Nuclear Cardiology: State of the Art 2021 PDF

Nuclear cardiology: state of the art Rebecca Schofield,1 Leon Menezes,2 Stephen Richard Underwood ‍ ‍3 ►► Additional material for this paper are available online. To view these files, please visit the journal online (http://dx. doi.org/10.1 136/heartjnl- 2019-315628). 1 Department of Cardiology, North West Anglia NHS Foundation Trust, Peterborough, UK 2 Institute of Nuclear Medicine, University College London Hospitals NHS Foundation Trust, London, UK 3 National Heart and Lung Institute, Royal Brompton Hospital, Imperial College London, London, UK Correspondence to Professor Stephen Richard Underwood, National Heart and Lung Institute, Royal Brompton Hospital, Imperial College London, London, UK; s runderwood@imperial.a c.uk Received 15 June 2020 Revised 4 December 2020 Accepted 11 December 2020 Published Online First 22 January 2021 ABSTRACT Radionuclide imaging remains an essential component of modern cardiology. There is overlap with the information from other imaging techniques, but no technique is static and new developments have expanded its role. This review focuses on ischaemic heart disease, heart failure, infection and inflammation. Radiopharmaceutical development includes the wider availability of positron emission tomography (PET) tracers such as rubidium-82, which allows myocardial perfusion to be quantified in absolute terms. Compared with alternative techniques, myocardial perfusion scintigraphy PET and single photon emission computed tomography (SPECT) have the advantages of being widely applicable using exercise or pharmacological stress, full coverage of the myocardium and a measure of ischaemic burden, which helps to triage patients between medical therapy and revascularisation. Disadvantages include the availability of expertise in some cardiac centres and the lack of simple SPECT quantification, meaning that global abnormalities can be underestimated. In patients with heart failure, despite the findings of the STICH (Surgical Treatment for Ischemic Heart Failure) trial, there are still data to support the assessment of myocardial hibernation in predicting when abolition of ischaemia might lead to improvement in ventricular function. Imaging of sympathetic innervation is well validated, but simpler markers of prognosis mean that it has not been widely adopted. There are insufficient data to support its use in predicting the need for implanted devices, but non-randomised studies are promising. Other areas where radionuclide imaging is uniquely valuable are detection and monitoring of endocarditis, device infection, myocardial inflammation in sarcoidosis, myocarditis and so on, and reliable detection of deposition in suspected transthyretin-related amyloidosis. IMAGING TECHNIQUES Radiopharmaceuticals Single photon emission computed tomography (SPECT) tracers of myocardial perfusion are widely established, with 99mTc-methoxy-isobutyl-isonitrile (MIBI) and 99mTc-tetrofosmin used more frequently than thallium-201 chloride. This is in part due to the lower resolution and myocardial count rate of thallium and the perception of a higher radiation burden to the patient. In clinical practice all three give comparable results,2 and the radiation burden to the patient is similar using standard activities of 1000 MBq MIBI, 1000 MBq tetrofosmin and 80 MBq thallium at 6, 7 and 8 mSv, respectively.34 In patients with mild coronary disease and when myocardial viability is an issue, thallium is a superior tracer and should probably be used more commonly. The situation with positron emission tomography (PET) tracers of myocardial perfusion is more complex with 15O-water and 13N-ammonia only available in centres with an on-site cyclotron due to their very short half-lives. Rubidium-82 is easier with commercially available generators, although it is expensive and only cost-effective when patient throughput is high. Although not currently commercially available, there has been much interest in 18 F-flurpiridaz, since it promises to be available in single patient doses from off-site radiopharmacies. Its first phase III trial has completed but is not yet published and a second phase III trial is ongoing.5 If early promise is fulfilled the tracer is likely to become the default for routine MPS PET. 18 F-fluoride PET is also a developing technique with the potential to image calcification related to degenerative and even inflammatory processes such as atheroma (see online supplemental file). INTRODUCTION © Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ. To cite: Schofield R, Menezes L, Underwood SR. Heart 2021;107:954–961. 954 Myocardial perfusion scintigraphy (MPS) remains the most frequently used coronary function imaging test in the UK and worldwide.1 Alongside radionuclide-based techniques of imaging myocardial perfusion, techniques using echocardiography, MRI and CT have developed, providing several options for investigation of possibly symptomatic coronary artery disease (CAD). Table 1 gives an overall summary of their strengths, weaknesses, accuracy and risks. Similarly, radionuclide- based techniques have developed to provide quantification of myocardial perfusion in absolute terms and reliable imaging of myocardial inflammation or infection and amyloid deposition. The aim of this review is to consider the expanding role of radionuclide imaging in the subspecialty of cardiac imaging. Some areas are still in the early stages of development, with limited evidence to support their value, but only those that promise clinical utility are included. Myocardial perfusion PET Although less widely available than MPS SPECT, PET has advantages. Depending on the radionuclide used, it has higher sensitivity and spatial resolution, and the overall study time is less for the patient at ~30 min. In addition, PET scanners are routinely associated with X-ray computed tomography (CT), providing additional anatomical information and potentially even sequential MPS and CT coronary angiography (CTCA) studies. Most importantly perhaps it can quantify myocardial perfusion in mL/g/min and hence myocardial perfusion reserve (figure 1; see online supplemental file).6 PET quantification may not offer benefit over qualitative SPECT images in patients with single- vessel or double- vessel disease, but it provides important information in patients with more widespread disease where perfusion reserve may be compromised in all areas. Likewise, where small- vessel disease or perfusion from collaterals Schofield R, et al. Heart 2021;107:954–961. doi:10.1136/heartjnl-2019-315628 Heart: first published as 10.1136/heartjnl-2019-315628 on 22 January 2021. Downloaded from http://heart.bmj.com/ on September 3, 2023 at Universidad Nacional Autonoma de Mexico. Protected by copyright. Review Table 1 Summary of common cardiology investigations for suspected or known ischaemic heart disease Accuracy against invasive angiography Modality Strengths Weaknesses Risk to patient Exercise ECG ►► Rapid, inexpensive and available. ►► Valuable assessment of exercise time and symptoms. ►► Comorbidities may prevent maximal exercise. ►► ECG changes may be uninterpretable. ►► Low sensitivity and specificity, ►► 1 in 20 000 risk of major especially in women. adverse events. Stress echocardiography ►► Accessible and available. ►► Ventricular and valve function. ►► No radiation. ►► Variable local expertise. ►► Less commonly combined with exercise. ►► Dependent on imaging windows. ►► Confounded by LBBB and arrhythmia. ►► Myocardial perfusion not routine. ►► Highly specific. ►► Less sensitive. MPS SPECT ►► Widely applicable without significant contraindications. ►► Exercise