University of Groningen
Role of quantitative and gated myocardial perfusion PET imaging
Monroy-Gonzalez, A. G.
DOI:
10.33612/diss.132603282
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2020
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Monroy-Gonzalez, A. G. (2020). Role of quantitative and gated myocardial perfusion PET imaging.
University of Groningen. https://doi.org/10.33612/diss.132603282
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CHAPTER
1 Nuclear Cardiology Department, National Cardiology Institute Ignacio Chavez,
Mexico City, Mexico
2 Medical Imaging Center, University Medical Center Groningen, Groningen, The
Netherlands
3 Echocardiography Department, ABC Medical Center, Mexico City, Mexico 4 Magnetic Resonance Imaging Department, National Cardiology Institute Ignacio
Chavez, Mexico City, Mexico
5 Physiology Department, Medicine Faculty, Universidad Nacional Autonoma de
Mexico (UNAM), Mexico City, Mexico
Published
Ann Nucl Cardiol 2019; 5 (1): 63-69. doi: 10.17996/anc.19-00100
General introduction: PET/CT with
13
N-ammonia
Adapted from:
PET/CT with 13N-ammonia: Characteristics and utility in coronary
artery disease
I. Carvajal-Juarez 1, A.G. Monroy-Gonzalez 2,
N. Espinola-Zavaleta 1,3, A. Meave-Gonzalez 4,
INTRODUCTION
13N-ammonia is a compound that has been developed as a positron
emission tomography (PET) tracer for the non-invasive assessment of myocardial perfusion [1]. It was approved by the United States Food and Drug Administration (FDA) in 2000 for cardiac PET imaging and in over the 2 decades of clinical utility it has proven to be useful in the assessment of coronary artery disease (CAD) giving important prognostic information in patients with clinical and subclinical disease [2]. From the list mode acquisition of 13N-ammonia PET study, it is possible to analyze static, gated and dynamic datasets facilitating an integrated assessment of the myocardium [2]. Firstly, static images are used to define the extent and severity of regional hypoperfusion comparing rest and stress images. Secondly, gated PET images allow automated quantification of left ventricular volumes and left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume, left ventricular end-systolic volume, diastolic function and contraction synchrony. Thirdly, dynamic reconstruction of the data allows the generation of time activity curves from the blood pool and myocardium to calculate absolute regional myocardial blood flow (MBF) in mL/g/min at rest and during vasomotor stress, and consequently quantitation of myocardial flow reserve (MFR) [3].
Production of 13N-ammonia
Ammonia is normally produced in the body, and it is freely permeable to all cell membranes [4]. In blood NH3 diffuses passively across cell membranes, where it equilibrates with its charged form ammonium (NH4) and gets trapped inside the cell by conversion through glutamine synthase to glutamine [5,6]. 13N-ammonia is a radiotracer with a longer physical half-life (t½) of 10 min in comparison to other radiotracers: 82Rubidium (82Rb) with t½ of 75 sec and 15O-water with t½ of 2 min [4-6]. Those radiotracers have the need of an onsite generator or an onsite cyclotron for their production, respectively, which translates in mayor logistical difficulties and higher costs. On the contrary, the physical t½ of 13N-ammonia allows to acquire studies in places where a cyclotron is located at relatively short distances from the cyclotron. This has been demonstrated to be feasible in Mexico City, where more than 500 studies have been acquired in a PET scanner that is located within 5 km from the regional cyclotron.
General introduction Pharmacokinetic parameters of 13N-ammonia
After intravenous injection, 13N-ammonia rapidly clears from the circulation. Uptake is mainly observed in the myocardium, lungs, brain, liver, kidneys and bladder [4,7]. In the myocardium, 13N-ammonia is removed from the blood and metabolically trapped within the tissues [5,8]. This linear relationship between the distribution of 13N-ammonia and the regional blood perfusion makes feasible the use of this radiotracer for the visualization of myocardial perfusion and the quantification of MBF. The high first-pass myocardial extraction fraction, the capture in the myocardial cells as 13N-glutamine and the relatively long physical t½ may account for the high contrast resolution. These properties confer statistically high counts rates to the myocardium, producing a high quality image of myocardial perfusion abnormalities on rest and stress [8]. Furthermore, 13N-ammonia is the radiotracer with the lowest positron range (barely 2.53 mm) over other perfusion radiotracers (82Rb with 8.6 mm and 15O-water with 4.14 mm) [6,8]. Positron range is the distance from positron emission to positron annihilation, which impairs resolution and introduces blurring [7,9]. Therefore, the positron range of 13N-ammonia results in an excellent high image resolution tracer,
Table1. 13N-ammonia basic characteristics and advantages
13N-ammonia
Supplied Cyclotron
Maximum energy (MeV) 1.20
Half life 9.96 min
First-pass extraction 80% (linear with increasing blood flow)
Data acquisition Dynamic, static, gated
Scan duration 20 min
Interval between doses 0-30 min
Method of detection Positron emission tomography
Positron range 2.53 mm
Stress Pharmacological
Imaging protocol
Patient preparation for pharmacologic stress with PET is the same as for 99mTc single photon emission computed tomography (SPECT). Patients must fast for a minimum of 4 hours, avoid smoking for at least 4 hours and avoid caffeine or theophylline intake for at least 12 hours before vasodilator stress (adenosine, dipyridamole and regadenoson have been evaluated using
13N-ammonia) [10,11]. The acquisition time of 13N-ammonia takes about 10–20 minutes approximately per phase, longer than the time required for 82Rb and 15O-water [10,12]. List mode acquisition is recommended because it allows flexibility in the timing and reconstruction of images (dynamic for MBF, static for myocardial perfusion and electrocardiography-gated for left ventricular ejection fraction, volumes and wall motion assessment).
