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Describe the concept of the vulnerable plaque and features associated with vulnerability.
Discuss techniques that may be useful for the identification of potentially vulnerable plaques.
Suggest how these imaging strategies may inform development of plaque stabilisation therapies.
Worldwide more than 17 million people die every year from cardiovascular disease (CVD) with this number projected to increase to over 23 million by 2030.1 Within Europe, CVD results in four million deaths annually, accounting for 47% of all-cause mortality. Between them, heart attacks and strokes are responsible for around 80% of this mortality.2 The vast majority of acute ischaemic vascular events occur in relation to an underlying atherosclerotic plaque. Plaque rupture is the dominant initiating event, responsible for 60–70% of acute coronary syndromes (ACS), while plaque erosion is responsible for most of the remainder.3 ,4 Irrespective of the mechanism, the consequence is exposure of a thrombogenic substrate to circulating blood. This in turn triggers platelet aggregation and the coagulation cascade which compromises vascular blood flow resulting in downstream end-organ ischaemia and infarction. These events occur abruptly and often without warning. Despite intensive therapies, they recur in as many as 25% of patients.
Until recently, the high-risk plaque has only been identified by retrospective analysis, predominantly from pathological examination of autopsy specimens. This has limited our ability to appreciate the dynamic nature of plaque vulnerability and rupture, and has placed a heavy reliance on invasive angiography to describe the anatomical luminal stenosis severity rather than plaque biology. Prospective identification of plaque rupture events has suggested that the majority of culprit lesions is non-flow limiting, and often overlooked by angiographic and traditional functional investigations. Novel imaging techniques now have the potential to identify the pathological structures and processes associated with plaque rupture. This in turn has raised hopes for strategies targeted at modifying the natural history of these lesions and a new era of stratified, or ultimately personalised, medicine may be dawning.
This article aims to provide readers with an overview of the current status of the identification of high-risk atherosclerotic plaque, how emerging investigative technologies have furthered our understanding of the natural history of vulnerability and the implications that this knowledge may pose for established or novel therapeutic strategies. Here, we will principally focus on the process of plaque rupture resulting in coronary and cerebrovascular events.
Atherosclerosis describes the process of lipid accumulation and modification within the vascular wall that underlies the development of arterial plaque. It arises from a complex interplay of local factors, such as vascular shear stress patterns and endothelial injury: in addition to systemic mediators, including circulating lipoproteins, hperglycaemia, environmental exposures and genetic predispositions. Fundamentally, it is a chronic inflammatory disorder governed by cellular and humoral components of the immune system.5 Its process can be subdivided into overlapping stages, which may remain clinically silent, or progress to the development of acute or chronic symptoms.
By early adulthood, there is near universal development of adaptive intimal thickening whereby vascular smooth muscle cells (VSMCs) accumulate within the superficial layers of the vessel wall at sites of low endothelial shear stress (ESS).6 ,7 Concomitantly these regions retain low density lipoproteins (LDL) which bind to subendothelial proteoglycans.8 Enzymatic reactions induce oxidisation of LDL and drive endothelial and VSMC expression of cellular adhesion molecules that promote migration and differentiation of circulating monocytes. The resultant scavenger macrophages in turn, phagocytose lipids and become foam cells within the developing ‘fatty streak’ or xanthoma.9 Many of these lesions remain dormant or regress while others develop an acellular lipid pool (pathological intimal thickening). In some cases a fibroatheroma forms as persistent apoptosis and necrosis of macrophages and VSMCs generates a necrotic core overlain with a collagen-rich surface layer. The direction of atherosclerotic progression reflects the relative balance of certain cellular subtypes of the innate and adaptive immune systems, predominantly macrophages and T helper (Th) cells, respectively. Acting via secreted cytokines, M1-type macrophages and Th1 lymphocytes promote chronic inflammation, in contrast to mediators released from M2-type macrophages and Th2 lymphocytes that attempt to pacify this process.10–13 Fortunately in the majority of cases a stable lesion phenotype emerges comprising abundant fibrotic and calcific tissue. Alternatively, ongoing expansion of the necrotic core and degradation of surface collagen may result in the archetypal high-risk plaque: the thin-cap fibroatheroma (TCFA). The hallmarks associated with vulnerability can be loosely categorised as those either related to the macroscopic structure of the plaque or to the biological processes occurring within it. Indeed histological and imaging data have consistently demonstrated that culprit plaques responsible for myocardial infarction have the following characteristics: a large plaque volume and lipid necrotic core, positive remodelling, peripheral neovascularisation, a thin fibrous cap, microcalcification, intraplaque haemorrhage (IPH) and chronic inflammation. Each of these represents a potential imaging target for in vivo identification of high-risk plaques and for guiding subsequent therapeutic modification (figure 1).
