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Imaging of the Coronary Arteries

Invited Review

Imaging Coronary Atherosclerosis:

Evolving Towards New Treatment Strategies

AUTHORS

Marc R Dweck MD PhD,1,2 Mhairi Doris MD,1 Manish Motwani MD PhD,3 Philip D Adamson MD,1 Piotr Slomka PhD,3 Damini Dey PhD,3

Zahi A Fayad PhD,2 David E Newby MD PhD,1 Daniel Berman MD.3

AUTHOR AFFILIATIONS

1 British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.2 Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.3 Cedars Sinai Medical Center, Los Angeles, United States

CORRESPONDING AUTHORDr Marc R DweckBritish Heart Foundation/University Centre for Cardiovascular ScienceRoom SU 305, Chancellor’s Building, University of Edinburgh49 Little France CrescentEdinburgh, EH16 4SB, United KingdomEmail: [email protected]: 0131 242 6515 Fax: 0131 242 6379

WORD COUNT: 6979

ABSTRACT: 191

FIGURES: 6

REFERENCES: 124

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Abbreviations

ACS acute coronary syndromeCAD coronary artery diseaseCCTA coronary computed tomography angiographyCVD cardiovascular diseaseECG electrocardiogramFDG fluorodeoxyglucose FRS Framingham risk scoreIVUS intravascular ultrasoundMI myocardial infarctionMR magnetic resonanceNIRF near infra-red fluorescenceNIRS near infra-red spectroscopyOCT optical coherence tomographyPCI percutaneous coronary interventionPET positron emission tomographySPECT single photon emission computed tomographyTCFA thin-cap fibroatheromaUSPIO ultra-small particles of iron oxide

Financial Support

MRD and DEN are supported by the British Heart Foundation (SS/CH/09/002/26360, FS/13/77/30488, SS/CH/09/002/2636, FS/14/78/31020, CH/09/002). DEN is the recipient of a Wellcome Trust Senior Investigator Award (WT103782AIA). MRD is the recipient of the Sir Jules Thorn Award for Biomedical Research 2015. ZF is supported by P NIH/NHLBI R01 HL071021; NIH/NHLBI R01 HL128056 and NIH/NBIB R01 EB009638,

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Abstract

Coronary atherosclerosis and the precipitation of acute myocardial infarction are highly complex processes making accurate risk prediction challenging. Rapid developments in invasive and non-invasive imaging technologies now provide us with detailed, exquisite images of the coronary vasculature that permit direct investigation of a wide range of these processes. These include sophisticated assessments of luminal stenoses and myocardial perfusion, complemented by novel measures of the atherosclerotic plaque burden, adverse plaque characteristics and disease activity. Together these can provide comprehensive individualized assessments of coronary atherosclerosis as it occurs in our patients. Not only can this provide important pathological insights but also information that can potentially be used to guide personalised treatment decisions.

This review describes recent advances in both established and emerging imaging techniques, focusing on the strengths and weakness of each approach. Moreover it discusses how these technological advances might be translated from attractive images in to novel imaging strategies and concrete improvements in clinical risk prediction and patient outcomes. This process will not be easy and the many potential barriers and difficulties to this journey are also reviewed.

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Introduction

Myocardial infarction is the leading cause of death in the Western world and a major health care burden. Whilst treatments have evolved rapidly over the past 50 years, myocardial infarction remains an unpredictable event and one that is frequently the first clinical manifestation of the underlying atherosclerotic disease process. Cardiovascular risk scores based on traditional risk factors are widely employed, but on an individual basis these remain imprecise in estimating the risk of myocardial infarction. The same is true of established imaging techniques, which have largely been developed to identify patients with angina who might gain symptomatic benefit from revascularisation. There is hope that recent rapid developments in coronary as well as myocardial imaging will further improve our understanding of the processes leading to myocardial infarction and ultimately deliver accurate personalized prognostic stratification and improved patient outcomes.

In recent years, advances have occurred in a variety of both invasive and non-invasive imaging techniques. Invasive coronary imaging relies on gaining access to the arterial system and administering contrast media and specially designed catheters down into the coronary vessels. Advances in catheter design and technology now allow for an array of additional invasive approaches, beyond the standard assessments of luminal stenosis. For examples coronary physiology can be routinely assessed using the fractional flow reserve (FFR), whilst coronary plaque imaging has become possible through intravascular ultrasound (IVUS), and, more recently, optical coherence tomography (OCT), near infrared spectroscopy (NIRS) and near infrared fluorescence (NIRF). Each approach provides different capabilities and potentially complementary information. Non-invasive imaging has witnessed similar developments. In assessing physiology, absolute quantitation of myocardial blood flow has become possible. Whilst detailed coronary plaque imaging is now feasible through developments in computed tomography (CT), cardiovascular magnetic resonance (CMR) and most recently positron emission tomography (PET).

In combination, this breadth of imaging technologies can provide a comprehensive, multifaceted evaluation of coronary atherosclerosis. In particular, we can directly evaluate and visualise the functional severity of individual luminal stenoses, the overall plaque burden, high-risk plaque characteristics and even disease activity as atherosclerosis proceeds in our patients. This review will describe the ability of established and emerging imaging modalities to inform about each of these key areas, their relative strengths and weakness and how they are currently employed in clinical practice (Table 1). Importantly it will also discuss how these advances might be utilized in the future, highlighting the potential for synergy between the different approaches but also the many barriers that exist to future translation. Indeed, whilst a new era of advanced imaging and precision medicine for atherosclerosis appears possible, its realization will be far from straightforward.

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Pathology Coronary atherosclerosis is an almost invariable pathological finding from middle age onwards. It is characterised by lipid deposition and modification within the vessel wall, and is frequently accompanied by inflammation and vascular matrix remodeling within discrete coronary plaques. These lesions may result in progressive obstruction of the coronary vascular lumen, causing symptoms of angina due to myocardial ischemia. Alternatively, sudden plaque rupture or erosion of individual lesions may precipitate coronary thrombosis and acute myocardial infarction. Improving our understanding of the processes leading to plaque rupture and erosion is therefore critical, with imaging well positioned to advance this knowledge.

Atherosclerosis is initiated by the deposition of low-density lipoprotein (LDL) within the arterial intima most frequently at sites of low shear stress and endothelial dysfunction. This lipid subsequently becomes oxidised triggering an inflammatory response consisting predominantly of macrophages that engulf lipid particles to form foam cells.1 These initial lesions often remain static for many years or even regress. However, in the presence of particular environmental insults and immune system imbalances, pro-inflammatory cellular phenotypes become established and promote ongoing inflammation, cell death, and proteolysis. Ultimately these processes drive progression towards the complex coronary lesions that are predisposed to acute plaque rupture and adverse events.

