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Quantification of myocardial blood flow using PET to improve the management of patients with stable ischemic coronary artery disease Hiroshi Ohira*,1, Taylor Dowsley1, Girish Dwivedi1, Robert A deKemp1, Benjamin J Chow1, Terrence D Ruddy1, Ross A Davies1, Jean DaSilva1, Rob SB Beanlands 1 & Renee Hessian1
ABSTRACT Cardiac PET has been evolving over the past 30 years. Today, it is accepted as a valuable imaging modality for the noninvasive assessment of coronary artery disease. PET has demonstrated superior diagnostic accuracy for the detection of coronary artery disease compared with single-photon emission computed tomography, and also has a wellestablished prognostic value. The routine addition of absolute quantification of myocardial blood flow increases the diagnostic accuracy for three-vessel disease and provides incremental functional and prognostic information. Moreover, the characterization of the vasodilator capacity of the coronary circulation may guide proper decision-making and monitor the effects of lifestyle changes, exercise training, risk factor modification or medical therapy for improving regional and global myocardial blood flow. This type of image-guided approach to individualized patient therapy is now attainable with the routine use of cardiac PET flow reserve imaging. After 30 years of predominantly research-based applications, PET technology has the capacity to dramatically change the practice of clinical cardiology by providing similar information with noninvasive imaging methods. The basic theories behind PET and single-photon emission computed tomography (SPECT) are similar; however, PET possesses important advantages over SPECT, including a higher count sensitivity, better spatial resolution and simple, accurate attenuation correction. PET can quantify regional tracer activity concentration (Bq/cc) and myocardial blood flow (MBF) in absolute units (ml/min/g tissue). Although MBF measurement has been reported using SPECT [1–5] , cardiac magnetic resonance (CMR) [6–9] or echocardiography [10–15] in selected laboratories, PET has been the most reliable and widely used modality to quantify MBF [16] . Quantitation of MBF is important for the management of coronary artery disease (CAD) as it removes us from the downfall of relative perfusion imaging by providing information on absolute regional flow under rest and stress conditions. Despite the increasing availability of PET, the use of absolute MBF quantification has not been as widespread, except in institutions with research interests or clinical expertise in this area. The aim of this article is to review: the assessment of absolute MBF measurements for the purpose of diagnosis, risk stratification, prognosis and monitoring therapeutic interventions and directing management;
KEYWORDS
• CAD • CBF • CFR • CMR • CT • MBF • PET • SPECT
MFI program, National Cardiac PET Center, Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, ON, Canada *Author for correspondence: [email protected] 1
10.2217/FCA.14.44 © 2014 Future Medicine Ltd
Future Cardiol. (2014) 10(5), 611–631
part of
ISSN 1479-6678
611
Review Ohira, Dowsley, Dwivedi et al. the detection of the early functional abnormalities of the coronary circulation; and the comparison with other noninvasive imaging modalities. Future perspectives will be also presented. Methodology of PET & perfusion tracers: 13 N-ammonia, 82Rb-rubidium, 15O-water & 18F-flurpiridaz PET, similar to SPECT, uses external detectors in order to image the distribution of injected radionuclide tracers. The images and subsequent information acquired with SPECT and PET reflect cardiac physiology rather than anatomy. The physiologic information obtained depends on the radioactive nuclides that are utilized and their imaging characteristics. PET cameras are ten- to 20-times more sensitive than conventional SPECT cameras [17] , as they use the annihilation radiation resulting from positron decay, which can be localized using coincidence detection without the need for physical collimators. There are newer semiconductor-based SPECT cameras that are more sensitive than scintillation camera SPECT systems, but these are still less sensitive than PET [18] . Current-generation PET cameras have a spatial resolution in the range of 4–6 mm, which enables the precise identification of perfusion defects. PET systems also incorporate algorithms that accurately and reliably correct for attenuation and scatter, either using radioactive isotope sources on older scanners or computed tomography (CT) on ‘hybrid PET–CT’ scanners [19] . The radiotracers used for myocardial perfusion imaging (MPI) for PET include rubidium-82 (82Rb), nitrogen-13-ammonia (13NH3), oxygen-15-water (15O-water) and flurpiridaz F-18 (18F-flurpiridaz). Each has unique properties that make one preferable over another in individual situations (Table 1) [20] . In the clinical setting, 82Rb and 13NH3 are the only PET perfusion tracers that have received US FDA approval and are reimbursed by the Center for Medicare and Medicaid Services. 15O-water is considered to be the ideal radiotracer for quantitative flow measurement because it freely diffuses between the blood pool and myocardium. It is, however, difficult to obtain clear static images, as there is poor contrast between the blood pool and the myocardium. 15O-water is mostly used for research purposes in North America and Japan, with some clinical application in Europe [20] . Production processes also differ, with 13NH3
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Future Cardiol. (2014) 10(5)
and 15O-water being cyclotron-produced radiotracers, with relatively short half-lives of 9.97 and 2.04 min, respectively (Table 1) . 82Rb has an ultrashort half-life of 1.27 min and is produced using a 82strontium/rubidium generator system, thus having the advantage of not requiring a cyclotron on site. 82Rb is most cost-effective of the PET perfusion tracers; therefore, 82Rb is most widely available for clinical use, especially in high-volume centers where 30–50 patients can be imaged on a weekly basis [21] . The quantification of MBF with 13NH3 and 15 O-water has repeatedly shown a high degree of reproducibility in clinical studies over a wide range of flows (0.5–5.0 ml/min/g) [22,23] . Recent clinical investigations using 82Rb MBF quantification have reported incremental prognostic value in large multicenter studies [24–28] . The technical methods for MBF quantification using dynamic PET imaging with 82Rb and 13 NH3 are well established, using compartmental analysis of arterial blood and tissue time–activity curves [26,29] . 18 F-flurpiridaz is a new radiotracer that is currently undergoing Phase III clinical testing. A cyclotron is required to produce 18F-labeled compounds; however, 18F-f lurpiridaz has a longer half-life of 110 min, which should enable centralized production and distribution in a similar manner to 18F-fluorodeoxyglucose. 18 F-flurpiridaz is also suitable for exercise stress PET imaging. Compared with the currently available PET perfusion tracers, 18F-flurpiridaz has excellent spatial resolution due to a very short positron range and high first-pass extraction, even at increased flow rates [30–33] . Coronary physiology & quantification of MBF with PET The coronary arterial system is responsible for controlling blood flow to the myocardium. In order to supply the local oxygen requirements of the myocardium, the coronary circulation is dynamically controlled by autoregulatory mechanisms [34] . This maintains an adequate MBF in order to meet myocardial demands in a variety of situations. The components of the coronary arterial system are: epicardial arteries (which can be imaged by invasive or CT coronary angiography); prearterioles and arterioles that are not visible, but are important in auto regulation by changing vessel resistance and subsequent blood flow; and the capillary bed where oxygen and nutrient exchange occurs with the