and/or pharmacological stress. ►► Assessment of myocardial viability, ischaemic burden and function, including effect of collaterals. ►► 3D coverage supported by normal databases. ►► Extensive data on prognostic value. ►► Observational data on improving outcome. ►► Cost-effective for overall diagnosis and management. ►► Variable local expertise. ►► Long or 2-hour patient commitment. ►► Sometimes confounded by artefact. ►► Underestimation of global abnormalities possible. ►► Highly sensitive for significant ►► Radiation. disease. ►► 1 in 10 000 risk of major ►► Specificity may suffer in adverse events. inexperienced hands. MPS PET ►► Rapid, widely applicable, without significant contraindications. ►► Assessment of myocardial viability, ischaemic burden and function, including effect of collaterals. ►► 3D coverage supported by normal databases. ►► Validated quantification of myocardial perfusion and perfusion reserve. ►► Expensive. ►► Need for cyclotron or high- throughput for rubidium generator, hence not widely available. ►► Exercise stress not possible. ►► Stressor remote from patient. ►► Highly sensitive and specific. CMR perfusion ►► Increasingly available. ►► No radiation. ►► Assessment of myocardial scar, perfusion, and ventricular and valve function. ►► Myocardial characterisation. ►► Incidental findings, aorta, valvular heart disease, cardiomyopathy and so on. ►► Quantitative perfusion becoming available. ►► Variable local expertise. ►► Highly sensitive. ►► Contraindications of obesity ►► May be less specific. (magnet bore), claustrophobia and some device implants. ►► Limited myocardial coverage for perfusion. ►► Artefact with arrhythmia and limited breath-hold. ►► Rare contrast allergy. ►► 1 in 10 000 risk of major adverse events. ►► Radiation. ►► 1 in 10 000 risk of major adverse events. ►► Rare contrast allergy. ►► 1 in 10 000 risk of major adverse events. Continued Schofield R, et al. Heart 2021;107:954–961. doi:10.1136/heartjnl-2019-315628 955 Heart: first published as 10.1136/heartjnl-2019-315628 on 22 January 2021. Downloaded from http://heart.bmj.com/ on September 3, 2023 at Universidad Nacional Autonoma de Mexico. Protected by copyright. Review Table 1 Continued Accuracy against invasive angiography Modality Strengths Weaknesses CTCA ►► Rapid and increasingly ►► Artefact from calcium, available. breathing and arrhythmia. ►► Stress not required. ►► Downstream perfusion not ►► Plaque characterisation. assessed. ►► Functional assessment of ►► Anatomy does not prove cause individual lesions (CT-FFR, of symptoms. better with lesser disease). ►► Some valve and myocardial characterisation. ►► Incidental findings, lungs and so on. ►► Highly sensitive, hence high negative predictive value. ►► Less specific. ►► ►► ►► ►► Invasive coronary angiography ►► Widely available and applicable. ►► Stress not required. ►► Accurate assessment of coronary lumen with optional functional assessment of individual lesions by FFR. ►► Basic assessment of ventricular and valve function with pressure measurements. ►► Evidence of improved clinical outcome with coronary functional assessment. ►► Anatomical standard against which other tests have been compared, but now better recognition of the distinction between anatomy and function. ►► Radiation. ►► 1 in 1000 risk of major adverse events. ►► Expensive and resource-i ntensive. ►► Arterial puncture. ►► Downstream perfusion not assessed. ►► Anatomy does not prove cause of symptoms. Risk to patient Contrast allergy. Nephrotoxicity. Radiation. 1 in 10 000 risk of major adverse events. CMR, cardiovascular magnetic resonance; CTCA, CT coronary angiography; 3D, three-dimensional; FFR, fractional flow reserve; LBBB, left bundle branch block; MPS, myocardial perfusion scintigraphy; PET, positron emission tomography; SPECT, single photon emission CT. compromises anatomical techniques such as invasive or CT-fractional flow reserve. Thus, PET can distinguish between different phenotypes of ischaemic heart disease including microvascular disease that can coexist with epicardial coronary obstruction, and it identifies patients who may benefit most from revascularisation.78 Interactions between epicardial coronary disease, plaque morphology, impaired endothelial function, ischaemic burden, microvascular dysfunction and metabolic activity are all relevant to the development of angina, in particular for women in whom epicardial coronary stenosis may not be the most important factor.9 Other imaging approaches Other imaging approaches include solid state gamma cameras, which have considerably improved sensitivity and resolution compared with conventional cameras and show promise for dynamic SPECT imaging of quantitative myocardial perfusion (see online supplemental file). ISCHAEMIC HEART DISEASE The optimal management of patients with known or suspected stable CAD has been an open question for many years despite the prevalence of the condition. Over the last two decades practice was converging on a functional or ischaemia-guided approach with a move away from the anatomical approach of invasive angiography. The rationale for this is that angina is a symptom arising from disturbance of coronary function, and knowledge of coronary anatomy does not necessarily provide a diagnosis for the symptom of chest pain. In addition, the presence, extent and depth of inducible perfusion abnormalities are closely related to the likelihood of future coronary events in stable disease; hence, it is possible to identify patients who may have most to gain from 956 optimal medical therapy or from intervention.10 The greatest challenge of the functional approach is to identify patients at high risk where that risk might be reduced. However, more recent National Institute for Health and Care Excellence (NICE) guidance has swung the pendulum back towards anatomical assessment (see the following section).11 The ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial appeared to cast doubt on the value of routine coronary angiography in patients presenting with stable chest pain and moderate or severe inducible ischaemia, compared with initial medical therapy alone but with angiography reserved for patients whose symptoms are insufficiently controlled.12 However, many patients in the trial were only mildly symptomatic, and they did not necessarily have severe ischaemia judged by imaging as opposed to by treadmill exercise testing, and the specificity of stress echocardiography in women for anatomically significant coronary stenosis was particularly low.13 It is therefore unclear whether the findings apply in populations with more significant disease. There was, for instance, a trend towards improved outcome in patients with more severe ischaemia that might have become significant with more accurate assessment of ischaemia. While there was an early symptomatic benefit in the routine invasive group, this was at the expense of a greater early event rate due to intervention-related complications. In contrast, a large observational study of 16 029 patients undergoing MPS PET using 82Rb showed an advantage for revascularisation over medical therapy with ischaemic burden over 5% of total myocardium, even smaller than the 10% ischaemic burden reported previously for MPS SPECT.1415 Although not prospectively randomised, propensity scoring was used to correct for the different risks between the groups and so Schofield R, et al. Heart 2021;107:954–961. doi:10.1136/heartjnl-2019-315628 Heart: first published as 10.1136/heartjnl-2019-315628 on 22 January 2021. Downloaded from http://heart.bmj.com/ on September 3, 2023 at Universidad Nacional Autonoma de Mexico. Protected by copyright. Review