Cardiovascular PET-CT imaging: a new frontier?

Clinical Radiology xxx (2016) 1.e1e1.e13

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Review

Cardiovascular PET-CT imaging: a new frontier? P.D. Adamson*, M.C. Williams, D.E. Newby Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK

art icl e i nformat ion Article history: Received in revised form 12 January 2016

Cardiovascular positron-emission tomography combined with computed tomography (PET-CT) has recently emerged as an imaging technology with the potential to simultaneously describe both anatomical structures and physiological processes in vivo. The scope for clinical application of this technique is vast, but to date this promise has not been realised. Nonetheless, significant research activity is underway to explore these possibilities and it is likely that the knowledge gained will have important diagnostic and therapeutic implications in due course. This review provides a brief overview of the current state of cardiovascular PET-CT and the likely direction of future developments. Ó 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Introduction Cardiovascular radiology has come a long way in the 120 years since Francis Williams first published his description of cardiac fluoroscopy.1 For much of the twentieth century, cardiac imaging was largely confined to imaging techniques comprising chest radiography, contrast angiography, radionuclide imaging, and echocardiography. Although there can be no doubt that these techniques enabled remarkable advances in our understanding and treatment of cardiovascular disease, they have limitations in revealing the cellular biology that drives these conditions. Ex vivo research has provided ever-greater understanding of the molecular determinants of atherosclerosis and structural heart disorders, but despite the development of cardiac computed tomography (CT) and magnetic resonance imaging (MRI), the ability to visualise these processes in vivo has remained constrained.

* Guarantor and correspondent: P.D. Adamson, SU305 Chancellor’s Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK. Tel.: þ44 131 242 6364. E-mail address: [email protected] (P.D. Adamson).

In this context, positron-emission tomography (PET) presents the enticing proposition of non-invasively imaging a myriad of physiological and pathological processes with highly specific and sensitive radiopharmaceuticals. When combined with the spatial detail afforded by CT or MRI, it is feasible to determine both anatomy and biology simultaneously. Notwithstanding this lofty promise, cardiovascular PET-CT imaging has had limited clinical impact to date; however, greater adoption of PET-CT is likely, as this technology becomes more widely available as a result of its growing applications in oncology. This review explores the recent development and current status of cardiovascular PET-CT with particular focus on its use in the functional imaging of myocardial ischaemia, atherosclerosis, valvular heart disease, and cardiac inflammation.

PET-CT imaging in the assessment of myocardial ischaemia and viability The assessment of myocardial ischaemia plays an integral part in the management of patients with known or suspected coronary artery disease, and it is in this role that cardiac PET-CT imaging has been most frequently employed to date. PET-CT myocardial perfusion imaging (MPI)

http://dx.doi.org/10.1016/j.crad.2016.02.002 0009-9260/Ó 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

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involves the acquisition of PET images at rest and during stress in order to identify areas of reversible ischaemia (Fig 1). Pharmacological stress agents that are used include adenosine, dipyridamole, and regadenoson. A variety of radiopharmaceuticals are available for myocardial perfusion imaging, each with differing characteristics. Important attributes of an ideal tracer include (i) high contrast (i.e., differential uptake) between adjacent structures and the myocardium; (ii) a linear relationship between tissue perfusion and tracer signal, with limited diffusion into ischaemic tissue that increases in proportion to myocardial blood flow (MBF) during cardiac stress; (iii) prolonged myocardial retention; and (iv) high spatial resolution (largely determined by positron range). Although agents with longer half-lives allow off-site production and the use of an exercise stress protocol, those with shorter half-lives afford reduced radiation exposure and faster imaging protocols. Tracers that are in current clinical use include rubidium-82 (82Rb),2 nitrogen-13 ammonia

