Nuclear cardiology for a cardiothoracic surgeon

Abstract

Cardiac surgeons are commonly faced with issues regarding the balance between the potential risk and the potential benefit of a surgical procedure. Nuclear cardiology procedures such as single-photon emission computed tomography and positron emission tomography provide the surgeon with objective information that augments standard clinical and angiographic assessments related to the diagnosis, prognosis, and potential benefit from any intervention. Myocardial perfusion is imaged with the use of radiopharmaceuticals that accumulate rapidly in the myocardium in proportion to the myocardial blood flow. Radionuclide lung imaging most commonly involves the demonstration of pulmonary perfusion using technetium-99 m macro aggregate albumin (Tc-99 m MAA), as well as the assessment of ventilation using inspired inert gas, usually xenon, or Tc-99 m-labelled aerosols. Nuclear cardiology is extensively used as a part of the work-up of ischemic heart disease and cardiac failure in deciding the optimal therapeutic strategy with its ability to predict the severity of the disease. It has also proved extremely useful in the management of congenital heart disease and the diagnosis of pulmonary embolism, among many other applications. Myocardial perfusion imaging is a basic adjunct to the noninvasive assessment of patients with stable angina, baseline electrocardiogram (ECG) abnormalities, post-revascularisation assessment, and heart failure. This review article covers a summary of basic concepts of nuclear cardiology about what a cardiac surgeon should be aware of. To many, it is just a perfusion test, but the versatility, reliability, and future of the technology are without a doubt.

Introduction

The ability to image myocardial perfusion, function, and metabolism noninvasively with nuclear techniques has led to the development of a field that has been validated extensively and provides useful diagnostic and prognostic information in the management of patients with known or suspected coronary artery disease (CAD). Moreover, nuclear cardiology procedures have been used widely in the evaluation of patients before both cardiac and noncardiac surgeries. Myocardial perfusion imaging (MPI) procedures, such as single-photon emission computed tomography (SPECT) and positron emission tomography (PET), have emerged not only as diagnostic tools, but also as prognostic tools which can provide data about myocardial perfusion, ventricular function, and myocardial viability, utilizing a single test. SPECT utilizes a gamma-emitting radioisotope as the racer while PET uses a positron-emitting radioisotope as the tracer [1, 2].

MPI was developed more than three decades ago as a two-dimensional technique using a potassium analogue, thallium-201 (Tl-201). Since then, various new radiopharmaceuticals with superior imaging properties such as technetium-99 m (Tc-99 m) have been developed and tomographic imaging has become the imaging standard, providing excellent 3-dimensional localization and extent determination of perfusion abnormalities [3].

The most common indication for the use of lung scintigraphy is the determination of the likelihood of pulmonary embolism. Although these studies are essentially qualitative, they have an advantage over most quantitative tests of global lung function, in distinguishing between diffuse and regional pulmonary disease. Most importantly, the ability to display both the regional airway and vascular integrity forms the basis of the noninvasive diagnosis of pulmonary emboli.

Discussion

Radionuclide imaging of cardiovascular system

Types of MPI

1. SPECT/CT

2. PET

SPECT

MPI is used to determine the adequacy of blood flow to the myocardium, especially in conjunction with exercise or pharmacologic stress for the detection and evaluation of CAD. It is also used to assess the myocardial viability in case of acute myocardial infarction (MI) and acute left ventricular failure.

Principle

Radionuclide MPI involves administering the radiopharmaceutical that distributes in the myocardium, along the territory of a coronary artery. The diagnosis of occlusive coronary disease is made by the visualization of relatively decreased myocardial deposition of the radiopharmaceutical in the myocardium distal to the site of vascular obstruction, compared to the adjacent myocardium supplied by normal coronary arteries. However, because coronary perfusion in resting patients may remain at near-normal levels at coronary artery narrowing of up to 90%, evaluation of patients at rest is insensitive for detecting even significant CAD. To increase the sensitivity of the examination, some form of stress, either exercise or pharmacologic stress to produce coronary blood flow greater than resting levels, is usually needed to render a flow differential between normal and abnormal coronary arteries that can be seen or digitally detected on myocardial perfusion images [4].

Cardiac images synchronized with the patient’s electrocardiogram (ECG) allow for an additional analysis of the ventricular function along with the myocardial perfusion evaluation. By synchronizing the collection of SPECT imaging data with the patient’s ECG, the degrading effects of ventricular wall motion can be eliminated or reduced. Gated SPECT has made a dramatic change in the perfusion imaging by allowing better identification of attenuation artefacts (breast and diaphragm), cine visualization of left ventricular wall thickening (flow/function relation), and an accurate estimation of left ventricular ejection fraction (LVEF) and left ventricular volumes [5].

