Cardiovascular diseases are the main cause of death in Brazil, and they are responsible for 30% of deaths worldwide every year.1 They are responsible for approximately 8% of total healthcare costs in Brazil, a figure which has been increasingly annually, in parallel with population aging.1 Teich and Araújo estimated that in 2011, approximately 200,000 events associated with acute coronary syndromes occurred in Brazil, entailing a massive impact of 3.88 billion Brazilian reals, considering only hospital and indirect costs, associated with loss of productivity.2 Considering these findings, it has been demonstrated that (preventive) measures play a crucial role in reducing morbidity and mortality, and they should be a priority in national healthcare policy design, as they have profound additional impacts on reducing costs and maintaining productivity. Another significant point, however, which has contributed to reducing the outcome of “cardiovascular death” and to justifying expenses, involves the use of tools which make accurate diagnosis of a determined condition possible (?) and which aid and guide the conduct of physicians, based on these results. Myocardial perfusion scintigraphy (MPS) plays a significant role in justifying financial resources for attending patients with established or potential cardiovascular disease.

One of the main fundaments of MPS is its good ability to identify low-risk patients, who do not require invasive intervention, in spite of established coronary disease, such as anatomical lesions on coronary angiography.3 Observational studies in the 1990’s have demonstrated that MPS was able to identify high- and low-risk groups, resulting in reduced costs for patients with coronary artery disease (CAD) and avoiding procedures that are not associated with improved patient health outcomes. A major prospective study carried out in the United States of America (USA) recruited 11,372 patients with stable angina, who were referred to either MPS or cardiac catheterization. Patients were adjusted by clinical risk, and the costs of direct cardiac catheterization (aggressive strategy) were compared to initial scintigraphy followed by selective catheterization in high-risk patients (conservative strategy). Although both strategies had similar adverse outcomes, such as cardiac death and non-fatal myocardial infarction, revascularization rates were higher (between 13% and 50%) in patients who underwent catheterization directly.4 This reflex of revascularizing anatomical lesions which do not determine ischemia led to unnecessary associated medical costs of around 5,000 dollars per patient in this study.4 Currently, the use of medical resources for conditions that do not have consequences for patients or that could be managed conservatively is known as “overtreatment.”5 The study of the impact of MPS on reducing costs has shown that its main function is to prevent patients who have low or moderate risks on single photon emission computed tomography (SPECT) from being treated with unnecessary catheterizations and revascularizations. Similarly to this North American study, Underwood et al.6 have demonstrated that strategies which incorporate myocardial scintigraphy to evaluate patients with stable coronary diseases are both cheaper than and as effective as strategies involving invasive anatomical assessment.6 Cerci et al.7 evaluated the impact of diagnostic exams on patients with CAD in different scenarios within Brazil’s public Single Health System (SUS, acronym in Portuguese). The study’s most relevant finding is that, although non-invasive functional tests are the most frequently solicited exams for evaluating patients with suspected or known CAD, the majority of healthcare costs for these patients are related to procedures/invasive treatment. In other words, in the Brazilian context, the costs of diagnostic exams continue to be significantly lower than those of invasive and therapeutic procedures. In this manner, it seems logical to affirm that, if scintigraphy exams are made available to patients attended by the SUS, there will be a similar impact on the reduction of healthcare costs, which has been the case in the USA and some countries in Europe. Another relevant piece of data from this study refers to the fact that the majority of patients who were revascularized had not undergone tests to document ischemic burden; only anatomical diagnostic techniques had been applied.7

Angiotomography (angio-CT) of coronary arteries offers very accurate, non-invasive anatomical assessment, and it has proved to be an excellent technique for ruling out obstructive coronary disease in low- to intermediate-risk patients. Angio-CT, however, has presented results similar to those of cardiac catheterization in relation to triggering a higher number of myocardial revascularizations, which do not necessarily (means) reduced cardiovascular outcomes. In a recent meta-analysis comparing angio-CT to functional methods, no differences were observed regarding the outcomes of death or cardiac hospitalization, but there was a 29% reduction in the number of non-fatal infarctions. On the other hand, the use of this method was associated with 33% and 86% higher rates of invasive coronary angiography and myocardial revascularization, respectively. It is not known whether the reduction in non-fatal infarctions may be attributed to the higher number of revascularizations, which is (unlikely) considering in light of other studies on stable CAD, or to the higher use of statins and aspirin associated with the recognition of anatomical coronary lesions.8 With the objective of elucidating the role of angio-CT on cost-effectiveness of approaches to stable CAD in comparison with myocardial scintigraphy, the Randomized Evaluation of Patients With Stable Angina Comparing Diagnostic Examinations (RESCUE) study, which is being developed, is expected to compare these strategies in a prospective, randomized manner.9

The authors of a recent meta-analysis published by the American Heart Association (AHA)/Circulation, have reinforced 2 important aspects of cost-effectiveness:10

The importance of performing appropriate exams as a way of (ensuring) their cost-effectiveness, especially techniques like MPS.

In Brazil, the main radiopharmaceuticals available for obtaining images of the myocardium are thallium-201 (²⁰¹Tl) and those labeled with technetium-99m (^99mTc), which mainly include 2-methoxy-isobutyl-isonitrile, known as Sestamibi (or MIBI), and tetrofosmin. Given that these are the most widely used, the specific methods used for acquiring images with them will be presented.

Thallium-201 or ²⁰¹Tl17 is a monovalent cation with biological properties analogous to those of potassium. It is both intracellular and absent in scar tissue, and it is thus designated for differentiating ischemic myocardium from fibrosis. It has a physical half-life of 73 hours, and it decays by electron capture to mercury-201 (²⁰¹Hg), and the photons emitted for imaging are primarily x-rays (of ²⁰¹Hg itself) between 68 and 80 kilo-electron volts (keV), in addition to lower quantities of gamma radiation in the energy range of 135 keV and 166 KeV. Upon intravenous injection, initial myocardial uptake is proportional to regional blood flow, depending on the integrity of the cellular membrane. It penetrates the cellular membrane via active transport, involving energy expenditure (Na⁺/K⁺ATPase system), with a high first-pass extraction fraction in the myocardium (the proportion of ²⁰¹Tl which is extracted from blood and absorbed by myocytes), of around 70% to 85%.

Maximum concentration of thallium-201 in the myocardium occurs approximately 5 minutes after injection, which is generally administered during peak exercise or clinical and/or electrocardiographic alterations triggered during an ET or a pharmacological test. It presents rapid disappearance or clearance from the intravascular compartment. Following initial distribution of the radioisotope throughout the myocardium, related to blood flow, the phenomenon of redistribution begins 10 to 15 minutes after injection. This is dependent on clearance or washout of thallium-201 from the myocardium, which no longer depends on blood flow but rather on the concentration gradient between myocytes and blood levels. Redistribution of thallium-201 is quicker in normal myocardium than in ischemic myocardium, resulting in different activities in these tissues (differential “washout”).

Due to the characteristics described and the ability to evaluate the integrity of the cellular membrane, thallium-201 has the additional property of studying myocardial viability, predominantly related to hibernating myocardium (Figure 1).18^-20 This represents the condition of resting left ventricular dysfunction, resulting from chronic hypoperfusion in myocardial regions where, although the myocytes have remained viable (alive), they have chronically depressed contractile function. Hibernation may also be seen as a “flow-contraction” agreement process, where metabolism remains dependent on residual myocardial flow in a manner sufficient for minimum substrate supply and inhibitory substance removal. Therefore, the condition of hibernation, notwithstanding reduced resting coronary flow, is not necessarily associated with the presence of chronic ischemia, given that oxygen supply and consumption ratio may be preserved.21^,22

Figure 1 Source: Adapted from Dilszian.277

Technetium-99m-labeled SESTAMIBI or MIBI (MIBI- ^99mTc):23^,24 The most frequently used marker for myocardial perfusion studies, is 2-methoxy-isobutyl-isonitrile, a stable, lipophilic, cationic compound belonging to the isonitrile family, which has the property of crossing cellular (sarcolemmal) membranes and binding to myocyte mitochondria through the mechanism of passive diffusion, depending on the electrochemical transmembrane gradient. It therefore involves no energy expenditure. It has a lower first-pass extraction fraction in the myocardium than thallium-201, of approximately 60%.25

It does not expressively present the phenomenon of redistribution, largely remaining retained within mitochondria. This property makes it necessary to deliver 2 separate injections of the radiopharmaceutical, 1 during the resting and 1 during the stress phase. This may be done either on the same day or on different days. As MIBI is not radioactive, it must be labeled with technetium-99m (^99mTc), which has a physical half-life of 6 hours and emits gamma photons in the energy range of 140 keV (photopeak). Similarly to thallium-201, initial myocardial uptake is proportional to regional blood flow, depending on the integrity of the cellular membrane. In this manner, a linear relationship is observed between the intravenous dose per gram of myocardium and blood flow per minute (Figure 2), starting at minimal flow ranges of approximately 2.0 to 2.5 milliliters per gram.minute^-1, values normally found in maximum exercise testings. When very high coronary flow are reached, generally over 3.0 mililiters per gram.minute ^-1, the linear relationship between this variable and myocardial uptake is lost, with decreased blood extraction of the radiopharmaceutical, in a phenomenon known as “roll off”.26^-28 Nonetheless, owing to higher energy emission (higher photopeak), measured in keV, it presents higher quality images, in comparison with thallium-201. Finally, the elimination of MIBI-^99mTc takes place through the hepatobiliary system, whereas elimination of thallium-201 is mainly achieved through the renal system. Regarding other isonitriles approved by the FDA for assessment of obstructive CAD, only tetrofosmin, whose properties are similar to those of MIBI-^99mTc, has been made available for clinical use.

Figure 2 Source: Adapted from Berman DS.116

Technological evolution of computerized systems has made it possible to divide the myocardium of the left ventricle (LV) into tomographic slices measuring only a few millimeters. In conventional gamma cameras (with iodide sodium crystals) the size of a pixel (the smallest component of a digital image) is 6.4 mm, and in CZT (cadmium zinc telluride semiconductors) technology it is 4 mm, representing related cross sections and, consequently, the method’s spatial resolution.29^-31 The resulting images facilitate the separation of nearby regions, improving contrast resolution and allowing for better detection of differences in concentrations of radioactivity in the myocardium. The SPECT technique also allows for detection of ischemic regions, even those that are small in size, i.e., approximately 2% of LV mass, in tissue with relatively normal tracer concentration.

Protocols: The preferred means of obtaining perfusion images of the myocardium and LV function with tracers labeled with technetium-99m (^99mTc) is known as the “1-day protocol” (Figure 3A), made up of 2 stages, (resting-stress or stress-resting). During the first step, the injected dose of MIBI-^99mTc, measured in millicuries (mCi) or megabecquerels (mBq), is three times lower than the dose administered during the second phase, thus avoiding the residual activity effect or “shining through” phenomenon. Another option is the “2-day protocol” (Figure 3B), where in each phase is performed on a separate day. In this case, similar doses and acquisition parameters are used. It is important to emphasize that, in situations where stress images are taken before resting ones, even if the perfusion images are normal, it is nevertheless important to obtain resting images, except in specific cases, given that analysis of LV function in both situations may provide relevant information, including the possibility of detecting patients with homogenous tracer distribution due to balanced severe coronary diseases. Furthermore, the detection of transient LV dilatation may also be useful in this case, and this requires that both phases be performed. However, in asymptomatic patients who have intermediate/low risks and no clinical evidence of CAD, who have undergone the stress phase as the initial MPS stage and whose perfusion images are normal, it is possible to dispense with the resting phase, in what is known as the “stress only protocol.” In this situation, recent studies have provided evidence that the test’s prognostic value is maintained and that diagnostic ability is similar to the costs of high sensitivity. Furthermore, the patient receives a lower dose of radioactive activity, and total exam time is reduced.32^,33

Figure 3

Cardiac images should be acquired synchronized with patient ECG, allowing for additional analysis of ventricular function, simultaneous with myocardial perfusion evaluation. This information adds data to the medical decision-making process within known incremental prognostic values, and it improves test accuracy, especially regarding specificity values. Considering this aspect, in situations where there are doubts between persistent perfusion defects and/or artifacts (due to breast or diaphragmatic attenuation), analysis of ventricular wall motility and thickness may contribute to differentiating these two causes. When apparent reduced relative uptake of a radiopharmaceutical is due to an artifact, the motility and systolic thickness of this wall are normal.