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Quantification of myocardial blood flow using PET for the management of patients with stable ischemic CAD
Review
Table 1. Characteristics of cardiac PET perfusion radiotracers. Characteristics
Radiotracer
82
Rb-rubidium
Isotope half-life Initial extraction (flow) Retention fraction (uptake) Production method Advantages
1.27 min 40–70% (stress–rest)
9.97 min 95–98% (stress–rest)
2.04 min 95–100% (stress–rest)
110 min >90%
30–55% (stress–rest)
60–90% (stress–rest)
Not retained in tissues
60–90% (stress–rest)
82
Sr/Rb generator Commercially available generator product Capability to assess quantitative flow Short half-life for rapid testing Low radiation dose
Cyclotron High contrast resolution Capability to assess quantitative flow Potential for use with exercise Low radiation dose
Cyclotron Ideal kinetics for flow quantification Short half-life for rapid testing Low radiation dose
Disadvantages
Low spatial resolution Lower retention at higher flow rates Short half-life precludes exercise stress
Needs on-site cyclotron Moderate retention at higher flow rates Heterogeneity; retention in the lateral wall is 10% less Lung uptake in smokers
13
N-ammonia
15
O-water
18
F-flurpiridaz†
Cyclotron High contrast resolution Potential to assess quantitative flow Potential for use with exercise Can be distributed from central production Needs on-site cyclotron Not yet commercially Short half-life precludes available exercise stress Moderate retention at higher Low spatial and contrast flow rates resolution (tissue Long half-life complicates equilibrium with blood rest–stress flow pool) quantification
Data taken from [30–33]. Adapted with permission from [20]. †
tissue. When coronary or epicardial arteries are narrowed by atherosclerotic disease, coronary autoregulation attempts to normalize coronary blood flow (CBF) by reducing the resistance of the distal perfusion beds at the arteriolar level, thus maintaining myocardial oxygen supply [35] . Gould et al. demonstrated that the response to a hyperemic stimulation in CBF (cc/min) was an important physiological parameter using a surgically implanted flow-meter in animal studies [36] . Resting flow measurements did not decrease unless a stenosis reached 85%. On the other hand, hyperemic flow after administration of a vasodilator decreased when there was a 50% stenosis (Figure 1) [36] . They were the first to define coronary flow reserve (CFR) as maximal flow divided by resting flow. CFR is a quantitative measure of the ability of coronary vessels to augment blood flow in response to increased oxygen demands or as compensation for a decreased oxygen carrying capacity of the blood. The concept of CFR has since evolved into an accepted functional measure of stenosis severity. CBF can be estimated using several techniques, including coronary catheterization with a Doppler flow wire, which measures flow velocity coronary sinus thermodilution, or xenon methods, and these are presented in units of ml/min
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[37,38] .
All of these techniques are invasive and thus have limitations for clinical practice. PET has evolved into the noninvasive imaging modality of choice for the quantification of MBF. MBF conceptually refers to a measurement not just of epicardial flow, but also microvascular flow and function. MBF can also be measured during stress and at rest, the ratio of which is termed ‘myocardial flow reserve’ (MFR). The terminology used for flow in PET in the literature can sometimes be confusing. CBF represents flow in ml/min, whereas MBF represents flow per unit mass in ml/min/g. CBF can be thought of the volume of flow passing through the coronary bed per unit of time, and can technically only be measured invasively in a coronary artery, whereas MBF is flow per unit of time for a unit of myocardial mass. Thus, strictly speaking, CBF and MBF are not the same [16,39] . However, both of these are used in the literature for the study of coronary flow using PET and both refer to the flow through an artery and microcirculation [39] . We prefer the term MFR, as it relates more to the primary measurements. It is now known that MFR can be abnormal in the absence of significant epicardial CAD, so this expands the scope of conventional relative
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Review Ohira, Dowsley, Dwivedi et al. MPI from identifying only ‘end-stage’ epicardial CAD to the ‘earlier’ identification and characterization of function abnormalities in coronary endothelial function and subclinical stages of CAD, or what has been termed ‘microvascular dysfunction’ [16,40–42] . The role of PET-MPI for the identification & characterization of CAD ●●Limitation of the relative assessment of
MBF in multivessel disease
Stress SPECT-MPI is a validated diagnostic procedure for patients with suspected CAD. It has a high sensitivity (82–87%) for the detection of flow-limiting epicardial coronary stenoses [43] , provides incremental prognostic information over clinical data and guides clinical decisionmaking with regards to management, particularly for coronary intervention. The diagnostic
accuracy and predictive value of MPI in patients with three-vessel CAD (3VD) and left-main CAD is less well documented. There is evidence suggesting that the assessment of myocardial perfusion using SPECT-MPI is less sensitive for identifying significant 3VD as well as left-main CAD, as the evaluation of myocardial perfusion is based on the relative tracer distribution. This assumes that the region demonstrating the highest accumulation of tracer uptake represents normal perfusion and is then used as the normal reference coronary territory. The uptake in the remaining myocardial segments is compared with this region of highest uptake or reference territory. If the region of greatest perfusion is supplied by a diseased vessel and is reduced, this may lead to an underestimation of the true extent of CAD if the remaining territories have similar uptakes [44–47] . In extreme cases, 3VD
5 y = 3.7-1.0(10-2)x + 2.4(10-4)x2-6.0(10-6)x3
Normalize mean flow – times initial control
r = 0.89 SQ DEV = 0.345
4
3
2
1
0
y = 1.0-1.9(10-2)x + 6.2(10-4)x2-5.2(10-6)x3 r = 0.84 SQ DEV = 0.021 0
20
40 60 Percentage lesion by diameter
80
100
Figure 1. The relationship between percentage circumflex arterial constriction by diameter with resting mean flow and hyperemic response after intracoronary injection of Hypaque in 12 consecutive dogs. Flows are expressed as ratios in order to control resting mean values at the beginning of each experiment. SQ DEV: Mean square of deviations. Reproduced with permission from [36].