PET

PET technology makes use of the decay of radioactive tracers, most commonly rubidium-82 (Rb-82) and 18-fluorine 2-fluoro-2-deoxy-d-glucose (¹⁸F-FDG), that are taken up by the organ of interest [6]. 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. 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. Myocardial perfusion studies using PET may be performed using different tracers, each of which possesses specific characteristics, advantages, and disadvantages. Rb-82 and ammonia labelled with nitrogen-13 (¹³NH₃) have been approved for clinical use by the Food and Drug Administration (FDA), and they are the most commonly used. Recent advances include the use of 18F-sodium fluoride (NaF), for the detection of hydroxyapatite in high-risk patients with coronary plaques and aortic stenosis.

SPECT versus PET-CT for MPI

Several technical advantages account for the improved image quality and diagnostic ability of PET compared with SPECT, including the high spatial resolution of reconstructed images, the high sensitivity in the identification of small concentrations of radiotracers, and above all the high temporal resolution, which allows dynamic sequences to be obtained to describe tracer kinetics and perform absolute measurements of myocardial blood flow (MBF). At the moment, cardiac PET using perfusion tracers represents the gold standard for quantifying myocardial absolute perfusion (ml/min/g), at both rest and stress acquisition, and coronary flow reserve, defined as the ratio between MBF at peak stress and MBF at rest. A typical rest-stress SPECT procedure takes 3 to 5 h to complete, while a rest-stress PET study using Rb-82 can be completed in 20 to 30 min. Emerging evidence consistently demonstrates that PET provides improved image quality, greater interpretive certainty, higher diagnostic accuracy, lower patient dosimetry, and shorter imaging protocols as compared to SPECT [7]. Recently, there has been a significant evolutionary leap in SPECT imaging, with the advent of high sensitivity gamma camera systems that utilize solid-state crystals and novel collimator designs configured specifically for cardiac imaging. Solid-state SPECT camera systems have facilitated dramatic reductions in both imaging time and radiation dose while maintaining high diagnostic accuracy. Further, solid-state SPECT cameras because of their higher sensitivity and temporal resolution allow assessment of MBF, thereby improving the diagnostic accuracy in patients with multivessel disease.

Radiotracers (Tables 1 and 2)

Table 1.

Comparison of different radionuclide agents used in spect [8, 9]

Radionuclide agent	Half-life	Effective dose (mill Sievert — mSv)	Mechanism of myocardial uptake	Redistribution	Comments
201 Thallium	72 h	15–20 mSv	Adenosine Triphosphatase (ATPase)–myocyte cell membrane integrity required	High	Poor quality images, redistribution advantageous for viability detection
99 m Tc sestamibi	6 h	8 mSv	Myocyte mitochondria	Minimal	Versatile agent, increasing use for viability detection
99 m Tc tetrofosmin	6 h	8 mSv	Not known	Nil	Underestimates ischemic burden, improved extracardiac clearance suggested, poorer extraction

Table 2.

Comparison of different radionuclide agents used in PET to assess perfusion [10]

Radionuclide agent	Half-life (minutes)	Production	Image resolution	Perfusion defect contrast	Comments
15O-water	2.06	On-site cyclotron	Intermediate	Intermediate	Requires on site cyclotron
13 N-ammonia	9.96	On-site cyclotron	Intermediate-high	Intermediate	Not practical for stress testing
82Rubidium chloride	1.25	Generator	Lowest	Lowest	Lower myocardial extraction fraction
11C-acetate	20.3	On-site cyclotron	Intermediate	Intermediate	Extensively metabolized inside cardiac myocytes to acetyl coenzyme A (CoA) and enters tricarboxylic acid cycle (TCA), due to its high first-pass myocardial extraction, recently, it has also been used to evaluate myocardial perfusion
18F-flurpiridaz	109	Regional cyclotron	Highest	Highest	Long half-life, in phase 3 of clinical trials

SPECT allows a noninvasive evaluation of MBF by using tracers such as Tl-201- and Tc-99 m-labelled perfusion tracers. PET, on the other hand, allows a noninvasive assessment of regional blood flow, cardiac function, and metabolism using physiologic substrates prepared with positron-emitting isotopes such as carbon, nitrogen, oxygen, and fluorine. Table 1 shows the agents that are currently in use.

Tc-99 m does not undergo selective myocardial extraction. Therefore, for assessment of myocardial perfusion, it must be bound to another compound (i.e. sestamibi or tetrofosmin) that selectively concentrates in the myocardium. Tc-99 m sestamibi and Tc-99 m tetrofosmin have similar characteristics; both are lipophilic cations that diffuse into cells with no active uptake. Their uptake and subsequent mitochondrial retention depend on blood flow and transmembrane energy potentials. Unlike Tl-201, Tc-99 m-labelled agents lack significant redistribution and therefore require two separate injections for stress and rest study. Both undergo hepatobiliary excretion.

To assess metabolism in PET imaging, ¹⁸F-FDG is used. ¹⁸F-FDG has also been used as an important radiotracer in the context of oncological, neurological, and cardiologic pathologies. ¹⁸F-FDG PET has been used for tracking glucose metabolism to test myocardial viability and imaging myocardial inflammation.