The estimated results of left ventricular ejection fraction (LVEF) that are conventionally considered normal vary according to technique and methodology employed. With the Gated-SPECT technique, this value is ≥ 50% for both sexes; there are few references with differentiated values for men and women, in addition to different established limits of normality. Due to specific aspects related to methodologies used to calculate LVEF, values found in individuals who are shorter and individuals with smaller ventricular cavities and/or hypertrophic ventricles, especially in women, may be overestimated, at times exceeding values of 75% to 80%.

Calculations of LVEF and ventricular volumes obtained by Gated-SPECT may be utilized for prognostic stratification. LVEF < 45% and end systolic volume (ESV) > 70 ml are associated with increased risks of cardiac death.42^,43 This analysis may be carried out either while resting or under stress; it should preferably be done during both steps, however, considering the possibility of detecting transient LV dysfunctions induced by physical exercise or pharmacological stress.

Cardiac arrhythmias pose difficulties to the acquisition of ECG-synchronized images and may significantly influence the results obtained for ejection fraction and produce artifacts in myocardial perfusion images. There is a technically defined time window for RR interval variation, generally around 20%, after which point heartbeats are rejected. This situation means that if there is an arrhythmia which produces variations between RR intervals above these established limits, such as persistent AF, the corresponding data from that specific cardiac cycle will be rejected, and there will consequently be lower counting statistics. In these cases, images should be acquired without ECG synchronization in order to avoid the occurrence of artifacts.

The basic principle of using cardiovascular stress associated with myocardial perfusion images consists of creating heterogeneity in blood flow between vascular territories irrigated by normal coronary arteries with significant obstructive stenoses.44^,45 The use of myocardial perfusion agents makes it possible to visualize this heterogeneity in regional blood flow. In practice, of all existing cardiovascular stressors, only ET and pharmacological tests have been used.

Both stress modalities, physical exercise and pharmacological vasodilation, have similar sensitivity and specificity for the detection of CAD via analysis of perfusion images.46^-48

Physical stress: ET is the associated method of choice for diagnostic and prognostic values, which have already been established in conformity with clinical, hemodynamic, and electrocardiographic variables obtained during exercise, which add incremental data to myocardial perfusion study. Stress tests have a higher chance of revealing abnormalities in patients with more severe and extensive obstructive arterial disease. Chest pain and/or decreased systolic blood pressure (SBP) during low levels of exercise are highly important findings that are associated with adverse prognoses and multivessel coronary disease. Other markers of unfavorable prognosis include high-magnitude ST segment depression, with a horizontal or downsloping aspect, which may appear early during low workloads or be characterized by late recovery after stress has ceased, present in multiple leads, among others (Table 9).

Some studies have incorporated stress test variables into diagnostic and prognostic scores.49 The most widely used in our context is the Duke prognostic score. Using Cox’s regression analysis, Mark DB et al. proposed50 and validated51 this score for use with the exercise treadmill test and the Bruce protocol. It is calculated by the following formula:

or

The angina index has a value of 0 (zero) if there are no symptoms during exercise, 1 (one) if non-limiting chest pain occurs, and 2 (two) if the pain is impeditive (growing intensity) as exercise proceeds. In accordance with the results of the regression equation, patients are classified as follows:

High-risk group: patients with scores ≤ -11, with an annual cardiovascular mortality rate ≥ 5%.

Finally, in patients considered low-risk, medical management is related to prevention measures. On the other hand, based on a growing base of evidence, these methods,52 especially MPS, have become of paramount importance for quantifying ischemic area, even in patients who are considered high-risk, with the aim of assisting and directing the medical approach to be adopted,53^-58 notwithstanding the unavailability of information from randomized clinical trials such as the “Ischemia Study,” which will be able to assist in better management of patients with extensive areas of the myocardium at risk.59

Furthermore, emphasis given to exercise as the primary stress-producing agent of choice within the cardiovascular system has become clear, given that it is the most physiological method for triggering myocardial ischemia, based on sympathetic stimulation and the increase in the main determinants of myocardial oxygen consumption (MVO₂), such as HR, blood pressure, and myocardial contractility. Likewise, exercise leads to coronary vasodilation through biochemical mechanisms, resulting in increased blood flow to the myocardium and greater oxygen supply, thus meeting the necessary demands imposed during the application of extreme effort. This ability to increase coronary blood flow, which reaches three to four times baseline values during peak exercise, in the absence of significant obstructive coronary lesions, conceptually represents the phenomenon known as “coronary reserve,” considered the main characteristic of MPS with radiopharmaceuticals. Moreover, with respect to the limitations and contraindications of this methodology,60 joint analysis of both stress test and cardiac imaging exams will play a fundamental role in the medical decision-making process, albeit in view of previous clinical information or pretest probability of obstructive CAD.

With relation to the main methodological aspects, the following stand out:

Prior venous access in an arm, in a “Y” shape (separate routes), for radiopharmaceutical injection during peak exercise and subsequent flush with saline solution, respectively.

Pharmacological tests: Represent excellent alternatives for evaluating patients with physical limitations or clinical impediments to undergoing efficacious exercise testing . The most frequent conditions are found in Table 10. They represent around 20% to 30% of all cases of scintigraphy referral and approximately 50% of elderly patients.62 The drugs used in these circumstances are dipyridamole, adenosine or regadenoson, and dobutamine. These drugs induce maximum vasodilation and increase coronary flow, allowing for assessment of coronary reserve, with diagnostic and prognostic power similar to that of exercise,63^,64 which has recently been extended to elderly patients and women.65^,66

In cases of left His bundle branch block or artificial pacemaker with ventricular stimulation, the first option is a pharmacological test with dipyridamole or adenosine, with the aim of avoiding what are known as false-positive results (alterations in relative radiopharmaceutical uptake, in the absence of obstructive lesions). These are caused by atypical movement of the interventricular septum, which occurs in these situations and is accentuated when myocardial scintigraphy is performed with ET. Reduced radiopharmaceutical uptake is often observed in these patients and is most frequently related to the septal region, which may be exacerbated by the stress test, as increased HR increases paradoxical septal motion and, consequently, reduces perfusion in this wall.67^,68

Primary vasodilators: Dipyridamole, adenosine, and regadenoson (not available for routine clinical practice in Brazil) provoke a significant increase in coronary flow in normal arteries and a small or nonexistent increase in arteries with functionally significant stenosis, thus resulting in relative heterogeneity of flow between LV walls. During maximum vasodilatation, when the radioisotope is injected, the difference in relative radiopharmaceutical uptake in LV walls will also be observed, making it possible to diagnose coronary disease:

Dipyridamole: the total dose of dipyridamole is 0.56 mg.kg^-1 up to a maximum dose of 60 mg or 6 vials (a 2-ml vial = 10 mg), administered intravenously (IV), preferably with a 4-minute infusion pump, diluted in 50 ml of saline solution (SS). It may, alternatively, be injected manually (with a 20-ml syringe), using the same dilution. Alternatively, a more elevated dose of 0.84 mg.kg^-1 may be used in select cases. The radiopharmaceutical is administered IV during hyperemia or maximum vasodilation, 2 to 4 minutes after the end of dipyridamole infusion (Figure 4). Dipyridamole inhibits the action of the enzyme adenosine deaminase, wich degrades endogenous adenosine, in addition to blocking reuptake of adenosine into the cellular membrane, with a consequent increase in extracellular concentration and resulting coronary vasodilation. Its biological half-life is approximately 45 minutes.

Figure 4

Accuracy for detecting CAD with the use of MPS is comparable between both drugs. It is worth reiterating that, in exams using dipyridamole and adenosine, modifications in the ST segment occur relatively infrequently, even in patients with obstructive CAD (lower sensibility). In some instances, only the relative difference in flow observed in patients with different degrees of luminal obstruction and coronary reserve will determine perfusion defects, and ischemia will not necessarily be present. For this condition, collateral circulation is necessary, which causes coronary steal, with consequent alterations in contractility. Nevertheless, the sensitivity of scintigraphy images associated with the use of pharmacological agents or stress tests is similar. Adverse effects or “paraeffects” of using these drugs23^,71 occur in approximately 50% of patients with dipyridamole and in up to 80% of patients with adenosine. Common side effects include headache, dizziness, flushed face, feeling hot, chest pain, ST alterations and others (Tables 11 and 12).72 These manifestations generally do not last long, and in most cases they may be reversed by administering intravenous aminophylline at 1 to 2 mg.kg^-1 or 72 mg (3 ml) to 240 mg (10 ml or 1 vial) 2 minutes after injecting the radiotracer, when MPS is associated with dipyridamole. When adenosine is used, there is no need to inject an antagonist, given its ultrashort half-life, from 2 - 10 seconds, the recommendation being simply to interrupt the infusion. When it is not medically possible to perform either the physical stress or the pharmacological dilation modality with dipyridamole or adenosine, intravenous administration of dobutamine solution may be the best option for assessing coronary reserve flow, with regards to increased MVO₂. Contraindications to dipyridamole and adenosine use are listed in Table 13.

It is, finally, important to stress that, with both dipyridamole and adenosine, no significant increases are observed in MVO₂, which, in clinical practice, is translated as the product of heart rate (HR) × systolic blood pressure (SBP), or the double product. During pharmacological stimulation, SBP values generally drop by around 10% while HR increases by approximately the same proportion, with no consequent increase in MVO₂.

Drugs that promote elevated myocardial oxygen consumption: These drugs represent an alternative for patients who cannot undergo ET or pharmacological stress with dipyridamole or adenosine. Examples include patients who have contraindications or limitations for stress test, as well as pulmonary obstructive disease with recent crises of bronchial hyperreactivity, arterial hypotension (SBP < 90 mmHg), and significant obstructive carotid artery lesions on both sides. This is also an alternative modality in patients indicated for dipyridamole or adenosine who have ingested substances derived from caffeine or methylxanthines (competitive antagonists) over the past 24 and 12 hours, respectively. The most commonly used is dobutamine, which acts on beta-1 (β-1) adrenergic receptors, with chronotropic and inotropic stimulation, depending on the infused dose, in addition to direct effects on beta-2 (β-2) receptors, with peripheral vasodilation response. This results in an increase in cardiac output, HR, and SBP, leading to an increase in MVO₂ and, consequently, in coronary vasodilation. Protocol: The protocol begins with venous administration of the solution (250 mg of dobutamine diluted in 250 ml of saline solution - 1 mg per 1 ml) via infusion pump at a dose of 10 ug.kg^-1.min^-1 for 3 minutes (first step), followed by 20 µg.kg^-1.min^-1 for 3 minutes (second step), adding 10 µg.kg^-1.min^-1 every 3 minutes (third and fourth steps) until the maximum dose of 40 µg.kg^-1.min^-1 has been reached (Figure 6).73^,74 In patients who have not reached submaximal HR and who do not have evidence of ischemia, it is possible to associate intravenous atropine (0.25 to 2 mg) and perform isometric stress with hand grip maneuvers (e.g., compressing a tennis ball). A Brazilian study has demonstrated that early use of atropine (following the first phase of dobutamine infusion) is safe and that it reduces infusion time and complaints during stress, without affecting diagnostic precision.75 Furthermore, the presence of perfusion defects induced by pharmacological vasodilatation and motility abnormalities triggered by stress aggregate incremental prognostic value to the test, which has recently been validated with the use of ultrarapid cameras (CZT technology).76 Contraindications to dobutamine use may be found in Table 14. Patients on betablockers should stop taking these medications for 48 to 72 hours before the test. Special attention should be given to patients with bronchospasm undergoing MPS with dobutamine, whose plasma half-life is around 2 to 3 minutes, considering that its antagonist is metoprolol at an intravenous dose of 5 mg and that it is contraindicated in the presence of pulmonary obstructive disease. The most frequent adverse events or paraeffects associated with administration of dobutamine solution are listed in Table 15. To reverse them, in addition to metoprolol, other intravenous short-acting betablockers, such as esmolol (0.5 mg.kg), which is available, should be injected after the first minute of radiotracer injection.