Ruptured culprit plaques frequently have specific histopathological characteristics, typified by the so-called thin-capped fibroatheroma (TCFA). These features include extensive inflammation, a large necrotic core, a thin fibrous cap, positive remodeling with a large plaque volume and microcalcification. The necrotic core forms as a consequence of accelerated extracellular lipid deposition, increasing inflammation, oxidative stress, hypoxia and cell death.1 It is separated from the lumen by a fibrous cap. In inflamed lesions this cap becomes thinned and weakened by the action of matrix metalloproteinases, predisposing it to rupture at sites of increased mechanical stress. The consequent exposure of the necrotic core to the circulating blood, can lead to extensive and occlusive thrombus formation causing myocardial infarction. Alternatively a less pronounced thrombogenic reaction can ensue resulting instead in sub-clinical rupture, healing and plaque growth. The factors dictating the magnitude of this thrombotic reaction are not well understood but appear related to both characteristics in the blood and plaque composition.

There is constant tension between pro-inflammatory forces and attempts by the body to heal and stabilize the coronary vasculature. Smooth muscle cells migrate from the arterial media and secrete components of fibrous matrix to strengthen the fibrous cap. Calcification also appears to occur as a healing response to the intense necrotic inflammation and cell death, and to be mediated by extracellular vesicles. However it does so in a two-step process, wherein the initial stages of microcalcification are associated with inflamed, potentially unstable plaques, whilst the later stages of macroscopic calcification appear to impart stability.2 Early mechanistic studies support this hypothesis with early stage microcalcification closely related to macrophage inflammatory activity (R2=0.93), and cell death, whilst regions of advanced calcification exist remote from areas of

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inflammation. 3-5 If the processes of fibrosis and macrocalcification prevail, a thick-cap fibroatheroma or heavily calcified lesion may form, effectively walling off the necrotic core from the blood pool.3 Conversely, in the presence of ongoing macrophage infiltration and the secretion of proteolytic enzymes, the TCFA will predominate.

Whilst the histological features described above typify atherosclerotic plaques prone to acute rupture, up to one third of acute myocardial infarctions are precipitated by a different process.6 Plaque erosion is caused by denudation of the plaque surface, which exposes the subintima and triggers thrombus formation. It is commonly observed in young females and smokers, yet despite its ubiquity the underlying pathophysiology is poorly understood. Myeloperoxidase and increased blood thrombogenicity have been implicated as important factors in the process of plaque erosion.7 However, identification of lesions at risk of erosion remains extremely challenging, largely because their characteristics are highly heterogeneous and different from those associated with plaque rupture. Indeed, current imaging technology has thus far failed to identify plaques at risk of erosion and the patients who have them. This is a major limitation with current techniques for risk prediction and an area in urgent need of further research.

Luminal Stenosis, Haemodynamic Obstruction, Myocardial IschaemiaTo date, imaging assessments of coronary artery disease have largely focused on detecting luminal stenosis, or obstruction to blood flow and downstream myocardial ischaemia (Figure 1). These assessments are widely used to estimate patient risk and to guide revascularization. Indeed, a large body of outcome data support this approach, demonstrating that a greater number of obstructive lesions and a larger myocardial ischaemic burden are both associated with a worse prognosis.8,9 However, the ability of this paradigm to prevent myocardial infarction is increasingly being questioned.

Invasive coronary angiography involves the intra-coronary administration of radio-opaque contrast to opacify the lumen and delineate any existing stenoses. The presence of luminal stenoses in 1, 2 or 3 vessels is associated with a step-wise increase in adverse outcomes.10,11 However, the visual assessment of luminal stenosis correlates poorly with haemodynamic significance, particularly for coronary stenosis between 30% and 80%. While this relationship can be improved using quantitative coronary angiography, multiple factors beyond luminal diameter, such as entrance effects, friction, and turbulence contribute to increased flow resistance across a particular stenosis.12 Therefore, the haemodynamic significance of lesions can be significantly under- or overestimated by assessment of coronary stenosis alone, particularly in the setting of multiple, eccentric, or irregular stenoses. These deficiencies have prompted the increasing use of invasive physiological assessments. Pressure wire-derived fractional flow reserve (FFR) has become the favored technique, providing a lesion-specific surrogate measure of flow limitation derived from the difference in arterial pressure proximal and distal to a coronary lesion of interest during maximal hyperemia. The use of FFR measurements to guide revascularization decisions appears to improve outcomes following intervention compared to standard visual estimations of stenosis13 and has therefore been widely adopted, revolutionizing interventional practice around the world. In particular FFR has helped to ensure that only those lesions causing obstruction to flow undergo intervention.13 Coronary flow reserve (CFR) is an alternative haemodynamic assessment, which can be performed by assessing the ratio of resting and hyperemic flow velocities. This approach assesses the combined

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effects of epicardial stenosis and microvascular disease; however, it has undergone less clinical validation and is less commonly performed than FFR. Catheters allowing simultaneous assessment of FFR and CFR are currently under investigation (DEFINE-FLOW NCT0238820).

Technological advances in CT now allow for high spatial resolution, non-invasive imaging of the coronary arteries. Coronary CT angiography (CCTA) is performed during a breath-hold using scanners with fast detector rotation times. The consequent rapid imaging times coupled with imaging during a breath-hold allows for elimination of problems relating to cardiac and respiratory motion. An extensive body of literature has evolved within a single decade, providing consistent evidence of excellent diagnostic accuracy for assessment of luminal stenoses compared to invasive angiography.14 Similar to coronary angiography, a step-wise deterioration in prognosis associated with 1, 2 and 3 vessel disease has been established in multiple studies using CCTA.15,16 CCTA has also documented the adverse prognosis associated with non-obstructive disease and confirmed the excellent prognosis for patients with a normal CCTA, with low event rates and a “warranty period” that extends for several years.17-19 Whilst difficulty persists with CCTA in patients with advanced calcification and high heart rates, further advances in CT including faster detector rotation times (providing 66 msec imaging with the most recent technology) improved spatial resolution, and dual-energy imaging, hold promise in overcoming these and other limitations. 20,21

The major current strength of CCTA is its negative predictive value, ranging from 95% to 100%. Coupled with the excellent prognosis of patients found to have normal coronary arteries, CCTA is perhaps most useful in ruling out coronary artery disease in those considered low or intermediate risk. The clinical utility of this approach in the emergency department (where most patients presenting with chest pain do not have acute coronary syndrome) has been tested in several randomised controlled trials with a recent meta-analysis demonstrating that CCTA reduced length of stay and provided cost savings, albeit with increased rates of invasive angiography and revascularisation.22 Similarly, in patients with stable symptoms of chest pain, CCTA provides effective risk stratification,23 improved diagnostic accuracy,24 reduced rates of normal coronary angiography, 25,26 better targeted therapy,26 and potentially reduced rates of myocardial infarction.26 These two indications have led to the widespread and rapidly growing adoption of CCTA in routine clinical practice worldwide.