PET imaging compares the regional distribution of myocardial glucose use to regional myocardial perfusion. Two sets of images are recorded and interpreted. The first is with ¹⁸F-FDG administered under conditions of glucose loading to determine the regional myocardial use of glucose, and the second is regional myocardial perfusion determined at rest (with 13 N-ammonia or 82Rb). The regional distribution of perfusion and that of ¹⁸F-FDG are compared. Regions of perfusion that deviate by ≥  − 2 standard deviation (SD) from the mean and regions of ¹⁸F-FDG uptake which deviate by ≥  + 2 SDs identify viable ischemic tissue.

The normal myocardium preferentially utilizes fatty acids for energy but switches to increased glucose utilization during periods of ischemia. In myocardial regions with ischemic dysfunction, myocardial glucose uptake may be increased, and thus FDG uptake will be enhanced, reflecting viability. Conversely, FDG will not accumulate in areas of fibrosis or scar. FDG uptake is then compared with resting perfusion imaging. Perfusion-metabolism is considered “matched” if areas of preserved flow show normal metabolic activity, and areas of reduced flow have diminished FDG uptake (scar); however, perfusion and metabolism may be discordant, or “mismatched”. In this scenario, FDG uptake will be present in areas of hypoperfusion, indicating that despite decreased blood flow, the myocardium is still metabolically active, hence viable.

One of the most important differences between nuclear cardiology and other techniques is the ability to easily quantify ischemic burden using commercially available software. This allows for accurate estimation of areas at risk of infarction as well as scar burden. The size of the scar and ischemic burden is directly related to prognosis.

Patient preparation

1. Beta antagonists and calcium channel antagonists should be discontinued for 5 half-lives before the test unless medically contraindicated

2. Patient should avoid caffeine-containing foods, beverages, and drugs for a minimum of 12 h before the test

3. Patient should be instructed to dress appropriately for exercise

4. Fasting of 6 h

Specifically, for FDG-PET, the test is performed following a 6- to 12-h fast followed by a glucose load. Under glucose-loaded conditions, FDG uptake by the normal myocardium is maximized, resulting in superior image quality and reduced regional variation in FDG uptake. There are several approaches to stimulate myocardial glucose uptake following oral or intravenous glucose loading. The most common method is to use 25–100 g of oral glucose followed by supplemental intravenous (IV) insulin as needed.

Protocol

For Tl-201

A single dose of Tl-201 (2.5 to 3.5 milli Curie — mCi) is injected at peak stress, and SPECT imaging is started within 10–15 min. Redistribution (rest) imaging is usually done 2–4 h later. For the assessment of myocardial viability, 2.5 to 3.5 mCi of Tl-201 is injected at rest (with rest imaging started within 15 min of injection) followed by redistribution imaging at 3–4 or 18–24 h [11].

For Tc-99 m sestamibi or Tc-99 m tetrofosmin

Two-day protocol

Stress and rest imaging is performed on two separate days, to avoid having residual activity from the first injection interfere with the interpretation of images reflecting the second injection. Also in larger patients (e.g. > 250 pounds or body mass index {BMI} > 35), the low dose radiotracer injection (in the first study) may result in suboptimal images and thus a 2-day imaging protocol with higher activities (18 to 30 mCi) for each injection is preferable [12].

One-day protocol

Both stress and rest studies are performed on a single day. The first study is performed using 8–12 mCi of the radiotracer (depending on patients BMI), with three times this activity used for the second dose/study [13]. However, the new solid-state SPECT cameras offer higher sensitivity thereby allowing for a reduction in dose and imaging time.

Stress testing

Diagnosis and risk stratification of CAD employs both exercise and pharmacological stressors to induce flow heterogeneity or functional abnormalities attributable to myocardial ischaemia. The rationale is that an increase in oxygen demand (exercise) or coronary blood flow (pharmacological stress) causes regional hypoperfusion or dysfunction in ischemic myocardial segments supplied by stenotic coronary vessels. Both stress modalities have similar sensitivity and specificity for the detection of CAD via analysis of perfusion images [14, 15].

The room where the test procedure is performed should be equipped with a resuscitation cart, a defibrillator, and appropriate cardioactive medication to allow prompt treatment of any emergency such as cardiac arrhythmias, atrioventricular block, hypotension, or persistent chest pain. An intravenous line is mandatory for injection of the tracer at the peak of the exercise test or after administration of vasodilator drugs. The equipment and supplies in the cart must be checked on a regular daily basis [16].

Exercise testing (ET)

ET is the method of choice for diagnostic and prognostic evaluation, which has 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 unfavourable 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 the stress has ceased, present in multiple leads, among others.

Two main types of exercise tests are distinguished:

1. Dynamic or isotonic exercise (bicycle ergometry)

2. Static or isometric exercise (treadmill protocol)

Exercise is preferred to pharmacological stress because it allows evaluation of physiological imbalance between oxygen supply and demand due to impaired flow reserve and identification of the ischemic threshold related to heart workload (calculated by multiplying the heart rate (HR) by the SBP at the peak of exercise). In patients without CAD, ET causes vasodilation and increases coronary blood flow to 2–2.5 times above baseline levels.