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Quantification of myocardial blood flow using PET for the management of patients with stable ischemic CAD may cause globally reduced perfusion, leading to normal relative MPI studies and no visual difference between the myocardial segments. This is known as ‘balanced ischemia’. Although it is uncertain how often this occurs, Berman et al. have noted that as many as 40% of patients with ≥50% stenosis in the left mainstem can have a normal- or low-risk SPECT scan [46] . Lima et al. reported that 40% of patients with significant multivessel CAD could not be correctly identified with SPECT-MPI using standard perfusion and function criteria [48] . Nonperfusion features, such as stress-induced transient ischemic dilatation of the left ventricle (LV) [49–51] , increased right ventricular uptake at stress [52,53] or a decrease in LV ejection fraction of greater than 5% [54] , have been evaluated and their presence suggests multivessel disease and an increased risk of adverse cardiovascular outcomes. The clinical utility of 13NH3 and 82Rb PETMPI for the detection of flow-limiting epicardial coronary lesions is also well established. Results from recent meta-analyses found a better accuracy of MPI with PET compared with SPECT [43,55] . Our group demonstrated that the weighted-mean sensitivity and specificity for 82Rb-PET were 90 and 88%, respectively, compared with 85 and 85%, respectively, for 99m Tc-based SPECT with ECG gating and attenuation correction. The areas under the curve between 82Rb-PET and 99mTc-based SPECT were 0.95 and 0.90, respectively (p < 0.0001), which confirms the higher accuracy of PET [43] . A second study confirmed these findings for all PET perfusions versus SPECT perfusions [55] . Taken together, these studies suggest that PET has higher diagnostic accuracy for detecting significant CAD than SPECT. Even with the high diagnostic accuracy of PET, the use of the relative assessment of myocardial perfusion shares the drawbacks of SPECT-MPI in patients with 3VD (Figure 2) . ●●Advantages of quantitative assessment of
MBF for the diagnosis of CAD
The measurement of absolute MBF during stress with 15O-water PET has a significant impact on the interpretation of myocardial perfusion. In patients with multivessel disease, the sensitivity and specificity of detecting disease per vessel with usual perfusion and function criteria were 38 and 68%, respectively. The corresponding values with the use of MBF analysis increased
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Review
to 96 and 94%, respectively [56] . A direct comparison of patients with 3VD (≥70%; n = 13) or single-vessel disease (≥70%; n = 10) based on coronary angiography was performed with both semiquantitative interpretation and quantification of tracer uptake as an estimate of MBF perfusion using 82Rb-PET [44] . Although resting uptake values were similar in both groups, wholeheart uptake during stress in the 3VD group was significantly lower than that with single-vessel disease. Standard relative MPI evaluation identified perfusion abnormalities in all segments in only 46% of patients with 3VD. By contrast, quantification of 82Rb retention as an estimate of MBF demonstrated decreased perfusion in all 3VD segments in 92% of patients. Similarly, another consecutive series of patients were studied who underwent 82Rb-PET and had angiography within 6 months [47] . Among 120 patients, 25 (21%) had severe 3VD, of which 88% (22/25) demonstrated globally reduced MFR (2.0) had an event-free period of 3 years compared with those with abnormal MFR [61] . Ziadi et al. demonstrated that flow quantification using 82Rb-PET predicted major adverse cardiac events independently of the summed stress score and clinical parameters (Figure 3) [62] . Murthy et al. further evaluated a total of 2783 consecutive patients and also demonstrated that the degree of reduction of MFR measured using 82Rb-PET predicted a
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Review Ohira, Dowsley, Dwivedi et al.
