Coronary artery disease imaging with total-body PET

Abstract

Coronary artery PET is a promising imaging tool that provides mechanistic insights into coronary artery disease, as well as clinical risk stratification. However, conventional PET systems remain limited by poor sensitivity and low signal-to-noise ratios (SNRs), hampering the robust assessment of coronary artery disease. The recent introduction of total-body PET scanners has enabled the simultaneous acquisition of data across multi-organ systems, with major enhancements in sensitivity and resultant effective resolution. These technological advancements facilitate the detection of lesions with lower radiotracer uptake signals and allow the complex systemic processes contributing to coronary artery disease to be unveiled, with important implications for clinical trial design and novel drug development. The aim of this review is to discuss the current literature on coronary artery PET and to explore how total-body PET systems can be employed to expand our current understanding of coronary artery disease.

Introduction

As the leading global cause of mortality, coronary artery disease remains a major public health concern.¹ Computed tomography coronary angiography (CTCA) can noninvasively identify coronary artery disease, allowing for appropriate modifications in management with beneficial outcomes for patients.^2,3 While CTCA can assess luminal stenosis and some plaque characteristics, it is unable to visualize disease activity directly. PET is a noninvasive imaging technique that can provide functional insight into such processes using targeted radioisotope-labeled ligands (radiotracers).⁴ Radiotracer uptake allows visual and quantifiable assessment of disease activity, which can be co-registered with structural imaging from CT or MRI. Hybrid imaging using the combination of both imaging assessments can provide greater insights than using structural assessment alone. The recent introduction of total-body or long axial field of view PET scanners is set to revolutionize the field of nuclear imaging, providing the opportunity to visualize multiple organ systems simultaneously with greater sensitivity and highly improved diagnostic accuracy.^5–8 In this review, we discuss total-body PET as a novel imaging modality to identify the different characteristics of coronary artery disease which has the potential to offer unprecedented understanding of its future treatment.

Coronary positron emission tomography

To date, PET assessment of coronary artery disease has been limited to myocardial perfusion studies. Indeed, PET myocardial perfusion imaging is considered the gold standard for the noninvasive assessment of myocardial ischemia secondary to obstructive coronary artery disease.^9,10 PET perfusion imaging is beyond the scope of this review. Instead, we focus on PET imaging as a marker of disease activity in the coronary vasculature.

PET imaging of the coronary arteries is challenging due to several key factors (Figure 1). First, the spatial resolution of PET is limited to around 3-5 mm,^6,11,12 which can exceed the calibre of even the main segments of the coronary tree.¹³ This means that any assessment of radiotracer uptake within the coronary arteries will be subject to partial volume effects making precise quantification difficult.¹⁴ Second, PET images of the relatively small coronary arteries demonstrate low signal-to-noise ratios (SNRs) owing to the inefficient detection of photons by conventional scanners. When the axial field of view is limited to 15 to 30 cm, less than 1% of photons emitted from annihilation events are successfully detected.^7,15 Given this inefficiency and the small target structures involved, high doses of radiotracer are needed, increasing the radiation exposure of the patient. Third, by its very nature, cardiac imaging is limited by motion artifacts, principally due to continuous cardiac movement throughout the cardiac cycle as well as superimposed respiratory and gross bodily movement.¹⁶ Finally, because coronary artery plaque lies immediately adjacent to the blood pool, there needs to be a high differential between blood pool signal and target radiotracer uptake to identify regions of disease activity. Without this contrast, the quantitative evaluation of coronary lesions via standard uptake values (SUVs) and target-to-background ratios (TBRs) are impeded. Moreover, where there is uptake of the radiotracer within the myocardium or pericardium, overspill effects will contaminate any signal from the coronary arteries given their close juxtaposition.¹⁴

Figure 1.

