresponding increase in the areas of mildly reduced flow capacity (yellow) from 10% to 26% of the LV. Therefore, this enlarging stress defect in the RCA distribution was likely the result of progressive diffuse disease in the other coronary arteries supplying the collaterals to the totally occluded RCA. Accordingly, coronary angiography confirmed the PET findings but could not quantify the diffuse CAD. Attempted PCI of the occluded RCA was not successful. Because the patient was asymptomatic with good LV function, CABG surgery was not indicated after the failed PCI of the chronically occluded RCA.
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Case 11: Severe Angina at High Coronary Flow—Abnormal Adenosine A1 Receptor?
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A 66-year-old man had continued intermittent atypical chest pain before and after PCI, with two stents to the LAD. Rather than perform another angiogram, his cardiologist requested PET for assessing progression of his CAD (Fig. 19–15). He developed moderately severe rest chest pain during initial rest perfusion imaging; rest imaging was normal and symptoms resolved spontaneously. Consequently, repeat rest imaging was followed by regadenoson stress imaging. All rest and stress images were normal. Stress perfusion and CFR showed extraordinarily high coronary flow capacity. However, at these very high flows, at the end of image acquisition, the patient developed extreme chest pain (the worst he had ever had), requiring intravenous aminophylline and metoprolol as well as two sublingual nitroglycerin for relief. There were no ECG changes. LVEF on ECG-gated PET perfusion images increased from 75% to 78% with normal wall motion. The high flows argued against either coronary spasm or microvascular disease. Regadenoson is considered to be a specific adenosine A2 agonist mediating coronary arteriolar vasodilation with weak affinity for the adenosine A1 receptor mediating cardiac pain. In this case, regadenoson triggered severe cardiac pain without ischemia, suggesting aberrant A1 receptor activation by possibly binding regadenoson, or a high density of partially activated A1 receptors, thereby causing severe angina despite high coronary flow mediated by A2 receptor agonism.
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Case 12: Abnormal Relative Stress Images That Miss Diffuse CAD
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A 72-year-old asymptomatic man had routine follow-up PET scan with abnormal stress test 15 years previously leading to angiogram then demonstrating a chronic total occlusion of the LAD. He had no PCIs at that time, and he remained asymptomatic. Fifteen years later, PET relative images (Fig. 19–16), showed a mid-anterior stress defect distal to the first septal perforator and first diagonal branches. The coronary flow capacity map showed myocardial steal, indicating collateral flow with diffuse underlying disease not apparent on relative images. With stability of a known occlusion for 15 years, stability of diffuse disease, absence of symptoms, and preserved left ventricular function, the patient elected for continued medical treatment.
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Case 13: Severe Microvascular Dysfunction Without Obstructive CAD
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A 78-year-old woman presented with angina manifest as jaw and arm pain for 11 years at rest and exertion that had progressed to limit her walking to 100 feet. She has hypertension and hyperlipidemia. Five coronary angiograms over the years showed no obstructive CAD. She was referred for dipyridamole PET-CT scan with images shown in Fig. 19–17. Relative stress perfusion images were normal (A). Global stress flow of 1.66 cc/min/g and CFR of 1.99 are moderately impaired without angina or ECG changes during dipyridamole stress. CT for attenuation correction showed no coronary calcium, and ELVF was 70% on gated perfusion images. These findings indicated microvascular dysfunction without calcific coronary atherosclerosis.
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Case 14: Saved from Unnecessary Coronary Angiogram
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A 43-year-old asymptomatic woman requested a second opinion and PET scan after a cardiologist recommended coronary angiography because of a positive ECG stress test performed at routine physical examination followed by a positive SPECT myocardial perfusion imaging reported to show mild anterior ischemia. Her PET images (Fig. 19–18) were normal with CFR of 3.9 and a coronary flow capacity map showing uniformly high-flow capacity comparable to that in young healthy volunteers.