Adjusted cardiac-event-free survival
Cardiac-event-free survival probability
1.00
0.95 * 0.90
SSS < 4 MFR ≥ 2 SSS ≥ 4 MFR ≥ 2
** SSS < 4 MFR < 2
0.85
*SSS < 4 MFR < 2 vs ≥ 2: HR: 2.4 (1.4, 4.4); p = 0.003
0.80
**SSS ≥ 4 MFR < 2 vs ≥ 2: HR: 4.6 (2.2, 9.7); p < 0.001 SSS ≥ 4 MFR < 2
0.75 0
50
100
150
200
250
300
350
400
450
500
Days
Figure 3. Myocardial flow reserve has incremental prognostic value and improves risk stratification in patients with abnormal and normal stress perfusion. The figure shows adjusted event-free survival for hard cardiac events and major adverse cardiac events. Arrows highlight the statistically significant differences in outcomes among subgroups. HR: Hazard ratio; MFR: Myocardial flow reserve; SSS: Summed stress score. Reproduced with permission from [62].
gradient of adverse outcomes, including death. In addition, 50% of patients with intermediate preMFR risk were correctly reclassified to high-risk or low-risk categories by adding MFR to the perfusion and functional information (Figure 4) [63] . The results of these and other studies indicate that routine assessment of MFR quantified by PET improves risk stratification (Table 2) [61–66] . In addition, the usefulness of MFR with PET has been shown to improve the prediction of prognosis in patients with nonischemic cardiomyopathy in the absence of coexistent coronary disease. Cecchi et al. showed that MFR was an independent predictor of clinical deterioration and death in patients with hypertrophic cardiomyopathy [67] . The prognostic implication of PET with flow quantification in patients with dilated cardiomyopathy was also reported by Neglia et al. [68] . This suggests that abnormal microcirculation predicts an increase in risk in patients with predominant myocardial abnormalities. Although we are starting to understand the role of MFR in establishing prognosis, we
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currently have no data on the cost–effectiveness of its use and there is no clinical trial evidence suggesting how it should be used routinely. Patient management with flow quantification in stable coronary disease Accurate identification, lifestyle modification and treatment of risk factors are the first steps in the treatment of stable CAD. Whether optimal medical therapy (OMT) alone or initial revascularization is more beneficial remains controversial [69–71] . A single-center observational study with patients presenting for SPECT-MPI showed that the extent of ischemic myocardium predicted reduction in the risk of death with revascularization compared with OMT for those patients with >10–12% of ischemic myocardium if there was no scar present (Figure 5) [72] . The COURAGE trial demonstrated that a strategy of initial PCI with OMT had no survival advantage over OMT alone in patients with stable CAD [73] . In this study, however, patients were randomized after an angiogram, suggesting that high-risk patients did not participate in the study. Others feel that
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Quantification of myocardial blood flow using PET for the management of patients with stable ischemic CAD the use of angiographic interpretation of the coronary anatomy did not allow for the research question to be properly answered. A gradient of benefit with revascularization, however, was noted in the MPI substudy of COURAGE, suggesting that patients with significant ischemia may have benefited from therapy to reduce this ischemia, which was more successfully achieved with PCI than OMT alone [74] (although subsequent analysis suggested that this may not be the case for scans that are read at the site of recruitment rather than the core laboratory [75]). Many prior studies suggest that extensive ischemia, as determined by MPI, identifies patients for whom an initial revascularization strategy may lead to an improvement in cardiovascular outcomes [72,76] .
Review
However, this issue is by no means clear and is under investigation in trials such as ISCHEMIA. The physiological or hemodynamic assessment of coronary artery stenosis has become increasingly important and interesting in the research and clinical setting. Visual assessment of the severity of coronary stenosis has been traditionally used to guide revascularization in patients with stable CAD. The pressure gradient across a stenosis can be measured invasively during angiography from which the functional severity of a lesion on CBF can be determined. This is calculated under conditions of maximum coronary vasodilation and is the ratio of distal coronary pressure to aortic pressure. It is referred to as the fractional flow reserve (FFR), although strictly speaking it Percentage
0
Pre-MFR risk
10
20
30
Low (1100)
16%
40
50
60
Intermediate (898)
17%
Post-MFR risk
34%
70
80
90
100
High (785)
86% 3% 11%
84%
49%
Annualized cardiac mortality %
12 10.5%
10 8 6 4.4%
4 2
0 Post-test risk patients
1.7% 0.2%
0.2% Low 927
Int. 173
3.4%
2.3%
Low Int. High 304 445 149
0.0% Low Int. High 22 89 674
Figure 4. Risk reclassification by myocardial flow reserve. In total, 50% of patients with intermediate pretest risk were reclassified to high- or low-risk categories using PET flow reserve. The top horizontal bar graph represents the distribution of risk across categories of 3% (red) per yearly risk of cardiac death as estimated by a model containing clinical risk factors, rest LVEF, LVEF reserve and the combination of myocardial scar and ischemia. The pie graphs represent the proportions of patients in each pre-MFR category reassigned to each risk category after the addition of MFR to the risk model. The vertical bar charts at the bottom represent the annualized rates of cardiac mortality in each of the post-MFR risk categories. Int.: Intermediate; LVEF: Left ventricular ejection fraction; MFR: Myocardial flow reserve. Adapted with permission from [63].
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619
Review Ohira, Dowsley, Dwivedi et al. Table 2. Studies of the prognostic impact of myocardial flow reserve. Author (year)
Subjects (n)
Follow-up duration (years)
Primary end point
Radiotracer
Tio et al. (2009) Herzog et al. (2009) Fukushima et al. (2011) Ziadi (2011) et al.
