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Review
Imaging of intracoronary thrombus
  1. Beth Whittington1,2,
  2. Evangelos Tzolos1,2,
  3. Michelle C Williams1,2,
  4. Marc R Dweck1,2,
  5. David E Newby1,2
  1. 1 BHF Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK
  2. 2 Edinburgh Imaging, Queen’s Medical Research Institute, Edinburgh, UK
  1. Correspondence to Dr Beth Whittington, Centre for Cardiovascular Sciences, The University of Edinburgh, Edinburgh, Edinburgh, UK; bwhittin{at}ed.ac.uk

Abstract

The identification of intracoronary thrombus and atherothrombosis is central to the diagnosis of acute myocardial infarction, with the differentiation between type 1 and type 2 myocardial infarction being crucial for immediate patient management. Invasive coronary angiography has remained the principal imaging modality used in the investigation of patients with myocardial infarction. More recently developed invasive intravascular imaging approaches, such as angioscopy, intravascular ultrasound and optical coherence tomography, can be used as adjunctive imaging modalities to provide more direct visualisation of coronary atheroma and the causes of myocardial infarction as well as to improve the sensitivity of thrombus detection. However, these invasive approaches have practical and logistic constraints that limit their widespread and routine application. Non-invasive angiographic techniques, such as CT and MRI, have become more widely available and have improved the non-invasive visualisation of coronary artery disease. Although they also have a limited ability to reliably identify intracoronary thrombus, this can be overcome by combining their anatomical and structural characterisation of coronary anatomy with positron emission tomography. Specific radiotracers which bind with high specificity and sensitivity to components of thrombus, such as activated platelets, fibrin and factor XIIIa, hold promise for the non-invasive detection of intracoronary thrombus. The development of these novel non-invasive approaches has the potential to inform clinical decision making and patient management as well as to provide a non-invasive technique to assess the efficacy of novel antithrombotic therapies or interventional strategies. However, these have yet to be realised in routine clinical practice.

  • myocardial infarction
  • positron emission tomography computed tomography
  • coronary angiography

https://doi.org/10.1136/heartjnl-2022-321361

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    Introduction

    The link between thrombotic occlusion of a coronary artery and necrosis of the myocardium was first demonstrated in postmortem examinations in the late 19th century. This pathological finding was associated with clinical features and became its own clinical entity: myocardial infarction.1 However, the role of thrombus in the aetiology of myocardial infarction continued to be debated until the 1950s,2 because intracoronary thrombus was an inconsistent finding at postmortem examinations, principally due to its spontaneous dissolution from endogenous fibrinolysis. The advent of invasive coronary angiography demonstrated the time-dependent presence of intracoronary thrombus in myocardial infarction. To this day, myocardial infarction remains the most serious manifestation of coronary artery disease and remains the leading cause of death worldwide.3

    Pathophysiology of arterial thrombosis and intracoronary thrombus

    The 19th century physician Rudolf Virchow’s work on the fundamental understanding of thrombosis is still considered to be one of the most important and lasting contributions to modern medicine. Virchow’s triad describes the three factors that predispose to the formation of thrombus: abnormalities in blood flow, the blood constituents and the vessel wall.4 While initially used to describe venous thrombosis, the same principles have been applied to arterial thrombosis. However, venous and arterial thrombus have differences in composition due to the conditions under which they form. Venous thrombus develops under low shear stress where there is rarely any damage to the underlying endothelial wall. The clot is formed predominantly through stasis or activation of the coagulation cascade. Histological analysis of venous thrombi demonstrates a predominance of fibrin and red blood cells: so-called ‘red thrombus’. This is in contrast to arterial thrombi which form at high shear rates, are often associated with vascular wall abnormalities and comprise predominantly platelets: ‘white’ thrombus.5

