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To review the wealth of knowledge associated with myocardial perfusion scintigraphy and the newer positron emission tomography techniques
To understand the role of Nuclear Cardiology with other complementary techniques
To appreciate the other expanding roles of Nuclear Cardiology in heart failure, device infection, sympathetic innervation and dyssynchrony.
Nuclear Cardiology is the most frequently used functional imaging test in the UK and throughout the world. It was the first test used to localise and quantify myocardial ischaemia. The wealth of evidence related to diagnosis and long-term prognosis in varying subgroups is unparalleled.1 Radionuclide ventriculography (RNV) provides a geometrically independent assessment of ventricular function which remains the gold standard. Nuclear techniques can be used in patients with renal dysfunction, obesity, dysrhythmias and claustrophobia.
Up until a few years ago, gamma camera hardware relied on the inexpensive technology of the 1960s, which has only recently undergone a revolution in response to improvements to complementary modalities. Radiation doses continue to fall.
Exciting developments in positron emission tomography (PET) and hybrid imaging are promising a bright future with a potential resurgence in popularity for this ‘workhorse’.
The mainstay of Nuclear Cardiology, myocardial perfusion scintigraphy (MPS), is performed using single photon emission computed tomography (SPECT) via a gamma camera. Worldwide, there is significant interest and investment in the role of PET in the assessment of myocardial disease.
Gamma cameras have used the scintillation properties of sodium iodide (NaI) since the 1960s. Solid-state detectors using cadmium zinc telluride (CZT) are available on modern systems which allow for a significant improvement in sensitivity, additional radiation dose reductions or reduced scanning time.2 On a new CZT system, a scan time of 4–6 min is achievable with a much lower injected dose than that used for a NaI gamma camera.
Iterative reconstruction with resolution recovery software is available for all modern systems. These computer programs maintain diagnostic sensitivity with subsequent additional radiation dose reductions and shortened acquisition times.3 In the UK, the dose reference limits (DRLs) are determined by the Administration of Radioactive Activities Committee. These DRLs are the maximum recommended injected radiation dose and are routinely not achieved as a result of adherence to as low as reasonably achievable (ALARA) principles. Stress-only protocols have also resulted in a drop in injected radiation dose down to as low as 0.99 mSv.4 Nevertheless, radiation is applied to the patient, and therefore each scan must be justified.
Although physiological stress remains the best option for patients undergoing MPS, new selective A2a receptor agonists, for example, regadenoson have transformed vasodilator stress protocols. Mild–moderate airways disease is no longer a contraindication, and bradycardia is much less frequent.5 Regadenoson can also be used safely in conjunction or immediately after physiological stress.6
The role of adenosine MPS immediately after acute myocardial infarction has been thoroughly evaluated and demonstrating good risk stratification as well as safety even when performed at day 1 post admission.7
The standard SPECT tracers for MPS (201Thallium, 99mTc-sestamibi and 99mTc-tetrofosmin) have been available for decades and are by no means perfect. The 99mTechnetium agents have a shorter half-life and a better photon energy window that suits gamma cameras, but have a lower extraction fraction and can underestimate myocardial flow compared with 201Thallium. Research into newer SPECT agents has been slow, but new tracers are in the pipeline.8–10
PET tracers are undergoing a revolution. The reliance on cyclotron-derived flow tracers (13Nitrogen ammonia and 15Oxygen water) has significantly hampered the ability to test myocardial perfusion using PET. However, the introduction of 82Rubidium has advanced PET myocardial perfusion to the forefront.11 Increasing interest in research applications beyond 18F-fluorodeoxyglucose (FDG) is an exciting area of research especially with the rediscovery of 18F-sodium fluoride (NaF) for the detection of hydroxyapatite in higher risk coronary plaques and aortic stenosis.
Table 1 lists the commonly used tracers and some of those in development for SPECT and PET.
The main use for nuclear techniques has been the identification of myocardial ischaemia, replacing the exercise treadmill electrocardiogram test to improve diagnostic accuracy and confidence.12 Hypoperfused areas at stress can be quantified easily and automatically. An increasing ischaemic burden is an independent indicator of major adverse cardiovascular events (MACE), irrespective of the method of ischaemia reduction, based on retrospective observation.13 MPS has also traditionally identified higher risk patients using indirect measures such as transient ischaemic dilatation, end-systolic volume >70 mL and lung uptake with 201Thallium.