It has recently been shown that CCTA can also be used to provide a non-invasive assessment of the fractional flow reserve (FFRCT). FFRCT

measurements have been evaluated in a recent meta-analysis demonstrating a similar sensitivity to coronary CCTA (83% vs. 86% per-vessel analysis) but improved specificity (78% vs. 56% per-vessel analysis) in the prediction of invasive FFR.27 FFRCT has also been reported to result in better targeted invasive angiography, reducing referrals to the cath lab and the frequency of non-obstructive disease in those patients that subsequently undergo the procedure.28 The potential of this approach to predict the response to percutaneous intervention (“virtual stenting”) has also been explored.29 Whilst of interest, FFRCT

analysis is expensive and it remains unclear how this technology can resolve the important issues of calcium blooming and motion artifact.

Magnetic resonance coronary angiography (MRA)—for assessment of coronary stenosis—is attractive in principle given the avoidance of ionising radiation.

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However in practice major challenges persist in correcting for coronary artery motion whilst delivering the necessary spatial resolution.30 Therefore, although its diagnostic accuracy is improving,31 coronary MRA remains inferior to CT and is rarely used in clinical practice.32

Myocardial perfusion imaging (MPI) can be assessed with radioactive tracers that distribute to the myocardium according to blood flow. In particular single-photon emission computed tomography (SPECT) and positron emission tomography (PET) can measure myocardial perfusion at rest and during stress, identifying regions of reversible ischaemia associated with obstructive luminal stenoses. Large-scale SPECT MPI studies in the 1990s established a step-wise increase in mortality with progressive ischaemic burden,33 resulting in the widespread adoption of this technique to risk stratify patients and guide their management. Indeed these prognostic data, coupled with its availability and physician familiarity, remain SPECT’s principal advantages. PET MPI is similar but allows myocardial perfusion and the coronary flow reserve to be quantified so that balanced ischemia and microvascular disease—processes that pose limitations for SPECT—can both be detected. PET MPI is usually performed with rubidium-82, which has an ultra-short half-life, although 13-N-ammonia and 15-O-water can also be used with an on-site cyclotron.

Hybrid imaging refers to the combination of functional imaging using radiotracers to target specific biological processes (e.g. myocardial perfusion, inflammation with 18F-FDG etc.) with anatomical imaging provided by CT or MRI. Hybrid PET/CT and SPECT/CT scanners allow for CT-based attenuation correction. With these scanners, coronary artery calcification can also be routinely assessed at the time of MPI, facilitating the interpretation of perfusion scans and providing a means for detection of non-obstructive CAD.34 While CCTA can be combined with PET MPI and SPECT MPI in a single scan,35-37 it is difficult to predict in advance which patients need both studies. Further evidence of incremental clinical benefit is required in large cohorts before the increased costs and radiation exposure of this hybrid approach as a routine can be justified in clinical practice.38

Radiation-free MPI is increasingly being performed, particularly in Europe, using cardiac magnetic resonance (CMR) imaging, which assesses the passage of gadolinium-based contrast media through the myocardium. This approach offers diagnostic accuracy that is at least as high as SPECT.39 CMR is of particular value in patients with severe coronary artery disease when additional information related to myocardial viability (delayed gadolinium enhancement) can aid clinical decision-making. Multiple MPI approaches are therefore available: deciding which to perform largely depends on local availability and expertise.

Limitations of the Stenosis-Ischaemia Approach The established imaging paradigm for coronary artery disease is based upon the above assessments of luminal stenoses and myocardial ischaemia. Whilst it is undoubtedly effective in improving the symptomatic status of patients with angina, limitations have emerged in terms of its ability to improve patient outcomes.40 This has led many to question whether we are in fact imaging the correct target. The first evidence to question this approach was the finding that the majority of lesions that go on to rupture and cause MI are in fact non-obstructive on antecedent angiography.41 Although an individual severe stenosis is associated with jet turbulence, reduced shear stress and higher occlusion rates, coronary occlusion and myocardial infarction most frequently evolve from

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mild to moderate stenoses.42,43 This is largely due to their much greater prevalence and also because mild/moderate lesions do not develop the protective collateral circulation often observed in severe, slowly developing stenoses.

The second piece of evidence came from randomised controlled trials comparing PCI with optimal medical therapy in the treatment of patients with established myocardial ischaemia. Despite PCI effectively reducing ischaemia, it failed to improve patient prognosis in either the COURAGE or BARI-2D studies.44

Similarly, in FAME-2, the use of FFR to guide revascularization did not reduce myocardial infarction or cardiovascular death compared to medical therapy– only subsequent revascularization was reduced on primary analysis.45,46 Therefore, whilst ischaemia is clearly related to symptoms, its prognostic value may actually be driven by its association with plaque burden and high-risk plaques, rather than a direct consequence of myocardial hypoperfusion. Recent studies showing a relationship between high-risk plaque features on CCTA and both FFR and myocardial ischaemia support this notion.47,48

For these reasons, and despite the prognostic data from large population studies, assessments of luminal stenosis and ischaemic burden provide imperfect prediction of hard clinical end-points in individual patients. Whilst they remain the current cornerstone of initial diagnostic strategies, awareness of these limitations has led to interest in alternative coronary imaging indices that may improve personalised patient risk-assessment.

Plaque BurdenSimple measures of the atherosclerotic plaque burden can be used as screening tools to assess for the presence and extent of atherosclerosis in a particular patient. Moreover, they provide powerful prognostic information, presumably on the basis that the more plaques a patient has the more likely it is that one will rupture or erode and cause an event. Such measures are possible using both invasive and non-invasive technology (Figure 2).

Intravascular ultrasound (IVUS) employs a miniaturized ultrasound transducer to record the reflection of high frequency sound waves, generating greyscale cross-sectional images of the arterial wall. This provides accurate assessments of luminal dimensions and plaque volume that can aid in the evaluation of luminal stenoses, particularly in the left main coronary artery.49,50 In addition IVUS can provide accurate quantification of plaque burden, acting as a powerful predictor of disease progression and adverse clinical outcomes.51,52 Indeed this feature has been widely utilised in trials seeking to measure the effect of medical therapies on atherosclerosis.53,54 However, in clinical practice, IVUS is time consuming and invasive, and cannot assess severe disease or small vessel disease because of the relatively wide caliber of the IVUS catheter. Global plaque burden is therefore much more easily quantified using non-invasive approaches.