Limitations of coronary PET. (A and B) Partial volume effect. A discrete lesion partially occupies several voxels at its periphery (A), as a result the values of intensity of the lesion within these voxels are averaged with the background creating blurring of the image (B). (C and D) Motion artifact leading to distortion and apparent duplication of the right coronary artery on attenuation correction computed tomography (blue arrow, C). Leading to difficulty determining whether focal [⁶⁸Ga]-FAPI-46 uptake originates from the right coronary artery (blue arrow, D). Motion artifact of the patient’s previous transcatheter aortic valve replacement can also be seen (green arrow, C). (E and F) Pericardial overspill into coronary arteries with a 5-mm radius volume of interest drawn around the left anterior descending artery (green lines). On axial imaging, there appears to be focal [⁶⁸Ga]-FAPI-46 uptake within the left anterior descending artery (blue arrow, E). However, on the coronal slice, there is apparent [⁶⁸Ga]-FAPI-46 overspill from the surrounding pericardium (blue arrow, F). Uptake of [⁶⁸Ga]-FAPI-46 at the site of the recent midline sternotomy can also be seen (green arrow, E).

Total-body PET scanners can address some of these prior limitations, making the coronary system a more attractive target for nuclear imaging (Table 1). The greater number of detectors and the increased axial field of view translates into a marked increase in the detection of co-incidences allowing for a much higher degree of sensitivity to be achieved in the central field of view.^6,19,23 While total-body PET scanners possess comparable spatial resolutions to conventional PET scanners,^11,17,18,24 such significant gains in sensitivity lead to improved SNRs and image quality. In turn, this facilitates the detection of lower thresholds of radiotracer uptake.^5,25,26 Furthermore, the increased axial field of view allows for simultaneous imaging of the coronary and wider cardiovascular system, enabling the study of the systemic nature of atherosclerosis as a disease process as well as inter-organ interactions. This combination of markedly increased sensitivity, which allows for an improved effective resolution and gated image quality, with the increased anatomical coverage in the axial direction greatly enhances the ability to characterize coronary artery disease and to understand it in its wider context.

Table 1.

Total-body versus conventional PET.

	Conventional PET 11 , 17 , 18	Total-body PET 6 , 19 , 20
Axial field of view (cm)	15-30	106-194
Spatial resolution (FWHM, mm)	∼3.5-5.8	∼2.9-5.8
Sensitivity (cps/kBq)	5-45	147-177
Effective temporal resolution (s)	5-1021	As low as 0.1
Radiotracer dose, [18F]-FDG (MBq/kg)	3.5-722,a	As low as 0.375

^aRecommended dose for a bed time of 2 minutes.

Abbreviations: Cm = centimeters; Cps/kBq = counts per second per kilobecquerel; FDG = fluorodeoxyglucose; FWHM = full width at half maximum; mm = millimeters; s = seconds.

Coronary image analysis

Coronary PET imaging is highly susceptible to motion artifacts arising from both physiological processes and patient movement. Myocardial contraction throughout the cardiac cycle causes deformation, rotation, and translation of the coronary arteries, which, when compounded by the additional motion of respiration and any gross subject movement, results in motion artifacts.^16,27,28 These phenomena are exacerbated by higher heart rates, due to a reduction in the duration of diastole, and pose a particular challenge when assessing the right coronary artery.²⁹ Misalignment between PET and CT images may also occur, owing to the temporal mismatch between the data acquisition of the 2 imaging modalities. Consequently, misalignment between PET and CT datasets creates artifacts on attenuation corrected images, impacting the quantitative evaluation of coronary PET.^30,31

Several tools exist to combat the impact of motion artifact in coronary PET imaging. Electrocardiographic (ECG) and respiratory tracking methods can be employed during the acquisition of PET data to provide timing information that corresponds to the different phases of the cardiac and respiratory cycle, respectively.²⁷ This timing information can then be used to reconstruct separate images for the different phases of the cardiac and respiratory cycle. For ECG-based motion tracking, retrospective “phase gating” is commonly used for cardiac PET motion correction, where list-mode data are sorted into bins corresponding to the phase of the cardiac cycle at which coincidence events were recorded.¹⁶ A limitation of gated image reconstruction is that each individual gated image uses fewer counts during reconstruction, which decreases the resulting image quality. To tackle this problem, motion correction models aim to optimize coronary plaque PET analysis by registering the gated images to a reference frame. In one such model, tubular volumes of interest are constructed around target vessels in the CT images using centerlines drawn through the vessel lumen as the focal point, which are used to identify volumes of interest in the gated PET images (Figure 2).^31,32 These volumes are then deformably registered to the end diastolic gate to produce an image corrected for motion using all the PET data. The resultant motion correction increases the recorded TBR values for coronary uptake, while simultaneously reducing noise.³¹

Figure 2.

