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Available online at www.sciencedirect.com

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Positron-Emitting Myocardial Blood Flow Tracers and Clinical Potential Thomas H. Schindler ⁎ Division of Nuclear Medicine, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

A R T I C LE I N FO

AB S T R A C T

Keywords:

Positron-emitting myocardial flow radiotracers such as

Coronary artery disease

82

Coronary circulation

applied in clinical routine for coronary artery disease (CAD) detection, yielding high

Ischemia

diagnostic accuracy, while providing valuable information on cardiovascular (CV) outcome.

Myocardial blood flow

Owing to a cyclotron dependency of 15O-water and 13N-ammonia, their clinical use for PET

Myocardial perfusion

myocardial perfusion imaging is limited to a few centers. This limitation could be overcome

15

O-water,

13

N-ammonia and

Rubidium in conjunction with positron-emission-tomography (PET) are increasingly

PET

by the increasing use of

Positron-emitting radiotracers

82

82

Rubidium as it can be eluted from a commercially available

Strontium generator and, thus, is independent of a nearby cyclotron. Another novel

F-18-labeled myocardial flow radiotracer is flurpiridaz which has attracted increasing interest due to its excellent radiotracer characteristics for perfusion and flow imaging with PET. In particular, the relatively long half-life of 109 minutes of flurpiridaz may afford a general application of this radiotracer for PET perfusion imaging comparable to technetium-99 m-labeled single-photon emission computed tomography (SPECT). The ability of PET in conjunction with several radiotracers to assess myocardial blood flow (MBF) in ml/g/min at rest and during vasomotor stress has contributed to unravel pathophysiological mechanisms underlying coronary artery disease (CAD), to improve the detection and characterization of CAD burden in multivessel disease, and to provide incremental prognostic information in individuals with subclinical and clinically-manifest CAD. The concurrent evaluation of myocardial perfusion and MBF may lead to a new era of a personalized, image-guided therapy approach that may offer potential to further improve clinical outcome in CV disease patients but needing validation in large-scale clinical trials. © 2015 Elsevier Inc. All rights reserved.

Within the last decade, myocardial perfusion imaging and flow quantification with positron emission tomography (PET) or PET/CT (computed tomography) have translated from a mere research tool to clinical cardiovascular (CV) practice.1–4 Although the basic principles of PET are similar to those of single photon emission computed tomography (SPECT), PET or

PET/CT affords technical advantages over gamma-technique SPECT, such as higher counting sensitivity, higher spatial resolution, and routine use of more accurate attenuation correction.5,6 Notably, PET scanners are full-ring devices that simultaneously measure two photons traveling in opposite directions at a 180° angle from each other from the annihila-

Statement of Conflict of Interest: see page 602. ⁎ Address reprint requests to Thomas Hellmut Schindler, M.D., Johns Hopkins University, School of Medicine, Division of Nuclear Medicine, Cardiovascular Nuclear Medicine, Department of Radiology and Radiological Science SOM, JHOC, 3225, 601 N. Caroline Street, Baltimore, MD 21287. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.pcad.2015.01.001 0033-0620/© 2015 Elsevier Inc. All rights reserved.

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589

Abbreviations and Acronyms

tion process at all angles, while convenCAD = coronary artery disease tional SPECT cameras CT = computed tomography necessitate time to rotate the detector CV = cardiovascular heads around the paFFR = fractional flow reserve tient. Given the full-ring device of LAD = left anterior descending PET/CT, it confers the LCx = left circumflex advantage of dynamic imaging of rapid alterLV = left ventricle or left ations or changes in ventricular radiotracer passage in MBF = myocardial blood flow the left ventricular (LV) cavity and myoMFR = myocardial flow reserve cardium that enables MPI = myocardial perfusion the quantification of imaging myocardial blood flow (MBF) in ml/g/min PET = positron emission with radiotracer kitomography netic modeling.7–10 RCA = right coronary artery More recently introduced high speed SD = standard deviation SPECT cameras, howSPECT = single photon emission ever, apply a bank of computed tomography independently conTc = technetium trolled detector columns with large-hole collimators allowing quantification of local tracer activity concentration of conventional SPECT tracers such as thallium-201 and technetium-99 m (Tc-99 m) labeled perfusion tracers and, thus, may also afford MBF quantification.11–13 This consideration has been emphasized by an investigation in a porcine model that demonstrated the principal feasibility of MBF quantification with a multipinhole dedicated cardiac

Fig 1 – Schematic illustration of cardiac PET and SPECT radiotracer uptake in relation to coronary blood flow. 15 O-water shows a close linear uptake while the initial linear extraction of most other radiotracers plateau at ≈2 ml/g/min. PET radiotracers 13N-ammonia and 82Rubidium are localized between 201thallium and 99mTc-SPECT radiotracers, whereas 99 mTc-teboroxime reveals a relatively high myocardial extraction fraction at higher flow rates. Interestingly, flurpiridaz approaches 15O-water to linear extraction. (With kind permission from Ref.66).

