What Is Ischemia and How Should This Be Defined Based on Modern Imaging?

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What Is Ischemia and How Should This Be Defined Based on Modern Imaging? Robert M. Bober ⁎, Eiman Jahangir John Ochsner Heart and Vascular Institute, Ochsner Clinical School, The University of Queensland School of Medicine

A R T I C LE I N F O

AB ST R A C T

Keywords:

How do we define myocardial ischemia? This is an important question for clinicians and

Coronary artery disease

one that, while conceptually straight forward, can be practically difficult to assess. In this

Coronary flow reserve

article we describe the various imaging methods available in cardiology to quantify

Fractional flow reserve

myocardial ischemia. Anatomic assessments of ischemia such as angiography, while the “gold standard”, have limitations. While some of these limitations can be mitigated with invasively measurements of fractional flow reserve or intravascular ultrasound, these tools have their own weaknesses. Non-invasive metabolic assessment, such as measuring glucose and fatty acid metabolism, are reliable in identifying ischemic, hibernating, or stunned myocardium but can be difficult to use clinically. Non-invasive physiologic assessment with myocardial perfusion agents with single photon emission tomography imaging and positron emission tomography (PET) with measurement of absolute myocardial flow additionally have their own strengths and weaknesses. In this article we review the data behind the various cardiac modalities used in defining myocardial assessments along with their strengths, practical use, and limitations. We conclude by discussing an integrative approach of relative uptake and absolute myocardial flow using cardiac PET imaging that allows for a more accurate assessment of ischemia along with cases demonstrating various scenarios available in cardiac PET imaging. © 2015 Elsevier Inc. All rights reserved.

“I shall not today attempt further to define the kinds of material I understand … and perhaps I could never succeed in intelligibly doing so. But I know it when I see it” – Justice Potter Stewart “I know it when I see it”, written in 1964 as part of the majority decision in Jacobellis v. Ohio.1 Supreme Court case regarding obscenity laws, is a common colloquial expression. Typically, it is used to convey a sentiment that an observable fact or condition lacks clearly defined parameters. Myocardial ischemia is one such condition. Clinically, we believe that we

know ischemia when we see it. An individual with exertional chest pressure and associated ST segment depression on electrocardiography (ECG) would be considered to “have ischemia”, likely due to obstructive coronary artery disease (CAD). But how should we define and quantify ischemia in the era of multi-imaging modalities? The rationale for defining and quantifying ischemia is relatively straightforward. First, CAD is the leading cause of death in the world.2 In the United States, CAD affects approximately 15 million Americans. It accounts for nearly

Statement of Conflict of Interest: 550. ⁎ Address reprint requests to Robert Bober, MD, FACC, John Ochsner Heart and Vascular Institute, Ochsner Clinical School, The University of Queensland School of Medicine, 1514 Jefferson Highway New Orleans, LA 20121. E-mail address: [email protected] (R.M. Bober). http://dx.doi.org/10.1016/j.pcad.2015.02.001 0033-0620/© 2015 Elsevier Inc. All rights reserved.

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Abbreviations and Acronyms CABG = coronary artery bypass grafting CAD = coronary artery disease CCTA = coronary computed tomography angiogram CFR = coronary flow reserve CMR = cardiac magnetic resonance CTFFR = computed tomography fractional flow reserve ECG = electrocardiography FA = fatty acid FCPHA = trans-9-F-18-Fluoro-3,4-methyleneheptadecanoic acid 18

F-FDG = F-18 labeled fluoro-deoxyglucose FFR = fractional flow reserve 123

I-BMIPP = 123I-βmethyl-Piodophenylpentadecanoic acid IVUS = intravascular ultrasound LAD = left anterior descending MACE = major adverse cardiac event MBF = myocardial blood flow MI = myocardial infarction MLA = minimum lumen area MPI = myocardial perfusion imaging N13 = nitrogen 13 ammonia OMT = optimal medical therapy PCI = percutaneous coronary intervention PET = positron emission tomography Rb-82 = rubidium 82-chloride RCA = right coronary artery SDS = summed difference scores SPECT = single-photon emission computed tomography SRS = summed rest scores SSS = summed stress scores Tc-99 m = technetium 99-m Tl-201 = thallium 201

11% of all deaths and more than 200 billion dollars in annual cost.3 Secondly, treatment for this disease is optimal medical therapy (OMT) either with or without adjuvant mechanical revascularization (percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG)). In theory and in practice, there appears to be a quantity or “threshold” of ischemia, albeit no standardized, where intervention poses a favorable risk/benefit relationship over Therefore, OMT.4–9 given its prevalent nature, a standardized definition of myocardial ischemia along with potential thresholds could quantify the effectiveness of medical therapy and mechanical coronary interventions, improve outcomes, and contain costs. Myocardial ischemia occurs when myocardial oxygen supply at the cellular or tissue level is insufficient to maintain myocardial metabolic demands. This oxygen “supply–demand mismatch” AKA “ischemia”, is most commonly associated with CAD; however, many other conditions (e.g. anemia, hypertrophic cardiomyopathy, increased sympathetic drive or catecholamine secreting tumor, hyperthyroidism, severe head trauma) can alter the supply–demand ratio