Coronary motion correction. This figure has been adapted from research that was originally published in the European Journal of Nuclear Medicine and Molecular Imaging by Kwiecinski et al.³² (A) Whole-vessel tubular and tortuous CT angiography derived volume of interest for [¹⁸F]-NaF uptake assessment in the left anterior descending artery (blue arrow). (B) Three-dimensional rendering of coronary CT angiography with superimposed tubular whole-vessel volumes of interest (light green) employed for evaluation of [¹⁸F]-sodium fluoride uptake (blue and red). Abbreviation: TBR = target-to-background ratio.

Data-driven methods have been used to track and to correct respiratory and gross patient movements.^33–35 For the latter, shifts in the center of mass (average location of annihilation events) are identified from the data set prior to reconstruction.³⁴ Furthermore, triple-gated motion correction results in greater coronary lesion TBRs and improves intra-observer reproducibility by up to 133%. Despite this, reproducibility coefficients have been found to be modest.²⁸ As SNRs increase, the accuracy of data-driven motion estimates, such as center of mass calculations, increase. Total-body PET may, therefore, overcome the limitations of data-driven motion correction, facilitating the development of robust models for coronary PET analysis.

Coronary artery PET imaging

Inflammation imaging

In atherosclerosis, vascular endothelial cell damage triggers the release of pro-inflammatory cytokines leading to a local inflammatory response.³⁶ Macrophages are critical potentiators of atherosclerotic inflammation³⁷ and contribute toward plaque rupture through their secretion of proteolytic enzymes.³⁸ Hence, vascular inflammation is closely associated with a high-risk plaque phenotype, providing a useful target for cardiac imaging.³⁹

[¹⁸F]-Fluorodeoxyglucose (FDG) is a glucose analogue which is readily taken up into cells via GLUT 1/GLUT 3 transporters and converted into [¹⁸F]-FDG-6-phosphate.⁴⁰ In atherosclerosis imaging, [¹⁸F]-FDG is thought to represent macrophage metabolism within hypoxic environments.^39,41 While numerous studies have demonstrated the ability of [¹⁸F]-FDG ability to detect vascular inflammation within large blood vessels,^42,43 its use in coronary imaging is severely limited because of the marked myocardial uptake of [¹⁸F]-FDG.^14,44 Despite optimal patient preparation to encourage a switch to free fatty acid metabolism through fasting or a high fat-low carbohydrate diet, up to a half of coronary territories remain uninterpretable due to myocardial [¹⁸F]-FDG uptake and overspill.¹⁴ Furthermore, [¹⁸F]-FDG uptake is not specific to pro-inflammatory M1 macrophages, reducing its specificity for atherosclerotic disease.³⁹ Such limitations have led to a shift toward identifying alternative radiotracers for use in coronary artery disease imaging.

The somatostatin type-2 (SST2) receptor is expressed on the surface of activated M1 macrophages.⁴⁵ Multiple gallium-labeled SST2 radiotracers exist, with the most frequently studied being [⁶⁸Ga]-DOTA-Tyr3-octreotate ([⁶⁸Ga]-DOTATATE), [⁶⁸Ga]-DOTA-Tyr3-octreotide ([⁶⁸Ga]-DOTATOC), and [⁶⁸Ga]-DOTA-1-NaI3-octreotide ([⁶⁸Ga]-DOTANOC).^46–50 In addition, DOTATATE can be bound to copper in the form of [⁶⁴Cu]-DOTATATE.⁴⁶ The [68Ga]-DOTA family of radiotracers bind to multiple SST receptors with varying affinities. [⁶⁸Ga]-DOTATATE demonstrates the greatest affinity for SST2 receptors, while [⁶⁸Ga]-DOTANOC also binds to SST3 and 5 receptors, and [⁶⁸Ga]-DOTATOC binds to the SST5 receptor.⁵¹