Figure 6

Combined stress: The association of dynamic stress with low workloads (e.g., until the second stage of the Bruce protocol or until feeling light fatigue, equivalent to the number 13 on the subjective Borg stress scale) and vasodilators has been shown to reduce subdiaphragmatic (hepatic) activity and improve the ratio of radiation activity emitted between the target organ and the viscera (background), with consequent improvements in image quality.77 It has similarly shown a decrease in the occurrence of adverse effects resulting from the infusion of dipyridamole or adenosine, as well as the incidence of atrioventricular blockage. This protocol is ideal for patients who are able to exercise but who are using medications that limit increases in HR (betablockers, antiarrhythmic drugs, et al.).

New drugs: There are 3 types of adenosine receptors (Table 16). The use of specific selective antagonists to A₂ receptors has shown evidence of adequate coronary hyperemia and lower intensity of systemic effects, especially chest pain and atrioventricular blockage. A double-blind, randomized (regadenoson or adenosine), multicenter study78 involving 784 patients has shown that diagnostic information is similar and that there were no serious adverse effects; regadenoson, however, was tolerated better than adenosine. Second-degree atrioventricular blockage occurred in 3 patients with adenosine and in no patients with regadenoson. Regadenoson’s short biological half-life minimizes and limits the duration of adverse effects, diminishing monitoring time. It is administered via bolus, and it is not necessary to adjust dose to body weight (Figure 7). Its use is promising in patients with chronic obstructive pulmonary disease. The incidence of serious complications79 with the performance of cardiovascular stress is related in Table 17.

Figure 7

Resting coronary flow is 1 ml.g.min^-1, increased 3- to 5-fold during maximal vasodilation or hyperemia, under physical or pharmacological stress (Figure 8).28 In the presence of obstructive coronary lesions, resting coronary flow decreases when luminal narrowing is greater than 80%, due to exhaustion of the coronary reserve. When physical or pharmacological stress are applied, early exhaustion of the coronary reserve is observed, and it then exhibits a drop, generally beginning with lesions with luminal narrowing of 50%.80 This information has currently been validated based on invasive measures of coronary flow reserve (CFR), fractional flow reserve (FFR), and instantaneous flow reserve (IFR), considered “standard” for characterizing myocardial ischemia; some have also been reproduced by non-invasive PET methods.81^-86 Tests with pharmacological stimulation using dipyridamole or adenosine associated with MPS are considered frequently to result in coronary flows in the range of 4 ml per gram of myocardium per minute,87^-89 generating homogenous relative uptake patterns of the radioisotopes in the myocardium, and scintigraphy images are considered normal when the coronary arteries are free of atherosclerotic processes. There are, however, specific situations in which patients with balanced multivessel disease (lesions in 3 arteries with similar coronary reserve) in which perfusion images appear with apparently homogeneous radiopharmaceutical distribution.90

Figure 8

From the conceptual point of view, it is necessary to comprehend that the generation of scintigraphy images is based on relative radiopharmaceutical uptake, which is injected intravenously during physical exercise or pharmacological test, predominantly in the LV myocardium. Comparison of radiopharmaceutical uptake between ventricular walls is expressed in images based on a scale of colors, created by specific computer programs, which, in addition to allowing for subjective analysis of perfusion, make semi-quantitative and quantitative evaluation of affected myocardial area possible.

Visual or qualitative analysis: By simply inspecting images resulting from perfusion tomography and ventricular function exams (Gated-SPECT technique), it is possible to assess blood flow and regional contractility of the LV myocardium indirectly. Tomography images are reconstructed as multiple slices along the anatomical axis of the LV, defined as corresponding regions and respective relations with coronary territory. The slices are taken on the short, long vertical, and long horizontal axes (Figure 9). Characterization of uptake of the radiopharmaceutical MIBI-^99mTc or Tetrofosmin-^99mTc during both exam stages (resting and stress, 1 day protocol) and thallium-201 during the stress and redistribution phases focuses on the anterior, septal, inferior , lateral, and apical regions of the LV (Figure 9). The short-axis projection uses transverse tomographic slices of the LV, sweeping from the apex or distal portion, through the middle of the cavity, to the basal portion. All regions and subdivisions are numerically identified, in accordance with the established scoring system, with the aim of standardizing segmentary analysis of the LV myocardium for perfusion study. Division into 17 segments has consensually been accepted, resulting in less interpretation subjectivity (Figure 10 and Table 18). Different radiopharmaceutical uptake and retention patterns allow for differentiation of normal, ischemic, and fibrotic tissues. The normal myocardium has similar uptake during both the stress and resting/redistribution phases, whereas the ischemic myocardium shows reduced relative uptake in stress images and normal uptake during resting/redistribution. Fibrotic tissue, on the other hand, shows reduced relative uptake during both study phases. If fibrotic tissue coexists with an ischemic yet viable myocardium, reduced relative uptake will be observed during the stress phase, with partial improvement during the resting/redistribution phase. Hibernating myocardium will also show persistent reduced uptake, or be it, reduced uptake that is similar in both the stress and the resting phases. To differentiate it from fibrotic tissue, it is possible to perform assessment of viable myocardium with thallium-201, in which case it is sometimes necessary to add another phase or stage, namely that of late redistribution or reinjection, interpreted in the same manner.

Figure 9

Figure 10

Semiquantitative analysis: With the aim of numerically assessing the intensity of radiopharmaceutical uptake (perfusion), within the established standards (17-segment model), specific scores have been developed: a) perfusion - considers the following numerical scale: 0 = normal; 1 = mildly reduced radiopharmaceutical uptake; 2 = moderately reduced uptake; 3 = severely reduced uptake; 4 = absence of radiopharmaceutical uptake. Scores of 3 or 4 are normally associated with coronary stenosis of > 90%. Therefore, the higher the number of affected segments is; the more extensive the process; the higher the summed scores, and the greater the severity will be. This has an unquestionable prognostic value for patients with CAD. The following calculations are achieved by the sum of values attributed to each segment: the sum of the values attributed to each segment during the stress phase is known as the “summed stress score” (SSS); this is repeated during the baseline or redistribution phase to obtain the “summed rest/redistribution score” (SRS). The difference between the SSS and the SRS is known as the “summed difference score” (SDS). According to Hachamovitch et al.56^,57 numerical SSS values < 4 are considered normal; between 4 and 8, mildly abnormal; between 9 and 13, moderately abnormal; and > 13, severely abnormal. It is worth emphasizing that SSS values < 4, which may not necessarily be zero, are understood as normal, because there are myocardial regions which show lower radiopharmaceutical concentrations in and of themselves and may, consequently, receive values other than zero.

Quantitative analysis:Polar maps are two- or three-dimensional reconstructions of the LV, initially elaborated with the proposal of encompassing relative radiopharmaceutical distribution throughout the heart in a single image. They are shown in circular form, resembling a target, for which reason they are also known as “bull’s eye plots.” Radiopharmaceutical uptake, which is representative of perfusion, is shown on a color scale, with the LV apex occupying the center of the target, while basal regions of the heart are represented by the outermost circle of the target (Figure 10). Programs capable of reconstructing these images also allow for percentage quantification of areas with reduced uptake by comparing the images to a databank of normal individuals of the same age and sex. Perfusion defects may also be quantified by the number of pixels in a determined region and by existing standard deviations in relation to normal perfusion areas.

We may also obtain polar maps with parameters relative to ventricular function, such as LV wall motility and systolic thickness. These methods of quantitative analysis serve as complements to assist in qualitative or semiqualitative visual analysis.

Evaluation of ventricular function with perfusion agents: In a manner analogous to that described for perfusion study, segmentary contractile analysis of the LV makes use of motility and systolic thickness scores for each segment, also considering division into 17 segments, visualized in the cross sections of the minor axis (distal, mid-cavity, and proximal regions) and the long vertical axis (anteroapical and inferoapical regions). Numerical values are attributed. Analysis of motility of LV walls is performed directly on the computer monitor, making the subendocardial contour visible. Analysis of systolic thickness should be directed to the color scale chosen for a group of images. When thickness is within normal limits, the color increment is observed toward the bottom of the scale. Furthermore, it is possible to obtain percentage of thickness in each region. For distal and middle slices of the minor axis, as well as for the apex, average normal thickness is around 40%, with a score of zero (0) Thicknesses between 30% and 40% are interpreted as borderline; those between 20% and 30% receive a score of 1 (mild reduction); 10% to 20%, a score of 2 (moderate to severe reduction); and less than 10%, a score of 3 (absence of thickness). In the proximal (or basal) cross section of the minor axis, thickness of around 20% is considered normal. A score of 1 is not used, but rather only scores of 2 and 3. Abnormalities in motility and thickness generally go hand-in-hand, with slight differences in gradation between the two (Table 19) and in the resulting sums. In some cases, we may observe discrepancy between results, for instance, following revascularization surgery and in the presence of left bundle branch block, in which the motility of the interventricular septum is compromised, whereas thickness is not.

Whenever possible, analysis of ventricular function should be performed at the baseline phase and after stress, with the purpose of detecting additionally indicative alterations in stunned or hibernating myocardium. The validated scores, which have been previously described, are recommended. Regarding the effect of global analysis of LV systolic function, LVEF is the parameter with the best reliability, and scores predominantly concentrate on segmentary analysis.

Furthermore, the subjective or qualitative assessment of images regarding results related to myocardial perfusion study, which have been previously described (homogenous distribution or normal uptake of the radiopharmaceutical in the myocardium; transient low uptake suggestive of ischemia; fixed low uptake suggestive of fibrosis; partially reversible low uptake suggestive of ischemia associated with fibrosis), should take the presence of the following types of artifacts into account:

Technical artifacts, resulting from inadequate image processing.

Even when isolated analysis of images is used to describe perfusion findings, interpret data, and write reports, medical comments and conclusions should be the result of the integration of all available pretest clinical data and data obtained during the performance of the stress or associated stimulus test within the denominated incremental prognostic value. In this sense, Bayes’ theory of conditional probability or the application of Bayesian principles assists in decision making by establishing that the risk of an event occurring after a test is influenced by the sensitivity and specificity of an applied method, as well as the pretest prevalence of the disease, all of which are incorporated into the estimation of post-test probability for characterization of myocardial ischemia and, consequently, CAD (Figure 12).129^,130

Figure 12

In this way, the diagnostic ability of a test is related to the population type selected, and it is may create tendencies or biases. For example, the selective referral of patients with “positive,” “altered,” or “ischemic” results for coronary cineangiography studies, in conjunction with few referrals of individuals with negative results, increases the chance of false-positive results with respect to true-negative results. This would be an equivocal methodology for evaluating the accuracy of a test, artificially decreasing the method’s specificity or its ability to select healthy individuals within a population.131^,132 On the other hand, sensitivity will expressively increase in patients referred with a high prevalence of symptoms.

Many possibilities may be present for medical management within different prevalences of clinically estimated CAD, emphasizing that the diagnostic power of conventional exercise testing or tests associated with MPS is at a maximum when the pretest probability of CAD is intermediate. However, for a given pretest probability, the post-test probability increases progressively with the severity of the alterations found, such as the amount of myocardium at risk or the sum of extent and intensity (ischemic burden) of perfusion modifications in the perfusion images with radiopharmaceuticals. In the extreme case of a study with severe abnormalities, post-test probability will be elevated regardless of pretest probability (Figure 13).130

Figure 13 Source: Adapted from Udelson JE et al.130

Furthermore, not only Bayesian analysis, but also statistical techniques that use multivariate analysis to estimate post-test risk may also provide important diagnostic information, with the following advantages: they do not require the tests to be independent of each another or the diagnostic indexes (sensitivity and specificity) to remain constant in populations with different disease prevalences. Thus, in the condition of continuous-scale diagnostic tests, changes in percentages of sensitivity and specificity should be taken into consideration when cutoff values for classifying individuals with and without a disease vary. Some results may even be expressed as the sum of sensitivity and specificity for an “optimal” cutoff value. However, owing to the fact that an optimal cutoff value is not relevant to a specific application, it is recommendable to plot these indexes under a range or scale of values of interest, generally distributed under a receiver operating characteristics (ROC) curve, expressed in a 2-axis graph, where the y axis represents sensitivity and the x axis = 1 − specificity, for variable cutoff values (Figure 14).133

Figure 14

The presence of transient or reversible defects in radiopharmaceutical uptake reflect ischemia, which is in itself associated with greater incidence of future events, when comparing normal images or images with persistent perfusion defects. Thus, in patients with suspected or proven chronic coronary disease, estimation of the quantity of myocardium at risk as assessed by semi-quantitative and quantitative analyses, extent, intensity, and degree of reversibility of existing defects, as well as measures of LVEF following physical or pharmacological stress, have prognostic value, indicating risk of events during clinical follow up.134^-138 Other scintigraphy markers of severity may stand out, such as apparent transient dilation of the LV, induced or accentuated by exercise or pharmacological tests,139^,140 which may translate to extensive subendocardial ischemia, in addition to high pulmonary uptake, translating to LV dysfunction. Furthermore, increased uptake in the walls of the right ventricle (RV) in multi-arterial patients whose lesions are predominantly in the left coronary territory, may suggest an imbalance in perfusion between ventricles.141^,142

Considering the scope and accumulated experience of MPS with radioisotopes in diverse clinical scenarios relating to CAD, guidelines and consensuses have suggested the main applications based on levels of evidence in the literature, and created scores that numerically classify indications as inappropriate; possible, but questionable; and appropriate143^,144 (additional details described in the Indications section).