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Clinical Patient Groups and the Color-Coded Ranges for the Coronary Flow Capacity Map
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The case examples demonstrate the power of quantitative perfusion, CFR, and coronary flow capacity for virtually every manifestation of CAD, where the coronary flow capacity map correlates with high statistical certainty with large classes of healthy young subjects and patients with clinical and subclinical CAD (Fig. 19–19 and Table 19–1). This extensive validation of the coronary flow capacity map serves to personalize management of CAD or forms the basis for randomized trials of intervention versus medical management by identifying patients with sufficiently large, physiologically severe CAD to optimally benefit from revascularization.31,37,40
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Heterogeneous Myocardial Perfusion: Simplifying Nature’s Complexity
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Resting and stress perfusion are variable in different regions of the heart because of differences in regional endothelial function, wall stress and thickness, regional workload, spatially variable systolic compression and relaxation, differing regional metabolic demands, and multiple control mechanisms as reviewed in the chapter on coronary blood flow (Chap. 34). This regional perfusion variability, or perfusion heterogeneity, is profoundly influenced by risk factors, early subclinical and clinically manifest coronary atherosclerosis, medications, emotions and emotional stress, physical activity or training, and food (even a single recent meal). Perfusion heterogeneity is commonly more prominent in resting perfusion, as in Fig. 19–20 (A with only lateral and inferior views) because vasodilatory stress substantially overrides autoregulation and many resting control mechanisms (B). Consequently, CFR (C) may show apparent severe regional perfusion defects (blue and green) caused by localized high rest perfusion or may show regional high CFR values (red) caused by low resting flow regions.
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The coronary flow capacity map integrates the regional variations in color-coded ranges of perfusion for the entire range of people from healthy young volunteers to patients having angina and significant ECG changes during dipyridamole stress. The percentage of the LV with low stress perfusion in cc/min/g (> 5% or approximately 10% in B) or with low CFR (18% in C) as stand-alone metrics overestimates severity compared to the coronary flow capacity map, accounting for both stress flow and CFR together that shows only mildly reduced flow capacity diffusely (yellow and orange) caused by mild, nonobstructive, calcific CAD. Perfusion heterogeneity provides important clinical insights into endothelial dysfunction and heterogeneous distribution of coronary atherosclerosis rather than being a limitation of quantitative perfusion of the technology. Overprocessing or oversmoothing images to eliminate perfusion heterogeneity destroys essential data that reveal important insights into coronary pathophysiology.
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Types of Stress for Quantitative Perfusion Imaging
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Quantitative perfusion imaging requires acquisition of the first-pass blood activity of the radionuclide perfusion tracer. Treadmill exercise precludes imaging this first-pass arterial input because of patient motion and the vertical position of PET scanners with horizontal gantries for supine patient positioning. Although supine exercise is reported for quantitative PET imaging,26,38,42 pharmacologic stress is the standard using either arteriolar vasodilators or dobutamine, as listed in Table 19–2, with their differing biological effects. Dipyridamole and adenosine are the oldest, best established for achieving near-maximum hyperemia and a CFR of 4.0 or higher in healthy volunteers required for the optimal diagnosis or assessment of the physiologic severity of CAD.
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Residual blood caffeine inhibits the hyperemic effects of these vasodilators, thereby invalidating diagnostic accuracy, as shown in Fig. 19–21. The baseline coronary flow capacity map shows no clinically significant abnormality after withholding caffeine for 24 hours but with residual blood caffeine levels of 1.0 μg/mL. After 48 hours of abstinence from caffeine and no measurable blood caffeine level, repeat rest-dipyridamole PET caused a large severe perfusion defect involving 25% to 30% of the LV in an RCA or LCX distribution with a minimum CFR of 0.69 indicating myocardial steal with stress perfusion reduced to 69% of rest perfusion. Myocardial steal is associated with collaterals beyond an occluded artery corresponding in this case to a chronic asymptomatic occlusion of a dominant RCA on angiogram.