In comparison to [¹⁸F]-FDG, [⁶⁸Ga]-DOTATATE uptake is much more discriminatory for the identification of the inflamed culprit coronary plaques in patients with acute coronary syndrome⁴⁷ (Figure 3). In non-culprit plaques, [⁶⁸Ga]-DOTATATE uptake is also increased in regions with high-risk features. Moreover, [⁶⁸Ga]-DOTATATE use is not associated with nonspecific myocardial uptake, a major improvement in comparison to [¹⁸F]-FDG. Interestingly, a sub-analysis exploring myocardial uptake as a marker of pathological inflammation demonstrated that [⁶⁸Ga]-DOTATATE values were higher in infarcted territories of myocardium than in non-infarcted regions.⁵² Myocardial [⁶⁸Ga]-DOTATATE activity also positively correlated with bone marrow activity (a surrogate for systemic inflammation). One key constraint of this approach is the low PET spatial resolution, resulting from the use of a gallium-based radiotracer. The average positron range of [⁶⁸Ga]-DOTATATE is 2.9 mm,⁵³ much longer than the 0.56 mm range of [⁶⁴Cu]-DOTATATE.⁵⁴ As positrons travel further from the site of emission prior to an annihilation event, more blurring is introduced, impeding image quality.

Figure 3.

Comparison between [⁶⁸Ga]-DOTATATE and [¹⁸F]-FDG coronary PET inflammation imaging. This figure has been adapted from research that was originally published in the Journal of the American College of Cardiology by Tarkin et al.⁴⁷ Images from a 57-year-old man with acute coronary syndrome who presented with deep anterolateral T-wave inversion. (A and B) [¹⁸F]-FDG PET uptake causes myocardial spillover and completely obscures the coronary arteries. In contrast, [⁶⁸Ga]-DOTATATE PET (C and D) clearly detects intense inflammation in this high-risk atherosclerotic plaque/distal portion of the stented culprit lesion (arrow and * on insert) and recently infarcted myocardium (* on panel D).

[⁶⁸Ga]-DOTATOC has been used with total-body PET to assess plaque vulnerability in patients with calcified coronary artery disease. Uptake of this tracer was seen in only a half of patients with calcific disease on CT.⁴⁹ Moreover, except for the left anterior descending artery, no correlation was found between vessel-level activity and calcification—likely reflecting the stabilized nature of the latter. There was however an apparent association between coronary [⁶⁸Ga]-DOTATOC uptake and a greater incidence of all-cause mortality and stroke. It should be noted that this retrospective study was limited by its patient population (oncology patients with no history of coronary artery disease), the lack of ECG gating and CTCA imaging, as well as the relative weakness of binding to SST2 receptors by the tracer.^49,51

Calcification imaging

Calcification contributes to the maturation and stabilization of coronary plaques.^55,56 Gross macroscopic calcification can easily be visualized on CT imaging, and coronary artery calcium scoring (CACS) provides prognostic risk stratification especially in those without known coronary artery disease.^57,58 However, at the plaque level, macroscopic calcification characteristically represents more stable low-risk disease,^59,60 and as such, CACS may fail to identify lesions or patients at the greatest risk of acute coronary events. In contrast, microcalcification (<50 µm) is thought to represent a process of active calcification and signal the presence of atherosclerotic lesions at high risk of rupture.^56,61 Due to its size, microcalcification is undetectable on structural imaging and instead relies on molecular imaging for its identification.