The activity injected depends on the equipment for scanning (2D=370MBq, 3D=555mBq). Contemporary, PET scanners operate in 3D acquisition mode, therefore, 13N-ammonia standard protocol involves an injection of 370 MBq at rest followed by a 10 minutes image acquisition protocol. After 30 minutes of delay, pharmacological stress is performed and a second 370 MBq injection of 13N-ammonia is injected and images are acquired [10,12]. As an alternative, it has been recently proposed a time-efficient protocol with the rest acquisition followed immediately by the stress acquisition and a residual activity correction [13]. It is important to flush the tracer injection line with enough saline in order to clear the tracer activity out of the cephalic, axillary and subclavian veins to avoid scatter from focal activity near the edge of the field of view leading to artifacts, especially on 3D scans [10,11].
13N-ammonia is a valuable agent for measuring either absolute or relative MBF. For measurements of absolute flow, dynamic acquisition is required to start at time of injection. Uptake is relatively rapid (typically 90 seconds) [10,14]. The static image should not include the initial rapidly changing uptake portion of the study. A minimum of 90 seconds should elapse between the end of infusion and the beginning of the static scan. Even though the arterial blood concentration of ammonia is often still quite significant even at 90 seconds after a rapid bolus injection, many published data are based on a 90-second delay before starting of imaging [10-14].
Several factors may affect the accuracy of this test, such as uncorrected non-uniform attenuation and photon scatter from extra-cardiac sources, particularly the liver. Attenuation artifacts are frequently observed due to the diaphragm as well as in obese patients and female patients [12]. However, all PET scans for cardiac imaging are currently performed in hybrid PET/ CT systems and have an inherent CT attenuation correction, which means that Hounsfield units (HU) generated by the CT scan can be converted into PET attenuation coefficients [15]. Initially, a scout CT acquisition must be
General introduction
performed to ensure proper patient positioning. Then, a CT transmission scan is acquired for subsequent attenuation correction. A second CT transmission scan is acquired for attenuation correction of the stress images [14]. CT-based attenuation correction typically adds less than 10 seconds to the cardiac scan time. It is important to keep in mind that the high speed of CT scans freezes the heart and lungs at one phase of the respiratory cycle, causing potential misalignment between CT-based transmission and emission scans [7]. Misalignment of the attenuation CT and PET emission images, potentially exacerbated by patient and respiratory motion during hyperemic stress, may introduce moderate to severe artifacts and can result in significant changes in MBF quantification [11]. Software realignment must be performed to minimize any remaining misalignment. Other techniques (e.g., cardiac motion frozen, respiratory gating, and 4D-CT) are under development for compensating respiratory motion [14].
Clinical Role of 13N-ammonia PET/CT
Diagnostic accuracy for Identifying obstructive CAD
The clinical utility of 13N-ammonia and 82Rb PET for identifying obstructive CAD is widely established [7, 14-18]. However, most of those studies have used 82Rb [7-12] and less is known regarding the diagnostic accuracy of PET with 13N-ammonia as myocardial perfusion radiotracer [10]. Fathala et al. reported a sensitivity of 90%, specificity of 90%, positive predictive value of 96%, negative predictive value of 76%, and diagnostic accuracy of 80% [16]. Identification of myocardial perfusion defects should characterize extent, severity and location, by using qualitative and semiquantitative scoring systems [7].