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The adenosine A2 agonist regadenoson is marketed for vasodilator stress myocardial perfusion imaging. When used according to the protocol recommended by the manufacturer, the maximum stress flow and CFR with regadenoson is only 80% of stress perfusion with dipyridamole in patients undergoing sequential stress imaging with both agents.64 Inadequate or submaximal vasodilator stress reduces the relative size and severity of stress perfusion defects compared to their size and severity with maximum hyperemia induced by dipyridamole or adenosine. The relative PET images for Case Y in Fig. 19–22 show a large dipyridamole-induced stress defect caused by a chronic asymptomatic LAD occlusion. The regadenoson stress defect in the same patient is substantially smaller and less severe, thereby failing to quantify size and severity.
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Submaximal stress has the opposite misleading effect on absolute perfusion by eliciting lower stress flow in cc/min/g compared to maximum stress, thereby erroneously appearing to reflect diffuse disease. In Case Z of Fig. 19–22, relative stress images (A, red) are both normal. However, stress perfusion in cc/min/g (B, blue) is moderately reduced to approximately 1.1 cc/min/g (by the right stress flow color bar scale) also indicated by the coronary flow capacity map (C, yellow by the color bar scale of combined stress flow of 1.1 cc/min/g and CFR of approximately 2.0). With dipyridamole, stress perfusion is 2.0 cc/min/g and the flow capacity is high (C, red). In a systematic study on the time course of regadenoson stress perfusion by PET using Rb-82, maximum perfusion occurred 55 seconds after the 10-second regadenoson infusion, achieving 90% of dipyridamole stress perfusion.64 Therefore, injecting radionuclide at 55 seconds after the 10-second regadenoson infusion produces greater hyperemia and was associated with better quantification of size and severity of stress-induced perfusion defects but not the same as dipyridamole. Finally, regadenoson has more adverse events than adenosine.65
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Technical Components of Quantifying Myocardial Perfusion
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Measuring myocardial perfusion in cc/min/g using radionuclides requires three components: the time-integrated arterial blood concentration of activity, the myocardial tissue activity, and the equation or model for calculating perfusion from these measured components (Fig. 19–23). Radiolabeled microspheres used in experimental animals are 100% trapped in the myocardium so that the model calculation of perfusion is a simple ratio with resulting units of cc/min/g. Radionuclides used clinically are variably trapped in myocardium with decreasing myocardial trapping or “extraction” declining as perfusion increases.
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The model for calculating flow from the measured arterial input function and myocardial uptake for the common clinical radionuclides employ a correction term for this flow-dependent extraction, E, in Fig. 19–23. The extraction fraction is expressed as a fraction of 1.0 for 100% extraction-like microspheres. At resting perfusion levels, the extraction for nitrogen (N)-13 ammonia is about 0.80 or 80%, falling to about 55% at maximum stress perfusion; for Rb-82, the resting extraction is about 65%, falling to 35% at maximum stress perfusion (Table 19–3).
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The extraction correction for each radionuclide can be determined in two ways. The extraction-perfusion relation can be experimentally determined in animals and inserted into the equation with the remaining two unknowns, arterial input and myocardial uptake activities, measured by the scanner for each pixel or specified region with perfusion in cc/min/g displayed regionally. The other method uses multicompartmental curve fitting of the arterial input and myocardial activities over time to account for extraction as part of the flow model equations to calculate perfusion in cc/min/g. The latter approach requires acquiring serial 10- to 15-second images for the first usually 2 minutes, followed by serial images every 30 to 60 seconds for at least 5 minutes in order to construct time activity curves of arterial input and myocardial activity with time. Each of these common radionuclides has a specific acquisition protocol and flow model.