344
7.1
13
256
5.4
Cardiac health MACE†
13
224
1.0
MACE‡
82
Rb
677
1.1
MACE†; cardiac death + MI
82
Rb Rb
Murthy et al. (2011)
2783
Cardiac death
82
1.4
Adjusted covariates
Hazard ratio
NH3
Age, sex
[66]
NH3
Age, diabetes, smoking, abnormal MPI Age, abnormal MPI (SSS ≥4)
4.1 (per MFR decrease of 0.5) 1.6 (MFR
Quantification of myocardial blood flow using PET to improve the management of patients with stable ischemic coronary artery disease Hiroshi Ohira*,1, Taylor Dowsley1, Girish Dwivedi1, Robert A deKemp1, Benjamin J Chow1, Terrence D Ruddy1, Ross A Davies1, Jean DaSilva1, Rob SB Beanlands 1 & Renee Hessian1
ABSTRACT Cardiac PET has been evolving over the past 30 years. Today, it is accepted as a valuable imaging modality for the noninvasive assessment of coronary artery disease. PET has demonstrated superior diagnostic accuracy for the detection of coronary artery disease compared with single-photon emission computed tomography, and also has a wellestablished prognostic value. The routine addition of absolute quantification of myocardial blood flow increases the diagnostic accuracy for three-vessel disease and provides incremental functional and prognostic information. Moreover, the characterization of the vasodilator capacity of the coronary circulation may guide proper decision-making and monitor the effects of lifestyle changes, exercise training, risk factor modification or medical therapy for improving regional and global myocardial blood flow. This type of image-guided approach to individualized patient therapy is now attainable with the routine use of cardiac PET flow reserve imaging. After 30 years of predominantly research-based applications, PET technology has the capacity to dramatically change the practice of clinical cardiology by providing similar information with noninvasive imaging methods. The basic theories behind PET and single-photon emission computed tomography (SPECT) are similar; however, PET possesses important advantages over SPECT, including a higher count sensitivity, better spatial resolution and simple, accurate attenuation correction. PET can quantify regional tracer activity concentration (Bq/cc) and myocardial blood flow (MBF) in absolute units (ml/min/g tissue). Although MBF measurement has been reported using SPECT [1–5] , cardiac magnetic resonance (CMR) [6–9] or echocardiography [10–15] in selected laboratories, PET has been the most reliable and widely used modality to quantify MBF [16] . Quantitation of MBF is important for the management of coronary artery disease (CAD) as it removes us from the downfall of relative perfusion imaging by providing information on absolute regional flow under rest and stress conditions. Despite the increasing availability of PET, the use of absolute MBF quantification has not been as widespread, except in institutions with research interests or clinical expertise in this area. The aim of this article is to review: the assessment of absolute MBF measurements for the purpose of diagnosis, risk stratification, prognosis and monitoring therapeutic interventions and directing management;
KEYWORDS
• CAD • CBF • CFR • CMR • CT • MBF • PET • SPECT
MFI program, National Cardiac PET Center, Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, ON, Canada *Author for correspondence: [email protected] 1
10.2217/FCA.14.44 © 2014 Future Medicine Ltd
Future Cardiol. (2014) 10(5), 611–631
part of
ISSN 1479-6678
611
Review Ohira, Dowsley, Dwivedi et al. the detection of the early functional abnormalities of the coronary circulation; and the comparison with other noninvasive imaging modalities. Future perspectives will be also presented. Methodology of PET & perfusion tracers: 13 N-ammonia, 82Rb-rubidium, 15O-water & 18F-flurpiridaz PET, similar to SPECT, uses external detectors in order to image the distribution of injected radionuclide tracers. The images and subsequent information acquired with SPECT and PET reflect cardiac physiology rather than anatomy. The physiologic information obtained depends on the radioactive nuclides that are utilized and their imaging characteristics. PET cameras are ten- to 20-times more sensitive than conventional SPECT cameras [17] , as they use the annihilation radiation resulting from positron decay, which can be localized using coincidence detection without the need for physical collimators. There are newer semiconductor-based SPECT cameras that are more sensitive than scintillation camera SPECT systems, but these are still less sensitive than PET [18] . Current-generation PET cameras have a spatial resolution in the range of 4–6 mm, which enables the precise identification of perfusion defects. PET systems also incorporate algorithms that accurately and reliably correct for attenuation and scatter, either using radioactive isotope sources on older scanners or computed tomography (CT) on ‘hybrid PET–CT’ scanners [19] . The radiotracers used for myocardial perfusion imaging (MPI) for PET include rubidium-82 (82Rb), nitrogen-13-ammonia (13NH3), oxygen-15-water (15O-water) and flurpiridaz F-18 (18F-flurpiridaz). Each has unique properties that make one preferable over another in individual situations (Table 1) [20] . In the clinical setting, 82Rb and 13NH3 are the only PET perfusion tracers that have received US FDA approval and are reimbursed by the Center for Medicare and Medicaid Services. 15O-water is considered to be the ideal radiotracer for quantitative flow measurement because it freely diffuses between the blood pool and myocardium. It is, however, difficult to obtain clear static images, as there is poor contrast between the blood pool and the myocardium. 15O-water is mostly used for research purposes in North America and Japan, with some clinical application in Europe [20] . Production processes also differ, with 13NH3