Fluorine-18-labeled sodium fluoride ([¹⁸F]-NaF) is a radiotracer that can be used in PET to quantify active microcalcification in vascular disease.^44,61–63 The fluoride ions from [¹⁸F]-NaF are integrated into hydroxyapatite, a core feature of atherosclerotic microcalcification. The greater surface area of these developing deposits increases fluoride ion integration as fluorapatite, generating higher signals at this active stage of the disease process compared to large established macroscopic deposits where much of the hydroxyapatite is internalized.^61,63 Further to this, the specificity of [¹⁸F]-NaF for hydroxyapatite ensures that there is low myocardial uptake resulting in clear visualization of the coronary vasculature.^14,44,63 In one validation study, [¹⁸F]-NaF showed a strong affinity for microcalcifications formed on human coronary smooth muscle cells grown in vitro.⁶¹ In addition, micro-PET-CT imaging of explanted human coronary tissue revealed that [¹⁸F]-NaF colocalized to regions of the coronary vasculature devoid of macrocalcification, implying the presence of microcalcifications. Histological analysis of PET-positive CT-negative carotid endarterectomy samples reinforced this finding, identifying microcalcifications at the site of high [¹⁸F]-NaF uptake.⁶¹ In a separate validation study, coronary plaques extracted from coronary endarterectomy samples had greater [¹⁸F]-NaF mean SUV values compared to the surrounding vessel intima.⁵⁹ High-risk specimens (lesions with ≥2 adverse features) had higher [¹⁸F]-NaF uptake compared to low-risk specimens. Moreover, there were positive correlations between [¹⁸F]-NaF uptake and other markers of adverse coronary plaque, particularly the presence of a necrotic core, a thin fibrous cap, intraplaque hemorrhage as well as microcalcification on histology.⁵⁹

Preliminary in vivo studies identified that coronary [¹⁸F]-NaF uptake is increased in patients with coronary artery disease and that it correlated with the coronary atherosclerotic plaque burden.⁴⁴ A subsequent follow-on study demonstrated the superiority of [¹⁸F]-NaF in comparison to [¹⁸F]-FDG in patients with stable and acute coronary artery disease.¹⁴ [¹⁸F]-NaF co-localizes with culprit lesions in patients following acute myocardial infarction (MI), while in those with stable coronary artery disease, it was associated with high-risk plaque features (positive remodeling and spotty calcification)¹⁴ (Figure 4). Patients with increased coronary [¹⁸F]-NaF PET uptake demonstrate greater progression of their plaque burden assessed with CT calcium scoring while patients without uptake did not, highlighting that this approach might differentiate patients with active and inactive disease states.⁶⁴ These findings and those of later studies^65,66 indicated that [¹⁸F]-NaF PET-CT could perhaps be used as a clinical technique to risk stratify patients with active coronary artery disease and formed part of the rationale for the creation of an international multicenter trial to test this theory.⁶⁷ The PRE¹⁸FFIR study investigated the association of coronary [¹⁸F]-NaF activity with cardiovascular outcomes in 704 patients following recent MI. While the study showed that increased total coronary plaque [¹⁸F]-NaF signal was associated with a composite risk of death or MI, it failed to demonstrate a relationship with its primary endpoint of death, MI, and unscheduled revascularization. In a secondary analysis, vessel-specific [¹⁸F]-NaF uptake was associated with the future risk of MI.⁶⁸ This risk was modified by interventional treatment at the time of MI, with patients who had not received percutaneous coronary intervention having a 4-fold increase in the risk of subsequent MI.

Figure 4.

Patients with stable angina and [¹⁸F]-fluoride uptake. This research was originally published in the Lancet by Joshi et al (supplementary materials).¹⁴ Representative examples for [¹⁸F]-fluoride uptake in patients with stable angina. (A-D) Computed tomography coronary angiograms; (E-H) [¹⁸F]-fluoride positron emission tomograms; (I-L) fused positron emission tomograms and computed tomography coronary angiograms.

Recently published trials have demonstrated the practicality of using [¹⁸F]-NaF PET as a marker of coronary artery disease modification in response to drug therapies.^62,69 In a single center observational cohort study, evolocumab therapy reduced noncalcified plaque burden in patients with coronary artery disease and promoted plaque stabilization, with significant reductions in coronary [¹⁸F]-NaF activity.⁶² Total-body PET imaging may build upon these findings, by assessing the efficacy of such therapies at reducing plaque burden across the entire vascular system.

