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Quantitative Assessment of Myocardial Blood Flow with SPECT Mario Petrettaa , Giovanni Stortob , Teresa Pellegrinoc , Domenico Bonaducea , Alberto Cuocolod,⁎ a
Department of Translational Medical Sciences, University Federico II, Naples, Italy Nuclear Medicine Unit, IRCCS Regional Cancer Hospital CROB, Rionero in Vulture, Italy c Institute of Biostructure and Bioimaging, National Council of Research, Naples, Italy d Department of Advanced Biomedical Sciences, University Federico II, Naples, Italy b
A R T I C LE I N F O
AB ST R A C T
Keywords:
The quantitative assessment of myocardial blood flow (MBF) and coronary flow reserve (CFR)
Myocardial blood flow
may be useful for the functional evaluation of coronary artery disease, allowing judgment of
Coronary flow reserve
its severity, tracking of disease progression, and evaluation of the anti-ischemic efficacy of
SPECT imaging
therapeutic strategies. Quantitative estimates of myocardial perfusion and CFR can be derived from single-photon emission computed tomography (SPECT) myocardial perfusion images by use of equipment, tracers, and techniques that are available in most nuclear cardiology laboratories. However, this method underestimates CFR, particularly at high flow rates. The recent introduction of cardiac-dedicated gamma cameras with solid-state detectors provides very fast perfusion imaging with improved resolution, allowing fast acquisition of serial dynamic images during the first pass of a flow agent. This new technology holds great promise for MBF and CFR quantification with dynamic SPECT. Future studies will clarify the effectiveness of dynamic SPECT flow imaging. © 2015 Elsevier Inc. All rights reserved.
Coronary flow reserve (CFR) Autoregulation of coronary circulation plays a major role in the control of myocardial blood flow (MBF).1,2 It is well known that as coronary artery disease (CAD) progresses, resting flow does not initially change, but MBF (such as that achieved by injecting a vasodilator) decreases progressively.3 In this setting, coronary autoregulation, reducing the resistance of distal perfusion beds, attempts to preserve adequate MBF and oxygen supply.4 Only a coronary stenosis exceeding approximately 80% of luminal diameter induces significant reductions in resting MBF, while attenuation of hyperemic flow is detectable in the presence of coronary stenosis of about 45%.3,5
CFR is the term used to describe the amount of additional MBF that can be supplied to the heart over baseline MBF, and is evaluated comparing hyperemic to resting flows.6 The absence of CFR implies maximal vasodilatation of the resistance vessels at rest and an inability to further increase MBF. Different terms are used to describe CFR7 (Table 1). Absolute CFR is the ratio of MBF during maximal hyperemia in a coronary artery to MBF in the same artery under resting conditions.8 Absolute CFR can be quantified invasively using intracoronary Doppler-based technique or thermodilution flow measurements, as well as by positron emission tomography (PET) using quantitative approaches of absolute tissue perfusion. Relative CFR is the ratio of hyperemic flow in a
Statement of Conflict of Interest: see page 613. ⁎ Address reprint requests to Alberto Cuocolo, MD, Department of Advanced Biomedical Sciences, University Federico II, Via Pansini 5, 80131 Naples, Italy. E-mail address: [email protected] (A. Cuocolo). http://dx.doi.org/10.1016/j.pcad.2014.12.007 0033-0620/© 2015 Elsevier Inc. All rights reserved.
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Abbreviations and Acronyms
coronary artery to hyperemic flow in a norACU = aortic time–activity curve mal artery.9 Relative CAD = coronary artery disease CFR may be assessed noninvasively using CCT = cardiac computed radionuclide perfutomography sion imaging. For this CFR = coronary flow reserve purpose, relative differences in regional CMR = cardiac magnetic perfusion during resonance maximal pharmacoFFR = fractional flow reserve logic vasodilatation or exercise stress test are LV = left ventricular expressed as fraction of MBF = myocardial blood flow flow to normal myocardial regions. AlternaPCI = percutaneous coronary tively, relative CFR may intervention be invasively estimated PET = positron emission by dividing absolute tomography CFR measurement in a stenotic vessel by CFR SPECT = single-photon emission measurements in recomputed tomography mote normally perfused coronary regions. Relative CFR is of limited value in patients with multivessel CAD.10 Moreover, in the presence of functional abnormalities in microcirculation, both absolute and relative CFR cannot accurately quantify coronary artery stenosis severity.11,12Fractional flow reserve (FFR) is the term used to describe the ratio of the maximum achievable MBF in the presence of a stenosis to the theoretic maximum flow in the same artery if the artery was normal.13 This is the basis of the pressure-derived method that is the invasive method of choice to determine the significance of a stenosis of moderate severity.14 This invasive functional assessment measures the stenosis related decline in distal coronary pressure during maximal hyperemia. Instantaneous wave-free ratio is a new adenosine-independent index of stenosis severity, calculated as the mean pressure distal to the stenosis during the diastolic wave-free period divided by the mean aortic pressure during the diastolic wave-free period.15 Studies using FFR demonstrated that ischemia-guided percutaneous coronary intervention (PCI) is superior to angiography-guided intervention.16 For discrete segmental stenosis, FFR equals relative CFR.13 However, flow-based CFR and pressure-based FFR may not show comparable severity for the same stenosis in roughly 40% of lesions17 and the discordance between FFR and CFR occurs even with purely invasive intracoronary technology using combined pressure-flow velocity wires, thereby reflecting physiology, not methodology.18 Numerous factors may influence CFR and FFR measurements (Table 2), such as the ability to achieve maximal coronary vasodilatation, heart rate, myocardial contractility, right atrial pressure, the presence of serial coronary stenosis, coronary resistance, and coronary collateral circulation.19–25 FFR is conceptually similar to relative CFR. Both relative CFR and FFR assume maximal vasodilatory responses of coronary resistance vessels and cannot identify the potential contribution of abnormalities in microcirculatory resistance control to the development of myocardial ischemia. Differently, absolute CFR reflects the summed effects of a coronary stenosis and abnormalities in the microcirculation. Noteworthy,
absolute CFR can be measured with PET, but not with singlephoton emission computed tomography (SPECT). The availability of a guide wire equipped with a pressure and Doppler velocity sensor together allows simultaneous invasive assessment of both stenosis and microvascular hemodynamics.26 The combined measurements of pressure drop across a stenosis and distal flow velocity during hyperemic conditions have the potential to identify mixed abnormalities and the contribution of stenosis and microcirculation to the net significance of a stenosis.27 Johnson et al.17 reviewed invasive CFR and FFR measurements in the literature and also compared cardiac PET followed by invasive FFR from analysis of clinical records from their institution. They found that, in the absence of significant diffuse CAD, normal CFR matches normal FFR, whilst FFR may be reduced with preserved CFR when diffuse CAD is minimal. Conversely, FFR may be adequate (non-ischemic) with reduced CFR when diffuse CAD is severe. There are two possible explanations for the observed disparities: 1) disease of the “normal reference vessel”; and 2) diffuse disease of the epicardial conduit vessel or isolated disease of the coronary microvasculature, or both. Interestingly, discordance between FFR and CFR with a normal FFR but reduced CFR, indicating predominant microvascular disease, is associated with a particularly unfavorable prognosis, whereas a preserved CFR in the presence of an abnormal FFR yields a long-term clinical outcome comparable with concordantly normal FFR and CFR.28 Recent advances in computational fluid dynamics seem to allow calculation of non-invasive FFR derived from cardiac computed tomography (CCT).29 Also cardiac magnetic resonance (CMR) is increasingly used to measure MBF and CFR.30 It must be outlined that the subendocardium and subepicardium have different MBF dynamics and, interestingly, CMR seems to have the potential to evaluate separately endocardial and epicardial myocardial perfusion and reserve.