Why the vulnerable plaque?
Before considering how to identify vulnerability, it is important to discuss the benefits of attempting to do so. Indeed, given that the underlying paradigm has been recognised for many decades and has only had modest impact on clinical care, it could be argued that we should abandon this objective in favour of the broader concept of managing the vulnerable patient. In reality, both of these strategies are worthy of pursuit if we are to reduce the morbidity associated with CVD. It is important to note that the process of vulnerability is not localised to a single plaque but reflects a high-risk internal milieu. Autopsy and in vivo imaging studies describe two distinct patient cohorts exhibiting contrasting natural histories. Patients with unstable coronary artery disease have an underlying proinflammatory state, with evidence of pancoronary vulnerability, high rates of coincident vulnerable plaques at baseline and the tendency to develop more over time. This translates in to high rates of plaque rupture, more rapid disease progression and a predisposition to myocardial infarction. Meanwhile the opposite appears true for lower-risk individuals with stable coronary artery disease, who have little in the way of disease activity, few vulnerable plaques and low event rates.14–18 In this way while not all vulnerable plaques will go on to cause cardiac events, identification of their widespread presence might more objectively identify vulnerable unstable patients at increased cardiovascular risk.
Imaging the vulnerable plaque
Ongoing delineation of the essential elements of vulnerability has paralleled a corresponding expansion in diagnostic approaches (table 1 and figure 2). The scope of technologies includes invasive and non-invasive imaging techniques that can be combined with the use of novel targeted probes to identify structural features or physiological processes of interest. These molecular markers remain largely preclinical but promise further insights into in vivo plaque biology. Coupling these tools with additional advances in systemic biomarkers raises the future potential for a stratified population-based approach to risk assessment and management (figure 3).
Non-invasive plaque imaging
B-mode ultrasonography is a readily available tool for assessing carotid plaque. Its key role to date has been in the quantification of stenosis severity, which correlates modestly with cerebrovascular clinical events and can help determine the relative merits of revascularisation.19–21 Measurement of the carotid plaque thickness (carotid intima-media thickness) is also possible, providing a measure of plaque burden that has been frequently employed as a surrogate end point in clinical studies. Beyond stenosis and wall thickness, it is possible to use plaque echogenicity to assess tissue composition with echolucent lesions demonstrating features of vulnerability including high lipid content, IPH and inflammation.22–24
CT angiography provides high spatial and temporal resolution imaging. In addition to describing luminal stenosis, its key strength lies in the capacity to image the vascular wall enabling quantification of atherosclerotic burden and detailed plaque characterisation that compares favourably with intravascular imaging and histology.25–30 CT calcium scoring quantifies the macroscopic calcification in the coronary arteries. Calcification is believed to occur as a healing response to intense plaque inflammation, reflecting an attempt at sequestration akin to chronic granulomatous disorders such as tuberculosis.31–33 The macroscopic calcium visible on CT (>200 µm) occurs in the latter stages of this process and has been associated with increased plaque stability.34 Although CT calcium scoring does not identify high-risk plaques directly it does provide a surrogate marker of plaque burden and powerful prediction of cardiovascular events, presumably on the basis that the mores plaque a patient has the more likely one is to rupture and cause an event.35 ,36 Detecting calcification earlier in its development may improve risk prediction by identifying inflamed plaques that are still in the process of healing. Indeed recent CT-derived evidence supports a much more nuanced role for calcium in plaque rupture with risk inversely related to mineral density.37 Microcalcification (5–50 µm in diameter) represents the very earliest stages of this healing process38 ,39 and has been consistently associated with high-risk and culprit atherosclerotic plaques. In part this may reflect the residual inflammation in the plaque and in part because finite element analysis has demonstrated that these deposits dramatically amplify tensile stresses within the cap.40 A critical window of microcalcification size (5–65 µm) can concentrate sufficient stress to overcome the structural integrity of the fibrous cap41–44 and therefore directly predispose to rupture.