order to assist management of CAD, the cost-effectiveness of an initial anatomical strategy may be reduced. The NICE guidance is in keeping with the SCOT-HEART study, however, which showed that routine CTCA after exercise ECG in patients with stable chest pain improved diagnostic certainty at 6 weeks and reduced coronary deaths and non-fatal myocardial infarction at 5 years, compared with standard care.17 MPS was only performed in 9% of patients, equally between groups, and so the study does not suggest how routine functional imaging might compare with CTCA. See online supplemental file for a discussion of relative numbers of cardiac imaging studies performed in the UK and the radiation risks involved in techniques using ionising radiation. Vulnerable plaque Figure 1 82Rb MPS PET in a patient who presented with atypical chest discomfort but with some exertional features. Selected tomograms are shown during regadenoson stress (left) and at rest (centre) with quantitative polar plots of stress perfusion (top right), rest perfusion (centre right) and perfusion reserve (bottom right). Stress perfusion is severely reduced at the apex (1, 1.0 mL/g/min), moderately reduced in the septum (2, 1.4 mL/g/min) and mildly reduced in the inferior wall (3, 1.8 mL/g/min). Elsewhere it is normal (>2 mL/g/min). Perfusion reserve follows a similar pattern. Angiography showed severe left anterior descending and right coronary artery disease. 82Rb, rubidium-82; HLA, horizontal long axis; MPS, myocardial perfusion scintigraphy; PET, positron emission tomography; SAX, short axis; VLA, vertical long axis. the findings have some validity. This study therefore supports routine assessment of ischaemic burden in patients with known CAD, and there is scope for further analysis of the ISCHEMIA trial regarding the generalisability of its findings. Diagnostic testing There are few direct comparisons of the various cardiac imaging techniques, and clinical practice tends to be determined by local expertise and facilities. Most would argue that access to all is required for the practice of modern cardiology and we have moved into an era where they should be used in a complementary fashion as opposed to being competitive. The anatomical test CTCA is now recommended by NICE as the first test in patients newly presenting with chest pain caused by suspected CAD,11 which appears counter to the findings of the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial, which showed no difference in all-cause mortality, myocardial infarction or unstable angina between patients investigated with an initial anatomical or a functional test (see online supplemental file).16 This may be because the NICE guidance was based primarily on the cost-effectiveness of tests for predicting significant CAD defined anatomically, but it did not consider costs or clinical outcome arising after the diagnostic phase. For instance, it is conceivable that if a functional test is required in Schofield R, et al. Heart 2021;107:954–961. doi:10.1136/heartjnl-2019-315628 Over half of the events in the CTCA arm of the PROMISE trial were in patients without obstructive CAD, implying that, in an ideal world, assessment of atheroma burden and its effect on myocardial perfusion might guide management.16 However, events related to non-obstructive plaque arise from its instability and there is still a need for early detection of plaque charinflammatory acteristics that might lead to thrombosis. Anti- therapy can improve cardiovascular outcomes and imaging of inflammation may be important. It is uncertain which aspect of arterial atheroma leads to accumulation of 18F-fluorodeoxyglucose (FDG), possibly inflammatory macrophages, macrophage hypoxia or vascular smooth muscle. Whichever, imaging FDG by PET in small rapidly moving coronary arteries is challenging and the technique must still be classed as experimental. Another difficulty in interpreting FDG activity in coronary arteries is the proximity to physiological myocardial activity. This can usually be suppressed by dietary manipulation (see online supplemental file), but other tracers do not suffer this disadvantage, including sodium 18F-fluoride18 and 68Ga-dotatate, a somatostatin subtype-2 receptor ligand that targets proinflammatory macrophages within atherosclerotic plaque19 and is also a marker of myocardial inflammation after myocardial infarction.20 Further studies will reveal whether these might have a clinical role. HEART FAILURE Viability and hibernation The assessment of myocardial viability and hibernation has been a developing topic for many years. Radionuclide tracers have an advantage in that they concentrate only in viable myocytes and hence allow viable myocardium to be imaged and quantified directly, as opposed to indirectly by other techniques such as myocardial function by echocardiography or myocardial scar by MRI.21 The clinical relevance of viability is usually in assessing the benefit of intervention following infarction and of hibernation in assessing the likelihood of recovery of function after abolishing inducible ischaemia. In this setting the STICH (Surgical Treatment for Ischemic Heart Failure) trial cast doubt on the value of assessing viability or hibernation.22 The more recent 10-year follow-up suggested the same, with reduced mortality in patients with ischaemia left ventricle (LV) dysfunction randomised to bypass grafting compared with those on medical therapy, but no relationship between myocardial viability and the beneficial effect of coronary artery bypass grafting.23 However, interpretation is confounded by the definition of viability, which boiled down to patients with small infarcts defined as viable and large infarcts as non-viable without any consideration of the presence of ischaemia that might benefit from intervention. In addition, 957 Heart: first published as 10.1136/heartjnl-2019-315628 on 22 January 2021. Downloaded from http://heart.bmj.com/ on September 3, 2023 at Universidad Nacional Autonoma de Mexico. Protected by copyright. Review the subset of patients undergoing viability assessment by imaging was not randomised. Fortunately, the PARR2 (PET and Recovery Following Revascularization) study had a more relevant definition of viability, which was mismatch between myocardial viability and perfusion assessed by PET, a parameter that is widely accepted for the detection of viable but hibernating myocardium that might improve in function after abolition of ischaemia.21 The initial randomised trial did not show benefit for PET,24 but early post-hoc analysis of patients who were managed appropriately based on the PET findings did show a relationship between the amount of hibernating myocardium and the benefit from revascularisation.25 26 The benefit was maintained at 5 years.27 Imaging of myocardial innervation Metaiodobenzylguanidine (mIBG) is a false neurotransmitter that emulates norepinephrine and concentrates in presynaptic sympathetic nerve terminals by virtue of the uptake-1 mechanism. Labelled with 123I this allows both the distribution of sympathetic nerve terminals to be imaged and sympathetic tone to be assessed from the rate of washout of tracer between images acquired 15 min and 4 hours after injection. In patients with heart failure myocardial mIBG activity can be reduced either because areas of ischaemia or scar have reduced innervation or because sympathetic tone is increased. The ADMIRE-HF (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure) study showed that the heart to mediastinal ratio was an independent predictor of heart failure progression, arrhythmia and cardiac death,28 although the technique is not widely used