Cardiac SPECT Myocardial perfusion imaging by SPECT is a well established technique for the diagnosis and workup of patients with known or suspected CAD and is commonly used to demonstrate ischemia and identify significant coronary artery stenosis. However, SPECT perfusion imaging can underestimate the extent of obstructive CAD.31 SPECT is also limited by pre-imaging, technical, patient related, and heart-related artifacts and pitfalls, including attenuation artifact and low depth dependent spatial resolution.32 Quantitative analysis of myocardial perfusion SPECT is feasible, and software tools developed by several groups are commercially available and are routinely used.33 Quantification of MBF can also be performed using the tracer kinetic method.34 Kinetics deals with the relation between time and matter, and in biological systems is used in order to describe mathematically and physically the transport, exchange, metabolism, and excretion of solutes and liquids. This occurs in and between organs, physiological compartments, or entire organisms. Two different classes of kinetics exist: nonlinear and linear models. For cardiac imaging, the tracer kinetic method is based upon monitoring the in vivo kinetics of a tracer whose concentration is dependent upon regional myocardial perfusion.
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Table 1 – Terms used to describe CFR.
Absolute flow reserve Relative flow reserve Fractional flow reserve
Description
Measurement Methods
Ratio of hyperemic flow in a coronary artery to flow in the same artery under resting conditions Ratio of hyperemic flow in a coronary artery to hyperemic flow in a normal artery Ratio of the maximum achievable flow in the presence of a stenosis to the theoretic maximum flow in the same artery if the artery was normal
Intracoronary Doppler, thermodilution, PET
Data are then analyzed using an appropriate kinetic model and myocardial perfusion can be estimated from the resulting kinetic parameters. Although widely used in PET research, this method has also been employed in conjunction with a number of other modalities including dynamic SPECT, and both dynamic contrast-enhanced CMR and CCT. In each case the principle is the same, although the details of the kinetic model and interpretation of the results differ, due to the characteristics of the tracer (radiopharmaceutical or contrast material) employed. Tracers such as thallium-20134 and Tc-99 m sestamibi35 and the rapidly exchanging agent Tc-99 m teboroxime36 have been largely investigated for perfusion studies, showing promise in the application of dynamic SPECT for cardiac imaging. Although the standard single-gamma camera configuration for SPECT is still commonly encountered in clinic inventories, it has been supplanted at many institutions by dual or triple-headed detector systems, with dual-headed detector systems being most prevalent. The detectors on these dual-headed detector systems are much larger than the original three-headed detector system, but the rotational speed of the modern systems with the most robust gantries is still limited to a single tomographic acquisition every 15 s. As a result, data processing techniques have emphasized the development of methods for processing kinetics directly from projection measurements.37 Different models describing SPECT myocardial tracer kinetics are illustrated in Fig 1. Due to the reduced sensitivity of dynamic SPECT and to the physics constrains of the image detection process, a one-compartment model is usually used to represent perfusion in the myocardium irrespective of the tracer used. However, it has been proposed that a two-compartment model is more appropriate for thallium-201 kinetics and that it is
SPECT Pressure-derived method
important to sample plasma to obtain an accurate input function.34 In some previous works, two- and three-compartment models have been used to model cardiac glucose metabolism and myocardial perfusion by SPECT tracers.36 Nevertheless, which is the optimum model to adopt is still debated.
Estimation of MBF and CFR using SPECT Tracers Attempts have been made to estimate CFR with single-photon tracers in order to obtain, with simple methods, data for quantitative functional assessment of CAD.38,39 Several researches suggested that it is possible to quantify CFR with this approach (Table 3). In particular, there are studies using dynamic planar scintigraphy in humans39–44 or dynamic SPECT in animals.34,45,46 The method used in these investigations is potentially open to implementation in most nuclear cardiology laboratories, and it could be adapted for general application (Fig 2). Taki et al.40 investigated in humans the relationship between the increase in myocardial sestamibi retention during hyperemia and hyperemic CFR measured by intracoronary Doppler guide-wire. The increase in sestamibi retention from baseline to adenosine-induced hyperemia was calculated using the formula validated by Melon et al.47: R(t) = Ct(t)/∫0t Ca(τ)dτ, where R is the absolute retention of the tracer (t), Ct is the radioactivity of the tracer in the myocardium, and Ca is the arterial radioactivity concentration. The tissue and arterial counts were measured with a gamma camera; thus the formula should be modified to take in account the correction factors for
Table 2 – Factors influencing CFR and FFR measurement. Main Issues Coronary vasodilatation Heart rate Myocardial contractility Right atrial pressure Serial coronary stenosis
Coronary resistance Coronary collateral circulation
Determining whether maximal vasodilatation has been achieved19 With an increasing heart rate, resting flow increases whereas maximal flow decreases because of a shortened perfusion time20 Contractility may influence CFR measurements, and this parameter is difficult to control in humans21 When calculating FFR, coronary lesions can be misclassified as insignificant when right atrial pressure is ignored22 It is not possible to distinguish the relative contribution of individual lesions to the overall pressure drop without direct measurement of coronary wedge pressure, as FFR does not reflect the sum of the pressures assessed at different points in the vessel23 Coronary reserve is dependent on the level of vascular resistance under control conditions, which in turn is affected by oxygen demand or impaired autoregulatory capacity24 Failure to induce pharmacologic hyperemia may result in a high value of the pressure-derived collateral flow index in patients with a well-developed collateral circulation25
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Fig 1 – Functional models describing SPECT myocardial tracer kinetics: one-compartment (A), two-compartment (B), and three-compartment (C) models. The differential equations describe the kinetics of the models. CEV represents the concentration of tracer uniformly distributed within the volume of the extra-vascular compartment/tissue; K1 (K21) and k2 (k12) (units of volume per minute) are the influx and wash out rate constants, respectively, which also take into account permeability and surface area of capillaries as well as volume of the compartment; k3 and k4 are the rate constants referred to extracellular space with (C1, free compartment) and without (C2, trapping compartment) communication with blood.