Coronary artery calcium (CAC) scoring using ECG-gated CT provides an accurate and simple measure of the overall atherosclerotic burden in the coronary arteries. Without the need for contrast, it quantifies macroscopic calcium within these vessels, which is pathognomonic of atherosclerosis. Whilst such macro-calcific plaques are themselves usually stable, the CAC score predicts prognosis probably because it provides a surrogate for the number of less stable, adjacent plaques. Many large studies, including two large population based studies, have demonstrated that adding calcium scoring to Framingham

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risk scores improves the prediction of coronary events.55 56Recently, the term the “power of zero” has been described for patients with no evidence by CT of coronary calcification. The long-term prognosis of this population is so good that preventive treatment that would have been indicated by guidelines can be downscaled.57 Recently, multiple additional assessments have been shown to add to the standard CAC score in assessment of prognosis, including the number of vessels with calcium, the plaque location, the number of calcified plaques, the proportion of the coronary tree with plaque, the density of coronary calcification, and plaque diffuseness.58 Whilst CT calcium scoring is increasingly being used in clinical practice the albeit small radiation doses are of some concern when considering repeat imaging or widespread screening programs.

Carotid ultrasound scanning (USS) is a well-established technique that is gaining major interest as a screening tool and method for assessing the atherosclerotic plaque burden. Despite not assessing the coronary arteries directly, it demonstrated equivalent prognostic information to coronary calcium scoring when compared head-to-head in the recent BIOIMAGE study.59 Carotid USS can assess the atherosclerotic plaque burden accurately, quickly (<5 minutes) and without ionizing radiation or the need for contrast. Moreover it is inexpensive and portable so that imaging can be readily performed outwith the hospital setting. This is of importance because carotid USS might potentially allow the screening of populations traditionally beyond the reach of healthcare systems including large parts of the developing world where MI rates are expanding dramatically.

Adverse Plaque CharacteristicsHistopathological post-mortem studies have consistently shown that culprit plaques responsible for plaque rupture and myocardial infarction have certain pathological characteristics including a thin fibrous cap, inflammation, a large necrotic core, intra-plaque haemorrhage and microcalcification. This has prompted extensive clinical research over the past 20 years as investigators searched for these so-called vulnerable plaques, using each of these adverse characteristics as a potential imaging target (Figure 3).

Virtual histology intravascular ultrasound (VH-IVUS) is an invasive technique that uses spectral analysis of the ultrasound backscatter signal to categorise plaque constituents in to fibrous, fibrolipidic, calcific and necrotic tissue in real time with good agreement with histology.60 Whilst other post-processing software systems have been developed including iMAP and integrated backscatter-IVUS, VH-IVUS remains the most widely studied.61

Although VH-IVUS lacks the resolution to image the thin fibrous cap, lesions with necrotic core in contact with the lumen have been termed VH-TCFAs. In the Prospective Natural-History Study of Coronary Atherosclerosis (PROSPECT) study, 596 VH-TCFAs were identified in 313 out of 623 patients.62 Whilst around half the lesions that went on to cause coronary events were VH-TCFAs, the majority of these events were hospitalisations with angina. Importantly only 6 patients had a subsequent myocardial infarction with a further 25 suffering a cardiac arrest or dying from a cardiovascular cause. The vast majority of these VH-TCFAs therefore did not result in an event and, whilst the positive predictive value improved if the presence of a large plaque volume (>70%) and small luminal area (<4.0 mm2) were also considered, this was not high enough to justify individual plaque intervention. Similar results were observed in the VIVA trial, where >600 VH-TCFAs were identified but only 2 patients subsequent sustained a myocardial infarction.60 Likewise in the ATHEROREMO-IVUS study 242

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patients had TCFAs yet only 7 went on to sustain an MI.63 The disappointing results of these three studies may in part reflect the tendency of VH-IVUS to overestimate the true prevalence of TCFA as well as the exclusion of patients with severe obstructive disease who could not undergo IVUS. Nevertheless they also point towards a more profound and general limitation when trying to identify individual vulnerable plaques: that these plaques ultimately do not themselves cause that many clinical events.

Optical coherence tomography (OCT) incorporates an intracoronary fibreoptic wire which emits light in the near infrared spectrum (wavelength 1250-1350 nm) and measures the backscatter from tissues during a rotational pullback along the artery.64 Image acquisition requires the generation of a blood-free field, using small flushes of saline or contrast media.65,66 A key advantage of OCT is its excellent axial resolution (12-18 vs 150-200 µm for IVUS), which permits detailed microstructural analysis of the superficial plaque layers.64 In particular OCT allows imaging of thrombus, plaque rupture and superficial plaque erosion with improved sensitivity than alternative modalities.67,68 It is also increasingly being used clinically to assess stent deployment and for post intervention complications.69 Detailed measurement of the fibrous cap thickness is also possible, providing a means of not only assessing plaque vulnerability, but also of monitoring disease progression and plaque stabilization in response to therapy.70 Interestingly OCT (as well as IVUS) can also be used in combination with computational fluid dynamics to assess local patterns of endothelial shear stress which hold promise in improving the prediction of plaque vulnerability and progression.54,71 However OCT lacks penetration, therefore whilst its ability to identify necrotic core, calcification and even macrophages has been described, it is not well-suited to assessing deeper structures within the plaque or total plaque burden.72

Near infrared spectroscopy (NIRS) exploits the fact that organic molecules absorb and reflect light differently at specific wavelengths. When near infrared light is emitted into a tissue, the spectrum of absorbance therefore reflects its chemical composition.73,74 This technique can be tuned to detect lipid within atherosclerotic plaque creating a ‘chemogram’ that can identify lipid rich lesions and quantify the Lipid Core Burden Index (LCBI).74-76 More recently, combined NIRS and IVUS imaging catheters have been used to measure both the plaque burden and the LCBI, demonstrating improved accuracy in the detection of fibroatheroma.77 In a small cohort of patients presenting with ST-elevation myocardial infarction, NIRS-IVUS imaging demonstrated that LCBI was able to differentiate acute culprit from non-culprit plaques.78 At present this remains a research tool, although the ability of hybrid NIRS-IVUS imaging to identify lipid-rich plaque and to improve cardiovascular risk prediction is currently under investigation (NCT02033694).