(13N-ammonia),3 and oxygen-15 labelled water (15O-water).4 82Rb is a generator-derived tracer with a half-life of 76 seconds.5 With the benefits of fast scan times, low radiation dose, and no requirement for an on-site cyclotron, it has become the most widely used agent for MPI. Its key limitations include poor spatial resolution and a non-linear relationship to MBF that may reduce its sensitivity for detecting mild stenoses. In comparison, 13N-ammonia, which had its first reported use more than 35 years ago,6 has a near-linear relationship between myocardial uptake and coronary flow, improved spatial and contrast resolution, and a half-life of 10 minutes. Its disadvantages include hepatic and pulmonary uptake and the potential for false-positive lateral wall perfusion defects. 15O-water has a half-life of 2 minutes and freely diffuses across cell membranes resulting in almost 100% first-pass extraction even at high flow rates and a true linear relationship with MBF. Consequently, it represents an excellent tracer for MBF quantification, but conversely, the lack of myocardial retention prevents the assessment of

Figure 1 PET MPI. Images from a 52-year-old female smoker with hypertension who presented with chest pain. Oxygen-15 PET-CT during (a) rest and (b) adenosine stress show a perfusion defect in the left anterior descending and circumflex artery territories (shown in blue). This was confirmed on invasive coronary angiography (c, d, arrows). Please cite this article in press as: Adamson PD, et al., Cardiovascular PET-CT imaging: a new frontier?, Clinical Radiology (2016), http:// dx.doi.org/10.1016/j.crad.2016.02.002

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relative myocardial perfusion. Both 13N-ammonia and 15Owater require on-site cyclotrons for production, which has restricted their availability. Important aims for future tracer development include a high extraction fraction, a short positron range for optimal resolution, and sufficiently long half-life to allow exercise stress protocols and delivery from a regional cyclotron. The most extensively investigated of these novel radiopharmaceuticals, 18F-labelled flurpiridaz, fulfils all these objectives being a cyclotron-derived tracer with an extraction fraction of above 90% and a half-life of 110 minutes.7,8 PET-CT MPI has been validated in animal studies using microspheres9 and in human studies. A recent meta-analysis showed that compared to invasive coronary angiography with fractional flow reserve, PET MPI had a sensitivity of 83% and specificity 89% for the detection of obstructive coronary artery disease, and notably, the presence of PET-determined ischaemia is associated with increased cardiac event rates and mortality.10,11 Additionally, PET-CT imaging can identify microvascular dysfunction that is underestimated by invasive coronary angiography alone. When compared to the more established technique of single-photon-emission CT (SPECT), PET-CT MPI has several advantages including greater diagnostic accuracy due to its higher spatial and contrast resolution.12,13 This image quality can be further enhanced with the use of cardiac and respiratory gating.14 Another benefit of PET-CT in comparison to SPECT is the ability to dynamically record tracer activity in a manner that, employing mathematical models, allows quantification of absolute MBF, reported in millilitres per minute per gram of myocardium (ml/min/g). Both global and segmental ventricular MBF can be assessed and ratios, such as myocardial flow reserve (MFR), can be calculated. Inter- and intra- observer variability is good, although the values obtained are dependent on the software employed.15 By overcoming the challenge of “balanced ischaemia”, quantitative assessment of absolute MFR assists in the diagnosis of three-vessel coronary disease compared with MPI alone.16 Finally, the hybrid nature of modern PETCT systems also elegantly facilitates the simultaneous assessment of coronary anatomy, including arterial distribution, and can describe both the angiographic and functional significance of atherosclerotic stenoses. The combined use of these imaging techniques remains technically challenging, but the potential exists to offer greater diagnostic specificity and positive predictive value than either technique in isolation.17,18 In the context of ischaemic heart disease, PET imaging may also have an application in optimising decision-making with regards to revascularisation of individuals with ischaemic cardiomyopathy. It is well recognised that chronic ischaemia can result in persistently dysfunctional, but ultimately viable myocardial tissue. In this setting, the underlying hibernating myocardial cells demonstrate avid glucose uptake, a feature that has helped establish PET-CT, using 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG), as the reference-standard method to assess myocardial viability. 18 F-FDG is a radiolabelled glucose analogue that becomes metabolically “trapped” within cells. When 18F-FDG is