the counting rate from the myocardium and the left ventricular (LV) blood pool, respectively, including attenuation factor, partial-volume effect, and sensitivity of the gamma camera.48 However, these correction factors are specific to the gamma camera system used and the individual patient but, theoretically, should be unchanged from imaging at baseline and at hyperemia, and seem to be unnecessary for calculation. Taki et al.40 expressed the change in sestamibi retention (R) from baseline (b) to hyperemic response (h) as “retention increase ratio” ðRIRÞ ¼ Rh t t ðt Þ=Rb ðt Þ ¼ cmh ðt Þ∫0 C bb ðτÞdτ=C mb ðt Þ∫0 C bh ðτÞdτ,where Cm are myocardial counts on the tomographic image (t), and Cb are the LV blood-pool counts during the first transit of sestamibi. Sestamibi retention increased as coronary flow velocity augmented, but reached the plateau at >2.5 to 3-fold the baseline blood flow velocity. In particular, for CFR values 2.5–3 times the baseline flow. Thus, sestamibi myocardial retention underestimates CFR, particularly at high flow rates. A limitation is that this technique evaluates the relationship between the increments of sestamibi retention and coronary flow velocity from baseline to hyperemia, rather than between absolute tracer retention and absolute coronary flow. Sugihara et al.38 presented a noninvasive method of obtaining CFR using planar and SPECT imaging with tetrofosmin. The approach is a “microsphere” method; it is assumed that the tracer sticks in the myocardial tissue so that MBF can be
calculated as the ratio of the counts in the tissue over the integral of the arterial concentration of the tracer up to the time of the SPECT measurement. The increased ratio of the MBF was calculated from the rest and dipyridamole stress studies as [(RMCs × PACr)/(RMCr × PACs) − 1] × 100, where RMCr and RMCs are counts (as measured by SPECT) in a myocardial region at rest and stress, respectively, and PACr and PACs are the area under the time–activity curve of the first transit counts measured by dynamic planar imaging in the pulmonary artery at rest and stress, respectively. With this method the CFR values are given in percentages. Sugihara et al.38 reported an MBF increased ratio of 46.9% ± 22.8% in healthy subjects. This corresponds to a CFR measurement of 1.47. Their results showed that the MBF increased ratio of infarcted regions and that of ischemic regions were both significantly decreased: 8.3% ± 12.2% and 11.2% ± 11.9%, respectively, which correspond to CFR of 1.08 and 1.11, respectively. They pointed out that the results obtained from their method are lower than those found with PET. The reasons for this could be due, in large part, to the limited extraction of tetrofosmin at high blood flow. Another factor is the accuracy of the input function; tetrofosmin interaction with red blood cells and plasma proteins may create difficulty in obtaining the true input. Ito et al.39 developed a method to estimate MBF index and CFR using dynamic and static data obtained with sestamibi. To validate the method, the results where compared with the values measured by oxygen-15-labeled water PET in patients with angiographically documented CAD and in a control group of normal volunteers. Quantitative analysis of MBF was
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Table 3 – Summary of studies validating CFR estimation using SPECT tracers in humans. Study
Tracer
Main Findings
Taki et al. 2001
Sestamibi
Sugihara et al. 200138
Tetrofosmin
Ito et al. 200339
Sestamibi
Storto et al. 200441
Sestamibi
For CFR values 2.5 times baseline flow. This method underestimates CFR, particularly at high flow rates. CFR values of 1.47 in healthy subjects, 1.08 in infarcted regions and 1.11 in ischemic regions. The results obtained from this method are lower than those found with PET. CFR estimated by dynamic acquisition correlated well with the values measured by PET. CFR using this method was significantly underestimated compared to PET. Good correlation between CFR values estimated by sestamibi and those measured by intravascular Doppler ultrasound in patients undergoing percutaneous coronary intervention. In patients with documented CAD, mean CFR estimated by sestamibi was 1.36, significantly lower than that in subjects with normal coronary vessels. The value of this technique in discriminating between significant and non-significant coronary artery stenosis remains to be determined.
40
based on the microsphere method, assuming that sestamibi is taken up by myocardial tissue. Based on the Sapirstein method and the Stewart–Hamilton principle,49 MBF can be calculated as: cardiac output × myocardial counts/total injected dose. Ito et al.39 calculated the cardiac output as the ratio of the injected dose to the area under the gamma-variate-fitted aortic time– activity curve (aorta ACU, counts/cm2 per minute) and MBF as the ratio of the counts in the tissue to the integral of the arterial concentration of the tracer up to the time of imaging using the formula: MBF = k1 × (injected dose/aorta ACU) × k2 × myocardial counts/injected dose, where k1 and k2 are the correction factors for the counting rate from the myocardium and the aorta ACU, and the extraction fraction of sestamibi, respectively, including the attenuation factor, partial volume effect, and sensitivity of the gamma camera. To take into account the LV weight, the LV edge of myocardium was delineated automatically on the short-axis SPECT images by the threshold method and LV weight (M, in gram) was estimated by LV volume with a myocardial gravity of 1.05. The MBF index was than obtained as: MBF/M. Because the baseline MBF is closely related to the rate–pressure product, MBF index at rest was corrected for the rate–pressure product by the following equation49: MBF index × (mean rate– pressure product at rest/individual rate–pressure product). The results of the study by Ito et al.39 indicated that the MBF index and CFR estimated by dynamic acquisition with sestamibi correlate well with the values measured by PET. However, despite the good linear correlation between the values measured by sestamibi imaging and those measured using PET, CFR using sestamibi was significantly underestimated. More recently, Storto et al.41 demonstrated a good correlation between CFR values estimated by sestamibi imaging and those measured by intravascular Doppler ultrasound in patients undergoing PCI. In patients with documented CAD, CFR estimated by sestamibi ranged from 0.78 to 2.51, with a mean measurement of 1.36, and it was significantly lower than that in subjects with no CAD. These results are similar to those previously reported by Sugihara et al.38 However, the value of this technique in discriminating between significant and non-significant CAD remains to be determined. Storto et al.41 also evaluated inter-observer and intra-observer reproducibility of SPECT-assessed CFR and found good reproducibility for both global and regional CFR. Previous investigations demonstrated
the potential clinical applications of SPECT-estimated CFR in patients with one-vessel CAD,50 peripheral artery disease,51 arterial hypertension,52 diabetes mellitus,53 and typical chest pain and normal coronary vessels.54 More recent studies have shown that estimated CFR using a combination of dynamic planar followed by static SPECT acquisitions can also provide prognostic information.44
Assessment of MBF and CFR by Dynamic SPECT Although many studies demonstrated that it is possible to estimate CFR using dynamic planar imaging with myocardial perfusion tracers in humans, they also highlighted the limitations of conventional SPECT systems for the dynamic collection of data necessary to quantify rapid changes in radiotracer concentration.55 It has been also noted that mechanical and patient safety constraints can limit the detector orbit to circular paths at increased distances from the patient during rapid image acquisition, resulting in degraded spatial resolution. Dynamic SPECT is a list mode acquisition developed for new semiconductor gamma cameras.37 This imaging procedure follows the dynamic process of the biochemical compound once it enters the blood, is transported by the blood, absorbed in organs and body tissues, and then either trapped within cells or on cell surfaces, or released back into the blood stream.56 The reconstruction of cardiac slices gains more contrast compared to standard reconstruction. Recent studies aimed to determine the feasibility of dynamic tomographic imaging for quantification of regional and global myocardial perfusion and CFR in a porcine model57 and in humans.58 Ben-Haim et al.58 evaluated the feasibility of dynamic tomographic SPECT imaging and quantification of a retention index to describe global and regional CFR using a dedicated solid-state cardiac camera equipped with cadmium-zinc-telluride crystals. Factor analysis was used to estimate blood-pool time–activity curves, used as input functions in a 2-compartment kinetic model. K1 values (sestamibi uptake) were calculated for the stress and rest images, and K2 values (sestamibi washout) were set to zero. CFR index was calculated as the ratio of the stress and rest K1 values. Standard perfusion imaging was evaluated semi-quantitatively, and total perfusion deficit of at least 5% was defined as abnormal.