partly because of its expense when simpler techniques such as brain natriuretic peptide and LVEF (left ventricular ejection fraction) measurement also have prognostic power. mIBG may have a role in assessing the need for implanted cardiac defibrillator (ICD) therapy since areas of viable myocardium that are not innervated may be a substrate for arrhythmia (figure 2). Early studies showed a relationship between mIBG activity and appropriate ICD discharge,29 but a recent study showed a more complex relationship with appropriate shocks occurring mainly in patients with intermediate myocardial mIBG activity (heart:mediastinum 1.4–2.2) and fewer shocks at both Figure 2 Polar SPECT plots using thallium-201 (left) and 123I- mIBG (right) in a patient with previous myocardial infarction, an occluded right coronary artery and an 80% distal left anterior descending stenosis. LVEF was 42% without evidence of arrhythmia and an implanted defibrillator was not indicated. There is little viable myocardium and no sympathetic innervation of the inferior wall (closed arrows), but there is a small area of viable but denervated myocardium in the apical anteroseptal region (open arrows). The patient presented with syncope and paroxysmal ventricular tachycardia, which was shown to be arising from the apical anteroseptal region. mIBG, metaiodobenzylguanidine; SPECT, single photon emission CT. 958 lower and higher levels of activity.30 From current evidence it is unlikely that the technique can be added to the criteria for ICD implantation, but further studies may provide additional information, particularly whether it may be helpful in patients with only mildly impaired LV function who may still be susceptible to arrhythmia. See online supplemental file for a discussion of imaging of ganglionated plexi as a supplement during ablation of atrial arrhythmias. MYOCARDIAL DISEASE AND INFECTION Endocarditis The incidence and mortality of infective endocarditis increase with age, comorbidity and the prevalence of prosthetic valves and implanted devices. Abnormal FDG uptake is a major criterion for infective endocarditis in the current European Society of Cardiology (ESC) guideline.31 The subsequent ESC- EuroObservational Research Programme registry reported the clinical presentation, aetiology and outcomes of 3116 patients worldwide.32 FDG PET was available in 70% of contributing countries but it was used in only 17% of patients, more commonly for prosthetic valves (25%) and implanted devices (26%) than for native valve infection (10%). It was more sensitive for prosthetic valve infection (67%) than for native valve infection (28%) and least sensitive for device infection (16%), although this last figure will be a marked underestimate relating to intracardiac infection, as opposed to device generator infection where it is more sensitive. The technique also has prognostic value (see online supplemental file). Figure 3 shows a patient where it was initially unclear if infection was on a prosthetic aortic valve or an implanted device, but it was localised to the valve by FDG PET and shown to progress to abscess formation on medical therapy. The scan thus had a major role in patient management. Figure 4 shows another patient where infection was not apparent on either the device generator or the intracardiac wires but was localised to the extracardiac wires by PET-CT, which again played an important role in patient management. White cell scintigraphy using autologous radiolabelled leucocytes has also been used extensively to detect infection, with sensitivity of 86% and specificity of 97% in infective endocarditis.33 The technique is more specific than FDG PET, particularly when postoperative healing or FDG activity in implanted synthetic fibres might be misleading, but it is less sensitive.34 Practical disadvantages include the need for ex vivo labelling of blood products and delayed imaging, up to 24 hours with technetium-99m and 48 hours or longer with indium-111. In practice FDG PET is now the usual initial imaging test for suspected infective endocarditis, particularly on prosthetic valves, and white cell scintigraphy is a useful second test when FDG is indeterminate. In pacemaker and other device-related infection white cell scintigraphy has a high negative predictive value of 95%35 and it may also have prognostic value.36 Sarcoidosis Without a specific biomarker, cardiac sarcoidosis can be difficult to diagnose. Serum ACE is frequently elevated during active disease, but it is non-specific. Endomyocardial biopsy showing non-caseating granuloma in the absence of alternative diagnoses confirms cardiac involvement but, in practice, positive extracardiac biopsy and supportive evidence from cardiac imaging are usually sufficient.37 Multiple imaging techniques are usually required, including echocardiography, CT, MRI and scintigraphy. Schofield R, et al. Heart 2021;107:954–961. doi:10.1136/heartjnl-2019-315628 Heart: first published as 10.1136/heartjnl-2019-315628 on 22 January 2021. Downloaded from http://heart.bmj.com/ on September 3, 2023 at Universidad Nacional Autonoma de Mexico. Protected by copyright. Review Figure 3 A patient had aortic valve replacement and coronary artery bypass grafting 4 years previously and an ICD 2 years previously. The patient presented with fever, necrotic fingertip lesions and Staphylococcus aureus bacteraemia. The aortic root appeared thickened on echocardiography and CT, but there were no other features of valve infection. It was unclear if the infection was on the valve and/or the ICD. The figure shows initial FDG PET (top left) fused with CT (bottom left) in the coronal plane. There is intense abnormal activity related to the valve and aortic root (solid arrow) but no abnormality associated with the ICD (top right of image). Initial medical management did not fully suppress the infection and subsequent PET-CT (right) showed extension into the soft tissue around the left main coronary artery (open arrow), confirmed on CT to be an abscess. There is also likely physiological activity in the basal anterior myocardium, although myocarditis could not be excluded (dotted arrow). FDG, 18F-fluorodeoxyglucose; ICD, implanted cardiac defibrillator; PET, positron emission tomography. Gallium-67 citrate scintigraphy has long been used as a non- specific marker of inflammation and its presence was a major diagnostic factor in the Japanese Ministry of Health diagnostic criteria.38 The imaging characteristics of the radionuclide are not ideal, however, and the technique can be insensitive, although improved by SPECT- CT.39 When characteristic patterns such as involvement of the lacrimal and parotid glands and thoracic nodes are present, it is very specific.40 More recently the sensitivity of FDG PET for the detection of inflammation has led to it becoming an essential investigation for the assessment of activity in many organs affected by sarcoidosis, particularly the heart, and it is among the criteria for the diagnosis of cardiac sarcoidosis recommended by the Heart Rhythm Society alongside gallium-67 scintigraphy and MRI for the assessment of myocardial scar.41 A meta-analysis has shown overall sensitivity and specificity of FDG PET for the detection of cardiac sarcoidosis of 90% and 81%, respectively, although the true specificity is likely to be higher because the studies used the Japanese Ministry of Health criteria as the diagnostic standard,38 and it is likely that FDG PET is more sensitive than the criteria, which do not include FDG abnormalities. FDG PET also has prognostic relevance in cardiac sarcoidosis, with abnormal scans significantly related to ventricular arrhythmia