Traditionally, a normal MPS with SPECT was reported to confer a good prognosis with a cardiac event rate of <1% per annum (p.a.) over a long warranty period. However, further detailed studies have confirmed that the number of risk factors, exercise capacity and heart rate response to vasodilators are independent predictors of MACE and affect the prognostic information provided by the MPS scan. Therefore, patients with a normal MPS and an exercise capacity of at least 10 metabolic equivalents (METS) have a cardiac death rate of <0.1% p.a.14 All-cause mortality with normal exercise MPS has been assessed over 11 years. In this study, the annual death rate in the absence of risk factors and the ability to achieve 9 METS was 0.2%. At least two risk factors (from diabetes, smoking or hypertension) and an exercise capacity of <6 METS resulted in an annualised death rate of 1.6%.15 Long-term outcome data over 11 years confirm the value of MPS data in patients with limited exercise capacity via multivariate analysis.16 However, a blunted heart rate response to vasodilator stress is an independent predictor of cardiac mortality.17 Therefore, MPS is now a mature and well-refined technique that incorporates the traditional assessments of ischaemic burden and left ventricular (LV) function and improves its prognostic value by using clinical variables such as risk factors, exercise capacity and heart rate response.
CZT gamma cameras are a relatively new technology but have already proved their worth in terms of diagnostic accuracy and prognostic ability as well as risk stratification according to the degree of ischaemic burden.18
Cardiac PET perfusion is more accurate and has a lower radiation dose compared with SPECT.19 PET allows for absolute flow quantitation and the subsequent measure of myocardial flow reserve (MFR). This has been tested in different areas, but one of the most interesting areas appears to be the relationship between flow reserve, atherosclerotic burden and revascularisation. In this study, the authors identified that flow reserve was associated with outcomes that were independent of the angiographic severity of disease and also indicated that patients with low flow reserve undergoing CABG had improved event rates compared with those undergoing PCI.20 Not unexpectedly the conventional relationship between angiographic severity and flow limitation/reserve is challenged, confirming the utility of understanding both flow reserve and atherosclerotic burden in the management of coronary artery disease (CAD).
One of the most important differences between nuclear cardiology and other techniques is the ability to easily quantify ischaemic 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 ischaemic burden is directly related to prognosis.21 Diagnostic certainty improves when automatic quantitative analysis is used to assist the reporter.22 Machine learning algorithms may eventually replace experienced readers in the future.23
Ischaemic defects are identified in patients with angiographically unobstructed epicardial vessels. This is thought to represent microvascular disease. PET perfusion through absolute flow quantitation at rest and at peak vasodilator stress allows for estimation of MFR. An impaired reserve is a sensitive predictor of cardiac death and progression to heart failure irrespective of the severity of epicardial coronary disease.24
Nuclear Cardiology techniques are ideally suited to assessing myocardial cell integrity and therefore viability. 201Thallium and the 99mTechnetium agents are taken up by both alive and dysfunctional myocardial cells as opposed to assessing scar burden which is the characteristic of late gadolinium-enhanced cardiac magnetic resonance imaging (CMR). The nuclear-based techniques have a higher sensitivity for detecting hibernating myocardium.25 ,26
FDG-PET is considered the gold standard method for viability assessment. The classic perfusion–metabolism mismatch identified by FDG-PET is a hallmark of myocardial viability. Although the original PARR-2 study did not confirm the primary endpoint, the subsequent post hoc intention to treat analysis confirmed that FDG-PET was able to predict outcome with revascularisation in patients with ischaemic cardiomyopathy.27
RNV remains one of the gold standard methods for the measurement of LV ejection fraction (LVEF). It was the first non-invasive method to assess LVEF, and newer techniques have only just achieved a similar level of reproducibility and error. The superiority of not having to rely on edge detection, the hallmark of echocardiography, magnetic resonance and computed tomography (CT), has meant that RNV has remained a powerful, reliable and accurate method for LVEF assessment. However, improvements in CMR and echocardiography have meant that these non-ionising techniques are used in preference to RNV. Significantly, advances in gamma camera technology mean that a LVEF acquisition over 5 min is possible at around 1 mSv.28 These impressive dose reductions and reproducibility may bring resurgence for this technique, especially in the chemotherapy patient undergoing evermore cardiotoxic regimes.