and illicit ischemia, even in the presence of preserved coronary blood flow.10–13 The prevalence of these conditions is less common than CAD and therefore, in general, evaluation of ischemia has mostly focused on the detection and hemodynamic significance of underlying CAD. Based on the acuity and severity of ischemia, symptoms such as angina or arrhythmias, possible myocardial stunning, hibernation or necrosis can occur. Ideally, a “gold standard” diagnostic test that could reliably quantify and measure oxygenation, or the lack thereof, per mass of myocardium under resting and/or hyperemic conditions would standardize the definition ischemia. However such a diagnostic test does not exist. Instead, traditional diagnostic testing for assessment of CAD does not assess decreased myocardial oxygenation, but instead assesses for surrogates of decreased myocardial oxygenation such as decreased radionuclide perfusion, regional wall motion abnormalities under stress conditions, or percent stenosis of a coronary vessel. More recent techniques such as noninvasive assessment of absolute myocardial blood flow (MBF) with positron emission tomography (PET) and invasive fractional flow reserve (FFR) have become increasingly utilized as surrogates for myocardial ischemia and have demonstrated improved prognostic and outcome data over traditional methods.7,8,14,15 The diagnostic tests can be broadly categorized into 3 main groups: 1) Anatomic (left heart catheterization with angiography, Intravascular Ultrasound (IVUS), Coronary Computed Tomography Angiogram (CCTA)), 2) Metabolic imaging with nuclear techniques and 3) Physiologic modalities (stress testing with various imaging techniques and FFR). Given the varying diagnostic techniques used as surrogate markers for ischemia and lack of a true “gold standard” definition of ischemia, it is not surprising that global consensus and standardization between modalities in defining ischemia are challenging and have led to confusion and controversy.16–18 A pervasive theme in cardiac literature over the past several decades has been the debate between “anatomy vs. physiology, which matters more?” Furthermore, another theme throughout the cardiac literature often compares one or two modalities vs. a “gold standard” (typically coronary angiography) with implications that the gold standard is “correct” and the other modalities inferior.19–22 In 2012, the ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) began enrolling patients with moderate–severe ischemia on stress myocardial perfusion imaging (MPI), echocardiography and stress cardiac magnetic resonance (CMR) imaging to determine if mechanical revascularization is superior to OMT.23 Researchers initially noted an unequal distribution of moderate–severe ischemia between modalities, which led to a collaborative effort to standardize “moderate–severe ischemia” among the various modalities.24 Shaw et al. shed light on the problem of standardization between modalities and offered a novel approach that avoided a “gold standard”. Namely, they assigned a risk-based threshold of ~ 5%/year coronary artery disease (CAD) death or infarct across the imaging modalities. As novel as this approach was, the fact remains that quantification and standardization of “what is ischemia?” have not been solved.

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The purpose of this review is threefold. First, we will review the common diagnostic categories of imaging techniques used to assess for ischemia secondary to CAD and how these modalities define ischemia. Second, we will then focus on the strengths and limitations of traditional nuclear techniques with single-photon emission computed tomography (SPECT) isotopes. Finally we will conclude with PET isotopes and the uses of absolute MBF in the assessment and quantification of ischemia.

Anatomic assessment of ischemia and FFR Angiography Since its inception in the late 1950’s, coronary artery angiography has been the gold standard for defining coronary anatomy and served as a measure for ischemia.25 As the first method available to identify diseased arteries it is understandable how this would become a standard for evaluating subsequent cardiac tests, albeit a poor one. Traditionally, a coronary stenosis of > 70% is considered significant and likely to cause ischemia. This value of 70% was derived from animal studies performed in the 1970s by Gould et al. at which time coronary flow reserve (CFR), a measurement of increases in blood flow in response to metabolic needs, was initially defined.26 Once CFR decreases, symptoms and ischemia typically occur. Through Gould’s work it was identified that CFR decreased once coronary stenosis became ≥ 75%.26 Once a stenosis was approximately 70% and approached 95%, CFR progressively reached a value of 1:1 indicating an inability for the myocardium to increase blood flow in response to metabolic need.26 This work and conclusions derived had multiple ripple effects since its publication. First it provided the rationale to utilize ≥70% stenosis of an epicardial vessel as a surrogate of ischemia, a metric incorporated into current clinical guidelines,27,28 and as a reference metric for detection of CAD by non-invasive means.29,30 Second, it defined the concept of CFR and the relationships between discrete epicardial stenosis and basal and hyperemic MBF. Thirdly, it gave birth to the concept of radionuclide imaging to identify regional perfusion defects attributed to discrete coronary stenosis. Despite the prevalent use of angiography, issues arise in using it to define ischemia including its poor resolution in identifying percent stenosis and the inability to measure physiologic impact of coronary stenosis. There are numerous issues with using angiography and anatomic percent stenosis as a surrogate for ischemia. The first lies in the fact that angiography is a two dimensional representation of a three dimensional structure. Therefore, to obtain a view of a lesion there must be at least 2 orthogonal views obtained to view a lesion. Even in the best of circumstances, there are numerous variables such as lesion length, eccentricity of lesions, or foreshortening and overlapping vessels that can lead to inadequate assessment of the anatomic structure, leading to missed lesions or intra-observer and inter-observer variability in assessing and defining the severity of the stenosis.25,31 Additionally, the measurement of percent stenosis requires the use of a