    Vessel wall damage due to coronary atherosclerotic plaque rupture or erosion is the most common cause of intracoronary thrombosis and the principal precipitating event in type 1 myocardial infarction (figure 1). Plaque disruption causes damage to the endothelial cell layer and exposure of the extracellular matrix, collagen and the highly thrombogenic atherosclerotic plaque itself. This leads to intense adhesion of platelets and the generation of fibrin to form thrombus which may or may not occlude the vessel. In addition to atherosclerotic plaque disruption, there are other important causes of coronary arterial thrombosis that include spontaneous coronary artery dissection and coronary thromboembolism. Spontaneous coronary artery dissection occurs when a haematoma develops within the coronary artery wall with or without the presence of an intimal tear. The subsequent development of a false lumen or intramural haematoma compresses the true lumen and results in coronary insufficiency restricting blood flow and encouraging the formation of intramural or intraluminal thrombus.6 Coronary embolism is principally caused by cardiogenic thromboembolism, especially thromboembolism from left atrial appendage during atrial fibrillation (figure 1), although other rarer causes, such as infective endocarditis or neoplasia, do occur. Up to 3% of myocardial infarctions may be due coronary embolism.7

    Figure 1
    Figure 1

    The role of intracoronary thrombosis in type 1 and type 2 myocardial infarction. Type 1 myocardial infarction is caused by thrombosis of an atherosclerotic plaque. Most type 2 myocardial infarctions are caused by non-thrombotic supply-demand imbalance (such as tachycardia, hypoxia, hypotension, anaemia, etc) but in some circumstances may be caused by thrombotic causes (such as spontaneous coronary artery dissection or coronary embolism). Imaging for the presence of thrombus can help distinguish between the types and causes of myocardial infarction. Created with Biorender.com.

    Stasis in the arterial circulation is not a common problem and is usually caused by acute vessel occlusion by thrombus itself. Even critical coronary stenoses are associated with normal coronary flow at rest, although the induction of collateral coronary flow can be a stimulus to ultimate vessel occlusion due to stasis from competitive flow. However, collateralisation and competitive flow can protect from acute myocardial infarction and often underlie the development of silent coronary occlusion in the absence of acute myocardial infarction. This can create challenges for imaging when coincidental chronic vessel occlusion is identified in a patient presenting with acute myocardial infarction. Similarly, disturbances of blood coagulation and thrombosis leading to acute myocardial infarction are uncommon but do occur and predominantly reflect an acquired thrombophilia. In contrast, this does not usually cause problems for non-invasive imaging, especially as coronary lesions are more commonly non-obstructive on coronary angiography.

    Current imaging techniques for intracoronary thrombosis

    Invasive coronary angiography

    Selective coronary angiography was first performed in 1958 by Dr Marson Sones. Since then, invasive coronary angiography has formed the foundation of understanding coronary artery disease and is regarded as the reference standard for the diagnosis and severity assessment of coronary artery disease. It provides a two-dimensional image of the vascular lumen with excellent resolution of the epicardial coronary arteries including the small calibre distal vessels. In the context of acute coronary syndrome, coronary angiography indirectly demonstrates the presence of intracoronary thrombosis through an abrupt occlusion of the coronary artery or a filling defect in partially occluded vessels indicating an atherosclerotic lesion with overlying thrombus (figure 2).

    Figure 2
    Figure 2

    Invasive coronary angiogram and optical coherence tomography images. (i) Patient presenting with chest pain and elevation of plasma cardiac troponin concentration with no ischaemic changes seen on ECG. Coronary angiogram (A) showing moderate left anterior descending (LAD) proximal filling defect suspicious of thrombus (white arrow). Optical coherence tomography (B) showing moderate lesion at first septal branch with adherent thrombus (white arrow). The patient was managed with medical therapy. (ii) Patient presenting with chest pain and ST-segment elevation on ECG with a recent diagnosis of atrial fibrillation. Coronary angiogram (C) showing mild plaque disease in proximal LAD, 50%–60% lesion at the first diagonal branch and occlusion of LAD beyond this point (black arrow). Optical coherence tomography images (D) showing diffuse plaque disease with small amount of thrombus in distal vessel (white arrow). A thick fibrous cap was intact throughout and the patient was treated with thrombus aspiration. The patient was diagnosed with a coronary embolism in the context of atrial fibrillation and was treated with anticoagulation. (iii) Patient presenting with chest pain and ST-segment elevation on ECG, previous percutaneous coronary intervention to the proximal LAD and circumflex arteries. Coronary angiogram (E) shows proximal LAD stent with mid-stent restenosis (black arrow). Optical coherence tomography (F) shows mid-stent thrombus burden (white arrow). The patient was treated with balloon dilatation.