ET

Indications	Contraindications	Indications for early termination
Detection of obstructive CAD in patients with intermediate pre-test probability of CAD	High-risk unstable angina/acute MI	Moderate-severe angina
Risk stratification of post-MI patients before discharge	Decompensated congestive heart failure	Marked dyspnea or fatigue
Risk stratification of patients with chronic stable CAD into low-risk and high-risk category	Uncontrolled hypertension	Dizziness or syncope
Risk stratification before noncardiac surgery in patients with known CAD	Uncontrolled cardiac arrhythmias	ST segment depression (> 2 mm) in any lead
	Acute aortic dissection	ST segment elevation (> 1 mm) without diagnostic Q waves in any lead (except V1 and aVR)
	Acute pulmonary embolism/severe pulmonary hypertension	Hypertensive response (systolic pressure > 250 mmHg or diastolic pressure > 110 mmHg)
	Acute myocarditis	Drop in systolic pressure > 10 mmHg from baseline

Pharmacological stress testing

Pharmacological stress is increasingly employed as an alternative to ET. Most patients referred to the nuclear cardiology laboratory are unable to perform a diagnostic exercise test owing to orthopaedic, neurological, systemic, or vascular disease. 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, which has recently been extended to elderly patients and women [17].

Two main types of pharmacological stress agents are.

1. Vasodilator stress (using adenosine/regadenoson or dipyridamole)

2. Catecholamine stress (using dobutamine)

Indications	Contraindications	Indications for early termination
Inability to perform adequate exercise due to noncardiac physical limitations	Bronchospastic disease	Severe hypotension (systolic blood pressure < 80 mmHg)
Baseline ECG abnormalities such as left bundle branch block, Wolff Parkinson white syndrome or permanent ventricular pacing	Second- or third-degree atrioventricular (AV) block	Development of symptomatic, persistent second-degree AV block or complete heart block
Risk stratification of clinically stable patients into low and high-risk groups, very early (1 day) after acute MI	Recent cerebrovascular accident (< 2 months)	Wheezing
	Severe aortic stenosis and significant left ventricular outflow tract obstruction	Severe chest pain associated with ST segment depression of 2 mm or more
	Unstable angina/acute MI
	Aneurysms or aortic dissection

Interpretation

Interpretation of stress-rest MPI images

Before the interpretation of perfusion images, the raw image datasets should be reviewed in cinematic display to look for any artefact that might arise because of patient motion or any abnormal extracardiac uptake which might degrade the image quality. Tc-99 m-sestamibi and Tc-99 m-tetrofosmin are known to show nonspecific uptake in malignancies such as breast cancer and lymphoma; therefore, any abnormal extra-cardiac uptake should be reported and thoroughly evaluated (Fig. 1). Next, the sinogram may be reviewed for any break or discontinuity in its normal smooth curvature, which signifies patient motion.

Fig. 1.

Single frame from a rotating cinematic display of a raw SPECT image dataset showing abnormal uptake of 99mTc sestamibi in the right breast (arrow) of a patient with biopsy confirmed breast malignancy

Stress and rest perfusion images are then evaluated in the traditional cardiac planes (i.e. short axis, horizontal long axis, and vertical long axis) to look for areas of decreased radiopharmaceutical concentration (i.e. perfusion defects). If the perfusion defect is worse in stress images as compared to rest images (i.e. reversible defect), it indicates myocardial ischemia (Fig. 2). If the perfusion defect appears identical on both stress and rest images (i.e. fixed defect), it could either represent infarcted myocardium or an attenuation artefact, which can be differentiated by reviewing ECG gated stress images. An attenuation artefact will exhibit normal wall motion and normal wall thickness, whereas an area of infarction will show abnormal wall motion and wall thickening. Alternatively, attenuation corrected stress and rest images are also of great value because they correct a defect that is caused by attenuation artefact.

Fig. 2.

Attenuation-corrected stress (StrAC)-rest (RstAC) myocardial perfusion imaging in short axis (SA; A), vertical long axis (VLA; B), and horizontal long axis (HLA; C) demonstrates a large reversible perfusion defect (arrows) in the left circumflex artery (LCx, inferoseptal wall) and left anterior descending artery territory (LAD, apex and anteroseptal segments). Polar map display (D) of LV radiotracer distribution during stress and rest. Numbers represent the normalized (percentage of maximal left ventricular uptake) radiotracer activity in each segment

For semiquantitative segmental analysis, polar maps are used. Polar maps (Fig. 3) are a two-dimensional display of the three-dimensional radiotracer distribution in the left ventricle. The cardiac apex occupies the centre, while the basal regions occupy the outermost parts of the polar plot. In a standard 17-segment model, the left ventricle (LV) is divided into 17 segments on a polar plot, with each segment representing ~ 6% of the LV myocardium. Myocardial perfusion values displayed on polar maps are normalized (i.e. percentage of the maximal left ventricular uptake) to the region of myocardium that has the highest counts and it is presumed that the region with the greatest activity has the best perfusion. As such, patients with a global reduction in myocardial perfusion (“balanced” ischemia due to multivessel disease or widespread CAD) may remain undetected or the extent and severity of the perfusion defect/CAD may be underestimated.