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“normal” reference segment. The normal segment may not be an accurate assessment of normal vessel size as it may be diffusely diseased leading to an underestimation of disease.26,32,33 In fact the poor relation between angiography determined stenosis and that determined postmortem has been demonstrated in numerous studies.33,34 Finally, the ability to discern angiographic differences between moderate and severe lesions is extremely difficult as the difference may be only a few tenths of a millimeter.25 Another inadequacy of angiography is that what appears to be an anatomically high-grade stenosis may have no significant physiologic effects on absolute MBF.35,36 Percent stenosis on angiography is often utilized as a “gold standard” for detection of “obstructive” CAD probably because the majority of decisions regarding mechanical revascularization are determined based on percent stenosis.37,38 However, there is robust literature – both clinical and pre-clinical – which clearly demonstrate that percent stenosis has only modest impact on MBF and ischemia.16,26,39 Only in recent years with techniques such as FFR or through stress testing, have we learned of the importance of physiologic directed PCI. Studies have demonstrated that revascularizing intermediate stenoses without understanding the physiologic significance of these stenoses does not improve outcomes.7,40 A study by Pijls et al. described that the 1 year risk of cardiac death or myocardial infarction (MI) related to stenosis of ≥ 75% was < 1% per year and did not improve with stenting.40 The Courage trial had similar findings demonstrating that PCI in patients with stable CAD did not reduce death, MI, or other major cardiovascular events in those with PCI based on angiographic assessment versus OMT.41 Thus the benefit of PCI based just on anatomic assessment does not appear to be better than OMT, and an improved, more physiologic measure of assessment is needed. Therefore, FFR, measured at the time of angiography, provides a physiologic tool for the measurement of hemodynamically significant stenosis.

Fractional flow reserve During angiography FFR is a physiologic measurement potentially obtained, which is quite different than CFR; here are several publications that discuss the relationship and distinction between FFR and CFR.42–44 Essentially, FFR is an invasive technique where the pressure drop across an anatomic lesion is measured, whereas CFR is a measure of flow across entire epicardial vessels and the corresponding microvasculature. From the perspective of an interventionalist, CFR is non-specific in determining the hemodynamic significance of a coronary lesion whereas FFR is specific for epicardial stenosis. Starting in the mid-1990’s this technique has been used for the assessment of ischemic CAD, and is accepted as a reference standard for physiologic measurement of coronary stenosis.45–47 The accepted values for which a lesion displays features of ischemia is when FFR falls below 0.75 to 0.80.48 It has been argued that using an FFR of < 0.74 reliably discriminates coronary stenosis even when not associated with inducible ischemia.49 Additionally, the lower the FFR value

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the larger the benefit in performing revascularization and if the FFR is > 0.75 to 0.8 thresholds, outcomes appear to be good without revascularization.7,40,50 Thus, FFR assessment of intermediate coronary lesions can help direct who will benefit from revascularization versus OMT alone.50 See Fig 1. A recent meta-analysis performed by Johnson et al. evaluated how the numeric value of FFR related to prognosis.6 Clinical events increased as FFR decreased and there was a larger benefit for revascularization among individuals with low baseline FFRs. Additionally, the FFR measured immediately after revascularization showed an inverse relationship with prognosis. They concluded that an FFR-assisted strategy could decrease revascularization procedures by approximately half compared to a purely anatomic-based strategy, leading to improved angina relief and fewer adverse events. This finding is important as it further adds to the evidence that an anatomic only strategy for revascularization is inferior to a combined anatomic and physiologic approach.

Intravascular ultrasound (IVUS) Another anatomic tool available in the assessment of ischemia is IVUS. It provides another anatomic view of the coronary artery with cross-sectional images of the artery and measurement of luminal areas. The benefit of IVUS over angiography is there are fewer anatomic limitations in the quantification of coronary artery stenosis and the visualization of diffuse disease. Therefore, it was once hypothesized to improve upon angiography’s ability in the anatomic assessment of ischemia. However, physiologic studies and outcome data have determined that despite the benefit in identifying anatomic plaque burden, its utility in assessing ischemia is poor, with FFR being a superior modality to assess the hemodynamic impact of coronary stenoses.51,52 In fact, recent expert recommendations discouraged the use of IVUS measurements for determination of revascularization decisions on non-left main coronary lesions.51 IVUS has a definitive role in determination of vessel size and success of stent deployment in addition for assessment of left main stenosis.51 IVUS has a role in identifying significant left main stenosis, but when evaluating other vessels for ischemia, it is less useful.51–56 When evaluating left main disease, a minimum lumen diameter (MLD) of 2.8 mm and a minimum lumen area (MLA) of 5.9 mm2 correlate well with an FFR of < 0.75.53 In individuals with a larger MLA, they can safely avoid revascularization,53 while those with a smaller area have higher event rates.57 The utility of IVUS in non-left main arteries is poor and lesion dependent.51,52,58–60 Some studies indicate that an IVUS MLA of < 4.0 mm2 correlates well with an FFR < 0.75 and ischemia on SPECT51 while others described that an MLA cut off is only useful in proximal and mid left anterior descending (LAD) lesions (MLA < 3.0 mm2 and 2.75 mm2, respectively) and not appropriate for other lesions.58 The limitation of IVUS in non-left main lesions is due to variability of physiologic significance on factors such as lesion location, length, eccentricity, and the prevalence of viable myocardium distal to the lesion.51,52 In fact, a study by Nam et al. demonstrated that while using both FFR and IVUS-guided PCI strategies for intermediate lesions led to