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Fig 2 – Estimation of CFR by radionuclide imaging using single-photon tracers: time–activity curve of blood pool (A) and global and regional tracer activity on representative short axis tomograms (B) in a normal subject; time–activity curve of blood pool (C) and global and regional tracer activity on representative short axis tomograms (D) in a patient with myocardial ischemia. Note that in the patient with ischemia the full-width-half-maximum (FWHM) of the curve is enlarged, which may translate prolonged vascular transit time.
The results of this pilot study show that the CFR index is lower in patients with perfusion defects and in regions supplied by obstructed coronary arteries. A challenge to the technique was a possible underestimation of high-flow rate retention estimates due to a nonlinear relationship between MBF and sestamibi extraction. In a more recent study, Wells et al.57 evaluated the measurement of MBF using a multi-pinhole dedicated cardiac SPECT camera in a pig model of rest and transient occlusion at stress using 3 common tracers: thallium-201, tetrofosmin, and sestamibi. Dynamic images were processed with kinetic analysis software using a 1-tissue-compartment model to obtain the uptake rate constant K1 as a function of microsphere MBF. Measured extraction fractions agreed with those obtained previously using ex vivo techniques. Converting K1 back to MBF using the measured extraction fractions produced accurate values and good correlations with microsphere MBF. These results demonstrate that noninvasive measurement of absolute MBF with stationary dedicated cardiac SPECT is feasible using common perfusion tracers. However, there are numerous technical issues that need to be addressed to increase the accuracy of dedicated cardiac SPECT systems for the measurement of absolute MBF (Table 4). The use of stationary high-sensitivity solid-state SPECT imaging systems holds great promise for the estimation of absolute MBF and CFR if all of these issues can be adequately addressed.
Conclusions The available data provide evidence that quantitative estimates of blood flow and CFR can be derived from SPECT myocardial perfusion images by use of equipment, tracers, and techniques that are available in most nuclear cardiology laboratories. In particular, good agreement has been reported between CFR estimated by SPECT imaging with Tc-99 m-labeled tracers and PET or intracoronary Doppler results. However, this method underestimates CFR, particularly at high flow rates. The recent introduction of cardiac-dedicated gamma cameras with solidstate detectors provides very fast perfusion imaging with improved resolution. The use of these detectors with the characteristic high-count rate capability allows fast acquisition of serial dynamic images during the first pass of a flow agent. From these images, time activity curves might be generated for the LV cavity (input function) and for myocardial tissue (output function) during stress and rest. Yet, this technique of dynamic flow measurement has still some limitations. Tc-99 m labeled tracers are not ideal flow agents, and their myocardial uptake is low at high flow rates. Even so, this new SPECT technology offers the opportunity for high-resolution myocardial perfusion imaging joined with dynamic imaging. With the increasing availability of dedicated cardiac cameras with solid-state
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Table 4 – Factors limiting the accuracy of dedicated cardiac SPECT systems for the measurement of absolute MBF. 99m
Tc-labeled radiotracers unfavorable kinetics Scatter correction Projection truncation Respiratory motion Cardiac motion Partial volume effect
14. 15.
16.
detectors, this technology offers great promise for MBF and CFR quantification with dynamic SPECT. Future studies will clarify the effectiveness of dynamic SPECT flow imaging.
17.
18.
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31. Lima RS, Watson DD, Goode AR, et al. Incremental value of combined perfusion and function over perfusion alone by gated SPECT myocardial perfusion imaging for detection of severe three-vessel coronary artery disease. J Am Coll Cardiol. 2003;42:64-70. 32. Burrell S, MacDonald A. Artifacts and pitfalls in myocardial perfusion imaging. J Nucl Med Technol. 2006;34:193-211. 33. Petretta M, Cuocolo R, Acampa W, et al. Quantification of myocardial perfusion: SPECT. Curr Cardiovasc Imaging Rep. 2012;5:144-150. 34. Iida H, Eberl S, Kim KM, et al. Absolute quantitation of myocardial blood flow with 201Tl and dynamic SPECT in canine: optimization and validation of kinetic modeling. Eur J Nucl Med Mol Imaging. 2008;35:896-905. 35. Tsukamoto T, Ito Y, Noriyasu K, et al. Quantitative assessment of regional myocardial flow reserve using tc-99 m-sestamibi imaging. Circ J. 2005;69:188-193. 36. Smith AM, Gullberg GT, Christian PE, et al. Kinetic modeling of teboroxime using dynamic SPECT imaging of a canine model. J Nucl Med. 1994;35:484-495. 37. Gullberg GT, Reutter BW, Sitek A, et al. Dynamic single photon emission computed tomography-basic principles and cardiac applications. Phys Med Biol. 2010;55:R111-R191. 38. Sugihara H, Yonekura Y, Kataoka K, et al. Estimation of coronary flow reserve with the use of dynamic planar and SPECT images of Tc-99 m tetrofosmin. J Nucl Cardiol. 2001;8: 575-579. 39. Ito Y, Katoh C, Noriyasu K, et al. Estimation of myocardial blood flow and myocardial flow reserve by 99mTc-sestamibi imaging: comparison with the results of O-15 H2O PET. Eur J Nucl Med Mol Imaging. 2003;30:281-287. 40. Taki J, Fujino S, Nakajima K, et al. Tc-99 m retention characteristics during pharmacological hyperemia in human myocardium: comparison with coronary flow reserve measured by Doppler flowire. J Nucl Med. 2001;42:1457-1463. 41. Storto G, Cirillo P, Vicario ML, et al. Estimation of coronary flow reserve by Tc-99 m sestamibi imaging in patients with coronary artery disease: comparison with the results of intracoronary Doppler technique. J Nucl Cardiol. 2004;11: 682-688. 42. Storto G, Soricelli A, Pellegrino T, et al. Assessment of the arterial input function for estimation of coronary flow reserve by single photon emission computed tomography: comparison of two different approaches. Eur J Nucl Med Mol Imaging. 2009;36:2034-2041. 43. Marini C, Giusti M, Armonino R, et al. Reduced coronary flow reserve in patients with primary hyperparathyroidism: a study by G-SPECT myocardial perfusion imaging. Eur J Nucl Med Mol Imaging. 2010;37:2256-2263. 44. Daniele S, Nappi C, Acampa W, et al. Incremental prognostic value of coronary flow reserve assessed with single-photon
45.