Thrombus imaging

Thrombosis is a key driver of multiple disease processes in the coronary arteries, including acute type 1 MI, where the rupture of high-risk atherosclerotic plaque triggers platelet activation, aggregation and occlusive thrombus formation.^70,71 Glycoprotein IIb/IIIa cell-surface receptors are specific to platelets and undergo conformational change when activated by mediators like thrombin, adenosine diphosphate and thromboxane A2. This activation allows platelets to bind to exposed vascular collagen fibers and aggregate.⁷² [¹⁸F]-GP1 is a fluorine-18 labeled radiotracer which binds with high-affinity to activated glycoprotein IIb/IIIa receptors.⁷³ To date, [¹⁸F]-GP1 has been utilized in PET imaging to detect activated platelets within the culprit vessels of patients following acute MI, with high accuracy⁷⁴ (Figure 5). [¹⁸F]-GP1 PET imaging has also identified type 2 MI secondary to thromboembolism, resulting in a change of diagnosis from type 1 to type 2 MI and change of clinical management.⁷⁵ Building upon this, an observational cohort study is currently underway to explore the ability of [¹⁸F]-GP1 to detect spontaneous coronary artery dissection (SCAD) and other causes of MI with nonobstructive coronary arteries (NCT06113510). Total-body PET will enable the simultaneous imaging of multiple anatomic sites, facilitating the identification of the origin of thromboembolic events, again providing greater diagnostic differentiation.

Figure 5.

Exemplar cases of coronary [¹⁸F]-GP1 uptake in patients treated for ST-segment elevation myocardial infarction. This figure has been adapted from an originally published in the Journal of the American College of Cardiology Cardiovascular Imaging by Tzolos et al.⁷⁴ Anterior (A), lateral (B), and inferior (C) myocardial infarction and corresponding [¹⁸F]-GP1 uptake from the corresponding culprit artery (blue arrows). Right to left: CT angiogram, and [¹⁸F]-GP1 positron emission tomographic and CT angiogram. [¹⁸F]-GP1 uptake was noted only in the infarct artery.

The surgical management of coronary artery disease may be enhanced through the insights gained by total-body [¹⁸F]-GP1 PET imaging studies. Coronary artery bypass graft (CABG) surgery remains the revascularization option of choice for left main stem and triple vessel coronary artery disease.⁷⁶ However, this major surgical intervention is associated with increased risks of periprocedural events including death (1%-2%), MI (2%-4%), stroke (1%-3%), and atrial fibrillation (15%-30%).⁷⁷ Saphenous vein conduits are particularly susceptible to graft failure in comparison to their arterial counterparts,⁷⁸ with their early failure being dominated by acute thrombosis secondary to trauma and damage to the vascular endothelium.⁷⁹ A recent systematic Cochrane review of interventions at the time of cardiac surgery concluded that further studies are needed to understand whether targeting inflammation or other biological pathways can prevent these adverse effects and complications.⁸⁰ The first noninvasive longitudinal cohort study to examine graft disease and the systemic cardiovascular consequences of CABG surgery using total-body PET is currently active (NCT06800430). It is hoped that this and other total-body PET imaging studies will provide greater diagnostic accuracy and mechanistic insights into the sub-types of coronary artery disease and the thrombo-embolic complications of its interventions.

Fibrosis imaging

Fibrosis forms in the later stages of atherosclerosis development, as fibrous caps containing collagen I and III fibers form over the necrotic core.⁸¹ Activated fibroblasts are crucial in myocardial repair and remodeling following MI, where they deposit extra-cellular matrix proteins to form a scar. Such myocardial fibrosis is protective in the acute phase following myocardial injury but may later be superseded by adverse remodeling.^81,83 Cardiac MRI with late gadolinium enhancement (LGE) and T1 mapping forms the clinical gold standard for the detection of myocardial fibrosis. However, MRI is unable to detect coronary plaque fibrosis due to limitations from its spatial resolution.⁸²