favorable outcomes, those with IVUS-guided PCI had a higher rate of interventions performed than those with FFR-guided approach without any increase in adverse event rates in the FFR-guided group.61 These findings appear to indicate that while both FFR and IVUS are able to identify significant lesions, using a physiologic tool (FFR) decreased rates of revascularization while maintaining good outcomes compared to an anatomic tool (IVUS). Thus while IVUS appears to provide more anatomic information, it does not appear to provide adequate information to assist with revascularization decisions or the assessment of ischemia.

Coronary computed tomography angiography (CTA) and computed tomography fractional flow reserve (CTFFR) Another anatomic modality for assessing ischemia is CTA. With the use of contrast injection, CTA allows for a visualization of the lumen of the coronary artery along with a characterization of the plaque.62,63 Studies have demonstrated that CTA has a high diagnostic accuracy and a high negative predictive value among symptomatic individuals for detecting obstructive CAD.64,65 When compared to invasive FFR alone, the addition of CTA measured aggregate plaque volume percent and atherosclerotic plaque characteristics improved identification of significant coronary lesions.66 With the recent addition of CTFFR, CTAs can provide both a physiologic and anatomic measure of coronary lesions, though there are limitations.67,68 The addition of CTFFR to typical CTA increases the specificity in identifying significant coronary lesions (>50% lumen reduction) (79% (95% CI: 72% to 84%) for CTFFR versus 34% (95% CI: 27% to 41%) for CTA alone).69 While increasing the accuracy of CTA to diagnose coronary lesions, it’s utility to identify ischemia remains unclear. While the DISCOVER-FLOW study demonstrated that CTFFR and invasive FFR were well correlated (r = 0.717, p < 0.001), the CTFFR uses population based general assumptions of how vessels react to hyperemia to make inferences on an individual’s response to hyperemia.68 Whether these assumptions will hold true in larger studies is unclear and needs to be evaluated prior to acceptance in general clinical practice. Additionally, the DeFACTO study which measured CTFFR also demonstrated superior discrimination compared to CTA alone, but the patient population included 70% who presented with angina (high risk group) thus limiting the data’s interpretation for assessment of ischemia in moderate risk groups.70 Studies thus far have not evaluated CTFFR among individuals with prior PCI or bypass surgery, limiting its utility in this population, a limitation not present with other imaging modalities. Finally, with CTA and CTFFR there is an exposure to radiation and contrast dye, along with a lack of perfusion data, thus while the use of CTA has a role in plaque and anatomy identification, the use of CTFFR should be limited until larger studies are available.

Metabolic assessment of ischemia The metabolic transition from free fatty acid (FA) utilization to glucose utilization appears to be the primary mechanism utilized in myocardium in order to maintain adequate ATP

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Fig 1 – FFR pullback of a hemodynamic LAD lesion. The FFR pressure recording demonstrates the composite effects of stenoses (yellow arrows) and diffuse disease on ischemia (FFR = .74) The arrows indicate the corresponding discrete stenotic lesions and gradients on the pressure tracing. With permission from the Journal of the American College of Cardiology.52

production and meet cellular energy demands.71,72 As such, radiolabeled derivatives of metabolism can become incorporated into these pathways and provide information regarding the state of cellular metabolism. This can be demonstrated using both single-photon emission computed tomography (SPECT) and positron emission tomography (PET) radiotracers. Conventional SPECT and PET techniques for assessment of ischemia primarily focus on myocardial perfusion, or lack thereof, as a marker for ischemia. However, with the advent of metabolic radiotracers, the ability to determine myocardial metabolic milieu, even hours after an ischemic event, continues to grow. Below is a discussion of the most common radiotracers used in identifying ischemia through metabolic changes.

F-18 labeled fluoro-deoxyglucose ( 18 F-FDG) Upon anaerobic conditions, myocardium increases the use of glucose metabolism in an effort to maintain cellular energy requirements and cellular viability.73 This uptake of glucose depends on glucose concentration in the plasma, rate of delivery to the heart, and rate of use by the myocardium74; 18 F-FDG, a glucose analog used in PET imaging, can be used to visualize this switch in metabolism from FA to glucose during ischemia.75–78 The benefits in identifying ischemia via metabolic changes lay in the fact that exercise-rest perfusion imaging underestimates the true extent of ischemia.79,80 Thus, combination imaging with both 18 F-FDG and perfusion imaging provides a more accurate diagnosis.