or death over 1.5 years, and patients with evidence of both myocardial inflammation and scar having a hazard ratio of 3.9 for adverse events.42 When monitoring Schofield R, et al. Heart 2021;107:954–961. doi:10.1136/heartjnl-2019-315628 Figure 4 A patient had previous infarction, impaired LV function and heart failure managed with cardiac resynchronisation therapy and defibrillator. The patient presented with fever and Staphylococcus aureus bacteraemia. There were no overt signs of device infection on examination or echocardiography. The figure shows FDG PET (top) fused with CT (bottom) in coronal (left) and transverse planes (centre) with maximum intensity projection (right). There is abnormal activity related to the wires in the brachiocephalic vein (closed arrows) but no abnormal activity associated with the generator or intracardiac wires. There were also abnormal foci in the lungs (open arrows), presumed infected emboli. FDG, 18F-fluorodeoxyglucose; LV, left ventricle; PET, positron emission tomography. treatment of cardiac sarcoidosis there is an association between suppression of myocardial inflammation and improvement in LV function,43 but it is not yet established whether suppression of inflammation reduces event rates or might even avoid the need for implanted defibrillator therapy since arrhythmias can be related as much to scar as to inflammation (figure 5). See online supplemental file for a discussion of the metabolic preparation required for FDG imaging of myocardial inflammation and of other relevant tracers. Amyloidosis When myocardial involvement with amyloid is suspected, echocardiography has some characteristic features but is usually unable to distinguish between different causes of myocardial hypertrophy or amyloid light chain (AL) from transthyretin-related Figure 5 PET-CT anterior maximum intensity projections in a patient who presented with malaise, breathlessness and palpitation. Sarcoidosis was confirmed on endobronchial ultrasound-guided lymph node biopsy. FDG PET images on presentation show intense LV and RV myocardial inflammation (closed arrows) and moderate bihilar lymphadenitis (open arrows). Twelve months after steroid and methotrexate treatment the lymphadenitis resolved and the myocardial inflammation was significantly reduced (right). FDG, 18F-fluorodeoxyglucose; LV, left ventricle; PET, positron emission tomography; RV, right ventricle. 959 Heart: first published as 10.1136/heartjnl-2019-315628 on 22 January 2021. Downloaded from http://heart.bmj.com/ on September 3, 2023 at Universidad Nacional Autonoma de Mexico. Protected by copyright. Review patients. Alternative methods of quantification have been used with regions of interest over the heart in an anterior planar view of the thorax and in a similar position over the contralateral lung, with a ratio of 1.5 distinguishing between AL and TTR amyloidosis with 97% sensitivity and perfect specificity.49 A meta-analysis of studies showed 92% sensitivity and 95% specificity for TTR provided that AL was excluded by plasma or urine testing.50 See online supplemental file for further information on the assessment and management of cardiac amyloidosis. CONCLUSION Figure 6 An elderly man with carpal tunnel syndrome was admitted to hospital following an assault. He had first-degree atrioventricular heart block and echocardiography showed left ventricular hypertrophy. The images show DPD whole body scintigraphy (left) and VLA, HLA and SA tomograms from SPECT-CT (right). There is diffuse LV myocardial activity that is more than rib activity, RV myocardial activity and reduced long bone activity. Endomyocardial biopsy confirmed amyloid deposition and there was no evidence of plasma cell dyscrasia. Sequencing of the TTR gene showed wild-type exons 2, 3 and 4. He was treated with diflunisal. CT, X-ray computed tomography; DPD, 3,3-diphosphonopropano-1,2-dicarboxylic acid; HLA, horizontal long axis; LV, left ventricle; RV, right ventricle; SA, short axis; SPECT, single photon emission computed tomography; TTR, transthyretin-related; VLA, vertical long axis. (TTR) amyloidosis. MRI also has characteristic features, particularly the kinetics of myocardial gadolinium contrast, native T1 imaging and imaging of extracellular volume, but it is also unable to distinguish between AL and TTR amyloidosis. In contrast, many different radionuclide tracers have been used to image the distribution of amyloid, including serum amyloid P-component (123I-SAP), 99mTc-aprotinin, 111In-antimyosin, beta-amyloid tracers (11C-PiB, 18F-florbetapir, 18F-flutimetamol, 18 F-florbetaben), 123I-mIBG, and 99mTc-labelled bone-seeking tracers such as pyrophosphate, hydroxymethylene diphosphonate and 3,3- diphosphonopropano-1,2- dicarboxylic acid.44 The bone-seeking tracers are most useful for TTR amyloidosis (figure 6) and the beta-amyloid tracers for AL amyloidosis.45 It has been known for many years that occasional myocardial activity of bone-seeking tracers can occur, but only more recently has diphosphonate or pyrophosphate imaging been studied more systematically.4647 Perugini et al48 first described a system of grading myocardial activity by comparison with bone and showed that more intense activity (grades 2 and 3) perfectly distinguished between AL and TTR cardiac amyloidosis in 25 patients with cardiac amyloidosis and 10 control 960 Nuclear cardiology provides the most common imaging test of myocardial perfusion, but clinical practice in known or suspected CAD varies both nationally and internationally, partly due to inconsistencies in expertise and in international guidelines. Direct comparisons, for instance between functional imaging techniques or between anatomical and functional approaches, may guide us to greater consistency, but until then these different approaches remain valid. Promising new radiopharmaceuticals are likely to extend the role of nuclear cardiology, and insights into the assessment of atheroma stability may lead to management of CAD based on personalised assessment of the phenotype as opposed to extrapolation of individual care from population studies. All techniques have their advantages and disadvantages, but recent developments in the radionuclide approach provide unique features that continue to justify it as an essential component of modern cardiology, particularly today in patients with infective and inflammatory disorders. Twitter Stephen Richard Underwood @SRUnderwood01 Contributors All authors have contributed equally to the writing and approval of this review article. Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Competing interests None declared. Patient consent for publication Not required. Provenance and peer review Not commissioned; externally peer reviewed. Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. ORCID iD Stephen Richard Underwood http://orcid.org/0000-0002-5777-1442 REFERENCES 1 Asher A, Ghelani R, Thornton G, et al. Uk perspective on the changing landscape of non-invasive cardiac testing. Open Heart 2019;6:e001186. 2 Kapur A, Latus KA, Davies G, et al. A comparison of three radionuclide myocardial perfusion tracers in clinical practice: the robust study. Eur J Nucl Med Mol Imaging 2002;29:1608–16. 3 Andersson M, Johansson L, Minarik D, et al. Effective dose to adult patients from 338 radiopharmaceuticals estimated using ICRP biokinetic data, ICRP/ICRU computational reference phantoms and ICRP 2007 tissue weighting factors. EJNMMI Phys 2014;1:9–21. 4 Verberne HJ, Acampa W, Anagnostopoulos C, et al. EANM procedural guidelines for radionuclide myocardial perfusion imaging with SPECT and SPECT/CT: 2015 revision. Eur J Nucl Med Mol Imaging 2015;42:1929–40. 