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Radionuclides for Quantifying Myocardial Perfusion
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PET radionuclides for myocardial perfusion imaging (see Table 19–3) have differing biological behavior, availability, and clinical advantages and disadvantages. The partially extracted radionuclides, cyclotron-produced N-13 ammonia and generator-produced Rb-82, are the most widely used with the largest literature as recently reviewed.31 The positron ranges and extraction or retention fraction vary with their definition and how they are measured. Each has a specific flow model incorporating the arterial input function, myocardial uptake, and flow-dependent extraction or retention, as described below. Both provide accurate measures of myocardial perfusion but with differing operational advantages and disadvantages.
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N-13 ammonia has a smaller positron range, associated sharper images, and a longer half-life that is less demanding of scanner performance suitable for three-dimensional (3D) cardiac imaging; the first-pass bolus for arterial input has much lower activity than Rb-82. On the other hand, it requires an on-site or nearby cyclotron, close coordination of patient imaging with the cyclotron run, and slower patient throughput because of the longer half-life of N-13 (10 minutes) requiring decay time between rest and stress images.
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Rb-82 has the most user-friendly generator source of the PET radionuclides, a short half-life permitting rapid serial rest-stress imaging or serial stress-stress images for research protocols, and a well-validated “simple” two-image acquisition protocol. However, the images are slightly less sharp than N-13 ammonia, although the small difference has no clinical consequences. The full dose of 40 to 50 mCi of Rb-82 for the first-pass arterial input requires high scanner performance optimal with two-dimensional (2D) imaging but not feasible with 3D scanners that, therefore, require half-dose Rb-82 to avoid saturating the scanner, as discussed in a later section. The radiation dose for both radionuclides are similar at 1 to 2 mSV per image, compared to three times that dose from the CT attenuation scan of a PET-CT scanner.
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O-15 produced by an on-site cyclotron requires the arterial input function and myocardial uptake but is 100% extracted by myocardium, an important theoretical advantage over the partially extracted radionuclides. However, myocardial uptake imaging is challenging because of its high concentration in the blood pool that requires subtraction of the blood-pool counts from the original image to visualize the myocardium. This subtraction requires acquiring a second set of images after a single inhalation of 40 to 50 mCi of O-15 carbon monoxide. Therefore, the imaging and processing protocol for the O-15 flow model is substantially more complex than the partially extracted tracers such as N-13 ammonia and Rb-82.50 O-15 has a short half-life of (2 minutes); thus, an on-site cyclotron is necessary. Because of its very short half-life and more complex processing, the images are somewhat noisy with greater variability, which is suboptimal for routine clinical applications and regional perfusion needed for clinical decisions. However, in experienced sites, it has provided important research data, particularly for validating in humans other radionuclides more suitable for clinical use, such as Rb-82.66
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F-18 flurpiridaz is a new perfusion tracer not yet approved by the US Food and Drug Administration.67 F-18 has a longer half life (110 minutes) than N-13 or Rb-82. Its first-pass extraction is reportedly 90%, and it requires its own specific flow model. However, the frequent claim that any one of the radionuclides is better than another because of higher extraction, as for O-15, fails to acknowledge that all of these perfusion tracers work well for measuring perfusion; the extraction characteristics are inherently incorporated into the specific flow model for each radionuclide. The disadvantage of F-18 flurpiridaz is its long half-life, which complicates quantitative timely sequential rest-stress quantitative imaging as well as requiring a nearby cyclotron. As addressed below, the primary source of variability in cc/min/g among the different perfusion tracers resides in the arterial input acquisition, not the radionuclide or details of flow models.
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Flow Models for Calculating Myocardial Perfusion in cc/min/g
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There are two basic flow models for calculating myocardial perfusion in cc/min/g (Fig. 19–24). After intravenous injection of radionuclide, the arterial activity rises rapidly, peaks, and then falls as the systemic circulation dilutes its concentration after intravenous injection. The spreading out of the arterial input activity is caused by cardiac output or systemic circulation diluting the activity concentration and dispersing it over time by multilength pathways or transit times through the lungs. Significant myocardial uptake begins as the broadened arterial pulse of activity passes into the coronary arteries off the aortic root.