Since 18 F-FDG is trapped in the myocardium after a metabolic switch from FA to glucose, this metabolic switch may be detected for up to 24 h after blood flow is restored allowing for delayed imaging.81–85 This concept is coined “ischemic memory”.82,86,87 By adding metabolic imaging to perfusion imaging, one may improve the ability to identify ischemia, even hours after the ischemic event. In 1986, Camici et al. first described an increase in myocardial glucose transport in post-ischemic myocardium among patients with exercise-induced ischemia.76 He et al. demonstrated improved sensitivity for identifying correct vascular territories with delayed 18 F-FDG imaging than perfusion imaging alone (sensitivity 67% versus 49%, respectively; p = 0.008) among individuals who developed exercise-induced ischemia.87 Similarly Dou et al. demonstrated that a metabolic signal with 18 F-FDG is more sensitive than that with sestamibi alone for detecting myocardial ischemia.82 Therefore, by using 18 F-FDG imaging it is possible to measure ischemia up to 24 h after the ischemic incident and improve the diagnosis of ischemia than with perfusion imaging alone.88

Fatty acid metabolic imaging With increased glucose metabolism during ischemia, FA metabolism decreases, and may persist for hours after resolution of ischemia, i.e. “ischemic memory”.83,86 Thus imaging FA metabolism, similar to 18 F-FDG, can identify ischemia even hours after the ischemic event. 123I-βmethyl-P-iodophenylpentadecanoic

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acid (123I-BMIPP) is an iodinated branch chain FA analog used in the imaging of FA uptake, oxidation, and storage in the myocardium using SPECT systems.89,90 123I-BMIPP is taken up by the myocyte and not further metabolized after the first step in its metabolic pathway.75,91 Therefore, 123I-BMIPP is trapped in the intracellular lipid pool, and after an ischemic event, decreases in its metabolism may persist for up to 30 h and can be imaged using SPECT cameras.75 Dilsizian et al. described the metabolic imprint of exercise-induced ischemia thirty hours after the onset of ischemia with 123I-BMIPP resting images.71 See Fig 2. This change in metabolism makes 123I-BMIPP a useful tool to evaluate for “ischemic memory” in the myocardium and can be acquired with rest imaging. Along with 123I-BMIPP, a new PET tracer is currently undergoing phase II multicenter clinical trials and has utility in studying myocardial FA uptake. Trans-9-F-18-Fluoro-3,4-methyleneheptadecanoic acid, (FCPHA) is a F-18 labeled modified FA. FCPHA injected after peak exercise correlates to regional FA uptake despite normal Tc-99 m SPECT imaging and demonstrates the extent of significant coronary stenosis better than technetium SPECT imaging.92 Similar to 123I-BMIPP, FCPHA imaging demonstrates changes in FA retention that remained in ischemic regions longer than non-ischemic myocardium.92 Another PET tracer used to measure FA metabolism is [11C] palmitate, a radiolabeled long-chain saturated FA compound.93 [11C] palmitate has been available for over a decade but due to the need for an on-site cyclotron, it has limited use. It is mainly used to study myocardial β-oxidation and intracellular lipid pool turnover but has utility in differentiating ischemic from infarcted tissue.75,93–95

Physiologic assessment with myocardial perfusion agents In the era of multimodality imaging, physiologic assessment of ischemia is possible with echocardiography, CMR, CCTA and nuclear (both SPECT and PET) techniques. The latter portion of this section will focus on absolute quantification of MBF by PET. However, as a primer, MPI with the low energy isotopes Thallium 201 (Tl-201) and Tc-99 m will be addressed as their historical perspective is necessary for understanding the role of PET. Specifics on hardware configuration and types of PET scanners will not be discussed here as they are discussed in detail by Slomka et al. in the current edition of this Journal.

Myocardial perfusion imaging with thallium and technetium Prior to discussions on the assessment of myocardial ischemia with PET, it is necessary to digress and give a historical perspective of myocardial perfusion scanning for the assessment of ischemia. Tl-201 planar imaging was the first widespread isotope and modality utilized for the assessment of myocardial ischemia and infarction. Initial animal studies in the 1970’s and early 1980’s identified the biologic properties and distribution of Tl-201 in normal, ischemia and infarcted myocardium.96–99 Throughout the 1980’s and early 1990’s there was robust literature that demonstrated the utility of Tl-201 planar and SPECT perfusion imaging to guide therapy for myocardial mechanical revascularization of ischemic and viable myocardial tissue.79,80 In 1977 the term “redistribution” was coined by Pohost et al. based on Tl-201’s kinetic