Unlike invasive coronary angiography, which only visualises the coronary lumen, CCTA allows assessment and characterization of coronary plaque. CCTA is widely used to categorise individual plaque as being calcified, non-calcified and mixed. Moreover it can be used to provide complete assessments of plaque burden,79,80 and also to identify a range of adverse plaque characteristics, including positive remodeling, low attenuation plaque, and spotty calcification. Positive remodeling is visualised as eccentric plaque formation with relative preservation of the lumen caliber, whilst a large necrotic core is associated with very low attenuation (<30 HU). Although true microcalcification is beyond the resolution of CT, spotty calcification has been described as a marker of early

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calcification and an adverse plaque characteristic.81 Several studies have demonstrated that, compared to patients with stable angina, subjects with acute coronary syndromes have more adverse CT features.81-83 Importantly, identification of such high-risk plaque characteristics also prospectively pinpoints patients at increased risk of subsequent acute coronary syndrome. Motoyama and colleagues studied 3158 patients with CCTA.84 They found high-risk lesions (defined by the presence of both positive remodeling and low-density necrotic core) in 294 patients who were subsequently ten-times more likely to suffer an acute coronary syndrome than patients without such plaque (16% event rate in patients with high risk plaque compared with 1% event rate in those without). A limitation of this approach is that the visual assessment of adverse plaque features is subjective and not highly reproducible, whilst manual quantitative plaque measurements are time consuming. However, automated quantification methods are in development, which have been validated against IVUS and offer promise to provide quick, accurate, reproducible quantitative assessments..85-87

Cardiovascular Magnetic Resonance Angiography provides excellent soft tissue contrast and is able to distinguish multiple high-risk plaque characteristics in the carotid artery. However, as noted above, translation in to the coronary arteries has been difficult due to problems with spatial resolution and cardiac motion. Adverse features such as positive remodeling can be identified in individual coronary arteries.88 However T1-weighted imaging is the only CMR approach capable of simultaneously assessing plaques across all 3 epicardial territories. It uniquely targets methaemoglobin, a component of acute thrombus and haemorrhage that has a very high signal on T1-weighted imaging. However, non-contrast T1-weighted MR imaging lacks spatial resolution and therefore needs to be co-registered with a dedicated coronary MRA before increased signal can be localised to the coronary vasculature. In subjects with angina, high-intensity T1-weighted plaques have evidence of either sub-clinical plaque rupture on OCT or intra-plaque haemorrhage.89 In patients with myocardial infarction, this approach demonstrated a sensitivity and specificity of ~90% for acute thrombus at the site of culprit plaque rupture.90 Similar to the CT data, this MR method for high-risk plaque detection also identifies patients at increased risk of future cardiovascular events. Noguchi et al studied 568 stable patients, of whom 159 were found to have high-intensity coronary plaque on T1-weighted imaging.91 Forty-one of these subjects (26%) subsequently had an adverse coronary event compared to 14 out of the 409 patients (3%) who did not have such plaques, with high-intensity plaque emerging as a strong independent predictor of adverse events on multivariate analysis. Unlike the imaging of coronary plaque with CCTA, coronary plaque imaging with MR remains exclusively investigational at this time.

Relationship Between the Vulnerable Plaque and the Vulnerable PatientThe search for the vulnerable plaque has been extensive and resource intensive, yet this approach has so far failed to impact clinical care. Whilst retrospective studies have successfully linked culprit plaque to different adverse imaging characteristics, prospective studies have suggested that these supposedly high-risk plaques only rarely go on to cause clinical events.62 The most likely explanation for this apparent discrepancy is that the vast majority of “high-risk” plaques actually heal without rupturing. Moreover, it appears that even if rupture does occur, this event is usually sub-clinical resulting in plaque growth rather than myocardial infarction.92,93 As a consequence, vulnerable plaques outnumber the clinical events that they cause and, at the individual plaque-level, appear relatively unlikely to result in myocardial infarction. Whilst combining multiple adverse plaque characteristics appears to improve this positive predictive value,62

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whether this will be sufficient to warrant plaque-specific revascularisation is the subject of considerable debate.94

The clinical CT and MR outcome data described above indicate that there is perhaps more hope that vulnerable plaque identification will prove of clinical utility at the patient-level, pinpointing those subjects at highest risk of myocardial infarction. Vulnerable plaques do not occur in isolation. Indeed, it is more common for multiple such plaques to be present at different sites in the vasculature.95 Whilst many will heal and remain clinically silent, with time other plaques in different locations will also become vulnerable (Figure 3).96 Ultimately during the course of this dynamic disease process, one such plaque may eventually rupture when the blood is sufficiently thrombogenic to trigger coronary thrombosis and myocardial infarction. Therefore, whilst on an individual basis vulnerable plaques may themselves be unlikely to cause events, their identification can help identify vulnerable patients with an active disease state who are at increased risk of myocardial infarction (Figure 3).9 Such vulnerable patients could then be targeted with aggressive systemic therapies to help pacify current and future high-risk plaques across the vasculature. Whilst attractive as a hypothesis, much work is required to assess whether such a strategy is clinically effective.

Disease Activity Increased disease activity is associated with more rapid disease progression, adverse plaque characteristics and a poor prognosis. Both invasive and non-invasive molecular imaging techniques are being developed to measure directly disease activity within the coronary arteries (Figure 4). In principle, any pathological process can be targeted subject to the availability of a suitable tracer and the relevant regulatory approvals.

Near Infrared Fluorescence (NIRF) imaging is an emerging invasive research tool, which can measure disease activity within the vasculature using fluorescent labeled tracers.65 Compared with conventional fluorescent imaging, NIRF utilises the near-infrared wavelength (700-900 nm) increasing tissue penetration and signal-to-noise due to reduced tissue autofluorescence.97 Moreover combined NIRF and OCT catheters have been developed that allow disease activity to be mapped onto precise anatomical images of the vasculature.

To date the only fluorescent agent approved for human use is indocyanine green (ICG), which is used to image the retinal and choroidal vessels. ICG is a water soluble and highly lipophilic fluorescent contrast agent, which binds to both high- and low-density lipoproteins (HDL and LDL).98 ICG localises to inflamed plaque in atherosclerotic rabbits and in excised human carotid endarterectomy specimens,98 perhaps reflecting macrophage phagocytosis of ICG-bound lipoproteins.98 Other more specific NIRF tracers are undergoing pre-clinical evaluation. These include NIRF agents activated by protease activity that localise to inflamed atherosclerotic plaques,99-101 and tracers targeting fibrin that appear to identify the initial stages of intravascular stent thrombosis.102 Much work is required to translate this approach into humans before ultimately trying to demonstrate clinical efficacy.