5 Moody JB, Poitrasson-Rivière A, Hagio T, et al. Added value of myocardial blood flow using 18F-flurpiridaz PET to diagnose coronary artery disease: The flurpiridaz 301 trial. J Nucl Cardiol 2020. doi:10.1007/s12350-020-02034-2 Schofield R, et al. Heart 2021;107:954–961. doi:10.1136/heartjnl-2019-315628 Heart: first published as 10.1136/heartjnl-2019-315628 on 22 January 2021. Downloaded from http://heart.bmj.com/ on September 3, 2023 at Universidad Nacional Autonoma de Mexico. Protected by copyright. Review 6 Murthy VL, Bateman TM, Beanlands RS, et al. Clinical quantification of myocardial blood flow using PET: joint position paper of the SNMMI cardiovascular Council and the ASNC. J Nucl Cardiol 2018;25:269–97. 7 Taqueti VR, Hachamovitch R, Murthy VL, et al. Global coronary flow reserve is associated with adverse cardiovascular events independently of luminal angiographic severity and modifies the effect of early revascularization. Circulation 2015;131:19–27. 8 Patel KK, Spertus JA, Chan PS, et al. Myocardial blood flow reserve assessed by positron emission tomography myocardial perfusion imaging identifies patients with a survival benefit from early revascularization. Eur Heart J 2020;41:759–68. 9 Taqueti VR, Shaw LJ, Cook NR, et al. Excess cardiovascular risk in women relative to men referred for coronary angiography is associated with severely impaired coronary flow reserve, not obstructive disease. Circulation 2017;135:566–77. 10 Underwood SR, Anagnostopoulos C, Cerqueira M, et al. Myocardial perfusion scintigraphy: the evidence. Eur J Nucl Med Mol Imaging 2004;31:261–91. 11. Available: https://www.nice.org.uk/guidance/cg95/chapter/Update-information [Accessed 10/03/2020]. 12 Maron DJ, Hochman JS, Reynolds HR, et al. Initial invasive or conservative strategy for stable coronary disease. N Engl J Med 2020;382:1395–407. 13 Reynolds HR, Shaw LJ, Min JK, et al. Association of sex with severity of coronary artery disease, ischemia, and symptom burden in patients with moderate or severe ischemia: secondary analysis of the ischemia randomized clinical trial. JAMA Cardiol 2020;5:773–86. 14 Hachamovitch R, Rozanski A, Shaw LJ, et al. Impact of ischaemia and scar on the therapeutic benefit derived from myocardial revascularization vs. medical therapy among patients undergoing stress-rest myocardial perfusion scintigraphy. Eur Heart J 2011;32:1012–24. 15 Patel KK, Spertus JA, Chan PS, et al. Extent of myocardial ischemia on positron emission tomography and survival benefit with early revascularization. J Am Coll Cardiol 2019;74:1645–54. 16 Douglas PS, Hoffmann U, Patel MR, et al. Outcomes of anatomical versus functional testing for coronary artery disease. N Engl J Med 2015;372:1291–300. 17 , Newby DE, Adamson PD, SCOT-HEART Investigators, et al. Coronary CT angiography and 5-year risk of myocardial infarction. N Engl J Med 2018;379:924–33. 18 Joshi NV, Vesey AT, Williams MC, et al. 18F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: a prospective clinical trial. Lancet 2014;383:705–13. 19 Tarkin JM, Joshi FR, Evans NR, et al. Detection of atherosclerotic inflammation by 68Ga-dotatate PET compared to [18F]FDG PET imaging. J Am Coll Cardiol 2017;69:1774–91. 20 Tarkin JM, Calcagno C, Dweck MR, et al. 68Ga-dotatate PET identifies residual myocardial inflammation and bone marrow activation after myocardial infarction. J Am Coll Cardiol 2019;73:2489–91. 21 Underwood SR, Bax JJ, vom Dahl J, et al. Imaging techniques for the assessment of myocardial hibernation. Report of a study group of the European Society of Cardiology. Eur Heart J 2004;25:815–36. 22 Bonow RO, Maurer G, Lee KL, et al. Myocardial viability and survival in ischemic left ventricular dysfunction. N Engl J Med 2011;364:1617–24. 23 Panza JA, Ellis AM, Al-Khalidi HR, et al. Myocardial viability and long-term outcomes in ischemic cardiomyopathy. N Engl J Med 2019;381:739–48. 24 Beanlands RSB, Nichol G, Huszti E, et al. F-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction and suspected coronary disease: a randomized, controlled trial (PARR-2). J Am Coll Cardiol 2007;50:2002–12. 25 Abraham A, Nichol G, Williams KA, et al. 18F-FDG PET imaging of myocardial viability in an experienced center with access to 18F-FDG and integration with clinical management teams: the Ottawa-FIVE substudy of the PARR 2 trial. J Nucl Med 2010;51:567–4. 26 D’Egidio G, Nichol G, Williams KA, et al. Increasing benefit from revascularization is associated with increasing amounts of myocardial hibernation: a substudy of the PARR-2 trial. JACC Cardiovasc Imaging 2009;2:1060–8. 27 Mc Ardle B, Shukla T, Nichol G, et al. Long-term follow-up of outcomes with F-18- fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction secondary to coronary disease. Circ Cardiovasc Imaging 2016;9:e004331. 28 Jacobson AF, Senior R, Cerqueira MD, et al. Myocardial iodine-123 meta- iodobenzylguanidine imaging and cardiac events in heart failure. Results of the prospective ADMIRE-HF (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure) study. J Am Coll Cardiol 2010;55:2212–21. Schofield R, et al. Heart 2021;107:954–961. doi:10.1136/heartjnl-2019-315628 29 Boogers MJ, Borleffs CJW, Henneman MM, et al. Cardiac sympathetic denervation assessed with 123-iodine metaiodobenzylguanidine imaging predicts ventricular arrhythmias in implantable cardioverter-defibrillator patients. J Am Coll Cardiol 2010;55:2769–77. 30 Verschure DO, de Groot JR, Mirzaei S, et al. Cardiac 123I-mIBG scintigraphy is associated with freedom of appropriate ICD therapy in stable chronic heart failure patients. Int J Cardiol 2017;248:403–8. 31 Habib G, Lancellotti P, Antunes MJ. Esc guidelines for the management of infective endocarditis. Eur Heart J 2015;2015:3075–128. 32 Habib G, Erba PA, Iung B, et al. Clinical presentation, aetiology and outcome of infective endocarditis. Results of the ESC-EORP EURO-ENDO (European infective endocarditis) registry: a prospective cohort study. Eur Heart J 2019;40:3222–32. 33 Juneau D, Golfam M, Hazra S, et al. Molecular imaging for the diagnosis of infective endocarditis: a systematic literature review and meta-analysis. Int J Cardiol 2018;253:183–8. 34 Salaun E, Habib G. Beyond standard echocardiography in infective endocarditis: computed tomography, 3-dimensional imaging, and multi-imaging. Circ Cardiovasc Imaging 2018;11:e007626. 35 Erba PA, Sollini M, Conti U, et al. Radiolabeled WBC scintigraphy in the diagnostic workup of patients with suspected device-related infections. JACC Cardiovasc Imaging 2013;6:1075–86. 36 Holcman K, Rubiś P, Ząbek A, et al. The prognostic value of 99mTc-HMPAO-labeled leucocyte SPECT/CT in cardiac device-related infective endocarditis. JACC Cardiovasc Imaging 2020;13:1739–51. 37 Judson MA, Costabel U, Drent M, et al. The WASOG sarcoidosis organ assessment instrument: an update of a previous clinical tool. Sarcoidosis Vasc Diffuse Lung Dis 2014;31:19–27. 38 Hiraga H, Yuwai K, Hiroe M. Diagnostic standard and guidelines for sarcoidosis. Jpn J Sarcoidosis Granulomatous Disord 2007;27:89–102. 39 Nakazawa A, Ikeda K, Ito Y, et al. Usefulness of dual 67GA and 99mTc-sestamibi single-photon-emission CT scanning in the diagnosis of cardiac sarcoidosis. Chest 2004;126:1372–6. 40 Kita T, Watanabe S, Yano F, et al. Clinical significance of the serum IL-2R level and Ga-67 scan findings in making a differential diagnosis between sarcoidosis and non- Hodgkin’s lymphoma. Ann Nucl Med 2007;21:499–503. 41 Birnie DH, Sauer WH, Bogun F, et al. HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis. Heart Rhythm 2014;11:1305–24. 42 Blankstein R, Osborne M, Naya M, et al. Cardiac positron emission tomography enhances prognostic assessments of patients with suspected cardiac sarcoidosis. J Am Coll Cardiol 2014;63:329–36. 