Ventricular volumes are easily calculated with both RNV and MPS/PET techniques using automated software algorithms. The additional prognostic value of end-diastolic and end-systolic volumes (ESV) to LVEF has been clearly defined. With MPS, an ESV >70 mL with a LVEF <45%, a fourfold increase in cardiac mortality rate than that with an ESV <70 mL.29 LV mass can also be identified with MPS, showing good correlation with echocardiography.30
Comparison of LVEF between RNV, echocardiography and CMR has confirmed that the volumes and ejection fraction are not interchangeable.31 LVEF derived from nuclear techniques tends to be higher than echocardiography and CMR, especially in smaller female patients.
MPS has been used to determine aetiology of new-onset heart failure.32 In this trial, MPS had an excellent negative predictive value (NPV) for the detection of extensive CAD causing new-onset heart failure. Preserved systolic function was identified in one-third of the patients with 41% having normal perfusion. Nuclear techniques allow for the identification of four crucial variables: ischaemia, viability, innervation and inflammation, which ultimately aid diagnosis, prognostication and treatment strategy.33
Although of limited use in routine clinical practice, SPECT can be used to assess LV myocardial dyssynchrony using a variety of commercially available software programs. These programs can be applied retrospectively to standard acquisition SPECT datasets that have used conventional tracers for MPS. No special preparation or technique is required. The software essentially uses the phase histogram to calculate the global dyssynchrony and represent this visually (see figure 1). The beauty of this technique is that it can be performed before and after cardiac resynchronisation therapy (CRT) implant and does not suffer from poor echocardiographic windows. More recent data have focused on RNV to successfully predict survival among patients with dyssynchrony undergoing CRT.34
123I-metaiodobenzylguanidine (mIBG) cardiac imaging can identify areas of myocardium that have been denervated through myocardial injury/ischaemia. These areas remain denervated even after successful revascularisation, and the area at risk on the scan represents the initial area of injury. In the context of heart failure with reduced LV function, there is a clear ability of 123I-mIBG imaging to further risk-stratify patients and provide additional prognostic data over and above LVEF and B-type natriuretic peptide data. A denervated and impaired LV has a higher likelihood of mortality, dysrhythmia and hospital admission with heart failure. The ADMIRE-HF trial was the first large-scale study to identify this property of 123I-mIBG imaging in a prospective manner.35 123I-mIBG imaging can also be used to risk-stratify in both ischaemic and non-ischaemic heart failure.36 Further studies are underway to assess the usefulness of 123I-mIBG SPECT imaging in decision-making for implantable cardiac defibrillator (ICD) implantation.
Novel imaging of the left atrial sympathetic ganglions to guide the position of EP catheters during AF ablation is currently undergoing a UK-based clinical trial (NCT02267889).
SPECT has been used to identify myocardial perfusion abnormalities associated with ventricular arrhythmias for some time. Inducible ventricular tachycardia (VT) is usually identified in the peri-infarct (or hypoperfused) zone on the resting scan. While CMR has been used in more contemporaneous practice, it is clear that it detects scar. Sympathetic innervation with either SPECT or more recently PET (with its superior spatial resolution) may provide better insights into VT substrate formation, especially if metabolic, perfusion and innervation variables are all identified.37 Clinical studies assessing perfusion, innervation and metabolism using PET have already been used to identify denervated but viable myocardium which appears to be particularly prone to ventricular arrhythmias requiring ICD therapy38 (figure 2).