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Future Cardiol. (2014) 10(5)
and 15O-water being cyclotron-produced radiotracers, with relatively short half-lives of 9.97 and 2.04 min, respectively (Table 1) . 82Rb has an ultrashort half-life of 1.27 min and is produced using a 82strontium/rubidium generator system, thus having the advantage of not requiring a cyclotron on site. 82Rb is most cost-effective of the PET perfusion tracers; therefore, 82Rb is most widely available for clinical use, especially in high-volume centers where 30–50 patients can be imaged on a weekly basis [21] . The quantification of MBF with 13NH3 and 15 O-water has repeatedly shown a high degree of reproducibility in clinical studies over a wide range of flows (0.5–5.0 ml/min/g) [22,23] . Recent clinical investigations using 82Rb MBF quantification have reported incremental prognostic value in large multicenter studies [24–28] . The technical methods for MBF quantification using dynamic PET imaging with 82Rb and 13 NH3 are well established, using compartmental analysis of arterial blood and tissue time–activity curves [26,29] . 18 F-flurpiridaz is a new radiotracer that is currently undergoing Phase III clinical testing. A cyclotron is required to produce 18F-labeled compounds; however, 18F-f lurpiridaz has a longer half-life of 110 min, which should enable centralized production and distribution in a similar manner to 18F-fluorodeoxyglucose. 18 F-flurpiridaz is also suitable for exercise stress PET imaging. Compared with the currently available PET perfusion tracers, 18F-flurpiridaz has excellent spatial resolution due to a very short positron range and high first-pass extraction, even at increased flow rates [30–33] . Coronary physiology & quantification of MBF with PET The coronary arterial system is responsible for controlling blood flow to the myocardium. In order to supply the local oxygen requirements of the myocardium, the coronary circulation is dynamically controlled by autoregulatory mechanisms [34] . This maintains an adequate MBF in order to meet myocardial demands in a variety of situations. The components of the coronary arterial system are: epicardial arteries (which can be imaged by invasive or CT coronary angiography); prearterioles and arterioles that are not visible, but are important in auto regulation by changing vessel resistance and subsequent blood flow; and the capillary bed where oxygen and nutrient exchange occurs with the
future science group
Quantification of myocardial blood flow using PET for the management of patients with stable ischemic CAD
Review
Table 1. Characteristics of cardiac PET perfusion radiotracers. Characteristics
Radiotracer
82
Rb-rubidium
Isotope half-life Initial extraction (flow) Retention fraction (uptake) Production method Advantages
1.27 min 40–70% (stress–rest)
9.97 min 95–98% (stress–rest)
2.04 min 95–100% (stress–rest)
110 min >90%
30–55% (stress–rest)
60–90% (stress–rest)
Not retained in tissues
60–90% (stress–rest)
82
Sr/Rb generator Commercially available generator product Capability to assess quantitative flow Short half-life for rapid testing Low radiation dose
Cyclotron High contrast resolution Capability to assess quantitative flow Potential for use with exercise Low radiation dose
Cyclotron Ideal kinetics for flow quantification Short half-life for rapid testing Low radiation dose
Disadvantages
Low spatial resolution Lower retention at higher flow rates Short half-life precludes exercise stress
Needs on-site cyclotron Moderate retention at higher flow rates Heterogeneity; retention in the lateral wall is 10% less Lung uptake in smokers
13
N-ammonia
15
O-water
18
F-flurpiridaz†
Cyclotron High contrast resolution Potential to assess quantitative flow Potential for use with exercise Can be distributed from central production Needs on-site cyclotron Not yet commercially Short half-life precludes available exercise stress Moderate retention at higher Low spatial and contrast flow rates resolution (tissue Long half-life complicates equilibrium with blood rest–stress flow pool) quantification
Data taken from [30–33]. Adapted with permission from [20]. †
tissue. When coronary or epicardial arteries are narrowed by atherosclerotic disease, coronary autoregulation attempts to normalize coronary blood flow (CBF) by reducing the resistance of the distal perfusion beds at the arteriolar level, thus maintaining myocardial oxygen supply [35] . Gould et al. demonstrated that the response to a hyperemic stimulation in CBF (cc/min) was an important physiological parameter using a surgically implanted flow-meter in animal studies [36] . Resting flow measurements did not decrease unless a stenosis reached 85%. On the other hand, hyperemic flow after administration of a vasodilator decreased when there was a 50% stenosis (Figure 1) [36] . They were the first to define coronary flow reserve (CFR) as maximal flow divided by resting flow. CFR is a quantitative measure of the ability of coronary vessels to augment blood flow in response to increased oxygen demands or as compensation for a decreased oxygen carrying capacity of the blood. The concept of CFR has since evolved into an accepted functional measure of stenosis severity. CBF can be estimated using several techniques, including coronary catheterization with a Doppler flow wire, which measures flow velocity coronary sinus thermodilution, or xenon methods, and these are presented in units of ml/min
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[37,38] .