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combined with concomitant resting myocardial perfusion imaging, a number of patterns of tracer uptake can be described that help distinguish hibernating but viable myocardium from regions of irreversibly damaged tissue. Early observational studies reported 18F-FDG PET-derived myocardial viability to be a good predictor of regional and global functional recovery after revascularization for patients with left ventricular dysfunction19,20 It can also predict improvements in heart failure symptoms21 and exercise capacity.22 Unfortunately, the landmark Positron Emission Tomography and Revascularization (PARR-2) study, which prospectively tested the hypothesis that 18FFDG PET imaging could be used to guide patient management, including decisions on revascularization, failed to demonstrate benefits overall.23 It is worth noting that this finding may underestimate the true value of the technique given a significant proportion of the study population were not treated in accordance with PET-determined management recommendations; although, ultimately, it would appear consistent with the outcomes of the more recent viability sub-study of the Surgical Treatment for Ischemic Heart Failure (STICH) trial.24 At present, the role for viability testing prior to revascularisation is unclear with recent European Society of Cardiology Guidelines offering only a weak statement in its favour.25

PET-CT imaging of coronary atherosclerosis It has long been recognised that most acute coronary syndromes (ACS) arise from thrombus formation on the surface of a disrupted coronary plaque.26e28 By definition, the vulnerable atherosclerotic plaque is a sine qua non for this process, and the ability to identify these high-risk lesions pre-emptively is the focus of much research.29 Many of the histological characteristics of vulnerable plaques, including a large lipidenecrotic core, positive arterial remodelling, thin fibrous cap, micro-calcification, and peripheral neovascularisation can now be identified in vivo with advanced intracoronary imaging, but the positive predictive value of such anatomical features remains limited.29e36 By offering insight into the biology of the plaque, however, PET-CT imaging has the potential to improve this process of risk stratification.37 Although a variety of potential tracers targeting numerous markers of vulnerability are undergoing preclinical investigation, the two agents most extensively described are 18F-FDG and 18F-sodium fluoride (18FeNaF; Table 1). 18

F-FDG and the detection of plaque inflammation

Inflammation is a central determinant of atherosclerotic progression. Immune cells, including activated macrophages, can be identified early in plaque development and establish a self-promoting population by secreting proinflammatory cytokines that act to undermine the structural integrity of the collagen cap, increasing the likelihood of plaque rupture.35,38,39 This inflammatory process is not localised but systemic, with elevated circulating biomarkers of inflammation and a globally increased incidence of vascular events.36,40e42

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Table 1 Examples of PET radiopharmaceuticals in clinical or research use. Tracer

Half-life

Target feature

Comments

Selected references

18

F-FDG

110 min

Metabolic activity/Inflammation

48, 49, 51,106e109

18

F-fluciclatide

110 min

18

F-flurpiridaz

110 min

avb3 and avb5 integrin receptors (involved in angiogenesis and fibrosis) Myocardial blood flow

18

F-choline

110 min

18

F-FDM

110 min

Macrophage activation (Incorporated in cell membranes) M2 macrophage sub-type

18

F-folate FeNaF

110 min 110 min

Macrophage activation Microcalcification

F-fluoromisonidazole F-galacto-RGD

110 min 110 min

11

C-choline

20 min

C-PK11195

20 min

Short half-life necessitates on site production Prospective human study of carotid disease completed

119

11

68

Ga-DOTATATE

68 min

Hypoxia Neoangiogenesis (binds to integrin avß3 expressed on endothelial cells) Macrophage activation (Incorporated in cell membranes) Macrophage activation (selective ligand of translocator protein/ peripheral benzodiapine receptor) Macrophage activation (binds to somatostatin receptor 2) Myocardial blood flow Myocardial blood flow Myocardial blood flow

Well-established in extra-cardiac imaging. Coronary use limited by myocardial uptake Currently being tested in a number of aortic and cardiovascular conditions Accurate test for myocardial ischaemia when compared with 99Tc SPECT Currently being assessed in prospective PARISK study (carotid disease) Pre-clinical animal studies have demonstrated proof of principle Ex vivo studies only Prospective human studies of coronary and extra-cardiac atherosclerosis completed Preclinical mouse model study Preclinical mouse model and ex vivo human carotid studies

In vivo retrospective studies performed. Currently being assessed in VISION study Cyclotron derived Cyclotron derived Generator derived

121e123

18

18 18

15

O-labelled water N-ammonia 82 Rb 13

122 sec 9.96 min 76 sec

110 and trial NCT01837160 8 111 112 113 79, 81, 114

115 116e118

120

4 3 2

FDG, 2-[18F]-fluoro-2-deoxy-D-glucose; FDM, 2-deoxy-2[18F]-fluoro-D-mannose; RGD, arginineeglycineeaspartic acid; DOTA-TATE, DOTA (1,4,7,10tetraazacyclododecane-1,4,7,10-tetraacetic acid)-octreotate; NaF, Sodium fluoride.