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emission computed tomography. J Nucl Cardiol. 2011;18: 612-619. Iida H, Eberl S. Quantitative assessment of regional myocardial blood flow with thallium-201 and SPECT. J Nucl Cardiol. 1998;5:313-331. Christian TF, Peters K, Keck B, et al. Gated SPECT imaging to detect changes in myocardial blood flow during progressive coronary occlusion. Int J Cardiovasc Imaging. 2008;24:269-276. Melon PG, Beanlands RS, DeGrado TR, et al. Comparison of technetium-99 m sestamibi and thallium-201 retention characteristics in canine myocardium. J Am Coll Cardiol. 1992;20:1277-1283. Taki J, Muramori A, Kinuya S, et al. Forward cardiac output measurement with first-pass technique using 99mTc-labeled myocardial perfusion imaging agents. J Nucl Med. 1999;40: 1874-1881. Sapirstein LA. Regional blood flow by fractional distribution of indicators. Am J Physiol. 1958;193:161-168. Vicario ML, Cirillo L, Storto G, et al. Influence of risk factors on coronary flow reserve in patients with 1-vessel coronary artery disease. J Nucl Med. 2005;46:1438-1443. Pellegrino T, Storto G, Filardi PP, et al. Relationship between brachial artery flow-mediated dilation and coronary flow reserve in patients with peripheral artery disease. J Nucl Med. 2005;46:1997-2002. Palmieri V, Storto G, Arezzi E, et al. Relations of left ventricular mass and systolic function to endothelial function and coronary flow reserve in healthy, new discovered hypertensive subjects. J Hum Hypertens. 2005;19:941-950. Storto G, Pellegrino T, Sorrentino AR, et al. Estimation of coronary flow reserve by sestamibi imaging in type 2 diabetic patients with normal coronary arteries. J Nucl Cardiol. 2007;14: 194-199. Storto G, Sorrentino AR, Pellegrino T, et al. Assessment of coronary flow reserve by sestamibi imaging in patients with typical chest pain and normal coronary arteries. Eur J Nucl Med Mol Imaging. 2007;34:1156-1161. Petretta M, Soricelli A, Storto G, et al. Assessment of coronary flow reserve using single photon emission computed tomography with technetium 99 m-labeled tracers. J Nucl Cardiol. 2008;15:456-465. Winant CD, Aparici CM, Zelnik YR, et al. Investigation of dynamic SPECT measurements of the arterial input function in human subjects using simulation, phantom and human studies. Phys Med Biol. 2012;57:375-393. Wells RG, Timmins R, Klein R, et al. Dynamic SPECT measurement of absolute myocardial blood flow in a porcine model. J Nucl Med. 2014;55:1685-1691. Ben-Haim S, Murthy VL, Breault C, et al. Quantification of myocardial perfusion reserve using dynamic SPECT imaging in humans: a feasibility study. J Nucl Med. 2013;54:873-879.
Available online at www.sciencedirect.com
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Quantitative Assessment of Myocardial Blood Flow with SPECT Mario Petrettaa , Giovanni Stortob , Teresa Pellegrinoc , Domenico Bonaducea , Alberto Cuocolod,⁎ a
Department of Translational Medical Sciences, University Federico II, Naples, Italy Nuclear Medicine Unit, IRCCS Regional Cancer Hospital CROB, Rionero in Vulture, Italy c Institute of Biostructure and Bioimaging, National Council of Research, Naples, Italy d Department of Advanced Biomedical Sciences, University Federico II, Naples, Italy b
A R T I C LE I N F O
AB ST R A C T
Keywords:
The quantitative assessment of myocardial blood flow (MBF) and coronary flow reserve (CFR)
Myocardial blood flow
may be useful for the functional evaluation of coronary artery disease, allowing judgment of
Coronary flow reserve
its severity, tracking of disease progression, and evaluation of the anti-ischemic efficacy of
SPECT imaging
therapeutic strategies. Quantitative estimates of myocardial perfusion and CFR can be derived from single-photon emission computed tomography (SPECT) myocardial perfusion images by use of equipment, tracers, and techniques that are available in most nuclear cardiology laboratories. However, this method underestimates CFR, particularly at high flow rates. The recent introduction of cardiac-dedicated gamma cameras with solid-state detectors provides very fast perfusion imaging with improved resolution, allowing fast acquisition of serial dynamic images during the first pass of a flow agent. This new technology holds great promise for MBF and CFR quantification with dynamic SPECT. Future studies will clarify the effectiveness of dynamic SPECT flow imaging. © 2015 Elsevier Inc. All rights reserved.
Coronary flow reserve (CFR) Autoregulation of coronary circulation plays a major role in the control of myocardial blood flow (MBF).1,2 It is well known that as coronary artery disease (CAD) progresses, resting flow does not initially change, but MBF (such as that achieved by injecting a vasodilator) decreases progressively.3 In this setting, coronary autoregulation, reducing the resistance of distal perfusion beds, attempts to preserve adequate MBF and oxygen supply.4 Only a coronary stenosis exceeding approximately 80% of luminal diameter induces significant reductions in resting MBF, while attenuation of hyperemic flow is detectable in the presence of coronary stenosis of about 45%.3,5
CFR is the term used to describe the amount of additional MBF that can be supplied to the heart over baseline MBF, and is evaluated comparing hyperemic to resting flows.6 The absence of CFR implies maximal vasodilatation of the resistance vessels at rest and an inability to further increase MBF. Different terms are used to describe CFR7 (Table 1). Absolute CFR is the ratio of MBF during maximal hyperemia in a coronary artery to MBF in the same artery under resting conditions.8 Absolute CFR can be quantified invasively using intracoronary Doppler-based technique or thermodilution flow measurements, as well as by positron emission tomography (PET) using quantitative approaches of absolute tissue perfusion. Relative CFR is the ratio of hyperemic flow in a
Statement of Conflict of Interest: see page 613. ⁎ Address reprint requests to Alberto Cuocolo, MD, Department of Advanced Biomedical Sciences, University Federico II, Via Pansini 5, 80131 Naples, Italy. E-mail address: [email protected] (A. Cuocolo). http://dx.doi.org/10.1016/j.pcad.2014.12.007 0033-0620/© 2015 Elsevier Inc. All rights reserved.