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The primary data needed for perfusion in cc/min/g are the area under the time-integrated curve of the arterial input activity and the “instantaneous” myocardial uptake at completion of the arterial input function. For Rb-82, the myocardial uptake is flat after the first 2 minutes, so that a single high-quality 5-minute image is obtained, representing the “instantaneous” myocardial uptake. As indicated above and in Fig. 19–24, the multicompartmental model acquires serial short images to construct arterial input and myocardial time activity curves that account for flow-dependent extraction from the time activity curves best fit to the compartmental model equation for calculating perfusion. A variation of this approach uses the experimental extraction-flow relation entered into the equation to simplify the best fit of the time activity curves for solving the equation for perfusion in cc/min/g.
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The “simple” or “retention” flow model for Rb-82 acquires a single, early phase, 2-minute first-pass arterial input image followed by a 5-minute myocardial uptake image (or a 10-minute myocardial image for N-13 ammonia), as in Fig. 19–24 and Fig. 19–25. Flow in cc/min/g is calculated using an experimentally determined extraction correction (the exponential term of Fig. 19–24).68 All flow models use iterative solutions for calculating perfusion in cc/min/g.
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An extensive literature addresses the several variations in radionuclides, flow models, and acquisition protocols for quantitative myocardial perfusion, supporting whichever one available is the “best” for that facility. Although “best” at any facility implies that its methodology is objectively selected and optimized, needing no change or critical internal comparison to alternatives, the method used at most sites is usually driven by convenience, prior experience, preexisting facilities, prior expertise in a given method, and particularly funding support. Established research PET facilities with on-site cyclotron generated radionuclides typically have physicists developing the more complex multicompartmental flow models and serial image acquisition protocols. Other PET sites that are primarily clinical may use the “simple” or simpler “retention” flow models for Rb-82 that are more widely available with simpler facility requirements.
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Direct comparison of the various models experimentally,68 theoretically,69 or clinically32,33,70 show that the “simple model” provides perfusion in cc/min/g comparable to multicompartmental models (Fig. 19–26) with less variability than multicompartmental models.32,69 In experimental animals, the simple model using a single arterial input image (A) correlated tightly with the compartmental model using serial images to construct time activity curves and with perfusion by radiolabeled microspheres (B).68 In patients, the simple model for Rb-82 (C) and 13-N ammonia (D) provided “higher sensitivity for detection and localization of abnormal flow and myocardial perfusion reserve…without the computational complexity and sensitivity to noise—of the multicompartmental model.”32
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The variability of stress perfusion of flow models parallels their complexity because the assumptions necessary to calculate flow introduce noise that their greater mathematical or theoretical precision fails to overcome. For example, the most complex distributive model developed to date had greater variability than standard versions for this reason and proved less clinically useful than simpler versions.71 However, most of the variability among different flow models does not result from the equations for calculating perfusion. Rather, the greatest variability in absolute perfusion is caused by variable arterial input imposed by short, noisy, serial images using back-projected regions of interest (ROIs),72 as discussed below.
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As a result of differences in PET scanners, radionuclides, acquisition protocols, and flow models, rest and stress perfusion in cc/min/g may be different among different PET centers. However, the ranges of CFR (myocardial perfusion reserve) are more comparable among different PET facilities because the ratio of stress to rest flow for CFR cancels out the acquisition and modeling factors; this leads to variations in the absolute perfusion in the numerator and denominator of this ratio.33 Complete integrated quantification of stenosis or diffuse CAD requires both CFR and stress flow in cc/min/g; therefore, reducing variability of absolute perfusion in cc/min/g is essential, as reviewed below.