properties and subsequently became synonymous for both ischemic and/or viable myocardium on relative perfusion imaging.100 Because lack of thallium redistribution at 4 h and 24 h underestimates reversible defects, the concept of thallium reinjection was introduced in 1990, which improved the accuracy of detecting myocardial ischemia and differentiating it from myocardial scar.101 By the late 1980’s, the terms “reversible” and “fixed” had been introduced into the vernacular and subsequently replaced the terms “redistribution” and “no redistribution” to describe ischemic and infarcted myocardium, respectively. By the mid- to late 1990’s, Tc-99 m labeled-sestamibi and tetrofosmin became available and due to superior image quality, Tc-99 m SPECT ultimately surpassed the use of Tl-201 SPECT. However, the vernacular terms “reversible” and “fixed” persisted and remained synonymous for “ischemia” and “infarction” respectively. The kinetic properties, myocardial uptake and stress test protocols of Tl-201 are quite different than those of the Tc99m based isotopes.102 Tl-201, is a potassium analog with high first pass extraction (85%), principal emission of 68–80 keV x-rays, redistribution after 10–15 min of injection and has a near linear relationship to absolute MBF under a wide variety of physiologic conditions.99 Tc-99 m labeled tracers are lipid soluble, cationic molecules with less first-pass extraction than Tl-201, principal emissions of 140 keV photons, and are retained within the mitochondria of cardiac myocytes with negligible redistribution.103 Tc-99 labeled tracers also demonstrate less retention at higher physiologic flows than Tl-201.29,102 Thus myocardial uptake of Tl-201 more closely represents MBF than that of Tc-99 m based perfusion agents. However, given its higher photon energy and dosimetry, Tc-99 m labeled tracers offer improved counts statistics and image superiority over Tl-201. The protocol for Tl-201 stress testing utilizes a single injection of Tl-201, which over time distributes throughout myocardial tissue and allows for serial imaging. As Tc-99 m labeled tracers undergo minimal redistribution over time, serial images require separate injections of isotope for resting and hyperemic conditions. One could consider Tc-99 m labeled rest and stress images as “snapshots of physiology” which are than compared. Hence, the terms “reversibility” and “fixed”, while true descriptors of Tl-201 physiology, are adopted and agreed upon misnomers with regards to Tc-99 labeled relative perfusion imaging.104 While some could argue that this opinion is semantic and moot, the emphasis and distinction here are that “fixed”, “reversible” and even “normal” on relative imaging become misleading and ambiguous when attempting to quantify ischemia or MBF in absolute terms, especially when one considers the uptake/ flow relationship of Tc-99 labeled tracers, soft tissue attenuation, and the poor image quality of Tl-201. Most contemporary outcome data and trials with Tl-201 and Tc-99 m tracers utilize these terms and definitions (or derivatives thereof) despite the noted limitations. Furthermore, there is a large amount of prognostic data that has been validated extensively for risk stratification in patients with suspected or known CAD using both Tl-201 and Tc-99 m SPECT perfusion scans.105–109 The composite data of these studies demonstrate that major adverse cardiac event (MACE) frequency increases proportionately with the extent of perfusion abnormalities. On

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Fig 2 – Angiogram demonstrating a high grade left circumflex lesion and the corresponding BMIPP SPECT defect secondary to altered fatty acid metabolism (“ischemic memory”). With permission from Nature Reviews Cardiology.138

the surface, the abundance of outcome data seems incongruent to the previous supposition that the terms “fixed”, “reversible” and “normal” on relative images are misleading and ambiguous. Therefore this must be reconciled. In general, the prognostic outcome data with Tl-201 and Tc-99 m SPECT perfusion scans have utilized a “summed scoring system” to quantify the size and severity of defects and overall represent composite measure of ischemic heart disease. Because of the relative nature of summed scoring, a region with poor perfusion may be identified only when it can be compared to a well-perfused region. If all myocardial regions in a given patient are poorly perfused, they may all appear normal (a finding known as “balanced” ischemia). See Fig 3. Conversely, interference from unusually distributed soft tissue can cause artifactual defects. As noted above, the reconciliation that is required to resolve the ambiguities with the standard definitions of ischemia becomes obvious when we recognize the limitations of the outcome data. The primary limitation is not one of detection of CAD, although “balanced ischemia” is possible, but of regional revascularization decisions. There are circumstantial data on the impact of regional revascularization on perfusion defects and the impact of revascularization on territories where no defect exists. The trials most often cited as “the link” demonstrating the prognostic benefits of SPECT MPI and revascularization are by Hachamovitch et al.4,9 These were large, retrospective, propensity matched studies between 1991 and 1999 which concluded that in cases in which greater than ≈ 10% of myocardium was deemed “ischemic,” revascularization had greater survival benefit when compared with optimal medical therapy. Unfortunately, regional perfusion abnormalities and their relationships with coronary anatomy were not taken into account or reported. In other words, revascularization on vessels supplying “normal” territories, or lack of revascularization on vessels supplying “ischemic” territories, was not accounted for and was certainly plausible. Hypothetically, a patient could have had a large reversible defect comprising 20% of the myocardium in the LAD distribution, and on angiography, a 70% right coronary artery (RCA) lesion and a 50% LAD lesion could