SPECT camera but needing further evaluation in its accuracy.14,15 PET/CT approaches for the assessment of regional MBF in ml/g/min implies the intravenous injection

Table 1 – Radiotracer characteristics and image acquisition for PET perfusion imaging and MBF quantification. Characteristics

15

13

82

Half-life Extraction fraction a Mechanism

2.4 minutes ≈ 100%

9.8 minutes ≈ 80%

78 seconds ≈60

109 minutes ≈94%

Production Positron range Data acquisition

Freely diffusible, metabolically inert Onsite cyclotron 4.14 mm Dynamic

Soluble, microsphere like, metabolically trapped Onsite cyclotron 2.53 mm Dynamic, static, gated

Soluble, microsphere like, metabolically trapped Regional cyclotron 1.03 Dynamic, static, gated

Scan duration Dose-2D Dose-3D

5 minutes 40 mCi 10 mCi

20 minutes 15–25 mCi 15 mCi

Interval between 7 minutes doses Image No interpretation Image quality N/A

30 minutes

Soluble, microsphere like Generator 8.6 mm Dynamic, static, gated 6 minutes 40–60 mCi 15–20 mCi 30–40 mCi 3D LSO 10 minutes

Yes

Yes

Yes

Excellent

Good

Excellent

O-Water

N-Ammonia

Rubidium

Flurpiridaz

20 minutes N/A 5 mCi N/A

Abbreviations: 2D = 2 dimenional; 3D = 3-dimensional; LSO = lutetium oxyorthosilicate; MBF = myocardial blood flow; N/A = not applicable; PET = positron emission tomography. a Extraction fractions are listed for baseline MBF (≈1 ml/g/min).

590

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during vasomotor stress, and the resulting myocardial flow reserve (MFR) signify and characterize impaired vasodilator function of the coronary circulation, commonly appreciated as a functional precursor of the coronary artery disease (CAD), measure its response to preventive medical intervention, improve detection and quantification of CAD burden, and potentially assess the flow-limiting effect of single lesions in multivessel CAD (Table 2). 18–26 This review aims to provide a comprehensive overview of current and emerging positron-emitting myocardial perfusion tracer, such as 15O-water, 13N-ammonia, 82Rubidium, and flurpiridaz, to quantify myocardial perfusion and MBF, and shortly outlines potential clinical applications.

Fig 2 – Arterial radiotracer input function and myocardial tissue response. From regions of interest assigned to the left ventricular blood pool and left ventricular myocardium on the serially acquired images, time activity curves are derived that denote the alterations in radiotracer activity (y-axis) in the arterial blood pool (counts/pixel/second) and in the myocardium (counts/pixel/second) as a function of time (x-axis). Through fitting of the time activity curves with the operational equation formulated from tracer-kinetic models, myocardial blood flows are obtained in absolute units (in ml/g/min). The blue line indicates the arterial radiotracer input function, and the red line the myocardial tissue response. (With permission from Ref.18).

of a positron-emitting perfusion tracer, such as 15O-water, 13 N-ammonia, 82Rubidium, and F-18–labeled perfusion tracers like flurpiridaz, dynamic acquisition of images of the radiotracer passing through the central circulatory system to its extraction and retention in the LV myocardium (Table 1) (Figs 1 and 2).7–9,16,17 For the time being, however, only13N-ammonia and 82Rubidium have received US Food and Drug Administration approval for clinical application of myocardial perfusion imaging with PET. From the clinical perspective, the visual analysis and comparison of relative radiotracer-uptake on stress-rest PET/CT images with a stress-induced regional perfusion defect commonly signify the culprit lesion or most-advanced epicardial lesion in the presence of CAD. Conversely, the concurrent quantification of MBF at rest,

Table 2 – Potential clinical hyperemic MBF and MFR.

use

of

PET-determined

1. Identification and characterization of subclinical CAD. 2. Incremental predictive value on future cardiovascular outcome. 3. Characterization of the extent and severity of CAD burden in multivessel disease. 4. Detection of “balanced” reduction in myocardial blood flow related to three vessel or main stem CAD. a Abbreviations: CAD: coronary artery disease; MBF: myocardial blood flow; MFR: myocardial flow reserve. a Effects of diffuse myocardial ischemia should be confirmed by a peak stress transient cavity dilation of the left ventricle during maximal vasomotor stress on gated PET images.