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The Arterial Input Function: The Achilles Heel of Quantitative Perfusion Imaging
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An extensive literature addresses all the components of quantitative perfusion imaging—scanners, radionuclides, imaging protocols, myocardial resolution, partial volume correction, flow models, and software—except one, the arterial input function. A single, excellent, unique recent editorial73 on the topic related to a detailed study of the issue,72 emphasizing the paucity of literature on this critical but neglected component of quantitative perfusion.
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For multicompartmental flow models, the short, serial images of the first-pass arterial activity are so noisy that an ROI cannot be reliably located directly on the aorta, left atrium (LA), or LV cavity for the arterial input function. For the same reason, the arterial ROI cannot be placed to avoid spillover activity from the immediately adjacent superior vena cava, right atrium, and pulmonary artery or its major branches having the highest activity after intravenous injection. Multicompartmental models based on these noisy, short, serial images therefore require locating the arterial ROI on late myocardial images just superior to the estimated atrioventricular ring at the base of the LV and back projecting it onto the early-phase noisy serial images. The position of this back-projected ROI is assumed to be the LA from which the arterial input curve is obtained.
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However, cardiac position, translation, and motion vary greatly during the cardiac and respiratory cycle at rest; movement of still several centimeters more occurs during the tachycardia and tachypnea that accompany the administration of vasodilator stress.74,75,76,77 In a systematic study, an ROI located on late myocardial images back-projected onto first-pass images were outside the LA or aortic root for significant portions of the cardiac cycle in a substantial number of patients,72 thereby giving erroneous perfusion values. Moreover, this study demonstrated that each individual has a personally optimal ROI in central either LA or aorta that avoids spillover from high-activity adjacent structures containing venous blood. No single ROI site was optimal for all patients or even for rest and stress in the same patient.
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An arbitrary fixed ROI in the LA or aortic root, particularly back-projected from late myocardial images, yielded erroneous arterial inputs (Fig. 19–27) and perfusion values in 50% or more of all patient studies (Fig. 19–28). Erroneous location of arterial ROI may cause profound life-threatening errors of quantitative perfusion imaging illustrated in Fig. 19–29. Incorrect ROI location that fails to capture the true arterial activity may cause the arterial input function to be too low, with resulting erroneously high perfusion measurements (A) compared to the true arterial input (B) proven by the angiogram.
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The commonly unrecognized great strength of the single 2-minute arterial input image of the simple model resides in its high-quality arterial images that allow optimal selection of the most reliable arterial input and therefore perfusion measurements. Arterial ROI selection is so critical that the details of venous or pulmonary artery anatomy adjacent to arterial input anatomy for perfusion imaging need review because they are not widely understood. Fig. 19–30 views the supine patient through the left side where the scanner tomographic planes are rotated counterclockwise and viewed from the feet looking toward the head in traditional radiologic views. Tomographic planes in this schematic labeled A, B, and C correspond to the CT and PET image planes of Fig. 19–31.
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In Fig. 19–31, the high-activity venous blood in the superior vena cava, right atrium, right ventricle, and pulmonary arteries is immediately adjacent to the LA and aortic root. In addition, the heart recoils downward and medially during systole and also moves inferiorly with inspiration, all motions that are greatly increased with the tachycardia and tachypnea during vasodilator stress over 2- to 3-centimeter ranges.74,75,76,77 A fixed back-projected ROI from late myocardial images is therefore commonly not over the optimal central LA or aorta site but may be over high-activity venous structures or low-activity lung.72
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With semiautomated software, the high-quality 2-minute arterial images allow rapidly placing five to eight ROIs over pulmonary artery, aorta, right ventricle, and LV sites, as well as several LA sites. The high activity in the pulmonary artery and right ventricle bracket the upper range of activity for selecting ROIs with no spillover from high-activity venous blood structures. Of all possible ROI sites for measuring arterial activity, the LA or aorta site with the highest activity without spillover from adjacent venous blood activity is the best arterial input activity for that image personalized for that patient. The optimal ROI may be different at rest conditions compared to stress is the same patient. These conclusions are based on repeated serial quantitative PET perfusion imaging for test-retest precision, day-to-day variability, and multiple ROIs in the same subject in more than 200 volunteers or patients and more than 6000 patients having clinical, protocol, and follow-up quantitative PET at the Weatherhead PET Center for Preventing and Reversing Atherosclerosis of the University of Texas at Houston.16,31,37,39,40,48,55,57,64,72,74,75,76,77 In this PET center, the technicians are highly skilled with every ROI checked for any potential errors, complete with perfusion, CFR, and coronary flow capacity maps within 3 to 5 minutes after image reconstruction by KLG.