Activated macrophages within the atherosclerotic plaque have high energy requirements and predominantly rely on anaerobic metabolism via the glycolytic pathway making them suitable targets for PET-CT imaging with 18F-FDG.43 Histological studies in animal models of atherosclerosis have provided proof of this concept by demonstrating tracer localisation to regions of macrophage differentiation into activated foam cells.44,45 Furthermore, the potential value of 18 F-FDG imaging to predict thrombotic events was established in a study involving atherosclerotic rabbits that were administered Russell’s viper venom, a potent pro-coagulant, with the intention of inducing plaque-related aortic thrombosis. Baseline 18F-FDG uptake was greater in those plaques that subsequently demonstrated thrombus formation, and therefore deemed to be vulnerable, than those that remained quiescent.46 The first clinical, prospective atherosclerotic study of 18FFDG PET-CT was undertaken in eight patients with recent stroke and reported uptake in symptomatic carotid plaques to be 27% greater than in the contralateral asymptomatic vessel.47 Using autoradiography of endarterectomy specimens, they were able to confirm that this uptake occurred in sites of macrophage rich plaque. Within the carotid circulation, 18F-FDG activity appears predictive of recurrent ipsilateral events and vascular uptake in general correlates with elevated concentrations of inflammatory biomarkers.44,48e53 Interest has grown in the potential for the physiological information provided by 18F-FDG PET imaging to be used as a surrogate end-point in cardiovascular drug

trials. This has been explored in a number of investigations of statin therapy that demonstrate reductions in atherosclerotic inflammation independent of the lipid lowering effects.54e57 In contrast, when 18F-FDG was used to study alternative cholesterol modifying agents, including inhibitors of both lipoprotein-associated phospholipase A2 and cholesteryl ester transfer protein (CETP), there were no apparent anti-inflammatory effects, which may explain their failure to improve hard clinical endpoints in subsequent clinical trials.58e62 Having established the principle that PET-CT imaging can accurately identify atherosclerotic inflammation, it should be emphasised that most vascular trials of 18F-FDG have imaged extra-cardiac arteries, and, although there have been some reports of a role in identifying coronary plaques responsible for myocardial infarction,63 the evidence is conflicting with potentially insurmountable challenges to be addressed.31 The most important of these is non-specific uptake of 18F-FDG by all metabolically active cells, including cardiomyocytes, that frequently obscure the signal arising from inflamed coronary lesions. Alternative tracers targeting inflammation that avoid this limitation are in development, but their diagnostic utility remains to be determined. 18

FeNaF and active microcalcification

Macroscopic coronary calcification, as quantified by Agatston scoring, is a recognised marker of cardiovascular

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risk and correlates with overall plaque burden, but in truth reflects a relatively advanced stage in the development of atherosclerotic lesions.64,65 It is increasingly apparent that the plaques most likely to trigger an acute coronary event frequently have minimal calcium content.66 Necrotic debris and matrix vesicles within these high-risk lesions create a nidus for hydroxyapatite crystallisation and these nascent microcalcifications cause strain concentration in the fibrous cap, increasing the likelihood of plaque rupture.67e73 Given that the risk of plaque disruption appears to decrease once these deposits are >65 mm, there is likely a degree of plaque stabilisation before the particles are large enough to be detected with clinical CT. 18 FeNaF is a PET tracer conventionally used in oncology imaging for identifying occult bony metastases.74 It demonstrates avid binding to microscopic hydroxyapatite and was serendipitously recognised to accumulate in a number of arterial locations.75e77 Vascular activity correlates with cardiovascular risk factors and can predict the subsequent