Perfusion and Flow Quantification
13N-ammonia has been validated and extensively used for quantitation of MBF and MFR. Currently, PET is considered the reference standard for the quantification of myocardial perfusion [15]. The reported weighted mean of MBF values at rest and stress are 0.71 mL/gr/min (range 0.61–1.1) and 2.58 mL/gr/min (range 1.86– 4.33), respectively and the mean of MFR is 3.54 (range 3.16–4.8) [10]. Investigations have aimed to identify the optimal threshold values of hyperemic MBFs or MFR for the diagnosis of epicardial obstructive lesions. Using 13N-ammonia, an hyperemic MBF threshold value of < 1.85 mL/gr/min and an MFR threshold value of < 2.00 reported the highest diagnostic accuracy for detecting ≥ 70% epicardial lesions [17-19]. Also
using 13N-ammonia, abnormal MFR (< 2.0) has demonstrated a sensitivity, specificity, and diagnostic accuracy of 96%, 80%, and 92% respectively for detecting ≥ 50% epicardial obstructive lesion [18,19].
The ability of myocardial perfusion tracers to assess regional MBFs and MFR not only allows to delineate clinical manifestations by identifying all epicardial lesions in patients with CAD but also allows to obtain prognostic information [19]. Herzog, et al [20] demonstrated that when quantitative 13N-ammonia PET studies identified stress-induced regional myocardial perfusion defects, an abnormally reduced MFR provided incremental information to the conventional stress 13N-ammonia perfusion PET study by predicting adverse outcomes. An abnormal global MFR < 2.0 was found to be independently associated with a higher annual event rate for major adverse cardiac events and cardiac death over 3 years compared with normal MFR [19,20].
Other clinical applications
13N-ammonia has also shown to have a role in the identification of subclinical manifestations in patients with diabetes mellitus type 2, hypertension and dyslipidemia [21]. The addition of coronary computed tomography angiography (CCTA) can be very helpful to differentiate patients with extensive obstructive CAD from those with predominantly microvascular dysfunction giving information to improve the specificity of PET, especially in the setting of abnormal MBF or MFR values [10]. This is important because a large proportion of symptomatic patients undergoing invasive diagnostic coronary angiography does not have obstructive CAD and a substantial proportion of patients with non-obstructive coronary atherosclerosis may have underlying microvascular dysfunction as the functional substrate of their angina symptoms [21]. Flow tracers such as 13N-ammonia, 82Rubidium, 18F-Flurpiridaz and 15O-water can identify microvascular dysfunction noninvasively by assessing reductions in hyperemic MBF in absolute terms (mL/gr/min) and/or MFR [20-22]. Furthermore, quantifying calcium allows an assessment of the extent of atherosclerotic plaque burden and an insight into the patient’s risk and prognosis [23]. Calcium score and CT angiography can be performed immediately after 13N-ammonia PET scan and coronary calcium score CT can also be used for attenuation correction of PET rest/ stress acquisitions with the advantage of dose reduction [24]. Additionally, gated PET allows the assessment of ventricular synchrony, which has shown
General introduction
to improve the selection of patients with heart failure who undergo cardiac resynchronization therapy [25].
Outline of thesis
While myocardial perfusion imaging with PET has gained popularity for the assessment of CAD during the last two decades, progress still needs to be made in to standardize protocols and to understand other potential clinical applications. Therefore, the aim of this thesis is to expand our understanding of quantitative myocardial perfusion and ventricular synchrony measured by 13N-ammonia PET.
Quantitative myocardial perfusion
Because it is fundamental that quantitative PET perfusion parameters provide reproducible results, chapter 2 explores the agreement in the quantification of myocardial perfusion by cross-comparison of implemented software programs (SPs).
Since many patients with angina pectoris do not have obstructive CAD,
chapter 3 evaluates the long-term prognostic value of quantitative myocardial
perfusion for the prediction of all-cause mortality and major adverse cardiac events in patients with chest pain and normal coronary arteries.
Myocardial bridging (MB) refers to a band of myocardium that abnormally overlies a part of a coronary artery. Until now, its clinical significance remains unclear. Therefore, chapter 4 quantitatively evaluates the influence of MB of the left anterior descending artery on myocardial perfusion. Similar to Chapter 3, the studied population in this chapter does not have obstructive CAD.
Transluminal Attenuation Gradient (TAG) is a measurement representing the gradient of intraluminal contrast that decreases along a coronary vessel, which can be easily calculated with standard coronary computed tomography angiography. Chapter 5 explores whether myocardial perfusion parameters are related to TAG.
Gated PET
During the PET scan, the acquisition of gated data allows to measure mechanical synchrony. Chapter 6 describes the diagnostic role of mechanical synchrony in patients with known or suspected CAD-related myocardial
ischemia, prediction of response to cardiac resynchronization therapy, and estimation of risk for adverse cardiac events in patients with heart failure. Furthermore, Chapter 7 explores the relationship between quantitative myocardial perfusion and synchrony parameters when accounting for perfusion defects in patients with chronic HF.
Final chapters
The final chapters will present the concluding remarks of this thesis as well as future perspectives.
General introduction
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General introduction
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