FDG-PET is now almost a routine test in specialist centres for the management of patients with cardiac sarcoidosis.39 FDG-PET allows for both identification of inflammation (intracardiac and extracardiac) and management of immunosuppression, where no biochemical marker is available to guide therapy.40
Cardiac device infection is becoming an increasing problem, given the ageing population, increasing patient comorbidities and increasing concerns over antimicrobial overuse and resistance. Determining the presence of implanted device infection is straightforward in most cases. However, diagnostic doubt does arise especially in more indolent cases or patients with potentially multiple sources of infection. The NPV of FDG-PET is high and should be considered in challenging cases. Even if clinical signs of an implanted device infection are underwhelming, then PET can still pick up cases of pocket infection.41
PET has also been used to increasing effect in prosthetic valve endocarditis (PVE) where echocardiographic imaging suffers from reduced diagnostic sensitivity.42 The sensitivity for the identification of PVE rose from 70% to 97% when FDG-PET was added to their diagnostic algorithm. Figure 3 demonstrates the use of FDG-PET in a diagnostically difficult PVE case, and found it very useful to identify the extracardiac sources of infection.43 Radiolabelled leucocyte SPECT imaging has also been shown to have an excellent specificity regarding PVE.44
European Society of Cardiology guidelines discuss the role of FDG-PET and leucocyte SPECT in cases of ‘possible’ infective endocarditis to identify the potential sources of infection.45 An algorithm for the investigation of possible PVE using PET and SPECT imaging has been proposed.46
Cardiac transthyretin (TTR) amyloidosis
Researchers in Italy noted cardiac uptake on 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) bone scans.47 The cardiac uptake of DPD has been recognised to be due to the presence of transthyretin (TTR) amyloidosis. This is an increasingly important and common disease state of the elderly that is present in 6% of patients with severe aortic stenosis undergoing valve replacement surgery48 and 13% of patients presenting with heart failure with preserved ejection fraction (HFPEF) to a centre in Spain.49 A much higher rate of pacemaker implantation was identified. The median survival for a diagnosis of HFPEF with TTR amyloidosis is approximately 3 years, and there are clinical drug trials targeting the TTR amyloid protein. A non-invasive diagnostic algorithm has been proposed for cardiac ATTR amyloidosis, which relies on the 100% positive predictive value of DPD scintigraphy combined with the absence of a monoclonal protein in the serum and urine50 (figure 4).
18F-florbetapir is one of several PET agents targeted at the amyloid protein. Early studies suggest it may have a role, however the ease of DPD imaging for ATTR amyloidosis may restrict its clinical use.51
Combining nuclear datasets with CT or magnetic resonance imaging is a very attractive proposition. The images can be acquired on one machine, SPECT-CT, PET-CT or PET-MRI, or on individual machines and then sophisticated software to coregister the images. Alternatively, the data can be acquired separately and then used in diagnostic algorithms.
Combining anatomical and functional datasets has already been explored. In asymptomatic diabetics, there is added value of selective MPS once there is significant coronary calcification present.52 The value of atherosclerotic burden and ischaemia to determine survival post non-cardiac surgery is also available.53 A high coronary calcium burden with an abnormal MPS had four times the MACE rate of a patient with a lower calcium score and normal MPS.
Integrating MPS with CT coronary angiography (CTCA) has already demonstrated prognostic value in patients with known or suspected CAD.54 A stenosis with a corresponding perfusion defect had a much higher MACE rate (figure 5).
However, software fusion methods are not always straightforward, and can be time-consuming. Hybrid techniques have given variable results in the assessment of patients with chest pain with some early positive55 results for the hybrid imaging technique. Radiation burden to the patient with a combined MPS and CTCA approach does require justification, as the dose may vary anywhere between 2 and 20 mSv depending on a large number of variables.
Imaging of coronary plaque with FDG has been reported.56 This is mainly due to the uptake of FDG in metabolically active cardiomyocytes obscuring out the signal from the much smaller coronary plaque. There may be ways to modify the FDG uptake process, but for the moment the FDG approach to coronary plaque imaging is progressing slowly. Vascular studies using FDG have focused on the extracardiac arteries, for example, carotids which are easier to image.57 Uptake in these vessels was greater in those with recent embolic stroke.58
Calcific aortic valve stenosis is another area that has been assessed with FDG-PET as well as NaF.59 Increasing inflammation with FDG, and active calcification with NaF, was associated with a lower aortic valve area.