All of these techniques are invasive and thus have limitations for clinical practice. PET has evolved into the noninvasive imaging modality of choice for the quantification of MBF. MBF conceptually refers to a measurement not just of epicardial flow, but also microvascular flow and function. MBF can also be measured during stress and at rest, the ratio of which is termed ‘myocardial flow reserve’ (MFR). The terminology used for flow in PET in the literature can sometimes be confusing. CBF represents flow in ml/min, whereas MBF represents flow per unit mass in ml/min/g. CBF can be thought of the volume of flow passing through the coronary bed per unit of time, and can technically only be measured invasively in a coronary artery, whereas MBF is flow per unit of time for a unit of myocardial mass. Thus, strictly speaking, CBF and MBF are not the same [16,39] . However, both of these are used in the literature for the study of coronary flow using PET and both refer to the flow through an artery and microcirculation [39] . We prefer the term MFR, as it relates more to the primary measurements. It is now known that MFR can be abnormal in the absence of significant epicardial CAD, so this expands the scope of conventional relative
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Review Ohira, Dowsley, Dwivedi et al. MPI from identifying only ‘end-stage’ epicardial CAD to the ‘earlier’ identification and characterization of function abnormalities in coronary endothelial function and subclinical stages of CAD, or what has been termed ‘microvascular dysfunction’ [16,40–42] . The role of PET-MPI for the identification & characterization of CAD ●●Limitation of the relative assessment of
MBF in multivessel disease
Stress SPECT-MPI is a validated diagnostic procedure for patients with suspected CAD. It has a high sensitivity (82–87%) for the detection of flow-limiting epicardial coronary stenoses [43] , provides incremental prognostic information over clinical data and guides clinical decisionmaking with regards to management, particularly for coronary intervention. The diagnostic
accuracy and predictive value of MPI in patients with three-vessel CAD (3VD) and left-main CAD is less well documented. There is evidence suggesting that the assessment of myocardial perfusion using SPECT-MPI is less sensitive for identifying significant 3VD as well as left-main CAD, as the evaluation of myocardial perfusion is based on the relative tracer distribution. This assumes that the region demonstrating the highest accumulation of tracer uptake represents normal perfusion and is then used as the normal reference coronary territory. The uptake in the remaining myocardial segments is compared with this region of highest uptake or reference territory. If the region of greatest perfusion is supplied by a diseased vessel and is reduced, this may lead to an underestimation of the true extent of CAD if the remaining territories have similar uptakes [44–47] . In extreme cases, 3VD
5 y = 3.7-1.0(10-2)x + 2.4(10-4)x2-6.0(10-6)x3
Normalize mean flow – times initial control
r = 0.89 SQ DEV = 0.345
4
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1
0
y = 1.0-1.9(10-2)x + 6.2(10-4)x2-5.2(10-6)x3 r = 0.84 SQ DEV = 0.021 0
20
40 60 Percentage lesion by diameter
80
100
Figure 1. The relationship between percentage circumflex arterial constriction by diameter with resting mean flow and hyperemic response after intracoronary injection of Hypaque in 12 consecutive dogs. Flows are expressed as ratios in order to control resting mean values at the beginning of each experiment. SQ DEV: Mean square of deviations. Reproduced with permission from [36].
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Quantification of myocardial blood flow using PET for the management of patients with stable ischemic CAD may cause globally reduced perfusion, leading to normal relative MPI studies and no visual difference between the myocardial segments. This is known as ‘balanced ischemia’. Although it is uncertain how often this occurs, Berman et al. have noted that as many as 40% of patients with ≥50% stenosis in the left mainstem can have a normal- or low-risk SPECT scan [46] . Lima et al. reported that 40% of patients with significant multivessel CAD could not be correctly identified with SPECT-MPI using standard perfusion and function criteria [48] . Nonperfusion features, such as stress-induced transient ischemic dilatation of the left ventricle (LV) [49–51] , increased right ventricular uptake at stress [52,53] or a decrease in LV ejection fraction of greater than 5% [54] , have been evaluated and their presence suggests multivessel disease and an increased risk of adverse cardiovascular outcomes. The clinical utility of 13NH3 and 82Rb PETMPI for the detection of flow-limiting epicardial coronary lesions is also well established. Results from recent meta-analyses found a better accuracy of MPI with PET compared with SPECT [43,55] . Our group demonstrated that the weighted-mean sensitivity and specificity for 82Rb-PET were 90 and 88%, respectively, compared with 85 and 85%, respectively, for 99m Tc-based SPECT with ECG gating and attenuation correction. The areas under the curve between 82Rb-PET and 99mTc-based SPECT were 0.95 and 0.90, respectively (p < 0.0001), which confirms the higher accuracy of PET [43] . A second study confirmed these findings for all PET perfusions versus SPECT perfusions [55] . Taken together, these studies suggest that PET has higher diagnostic accuracy for detecting significant CAD than SPECT. Even with the high diagnostic accuracy of PET, the use of the relative assessment of myocardial perfusion shares the drawbacks of SPECT-MPI in patients with 3VD (Figure 2) . ●●Advantages of quantitative assessment of
MBF for the diagnosis of CAD
The measurement of absolute MBF during stress with 15O-water PET has a significant impact on the interpretation of myocardial perfusion. In patients with multivessel disease, the sensitivity and specificity of detecting disease per vessel with usual perfusion and function criteria were 38 and 68%, respectively. The corresponding values with the use of MBF analysis increased
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to 96 and 94%, respectively [56] . A direct comparison of patients with 3VD (≥70%; n = 13) or single-vessel disease (≥70%; n = 10) based on coronary angiography was performed with both semiquantitative interpretation and quantification of tracer uptake as an estimate of MBF perfusion using 82Rb-PET [44] . Although resting uptake values were similar in both groups, wholeheart uptake during stress in the 3VD group was significantly lower than that with single-vessel disease. Standard relative MPI evaluation identified perfusion abnormalities in all segments in only 46% of patients with 3VD. By contrast, quantification of 82Rb retention as an estimate of MBF demonstrated decreased perfusion in all 3VD segments in 92% of patients. Similarly, another consecutive series of patients were studied who underwent 82Rb-PET and had angiography within 6 months [47] . Among 120 patients, 25 (21%) had severe 3VD, of which 88% (22/25) demonstrated globally reduced MFR (2.0) had an event-free period of 3 years compared with those with abnormal MFR [61] . Ziadi et al. demonstrated that flow quantification using 82Rb-PET predicted major adverse cardiac events independently of the summed stress score and clinical parameters (Figure 3) [62] . Murthy et al. further evaluated a total of 2783 consecutive patients and also demonstrated that the degree of reduction of MFR measured using 82Rb-PET predicted a
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Review Ohira, Dowsley, Dwivedi et al.