A new era of non-invasive molecular imaging is with us, allowing us to measure the activity of specific disease processes within the heart.103,104 Hybrid PET/CT systems have led the way, making use of tracers developed largely for oncological indications.105,106 The first PET tracer to be widely studied in the

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vasculature was 18F-fluorodeoxyglucose (18F-FDG). This glucose analogue labels cells with high metabolic requirements, including vascular macrophages which use more glucose than surrounding cells, particularly in hypoxic conditions.107,108 18F-FDG is most commonly assessed in the carotid arteries and aorta, where uptake correlates closely with macrophage burden, is increased in patients following MI109 and localises to the culprit plaque following stroke.107 Indeed this approach is increasingly being used to assess the anti-inflammatory properties of new medication in phase 2 clinical trials, accurately mirroring their clinical efficacy.110-112 Finally, preliminary studies have suggested that the large vessel 18F-FDG signal may provide independent prognostic information. A retrospective study of 513 patients who underwent PET imaging for oncological evaluation (but ultimately did not have cancer or inflammatory disease) showed that aortic 18F-FDG uptake provided independent prediction of cardiovascular events after a median of 4.2 years of follow up (HR 4.71, p<0.001).45,46 Similarly in 1,089 asymptomatic adults being screened for cancer, increased carotid 18F-FDG uptake predicted future stroke with incremental value above the Framingham Risk Score.47,48 Interpretation of these data is limited by the patient populations studied. However the large BIOIMAGE study will address this issue in a prospective cohort of patients with cardiovascular risk factors and help inform as to whether this technique has a role in clinical practice (NCT00738725).

Unfortunately, application of 18F-FDG PET plaque imaging to the coronary arteries has proved challenging.113,114 This is largely because glucose is the predominant energy source of the myocardium and, as a consequence, 18F-FDG uptake in the left ventricle frequently obscures activity within the coronary arteries.115 Interest has therefore grown in the potential use of alternative, more specific PET tracers. One such alternative is 18F-fluoride, a positron emitting tracer which binds preferentially to regions of vascular microcalcification beyond the resolution of CT.116 In so doing 18F-fluoride detects areas of newly developing vascular and valvular calcification. Indeed in the valves of patients with aortic stenosis, 18F-fluoride uptake identifies where new macroscopic deposits of calcium are going to develop and predicts disease progression.103,117

In carotid atheroma, 18F-fluoride uptake localises to culprit plaques and is again associated with histological markers of calcification activity as well as cell death and inflammation.115 In the coronary arteries, increased 18F-fluoride can be localised to individual coronary plaques with little background uptake, identifying patients with high Framingham Risk Scores,118 and plaques with multiple adverse features on VH-IVUS and CT (microcalcification, positive remodeling, necrotic core). 115,119 Importantly 18F-fluoride also precisely localizes to the culprit plaque in ~90% of patients with recent MI, although absolute uptake in this cohort is not as high as in the patients with stable disease. 115,120 Whilst this early research is limited by small patient numbers, the ability of 18F-fluoride PET to identify prospectively patients at increased risk of myocardial infarction is currently the subject of a large multicentre observational study of 700 patients (PREFFIR NCT02278211).

These studies have demonstrated the feasibility of PET imaging in the coronary arteries and that assessing disease activity in these vessels is possible. Moreover, rapid advances in scanner technology and image analysis software now allow PET images to be ECG and respiratory gated and then co-registered with contrast CT scans. This allows more precise localisation of the PET signal within the coronary tree,115 that can be further improved with advanced motion-correction image analysis (Figure 4).121 This approach therefore looks set to be of major utility in the research environment, particularly if novel tracers can be

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successfully developed. Currently alternative more specific PET tracers for inflammation are being investigated including 68Ga-dotatate which is already approved for human use and 18F-fluorodeoxymannose which is not.122,123 The advent of PET/MR also promises progress related in particular to reduced radiation exposure,124 which is high with PET/CT and ultimately may limit its clinical uptake.

Multi-Parametric Imaging Imaging markers of luminal stenosis, myocardial ischaemia, plaque burden, adverse plaque characteristics and disease activity provide complementary information with respect to coronary atherosclerosis, itself a complex, multi-faceted condition. It is hoped that novel imaging approaches combining these different factors might deliver, not only pathological insight, but also major improvements in cardiovascular risk prediction. Early evidence supports this hypothesis. In the study by Motoyama et al, whilst the presence of high-risk CT plaque characteristics identified patients more likely to have a future ACS, risk prediction was improved further when the presence of an obstructive coronary lesion was added to the model.84 Indeed, patients positive for both measures had an ACS event rate of >25% at 4 years: arguably high enough to justify aggressive and expensive treatment strategies. Similarly in the PROSPECT, VIVA and ATHEROREMO-IVUS studies, combining the presence of a TCFA with a luminal area <4 mm2 and a high-plaque burden led to a step-wise improvement in prognostication albeit largely related to subsequent revascularisation procedures.62 Imaging modalities that can evaluate multiple different atherosclerotic plaque characteristics in a single scan therefore hold considerable potential advantages, as do imaging strategies employing more than one modality.

Evolution of Novel Imaging Strategies for Coronary AtherosclerosisThe treatment of coronary artery disease has two major focuses. The first is the identification and relief of anginal symptoms. The second is to identify patients at increased risk of myocardial infarction so that preventative treatments can be introduced and adverse events averted. These treatments include lifestyle measures, simple medical interventions (e.g. aspirin, statins), the treatment of risk factors, and coronary artery bypass grafting in patients with left main stem or multi-vessel disease. We also now have novel agents in particular PCSK9 inhibitors, that dramatically lower LDL cholesterol, have minimal side effects, and are widely anticipated to be highly efficacious. However, these drugs are also extremely expensive. Their use will therefore require careful targeting to those at highest risk, leading to an important potential application of improved risk stratification methods.

Imaging PlaquesThe current paradigm of coronary imaging is based around the detection of discrete areas of obstructive luminal stenoses and the myocardial ischaemia that these cause. Whilst this approach remains of major utility in the relief of angina, PCI guided by these approaches has consistently failed to reduce the incidence of myocardial infarction. Strategies based around identifying individual vulnerable plaques have proved similarly ineffective, being limited by the relative ubiquity of these lesions compared to clinical events. Therefore, despite extensive time, effort and financial investment, imaging strategies targeting individual plaques have largely failed to improve the natural history of atherosclerosis.

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Imaging PatientsAn imaging strategy that instead assesses the atherosclerotic disease process across multiple plaques and territories might prove more effective. Crucially this approach need not rely on pinpointing the individual plaque that will cause an event. Rather it focuses upon identifying vulnerable patients with extensive atherosclerosis, increased disease activity and multiple high-risk plaque characteristics who are at increased overall risk of an adverse cardiovascular event. These plaques may occur anywhere in the coronary or indeed the carotid circulation. The positive predictive value of such a patient-approach is therefore likely to be considerably higher than an individual plaque strategy, allowing treatment decisions to be made with greater confidence of benefit. Moreover it is more closely aligned to the systemic treatments already known to improve prognosis.