CT imaging has additionally reinforced our recognition that arterial expansion begins early in plaque development and that substantial plaque growth can be accommodated by this positive remodelling without luminal compromise. Mechanistically it appears that macrophages are central in this process by releasing proteases into the necrotic core that have a similar degradative effect on the arterial wall as they do on fibrous cap.13 Experimental arterial models derived from in vivo imaging data have revealed how positive remodelling promotes low ESS and high plaque wall stress—both key contributors to vulnerability.45–47 From a clinical perspective, the CT detection of low attenuation plaque within a positively remodelled coronary segment shows clear association with additional features of plaque vulnerability and may act as a surrogate marker for the presence of TCFA.28 ,29 ,48 In one prospective study the presence of these two features in combination resulted in a 40-fold increase in clinical events.49
MRI avoids the use of ionising radiation, provides excellent soft tissue contrast, and, within the carotid artery can distinguish stable fibroatheromas from those with thin or ruptured caps.50 One particularly important attribute is the ability to detect neovascularisation and resultant IPH. This process occurs within the expanding and increasingly hypoxic necrotic core that causes immature microvessels to develop from the vasa vasorum. This vascular network is fragile and prone to IPH that in turn provokes further inflammation and plaque growth.51 Autopsy studies have suggested a relationship between IPH and clinical events52 but it has been unclear whether the plaque haemorrhage triggered plaque rupture or vice versa.53 Prospective serial imaging studies of the carotid circulation with MRI support the former hypothesis and have associated the presence of IPH with an annualised cerebrovascular event rate approaching 20%.54 ,55
Assessment of coronary atherosclerosis has previously proven challenging as a result of modest spatial resolution, long scan times and cardiac motion. Attempts to address these issues are ongoing and, under optimal conditions, it now compares favourably with CT for anatomical detection of coronary stenoses.56 ,57 The presence of high-intensity coronary plaque on T1-weighted images corresponds with high-risk plaque features as determined by intravascular ultrasound and is similarly predictive of future cardiac events.58 ,59
Tissue characterisation can be further improved through the use of gadolinium-based contrast media that accumulate in regions of plaque inflammation and a variety of targeted contrast agents are now also under investigation.60–62 The majority remain preclinical although ferumoxytol, an ultrasmall superparamagnetic particle of iron oxide, has approval for clinical use and may allow non-invasive detection of tissue macrophages.63
Nuclear imaging (positron emission tomography and single-photon emission CT)
Single-photon emission CT (SPECT) and positron emission tomography (PET) allow in vivo assessment of structural and physiological features of plaque that may predict vulnerability. Both report the distribution of a chosen tracer with remarkable sensitivity, detecting concentrations in the picomolar range, creating the ability to develop specific agents with unique targets of interest.64 Until recently PET and SPECT were hampered by poor spatial resolution (∼4 mm for PET, ∼10 mm for SPECT). This limitation is being addressed with the introduction of hybrid imaging whereby PET scans can be co-registered with high resolution CT or MRI.