Nuclear cardiology is connected to the assessment of cardiovascular physiology, currently encompassing metabolism, innervation, myocardial perfusion, ventricular function, and synchronism. It has a capability for early detection of cardiovascular physiopathological alterations, allowing for interventions which may interrupt or revert the disease condition before structural alterations are established in a definitive, evolutive, and irreversible manner. To represent cardiac physiology, images are formed using the principle of radiotracers or tracers,29 in which the exchange of stable atoms with their isotopes does not alter the biological properties of the organism where the images are being obtained.

Radioactive labeling is performed with minimal quantities of chemical substances, resulting in a radiopharmaceutical that may be used to truly represent physiological or biochemical state of unlabeled molecules . In this manner, alterations to the physiology being evaluated and toxicity effects do not occur. These characteristics are different from other imaging methods which use elevated concentrations of chemical substances to create sufficient contrast and, consequently, obtain images of the functional situation and anatomical aspects of the organ under study.145 The images in this specialty are digital; they either use “pixels” as units of measurement for resolution or are transformed into a digital matrix, emphasizing that “pixel” values of images of the ventricular myocardium are directly proportional to physiological cardiovascular properties. Physical phenomena such as the “Compton scattering effect,” the “photoelectric effect,” and geometric distortions should, however, be considered,146 given that they tend to interfere with direct proportionality, in a manner that is decreasing as equipment and image reconstruction techniques technologically evolve. Furthermore, another factor related to acceptance and preference of nuclear cardiology for detecting myocardial perfusion defects is the elevated, superior resolution contrast (allowing for differentiation between normal and decreased perfusion) in comparison with other imaging methods,147^,148 even considering lower spatial resolution. There is also a peculiar aspect, namely, that the myocardium (organ of interest) appears emphasized due to the greater brightness in comparison with underlying structures (background) and, consequently, provides excellent signaling, which facilitates the development of integrated, computerized algorithms for SPECT and PET techniques. These programs, which automatically process and objectively quantify images, have good comprehension, and they are well validated and internationally utilized.149^-151 From the conceptual point of view, it is necessary to grasp that scintigraphy image generation is based on relative uptake of the radiopharmaceutical in the myocardium of the LV, when it is injected intravenously during physical exercise or pharmacological tests. The comparison of radiopharmaceutical uptake between ventricular walls is expressed in images based on a color scale, created by specific computer programs which, in addition to allowing for subjective analysis of perfusion, make it possible to conduct semi-quantitative and quantitative evaluation of affected myocardial area. During visual evaluation of scintigraphy images, the following are taken into consideration: homogenous distribution patterns or normal radiopharmaceutical uptake in the myocardium, transient low uptake suggestive of ischemia, fixed low uptake suggestive of fibrosis, and partially reversible low uptake suggestive of ischemia associated with fibrosis24^,152 (Examples are provided in the Methodology and Tutorial Cases sections).

Continuous chest pain is one of the most common symptoms in emergency units, accounting for approximately 8 million annual visits in the USA.153 Although approximately 50% of patients are admitted for diagnostic definition, only 30% of visits will correspond to the condition of acute coronary syndrome (ACS), 2% to 4% of whom will be inappropriately discharged from the hospital (Figure 15), leading to serious risks of severe events, in addition to legal-medical problems. Considering these implications, as well as hesitation to discharge patients with acute myocardial infarction (AMI), assessment of patients with atypical chest pain in emergency unit has emphasized admission for posterior clarification and risk stratification. With the development of more sensitive cardiac biomarkers in conjunction with more precise non-invasive exams and validated clinical parameters, early identification of low-risk patients has been carried out more rapidly. In this process of diagnostic and prognostic assessment, the following play an important role: resting ECG, cardiac enzymes, and non-invasive exams such as ET, MPS, Doppler echocardiogram, and coronary angio-CT, in addition to cardiac resonance in specific cases. The choice of recommended imaging method should be based on the procedures available, local institutional experience, and present clinical situation. The exam with the highest diagnostic accuracy and negative predictive value (NPV) will offer more precise risk stratification, which is fundamental to decision making regarding need for hospital admission or safe discharge from the emergency unit.

Figure 15 Source: Adapted from Amsterdam EA.154

In addition to the 2 physiopathological conditions described (Non-ST segment Elevation Myocardial Infarction - NSTEMI and ST segment elevation myocardial infarction - STEMI), unstable angina also stands out, which does not feature myocardial necrosis as an initial consequence.155^,156 Nevertheless, unstable plaque and evolutive phenomena of erosion and rupture may progress to infarction and related complications, such as severe arrhythmias, ventricular dysfunction, and death. Conditions of vasospasm, in epicardial coronary arteries or with microvascular disease, have additionally been implicated in ACS without thrombosis and myocardial infarction, in the absence of obstructive lesions.157^-159 It is, finally, important to emphasize that, in patients with documented ACS and intermediate- to high-risk patients, invasive coronary cineangiography and percutaneous revascularization represent the most frequent forms of initial assessment, and non-invasive imaging methods are reserved for clinically stable situations and low- to intermediate-risk patients, with the aim of reclassifying risk, diagnosis, and stratification in the post-event phase.160^,161

Precise diagnosis for appropriate conduct in UA or AMI, whether with clinical treatment or invasive strategy via catheterization and angioplasty.

Following serial evaluation of ECG, without modifications, in addition to normal cardiac enzymes and clinical situation characterized as low- to intermediate-risk, non-invasive functional exams may play an important role in risk stratification of patients with acute chest pain. The choice of MPS, cardiac resonance, or angio-CT will depend on the objective and the clinical question to be answered.

Exercise testing: constitutes an important strategy for assessing patients with suspected ACS following stabilization, and it aids prognosis and medical management . Patients with chest pain in the emergency room, once they have been identified as low-risk, may undergo ET, a normal result of which confers low annual risk of cardiovascular events, allowing for earlier and safer discharge from the hospital.164 Brazilian and international guidelines recommend ET as a first-choice exam for risk stratification in patients who are able to exercise, as the procedure is low-cost and widely available, and it has a low rate of complications, similar to that of tests conducted in normal conditions.165 A treadmill or a cycle ergometer may be used, following appropriate protocols for the patient’s clinical conditions, such as the ramp protocol or the modified Naughton or Bruce protocol. Logistics related to performing ET in the emergency unit may, however, be compromised as a result of unavailable operational personnel or infrastructure during certain periods (e.g. weekends or night shifts).

Myocardial perfusion defects evaluated with the use of radiopharmaceuticals and induced by stress are well established as a technique with diagnostic and prognostic capability for the identification of flow-limiting coronary diseases. In MPS, interpretation has mainly been qualitative, semiquantitative, and quantitative, assessing regional perfusion in relative terms.95^,102^,121^,192^-196

PET consists of a specific method in nuclear medicine. It is different from the widely used gamma camera or Anger camera employed in MPS for the technique commonly known as SPECT. PET, differently from SPECT, uses emitters of positrons, particles similar to electrons (except for the fact that they have a positive electric charge), with very short half-lives. The principle of PET consists of the detection of 2 photons (gamma rays) that are emitted in diametrically opposite directions to occasion annihilation of the positron upon encountering an electron in the periphery of the atom. This detection occurs through a series of crystals arranged throughout the 360 degrees of a ring-shaped detector surrounding the patient. The detection of the 2 photons emitted in diametrically opposite directions, at exactly 180 degrees, with an existing coincidence circuit in the PET equipment, making it different from SPECT, which uses single photons.197

Since PET cameras have incorporated electronic collimation, mechanical collimators made of lead have not been made necessary, allowing for greater sensitivity than in SPECT systems. The sensitivity of current 3D PET systems is 5 times greater than of the older 2D PET ones. On the other hand, there is more attenuation in PET studies than in SPECT, making attenuation correction necessary to the reconstruction of PET images. The most current systems, which have a resource known as time of flight (TOF), are based on the speed of light to localize the annihilation event in a much smaller directional ray than in conventional PET cameras, resulting in increased spatial resolution.

This method has already been established as the standard for assessing myocardial viability (See the Myocardial Viability section), with the use of a glucose analogue labeled with fluorine-18 (¹⁸F-FDG), a technique which, although it is not widely used in Brazilian clinical practice, is widely viable in most nuclear medicine centers where PET is available in Brazil. Its use for the assessment of myocardial perfusion is not necessarily a new technique, as it dates back to more than 30 years ago and has since been evolving.198^-200 Nonetheless, its clinical use has remained restricted for many years owing to its methodological complexity, high operational costs, and low availability of devices and tracers. Recent technological advances have reduced the costs, and its increasingly frequent use in oncology has resulted in increased equipment availability. Nowadays, non-invasive estimation of absolute coronary flow and flow reserve with this technique has become possible and has been validated.197 The scenario is contrary in Brazil, however. In spite of a small amount of experience using research protocols, this method is not available in clinical practice. Even though PET cameras are distributed throughout the country, there is a lack of other radiotracers for the modality as well as a lack of economic viability.

Different available radiotracers make it possible to identify vasoactive, metabolic, or neurological processes that are present in diverse cardiomyopathies and atherosclerosis, on the molecular level. The images acquired allow for evaluation of the cardiovascular system on different levels, including: perfusion,201^-203 metabolism,204^-207 sympathetic innervation,208^,209 and inflammation;210^-212 depending on the tracer utilized. Myocardial perfusion studies using PET may be performed using different tracers, each of which possesses specific characteristics, advantages, and disadvantages (Table 24).

Rubidium-82 (⁸²Rb) and ammonia labeled with nitrogen-13 (¹³NH₃) have been approved for clinical use by the Food and Drug Administration (FDA), and they are the most commonly used in the USA. On the other hand, water labeled with oxygen-15 (¹⁵O-H₂O) has been used mainly for research in the USA, as it diffuses freely between blood and the myocardium, which makes it ideal for quantitative flow measures. In South America and Brazil, associated costs, especially with tracers, have limited their use. Initial experience with myocardial perfusion using PET and ⁸²Rb have been conducted at the Heart Institute of São Paulo (InCor, acronym in Portuguese).213 As ⁸²Rb is the only one of these tracers produced in a generator system, from strontium-82, it has an advantage in relation to the others whose production depends on a cyclotron. These generators may be transported, and, specifically in case of Brazil, they may be imported especially for this purpose. Their short physical half-life of 76 seconds constitutes another favorable aspect, given that it implies very low dosimetry for the patient, with estimated exposure lower than 2 milliSieverts (mSv), in a stress and resting protocol, including tomography for attenuation correction. On the other hand, stress with exercise becomes unviable, considering the elevated costs, making it possible only in high-volume centers that perform around 40 exams weekly.214 Payment tables for medical procedures in Brazil, to date, restrict the payment of PET for oncological indications, which complicates its use for cardiology. The use of ¹³NH₃ requires a cyclotron, the installation of which has extremely high costs, but it provides high contrast images, due to its high first-pass extraction fraction. It offers good accuracy for absolute measure of myocardial blood flow (MBF), and its relatively long half-life of approximately 10 minutes, makes physical exercise viable.215

¹⁸F-flurpiridaz is a new tracer. Although its production requires a cyclotron, its labeling with fluoride-18 makes it possible to utilize the production and distribution systems that are already widely available for oncological use of PET. Due to its relatively long half-life of 110 minutes, it is appropriate for associated use with an exercise testing, and its high first-pass extraction fraction also makes it ideal for flow quantification. Its use is currently being evaluated in a phase-III study.216^-220

PET has advantages over conventional SPECT, including higher spatial resolution and contrast rate, higher sensitivity than the tracers classically used in MPS (thallium-201 and technetium-99m-labeled radiopharmaceuticals), and higher specificity, considering the attenuation correction system based on coupled CT, which results in better capability to differentiate true perfusion defects from attenuation artifacts.201^,221^-223 These advantages are notably applied to some special populations, such as obese patients and women with voluminous breasts, in whom gamma ray attenuation in soft tissue may be a factor of greater importance to the final quality of cardiac images.