    Despite its widespread use, there are limited data on the sensitivity and specificity of invasive coronary angiography for the detection of intracoronary thrombosis in acute myocardial infarction, because there is no gold standard apart from near immediate postmortem examination. Studies have used a variety of methods to address this including aspiration thrombectomy with histological analysis8 and adjunctive imaging modalities, such as angioscopy.9 These studies have suggested that coronary angiography using multiple angiographic views has low sensitivity but high specificity for the identification of intracoronary thrombus (table 1). Due to this limitation, other imaging adjunctive imaging modalities are often applied at the time of the procedure to improve diagnostic performance.

    View this table:
    Table 1

    Imaging modalities in detecting intracoronary thrombus

    Angioscopy

    Angioscopy is often considered to be the gold standard for identifying intracoronary thrombus with a high sensitivity (100%) and specificity (93%)9–11 (table 1). Angioscopy provides a high-definition three-dimensional view of the structure and surface of the intima and media of coronary arteries. This can provide information on the surface appearance and integrity of the plaque as well as the presence of thrombus including the differentiation between white and red thrombus (figure 3). This can help to guide intracoronary thrombolysis and treatment strategies during percutaneous coronary intervention.12

    Figure 3
    Figure 3

    Atherosclerotic coronary plaques directly visualised by angioscopy. (A) shows white plaque, (B) shows yellow plaque and (C) shows plaque rupture and red thrombus. Image from Yonesu et al. Advances in intravascular imaging: new insights into the vulnerable plaque from imaging studies’. Korean Circ J 2018 Jan;48 (1):1–15. https://doi.org/10.4070/kcj.2017.0182.51 Reused with permission.

    Angioscopy does have several major limitations. As well as being an invasive procedure, it can only be used to study proximal relatively large calibre non-tortuous vessels. Visualisation can cause vessel injury and requires blood displacement by saline which can induce ischaemia. Finally, the qualitative nature of angioscopy findings has limited its application. There have been some attempts at image quantification, such as quantitative colorimetric measures analysis,12 although further major advances are needed to improve the practical application and analysis of this technique. These challenges and the limited availability of this technique preclude its routine use in clinical practice.

    Intravascular ultrasound

    Intravascular ultrasound uses a 3-French catheter and motorised pullback device to generate a three-dimensional cross-sectional image of all three coronary arterial wall layers and the vessel lumen. Its primary use is to characterise plaque morphology, plaque burden, stent sizing and placement and to identify malposition and complications of stent implantation.13 Although case reports support its potential utility14 (figure 4), intravascular ultrasound is an insensitive and unreliable method for the identification of intracoronary thrombus as it cannot differentiate between echolucent plaques and acute thrombus10 (table 1). The physical size of the catheter can also prevent imaging severely stenotic lesions, and severe lesion calcification can obscure deeper structures due to the acoustic shadows dense calcification generates.15

    Figure 4
    Figure 4

    Intracoronary thrombus on intravascular ultrasound. Panel A and B showing echolucent intraluminal masses indicating thrombus (white arrows) during percutaneous intervention to the left anterior descending artery. Images courtesy of Dr Rong Bing.

    Optical coherence tomography

    Optical coherence tomography uses a light-based imaging technique to provide high-resolution images of the arterial intima. With a resolution of 5 μm, optical coherence tomography can better delineate the three layers of the arterial wall compared with intravascular ultrasound, although its penetrance is limited and is often unable to image the outermost vessel structures. It can provide a detailed assessment of coronary dissection, stent apposition and thrombus formation (figure 2).16 The difference in the refractive index between blood and plasma allows for the detection of intracoronary thrombus with a very high sensitivity of nearly 100%.17 18 However, like angioscopy, it does require a blood-less field of view which is usually obtained by intracoronary injection of contrast medium. One of the most important potential practical applications of optical coherence tomography is aiding the detection of the culprit lesion with adherent thrombus. However, as with intravascular ultrasound, optical coherence tomography cannot assess severely stenotic disease due to the size of the imaging catheter. Moreover, even when the catheter can cross the stenotic lesion of interest, imaging is often not possible because insufficient contrast medium can pass the lesion to provide an adequate blood-less field of view. This is a major limitation of these invasive techniques and means that only mildly stenotic or non-obstructive lesions can be assessed.