The scope of targeted radiopharmaceuticals is near limitless and is comprehensively described elsewhere.65 ,66 With regards to PET tracers, most remain in early development stages except 18F-fluorodeoxyglucose (18F-FDG) and 18F-sodium fluoride (18F-NaF) which have been used for several decades in the oncology setting and more recently adapted to vascular imaging. 18F-FDG is a radiolabelled glucose analogue that is taken up by metabolically active tissues and indicates increased macrophage activity within plaque.67 Uptake in carotid atherosclerosis is associated with recent cerebrovascular events,68 corresponds with high-risk plaque features such as positive remodelling and ulceration,69 and predicts recurrent ipsilateral events.70 Similar uptake can be seen in a wide variety of vascular territories including the coronary arteries.71 Unfortunately, as a non-specific metabolic marker, coronary imaging is made difficult by intense uptake in the closely adjacent myocardium that represents a significant challenge to the future coronary application of this tracer.72
18F-NaF demonstrates avid binding to hydroxyapatite with minimal myocardial uptake. It was recently discovered to accumulate in a variety of vascular wall locations and represents a unique tool for in vivo detection of early active microcalcification below the limits of detection by CT.73 ,74 In support of this hypothesis are several intriguing studies demonstrating tracer accumulation is not always concordant with CT determined calcification but instead predicts the subsequent development of advanced cardiovascular calcification.75–77 Its potential for identification of vulnerable plaques has been assessed in peripheral and coronary vessels, and histologically validated with carotid endarterectomy specimens.73 ,75 ,78 In patients with clinically stable coronary disease it predicts the presence of high-risk features on intravascular imaging. Finally, in patients with recent myocardial infarction, it appears to identify accurately the culprit plaque.78 Further studies seeking to replicate these findings prospectively in larger, multicentre cohorts are now underway (NCT02110303, NCT02278211).
Coronary flow dynamics
Routine revascularisation of stenoses assessed solely by coronary angiography has not been shown to reduce the risk of future cardiovascular events when compared with optimal medical therapy.79 However, augmenting visual assessment with the use of fractional flow reserve (FFR) determined myocardial ischaemia, does reduce rates of urgent revascularisation, indeed on this basis, the FAME-II trial was terminated early. Yet this trial was similarly unable to demonstrate a reduction in the rate of myocardial infarction,80 leading many to question whether obstruction to flow in the coronary arteries contributes importantly to the risk of plaque rupture. From a mechanistic perspective it seems plausible that disturbed coronary flow and the consequent changes in shear and mechanical stresses, induced by these FFR positive lesions, would contribute to atherosclerotic progression and plaque rupture. The PREDICTION study, using 3D vascular profiling, identified the presence of low ESS distal to the site of maximal stenosis to predict progressive loss of luminal area and increase in plaque burden.81 Furthermore, it appears that plaque-mediated pertubations in shear stress may promote platelet sensitisation, lowering their threshold for activation and potentiating the risk of subsequent thrombosis.82 ,83 Whether such assessments of haemodynamic obstruction can help predict myocardial infarction in isolation or when incorporated into clinical risk prediction models remains unclear and a topic of great clinical relevance.