The objective of evaluating myocardial perfusion via PET is to detect physiologically significant coronary stenoses, aiding clinical management of patients with known or suspected CAD and patients who, although they have no known diseases, possess risk factors, in order to evaluate atherosclerosis progression. Other objectives include determining the cause of ischemic symptoms to recommend clinical treatment or revascularization, estimating potential for future adverse events, and improving patient survival. One of its strengths is that it is the non-invasive modality of choice for accurately quantifying MBF. It allows for quantification in absolute terms of ml.min per gram of myocardium in stress and resting phases. The ratio between the 2 flows is known as the myocardial flow reserve (MFR), a valuable parameter that makes it possible to overcome one of the currently existing limitations to conventional perfusion imaging with SPECT when evaluating patients with multivessel CAD.

Results of invasive studies (FAME-1 and FAME-2) that analyzed FFR demonstrated its value in evaluating functional significance of single-vessel stenoses.224^,225 Some studies have provided evidence of a correlation between regional MFR and FFR measured invasively without comparing them directly, however.113^,226

Quantitative PET measures of MBF in absolute terms represent a paradigm change in the evaluation and management of patients with CAD, with a disassociation from the anatomical gold standard of coronary cineangiography, which had previously been established for decades, and a return to functional assessment. These measures additionally make it possible to expand the use of perfusion imaging within the current scenario, with the aim of detecting flow-limiting epicardial lesions, for earlier stages of atherosclerosis, microvascular dysfunction (Figure 17), and evaluation of balanced flow reductions in triple-vessel disease. They also offer an opportunity to monitor responses to changes in lifestyle or risk factors and therapeutic interventions.227^,228

Figure 17 Source - INCOR - FMUSP - SP.

Two recent meta-analyses evaluating methodology have indicated that PET has superior accuracy in comparison with SPECT. The first meta-analysis compared PET with SPECT synchronized with ECG and associated with attenuation correction. In analysis with a ROC curve, the area under the curve for PET and SPECT was, respectively, 0.95 and 0.90 (p < 0.0001), showing a small superiority for PET. The second meta-analysis indicated ⁸²Rb as the most used tracer, resulting in higher sensitivity for PET. Specificity, on the other hand, although superior, was not statistically significant.222

Regarding prognosis, similarly to SPECT, for which data are abundant, robust, and well established, normal myocardial perfusion with PET is indicative of good prognosis, with cardiac events varying between 0.09% and 0.9% during 1 year of follow-up, depending on the population analyzed. On the other hand, adverse events increase with the extent of perfusion defects on PET. A recently published register including more than 7,000 patients demonstrated that the hazard ratio of cardiac death increased with every 10% increment of extent of perfusion defects, classified as mild, moderate, and severe, respectively, hazard ratio: 2.3 (95% CI: 1.4-3.8; p = 0.001); hazard ratio: 4.2 (95% CI: 2.3-7.5; p < 0.001), and hazard ratio: 4.9 (95% CI: 2.5-9.6; p < 0.0001), in relation to a normal exam.221

Preparations include a 6-hour water-only fast. Patients should avoid caffeine and foods or medications containing xanthines (theophylline, theobromine) for at least 24 hours. Generally speaking, stress protocols are generic for all types of perfusion agents, bearing similarities to those of MPS with SPECT, with specific differences in accordance with acquisition protocols.

Current dosimetry for studies with rubidium-82 (⁸²Rb) in adults, considering maximum administered activity per 60-mCi dose, may vary from 1.1 to 3.5 mSv of total effective dose. With the current advances in instrumentation of PET cameras, studies with good diagnostic quality may be acquired with injected activities that vary from 20 to 40 mCi per resting and stress dose, resulting in even lower exposure. In studies with ammonia labeled with nitrogen-13 (¹³NH₃), the habitual activity is 10 to 20 mCi per dose (which corresponds to 1.48 mSv per dose). Doses of up to 25 to 30 mCi may be used in patients with high body mass index (BMI), with relatively lower dosimetry as a function of its shorter half-life and the low energy of its positron.

The evolution of imaging systems has allowed for the development of PET/CT capable of performing hybrid imaging, or be it, using CT not only for attenuation correction but also for quantification of CS and acquisition of coronary angio-CT, in addition to allowing for the fusion of these images, facilitating the integration of anatomical and functional information. Another great advance is that of PET systems incorporated to PET/MR. This new hybrid imaging modality has enormous potential for structural-functional evaluation, tissue characterization, and reduced exposure to radiation.229^-231 This, thus, amplifies the possibility of developing new studies, with the aim of expanding data on clinical applications and diagnostic and prognostic benefits of PET in studies of more diverse cardiovascular conditions.

Objective measures of coronary flow reserve will certainly be able to be extended to the MPS-SPECT method, providing evidence of nuclear medicine’s ability to carry out quantifications of MBF and allowing for additional parameters for evaluating perfusion, as well as myocardial reserve, with a resulting impact on clinical management of patients, which will objectively orient decisions about revascularization (Figure 18).232

Figure 18 Source: Adapted from Taqueti VR et al.232

Provided that availability barriers are overcome and costs of both imaging systems and tracers are reduced, especially in developing countries such as Brazil, the growing application of this new methodology has a promising outlook in cardiology.

Technological evolution has facilitated the development of excellent tools for both establishing diagnosis and estimating prognosis of CAD. These advances allow us to evaluate different aspects of anatomy and physiology of the heart non-invasively, with great accuracy. Most importantly, today we are able to rely on methods which help establish the best course of treatment in the most diverse clinical situations of patients with suspected or known diseases, whether they are symptomatic or asymptomatic. This wide range of alternatives presents an additional challenge to doctors, namely, that of defining the best strategy and the most rational complementary sequence of evaluation possible, regarding use of resources for diverse clinical situations, guaranteeing not only the highest accuracy in evaluation, but also the best benefits, considering healthcare costs. Doctors generally should seek to orient initial investigation with the aim of using the lowest number of diagnostic exams for an effective evaluation. However, in this era of multimodalities, it has become necessary to perform more than 1 exam in order to make the best therapeutic decision. Combined assessment of different phenomena of the heart is often necessary, for instance, to define physiological repercussions of an anatomical lesion.

Two questions linked to the bases of medical semiology and to the essence of medicine ask, “Who is the patient?” and “What information is the doctor looking for?” In this approach, the application of good techniques, such as anamnesis and complete physical examination, has become clear in clinical medicine, enabling doctors to formulate their initial patient profiles and to establish the most probable diagnostic hypotheses. Joint estimation of the pre-test probability of the disease233 and knowledge regarding the accuracy of a test to determine post-test probability of a true or false result (Bayes’ Theorem) are implicit and no less important. The application of this basic principle, associated with knowledge regarding what different diagnostic tools may offer, allows for the elaboration of better investigation strategies. Confirming or excluding the presence of CAD from the anatomical point of view or, alternatively, investigating the physiological repercussions of myocardial ischemia via stress tests have distinct implications for patient management. Whether to look for one response or another will depend on the patient at hand and the question the doctor wishes to answer.

Exercise testing (ET), also known as ergometric test, stress or exercise tests, showing evidence of good performance (high workload) with normal results and MPS showing absence of ischemia do not represent absence of CAD indeed . In the presence of CAD, however, these findings are associated with better prognosis in relation to patients with ischemia, given that their use is extremely useful for risk stratification of patients with or without this disease. On the other hand, it is important to know that methodologies based on the anatomy of coronary arteries, such as coronary angio-CT, may also stratify risk, but the presence of atherosclerosis detected by this modality does not necessarily imply poor prognosis or, much less, mean that the patient will necessarily benefit from myocardial revascularization procedures. It may merely represent that prognosis is worse that that of an individual without atherosclerosis. It is, thus, worth reaffirming that it is necessary for doctors to possess global knowledge of their patients and also to delineate clearly the investigation strategy for the question they are seeking to answer. Basic knowledge regarding advantages and disadvantages of available procedures are implicit, making the absolute most of the technological evolutions that have occurred in recent years. Initially speaking, all modalities which have been covered may be used for diagnosis and prognosis. It is, however, evident that they all have strengths and limitations, which are not necessarily uniform for all patients; or be it, there are determined patient characteristics which may make one test superior or inferior to another (Table 25).

Once the doctor has answered the 2 initial questions, “Who is the patient?” and “What is the main diagnostic hypothesis?” he or she needs to answer the third question: “What is the most appropriate test for this patient and for the question I want to answer?” To answer this question, it is essential to know the main advantages and disadvantages of the exams, integrating the results of Bayes’ theorem and, thus, defining post-test probability. It is, moreover, necessary to identify when continuous or complementary analysis will be required in order to obtain additional information for better patient management (Figure 19).

Figure 19 Source: Vitola JV.234

Of the techniques that have been covered, angio-CT is the most recent, showing great technological evolution, notably over the past 10 years. Data from important clinical studies have consolidated and recognized the value of this modality, as well as how to integrate it with other available tools. Before the advent of angio-CT, studies of patient anatomy presented greater difficulties, as it was mainly obtained via cardiac catheterization, with all the limitations, complications, and costs associated with invasive interventions. The development of a non-invasive, relatively simple and quick imaging technique has, in recent years, made it possible to recover the role of anatomical evaluation of the heart as a diagnostic and prognostic tool, thus integrating angio-CT into the multimodality scenario. Tests that allow for evaluation of cardiac physiology, such as ET and nuclear cardiology with MPS, have been routinely utilized for many decades, and, as they are not invasive, they have been employed for a large number of patients with suspected or known CAD. A great deal has been learned about these tools’ capabilities for diagnosis and, especially, for establishing prognosis and defining better courses of treatment.

Since the beginning of ET, initially in the 1950’s, followed by MPS in the 1970’s, information obtained has emphasized the great value of physiology, especially for evaluated coronary reserve flow, with highly consistent data for stratifying risk of cardiac death in patients with known or suspected CAD. Different physiological variables assist in characterizing patients as low-, intermediate-, or high-risk. The results of these tests, however, are not always in agreement, when comparing physiological tests to each another (ET with MPS) or to anatomical tests (angio-CT and catheterization). Potential “disagreements” and situations that may generate doubts are more common when comparing anatomy and physiology, especially at this moment, with the expanded use of angio-CT.

The scope of this text is not to revise details in relation to the variables involved, but rather to integrate information obtained from different available non-invasive tools, especially the interrelations between MPS, angio-CT, and ET. Summarily, the main variables of ET that represent high risk are: low functional capacity, greater magnitude of ST depression, occurrence in multiple leads, descending ST segment, ST-segment elevation in leads without Q waves, depressed chronotropic response, drop in blood pressure during stress, the presence of complex ventricular arrhythmia, manifestations of angina during low workloads, among others. In MPS, the principal markers of severity are: extensive perfusion defects with severe intensity, especially transient defects (transient reduced uptake) in more than 1 territory and mixed fibrosis patterns associated with ischemia (persistent reduced uptake associated with transient reduced uptake), stress-induced LV dilation, tracer uptake in the RV and the lungs, low LVEF, and LV with or without transient dilation associated with stress.