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progression of macroscopic calcification.78 Within the carotid circulation, 18FeNaF localises to plaque regions with increased calcification activity (Fig 2).79,80 Furthermore, in contrast to 18F-FDG, myocardial uptake is minimal, making coronary imaging a viable proposition. One significant characteristic of 18FeNaF binding is that it exhibits a close relationship to the exposed surface area of available hydroxyapatite.80 As large numbers of microcalcifications coalesce into large calcific nodules, there is a corresponding fall in both exposed surface area and tracer binding (Fig 3). This may explain the apparent discrepancy noted in one coronary imaging study where almost half of patients with coronary artery calcium scores >1000 demonstrated no 18 FeNaF uptake (Fig 4).77,81 Importantly, in a prospective study involving patients with myocardial infarction, 18 FeNaF activity was consistently increased within culprit plaques.79 The same group also compared PET-CT imaging with radiofrequency backscatter-intravascular ultrasound in a stable coronary artery disease cohort and found a clear

Figure 2 Histological validation of 18FeNaF uptake in the carotid artery. (aeb) In-vivo and (ced) ex-vivo PET-CT images showing co-localisation of 18FeNaF uptake (yellow-orange) to the site of plaque rupture with adherent thrombus on excised carotid endarterectomy tissue (eef). Histology of the 18FeNaF-positive region shows a large necrotic core (Movat’s pentachrome, magnification 4, g), within which increased staining for tissue non-specific alkaline phosphatase can be seen as a marker of calcification activity on immunohistochemistry (magnification 4, h; magnification 10, i). Re-produced from Joshi et al.79 Please cite this article in press as: Adamson PD, et al., Cardiovascular PET-CT imaging: a new frontier?, Clinical Radiology (2016), http:// dx.doi.org/10.1016/j.crad.2016.02.002

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Figure 3 18FeNaF binds to regions of microcalcification prior to the presence of CT determined macrocalcification. 18Fe NaF binds in relation to the exposed surface area of hydroxyapatite. This explains why uptake is proportionally greatest in the early, active stage of microcalcification whilst the plaque remains vulnerable to rupture. This stage precedes the potential development of stable, macroscopic calcification that is detected by traditional CT imaging. Reproduced from Adamson et al.124

correlation between tracer uptake and high-risk features such as spotty calcification and large necrotic cores.79 It is plausible, although yet to be proven, that as increased 18 FeNaF binding denotes a more active process of calcification, it may consequently prove a better predictor of vascular risk than the anatomical information available from CT coronary angiography. Trials to explore this hypothesis are underway (NCT02278211, NCT02110303).

PET-CT imaging in aortic valve disease Calcific aortic valve disease (CAVD), predominantly manifesting as aortic stenosis (AS), is the commonest form of valvular heart disease in industrialised nations.82 To date, cardiac ultrasound has been the principal investigation for its diagnosis, utilising measures of flow acceleration across

the stenotic valve to classify disease severity. Echocardiography has the benefits of low cost, widespread availability, and lack of ionising radiation, but has an important weakness with regards to understanding the significant heterogeneity seen in rate of disease progression.83 Biologically, CAVD shares many similarities with atherosclerosis, namely, an initiation phase characterised by lipid deposition causing endothelial injury and inflammation, which in turn gives rise to later stages of pathological calcification.84 Consequently, it is a disease process that lends itself to similar PET imaging techniques. A number of investigators have assessed the ability of PET-CT imaging to fulfil this role. One small early study of patients with known AS using 18F-FDG demonstrated a correlation between tracer activity and disease severity, and reported increased uptake to be predictive of more rapid

Figure 4 18FeNaF PET-CT imaging can distinguish active from stable coronary calcification. 18FeNaF binds to regions of nascent microcalcification in proportion to the exposed surface area of hydroxyapatite and does not directly relate to the total volume of atherosclerotic calcification. In individuals with similar CT-determined features of coronary calcification, focal uptake of the tracer can identify plaque undergoing active calcium deposition (a) and distinguish this from macroscopically similar but physiologically stable plaque (b). Please cite this article in press as: Adamson PD, et al., Cardiovascular PET-CT imaging: a new frontier?, Clinical Radiology (2016), http:// dx.doi.org/10.1016/j.crad.2016.02.002