Fibroblast activation protein (FAP) is a transmembrane glycoprotein that is selectively expressed on the cell surface of activated fibroblasts.⁸⁴ Fibroblast activation protein inhibitors (FAPIs) can be labeled with fluorine-18 ([Al¹⁸F]-FAPI) or gallium-68 ([⁶⁸Ga]-FAPI) creating a range of radiotracers for use in PET imaging.⁸⁵ Myocardial [⁶⁸Ga]-FAPI activity after MI positively correlates with LGE,^86–88 and negatively correlates with left ventricular systolic function on echocardiography.^87,89,90 Importantly, [⁶⁸Ga]-FAPI provides different and complementary information to LGE, being commonly observed in areas without underlying LGE,⁸⁷ including in MI when it frequently extends beyond the immediate infarct zone into the peri-infarct zone.^86–88 The first prospective longitudinal study using [⁶⁸Ga]-FAPI-46 PET-MRI in patients after MI confirmed increased fibroblast activation following acute MI.⁹¹ Patients with acute ST elevation MI underwent repeat [⁶⁸Ga]-FAPI-46 PET-MRI up to 1-year post infarction. Left ventricular [⁶⁸Ga]-FAPI-46 activation was greatest within the first 2 weeks of MI and then gradually declined over time, with low level fibroblast activation still observed many years and decades following the infarct. The volumes of [⁶⁸Ga]-FAPI-46 at these time points were inversely correlated with left ventricular ejection fraction (LVEF) and increased with the size of myocardial scarring on cardiac MRI.⁹¹

Presently, no dedicated coronary imaging studies utilizing [⁶⁸Ga]-FAPI exist, largely driven by concerns over spatial resolution and partial volume effects of contemporary PET scanners.^82,92 This provides a novel opportunity to harness [⁶⁸Ga]-FAPI total-body PET imaging, using its higher sensitivity and effective resolution to finally unlock the insights held by coronary [⁶⁸Ga]-FAPI imaging (Figure 6).

Figure 6.

Coronary [⁶⁸Ga]-FAPI-46 uptake. A patient with recent coronary artery bypass graft surgery (NCT06800430). (A and B) [⁶⁸Ga]-FAPI-46 uptake visualized in the left main stem on axial imaging with apparent co-localization to hypo attenuated plaque (blue arrows). Uptake of [⁶⁸Ga]-FAPI-46 at the site of the recent midline sternotomy can also be seen (green arrows). (C and D) Localization of [⁶⁸Ga]-FAPI-46 uptake to the left main stem confirmed on oblique imaging (blue arrows). Pericardial and myocardial uptake of [⁶⁸Ga]-FAPI-46 can be visualized, in-keeping with recent coronary artery bypass graft surgery (A and C).

Future perspectives

Total-body PET is set to dramatically change the field of coronary imaging. The high sensitivity of total-body PET systems will facilitate the detection of coronary artery disease at earlier stages, as weaker signals from targeted biological processes are more readily detected.⁵ This in turn will provide greater diagnostic accuracy and optimization of clinical management for patients with diagnostic uncertainty. One example of this is the identification of acute type I MI despite nonobstructive coronary arteries (MINOCA). Coronary artery thrombus resulting from SCAD has already been detected using conventional [¹⁸F]-GP1 PET-CT⁷⁴ (Figure 7). Total-body PET is likely to offer improved discrimination, increasing the rate of accurate diagnosis and preventing the inappropriate use of dual antiplatelet therapies in patients with SCAD.⁹³ In a similar sense, the coronary foci of systemic diseases will be better characterized with total-body imaging. Coronary involvement from vasculitides such as polyarteritis nodosa and Kawasaki disease is an important differential in young patients presenting with features of acute coronary syndrome, without conventional risk factors.⁹⁴ However, the treatment of vasculitis is vastly different from that of acute coronary syndrome, with immunotherapies and steroids forming the cornerstone of management. The timely identification and appropriate treatment of coronary vasculitis is vital to minimize the risk of coronary thrombosis and aneurysm formation.⁹⁴ Total-body PET with inflammatory radiotracers like [¹⁸F]-FDG or [⁶⁸Ga]-DOTATATE will provide simultaneous evaluation of multiple vascular beds, identifying systemic uptake and distinguishing patterns of vasculitic inflammation from those of atherosclerotic disease.⁹⁵ Furthermore, the utilization of ultra-low radiotracer doses possible with total-body PET will facilitate the longitudinal monitoring of coronary disease activity in response to immunotherapies without exposing patients to excessive levels of radiation.