Perhaps the most comprehensively investigated diagnostic tool for plaque vulnerability is intravascular ultrasound (IVUS). Using an intracoronary catheter, detailed grey-scale images of the vessel wall can be obtained and analysed in real time. More recently, software using spectral analysis of radiofrequency backscatter has been developed to allow crude tissue characterisation. This technique was validated with ex vivo histology and correlates with four plaque tissue types: fibrotic, fibrofatty, calcific and necrotic.84–86 Three important prospective studies have sought to determine whether features detected on IVUS might predict plaque-related recurrent events. The strongest predictors were virtual-histology-IVUS determined TCFA, large plaque burden and reduced luminal area but unfortunately these characteristics were too ubiquitous and had insufficient predictive accuracy to be of significant clinical use.87–89
Optical coherence tomography
Frequency-domain optical coherence tomography (OCT) makes use of the shorter wavelength of light and this increases spatial resolution by an order of magnitude compared with IVUS. However, this increased resolution is at the cost of reduced tissue penetration (1–3 mm) and the requirement for a blood-free field, usually generated by contrast flushing during imaging.90 With an axial resolution of 10–20 µm, OCT has greater sensitivity than IVUS for detecting plaque rupture,91 and, importantly allows in vivo diagnosis of plaque erosion as a cause of ACS.6 ,92–95 Plaque characterisation is feasible with cholesterol and calcific deposits producing low backscattering signal while fibrous tissue produces high backscatter.6 It may even be possible to detect macrophage accumulation.96 ,97 The greatest advantage of OCT, however, is the ability to determine directly the integrity of the fibrous cap and make accurate measurements of cap thickness: a vital contributor to plaque vulnerability and potential target in future therapeutic trials.98
Spectroscopy is a well developed tool within analytical chemistry for identifying organic molecules. The underlying principle relates to different molecular bonds absorbing light at specific wavelengths. An intracoronary imaging catheter is now available that determines coronary plaque composition based on its characteristic spectroscopic signature.99 It employs the ability of near-infrared light (780–2500 nm wavelength) to ‘see’ through blood and uses an automated algorithm to generate a longitudinal image of the scanned artery known as a ‘chemogram’. A numerical score, known as the lipid core burden index, can be calculated. Recently a coronary catheter that combines near-infrared spectroscopy (NIRS) and IVUS imaging components has become available allowing both techniques to be performed simultaneously with accurate co-registration of images. Validation studies have been performed ex vivo and compared with histology in explanted hearts,100 and in vivo in the Spectroscopic Assessment of Coronary Lipid trial.101 The ability of NIRS-IVUS hybrid imaging to detect vulnerable plaques is currently being assessed prospectively in the Lipid Rich Plaque study (NCT02033694).
Raman spectroscopy is a related technique being investigated for plaque characterisation based on light scatter between molecules creating a unique shift in reflected frequency. It has the potential to determine individual chemicals with greater specificity than NIRS but has been more difficult to implement in vivo and it remains a research tool.102
Two important and inter-related pathways in imaging the vulnerable plaque are in progress. The first of these relates to the development of a broad array of molecular markers targeted at specific characteristics present in high-risk lesions. These probes can be conjugated with tracers that can be detected by existing imaging tools such as PET.66 Second there are a number of additional intracoronary imaging modalities under investigation. One of the most interesting of these is near-infrared fluorescence that detects, with high sensitivity, fluorochromes coupled with probes that bind to molecular indicators of plaque biology, identifying features such as protease activity or fibrin deposition.103 ,104 near-infrared fluorescence, when combined with either IVUS or OCT, holds the potential to allow simultaneous hybrid structural and functional imaging.105 ,106 Such developments, however, remain preclinical to date and are described in more detail elsewhere.107–109
What are the clinical implications of identifying the vulnerable plaque?
While the ability for serial, non-destructive plaque imaging creates the opportunity to better understand plaque biology and the processes by which atherosclerotic lesions develop over time, the ultimate goal of identifying high-risk plaques is to provide accurate event prediction and enable targeted interventions. This could allow more intensive pharmacological strategies in high-risk individuals or potentially procedures that target focal plaque stabilisation. Alternatively, it may obviate the need to use expensive novel therapies in those unlikely to derive benefit thereby optimising use of limited resources. Although this ideal remains an elusive long-term goal, we believe there are important additional opportunities for detailed plaque characterisation that justify continued research.
Therapeutic targeting in primary and secondary prevention
In addition to encouraging healthy lifestyle modification, consensus guidelines for the management of asymptomatic individuals identified to be at elevated cardiovascular risk frequently recommend pharmacological interventions including antiplatelet agents, as well as blood pressure and cholesterol lowering medications. Such a strategy results in substantial overtreatment and undertreatment given most patients would remain asymptomatic in the absence of intervention, and, an important minority continue to have clinical events despite it. A similar dilemma exists in individuals with known, clinically stable vascular disease, or high-risk patients undergoing non-cardiac surgery. These groups are typically already receiving aspirin and statin therapy, and the evidence for further treatment escalation in the absence of ongoing symptoms is currently unclear. It seems plausible that determining the widespread presence or absence of vulnerable plaques in these cohorts may allow incremental gains in patient risk stratification and more rational drug prescribing.