Researchers at the University of Edinburgh have taken a PET bone tracer (NaF) and identified its use in determining the activity of hydroxyapatite in both coronary plaque60 and aortic valve stenosis.61 A series of studies covering the basic and clinical science have brought this technology to the forefront of cardiac PET research. Comparison with FDG has confirmed that NaF is a more useful marker of calcific plaque activity in a small prospective trial62 (figure 6). This hypothesis will be tested in a larger multicentre trial for coronary disease (NCT02278211). Aortic valve stenosis has not been forgotten and will be assessed in a pharmacological trial investigating disease-modifying agents (NCT02132026).
Angiogenesis, hypoxia, apoptosis and macrophages
A whole host of PET tracers are working their way through preclinical trials to identify their worth in cardiovascular (CV) diseases; the list in table 1 is by no means exhaustive. The majority have been identified from oncology where angiogenesis and hypoxia can help identify areas of rapidly growing tumours. Translating these tracers to CV uses will take time and effort, but efforts are ongoing.63 The emergence of PET-MRI may provide a suitable test bed for these tracers where the combination of tissue characterisation from MRI and molecular imaging from PET promises much.64 ,65
The radiation dose has always been the Achilles’ heel in nuclear cardiology. There is considerable SPECT dose variation around the world; however, the latest published data confirm the lowest and strictest practices, with the highest quality images, are employed in Europe with a mean patient dose of 8.0 mSv in real-world collaboration.66 Newer hardware technology, software improvements and increasing use of stress-only protocols have meant that low doses are routinely achievable to a level reliably around 1–2 mSv. There is little data to support that all low-dose radiation exposure is harmful. However, rates of medical radiation exposure are increasing, more so with CT, and therefore all exposures must be justified and follow the principle of ALARA. Using statistical modelling may be one way of determining risk from radiation exposure.67 In this detailed analysis, all UK nuclear medicine techniques in 2010 were estimated to have caused an excess of 19 cancers. This is compared with 1861 with diagnostic radiology (eg, CT) and 1380 from radiotherapy. When these excess cancers are weighed up against the lives saved from heart disease, then one can see a fall in deaths from CV disease at the same time as increases in all forms of medical diagnostics and interventions (https://www.bhf.org.uk/research/heart-statistics, accessed 1 May 2016), although a causal link cannot be inferred.
The doses received from perfusion PET are lower than that from SPECT. 82Rubidium is approximately 4 mSv. 13N-ammonia and 15O-water are even lower. Modern 64 detector PET cameras also routinely undertake CT coronary angiography to allow anatomical as well as functional imaging.
‘Prediction is very difficult, especially if it’s about the future’ (Niels Bohr).
How apt. So, here are my predictions:
Cardiac positron emission tomography (PET)-CT and especially PET-MRI will emerge as useful research tools, especially with molecular markers.
The UK may struggle to provide cardiac perfusion PET-CT due to lack of capacity, lack of access to isotopes and lack of a coordinated nationwide approach to cardiac PET.
PET-CT will become almost indispensable in complex patients with possible prosthetic valve endocarditis, implanted device infections and sarcoidosis.
Single photon emission computed tomography imaging for ischaemic heart disease will probably not expand in the short term; however, the ownership of the technique will be more difficult to predict. Will UK cardiologists realise its true potential and engage with current services? How will nuclear medicine/radiology services react?
Hybrid imaging, where perfusion and anatomy datasets are combined, will become the standard approach in the assessment of coronary artery disease.
This review article covers a summary of some of the current and future uses of Nuclear Cardiology. To many, it is just a perfusion test. The versatility, reliability and future of the technology are without doubt. Whether it evolves to maintain its mantle of ‘run of the mill’ ischaemia testing or moves over into ‘exciting’ non-ischaemia fields that will stimulate further academic interest is a prediction too far.
Nuclear perfusion imaging is a powerful technique to identify ischaemia, viability and function of the heart, with an associated wealth of evidence.
Non-ischaemic indications are increasing and providing insights into complex conditions.
Positron emission tomography has enormous clinical and research potential.
Radiation doses are low and are falling.
Technology (cameras, tracers and stress agents) is transforming Nuclear Cardiology.
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