Figure 7.

Coronary [¹⁸F]-GP1 uptake in a patient with spontaneous coronary artery dissection. This research was originally published in the Journal of the American College of Cardiology Cardiovascular Imaging by Tzolos et al. (supplementary materials).⁷⁴ Patient with anterior ST-elevation myocardial infarction. (Left) Distal left anterior descending coronary artery tapering suggestive of spontaneous coronary artery dissection (green arrow) and (Middle and Right) subsequent [¹⁸F]-GP1 PET and computed tomography angiogram with uptake in the distal left anterior descending coronary artery.

Immuno-PET harnesses radiolabeled monoclonal antibodies (or fragments) to image biological processes with improved specificity.⁹⁶ In addition to vasculitis, immune cells are heavily implicated in atherosclerotic disease, where pro-inflammatory CD8+ T cells are pro-atherosclerotic and regulatory CD4+ T cells confer athero-protection.⁹⁷ Total-body PET systems have already been used to conduct the first-in-human immuno-PET study using zirconium-89 labeled “mini-bodies” (⁸⁹Zr-Df-Crefmirlimab) to target CD8+ T-cells.⁹⁸ Until now, immuno-PET imaging of the cardiovascular system has been limited to animal models.⁹⁶ The design of in-human immuno-PET cardiovascular imaging studies may identify patients with active CD8+ T cells in coronary artery disease, providing targeted risk stratification. Furthermore, total-body PET, with its capabilities for delayed imaging and systemic kinetic modeling,⁹⁸ could be instrumental in accelerating the development of novel therapeutic agents, such as chimeric T cells⁹⁹ and interleukin therapies,¹⁰⁰ by providing vital information on the optimal timing for their initiation and strategies for dose escalation.

Conclusion

Total-body PET imaging is an emerging and powerful tool that can offer deeper mechanistic insights into coronary artery disease. Its ultra-high sensitivity provides the opportunity for earlier diagnosis, refined risk stratification, and longitudinal monitoring of coronary artery disease. Subsequent insights gained from cutting-edge total-body PET studies will inform the innovation of novel therapies targeted against coronary artery disease.

Conflicts of interest

M.G. is a full-time employee at Siemens Healthcare Ltd, Camberley, United Kingdom. M.C.W. is a guest editor for this special feature. She has also given talks for Canon Medical Systems, Siemens Healthineers, GE Healthcare, and Novartis and performed consultancy for FEOPS, Novartis, and Canon Medical Systems. SOFIE provide the authors at the University of Edinburgh with the [⁶⁸Ga]-FAPI-46 precursor free of charge. Although they have approved its content, they did not contribute to or influence the creation of this article. Life Molecular Imaging GmbH provide reagents for radiotracer production at the University of Edinburgh. They did not contribute to or influence the creation of this article. There are no other declarations of relevance to this manuscript.

Funding

L.E.C. is funded by a British Heart Foundation (FS/CRTF/25/24719). C.B. is funded by Medical Research Council (MR/Y009770/1). P.S. is supported by the National Heart, Lung, and Blood Institute (R35HL161195); participates in software royalties for QPET software at Cedars-Sinai Medical Center; and has received grants from Siemens Medical Systems. D.E.N. is funded by the British Heart Foundation (CH/09/002/26360, RG/F/22/110093, RE/24/130012). M.R.D. is funded by the British Heart Foundation (FS/SCRF/21/32010). M.C.W. is funded by the British Heart Foundation (FS/ICRF/20/26002).