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disease progression.85 The same group subsequently found valvular localisation of 18F-FDG to predict incident development of calcification in individuals without a pre-existing diagnosis of AS.86 Dweck and colleagues performed the largest prospective study to date, involving 121 patients, and covering the entire spectrum of AS severity.87 Each participant underwent cardiac PET-CT imaging with both 18 F-FDG and 18FeNaF. Increasing severity of AS was associated with increased uptake of both tracers, although the correlation was strongest for 18FeNaF. Furthermore, the intensity of the tracer signal also corresponded with the rate of disease progression over 2 years, and, the anatomical location of 18FeNaF binding at baseline predicted the subsequent spatial distribution of de novo calcium deposition (Fig 5).88 Perhaps most importantly, the prognostic value of 18 FeNaF imaging remained, albeit attenuated, after adjustment for recognised clinical risk factors including baseline valvular calcium scoring. Analogous to its proposed role in atherosclerotic disease, PET imaging of CAVD has been purported to offer the dual promise of enhancing our ability to risk stratify patients and providing a valuable surrogate marker of treatment efficacy of potential novel disease modifying agents. With regards to the former proposition, it remains unclear whether the incremental prognostic information offered by currently

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available tracers over simple CT-based calcium scoring is sufficient to justify widespread adoption.89 This situation may change with the introduction of novel targeted radiopharmaceuticals, but for now, the primary role for PET-CT imaging in this context is as a research tool. In this role, a number of interesting projects are underway, including a multicentre observational study of aortic valve bioprostheses to determine whether 18FeNaF PET-CT imaging can inform the process of valve design by enabling early prediction of valve longevity (NCT02304276), and a randomised pharmacological trial testing the ability of calcium-modifying agents to delay disease progression (NCT02132026).

Additional roles for cardiovascular PET-CT imaging Endocarditis and cardiac device infections By identifying occult sites of inflammation, 18F-FDG has important potential to improve the detection of endocarditis and, increasingly, cardiovascular device infections.90 As described in a number of case reports, this has particular relevance in the setting of potential prosthetic valve infections, which are technically challenging to

Figure 5 Change in aortic valve CT calcium score and 18FeNaF PET activity after 1 year. (aeb) Coaxial short axis views of the aortic valve from two patients with mild AS (top and bottom). On baseline CT images (left) established regions of macrocalcification appear white. Baseline fused 18 FeNaF PET and CT images (middle) show intense 18FeNaF uptake (red, yellow regions) both overlying and adjacent to existing calcium deposits on the CT. One-year follow-up CT images (right) demonstrate increased calcium accumulation in much the same distribution as the baseline PET activity. Reproduced from Dweck et al.78 Please cite this article in press as: Adamson PD, et al., Cardiovascular PET-CT imaging: a new frontier?, Clinical Radiology (2016), http:// dx.doi.org/10.1016/j.crad.2016.02.002

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Figure 6 18F-FDG PET-CT in prosthetic device infections. PET-CT of infected composite aorta graft (white arrows) inserted 16 years previously. Note the two foci in the thoracal columna (yellow arrows). Reproduced from Bruun et al.90

exclude on echocardiography (Fig 6).91,92 The recently updated European Society of Cardiology guidelines for the management of endocarditis have proposed supportive findings on 18F-FDG PET-CT imaging be included as a major criterion in determining this diagnosis.93 Such an endorsement is unsurprising given the detrimental consequences that may occur with a delayed diagnosis and this application for PET-CT imaging is likely to be met with enthusiasm in centres where the technology is available.

isotope and the non-radioactive targeting molecule. Radionuclides in current use can have half-lives from a few minutes (e.g., 82Rb and 15O) to more than an hour (e.g., 18F and 68Ga). The scope for molecular targeting of radiopharmaceuticals is near limitless and an ever-expanding list of tracers is being investigated. The most currently available tracers were developed for the purpose of oncology staging and suffer from non-specific uptake when used for cardiac imaging. It seems likely, however, that increasingly targeted agents will become available in the future.