43 Osborne MT, Hulten EA, Singh A, et al. Reduction in ¹⁸F-fluorodeoxyglucose uptake on serial cardiac positron emission tomography is associated with improved left ventricular ejection fraction in patients with cardiac sarcoidosis. J Nucl Cardiol 2014;21:166–74. 44 Chen W, Dilsizian V. Molecular imaging of amyloid deposits for early diagnosis of cardiac amyloidosis and monitoring treatment response. JACC: Cardiovascular Imaging, 2020. (accessed 2020-05-26). 45 Cuddy SAM, Bravo PE, Falk RH, et al. Improved quantification of cardiac amyloid burden in systemic light chain amyloidosis: redefining early disease? JACC Cardiovasc Imaging 2020;13:1325-1336. 46 Dorbala S, Ando Y, Bokhari S, et al. ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: Part 1 of 2-evidence base and standardized methods of imaging. J Nucl Cardiol 2019;26:2065–123. 47 Dorbala S, Ando Y, Bokhari S, et al. ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: Part 2 of 2-Diagnostic criteria and appropriate utilization. J Card Fail 2019;25:854865. 48 Perugini E, Guidalotti PL, Salvi F, et al. Noninvasive etiologic diagnosis of cardiac amyloidosis using 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy. J Am Coll Cardiol 2005;46:1076–84. 49 Bokhari S, Castaño A, Pozniakoff T, et al. 99mTc-Pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidosis. Clinical Perspective. Circ Cardiovasc Imaging 2013;6:195–201. 50 Treglia G, Glaudemans AWJM, Bertagna F, et al. Diagnostic accuracy of bone scintigraphy in the assessment of cardiac transthyretin-related amyloidosis: a bivariate meta-analysis. Eur J Nucl Med Mol Imaging 2018;45:1945–55. 961 Heart: first published as 10.1136/heartjnl-2019-315628 on 22 January 2021. Downloaded from http://heart.bmj.com/ on September 3, 2023 at Universidad Nacional Autonoma de Mexico. Protected by copyright. Review Supplemental material BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance placed on this supplemental material which has been supplied by the author(s) Heart Nuclear Cardiology: State of the Art Online Supplement Rebecca Schofield MB, ChB,1 Leon Menezes (FRCR, FRCP),2 S. Richard Underwood DM, FRCP, FRCR3 1 Consultant Cardiologist, North West Anglia NHS Foundation Trust, Peterborough City Hospital. Bretton Gate, Peterborough PE3 9GZ 2 Consultant Radiologist & Nuclear Medicine Physician, UCL Institute of Nuclear Medicine, University College London Hospitals NHS Foundation Trust, 235 Euston Road, London NW1 2BU 3 Emeritus Professor of Cardiac Imaging, Imperial College London, Royal Brompton Hospital, Sydney St, London SW3 6NP Contact details S. Richard Underwood MA, DM, FRCP, FRCR, FESC, FACC, FASNC Emeritus Professor of Cardiac Imaging, Imperial College London Royal Brompton Hospital Sydney St, London SW3 6NP [email protected] Schofield R, et al. Heart 2021;0:1–8. doi: 10.1136/heartjnl-2019-315628 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance placed on this supplemental material which has been supplied by the author(s) Supplemental material Nuclear Cardiology: State of the Art Heart Online Supplement Imaging Techniques Radiopharmaceuticals 18 F‐sodium fluoride has shown its value in oncology for imaging bony metastatic disease.1 Its application in the cardiovascular system is still within the research setting but it is known to concentrate in areas of microcalcification that develop in response to vascular damage. Applications include imaging of carotid and coronary plaque, aortic aneurysm, aortic stenosis and degeneration of bioprosthetic valves.2 Early uptake in the aortic valve appears to predict degeneration and macrocalcification and, although drugs such as statins have failed to show clinical benefit,3 other drugs used for the treatment of osteoporosis are currently being investigated.4 Gamma Cameras Conventional gamma cameras rely upon scintillations detected and localised in a large sodium iodide crystal by an array of photomultiplier tubes. The detection technology dates to the 1950s5 although developments in hardware and software have led to it being the mainstay of modern nuclear medicine, including SPECT, multiheaded cameras, attenuation correction and iterative reconstruction. However, the technology has relatively low sensitivity and resolution requiring 15 to 30 minutes for acquisition of a tomographic image with resolution of 10‐15mm. More recently, the development of solid‐state cameras using cadmium zinc telluride crystals and directly coupled detectors has led to a new generation of cameras with approximately five times the sensitivity and twice the resolution.6 This can be used to reduce imaging time and/or radiation exposure with tomographic cardiac studies completed in ~5 minutes and radiation dose to the patient of 3‐4mSv. Comparison with standard technology has shown improved accuracy for diagnosis and for prognosis.7 Hybrid Imaging Early hybrid imaging required co‐registration of images acquired on separate scanners but showed that specific coronary arteries could more easily be attributed to areas of inducible ischaemia, particularly distinguishing between circumflex and right coronary territories.8 However, dual‐gantry scanners now routinely combine SPECT or PET with CT and even PET with MRI. Image acquisition is sequential for SPECT‐CT and PET‐CT but simultaneous for PET‐MRI, and the lack of patient motion between acquisitions means that images can be more accurately fused and compared. Page 2 of 13 Schofield R, et al. Heart 2021;0:1–8. doi: 10.1136/heartjnl-2019-315628 Supplemental material BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance placed on this supplemental material which has been supplied by the author(s) Nuclear Cardiology: State of the Art Heart Online Supplement PET‐MR hybrid imaging has required the development of positron detectors that are insensitive to magnetic fields and larger bore magnets with enough space between the magnetic gradient and radiofrequency detector coils.9 Scanners cost several millions of pounds/dollars/euros and so are not accessible outside major centres. The clinical value beyond separate PET and MR scanners remains unclear, but in cardiac imaging major areas of interest have been the assessment of sarcoidosis and myocarditis where myocardial FDG signal is more sensitive for inflammation that MRI, in contrast to myocardial scar where MRI is more sensitive.10 In acute myocardial infarction, PET‐MR can provide an assessment of myocardial salvage after primary intervention, which has obvious prognostic implications as well as potentially guiding research on acute intervention and other therapies.11 Myocardial Perfusion PET Although myocardial perfusion reserve is referred to elsewhere as coronary flow reserve or myocardial flow reserve, it is neither coronary nor flow and the term myocardial perfusion reserve is preferable. The distinction between coronary and myocardial is important since the latter matters most to the myocyte in terms of oxygen delivery and it is affected not only by epicardial coronary flow but by collateral vessels and by abnormalities of the small vessels.12 The distinction between flow and perfusion may be more semantic but the former should be used for bulk flow of a fluid and is measured in mL/min and the latter should be used for more diffuse passage of a fluid through a solid and is measured in mL/g/min. Myocardial perfusion reserve also differs from fractional flow reserve (FFR), which is a measure of the functional significant of an epicardial coronary stenosis or stenoses without allowing for distal disease, collaterals, etc.13 Dynamic Myocardial Perfusion