Conversely, aspects associated with low risk on the ET are represented by high functional capacity, absence of important ST-segment abnormalities or stress angina, good hemodynamic response with appropriate increase in HR and blood pressure, and absence of complex ventricular arrhythmias. In relation to MPS, markers of good prognosis are associated with normal myocardial perfusion and preserved LV ventricular function. Most of the time, especially in the most severe cases, diagnostic modalities are in agreement, or be it, a patient with high-risk ET findings will, likely, show significant MPS defects, corresponding to coronary anatomy compatible with advanced CAD. There are, however, different scenarios in which disagreeing results present challenges to better patient management.

The cases subsequently exposed are intended to integrate clinical data with the use of multimodalities, extending discussions within the medical decision-making process for understanding, interpreting, and suggesting conduct for dealing with agreements and, especially, disagreements. Figure 20 illustrates a concept in which the doctor begins evaluation using medical procedures of anamnesis and physical examination during the initial phase (I), formulating the main diagnostic hypotheses, which are fundamental aspects for defining the best investigation strategy. Subsequently, depending on the questions formulated, relatively simple or more basic diagnostic tests are obtained (II), such as: resting ECG, ET, resting ECHO and, eventually, CS. Subsequently, in accordance with the need for additional information and depending on the diagnostic hypotheses considered, the doctor may consider the application of more advanced non-invasive imaging techniques (III), such as angio-CT, MPS, and, potentially, cardiac magnetic resonance. Applying scientific knowledge regarding diagnostic and prognostic value, to both basic tests and more advanced non-invasive imaging methods, it is possible to establish filters for selecting patients who will really require invasive testing, such as cardiac catheterization (IV), notably with the aim of planning for myocardial revascularization.

Figure 20

In some patients with chronic CAD and ventricular dysfunction, revascularization may significantly improve symptoms, ventricular function, and mortality. Physiopathological conditions and acute and chronic mechanisms of adaptation to temporary reduction of coronary flow include stunning, hibernation, and preconditioning, either separately or coexisting in the same patient.261 Evaluation of myocardial viability is, consequently, important to the therapeutic decision-making process for patients with ventricular dysfunction (class of recommendation I, level of evidence B) without angina,262^-266 given that functional improvement will not occur in the presence of fibrosis. Several non-invasive imaging techniques are available for detection of viable myocardium, including stress echocardiography with dobutamine, cardiac resonance, and nuclear imaging with SPECT or PET. These methods evaluate different myocardial characteristics and, thus, present variations in sensitivity and specificity.261 In the SPECT technique, the use of thallium-201 (201Tl) is the established method for evaluating myocardial perfusion and the integrity of the cellular membrane. In comparison with other radiopharmaceuticals and available techniques, this has become the choice for determining viability.267^,268

Additionally and in conjunction with these non-invasive techniques, whose aim is to obtain functional and/or anatomical information, constituting the basis of the physiopathological approach to underlying HF, multiple detector CT is also appropriate.

However, the selection of imaging modalities, whose purpose is to assess CHF and, specifically, viability of a dysfunctional myocardium, depends on the clinical information that is required for adequate patient management (Table 26), with inherent questions and affirmations, such as:

Is the etiological cause of the cardiomyopathy in question ischemic or non-ischemic?

It had initially been established that the recovery of ventricular function, when a hibernating myocardium was revascularized, should indicate that structural changes were absent or minimal, as observed in experimental models of stunned myocardium. However, since the beginning of the 1980’s, it has been known that chronically dysfunctional myocardial segments demonstrate distinct morphological changes under microscopy.273

There is a combination of normal, atrophic, and hypertrophic myocytes, with or without evidence of necrosis. Electron microscopy shows loss and/or disorganization of myofilaments and alterations in sarcoplasmic reticulum and mitochondria. These structural changes may contribute to slow functional recovery following revascularization.274

The differentiation between the presence and absence of viability is highly relevant in patients under consideration for revascularization. Many patients who demonstrate viability associated with severe LV dysfunction may still be candidates for revascularization, but not for cardiac transplant.275

The term viable myocardium, regardless of the contractile state of the myocardium, should be understood differently in the context of CHF and viability study, given that the main objective is to predict improvement in LV function following revascularization.

Stress and redistribution - two steps or image acquisition series/one injection of ²⁰¹Tl: This is a conventional technique with image acquisition between 2 and 10 minutes (a maximum of 15 minutes) following injection of ²⁰¹Tl during peak stress (first step). These images reflect initial distribution of the radioisotope dependent on blood flow and, thus, regional myocardial flow. Two to four hours after initial intravenous administration of the radioisotope, in the resting condition (second step), a new series of images is obtained, representing the “redistribution phase,” related to the continuous exchange of ²⁰¹Tl throughout the myocardium and extracellular behavior. This protocol has been designed to study ischemia, and it is not sufficient for characterization of viability, given that viable tissues may not exhibit improvement in radiopharmaceutical uptake (reversibility) within conventional time periods for redistribution images, giving the apparent impression of persistent reduced radioisotope uptake or fibrosis.

This non-invasive exam is the reference for detecting myocardial viability, as it simultaneously offers information on myocardial perfusion and metabolism. In normal fasting and aerobic metabolism conditions, while resting, long-chain free fatty acids (FFA) represent around 65% to 70% of energy supply to the cardiac muscle, with a lower participation of glucose (15% to 20%),21 whereas, in post-prandial conditions, glucose becomes the preferred substrate. In the presence of ischemia, the oxidative metabolism of FFA is diminished and glucose also becomes the preferred myocardial substrate. In this manner, even if the energy produced by anaerobic glycolysis is not enough to maintain myocardial contractility, it is vital for the preservation of cellular membrane integrity, which is characteristic of dysfunctional, yet viable myocardium. Some positron emitters, such as fluorine-18, labeling a glucose analogue or fluorodeoxyglucose (FDG), may be used to evaluate viable (or hibernating) myocardium, which is defined as metabolically active tissue, in the presence of a coinciding perfusion defect. FDG-¹⁸F penetrates the cells of the myocardium by the same transport mechanism as glucose and, following phosphorylation to FDG-6-P, remains in the intracellular medium in proportion to the rate of glycolysis, reflecting the quantity of viable tissue. Patients are typically prepared for imaging with administration of glucose overload and subsequent doses of insulin, prior to intravenous injection of 5 to 15 mCi of FDG-¹⁸F. Images are acquired 45 to 90 minutes after the administration of the tracer, lasting, approximately, 15 to 30 minutes. Low-dose CT is required for attenuation correction. The combination of perfusion and metabolism imaging via PET has a sensitivity of 88% and a specificity of 74% for myocardial viability.284 Some differences exist for patients with diabetes, for whom the preferred form of viability evaluation is with ²⁰¹Tl or agents bound to ^99mTc. It is also important to remember that the radioisotope fluorine-18 or ¹⁸F is produced in a cyclotron, consisting of the bombardment of enriched water labeled with oxygen-18 or 18O and decaying via positron emission, with an energy range of 511 keV. Its half-life is 110 minutes, allowing for the best spatial resolution among radiotracers used for PET.

When using PET for joint analysis of metabolism with FDG-¹⁸F and perfusion (positron emitters are not available for this in clinical practice in Brazil), an excellent predictive value for functional recovery has been observed. Measurements of MBF are typically performed with rubidium-82 (⁸²Rb) or ammonia labeled with nitrogen-13 (¹³NH₃). Based on the concept of hibernating myocardium, segments with reduced perfusion, but with preserved FDG uptake (known as mismatches), are classified as viable, with functional improvements following adequate revascularization. However, when perfusion and FDG uptake are diminished or apparently absent (matches), this reflects an absence of viability (areas of fibrosis), which do not show improvements after revascularization. Finally, the combined approach to blood flow-FDG mismatches has been widely document as a predictor of post-revascularization regional improvements in motility, as well as improvements in symptoms of HF, exercise capacity, and prognosis. The PET and Recovery after Revascularization (PARR-2) study,285 which is still the only randomized prospective study to evaluate the benefits of results of a management strategy assisted by PET in patients with severe LV dysfunction, evaluated 430 randomized individuals for viability study with PET or conventional treatment without the use of PET. Results of primary analysis after 12 months of follow-up have showed a tendency toward improved results in the FDG-assisted PET, which was not statistically significant. On the other hand, post-hoc analysis, including only patients who adhered to the management strategy recommended based on the findings of FDG PET, showed significant improvements in mortality with the PET-assisted approach, when compared to standard care. Di Carli et al.286 demonstrated that small areas of viable myocardium (more than 5%), identified by PET, stratified patients into subgroups of high-risk of cardiac events in a year. Equally, comparative studies on viability between PET and SPECT with ²⁰¹Tl demonstrated agreement of results in 80% of cases.

A classic meta-analysis involving 24 studies and 3,088 patients (Left Ventricular Ejection Fraction - LVEF 32% ± 8%), with the use of different imaging methods, demonstrated that patients with viability had significant reductions in mortality when comparing surgical revascularization treatment and clinical treatment, with no benefits for either group in the absence of viability (Figure 51).287

Figure 51

In contrast, a recent multicenter prospective randomized study, known as the Surgical Treatment for Ischemic Heart Failure (STICH) study,288 was unable to show benefits regarding mortality between patients randomized into revascularization surgery (CABG), in comparison with optimized medical therapy (OMT), in primary intention-to-treat analysis, for patients with dilated cardiomyopathy (LVEF ≤ 35%) of ischemic etiology (the first of 2 tested hypotheses, involving 99 centers in 22 countries).

SPECT and/or Doppler echocardiography, associated with a low dose of dobutamine, were used to characterize viability, based on established methodological criteria. Of the 1,212 patients included for evaluation, 601 underwent the aforementioned viability studies, comparing 298 receiving medical therapy and surgical revascularization (CABG Group) to 303 patients with OMT. Of the total of 478 patients with viable myocardium, the outcome of death occurred in 178 (37%), in contrast with 58 (51%) of deaths in 114 patients without viability (hazard ratio: 0.64; 95% CI: 0.48-0.86; p = 0.003). However, after adjusting for other baseline variables, the association with mortality was not significant (p = 0.21). There was significant crossover between the 2 groups and the analysis in question was in favor of better results with CABG.

In spite of these negative findings, recognizing biases in critical analysis of the results in this occasion, it is understood that, in the real world, faced with current evidence,289^-291 viability study may be of assistance when choosing the best treatment in selected populations, leading to better prognosis in evolution.

Given that exposure to high doses is a source of concern, considering the possibility of biological effects of ionizing radiation, which are known as deterministic (those which occur above certain limits of absorbed dose in a determined tissue, including skin erythema, loss of hair, and, possibly, direct cardiac toxicity) and stochastic (those whose radiation causes damage that may lead to malignancy which is generally long-term),319^,320 there has been a demand for new technology to reduce doses of radiotracers, maintaining image quality and diagnostic accuracy. In this context, new cameras with CZT detectors have been launched in recent years. Differently from traditional Anger cameras, gamma radiation is directly converted into an electric pulse when it comes into contact with CZT detectors, increasing energy resolution and dispensing with photomultipliers, which makes the detectors much finer, lighter, and more sensible to photon detection. Protocols have suggested that it is possible to combine faster exams with lower dosimetry. Owing to high costs, they are still not widely used in Brazil, where there are few more than a dozen gamma cameras with this new technology , which has already begun to contribute relevant publications to the international scenario.321

One of the limitations, known as the “Achilles heel” of myocardial perfusion image interpretation is the attenuation which gamma rays undergo when they pass through tissues before reaching the detector. The problem lies in the fact that attenuation may simulate myocardial perfusion defects, and their recognition as cases of “false-positive” results greatly depends on the observer’s experience. These defects occur more frequently in the inferior wall in men (especially in patients with abdominal obesity), and they are described as diaphragmatic attenuation. In women, they are most commonly found in the anterior wall, due to attenuation caused by breast tissue. These imaging defects are more common in obese patients, for which reason they require higher injected doses. When the defects found are tenuous, when they occur in a similar way during resting and stress, and when they are accompanied by thickness in the walls of LV without abnormalities, the myocardial perfusion study may frequently be interpreted as normal, thus sparing the patient other investigations, both those that involve radiation and those that do not, and minimizing costs. Another way to lower the attenuation artifacts is to apply specific machines with other sources of radiation, such as an x-ray emitting tomograph, which calculates tissue attenuation factors and applies attenuation correction to the photons emitted by the radioactive tracer, reducing the effects of attenuation by means of software. This equipment, however, adds costs to the exam, and it is difficult in terms of financial viability. Even in the USA, which is the country with the highest volume of myocardial scintigraphy studies, it is estimated that only 20% of medical services routinely apply this method. Finally, another method, which is widely applied in practice to resolve apparent defects in uptake generated by attenuation of gamma photons when they penetrate tissue, is to acquire images in the prone and supine positions , especially during the stress phase, which significantly reduces the artifacts described. Some services have routinely implemented this practice, even considering the increased gamma camera utilization time with a new image acquisition series.