Adjusted cardiac-event-free survival
Cardiac-event-free survival probability
1.00
0.95 * 0.90
SSS < 4 MFR ≥ 2 SSS ≥ 4 MFR ≥ 2
** SSS < 4 MFR < 2
0.85
*SSS < 4 MFR < 2 vs ≥ 2: HR: 2.4 (1.4, 4.4); p = 0.003
0.80
**SSS ≥ 4 MFR < 2 vs ≥ 2: HR: 4.6 (2.2, 9.7); p < 0.001 SSS ≥ 4 MFR < 2
0.75 0
50
100
150
200
250
300
350
400
450
500
Days
Figure 3. Myocardial flow reserve has incremental prognostic value and improves risk stratification in patients with abnormal and normal stress perfusion. The figure shows adjusted event-free survival for hard cardiac events and major adverse cardiac events. Arrows highlight the statistically significant differences in outcomes among subgroups. HR: Hazard ratio; MFR: Myocardial flow reserve; SSS: Summed stress score. Reproduced with permission from [62].
gradient of adverse outcomes, including death. In addition, 50% of patients with intermediate preMFR risk were correctly reclassified to high-risk or low-risk categories by adding MFR to the perfusion and functional information (Figure 4) [63] . The results of these and other studies indicate that routine assessment of MFR quantified by PET improves risk stratification (Table 2) [61–66] . In addition, the usefulness of MFR with PET has been shown to improve the prediction of prognosis in patients with nonischemic cardiomyopathy in the absence of coexistent coronary disease. Cecchi et al. showed that MFR was an independent predictor of clinical deterioration and death in patients with hypertrophic cardiomyopathy [67] . The prognostic implication of PET with flow quantification in patients with dilated cardiomyopathy was also reported by Neglia et al. [68] . This suggests that abnormal microcirculation predicts an increase in risk in patients with predominant myocardial abnormalities. Although we are starting to understand the role of MFR in establishing prognosis, we
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currently have no data on the cost–effectiveness of its use and there is no clinical trial evidence suggesting how it should be used routinely. Patient management with flow quantification in stable coronary disease Accurate identification, lifestyle modification and treatment of risk factors are the first steps in the treatment of stable CAD. Whether optimal medical therapy (OMT) alone or initial revascularization is more beneficial remains controversial [69–71] . A single-center observational study with patients presenting for SPECT-MPI showed that the extent of ischemic myocardium predicted reduction in the risk of death with revascularization compared with OMT for those patients with >10–12% of ischemic myocardium if there was no scar present (Figure 5) [72] . The COURAGE trial demonstrated that a strategy of initial PCI with OMT had no survival advantage over OMT alone in patients with stable CAD [73] . In this study, however, patients were randomized after an angiogram, suggesting that high-risk patients did not participate in the study. Others feel that
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Quantification of myocardial blood flow using PET for the management of patients with stable ischemic CAD the use of angiographic interpretation of the coronary anatomy did not allow for the research question to be properly answered. A gradient of benefit with revascularization, however, was noted in the MPI substudy of COURAGE, suggesting that patients with significant ischemia may have benefited from therapy to reduce this ischemia, which was more successfully achieved with PCI than OMT alone [74] (although subsequent analysis suggested that this may not be the case for scans that are read at the site of recruitment rather than the core laboratory [75]). Many prior studies suggest that extensive ischemia, as determined by MPI, identifies patients for whom an initial revascularization strategy may lead to an improvement in cardiovascular outcomes [72,76] .
Review
However, this issue is by no means clear and is under investigation in trials such as ISCHEMIA. The physiological or hemodynamic assessment of coronary artery stenosis has become increasingly important and interesting in the research and clinical setting. Visual assessment of the severity of coronary stenosis has been traditionally used to guide revascularization in patients with stable CAD. The pressure gradient across a stenosis can be measured invasively during angiography from which the functional severity of a lesion on CBF can be determined. This is calculated under conditions of maximum coronary vasodilation and is the ratio of distal coronary pressure to aortic pressure. It is referred to as the fractional flow reserve (FFR), although strictly speaking it Percentage
0
Pre-MFR risk
10
20
30
Low (1100)
16%
40
50
60
Intermediate (898)
17%
Post-MFR risk
34%
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High (785)
86% 3% 11%
84%
49%
Annualized cardiac mortality %
12 10.5%
10 8 6 4.4%
4 2
0 Post-test risk patients
1.7% 0.2%
0.2% Low 927
Int. 173
3.4%
2.3%
Low Int. High 304 445 149
0.0% Low Int. High 22 89 674
Figure 4. Risk reclassification by myocardial flow reserve. In total, 50% of patients with intermediate pretest risk were reclassified to high- or low-risk categories using PET flow reserve. The top horizontal bar graph represents the distribution of risk across categories of 3% (red) per yearly risk of cardiac death as estimated by a model containing clinical risk factors, rest LVEF, LVEF reserve and the combination of myocardial scar and ischemia. The pie graphs represent the proportions of patients in each pre-MFR category reassigned to each risk category after the addition of MFR to the risk model. The vertical bar charts at the bottom represent the annualized rates of cardiac mortality in each of the post-MFR risk categories. Int.: Intermediate; LVEF: Left ventricular ejection fraction; MFR: Myocardial flow reserve. Adapted with permission from [63].
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Review Ohira, Dowsley, Dwivedi et al. Table 2. Studies of the prognostic impact of myocardial flow reserve. Author (year)
Subjects (n)
Follow-up duration (years)
Primary end point
Radiotracer
Tio et al. (2009) Herzog et al. (2009) Fukushima et al. (2011) Ziadi (2011) et al.
344
7.1
13
256
5.4
Cardiac health MACE†
13
224
1.0
MACE‡
82
Rb
677
1.1
MACE†; cardiac death + MI
82
Rb Rb
Murthy et al. (2011)
2783
Cardiac death
82
1.4
Adjusted covariates
Hazard ratio
NH3
Age, sex
[66]
NH3
Age, diabetes, smoking, abnormal MPI Age, abnormal MPI (SSS ≥4)
4.1 (per MFR decrease of 0.5) 1.6 (MFR