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Abbreviations and Acronyms
coronary artery to hyperemic flow in a norACU = aortic time–activity curve mal artery.9 Relative CAD = coronary artery disease CFR may be assessed noninvasively using CCT = cardiac computed radionuclide perfutomography sion imaging. For this CFR = coronary flow reserve purpose, relative differences in regional CMR = cardiac magnetic perfusion during resonance maximal pharmacoFFR = fractional flow reserve logic vasodilatation or exercise stress test are LV = left ventricular expressed as fraction of MBF = myocardial blood flow flow to normal myocardial regions. AlternaPCI = percutaneous coronary tively, relative CFR may intervention be invasively estimated PET = positron emission by dividing absolute tomography CFR measurement in a stenotic vessel by CFR SPECT = single-photon emission measurements in recomputed tomography mote normally perfused coronary regions. Relative CFR is of limited value in patients with multivessel CAD.10 Moreover, in the presence of functional abnormalities in microcirculation, both absolute and relative CFR cannot accurately quantify coronary artery stenosis severity.11,12Fractional flow reserve (FFR) is the term used to describe the ratio of the maximum achievable MBF in the presence of a stenosis to the theoretic maximum flow in the same artery if the artery was normal.13 This is the basis of the pressure-derived method that is the invasive method of choice to determine the significance of a stenosis of moderate severity.14 This invasive functional assessment measures the stenosis related decline in distal coronary pressure during maximal hyperemia. Instantaneous wave-free ratio is a new adenosine-independent index of stenosis severity, calculated as the mean pressure distal to the stenosis during the diastolic wave-free period divided by the mean aortic pressure during the diastolic wave-free period.15 Studies using FFR demonstrated that ischemia-guided percutaneous coronary intervention (PCI) is superior to angiography-guided intervention.16 For discrete segmental stenosis, FFR equals relative CFR.13 However, flow-based CFR and pressure-based FFR may not show comparable severity for the same stenosis in roughly 40% of lesions17 and the discordance between FFR and CFR occurs even with purely invasive intracoronary technology using combined pressure-flow velocity wires, thereby reflecting physiology, not methodology.18 Numerous factors may influence CFR and FFR measurements (Table 2), such as the ability to achieve maximal coronary vasodilatation, heart rate, myocardial contractility, right atrial pressure, the presence of serial coronary stenosis, coronary resistance, and coronary collateral circulation.19–25 FFR is conceptually similar to relative CFR. Both relative CFR and FFR assume maximal vasodilatory responses of coronary resistance vessels and cannot identify the potential contribution of abnormalities in microcirculatory resistance control to the development of myocardial ischemia. Differently, absolute CFR reflects the summed effects of a coronary stenosis and abnormalities in the microcirculation. Noteworthy,
absolute CFR can be measured with PET, but not with singlephoton emission computed tomography (SPECT). The availability of a guide wire equipped with a pressure and Doppler velocity sensor together allows simultaneous invasive assessment of both stenosis and microvascular hemodynamics.26 The combined measurements of pressure drop across a stenosis and distal flow velocity during hyperemic conditions have the potential to identify mixed abnormalities and the contribution of stenosis and microcirculation to the net significance of a stenosis.27 Johnson et al.17 reviewed invasive CFR and FFR measurements in the literature and also compared cardiac PET followed by invasive FFR from analysis of clinical records from their institution. They found that, in the absence of significant diffuse CAD, normal CFR matches normal FFR, whilst FFR may be reduced with preserved CFR when diffuse CAD is minimal. Conversely, FFR may be adequate (non-ischemic) with reduced CFR when diffuse CAD is severe. There are two possible explanations for the observed disparities: 1) disease of the “normal reference vessel”; and 2) diffuse disease of the epicardial conduit vessel or isolated disease of the coronary microvasculature, or both. Interestingly, discordance between FFR and CFR with a normal FFR but reduced CFR, indicating predominant microvascular disease, is associated with a particularly unfavorable prognosis, whereas a preserved CFR in the presence of an abnormal FFR yields a long-term clinical outcome comparable with concordantly normal FFR and CFR.28 Recent advances in computational fluid dynamics seem to allow calculation of non-invasive FFR derived from cardiac computed tomography (CCT).29 Also cardiac magnetic resonance (CMR) is increasingly used to measure MBF and CFR.30 It must be outlined that the subendocardium and subepicardium have different MBF dynamics and, interestingly, CMR seems to have the potential to evaluate separately endocardial and epicardial myocardial perfusion and reserve.
Cardiac SPECT Myocardial perfusion imaging by SPECT is a well established technique for the diagnosis and workup of patients with known or suspected CAD and is commonly used to demonstrate ischemia and identify significant coronary artery stenosis. However, SPECT perfusion imaging can underestimate the extent of obstructive CAD.31 SPECT is also limited by pre-imaging, technical, patient related, and heart-related artifacts and pitfalls, including attenuation artifact and low depth dependent spatial resolution.32 Quantitative analysis of myocardial perfusion SPECT is feasible, and software tools developed by several groups are commercially available and are routinely used.33 Quantification of MBF can also be performed using the tracer kinetic method.34 Kinetics deals with the relation between time and matter, and in biological systems is used in order to describe mathematically and physically the transport, exchange, metabolism, and excretion of solutes and liquids. This occurs in and between organs, physiological compartments, or entire organisms. Two different classes of kinetics exist: nonlinear and linear models. For cardiac imaging, the tracer kinetic method is based upon monitoring the in vivo kinetics of a tracer whose concentration is dependent upon regional myocardial perfusion.
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Table 1 – Terms used to describe CFR.
Absolute flow reserve Relative flow reserve Fractional flow reserve
Description
Measurement Methods
Ratio of hyperemic flow in a coronary artery to flow in the same artery under resting conditions Ratio of hyperemic flow in a coronary artery to hyperemic flow in a normal artery Ratio of the maximum achievable flow in the presence of a stenosis to the theoretic maximum flow in the same artery if the artery was normal
Intracoronary Doppler, thermodilution, PET
Data are then analyzed using an appropriate kinetic model and myocardial perfusion can be estimated from the resulting kinetic parameters. Although widely used in PET research, this method has also been employed in conjunction with a number of other modalities including dynamic SPECT, and both dynamic contrast-enhanced CMR and CCT. In each case the principle is the same, although the details of the kinetic model and interpretation of the results differ, due to the characteristics of the tracer (radiopharmaceutical or contrast material) employed. Tracers such as thallium-20134 and Tc-99 m sestamibi35 and the rapidly exchanging agent Tc-99 m teboroxime36 have been largely investigated for perfusion studies, showing promise in the application of dynamic SPECT for cardiac imaging. Although the standard single-gamma camera configuration for SPECT is still commonly encountered in clinic inventories, it has been supplanted at many institutions by dual or triple-headed detector systems, with dual-headed detector systems being most prevalent. The detectors on these dual-headed detector systems are much larger than the original three-headed detector system, but the rotational speed of the modern systems with the most robust gantries is still limited to a single tomographic acquisition every 15 s. As a result, data processing techniques have emphasized the development of methods for processing kinetics directly from projection measurements.37 Different models describing SPECT myocardial tracer kinetics are illustrated in Fig 1. Due to the reduced sensitivity of dynamic SPECT and to the physics constrains of the image detection process, a one-compartment model is usually used to represent perfusion in the myocardium irrespective of the tracer used. However, it has been proposed that a two-compartment model is more appropriate for thallium-201 kinetics and that it is
SPECT Pressure-derived method
important to sample plasma to obtain an accurate input function.34 In some previous works, two- and three-compartment models have been used to model cardiac glucose metabolism and myocardial perfusion by SPECT tracers.36 Nevertheless, which is the optimum model to adopt is still debated.