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Dedicated mathematical models focusing on the details and mathematical precision of complex multicompartment models largely overlook variability of the arterial input function resulting from heart translation and motion during the cardiac cycle.74,75,76,77 These arterial input errors may cause errors in perfusion measurements that are greater than what could be ascribed to the flow models.74,75,76,77 The simple retention models appear to have the greatest ease of application for routine clinical use with the least variability.32,33,68,69,70,71,72,73,74,75,76,77 However, there is not, and will likely will not be, a standardized protocol given the wide range of radionuclides, protocols, and flow models already in place. Nevertheless, as discussed below, for all the different approaches there is a relatively simple standard of performance for accuracy of whichever tracer, protocol, or flow model used that makes quantitative perfusion a universal measure, a universal vital sign, such as blood pressure, regardless of the specific technology used to measure it.
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The Universal Standard of Performance for Quantitative Myocardial Perfusion
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The standards to which we adhere are based on well-established physiologic facts of maximal and minimal myocardial perfusion proven in experimental models and in humans long before cardiac PET or magnetic resonance imaging (MRI) even existed. In experimental models and healthy young humans, that CFR is 4.0 or higher was established in humans as early as 1973,78 followed by confirmatory invasive measurements79,80,81,82,83 and reconfirmed by later PET literature recently summarized for 14,962 individuals previously reported.31 For healthy young volunteers without risk factors and no detectable blood caffeine, CFR by PET averaged 4.2 ± 0.8; absolute stress perfusion in cc/min/g, 2.9 ± 0.5 cc/min/g45; and transmural myocardial scar perfusion, 0.2 cc/min/g.31,40,57
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Accordingly, for the many variations in PET protocols for quantifying myocardial perfusion to define physiologic severity, the simple standard performance test combining measurement accuracy and clinical coronary pathophysiology to ensure correct clinical decisions is the capacity to measure (1) rest perfusion of 0.2 cc/min/g in transmural scar in at least five patients to test low perfusion accuracy and (2) regional and global CFR of 4.0 or higher and stress perfusion of 2.9 cc/min/g or higher on two sequential rest-stress PET perfusion studies in the same subject with ± 15% variability for at least 15 young healthy volunteers with no risk factors and no measurable blood caffeine levels.40,55
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Most cardiac PET literature is based on using 2D scanners, initially with rotating rod attenuation correction and more recently PET-CT scanners with CT attenuation correction. At present, only 3D PET-CT scanners are manufactured largely for cancer applications. The CT attenuation correction of the PET-CT scanner may provide slightly better reconstructed resolution with sharper images than rotating rod attenuation correction. However, this small difference has little clinical impact. PET-CT also detects coronary calcification that is useful clinically for identifying clinical or subclinical coronary atherosclerosis, but also incurs two to three times the radiation dose as the rotating rod.
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2D scanners have lead septa and in-plane reconstruction algorithms that reduce random coincidences and allow first-pass acquisition of full dose 50 mCi of Rb-82 with high-quality, high-count arterial and myocardial images without scanner saturation. 3D scanners lack septa and therefore have greater sensitivity acquiring more counts that, however, include high random coincidences. Therefore, the first-pass arterial activity of full dose Rb-82 (40-50 mCi) saturates the scanner or shuts down acquisition of 3D scanners and some older 2D scanners (Fig. 19–32), thereby precluding quantitative perfusion measurements.