be seen. At the time of the data collection of the study, FFR was not in common clinical use. In this hypothetical example PCI of the RCA could have been considered appropriate care. The LAD would likely not have been mechanically revascularized. Under these circumstances, the global concordance between angiography and SPECT MPI would be applauded and the reported sensitivity and specificity for detection of disease (i.e., 50% or 70%) would be high. However, utilizing angiography as the “gold standard” SPECT MPI would be deemed inaccurate based on the discrepancy between the location of the “ischemic” area on SPECT and the “occlusive” vessel seen on angiography. See Case Study 1 as an illustration of this scenario. Another hypothetical yet plausible situation would be a case where SPECT perfusion demonstrated an inferior reversible defect comprising 15% of the myocardium and angiography demonstrating “three vessel obstructive disease”. In this clinical scenario, the treatment options between 3 vessel CABG or 1 vessel PCI have profound implications with regards to morbidity and cost. While these hypothetical situations may seem unlikely, data from Tonino7,110 and Melikian111 in addition to outcomes from COURAGE,41 BARI-2D112 and FAME7,110 suggest the high likelihood that these types of situations are commonplace. Given the overall large volume of patients in these observational studies, one can reasonably conclude that a decision to revascularize large reversible perfusion defects probably results in net benefit when applied to populations. However, one must remain cautious when applying these generalizations to specific individuals. Furthermore, since the time of enrollment of these studies, there has been substantial improvement in medical therapy including common use of dual antiplatelet agents, ace-inhibitors in addition to more aggressive statin utilization which could mitigate MACE in medically treated groups. As noted above, the ongoing, prospectively designed ISCHEMIA trial has standardized a definition of moderate–severe ischemia among SPECT MPI, echocardiography and CMR, and seeks to determine whether revascularization is superior to OMT.113 Hopefully, in their analysis, authors will address the impact of regional revascularization with regards to perfusion defects.

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In sum, taking into account the specific properties of the currently used SPECT isotopes, their relationships to myocardial flow and uptake, the relative nature of SPECT perfusion imaging and the limitations of revascularization outcome data, where do we stand in terms of quantifying ischemia? Does “reversibility” equal “ischemia”? Can there be “ischemia” without reversibility? Is there a better way to quantify ischemia than the summed scoring system? Is there a benefit in revascularization of territories with “normal” perfusion and high-grade disease on angiography secondary to “balanced ischemia”? Although there is no consensus of answers to these questions, myocardial perfusion with quantification of absolute myocardial flow with PET extends the scope of conventional relative imaging and allows for discrete characterization of the spectrum of CAD from the pre-clinical to the advanced stages of CAD.

Physiologic assessment with PET Standard relative PET imaging Noninvasive myocardial perfusion imaging by PET offers high spatial resolution, attenuation correction and is the gold standard for assessment of absolute MBF under both resting and hyperemic conditions.114–120 There are currently 3 available radioisotopes available that have been validated extensively for both MPI and quantification of MBF. These are H20-15, Nitrogen 13 ammonia (N13), and Rubidium 82 (Rb-82). The first two require a nearby cyclotron for production and Rb-82, due to its extremely short half of 75 s, requires a generator that infuses directly into the patient. Traditional static imaging with PET (without quantification of absolute MBF) is similar to SPECT MPI with the exception that proper PET attenuation correction removes soft tissue artifacts. As with SPECT perfusion with Tc-99 m, serial imaging with PET requires separate injections of isotope for resting and hyperemic conditions. This is due to the short half-lives of the PET isotopes. Furthermore, with higher count rates and statistics, image quality, interpreter certainty and detection of CAD appear to be better with PET than with SPECT.19 Interpretation and diagnosis of “ischemia” and/or “infarct” with PET are similar to SPECT with regards to the standard vernacular terms “reversible” and “fixed”. In addition, prognostic outcome data for relative PET imaging are similar to SPECT in that the frequency of MACE increases with the extent of perfusion defects.121–123

Absolute MBF with PET In the paper from 2013, Gould et al. comprehensively reviewed the reproducibility and variability of quantification of MBF with PET. This review demonstrated that while there is some imprecision with PET derived flow, the imprecision is within similar ranges for other common cardiac related measurements including percent stenosis on angiography and ejection fraction on echocardiography.18 The absolute MBF data cited in this review were obtained from experienced sites with “homegrown” software and with PET scanners operating in 2D mode. In the current era, most manufacturers only offer PET scanners with 3D acquisition. This raises the question of whether quantification of absolute flow with PET can be performed reliably on 3D PET systems, with less experienced and less sophisticated users, relying on commercially available “plug and play” software. The RUBY-10 study measured and compared results of absolute