Fig. 3.

Polar (a-b) and three-dimensional (c) quantitative images demonstrate the value of SPECT in predicting the extent, severity, and reversibility of the perfusion defect—that is, the total ischemic burden. Standard nomenclature for the 17 segments is outlined above

For segmental scoring of the intensity of radiopharmaceutical uptake (perfusion), specific scores have been developed. One such scoring system compares the normalized polar map of the patient with a database (i.e. normalized polar maps obtained from subjects with verified normal LV perfusion) and assigns a perfusion score (between 0 and 4) to each of the 17 segments (Fig. 4). A score of 0 indicates, no statistically significant difference between the patient’s perfusion data and the database norm. Scores of 1, 2, and 3 represent mild, moderate, and severe reduction in perfusion respectively and a score of 4 indicates absent perfusion. A “summed stress score” (SSS) is obtained by adding the values attributed to each segment during the stress phase. This is repeated during the rest/redistribution phase, to obtain the “summed rest/redistribution score” (SRS). The difference between the SSS and SRS is known as the “summed difference score”. It must be emphasized that the polar maps are only complementary to promote more accurate and consistent reporting and do not replace the perfusion images. The reporting physician must review both the perfusion images and polar maps carefully before writing the final report.

Fig. 4.

Image of the polar plot depicting the perfusion score of each segment during the stress and rest phases of the same MPI study as in image 2

The final nuclear cardiology report should include information on perfusion defect with respect to its size, severity, location (likely vascular territory involved), and reversibility as well as information on LV cavity size, LV wall motion, presence or absence of lung or right ventricle (RV) uptake (poor prognostic indicator in Tl-201 perfusion imaging), stress protocol used (whether exercise of pharmacological), duration of stress/exercise, HR and blood pressure at baseline and peak exercise, relevant ECG changes, and patient symptoms during stress, if any [18, 19].

Limitations

The major drawback of conventional MPI using SPECT is that it measures relative perfusion, i.e. it compares the regional myocardial perfusion relative to the region with the highest tracer uptake (perfusion). Thus, a patient with a multivessel disease or a global reduction in the myocardial perfusion may remain undetected or the extent of CAD may be under-estimated. In such cases, assessment of the transient ischemic dilatation (TID), apparent dilation of the LV cavity on stress, due to subendocardial ischemia and post-stress LV dysfunction (i.e. fall in LVEF on stress compared to rest), may help detect multivessel CAD [20].

Moreover, MPI using PET and solid-state gamma cameras with their ability to quantify MBF may help overcome these drawbacks of traditional SPECT MPI imaging.

Interpretation of PET viability study

Currently, using PET with the perfusion and metabolic tracers is the gold standard for the assessment of myocardial viability. It is based on the principle that a healthy myocardium preferentially utilizes fatty acids as the energy source, whereas in the ischemic state, the metabolism is shifted towards glucose as the preferred energy source. FDG-PET can be used to detect this shift in metabolism in the viable myocardium.

It has been reported that 31 to 61% of people with ischemic LV dysfunction have 25 to 30% of viable myocardium. This is believed to be the minimum amount of viable myocardium required for functional recovery after revascularization [21].

For the subgroup of CAD patients with severe LV dysfunction (ejection fraction < 30%) and symptoms of heart failure refractory to medical therapy, the remaining options are revascularization or heart transplantation [22]. Lack of donor hearts, dearth of finances, and complications associated with life-long immunosuppression limit the chances of a successful heart transplant. Coronary artery bypass grafting (CABG), on the other hand, is relatively inexpensive and, in our own experience, has been found to be a feasible option for such patients.

Revascularization has been associated with improved survival in those patients with viable myocardium. [23] The probability of reversing LV remodelling and improving LV systolic function with medical therapy and/or revascularization is greater with increased proportions of viable myocardium on noninvasive imaging. In such circumstances, a high-quality test is critical to assess the presence or absence of hibernating myocardium, to determine whether these patients should undergo revascularization, receive a heart transplant, or remain on medical therapy. Allman et al. [24] demonstrated in a meta-analysis of mostly observational studies that patients with viability treated by revascularization had a near 80% reduction in mortality. Those without viability had no difference in the mortality between medical therapy and revascularization.

To date, there have been two major prospective randomized trials comparing the outcome in patients with ischemic heart failure who underwent viability assessment: Positron emission tomography And Recovery following Revascularization phase 2 (PARR-2) [25] and Surgical Treatment for Ischemic Heart Failure (STICH) viability substudy trials [26].

STICH was a multicenter, unblinded, randomized control trial evaluating the role of surgical coronary artery revascularization in ischemic cardiomyopathy with ejection fraction (EF) ≤ 35%. The main finding was that after a median follow-up of 10 years, surgical revascularization improved all-cause mortality and cardiovascular mortality. A substudy of this trial assessed the 601 patients who underwent myocardial viability evaluation, which revealed that the mortality was lower in those with viable myocardium (37%) versus those with nonviable myocardium (51%), but it did not reach a statistical difference.