SPECT It remains a moot point whether PET should replace SPECT as the default form of radionuclide imaging for myocardial perfusion,14,15 but PET is currently routinely used in only the minority of centres, primarily large ones that are oriented towards teaching and research. These are more likely to have access to a cyclotron to provide the short‐lived perfusion tracers 13N‐ammonia or 15O‐water, or to have large numbers of studies that reduce the per‐patient cost of the generator‐produced 82Rb. In this setting, the ability of dynamic SPECT imaging of myocardial perfusion using solid‐state cameras is of interest and several groups have assessed its accuracy by comparison with dynamic PET.16,17 The WATERDAY study compared myocardial perfusion assessed by dynamic SPECT and 15O‐ Page 3 of 13 Schofield R, et al. Heart 2021;0:1–8. doi: 10.1136/heartjnl-2019-315628 Supplemental material BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance placed on this supplemental material which has been supplied by the author(s) Nuclear Cardiology: State of the Art Heart Online Supplement water PET with invasive FFR and showed good agreement for myocardial perfusion measured by SPECT and PET and good agreement between both and FFR.18.19 The PACIFIC trial showed that MPS PET using oxygen‐15 water is more accurate than MPS SPECT for the detection of coronary obstruction defined angiographically with fractional flow reserve,20 but when studies were judged to be of good quality, the accuracy was the same at 85%.21 However, whereas 86% of PET studies were judged to be of good quality only 52% of the SPECT studies were. The EVINCI study was similar with 85% accuracy for PET and 70% accuracy for SPECT, but for good quality studies the accuracies were similar at 80% PET and 84% SPECT.22 Ischaemic Heart Disease Diagnostic Testing Post hoc analysis of the PROMISE population looked at diagnostic strategies in 1908 diabetic patients with interpretable non‐invasive tests.23 Those who underwent CTCA had a lower incidence of cardiovascular death or infarction than those who underwent functional testing, largely driven by a lower rate of non‐fatal infarction, but there was no difference between CTCA and functional testing for the broader outcomes of death, infarction or hospitalization for unstable angina. A concern however is that patients were excluded from the study if images were not interpretable, for instance because of extensive coronary calcification compromising CTCA, meaning that event rates in diabetic patients in the CTCA arm were much lower than would be expected. However, the data reinforce the importance of aggressive medical therapy in diabetic patients with CAD without necessarily the need for further diagnostic imaging. Almost all UK hospitals will have access to a gamma camera and hence to MPS, although only 60‐ 65% of hospitals perform it.24 MPS is the most commonly performed coronary functional imaging test with 85‐90,000 MPS studies performed each year in the UK between 2015 and 2017. Numbers of echocardiograms and MRI studies have been slowly increasing with ~61,500 stress echocardiograms and ~15,500 stress perfusion MRI studies in 2017. CTCA studies have also been increasing, particularly since 2015, with ~71,000 studies in 2017. Counting all stress coronary functional imaging test together the UK numbers in 2016‐17 came to ~2500 per million population or with CTCA to ~3600 per million population, which is not far short of the 4000 per million population supported by NICE in 2003.25 Page 4 of 13 Schofield R, et al. Heart 2021;0:1–8. doi: 10.1136/heartjnl-2019-315628 Supplemental material BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance placed on this supplemental material which has been supplied by the author(s) Nuclear Cardiology: State of the Art Heart Online Supplement Radiation Several cardiology tests involve exposure of the patient and potentially staff to ionising radiation.26,27 When it is possible to obtain equivalent information with tests that do not involve radiation this is generally considered desirable, which is particularly relevant for tests of coronary function. In practice it is rarely so simple since risk and benefit must both be considered, and the tests do not necessarily provide equivalent information.28 In any individual centre experience and confidence in tests may differ and lead to natural preferences. Patient preference must also be considered. The significance of radiation will depend upon the patient and in an elderly patient with heart failure the risk may be significantly less than in a woman of child‐bearing age. In any event, the risk of low and moderate doses of radiation is controversial. While high single doses of radiation are known to cause cancer, the significance of exposures below, for instance, 10mSv is unclear. 29 Counter to the linear‐no‐threshold hypothesis of the relationship between radiation dose and adverse events, where all doses are considered harmful, there is the phenomenon of hormesis, where low exposures may upregulate DNA repair mechanisms. Similarly, the fact that mankind has evolved in a low dose environment suggests that we may have evolved to be immune. It is therefore reasonable to say that the adverse effects of radiation involved in most cardiology procedures are uncertain and that radiation exposure should be minimised if possible, but not at the expense of denying patients the most appropriate investigation for their individual circumstances. Heart Failure Imaging of Myocardial Innervation A developing area for mIBG imaging is that of atrial arrhythmia, particularly atrial fibrillation. Despite their small size, it has been possible to image ganglionated plexi that contain both sympathetic and parasympathetic synapses using mIBG and sensitive solid‐state gamma cameras.30 Ablation of these plexi either during surgical or endocardial ablation of atrial fibrillation can improve initial success of the procedure,31 and pre‐operative localisation of the plexi might be used to guide endocardial ablation by providing three‐dimensional maps of their location. However, the technique is not easy and further studies are required, particularly a prospective study of image guided ablation compared with conventional ablation. Page 5 of 13 Schofield R, et al. Heart 2021;0:1–8. doi: 10.1136/heartjnl-2019-315628 Supplemental material BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance placed on this supplemental material which has been supplied by the author(s) Nuclear Cardiology: State of the Art Heart Online Supplement Myocardial Disease and Infection Endocarditis FDG PET has prognostic as well as diagnostic value. In a single centre registry of 173 consecutive patients with confirmed prosthetic valve infection, abnormal FDG activity was associated with increased likelihood of adverse outcome, particularly if activity was moderate or intense.32 Other independent predictors were raised CRP and severe regurgitation. In patients with native valve endocarditis abnormal FDG activity was not associated with major adverse events but it was associated with new embolic events. Additional studies would help to define whether FDG PET might be used to assist triage between medical therapy and surgery. Sarcoidosis Normal myocardial metabolism includes glucose, fatty acids, ketones and amino acids according to availability hence, unless metabolically prepared, normal myocardial FDG activity will mask abnormal activity related to inflammation and a strict diet is required before FDG injection. Practice differs between centres but 18 hours of zero or low carbohydrate (

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