Estimation of MBF and CFR using SPECT Tracers Attempts have been made to estimate CFR with single-photon tracers in order to obtain, with simple methods, data for quantitative functional assessment of CAD.38,39 Several researches suggested that it is possible to quantify CFR with this approach (Table 3). In particular, there are studies using dynamic planar scintigraphy in humans39–44 or dynamic SPECT in animals.34,45,46 The method used in these investigations is potentially open to implementation in most nuclear cardiology laboratories, and it could be adapted for general application (Fig 2). Taki et al.40 investigated in humans the relationship between the increase in myocardial sestamibi retention during hyperemia and hyperemic CFR measured by intracoronary Doppler guide-wire. The increase in sestamibi retention from baseline to adenosine-induced hyperemia was calculated using the formula validated by Melon et al.47: R(t) = Ct(t)/∫0t Ca(τ)dτ, where R is the absolute retention of the tracer (t), Ct is the radioactivity of the tracer in the myocardium, and Ca is the arterial radioactivity concentration. The tissue and arterial counts were measured with a gamma camera; thus the formula should be modified to take in account the correction factors for
Table 2 – Factors influencing CFR and FFR measurement. Main Issues Coronary vasodilatation Heart rate Myocardial contractility Right atrial pressure Serial coronary stenosis
Coronary resistance Coronary collateral circulation
Determining whether maximal vasodilatation has been achieved19 With an increasing heart rate, resting flow increases whereas maximal flow decreases because of a shortened perfusion time20 Contractility may influence CFR measurements, and this parameter is difficult to control in humans21 When calculating FFR, coronary lesions can be misclassified as insignificant when right atrial pressure is ignored22 It is not possible to distinguish the relative contribution of individual lesions to the overall pressure drop without direct measurement of coronary wedge pressure, as FFR does not reflect the sum of the pressures assessed at different points in the vessel23 Coronary reserve is dependent on the level of vascular resistance under control conditions, which in turn is affected by oxygen demand or impaired autoregulatory capacity24 Failure to induce pharmacologic hyperemia may result in a high value of the pressure-derived collateral flow index in patients with a well-developed collateral circulation25
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Fig 1 – Functional models describing SPECT myocardial tracer kinetics: one-compartment (A), two-compartment (B), and three-compartment (C) models. The differential equations describe the kinetics of the models. CEV represents the concentration of tracer uniformly distributed within the volume of the extra-vascular compartment/tissue; K1 (K21) and k2 (k12) (units of volume per minute) are the influx and wash out rate constants, respectively, which also take into account permeability and surface area of capillaries as well as volume of the compartment; k3 and k4 are the rate constants referred to extracellular space with (C1, free compartment) and without (C2, trapping compartment) communication with blood.
the counting rate from the myocardium and the left ventricular (LV) blood pool, respectively, including attenuation factor, partial-volume effect, and sensitivity of the gamma camera.48 However, these correction factors are specific to the gamma camera system used and the individual patient but, theoretically, should be unchanged from imaging at baseline and at hyperemia, and seem to be unnecessary for calculation. Taki et al.40 expressed the change in sestamibi retention (R) from baseline (b) to hyperemic response (h) as “retention increase ratio” ðRIRÞ ¼ Rh t t ðt Þ=Rb ðt Þ ¼ cmh ðt Þ∫0 C bb ðτÞdτ=C mb ðt Þ∫0 C bh ðτÞdτ,where Cm are myocardial counts on the tomographic image (t), and Cb are the LV blood-pool counts during the first transit of sestamibi. Sestamibi retention increased as coronary flow velocity augmented, but reached the plateau at >2.5 to 3-fold the baseline blood flow velocity. In particular, for CFR values 2.5–3 times the baseline flow. Thus, sestamibi myocardial retention underestimates CFR, particularly at high flow rates. A limitation is that this technique evaluates the relationship between the increments of sestamibi retention and coronary flow velocity from baseline to hyperemia, rather than between absolute tracer retention and absolute coronary flow. Sugihara et al.38 presented a noninvasive method of obtaining CFR using planar and SPECT imaging with tetrofosmin. The approach is a “microsphere” method; it is assumed that the tracer sticks in the myocardial tissue so that MBF can be
calculated as the ratio of the counts in the tissue over the integral of the arterial concentration of the tracer up to the time of the SPECT measurement. The increased ratio of the MBF was calculated from the rest and dipyridamole stress studies as [(RMCs × PACr)/(RMCr × PACs) − 1] × 100, where RMCr and RMCs are counts (as measured by SPECT) in a myocardial region at rest and stress, respectively, and PACr and PACs are the area under the time–activity curve of the first transit counts measured by dynamic planar imaging in the pulmonary artery at rest and stress, respectively. With this method the CFR values are given in percentages. Sugihara et al.38 reported an MBF increased ratio of 46.9% ± 22.8% in healthy subjects. This corresponds to a CFR measurement of 1.47. Their results showed that the MBF increased ratio of infarcted regions and that of ischemic regions were both significantly decreased: 8.3% ± 12.2% and 11.2% ± 11.9%, respectively, which correspond to CFR of 1.08 and 1.11, respectively. They pointed out that the results obtained from their method are lower than those found with PET. The reasons for this could be due, in large part, to the limited extraction of tetrofosmin at high blood flow. Another factor is the accuracy of the input function; tetrofosmin interaction with red blood cells and plasma proteins may create difficulty in obtaining the true input. Ito et al.39 developed a method to estimate MBF index and CFR using dynamic and static data obtained with sestamibi. To validate the method, the results where compared with the values measured by oxygen-15-labeled water PET in patients with angiographically documented CAD and in a control group of normal volunteers. Quantitative analysis of MBF was
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Table 3 – Summary of studies validating CFR estimation using SPECT tracers in humans. Study
Tracer
Main Findings
Taki et al. 2001
Sestamibi
Sugihara et al. 200138
Tetrofosmin
Ito et al. 200339
Sestamibi
Storto et al. 200441
Sestamibi
For CFR values 2.5 times baseline flow. This method underestimates CFR, particularly at high flow rates. CFR values of 1.47 in healthy subjects, 1.08 in infarcted regions and 1.11 in ischemic regions. The results obtained from this method are lower than those found with PET. CFR estimated by dynamic acquisition correlated well with the values measured by PET. CFR using this method was significantly underestimated compared to PET. Good correlation between CFR values estimated by sestamibi and those measured by intravascular Doppler ultrasound in patients undergoing percutaneous coronary intervention. In patients with documented CAD, mean CFR estimated by sestamibi was 1.36, significantly lower than that in subjects with normal coronary vessels. The value of this technique in discriminating between significant and non-significant coronary artery stenosis remains to be determined.