With respect to performing stress exam alone in order to reduce radiation by avoiding the resting dose, the following should be considered:

It is possible for the observing doctor to succeed in interpreting a study as “absence of ischemia,” based only on stress imaging, thus avoiding the resting injection. In order to do this, the observer must be confident that the image is perfectly normal and free of any perfusion defects, including “attenuation artifacts,” which are generally recognized by comparing stress and resting images. The alternative is described above, routinely applying attenuation correction, but this would involve increased costs.

In summary, in this section, various ways to reduce radiation exposure in patients undergoing nuclear cardiology exams have been covered. By means of relatively simple adjustments to protocols, injected doses may be optimized, guaranteeing image quality and, most of all, reliability of findings in an exam which is of great clinical importance to orient patient management.

Autonomic cardiac innervation plays a fundamental role on cardiac performance by regulating myocardial blood flow, HR, and myocardial contractility. In several cardiac diseases, cardiac neuronal function is altered and frequently associated with worse evolution. Dysregulation of the autonomic cardiac nervous system increases the risk of potentially lethal arrhythmias and may be a marker of poor prognosis. Scintigraphy imaging of distribution and cardiac neuronal function facilitates the comprehension of the physiopathology of various diseases that affect the heart and may guide treatment, with consequent improvements to clinical results.322

The autonomic cardiac nervous system encompasses sympathetic and parasympathetic innervation, with its norepinephrine (NE) and acetylcholine neurotransmitters, respectively. These work in equilibrium, and they exert stimulating effects, via adrenergic receptors, and inhibitory effects, via muscarinic receptors, both of which are responsible for electrophysiological and hemodynamic adaptations in the cardiovascular system, in response to bodily demands.322

In this way, sympathetic stimuli are controlled by cerebral regulatory centers that integrate signals coming from other parts of the brain and receptors in the body. Efferent signals follow descending pathways in the spinal cord and make synapses with preganglionic fibers that emerge at levels T1 to L3. In this sequence, they establish synapses with the paravertebral stellate ganglion and innervate the RV, in addition to the anterior and lateral regions of the LV. In the heart, sympathetic nerves follow the coronary arteries in the subepicardium and then penetrate the myocardium.322^,323

Parasympathetic fibers are scarce in number in comparison with sympathetic fibers, and they originate in the marrow, following the vagus nerve. They begin in the epicardium, crossing the atrioventricular groove and penetrating the myocardium. They are located in the subendocardium, predominantly innervating the atria, but they are less dense in the ventricles, with the exception of the inferior wall. They greatly control the function of sinoatrial and atrioventricular nodes.322

Metaiodobenzylguanidine (MIBG) is a molecule with a structure similar to that of NE, obtained by means of modifications to the molecular structure of guanethidine (a false neurotransmitter, also an NE analogue), which acts selectively on sympathetic nerves, without, however, being metabolized by monoamine oxidase or catechol-O-methyltransferase or exercising a stimulating effect, as NE does. For the objective of diagnosis, MIBG is labeled with iodine-123, forming the radiotracer MIBG-¹²³I,322^-325 demonstrating a good correlation between myocardial uptake of MIBG-¹²³I and NE content in cardiac tissue.325 After the radiopharmaceutical is injected via intravenous administration, it spreads throughout synaptic space, and is taken up, concentrated, and stored in presynaptic nerve endings in a manner similar to that of NE. MIBG-¹²³I is retained and localized in cardiac sympathetic nerve endings with scintigraphy images obtained by a conventional gamma camera.322^-325

The radioisotope iodine-123 predominantly emits gamma photons with an energy of 159 keV and a physical half-life of 13.2 hours, making image acquisition easy and well tolerated. MIBG-¹²³I is widely used in Europe and Japan, and it has recently been approved for cardiac use in the USA.326 In Brazil, this technique is available in some centers. Cardiac scintigraphy with MIBG-¹²³I directly evaluates global and regional sympathetic function of the heart, including uptake, reuptake, storage, and NE release processes in presynaptic nerve endings.327

Intravenous injection of MIBG-¹²³I is administered while resting, at least 30 minutes after oral administration of potassium iodide syrup or an iodine-containing solution, in order to block and protect the thyroid. Medications that may potentially interfere with catecholamine uptake, such as antidepressants, and some calcium channel blockers should be suspended for at least 24 hours before administration of the radiopharmaceutical. On the other hand, betablockers, angiotensin converting enzyme inhibitors (ACEI), and/or angiotensin receptor blockers (ARB) do not need to be discontinued.328 Approximately 15 minutes and 4 hours after administration of MIBG-¹²³I, static images and tomography images (SPECT) of the thorax are obtained in anterior projection, with the patient in dorsal decubitus, with the left arm raised above the thorax. While tomography images are optional, they help evaluate myocardial sympathetic activity and compare with the perfusion study (see the subsequent topic “Evaluation of arrhythmias”). Global cardiac uptake of MIBG-¹²³I is evaluated by static imaging of the thorax (Figure 52). The following 2 fundamental parameters are visually and semiquantitatively analyzed: the relation between cardiac and mediastinal uptake (heart to mediastinum ratio [HMR]) in early images (15 minutes after injection) and late imaging (4 hours after injection) and the myocardial washout rate (WR) of MIBG-¹²³I.322^-324^,327^-330

Figure 52

Normal HMR values vary from 1.9 to 2.8 with an approximate average of 2.2 ± 0.3 in late images, with results ≥ 1.6 considered predictive of lower risks.331 HMR reflects the density of receptors and, probably, depicts the integrity of presynaptic nerve endings and of the uptake 1 receptor. This elevated index indicates a predominant localization of the radiotracer in the myocardium, which is expected in normal hearts, to the extent that the finding of reduced HMR indicates lower myocardial uptake of MIBG-¹²³I, translating as reduced density of cardiac adrenergic receptors. Late HMR combines information on neuronal function of uptake and the release of storage vesicles in cardiac nerve endings. Figures 53 and 54 show images of patients with normal and altered HMR, respectively.

Figure 53

Figure 54

Myocardial washout rate (WR) of MIBG-¹²³I is also an important measure of cardiac sympathetic innervation. WR is calculated as the difference in myocardial uptake between the early and late phases and is determined by the percentage of reduction in uptake between these steps, reflecting the amount of catecholamines released in the cardiac synaptic cleft. Cardiac sympathetic hyperactivity is associated with reduced retention of MIBG-¹²³I in late images (reduced late HMR) and increased WR. Normal WR control values are 10% ± 9%.332 Higher values are predictive of worse prognosis,333 although there are several methods for determining this ratio in the literature. Intra- and inter-observer variability of these measurements is less than 5%.328

Imaging studies of cardiac adrenergic activity may be useful in several clinical scenarios (Table 30), including: HF, ventricular arrhythmias (associated with HR and primary arrhythmias), ischemic heart disease, DM, patients undergoing cardiotoxic chemotherapy, pre- and post-cardiac transplant, Takotsubo syndrome, and cardiac involvement due to systemic conditions, as in Parkinson’s disease. Generally speaking, this exam has been established to have an effective capacity for risk stratification of patients with the previously described conditions, but the utility of this information in improving clinical results of patients has not yet been demonstrated.331

The diagnostic and prognostic potential for evaluating the autonomic nervous system with nuclear cardiology is great. A growing amount of evidence has shown that cardiac scintigraphy with MIBG-¹²³I may assist in selection of patients for more sophisticated HR treatments, such as CRT, as well as new medical approaches, and ICD implants for primary prevention. It is also a valuable tool for cardiovascular risk stratification (potentially lethal ventricular arrhythmias, progression of HF, and cardiac death). Due to the high sensitivity of autonomic nervous system fibers to ischemic injury and delayed recovery, myocardial scintigraphy with MIBG-¹²³I is also useful as an ischemic memory marker or for the recognition of Takotsubo syndrome. Greater clinical experience with this method will, however, be necessary, with the aim of improving positive and negative predictive values, for the sake of greater differentiation of patients with low and high risks, thus contributing to more effective use of medical resources. Japan is the only country where the utility of this imaging technique has been characterized in guidelines. Data related to cost-effectiveness are still limited, and low availability in clinical practice make it difficult to use on a large scale.

The applications of nuclear cardiology go beyond MPS for ischemic heart disease. Some of the indications which will be discussed are not relatively recent in the literature, but they are still little utilized within our context. In comparison to conventional investigation methods, new non-invasive methods of nuclear medicine in cardiology have the potential to improve early detection of affected myocardium, allowing for quantification of disease activity, orienting therapeutic interventions, and monitoring success of treatment.

Early diagnosis of infectious endocarditis (IE) continues to be challenging. The pathology should, essentially, be suspected in the presence of fever of unknown origin, especially in association with laboratory signs of infection, anemia, microscopic hematuria, or manifestations of septic embolism. The modified Duke criteria, which are considered a reference, include clinical, microbiological, and echocardiography findings, resulting in a general sensitivity around 80%.395 Some limitations, however, stand out, especially in patients with prosthetic valves (PV) and cardiac implantable electronic devices (CIED),396 implying inadequate classification of up to 24% of patients with proven IE.395 Advanced imaging techniques for early, sensitive diagnosis of IE are, in fact, valuable tools in clinical practice. The combination of both evaluation of myocardial metabolism of glucose via PET/CT using a glucose analogue labeled with ¹⁸F, fluorodeoxyglucose (FDG) (FDG-¹⁸F - PET/CT), and modified Duke criteria resulted in increased sensitivity, without large alterations in specificity.397 Although FDG-¹⁸F - PET/CT is not reliable for evaluation of native valve endocarditis,398 it may accurately diagnose endocarditis in valve prostheses and its systemic complications.399 In recognition of its utility, FDG-¹⁸F - PET/CT was included in the European Society of Cardiology Guidelines, in 2015, as a diagnostic criterion (class of recommendation IIb) for IE in patients with valve prostheses.400 One option for further improving FDG-¹⁸F - PET/CT imaging is the incorporation of angio-CT (PET/angio-CT), resulting in sensitivity, specificity, positive predictive value, and negative predictive values of 91%, 91%, 93%, and 88%, respectively.401 As a more specific alternative to FDG-¹⁸F - PET/CT, guidelines on IE include scintigraphy using marked leukocytes with SPECT/CT imaging. SPECT/CT is the combination of nuclear medicine tomography imaging (SPECT) and anatomical imaging via CT, greatly increasing diagnostic accuracy. However, notwithstanding the proven value of this technique for detecting endocarditis402^,403 (Figure 56), its widespread application is compromised due to limited sensitivity and the difficulty of locating inflammatory foci, but the very high specificity of scintigraphy with marked leukocytes for infection, when using SPECT/CT imaging, may be particularly useful in cases where diagnosis remains uncertain following echocardiography and FDG-¹⁸F - PET/CT, especially in patients who have undergone cardiac surgery over the past 2 months.404^-407 As an additional possibility, the simultaneous combination of scintigraphy with marked leukocytes and MPS, acquired to improve localization of infectious points in relation to the valve plane defined by perfusion. Limitations to performing SPECT/CT with marked leukocytes are: the need for a specific structure with laminar flow, the manipulation of blood components, procedure duration, and inferior spatial resolution in relation to PET/CT.400

Figure 56 Personal source (courtesy of Dr. Alan Chambi).

Furthermore, new bacteria-specific tracers have become available, such as carbohydrates, which are metabolized exclusively by bacteria or antibodies directed against components of the bacterial cell membrane. For example, the protein component of the pilin structure of Enterococcus faecalis is being developed.408 This recent study has demonstrated the superior quality of images and another possibility for differentiating between infectious and inflammatory causes of endocarditis.