Positron-emitting perfusion tracers Measurements of regional MBF in ml/g/min are performed with intravenous application of different perfusion radiotracers like 15 O-water, 13N-ammonia, or 82Rubidium and radiotracer kinetic modeling (Table 1) (Figs 1 and 2).115O-water and 13N-ammonia are cyclotron produced with relatively short physical half-lives of 9.8 and 2.4 minutes, respectively (Table 1). MBFs acquired with 15O-water and 13N-ammonia have been widely validated against independent microsphere blood flow measurements in animals and have yielded highly reproducible values over a range of 0.5 to 5.0 ml/g/min.8,16 In addition, measurements of MBF with 15O-water and 13N-ammonia in humans yield comparable estimates over a wide range of flow.27,28 The dependency of 15O-water and 13N-ammonia for MBF calculation on the availability of an on-site cyclotron, however, has limited a more widespread clinical application of these radiotracers. 82 Rubidium as myocardial perfusion tracer, on the other hand, affords an ultra-short 75 seconds of physical half-life that is available through a Strontium-82/Rubidium-82 generator system with a 4–5 week shelf life. 82Rubidium, therefore, is independent of the presence of a nearby cyclotron that again, in recent years, has triggered an increased clinical use for PET myocardial perfusion imaging in CAD detection.25,29,30 In function of the patient volume, 82Rubidium or 13N-ammonia is used for the assessment of cardiac perfusion and flow quantification with PET. The main advantages of 82Rubidium over 13N-ammonia can be seen in the ultra-short physical half-life of 75 seconds (Table 1), which enables fast sequential assessment of stress and rest myocardial perfusion at short time intervals (e.g. 10 minutes), and its independence from a nearby cyclotron. The high costs of the Strontium-82/ Rubidium-82 generator, however, necessitate a relatively high patient volume to render 82Rubidium PET cost effective. Accordingly, 82Rubidium PET myocardial perfusion imaging is commonly performed in clinical centers with a higher patient volume. Because 13N-ammonia as a flow tracer has a physical half-life of about 10 minutes, a stress-rest myocardial perfusion exam with PET may last up to 90 minutes hampering the general patient flow in PET centers. Nevertheless, centers that preferentially use treadmill exercise testing and cardiac SPECT perfusion studies in CAD detection may have a lower volume for myocardial perfusion studies with PET. Under such circumstances, 13N-ammonia as flow tracer may be given preference

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Fig 3 – Parametric display of MBF and MFR with 15O-water in a 58 year old patient with typical angina chest pain. (A) Positron emission tomography (PET) signifies a perfusion defect with an abnormal hyperemic perfusion of 1.26 ml/min/g and a myocardial flow reserve (MFR) of 1.61 in the area supplied by the left anterior descending (LAD) artery. (B) Invasive coronary angiography demonstrate angiographic significant > 70% luminal narrowing of the proximal LAD artery. Invasively measured fractional flow reserve (FFR) demonstrates an abnormal FFR of 0.43. (CX = circumflex artery; RCA = right coronary artery). (With kind permission from Ref.2).

as it can be produced by the cyclotron on demand and, thus, renders its application more cost effective.18 In a few centers in Europe, parametric mapping of hyperemic MBFs, as determined with 15O-water and PET, has been introduced and applied clinically for CAD detection.1,2 This opens another avenue for clinical centers focusing on the cyclotron-dependent production of 15O-water with a short half-life of 2.4 minutes allowing a high throughput of patients. One disadvantage of PET flow studies is that treadmill exercise testing commonly is not performed, as it would not allow the quantification of MBF. This is because the time interval between radiotracer injection at

peak treadmill exercise test and image quantification in the PET scanner does not permit the acquisition of the in-put function in the LV and the initial part of the myocardial response curve of radiotracer accumulation needed for MBF calculation (Fig 2).8 Another possibility is to let the patient perform supine bicycle exercise stress in the PET scanner. 31 This would allow the injection of the radiotracer at peak stress and immediate data acquisition with PET for a reliable MBF quantification. While this approach to quantify MBF with 15O-water PET during supine bicycle exercise is feasible, it may be seen as suboptimal stress test as the predicted workload achieved is only 70%.31

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Characteristics of positron flow tracers 15