    Non-invasive imaging techniques

    CT coronary angiography

    CT coronary angiography is a widely used non-invasive imaging technique for the assessment of coronary artery disease in patients presenting with stable and unstable chest pain.19 The literature relating specifically to detection of intracoronary thrombus by CT coronary angiography remains sparse. It comprises case reports of patients presenting with atypical presentations for acute coronary syndrome, in-stent thrombosis detection or postmortem studies.20–22 As CT imaging is based on attenuation densities, thrombus may be confused with low-attenuation plaque and these can be challenging to distinguish (figure 5). Until more directed studies are undertaken, the accuracy of CT coronary angiography to detect intracoronary thrombus remains uncertain, but is unlikely to be sufficiently robust for clinical use.

    Figure 5
    Figure 5

    18F-GP1 positron emission and CT. Intracoronary thrombus in a patient presenting with inferior ST-segment elevation myocardial infarction. (A) Invasive coronary angiogram shows a filling defect in the proximal right coronary artery (RCA) suggestive of thrombus (white arrow), with a further thrombus apparent in the distal RCA and an occlusion of the posterior left ventricular branch. The patient was treated with thrombus aspiration and stent insertion to the posterior left ventricular branch. Hybrid positron emission tomography and CT (B,C) performed 8 days after the invasive coronary angiogram. Area of low attenuation suggestive of a large area of residual thrombus or non-calcified plaque on the CT coronary angiogram. 18F-GP1 uptake (D,E) confirmed the presence of thrombus. Images courtesy of Dr Evangelos Tzolos.

    Magnetic resonance imaging

    Despite recent advances in MRI and the potential to obtain high-quality imaging, several challenges remain for magnetic resonance coronary angiography.23 The small calibre of the coronary vessels and coronary plaques as well as the cardiac and respiratory motion make it very challenging to obtain high fidelity images of the coronary arteries. Combined with prolonged acquisition times, this technique is not currently being used in routine clinical practice and magnetic resonance coronary angiography continues to be predominantly a research tool.

    Acute thrombus and intraplaque haemorrhage contain met-haemoglobin which has a short T1 relaxation time on MRI. Non-contrast-enhanced MRI can exploit this phenomenon to detect acute thrombus in pulmonary embolism, deep venous thrombosis and acute arterial occlusion or haemorrhage in complex carotid artery plaque.24 25 In magnetic resonance coronary angiography, high-intensity plaque on T1-weighted MRI correlates with vulnerable coronary plaque features on intravascular ultrasound and CT coronary angiography26 and is a predictor of future cardiac events.27

    The pathological features of coronary high-intensity plaques are debated, because of the lack of histological correlation. However, they are thought to represent both intraplaque haemorrhage as well as intraluminal thrombus. In early clinical studies, non-contrast-enhanced T1-weighted MRI was performed within 24–72 hours of patients presenting with acute coronary syndrome and prior to invasive coronary angiography. High signal intensity corresponded to thrombus seen on invasive coronary angiography and this was confirmed by histology in a small number of cases where thrombectomy was performed (table 1).28 Using optical coherence tomography, coronary high-intensity plaques on MRI correlated with intracoronary thrombus with a sensitivity of 92%, specificity 60% and positive predictive value of 75%, with good interobserver agreement.29 In contrast, coronary high-intensity plaque correlated with coronary intraplaque haemorrhage rather than intraluminal thrombosis (figure 6) in patients with stable coronary artery disease who underwent directional coronary atherectomy.30 Thus, coronary high-intensity plaques can identify intraluminal thrombus or intraplaque haemorrhage depending on the presentation and stability of coronary artery disease of the patient population in which it is being assessed.

    Figure 6
    Figure 6

    T1-weighted MRI coronary atherosclerosis T1-weighted characterisation with integrated anatomical reference (CATCH) of intracoronary thrombus. MRI from a patient who presented with an anterior ST-elevation myocardial infarction which was treated with a stent in the mid-left anterior descending coronary artery. MRI images show increased signal on the black blood CATCH sequence in the distal left anterior descending coronary artery (A) and corresponding bright blood CATCH angiogram (B), in keeping with thrombus in the distal vessel.

    The use of contrast media to provide a magnetic resonance coronary angiogram can be interpreted alongside the T1-weighted images and improve the sensitivity and specificity of this technique.31 Thrombus-specific MRI contrast media that target fibrin have been described and demonstrated feasibility for acute and subacute in vivo thrombus in a rabbit model of aortic thrombosis32 and subsequently a porcine model of coronary thrombosis.33 However, no robust thrombus-specific contrast agent has been clinically validated in humans.