How might such a strategy work? We would advocate a tiered approach using simple cheap tests for initial screening followed by more complex scans that would progressively refine patient risk-stratification and direct treatment. One of many potential approaches is outlined here for illustration and would clearly require intensive investigation before it could be recommended (Figure 5). This would involve screening with carotid ultrasound or coronary artery calcification as the first step to identify patients with atherosclerosis and further those with advanced plaque burden. This information could then be used to direct lifestyle interventions, and the targeted prescription of simple medication such as statins and aspirin. Focused screening in high-risk or disadvantaged communities might help maximise cost-effectiveness and clinical impact. Patients found to have advanced plaque burden would then proceed to more advanced non-invasive imaging approaches. We would currently advocate CCTA given its ability to simultaneously assess coronary plaque burden, luminal stenosis and high-risk plaque characteristics and the emerging prognostic data supporting combined assessment of these factors. Patients deemed at high-risk on this scan could then be targeted with intensive and potentially expensive therapies as appropriate (e.g. PCS-K9 inhibitors, dual anti-platelet therapy, revascularisation etc.). In patients with extensive coronary calcification, renal failure, or known coronary artery disease, ischemia testing might be used for further risk stratification and helping guide revascularization decisions. With future imaging development, further tiers of stratification could be added. For example PET imaging could be used in those with adverse CT findings to measure disease activity and to differentiate between patients with active versus burnt out stable atheroma. Invasive imaging would be reserved for those patients being considered for revascularisation, where advanced imaging might help guide and optimise this procedure.

Barriers to future implementationWhilst the past 10-15 years has witnessed a remarkable expansion in cardiovascular imaging technology, considerable work is still required in order to translate these advances in to improved clinical practice. Perhaps the major challenge is demonstrating that these approaches can truly deliver personalised patient management and improved outcomes. Whilst mechanistic and observational data are an important part of that process, randomised controlled trials will be essential to confirm the clinical efficacy of any new imaging modality or strategy.

Another key issue is that imaging is expensive, particularly when compared with risk factor assessments and blood biomarkers. The cost-effectiveness of any

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imaging strategy must be carefully evaluated and demonstrated to be the equivalent of simpler methods. Moreover combined approaches using risk factors and blood biomarkers (e.g. high sensitivity troponin) to select subsequent imaging are attractive and should be explored carefully.

The radiation exposure associated with CT and nuclear imaging must also be considered. In particular this a major concern for any strategy likely to involve repeated scans over a patient’s lifetime. In this context the development of low-radiation and radiation-free imaging remains an important yet challenging goal. Importantly, technologic improvements are leading to marked reduction in radiation dose with coronary CTA as well as with nuclear techniques. Indeed the average radiation dose from CCTA with current scanners and protocols is approaching the 1 mSv mark—one third that coming from annual background radioactivity. Finally, mechanistic studies to improve the remaining gaps in our pathophysiological understanding are crucial. In particular the issue of plaque erosion needs to be addressed and imaging methods developed to better predict this key pathological process.

Conclusions

Advances in cardiac imaging now allow coronary atheroma to be visualised directly using both invasive and non-invasive strategies. This can provide detailed and complementary information with respect to disease burden, luminal stenoses, myocardial ischemia, adverse plaque characteristics, and disease activity. Whilst this has already improved our understanding of the disease process, considerable work remains in order to translate this information in to accurate risk prediction tools and improved clinical care and outcomes for our patients with coronary artery disease.

Key Points

Advances in invasive and non-invasive imaging of the coronary arteries have progressed our understanding of the mechanisms responsible for the precipitation of acute myocardial infarction, a leading cause of death worldwide.

Imaging can provide assessments of luminal stenosis, plaque burden, plaque characteristics and disease activity as well as ischemia. These provide complementary and potentially synergistic information with respect to coronary atherosclerosis.

Advances in imaging techniques offer potential in identifying those subjects at highest risk of myocardial infarction; the vulnerable patient. These patients might then be targeted with aggressive therapy in order to prevent such events from occurring.

The next challenge is to demonstrate that these imaging techniques can have a beneficial and cost-effective impact on cardiovascular outcomes for patients with coronary artery disease.

AcknowledgementsWe would like to thank Dr. Michelle Williams and Dr. Charles Taylor for providing images used as part of Figure 1.

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Table 1. A summary of current and emerging invasive and non-invasive imaging technologies.

Imaging Modality Current or Potential Value Current Limitations or

Future Challenges

Currentlyin Clinical

Use

Invasive

Coronary Angiography

Well established assessment of luminal stenosis. FFR improves identification of haemodynamic

obstruction

Lumenogram: does not image plaque.

IVUSVH-IVUSIB-IVUS

iMAP

Provides assessment of plaque burden and identification of

vulnerable plaque characteristics

Lacks resolution to image fibrous cap and so may

overestimate TCFA.Can only assess disease in

the absence of critical stenoses.

OCT

Excellent axial resolution enables assessment of

superficial plaque features including thrombus, erosion and

stent apposition.

Poor depth of penetration limits assessment of deep

plaque structures and plaque volume.

Lacks outcome data.

Non-invasive

CCTA

High negative predictive value in detecting coronary artery

disease.Can also measure plaque burden & identify adverse

plaque characteristics.

Stenosis severity may be over estimated in the presence of

coronary calcification.Radiation exposure.

Nuclear perfusion imaging (SPECT,

PET)

Widely used to detect myocardial ischaemia.

Extensive observational outcome data.

Radiation dose.Treating ischaemia does not

necessarily improve prognosis.

CMR perfusion imaging

Radiation free assessment of myocardial perfusion.

Similar diagnostic accuracy to SPECT.

Contraindications to CMR (eg cardiac devices).

Lacks its own outcome data.

Emerging Technologies

Invasive NIRS-IVUS Quantification of plaque lipid

burden.Prospective outcome data

awaited.

Non-invasive

MRCA Excellent soft tissue contrast.No ionizing radiation.

Long scanning protocols.Poor spatial resolution.

Contraindications.

PET/CTMeasures disease activity in the

coronary arteries and large vessels.

Radiation exposure. Expense of scanners.

Prospective outcome data awaited.

FFRCT

Non-invasive assessment of FFR. Potential to improve

specificity of CT and improve selection of patients for invasive

angiography.

Extensive image analysis. Impact of artifact unclear.

Investigative Techniques

Invasive NIRFInvasive assessment of

coronary disease activity.High spatial resolution.

Requires development and clinical approval of molecular

tracers and catheters.

Non-invasive PET/MR

Allows disease activity to be measured at low radiation

doses.

Expense & not widely available. Limited MR

assessment of coronary

26


arteries.