O-water

Quantitative assessment of regional MBF with 15O-water and PET correlates closely with flow values as assessed by microspheres.16 Since 15O-water is a freely diffusible radiotracer in both the vascular space and myocardium, visualization of myocardial activity, however, necessitates correction for activity in the vascular compartment. This can be done by acquiring a separate scan after inhalation of 15O-carbon monoxide which labels red blood cells that denote the vascular space, which then can be subtracted from the 15 O-water images resulting in visualization of the myocardium.16,32 Another possibility to consider is the employment of a factor analysis for the separation between blood pool and myocardial tracer uptake and their alterations over time.33 Since 15O-water has a ≈ 95% first pass extraction fraction into the myocardial space (Table 1), the myocardial uptake of 15O-water commonly parallels regional blood flow even at hyperemic range (Fig 1).34–36 MBF calculation with 15 O-water therefore can be performed with a simple 1-compartment tracer kinetic model and MBF values closely parallel independent microsphere blood flow measurements as reference.16,36 A “roll-off phenomenon” with prominent non-linear myocardial radiotracer uptake with increasing blood flow during hyperemic flow stimulation, as described for 13N-ammonia and 82Rubidium with lower first pass extraction fractions of ≈ 80 and ≈ 60%, respectively, virtually does not exist for 15O-water (Fig 1).18,37 Consequently, radiotracer-kinetic models for MBF quantification with 15 O-water do not really need to correct for a relative underestimation of hyperemic MBFs as it is the case for 13 N-ammonia and 82Rubidium.7,8,10,38–40 With these advantages, 15O-water and PET determined MBF values are commonly considered as the “non-invasive” gold standard for MBF measurements in humans.18,20,41 The short physical half-life of 15O-water (2.4 minutes) also affords rapid and repeated MBF measurements at short intervals of 10 to 15 minutes for research purposes. Static 15O-water images of

the myocardium, on the other hand, are commonly of lower count density due to subtraction of the blood pool from the 15 O-water images, rapid clearance of 15O-water and its short half-life. Such low count 15O-water images are not suitable for the visual analysis of relative radiotracer uptake of the LV and, thus, they are not used clinically for CAD detection.9 Interestingly, in order to overcome the latter limitation of static 15O-water images, parametric mapping of hyperemic MBF and MFR values, as determined with 15O-water PET, has been developed42–44 and applied in the clinical setting (Fig 3A).1,2,45 Several quantitative flow studies with 15 O-water have demonstrated an improved diagnostic accuracy for the detection of CAD.1,45,46 The exact cut-off values of hyperemic MBFs and MFR values in the detection of flow-limiting CAD have been a matter of ongoing debate.46 More recently, Danad et al.2 investigated 330 patients undergoing quantitative 15O-water PET and invasive coronary angiography in concert with invasive fractional flow reserve (FFR) measurements. A stenosis > 90% and/or FFR ≤ 0.80 was defined flow-limiting, while a stenosis 0.80 was not. Receiver-operating curves identified optimal cut-off values of 15O-water and PET-determined hyperemic MBF and MFR were 2.3 ml/g/min and 2.50, respectively, for CAD detection.2 This parametric approach of 15O-water PET with visualization of hyperemic MBF and MFR values of the LV yielded a reasonable diagnostic accuracy of 85% for the identification of flow-limiting epicardial lesions when defined by an abnormal FFR (Fig 3B). Vice versa, a normal 15O-water PET determined hyperemic MBF of > 2.3 ml/g/min excluded the presence of flow-limiting stenosis with a high negative predictive value (90% per patient and 95% per vessel). Such an elegant approach using parametric imaging of hyperemic MBF with 15O-water is also attractive from the practical point of view. In patients with a normal medical history and/or normal LV wall motion on echocardiographic images, stress only MBF images with 15O-water PET study would increase patient flow, reduce radiation exposure and expenses for perfusion studies.20 A general problem that pertains to the non-invasive assessment of MBFs is the relatively low specificity of an abnormal MFR as it can be related to advanced, flow-limiting