    Positron emission tomography imaging

    Positron emission tomography imaging approaches are currently being developed to allow for targeted molecular imaging of thrombus. This imaging technique is potentially well suited to the detection of small areas of thrombus given its high sensitivity. The most promising radiotracer for the detection of intracoronary thrombus is the novel radiotracer, 18F-GP1: a fluorine-18 labelled analogue of elarofiban, a high-affinity selective glycoprotein IIb/IIIa receptor antagonist. Activated platelets not only have a high expression of the glycoprotein IIb/IIIa receptor but elarofiban preferentially and specifically binds to activated glycoprotein IIb/IIIa receptors enhancing its ability to detect fresh platelet-rich thrombus. Lohrke et al showed accumulation of 18F-GP1 in both venous and arterial thrombi in cynomolgus monkeys.34 The first preliminary clinical studies confirm its high sensitivity and specificity for detecting a range of in vivo venous and arterial thrombi in humans.35 36

    Recent studies have explored the use of 18F-GP1 positron emission tomography in the detection of intravascular arterial thrombus in cardiovascular disease37 and specifically acute myocardial infarction.38 39 Coronary thrombectomy specimens from patients undergoing primary percutaneous coronary intervention underwent autoradiography with 18F-GP1, and this showed that 18F-GP1 uptake co-localised with CD41 immunohistochemistry confirming binding to platelet glycoprotein IIb/IIIa receptors.39 This was further assessed in patients presenting with acute myocardial infarction using combined 18F-GP1 positron emission tomography with CT coronary angiography. This approach was able to identify intracoronary thrombus in the culprit artery of patients with acute myocardial infarction with excellent sensitivity and specificity (table 1). Indeed, on CT coronary angiography low-attenuation lesions were apparent that may or may not represent thrombus (figure 5). However, co-localisation of 18F-GP1 uptake was able to identify the culprit plaque and the associated acute thrombosis.

    This technique does appear to be specific with no demonstrable 18F-GP1 uptake in non-culprit coronary arteries even when percutaneous intervention had been performed or where there was substantial bystander disease. However, the technique does have some limitations and was unable to identify intracoronary thrombus in all patients with recent myocardial infarction, with some false negative scans. This predominantly occurred in those who were imaged beyond 7 days from acute infarction suggesting dissolution of intracoronary thrombus following commencement of antithrombotic therapy and highlights the need to perform 18F-GP1 positron emission tomography early after acute thrombosis. Co-incidentally, 18F-GP1 uptake was also seen in the myocardium in a third of cases of myocardial infarction, suggesting the presence of intramyocardial haemorrhage or microvascular obstruction. Furthermore, those with large myocardial infarctions also had a high incidence of ventricular thrombus formation requiring initiation of anticoagulant therapy.

    Clinical applications and future directions

    Diagnosis of myocardial infarction

    The diagnosis of myocardial infarction has been revolutionised with the advent of cardiac troponin measurement which provides exceptional sensitivity for the detection of myocardial damage. This has led to the realisation that there are many causes and types of both acute myocardial infarction and myocardial injury, and that elevation of high-sensitivity cardiac troponin lacks specificity for the diagnosis of type 1 myocardial infarction. This is clinically important since those with type 1 myocardial infarction require short-term in-hospital anticoagulation and short-term to medium-term dual antiplatelet therapy whereas for those with type 2 myocardial infarction or acute myocardial injury, such a therapeutic strategy will be either ineffective or potentially harmful. Type 2 myocardial infarction is defined by oxygen supply and demand imbalance caused by a pathophysiological mechanism other than acute atherosclerotic plaque rupture leading to coronary atherothrombosis. Most type 2 myocardial infarctions are due to either a reduction in oxygen supply or an increase in oxygen demand due to a range of conditions where intracoronary thrombus formation is not part of pathophysiology. However, some causes of type 2 myocardial infarction do involve intracoronary thrombus formation, such as spontaneous coronary artery dissection or coronary thromboembolism (figure 1). Therefore, the identification of intracoronary thrombus is a central tenet of the diagnosis of type 1 myocardial infarction and differentiating the potential causes of type 2 myocardial infarction which is embodied in the fourth Universal Definition of Myocardial Infarction.40 Thus, any technique that can assist with the detection of intracoronary thrombus will be clinically impactful. This will be particularly useful for patients with suspected type 2 myocardial infarction (figure 7)38 and those with myocardial infarction and non-obstructive coronary artery disease.41