CIED have been increasingly used over recent years,400 with elevated rates of infection (1% to 3%), and they are associated with 1-year mortality over 10%.409 Doppler echocardiography is the first line imaging method for evaluation of suspected CIED infection, but its use is limited for investigating infection in extra-cardiac leads and device pockets. Both FDG-¹⁸F - PET/CT and SPECT/CT scintigraphy with marked leukocytes have demonstrated additional value for diagnosis of infections related to CIED or pacemaker. FDG-¹⁸F - PET/CT has been shown to be especially useful for diagnosing device pocket infections, but it is less reliable for diagnosing infections in the metallic device.410^,411 The presence of a focal hotspot is considered the best criterion for infection,412 (Figures 57 and 58). It is worth noting that exam accuracy depends on patient preparation and post-implant interval, which is the case with applications involving FDG-¹⁸F. Mild FDG-¹⁸F uptake has been reported to be nonspecific in patients with CIED or pacemaker with no suspicion of acute-phase infection (≤ 2 months) following cardiac surgery.410 Moreover, attenuation correction artifacts due to metallic implants should be avoided by means of close evaluation of images without attenuation correction.

Figure 57 Source: INCOR, FMUSP, SP.

Figure 58 Source: INCOR, FMUSP, SP.

Both FDG-¹⁸F - PET/CT and scintigraphy with marked leukocytes via SPECT/CT seem to be beneficial in diagnosing infections related to ventricular assist devices (VAD).413^,414 FDG-¹⁸F - PET/CT is especially sensitive to infection in these devices. In a small retrospective study, sensitivity to VAD infection was 100%, and specificity was 80%. Furthermore, in 85% of cases, PET imaging had an impact on clinical management of patients.415

The role of FDG-¹⁸F - PET/CT in investigating extracardiac complications of infection was also studied. In a retrospective analysis of patients with suspected CIED infection, the performance of full body PET also identified septic embolism or infection disseminated into other sites in 28% of cases.416 These results were confirmed in a prospective study on known device endocarditis.417 In this cohort, FDG-¹⁸F - PET/CT found septic embolism in 10 patients (29%), including 7 cases of spondylodiscitis, 4 of which were not clinically visible and which resulted in significant modifications to therapy.

Guided myocardial biopsy may be another application of FDG-¹⁸F - PET/CT, as shown in other diseases.418 Furthermore, MR and PET/CT seem to be complementary in nature.419 Investigation of the incremental value of PET/MR, a new integrated imaging modality, may have great potential for diagnosing endocarditis.

The most common causes of myocarditis are viral infections. Other causes include other types of infections, autoimmune disorders, or drug interactions. Clinical manifestations of myocarditis are highly variable, ranging from subclinical disease to sudden death. This spectrum also reflects the extent to which this histological disease’s severity, etiology, and stage of clinical presentation may vary. Inflammation of the myocardium may be focal or diffused, involving any of the cardiac chambers. Endomyocardial biopsy is currently the gold standard for diagnosis, but it has a low sensitivity (20-30%) and significant associated risk.420 MR is considered the imaging method of reference for non-invasive diagnosis of myocarditis, given that it allows for detection of several characteristics such as inflammatory hyperemia and edema, necrosis, and myocardial scarring, alterations in ventricular size and geometry, regional and global abnormalities in the movement of walls, and identification of pericardial effusion.421 MR criteria for diagnosis of myocarditis have been summarized in what are known as the Lake Louise Criteria.422 MR, however, has limitations that are particularly evident in chronic myocarditis, with low diagnostic precision (50% accuracy).423

Using FDG-¹⁸F - PET/CT, following adequate patient preparation with a carbohydrate-free diet, it is possible to visualize acute inflammation suggestive of active myocarditis. PET imaging may help distinguish active and chronic forms of the disease, following established working protocols.424^,425 In a prospective study of 65 patients with suspected myocarditis, FDG-¹⁸F - PET was in agreement with MR findings.426 MR and FDG-¹⁸F - PET/CT seem to be complementary in nature.419 For this reason, cardiac PET/MR has potential as a diagnostic tool for myocarditis and a new field of research.427^-429

There are multiple causes of acute or chronic pericardial inflammation, including infections (viral, bacterial, or fungal), myocardial infarction, trauma, malign diseases (primary pericardial neoplasm, pericardial metastases, or paraneoplastic syndrome), autoimmune or inflammatory diseases, and metabolic disorders (uremia). Pericarditis may also be iatrogenic, as a collateral effect of medication. Radiotherapy or idiopathic causes are other possible origins. Although its etiology is variable, the pericardium’s response to different causes is not specific. Inflammation of pericardial layers and increased production of pericardial fluids are the most common, and they often manifest as chest pain. In the same manner, Doppler echocardiography stands out as a priority for diagnosis and therapeutic follow-up of pericarditis, externalizing findings such as pericardial effusion and thickness. Generally, CT and MR also allow for evaluation of pericardial effusion and thickness, allowing for better differentiation of pericardium and pericardial fluid.430

The use of FDG-¹⁸F - PET/CT in pericarditis is generally complementary, and it demonstrates the ability to detect inflammatory tissue, even in the absence of obvious anatomical changes.431^,432 Non-infectious inflammatory pericarditis shows mild to moderate FDG-¹⁸F - PET uptake in the pericardium, with diffuse or focal uptake pattern. The literature is still scarce on the utility of FDG-¹⁸F - PET/CT for differential diagnosis of the underlying causes of this pathology. Some studies relate the possibility of differentiating infectious/inflammatory pericardial disease and neoplastic/metastatic disease, given that malignity, generally, presents intense metabolic activity.433 Constrictive or effusive pericarditis, an uncommon complication of chemotherapy, may also present pericardial uptake of FDG-¹⁸F, with mild intensity and wide distribution.431 Only a few case reports are available in the literature, and larger studies are still necessary to determine the accuracy of FDG-¹⁸F - PET/CT for pericarditis.

Sarcoidosis is a granulomatous disease whose etiology is unknown. It most commonly affects the lymphatic ganglia and the lungs, but it may involve any system of organs.434 The heart is frequently affected,435^,436 and this represents one of the main causes of death due to this pathology in Japan and the USA.437 Due to its multifocal aspect and the irregular manner in which sarcoidosis affects the myocardium, the sensitivity of endomyocardial biopsy is extremely low (20% to 30%).438 In comparison with MR, the advantages of FDG-¹⁸F - PET/CT include the value of functional metabolic information, the detection of active inflammation, the potential for identifying cardiac and extracardiac involvement (Figure 59) of sarcoidosis, and the possibility of performing imaging in patients with CIED or renal insufficiency. In order to evaluate extracardiac involvement, it is important to perform full-body imaging.

Figure 59 Personal source (courtesy of Dr. Evandro T. Mesquita).

Sarcoidosis normally manifests as an irregular focal uptake pattern. FDG-¹⁸F - PET/CT has demonstrated that it detects active cardiac and extracardiac forms reliably, with sensitivity between 81% and 89% and specificity between 78% and 82%, respectively.439^,440 It is necessary to pay attention to the patient preparation required for image acquisition in these cases. It is essential for the patient’s diet to be low in carbohydrates and rich in fat the day before the exam and for the patient to be in fasting conditions in order to guarantee that there is no physiological uptake in the myocardium.

FDG-¹⁸F - PET/CT may often be combined with MPS synchronized with ECG (Figure 60), with the objective of ruling out CAD or even identifying resting perfusion defects suggestive of inflammation-induced tissue damage.441^,442

Figure 60 Source: INCOR, FMUSP, SP.

In addition to this, FDG-¹⁸F - PET/CT in combination with perfusion imaging has shown evidence of prognostic capability in patients with sarcoidosis,443 orienting myocardial biopsy,418 and demonstrating valor for predicting response and monitoring therapy.444

The CA is a rare form of cardiomyopathy. Frequently subdiagnosed, it is characterized by extracellular deposition of fibrils, composed of varied serum protein subunits, which have low molecular weight. Although more than 30 different amyloid proteins have been described, the 2 that most frequently infiltrate the heart are: light chain immunoglobulin (AL) and transthyretin (TTR). The AL and TTR forms possess different clinical courses, prognoses, and distinct forms of treatment. In the AL form, fibrils are composed of light-chain immunoglobulins and produced by a population of plasma cell clones located in the bone marrow. In the TTR form, deposits are made up of anomalous monomers or dimers of the hepatic tetrameric protein whose origin may be related to genetic mutations of familial origin (mutated TTR or [mTTR]) or the wild type, formerly known as the senile type (sTTR). More than 100 known mutations are related to mTTR and to autosomal dominant inheritance, which may affect individuals in any age group, especially middle-aged men. The most common manifestation of CA is HF with preserved ejection fraction. In its final stage, it is present as restrictive cardiomyopathy, implying very poor prognosis. Definitive diagnosis requires amyloid deposits on endomyocardial biopsy or, in patients with suggestive cardiac findings, amyloid deposits on histological exams of other tissues (e.g., abdominal fat, rectum, or kidneys).445

Echocardiography is the initial non-invasive exam of choice for diagnosing CA, but its specificity is limited.446However, complementary sequence with MR, which has satisfactory sensitivity, may suggest a pattern of cardiomyopathy due to amyloid deposition, except in patients with moderate to severe kidney disease.

It has been reported that scintigraphy with intravenous administration of bisphosphonate radiotracers labeled with 99m-technetium (Pyrophosphate-^99mTc is the most used in Brazil) localizes cardiac amyloid deposition. It is considered sensitive and highly specific for TTR CA, identifying the disease early at onset.447^,448 One hypothesis for the binding of these bone markers to amyloid fibers is related to the higher quantity of calcium present in TTR protein, in relation to AL. In a recent multicenter study which included 1,217 patients with suspected CA, the combination of moderate to accentuated increase in myocardial uptake of the radiotracer and the absence of specific monoclonal protein in blood serum or urine, had specificity and positive predictive value of 100% for the TTR form of CA. However, scintigraphy with bisphosphonate radiotracers does not reliably detect other types of CA, and it cannot be used quantitatively for therapeutic monitoring.418

The intensity of the concentration of Pyrophosphate-^99mTc in the cardiac area is correlated to the amyloid subtype. Degree of concentration is compared to bone uptake in the ribcage, considering the following: degree 3, greater uptake than the ribs; degree 2, equal to the intensity of concentration in the ribs; degree 1, lower concentration than in the ribs; and degree zero, no significant cardiac tracer concentration. Severely increased concentration (degrees 2 and 3) (Figure 61) is strongly associated with TTR CA, to the extent that some authors suggest dispensing cardiac biopsy in these situations. Less intense increased concentration (degree 1) and absence of increased concentration suggest the AL form, when there is clinical suspicion. Semiquantitative analysis of radiotracer uptake should also be performed (Figure 62).449

Figure 61 Personal source (courtesy of Dr. Rafael Willain Lopes).

Figure 62 Source: INCOR, FMUSP, SP.

A potential bone radiotracer for PET amyloid imaging is sodium fluoride labeled with ¹⁸F, or Sodium fluoride-¹⁸F. It has been described in single case series, whereas another study identified no increase in uptake of this tracer with TTR CA,450^-452 indicating the need for further studies to investigate the potential value of PET/CT with Sodium fluoride-¹⁸F for CA.

A small amount of available data has demonstrated the limited application of FDG-¹⁸F - PET/CT for evaluation of CA.453^,454 Up to the present moment, the most promising alternatives include other specific amyloid markers, such as the Pittsburgh B compound labeled with carbon-11 (PIB-¹¹C),455^,456 as well as other compounds labeled with ¹⁸F, such as Florbetapir457^,458 and Florbetaben.459 All studies have reported promising results for diagnosis of CA, given that PIB-¹¹C presents uptake in AC. It has additionally been demonstrated that PIB-¹¹C has lower uptake in patients who have been treated with chemotherapy, in comparison with patients still undergoing treatment. Thus, PIB-¹¹C - PET has the potential to be used for therapeutic monitoring of patients with light-chain CA as a marker of disease activity.460

New applications of nuclear medicine in cardiology (Table 32) represent an important area which is little explored in our context. They have the capability to detect functional alterations in these pathologies, indicating whether a disease is or active or not and assisting in therapeutic monitoring. Cardiologists’ knowledge of these applications will be essential to their proper use and to the dissemination of these diagnostic methods.