PARR-2 was a randomized controlled trial to assess the effectiveness of 18-F-FDG-PET-assisted management in patients with severe ventricular dysfunction and CAD. Patients were randomized into management assisted by FDG-PET (n = 218) or standard care (n = 212). At 1 year, the PARR-2 trial did not show a significant difference between the groups in the primary outcomes that included death for cardiac causes, acute myocardial infarction, or hospital stays for cardiac cause (30% versus 36% p = 0.15). In the PET group, however, there was a significant decrease in primary outcome over the follow-up period.

Although the value of viability imaging may have been called into question by the STICH and PARR-2 trial, several studies have reinforced the relationship between the extent of hibernating myocardium and improvement in patient outcome, LVEF, and quality of life. In general, there is an accepted utility in using viability imaging in patient populations where decisions for revascularization are most difficult.

Clinical applications in adult cardiac disease

1. Diagnosis of CAD — stress and rest or redistribution myocardial perfusion is well recognized as an imaging modality for the detection of CAD (Table 3) [27].

• 2.Prognosis and risk stratification in CAD

Table 3.

Sensitivity and specificity of various tests in the diagnosis of CAD

Test	Sensitivity	Specificity
Exercise Treadmill Test	68%	77%
Exercise SPECT MPI	88%	70%
Vasodilator SPECT MPI	89%	77%
Dobutamine SPECT MPI	84%	79%
Vasodilator Rubidium-82 PET	90%	88%
Stress Echocardiography	84%	70–77%

Stress testing variables associated with a worse prognosis [28]
Perfusion parameters
• Multivessel disease pattern
• Large reversible (ischemic) defect
• Large scar > 14% of left ventricle
• Transient left ventricular dilation with stress
• Right ventricular uptake
• Resting left ventricular dysfunction
• Pulmonary uptake of the tracer
Nonperfusion parameters
• Poor exercise capacity
• Angina at a low workload
• Dynamic ST-T segment depression > 3 mm with exercise
• Exercise-induced ventricular arrhythmia
• Vasodilator stress induced ST-segment depression > 1 mm In general, in our experience, we have found out that patients with mild to moderately reduced perfusion or those with small perfusion defects (involving < 10% LV myocardium) on stress MPI can be medically managed, while those with reversible perfusion defects of moderate to severe intensity or reversible perfusion defects involving > 15% of the LV myocardium will benefit from revascularization [29]

• 3.Evaluation of the need for intervention — when epicardial luminal narrowing exceeds 50%, it is commonly paralleled by a decrease in MBF reserve and the manifestation of myocardial ischemia. It should be kept in mind, however, that despite the well-described inverse relationship between severity of coronary artery stenosis and myocardial flow reserve (MFR), a high degree of variability in the individual flow responses may exist, in particular when the coronary artery luminal narrowing is of intermediate severity. [30] In the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial [31] that was concluded in 2008, it was found out that the medical treatment of cardiovascular risk factors in patients with SPECT-determined regional myocardial perfusion defects over a 1-year follow-up was associated with a significant reduction in an ischemic burden and a favourable clinical outcome.
• 4.Evaluation of myocardial revascularization — when properly timed, stress myocardial scintigraphy can document procedural success and can diagnose restenosis, defined angiographically as a return to more than 50% stenosis. Stress MPI is superior to both clinical findings and exercise ECG in predicting graft patency.
• 5.Myocardial viability assessment — in certain circumstances, it is important to distinguish fixed perfusion defects caused by a myocardial scar from fixed defects representing viable but nonfunctional salvageable myocardium. This is especially true when revascularization procedures are under consideration as a means of restoring perfusion. [32] According to McArdle et al., [33] viability scan is appropriate in patients with known or strongly suspected ischemic HF (New York Heart Failure Association) NYHA ≥ II, moderate to severe left ventricular dysfunction (LVEF < 40%), moderate to large perfusion defects, no significant ischemia, significant comorbidities, and/or poor vessel targets. According to the American College of Cardiology/American Heart Association/American Society for Nuclear Cardiology (ACC/AHA/ASNC) Radionuclide Imaging guidelines published in 2003, [34] Nuclear imaging for the assessment of myocardial viability for consideration of revascularization in patients with CAD and LV dysfunction who do not have angina is a class 1 recommendation. According to the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) heart failure guidelines published in 2013, [35] viability assessment is reasonable before revascularization in HF patients with CAD, forming a class IIa recommendation.
• 6.Evaluation of acute chest pain in the emergency department
• 7.Preoperative risk assessment for noncardiac surgery
• 8.Left bundle branch block (LBBB) with CAD — because LBBB renders ECG stress testing nondiagnostic, a noninvasive diagnosis of CAD is often sought by using radionuclide MPI. Patients with LBBB may demonstrate reversible septal or anteroseptal perfusion abnormalities during maximal exercise stress in the absence of demonstrable CAD.
• 9.Fundamental assessment of biventricular function and copresence of CAD in valvular heart disease and patients with heart failure
• 10.Infective endocarditis (IE) and cardiovascular implantable electronic device infection (CIED) — although echocardiography remains an important initial test in the evaluation of these patients, cardiac imaging plays an important role in the diagnosis and management of patients with CIED infection or IE. Both ¹⁸F-FDG PET and radiolabelled white blood cell single-photon emission computed tomography/computed tomography (WBC SPECT/CT) have been studied in these situations. In their 2015 guidelines for the management of IE, the European Society of Cardiology (ESC) addressed the use of nuclear medicine imaging for the diagnosis of IE [36].
• 11.Cardiac transplant evaluation — Tc-99 m-labelled annexin V is used to identify graft rejection noninvasively. Apoptosis exposes a phospholipid phosphatidylserine (PS) that is normally confined to the inner leaflet of the cell membrane bilayer. Annexin’s high affinity for binding to PS is the basis for apoptosis imaging [37].