Improved efficiency of drug development
Novel cardiovascular medications are continually in development but large-scale, long-term trials to determine their clinical benefits are costly to perform and create unfortunate delays in their use. Evidence is now emerging that techniques to monitor plaque vulnerability may provide useful surrogate end points that can inform and focus the findings of later Phase III studies. Proof of principle for this concept was seen in two statin studies using 18F-FDG PET imaging of vascular inflammation that have shown reductions independent of their effect on LDL (figure 4), lending support to the much discussed pleiotropic effects of this drug class and perhaps explaining the benefit of rosuvastatin in patients with normal cholesterol concentrations but elevated C reactive protein.110–112 In contrast, inhibitors of proinflammatory lipoprotein-associated phospholipase A2, failed to modify PET determined vascular inflammation, which predicted the subsequent failure to improve hard clinical end points in a larger clinical trial.113–115 A similar relationship was seen in a study of dalcetrapib—a cholesteryl ester transfer protein inhibitor—where no impact on vascular inflammation was detected pre-empting the neutral findings of the subsequent trial assessing clinical end points.116 ,117 The impact that other novel lipid lowering agents may have on plaque stability in humans is unknown, but promisingly, the PCSK9 antibody alirocumab reduced plaque macrophage and necrotic core content while increasing collagen in a mouse model of atherosclerosis.118 It is easy to see how a similar approach using features of coronary plaque vulnerability as surrogate markers of treatment efficacy could be applied to a broad spectrum of pharmacological interventions. Meanwhile it is also worthwhile considering the role of coronary stenting in plaque passivation. The pilot SECRITT trial performed serial OCT imaging of non-obstructive TCFA before and 6 months after stenting and demonstrated an increase in fibrous cap thickness. A similar study using IVUS determined vulnerability in a larger cohort to guide implantation of an absorbable scaffold is ongoing (NCT02171065).
Optimised management of patients with acute coronary syndromes
The current invasive approach to the management of ACS is to stent the culprit lesion with the intention of relieving luminal obstruction and stabilising the plaque surface. In practice, this strategy is typically driven by the severity of angiographic stenosis, which, particularly in cases of multifocal lesions, may not always correlate with the true location of culprit plaque rupture. Accurate identification of ruptured or vulnerable plaques however, could be employed to reliably determine the culprit site and additionally guide decisions concerning the optimal interventional strategy for non-culprit lesions. This has particular importance in light of recent trials suggesting patients may benefit from early and complete revascularisation of high-risk bystander disease.119 ,120
Questions also remain around how to manage the 10% of patients with ACS with no obstructive disease identified on angiography.121 The ability to determine if plaque rupture is to blame or an alternative diagnosis, coronary or non-coronary, should be considered has major therapeutic and prognostic implications. The potential benefits of this approach were raised by one report suggesting OCT diagnosed plaque erosion may be safely managed conservatively without coronary stenting.93
Limitations of the vulnerable plaque paradigm
It is important to recognise that despite the years of research undertaken, our ability to predict with certainty which plaque will result in a future cardiac event remains suboptimal. Three points in particular are worth noting.
Plaque vulnerability is multifactorial
Most investigative tools provide information on a limited number of features of plaque vulnerability. For example, CT angiography can detect the presence of spotty calcification and positive remodelling but cannot measure fibrous cap thickness or describe the inflammatory processes occurring within the necrotic core. Correspondingly, OCT can accurately quantify cap thickness but has limited capacity to describe tissue characteristics deep within the plaque. This in part may explain the ubiquitous nature of these high-risk imaging features and the observed low predictive value. Accurately predicting which plaques will rupture or erode is a major challenge that is likely to require hybrid or multimodal imaging approaches so that multiple high-risk features can be identified simultaneously and the predictive capability improved.