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Therefore, for 3D scanners, the dose of Rb-82 has to be reduced to 20 to 25 mCi infused slowly over 30 to 60 seconds. Higher doses lower noise equivalent counts rate by 50% (Fig. 19–33).74,84 Although studies from a site experienced in 3D PET for cardiac PET with Rb-82 report adequate quality images, primarily global perfusion measurements are reported or used clinically as guides to the angiogram on which clinical decisions rely without demonstrating regional perfusion for clinical guidance shown in the examples above. For N-13 ammonia or F-18 radionuclides that are given in lower doses of 10 to 20 mCi, scanner saturation is not an issue with either 2D or 3D PET scanners.
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Most PET scanners have sufficiently comparable reconstructed resolution as to constitute little differentiation among them for cardiac PET. However, the order of magnitude better resolution of PET over SPECT at heart depth in the chest is a powerful advantage for PET, as illustrated in Fig. 19–34. For SPECT imaging of an unmoving static Jaszczak phantom under ideal imaging conditions, any negative defect having no activity that is smaller than 3 centimeters in diameter fails to be detected. In addition on the SPECT images, attenuation also reduces activity recovery in the center of the 20-cm phantom by 50%, thereby creating attenuation artifacts. In contrast, PET imaging sees all the abnormal cold spots with no central attenuation less.
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The final critical component of the scanner is software to display and shift attenuation or emission data in order to achieve correct coregistration (Fig. 19–35). Despite alignment by external body markers in this case, both rest and stress helical CT images do not coregister with the emission data, thereby causing severe abnormalities that are misregistration artifacts. However, the cine CT shifted to achieve correct coregistration provides accurate size and severity of a mild-to-moderate medium-sized stress defect in the distribution of a chronically occluded collateralized ramus intermedius coronary artery on angiogram.
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With both rotating rod and CT attenuation data, misregistration is common in 20% to 40% of all cases, because of cardiac position changing within the chest attenuating structures differentially at rest and stress even with the patient body position unchanged compared to external markers.74,75,76,77 This misregistration may cause gross artifactual abnormalities or reduce accuracy of quantitative perfusion measurements.74,75,76,77
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Over the breathing and heart cycles, cine CT for attenuation correction averages the Hounsfield density units of chest attenuating structures, diaphragm, and heart motion over several breathing and heart cycles.58,59,60,61 The resulting cumulative or averaged attenuation data are more comparable to the 5-minute emission image acquisition. In contrast, a short helical CT attenuation scan at some point in the cardiac or respiratory cycle or breath-hold may not coregister with the emission data acquired over 5 minutes with multiple cardiac and breathing cycles. In Weatherhead PET Center at the University of Texas at Houston, every case is checked for misregistration and corrected in order to ensure optimal perfusion quantification even in the absence of relative perfusion defects.
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Standard CT attenuation correction incurs a higher radiation dose than rotating rod attenuation correction. Accordingly, modifying the CT dose for lower resolution suitable for attenuation correction and using a single poststress CT scan reduces total dose for a rest-stress study to approximately 7 to 8 mSv.77
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Complexity Made Simple: Quantitative Myocardial Perfusion for Personalized Coronary Care
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Coronary blood flow is a determinant of survival and quality of life. As a basic vital sign, its accurate measurement should guide cardiovascular management (Fig. 19–3631) based on physiologic knowledge and careful technology serving to eliminate inappropriate procedures and maximize patient outcomes. Of the single views of 12 different cases in Fig. 19–36, the coronary flow capacity maps definitively identified and quantified patients with excellent flow capacity, those with risk factors only, those with mild to moderate focal and/or diffuse CAD optimally managed medically, and those requiring angiography or potentially appropriate revascularization.
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