Cardiac sarcoidosis Another niche, but important role for PET-CT imaging appears to be in the detection of cardiac infiltrative disorders. In the setting of possible cardiac sarcoidosis increased myocardial uptake of 18F-FDG not only offers greater sensitivity than SPECT imaging, but can also be analysed quantitatively to monitor disease activity and therapeutic response.94e96 Based on these attributes, patchy myocardial tracer uptake now forms one of the diagnostic criteria for cardiac sarcoidosis and the 2013 European Association of Nuclear Medicine/Society of Nuclear Medicine and Molecular Imaging guidelines endorse the use of 18F-FDG PET-CT imaging in suspected cases.97,98

Cardiovascular PET-CT limitations and future directions Tracer selection The clinical utility of PET imaging is critically dependent on appropriate selection of both the positron-emitting

Cardiac motion and tracer localisation Constrained by the laws of physics, PET imaging has a fundamental limit of spatial resolution that varies to some extent between radionuclides but for tracers employing 18F is in the range of 2e4 mm.99 A more clinically relevant limit relates to cyclical cardiac and respiratory motion that can shift the region of interest by 20 mm or more (Fig 7).100 In order to detect sufficient decay events, the PET scan is performed over a prolonged period, often greater than 15 minutes. The image is then co-registered, based on bed positioning with a CT captured in under a minute and electrocardiogram (ECG)-gated to the diastolic phase of the cardiac cycle. A rough approximation of CT gating can be achieved by only using PET data obtained during the third quarter of the ECG-determined cardiac cycle. This unfortunately represents an imperfect solution resulting in a 75% reduction in PET signal, which increases image noise and still does not allow for the effects of respiration. Fortunately, alternative approaches to address this are in development, such as motion-correction software that can analyse and co-

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Figure 7 Respiratory motion during PET-CT. (aeb) Coronary PET-CT image performed during inspiration showing misalignment of images. The right coronary artery on the CT image (white arrow) is more anterior than the source of tracer uptake identified on the PET signal (red arrow). Similarly the CT determined aortic root (white circle) is anterior to the PET signal arising from active calcification of the aortic wall (red circle). (ced) Unenhanced PET-CT image performed in the same patient during expiration showing close alignment of both the right coronary artery and aortic root images. Re-produced from Adamson et al.37

register list mode PET datasets with CT-derived anatomical models.101 A recent feasibility study reported such an approach to reduce image noise and increase measured tracer uptake values.102

Radiation exposure Enthusiasm for greater adoption of PET-CT imaging must be tempered by a growing recognition of the need to minimise patient exposure to sources of ionising

radiation.103 Keeping exposure “as low as reasonably achievable” need not preclude the use of this technology as effective doses of <5 mSv can be achieved through appropriate patient selection and tailored imaging protocols, which is within the range of alternative imaging techniques.104 The recent introduction of hybrid PET-MRI systems may facilitate further dose reductions creating the potential for serial imaging studies to examine the natural history of molecular processes within cardiovascular tissues.

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Conclusion Cardiac PET-CT has clear potential to improve our understanding of pathological processes, clarify diagnoses, and guide therapeutic advances. To date, cardiovascular adoption of this imaging technique has been understandably restrained by high costs, limited availability, technological challenges, and persistent uncertainty concerning its true clinical value. Regardless, progress towards addressing many of these concerns is occurring and it is likely that barriers to access will fall as demands from oncology services sees systems installed in greater numbers. Already it appears to have established a small but important role in the diagnosis of cardiac device infections and sarcoidosis. It can also be reliably used to detect cardiac ischaemia. Given the important advantages of lower radiation exposure and improved diagnostic accuracy, it may be that PET-CT increasingly supplants SPECT in regions like North America, where nuclear MPI has been widely adopted. In Europe, however, where this use of nuclear imaging remains less common,105 it is unclear whether PET-CT offers sufficient benefits over non-nuclear techniques to merit a change in practice. Whether PET-CT has any role in prognostic stratification of atherosclerotic and valvular heart disease is particularly uncertain and the results of prospective imaging studies will be received with interest.

Acknowledgements P.D.A. is supported by a New Zealand Overseas Training and Research Fellowship (1607) and Edinburgh and Lothian Health Foundation (50-534). M.C.W. and D.E.N. are funded by the British Heart Foundation (FS/11/014 and CH/09/002). D.E.N. is the recipient of a Wellcome Trust Senior Investigator Award (WT103782AIA).

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