Clinical applications in congenital heart disease

1. Coronary artery anomalies — the diagnosis of anomalous origin of a coronary artery is usually made through echocardiography or cardiac catheterization or both. Myocardial perfusion scintigraphy can be useful in the postoperative follow-up, evaluating the extension of the ischemic myocardium, which is related to the delay in functional recovery. This information can be integrated with the presence of viable myocardium on FDG imaging, providing valuable prognostic data [38].

2. Transposition of great arteries — assessment of myocardial perfusion is often required during the follow-up after surgical interventions involving mobilization or reimplantation of coronary arteries or both. Patients treated with arterial switch operation often show reduced coronary flow reserve and perfusion defects during the follow-up [39].

3. Kawasaki disease — it is an acute, self-limiting medium vessel vasculitis with a peak incidence in children below 8 years of age. The role of myocardial perfusion scintigraphy is mainly during the follow-up of patients with persistent coronary aneurysms, to detect the presence of ischemia and to evaluate its extension [40].

4. Tetralogy of Fallot (TOF) — most of the indications for which nuclear scintigraphy was used in the past have been largely replaced by magnetic resonance imaging (MRI) in the current era. However, nuclear scintigraphy retains its role in the assessment of right ventricular function particularly in children who are claustrophobic and also children with MRI incompatible pacemakers. Also, nuclear scintigraphy has its role in differential lung perfusion especially in presence of left pulmonary artery stenosis and it is also used in the evaluation of pulmonary ventilation as well as ventilation/perfusion mismatch which is frequently present in cases of repaired TOF [41].

5. Right ventricular overload — normally RV is not visualized on MPI. RV is visualized in pressure and volume overload seen as interventricular septal flattening (inverted D sign). In cases where morphological RV functions as a systemic ventricle, MPI can assess perfusion defects [42].

Radionuclide imaging of other systems

Radionuclide lung imaging

Gravity and patient position have a significant impact on both ventilation and perfusion. Normally, ventilation in the lower portion of the lung is about 150% of that in the apex.

Pulmonary perfusion is also unevenly distributed throughout the lungs. Maximal pulmonary blood flow normally occurs in the lung zone bracketing the junction of the lower third and upper two-thirds of the lungs. In the normal, upright patient, both ventilation and perfusion increase progressively from the lung apex to the bases; however in the supine position, it is less prominent [43].

Radiotracers

Perfusion imaging agents

Technetium-99 m Macro Aggregate Albumin (Tc-99 m MAA ) is the radiopharmaceutical used for pulmonary perfusion imaging. It localizes by the mechanism of capillary blockade.

Tc-99 m MAA should be injected during quiet respiration, with the patient supine to minimize the normal perfusion gradient between the apex and lung base.

Ventilation imaging agents

1. Radiolabelled aerosols — Tc–diethylenetriamine pentaacetic acid (DTPA) aerosol

2. Radioactive gases — Xenon-133 (¹³³Xe)

Clinical applications

1. Pulmonary embolism — despite the increasing use of spiral computed tomography (CT) angiography, the ventilation/perfusion lung scan continues to play an important role as a noninvasive procedure for the diagnosis of pulmonary emboli. A positive predictive value of a perfusion scan as compared with combined ventilation/perfusion (V/Q) images can be improved from 59 to 92% excluding a significant number of nondiagnostic scans. Currently, the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED II) criteria is used for the interpretation of V/Q scan. Although computed tomography pulmonary angiogram (CTPA) is the current gold standard, there are various clinical situations in which VQ scan is preferred, particularly renal failure, contrast material allergies, young females, and patients who cannot fit into the CT scanner. Since VQ scan can demonstrate early changes in lung perfusion and ventilation, there has been an increase in appreciation of its value in the evaluation of lung transplants in recent times. It is used in pre-transplant planning and in post-transplant evaluation, not only for the detection of complications but also as a surveillance tool to detect early subclinical signs of allograft dysfunction [44].

   VQ scan has a 50-fold lower radiation dose to the breast as compared to the conventional CT [45, 46].