Fig 4 – 13N-ammonia myocardial perfusion PET/CT study in a 38 year old cardiovascular risk individual with exercise-related chest pain and left main disease. (A) Invasive coronary angiography signifies a proximal narrowing of ≈50% of the left main (LM) vessel. In addition, the mid left anterior descending artery (LAD) contains a ≈30% narrowing after the first diagonal branch, while a ≈40% narrowing is noted in the left circumflex artery (LCx) proximal to the second marginal branch. (B) The right coronary artery (RCA) and its branches are free of disease. (C) 13N-ammonia myocardial perfusion and flow PET/CT study were performed in order to evaluate the hemodynamic significance of the LM lesion. Regadenoson-stress and rest 13N-ammonia PET/CT images in corresponding short-axis (top), vertical long-axis (middle), and horizontal long-axis (bottom) slices demonstrate a widely homogenous and, thus, normal radiotracer-uptake of the left ventricle. (D) Corresponding display of myocardial perfusion on polar map and in 3D. (E) Regional myocardial blood flow quantification (MBF) and myocardial flow reserve (MFR) calculation with 13N-ammonia PET/CT and tracer kinetic modeling. The summarized quantitative data denote reduced hyperemic MBFs (10% myocardium at stress), were identified in 56% of patients visually and 59% semiquantitatively. Adding the evaluation of LV wall motion on post-stress gated SPECT to MPI, however, increased the detection of high risk individuals to 83% of patients. In principle, the limited diagnostic value of conventional scintigraphic MPI may be overcome by the concurrent assessment of hyperemic MBF and MFR to MPI with PET.18 Stress-induced and balanced ischemia of the LV myocardium can be unmasked by diffuse reductions in hyperemic MBF and MFR.21,22,24 Diffuse reductions of hyperemic MBF, however, cannot reliably differentiate between hemodynamically obstructive CAD lesion from non-obstructive, diffuse atherosclerosis or microvascular dysfunction as a recent comparative study between PET-determined flows and invasive coronary angiography outlines.24 Consequently in patients with suspected CAD, balanced decreases in hyperemic MBFs that raise the suspicion for significant left-main and/or three vessel CAD related stress-induced diffuse ischemia should always be confirmed by a “peak” stress transient ischemic cavity dilation of the LV associated with a global hypokinesis on gated PET images indicative of myocardial stunning (Fig 9).25,26 Conversely, normal hyperemic MBFs and MFRs, respectively, have a high negative predictive value of 97% in excluding high-risk CAD on coronary angiography non-invasively with PET.24 Additional information comes also from the assessment of the LV ejection reserve (ΔLVEF = stress LVEF − rest LVEF). 26 As it was observed, an LVEF reserve of more than + 5% had a positive predictive value of only 41% but a negative predictive value of 97% for excluding severe left main/3-vessel CAD. A normal to high LVEF reserve therefore may be a useful tool to rule out significant left main and/or three vessels disease.26 In aggregate, combining hyperemic MBFs, MFR, LVEF at “peak”

stress as well as adding the LVEF reserve may allow the differentiation between left main/3-vessel CAD induced diffuse ischemia, its exclusion, and the presence of predominantly microvascular dysfunction (Fig 9). This evolving concept, however, needs to be further evaluated in large-scale clinical trial.

Conclusions In recent years, positron-emitting flow radiotracers such as 13 N-ammonia and 82Rubidium for myocardial perfusion and flow quantification with PET have emerged in clinical routine, yielding high diagnostic accuracy in the detection and characterization of the CAD. 15O-water-PET flow quantification is commonly used for research protocols, while a few European centers have introduced a parametric mapping approach for hyperemic MBFs with initial clinical validation. Since 15O-water and 13N-ammonia both are cyclotron dependent, a widespread clinical use of these myocardial perfusion radiotracers and PET is not possible. Conversely, since 82 Rubidium can be eluted from a commercially available 82 Strontium generator, a marked increase in clinical application of MPI with PET has ensued. In addition, flurpiridaz, as an F-18-labeled perfusion tracer, has gathered strong interest as it affords excellent radiotracer characteristics for perfusion and MBF quantification. The relatively long half-life of 109 minutes of flurpiridaz may pave the avenue for a general application of this radiotracer for PET perfusion imaging comparable to 99mTc-labeled SPECT, but the results of an ongoing phase 3 clinical trials and FDA approval need to be awaited. The concurrent ability of PET in conjunction with several radiotracers to assess MBF in ml/g/min has contributed to unravel pathophysiological mechanisms underlying CAD, to improve the detection and characterization of CAD burden in multivessel disease, and to provide incremental prognostic information in CAD individuals. PET myocardial perfusion and flow quantification have the potential to start a new era of a personalized, image-guided therapy approach that may contribute to further improve clinical outcome in CAD patients needing validation in large- scale clinical trials.

Statement of Conflict of Interest No potential conflict of interest exists and all sources of funding for the work are acknowledged as follows.

Acknowledgments This work was supported by a departmental fund of Johns Hopkins University, Baltimore, MD, USA; and a Research Grant of the Swiss National Science Foundation (SNF: 3200B0-122237, Dr. Schindler), with contributions of the Clinical Research Center, University Hospital and Faculty of Medicine, Geneva, and the Louis-Jeantet Foundation, Gustave and Simone Prevot, and Swiss Heart Foundation.

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