    Figure 7
    Figure 7

    Type 2 myocardial infarction from coronary embolisation of left atrial thrombus. Invasive coronary angiography shows a proximally occluded left circumflex artery (A; arrow) and a persistent filling defect following recanalisation (B; arrow). 18F-GP1 positron emission tomography and CT shows uptake co-localised to the stented coronary segment indicating thrombus behind the stent (C; arrow) and further uptake corresponding to a filling defect in the left atrial appendage (D; arrow). Ao, aorta; LA, left atrium; PA, pulmonary artery; RA, right atrium. Taken from Tzolos et al 38 with permission.

    Both invasive and non-invasive imaging approaches will be crucial to advancing the diagnosis and management of patients with suspected coronary thrombosis.

    Development of novel antithrombotic strategies

    Antithrombotic therapies continue to be developed to enhance efficacy (resolution of thrombosis) with the promise of better safety (preserved haemostasis). Various novel anticoagulant and antiplatelet therapies are currently under evaluation, such as selective thrombin inhibitors,42 factor XIa inhibitors43 44 and protease-activator receptor type 4 antagonists.45 However, the development and assessment of such interventions is challenging especially for arterial and coronary thrombosis, often necessitating invasive angiography for phase II evaluation.46 The development of highly sensitive and specific non-invasive assessments will be a major advance to confirm target engagement and to test such therapeutic interventions in early phase II clinical trials.

    Future approaches

    The future development of non-invasive imaging will need to rely on highly sensitive and specific techniques for the identification of thrombus. Arguably, this is most likely with positron emission tomography which has several orders of magnitude greater sensitivity than other techniques such as MRI or CT. Further advances are therefore likely to relate to radiotracer development and there are several emerging novel radiotracers.

    Thrombus is an intricate combination of fibrin and platelets. The radiotracer, 64Cu-FBP8, has high affinity for fibrin and has been used in rodent models to detect multisite thrombus, and more recently in humans, for the detection of left atrial appendage thrombosis. It has good accuracy for the detection of both acute and older thrombus when compared with transthoracic echocardiography.47 48 However, its use is yet to be explored in coronary arteries. Another potential approach is 18F-ENC2015, a radiotracer targeting factor XIIIa which crosslinks fibrin to stabilise acute thrombus formation. It rapidly and selectively binds to acute thrombus in an in vivo rodent model and an ex vivo human translational model.49 Whether this will be translated into the clinic remains to be established.

    Conclusions

    Intracoronary thrombus detection has been of great interest for many decades and is crucial in the diagnosis and management of cardiovascular disease, especially acute myocardial infarction and stroke. Its identification and characterisation remain challenging with current imaging techniques used in routine clinical practice being predominately invasive, indirect and impractical for widespread use. Future non-invasive imaging techniques hold promise but further exploration is needed before their clinical applicability can be established.

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    Ethics approval

    Not applicable.

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    Footnotes

    • Twitter @imagingmedsci, @MarcDweck

    • Contributors BW drafted the manuscript, which was critically reviewed by DEN, MCW, MRD and ET. All authors approved the final submission.

    • Funding BW (FS/CRTF/21/24129), ET (FS/CRTF/20/24086), MCW (FS/ICRF/20/26002, FS/11/014, CH/09/002) DEN (CH/09/002, RG/16/10/32375, RE/18/5/34216) and MRD (FS/14/78/31020) are supported by the British Heart Foundation. DEN is the recipient of a Welcome Trust Senior Investigator Award (WT103782AIA). MRD is supported by the Sir Jules Thorn Biomedical Research Award 2015 (15/JTA). MCW is supported by The Chief Scientist Office of the Scottish Government Health (PCL/17/04) and Academy of Medical Sciences (SGL016/1059).

    • Competing interests MCW has given talks for Canon Medical Systems and Siemens Healthineers. MRD and DEN are on the Editorial Board for BMJ Heart.

    • Provenance and peer review Commissioned; externally peer reviewed.