Vulnerable plaques are common, clinical events (comparatively) rare
In many cases, potentially vulnerable plaques may heal without surface disruption. Additionally, plaque erosion or rupture can occur in the absence of clinical symptoms. Multiple such events may occur concurrently, either in the coronary circulation or elsewhere in the vascular system and the resultant, non-obstructive thrombus is organised and becomes incorporated into the underlying atherosclerotic lesion.3 ,15 ,16 ,122 An individual plaque focused approach may therefore not be feasible.123 However at the patient level it may be that individuals with the greatest number of vulnerable plaques are statistically more likely to experience a clinical event. Again we believe an integrative approach is likely to be most successful, perhaps combining such measures of vulnerability/disease activity with assessments of plaque burden, and haemodynamic obstruction to provide complimentary prognostic information. However it should be noted that other non-plaque related factors may also need to be considered including the coagulations status of the blood, environmental exposures and myocardial sensitivity to ischaemia.124
Predicting plaque erosion remains elusive
Plaque erosion events can be determined on OCT as the presence of luminal thrombosis with an intact fibrous cap. Eroded culprit plaques tend to show more advanced stenosis and greater inflammation than non-eroded non-culprit plaques but are less stenotic with fewer macrophages and T lymphocytes, less calcification and thicker caps when compared with ruptured culprit plaques.125 ,126 The underlying lesion morphologies are heterogeneous including pathological intimal thickening and fibroatheroma making prospective identification challenging.127 Given around a third of all ACS are related to plaque erosion, this represents a substantial cohort unaddressed by current approaches to detecting vulnerability although novel molecular techniques targeting myeloperoxidase, an important feature in eroded plaques, are under investigation.128
The vulnerable plaque is the focal manifestation of a systemic process. It directly contributes to the majority of acute cardiovascular events and is consequently responsible for substantial morbidity and mortality. Recent advances in imaging have improved our ability to detect this lesion in vivo and may offer the possibility for prospective identification. Unfortunately vulnerable plaques are common in relation to clinical events and it remains to be clarified which are the critical determinants of the divergent natural history of these apparently high-risk lesions. Nevertheless, progress is being made and already we have seen tantalising hints of the impact such knowledge may have on patient care. Ultimately it is to be hoped that these advances will enable truly personalised approaches to prognostication and implementation of therapeutic strategies.
Acute cardiovascular events typically occur unpredictably and the incidence of such events remains high despite current approaches to risk assessment and management.
The majority of such events arise from thrombus formation on the surface of a disrupted atherosclerotic plaque resulting in end-organ ischaemia.
Autopsy studies have identified a number of features that are commonly present in these lesions giving rise to the concept of the so-called ‘vulnerable plaque’. These features include thin fibrous caps, large necrotic cores, active inflammation, microcalcification and positive arterial remodelling.
The vulnerable plaque does not occur in isolation but reflects a systemic inflammatory process with a high prevalence of coincident high-risk plaques present throughout the entire vascular system. Identifying the vulnerable plaque consequently implies the presence of a high-risk internal milieu and may therefore aid identification of the vulnerable patient.
Novel imaging techniques, including non-invasive and interventional approaches, can now detect these features in vivo in culprit and clinically silent atherosclerotic lesions. In particular, recent developments in molecular imaging with targeted probes are providing unique insights into the biological processes leading to vulnerability in advance of recognisable anatomical changes.
Vulnerable plaque imaging remains largely investigational at present with long-term, clinical end point trials needed before widespread adoption of such an approach is warranted.
Once validated, such techniques have the potential to significantly improve risk stratification of an individual, allowing tailored approaches to therapeutic decisions in the primary and secondary prevention setting. Individualising assessment of the risk/benefit profile seeks to reduce ischaemic events while minimising iatrogenic harm and rationalising use of constrained medical resources.
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Contributors PDA wrote the draft. MRD and DEN made substantial contributions in revising the final work.
Funding PDA is supported by the New Zealand Heart Foundation. MRD and DEN are supported by the British Heart Foundation (FS/14/78/31020 and CH/09/002) and the Wellcome Trust (WT103782AIA).
Competing interests None declared.
Provenance and peer review Commissioned; externally peer reviewed.
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