   1. During the interpretation of ventilation-perfusion scintigraphy studies, ventilation and perfusion imaging are used in conjunction. Three types of defects can be found: (Fig. 5)

      • i.
        Matched — ventilation and perfusion defects are concordant with each other. This occurs when the perfusion defect is in correspondence with the ventilatory abnormality.
      • ii.
        Mismatched — defect in perfusion with either normal or near-normal ventilation. Mismatched defects can be seen in pulmonary embolism, veno-occlusive disease, tumour obstructing an artery, or radiation therapy.
      • iii.
        Reverse mismatched — defect in ventilation with either normal or less severe corresponding perfusion defect
   2. Defect size can be calculated as:

      • i.
        Large — more than 75% of segment
      • ii.
        Moderate — 25 to 75% of segment
      • iii.
        Small — less than 25% of segment

2. Modified PIOPED II criteria — classifies V/Q scan as nondiagnostic, normal, very low probability, and high probability.

3. Planning lung resection for malignancy — the use of quantitative lung perfusion scanning has been of help in determining a patient’s ability to undergo resection of the lung. If the region to be resected has a similar distribution of ventilation and perfusion as does the rest of the lung, the postoperative reduction in lung function will be proportional to the volume of the resection. Pulmonary function will not be affected by the resection if the region to be removed has no significant function with regard to ventilation-perfusion distribution. Postoperative pulmonary function will be increased when the region to be resected contains a major impediment to the distribution of ventilation and perfusion. The minimum pulmonary function that is sufficient for a patient to carry on with their routine activities is not well documented. [47] Olsen et al. [48] reported a forced expiratory volume (FEV) during the first second of 0.8 l as the minimum postoperative ventilation volume that can accommodate cardiac output without producing arterial hypoxemia or pulmonary hypertension.

4. Assessment for branch pulmonary artery stenoses is important in several congenital cardiac conditions including TOF (usually central stenoses), arterial switch for d-transposition with subsequent pulmonary artery compression or stenosis, and Williams syndrome (usually peripheral stenoses) [49, 50].

5. Degree of intracardiac shunting — in this era where cardiac MRI is well established, the presence of intracardiac shunts may be detected by scintigraphy. When right to left shunting is evident, the magnitude of the shunt may be quantitated by comparing lung counts to brain counts [51].

6. Chronic obstructive pulmonary disease — pulmonary ventilation imaging is most helpful in characterizing the regional distribution of airway abnormalities and, to a lesser extent, in delineating the clinical severity of the disease.

7. Fontan circulation — lung perfusion scanning has been a standard procedure in the evaluation of pulmonary blood flow distribution in patients corrected following the principle of Fontan circulation [52].

Fig. 5.

Axial SPECT (A), corresponding CT (B), and fused SPECT/CT (C) images showing a segmental wedge-shaped perfusion defect (arrow) in the anterior segment of RUL with no definite morphological abnormality on the corresponding CT images — a mismatched defect. The scan is positive for pulmonary embolism according to the PISAPED criteria. Axial SPECT (D), corresponding CT (E), and fused SPECT/CT (F) images of the same patient showing reduced perfusion in the inferior lingular segment of LUL with emphysematous/bullous changes in the corresponding CT images (arrowhead) — a matched defect

Radionuclide imaging of lymphatic system

Inadvertent transection of the thoracic duct or its tributary can result in chylothorax. Radionuclide scintigraphy of the lymphatic system (lymphoscintigraphy) is a method of confirming the diagnosis and potentially localizing the site of the leak.

Radiotracers

Tc-99 m-labelled tracers such as sulphur colloid, albumin‐nanocolloid, phytate, and antimony sulphide are the most commonly used agents. The radiotracer can be injected intradermally or subcutaneously. Intradermal injections seem to be associated with rapid lymphatic transport and better tracer kinetics than a subcutaneous method. [53] Usually, a subcutaneous injection of the tracer is given in the second webspace of both hands or the first web space of the foot and anterior and posterior partial whole‐body planar images are acquired using a high‐resolution computerized gamma camera.

Clinical applications

1. Chylothorax — the tracer is injected subcutaneously into the dorsum of the foot and passes spontaneously into adjacent lymphatic vessels. This makes it much more convenient than X-ray lymphangiography which is both tedious and technically difficult as it requires injection of contrast directly into lymphatic vessels. After a 30-min delay, anterior and posterior images of the chest are acquired by dynamic planar imaging at 1-min intervals for up to 60 min [54, 55].

2. Protein-losing enteropathy (PLE) is a condition in which there is a chronic leak of protein into the gut either due to loss of integrity of the mucosal barrier or due to secondary lymphangiectasia from elevated central venous pressures. PLE has also been seen in Fontan patients, transposition patients palliated with the Mustard/Senning procedure, in TOF with volume-overload right heart failure, and in isolated severe tricuspid regurgitation. Scintigraphy has been employed in the past to make the diagnosis of PLE, although its use is now primarily historical.

Author contribution

1. AKM — manuscript writing.

2. HS — conceptualization.

3. VB — manuscript writing.

4. JR — manuscript editing.

5. AS — manuscript editing.

Availability of data and material

Yes.

Code availability

Not applicable.

Declarations

Ethical approval

This manuscript was approved by the departmental ethics committee.

Informed consent

Not applicable.

Conflict of interest

None.