40
based on the microsphere method, assuming that sestamibi is taken up by myocardial tissue. Based on the Sapirstein method and the Stewart–Hamilton principle,49 MBF can be calculated as: cardiac output × myocardial counts/total injected dose. Ito et al.39 calculated the cardiac output as the ratio of the injected dose to the area under the gamma-variate-fitted aortic time– activity curve (aorta ACU, counts/cm2 per minute) and MBF as the ratio of the counts in the tissue to the integral of the arterial concentration of the tracer up to the time of imaging using the formula: MBF = k1 × (injected dose/aorta ACU) × k2 × myocardial counts/injected dose, where k1 and k2 are the correction factors for the counting rate from the myocardium and the aorta ACU, and the extraction fraction of sestamibi, respectively, including the attenuation factor, partial volume effect, and sensitivity of the gamma camera. To take into account the LV weight, the LV edge of myocardium was delineated automatically on the short-axis SPECT images by the threshold method and LV weight (M, in gram) was estimated by LV volume with a myocardial gravity of 1.05. The MBF index was than obtained as: MBF/M. Because the baseline MBF is closely related to the rate–pressure product, MBF index at rest was corrected for the rate–pressure product by the following equation49: MBF index × (mean rate– pressure product at rest/individual rate–pressure product). The results of the study by Ito et al.39 indicated that the MBF index and CFR estimated by dynamic acquisition with sestamibi correlate well with the values measured by PET. However, despite the good linear correlation between the values measured by sestamibi imaging and those measured using PET, CFR using sestamibi was significantly underestimated. More recently, Storto et al.41 demonstrated a good correlation between CFR values estimated by sestamibi imaging and those measured by intravascular Doppler ultrasound in patients undergoing PCI. In patients with documented CAD, CFR estimated by sestamibi ranged from 0.78 to 2.51, with a mean measurement of 1.36, and it was significantly lower than that in subjects with no CAD. These results are similar to those previously reported by Sugihara et al.38 However, the value of this technique in discriminating between significant and non-significant CAD remains to be determined. Storto et al.41 also evaluated inter-observer and intra-observer reproducibility of SPECT-assessed CFR and found good reproducibility for both global and regional CFR. Previous investigations demonstrated
the potential clinical applications of SPECT-estimated CFR in patients with one-vessel CAD,50 peripheral artery disease,51 arterial hypertension,52 diabetes mellitus,53 and typical chest pain and normal coronary vessels.54 More recent studies have shown that estimated CFR using a combination of dynamic planar followed by static SPECT acquisitions can also provide prognostic information.44
Assessment of MBF and CFR by Dynamic SPECT Although many studies demonstrated that it is possible to estimate CFR using dynamic planar imaging with myocardial perfusion tracers in humans, they also highlighted the limitations of conventional SPECT systems for the dynamic collection of data necessary to quantify rapid changes in radiotracer concentration.55 It has been also noted that mechanical and patient safety constraints can limit the detector orbit to circular paths at increased distances from the patient during rapid image acquisition, resulting in degraded spatial resolution. Dynamic SPECT is a list mode acquisition developed for new semiconductor gamma cameras.37 This imaging procedure follows the dynamic process of the biochemical compound once it enters the blood, is transported by the blood, absorbed in organs and body tissues, and then either trapped within cells or on cell surfaces, or released back into the blood stream.56 The reconstruction of cardiac slices gains more contrast compared to standard reconstruction. Recent studies aimed to determine the feasibility of dynamic tomographic imaging for quantification of regional and global myocardial perfusion and CFR in a porcine model57 and in humans.58 Ben-Haim et al.58 evaluated the feasibility of dynamic tomographic SPECT imaging and quantification of a retention index to describe global and regional CFR using a dedicated solid-state cardiac camera equipped with cadmium-zinc-telluride crystals. Factor analysis was used to estimate blood-pool time–activity curves, used as input functions in a 2-compartment kinetic model. K1 values (sestamibi uptake) were calculated for the stress and rest images, and K2 values (sestamibi washout) were set to zero. CFR index was calculated as the ratio of the stress and rest K1 values. Standard perfusion imaging was evaluated semi-quantitatively, and total perfusion deficit of at least 5% was defined as abnormal.
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Fig 2 – Estimation of CFR by radionuclide imaging using single-photon tracers: time–activity curve of blood pool (A) and global and regional tracer activity on representative short axis tomograms (B) in a normal subject; time–activity curve of blood pool (C) and global and regional tracer activity on representative short axis tomograms (D) in a patient with myocardial ischemia. Note that in the patient with ischemia the full-width-half-maximum (FWHM) of the curve is enlarged, which may translate prolonged vascular transit time.
The results of this pilot study show that the CFR index is lower in patients with perfusion defects and in regions supplied by obstructed coronary arteries. A challenge to the technique was a possible underestimation of high-flow rate retention estimates due to a nonlinear relationship between MBF and sestamibi extraction. In a more recent study, Wells et al.57 evaluated the measurement of MBF using a multi-pinhole dedicated cardiac SPECT camera in a pig model of rest and transient occlusion at stress using 3 common tracers: thallium-201, tetrofosmin, and sestamibi. Dynamic images were processed with kinetic analysis software using a 1-tissue-compartment model to obtain the uptake rate constant K1 as a function of microsphere MBF. Measured extraction fractions agreed with those obtained previously using ex vivo techniques. Converting K1 back to MBF using the measured extraction fractions produced accurate values and good correlations with microsphere MBF. These results demonstrate that noninvasive measurement of absolute MBF with stationary dedicated cardiac SPECT is feasible using common perfusion tracers. However, there are numerous technical issues that need to be addressed to increase the accuracy of dedicated cardiac SPECT systems for the measurement of absolute MBF (Table 4). The use of stationary high-sensitivity solid-state SPECT imaging systems holds great promise for the estimation of absolute MBF and CFR if all of these issues can be adequately addressed.
Conclusions The available data provide evidence that quantitative estimates of blood flow and CFR can be derived from SPECT myocardial perfusion images by use of equipment, tracers, and techniques that are available in most nuclear cardiology laboratories. In particular, good agreement has been reported between CFR estimated by SPECT imaging with Tc-99 m-labeled tracers and PET or intracoronary Doppler results. However, this method underestimates CFR, particularly at high flow rates. The recent introduction of cardiac-dedicated gamma cameras with solidstate detectors provides very fast perfusion imaging with improved resolution. The use of these detectors with the characteristic high-count rate capability allows fast acquisition of serial dynamic images during the first pass of a flow agent. From these images, time activity curves might be generated for the LV cavity (input function) and for myocardial tissue (output function) during stress and rest. Yet, this technique of dynamic flow measurement has still some limitations. Tc-99 m labeled tracers are not ideal flow agents, and their myocardial uptake is low at high flow rates. Even so, this new SPECT technology offers the opportunity for high-resolution myocardial perfusion imaging joined with dynamic imaging. With the increasing availability of dedicated cardiac cameras with solid-state
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Table 4 – Factors limiting the accuracy of dedicated cardiac SPECT systems for the measurement of absolute MBF. 99m
Tc-labeled radiotracers unfavorable kinetics Scatter correction Projection truncation Respiratory motion Cardiac motion Partial volume effect
14. 15.
16.
detectors, this technology offers great promise for MBF and CFR quantification with dynamic SPECT. Future studies will clarify the effectiveness of dynamic SPECT flow imaging.
17.
18.
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