27


Figures

Figure 1. Imaging Assessments of Luminal Stenosis, Haemodynamic Figure 1. Obstruction and Myocardial ischemia in Different Patients. Invasive coronary angiogram demonstrating intermediate stenosis in the proximal LAD (a). CT coronary angiogram in the same patient demonstrating >50% stenosis in the proximal LAD (arrow) (b). FFR-CT image, again in the same patient, highlighting that this lesion is functionally significant (FFRct 0.74) (c). PET perfusion measurements of absolute myocardial blood flow during rest (d) and stress (e), resulting in impaired myocardial flow reserve in the inferior wall during stress (arrow). Stress CMR perfusion study with perfusion defect in the inferior wall (arrow) (f). Fused CCTA and CT perfusion images demonstrating stenosis in the left anterior descending artery (white arrow) and a corresponding myocardial perfusion defect in the anterior wall of the left ventricle (purple/black regions) (g). Figures d and e reprinted from Dey et al Circulation: Cardiovascular Imaging 2015;8:e003255.36 Figures a-c are derived from the same patient. Figures d-g represent different subjects.

ca

fed

gb

FFRCT 0.74

28


Figure 2. Imaging of Atherosclerotic Plaque Burden. CT calcium scoring demonstrating macroscopic coronary calcification (a). IVUS of coronary plaque demonstrating outline of vascular lumen (red) and plaque (orange) (b). Cross-sectional black-blood MR image of carotid plaque before (c) and after aggressive lipid lowering therapy (d), demonstrating reduction in plaque area.

Figures c and d reproduced from Corti et al, Effects of lipid lowering by simvastatin on human atherosclerotic lesions, Circulation 2001;104:1524-4539 (permission requested).

a

dc

b

29


Figure 3. Imaging of Adverse Plaque Characteristics. CT coronary angiogram demonstrating an atherosclerotic plaque with evidence of positive remodeling (a), and low attenuation necrotic core (red arrows) (b). MR image demonstrating high-intensity signal on T1-weighted imaging (c) localizing to the left anterior descending artery after co-registration with MR angiogram (d). VH-IVUS image of coronary plaque with evidence of necrotic core (red areas), minimal fibrous tissue (green) and spotty calcification (white) (e). OCT image of ruptured coronary plaque (red arrow) with luminal thrombus (white arrow) (f). NIRS-IVUS image of lipid-rich coronary plaque (yellow signal corresponds to underlying lipid-rich regions) (g). Plaques with adverse characteristics seldom occur in isolation and often affect multiple coronary territories simultaneously (h). Many plaques will heal whilst new vulnerable lesions develop (i). During the course of this dynamic disease process one such plaque may rupture and cause a myocardial infarction (j). Therefore, whilst individual vulnerable plaques may themselves be unlikely to cause events, their identification can identify vulnerable patients at increased risk of myocardial infarction.

Images C and D are reproduced with permission from Noguchi et al JACC 2011.

b

jih

g

dc

e f

a

30

Dweck Marc, 04/06/16,

The red arrows have disappeared


Figure 4. Imaging of Atherosclerotic Disease Activity. Fused PET/CT image of 18F-fluoride uptake within the proximal right coronary artery (a). Motion corrected 18F-fluopride PET image superimposed on rendered CCTA volume with increased uptake within the right, left anterior descending and left circumflex coronary arteries (b). Fused PET/CT image of 18F-fluoride uptake within proximal left anterior descending artery (c). Fused PET/CT image of 18F-FDG uptake within carotid plaque (d) which resolved following 3-month treatment with statin therapy (e). Images of a cadaveric human coronary artery with a stent containing Cy7-labeled fibrin in vitro. (f and g) OCT cross-sectional image with thrombus (yellow asterisks) (f); OCT cross-sectional image with stent struts and micro-thrombi (yellow asterisk) (g); NIRF cylindrical rendering of fibrin signal acquired using a dual-modality imaging catheter (h), with increased signal corresponding to the sites of thrombus formation on the stents.

Figure b reprinted from Rubeaux et al, Journal of Nuclear Medicine 2016; Jan;57(1):54-9 Figures d and e reprinted from Tahara et al, Journal of the American College of Cardiology 48(9):1825-31 copyright 2006. Permission requested.Figures f, g and h reprinted by permission from Macmillan Publishers Ltd: Nature Medicine;17(12):1680-84, copyright 2011.

b

d e

c

a

LCX 1.8

LAD 2.4RCA 1.6

h

gf

31


Figure 5. Imaging Pathway for the Assessment of Patients with Chest Pain.Following initial clinical assessment, symptomatic patients with suspected angina may be assessed by non-invasive imaging modalities (either CT or perfusion imaging depending on local expertise) to identify the presence and extent of perfusion abnormalities or obstructive luminal stenoses. These results can then be used to stratify risk and guide the prescription of medical therapy. In patients identified as high-risk (e.g. by the presence of 3 vessel disease or a large ischaemic burden), or in those with recalcitrant symptoms, invasive coronary angiography should be performed with adjuvant FFR or IVUS as necessary. These tests can then guide the need for revascularisation by percutaneous coronary intervention or coronary artery bypass grafting.

High-riskLarge Ischemic Burden

3VD / LMSOngoing Symptoms

RevascularisationPCI

CABG

Lifestyle ModificationOptimal Medical Therapy

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Figure 6. Possible approach using multi-modality imaging to stratify risk in patients with atherosclerosisAdvances in imaging technology now allow multiple different atherosclerotic features to be assessed using both invasive and non-invasive technology. The challenge is to use these advances to improve patient risk stratification, to guide clinical management and ultimately to reduce adverse cardiovascular events. A possible future approach to patient assessment and risk stratification is presented. Initial screening with risk factor assessment and simple strategies to measure plaque burden may be used in large populations, guide lifestyle interventions and the prescription of aspirin and statins. In those with advanced plaque burden more advanced imaging using assessments of luminal stenosis, myocardial ischemia and plaque characteristics can then be used to identify those at the highest risk of future events. Combined information is likely to provide complimentary results. These vulnerable patients could then be targeted with powerful yet expensive systemic therapies that are emerging (e.g. PCS-K9 inhibitors) or dual antiplatelet therapy where the potential for bleeding may be outweighed by the high cardiovascular risk. As further data emerges, the use of hybrid imaging (e.g. PET/CT) may further refine advanced non-invasive risk stratification, differentiating patients with active disease versus those with burnt out stable atheroma. Finally, in those patients being considered for revascularisation, advanced invasive imaging including FFR and other emerging approaches can be used to optimise decisions regarding percutaneous intervention (PCI) or coronary artery bypass grafting (CABG).

33


Adverse Plaque Characteristics

CCTA

Number of patients affected

Potential clinical impact

AdvancedImaging

Invasive Imaging

Luminal Stenosis & IschaemiaCTCA, SPECT

(FFRCT)

(Disease Activity)PET/CT

Plaque BurdenCarotid UltrasoundCT Calcium Scoring

Invasive Coronary Angiography

FFR, NIRS, IVUS, OCT, NIRF

Clinical Assessment Cardiovascular risk factors, risk scores

Non-Invasive Imaging

Aspirin, statins

Lifestyle modification

PCI CABG

Aggressive systemic therapy

e.g. DAPTPCSK9 inhibitors

34