myocardial blood flow on ten different software packages with data acquisition from a sole scanner operating in 3D mode.124 The results demonstrate that although software programs utilizing the same kinetic model provide consistent results, there is significant variation with software packages utilizing different kinetic models. Furthermore, the results were not compared to an invasive gold standard such that accuracy of any of the software packages was not confirmed. Further studies will be necessary to evaluate the accuracy of various software packages, kinetic models and scanner types with invasively derived data. Values of absolute MBF and CFR among a variety of conditions have been reported over the past ≈ 25 years. Global (whole heart) absolute flow in normal individuals at rest and stress is typically ≈ 75–1.1 cc/min/g and ≥3.0 cc/min/g respectively.18,113 Thus, normal global CFR tends to be > 3.0 cc/min/g. Basal resting flow in regions with non-viable, transmural myocardial infarction are ≈ .25 cc/min/g with “border zones” or non-transmural infarction zones ≈ 4–.6 cc/min/g.125 As regional CAD and/or microvascular dysfunction progresses, resting flow remains fairly constant whereas regional absolute flow at hyperemia decreases, thus leading to regional and global reduction in CFR.126–128 Furthermore, numerous studies have demonstrated the incremental prognostic value of absolute flow over conventional metrics including resting left ventricular ejection fraction and relative perfusion scores.14,15,129,130 The composite findings of these studies demonstrate that the frequency of MACE is inversely proportional to absolute stress flow and CFR. Furthermore, outcomes were still favorable in patients with “reversible” defects provided that absolute stress flow or CFR was preserved. In other words, flow trumps relative perfusion with regards to long-term outcomes. Therefore the question remains at what point does absolute hyperemic flow and/or CFR becomes “ischemic”? Thus far, the largest studies attempting to establish ischemic “thresholds” for absolute MBF have used different “gold standards” for reference. The first study by Johnson and Gould used an “I know it when I see it” approach on 1674 PET scans. They identified low-flow thresholds by defining definite ischemia as having: 1) a relative stress induced perfusion defect in addition to the development of either or both 2) ST-segment depression or 3) severe angina during stress testing. Indeterminate features of ischemia were defined as having at least one of the findings.131 They concluded that the optimal separation between groups with definite ischemia and no ischemia occurred at hyperemic myocardial flow of .91 cc/min/gm with concomitant CFR <1.74. The optimal separation between groups with indeterminate features of ischemia and no ischemia occurred at hyperemic myocardial flow of 1.12 cc/min/gm and CFR < 2.03.131 The second study by Danad et al. prospectively enrolled 330 patients to undergo PET stress testing in patients referred for angiography. PET derived absolute MBF was compared to invasively derived FFR. Hemodynamically “significant stenosis” was defined as > 90% stenosis or an FFR ≤ 0.80.132 The pertinent findings in this study demonstrated that average hyperemic flows and CFR of ≈ 1.73 cc/min/g and 1.99 cc/min/g respectively occurred in regions with “significant stenosis”. They also concluded that the optimal cutoff > 2.3 cc/min/g excludes the presence of hemodynamically significant stenosis with a high negative

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Fig 3 – SPECT MPI showing an ischemic zone in the inferolateral wall consistent with left circumflex stenosis. The inferoseptum, septum and anterior walls demonstrate normal perfusion in the LAD and RCA territories. Corresponding angiogram with multivessel FFR measurements demonstrates ischemia in all major epicardial vascular territories. The LAD and RCA stenoses were not detected because of tracer properties and relative imaging. With permission from the Journal of the American College of Cardiology.52

predictive value (96% per vessel).133 While “ischemic” or “significant” values in these two studies on the surface may seem rather disparate, one can reconcile these differences by recognizing they compositely identified “ischemic boundaries”. Johnson and Gould identified low flow thresholds associated with clinical ischemia whereas Danad et al. identified regional average flows in zones with hemodynamically significant stenosis in addition to a lower limit of “normal” flows where hemodynamically significant stenosis is highly unlikely. While there is still some debate what the upper and lower ends of the “ischemic boundaries” are, there is a growing consensus based on these two studies. Subsequent studies where regional low flow is paired with a switch to FA metabolism, possibly with the use of 123I-BMIPP or FCPHA, could refine these values.

Integrating relative uptake and absolute MBF As noted above, relative imaging is limited due to the lack of a standardized unit of myocardial perfusion, underestimation of multivessel disease and overestimation of mild singlevessel disease. These limitations have profound implications

for drawing conclusions on past and future studies in addition to decisions for revascularization on the individual level. On the other hand, most practitioners recognize these limitations and find clinical relevance with the traditional methods for defining and reporting ischemia. With the addition of absolute MBF, the aforementioned limitations are nullified; however, new problems occur. The problems are essentially how one reports the various findings, which thresholds are utilized and the nomenclature used. There is currently no standardized method or nomenclature set forth by any official committee. However, a novel and powerful construct has been published by Johnson and Gould134 which has been incorporated by others.135 This proposed framework integrates absolute flows and CFR onto a 2-dimensional scatter plot and incorporates “ischemic” low flow thresholds from their earlier publications (Fig 4). Color-coded data points from the scatter plots are spatially arranged anatomically and used to create an anatomic comprehensive flow map. These flow maps yield 6 unique groups where flow capacities range from normal to severely reduced. Incorporation of the flow maps with relative images yields a comprehensive

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Fig 4 – Scatter plot of CFR versus absolute stress flow — with permission from the Journal of the American College of Cardiology: Cardiology Imaging.134 The clinical ranges for CFR, stress flow and rest flow and ischemic thresholds have been described.18,113,115,125,126,128,131 In the framework proposed by Johnson and Gould, CFR and stress flow are plotted against each other to create “zones” of flow capacity. As resting flows are dependent on both CFR and stress flows, they are inherently defined as well. Physiologic resting flows values are therefore plotted as the dashed–dotted lines with varying slopes. view of physiology that goes beyond traditional definitions and requires new nomenclature. Relative images don’t necessarily mirror flow capacity. One can appreciate reversibility without ischemia as well as ischemia without reversibility (Fig 5). There are multiple benefits of this solution. First, it allows for standardization of the size and severity of ischemia in absolute terms. Although various centers could differ in their “low flow” definitions, boundaries of ischemia and cutoffs for revascularization, the values of flow and CFR would remain absolute. Secondly, revascularization decisions and the measurement of success of revascularization can be based on absolute numeric values and not simply the change in relative images or improvement in percent stenosis on angiography.136 Case 1 illustrates this point and further demonstrates the limitations and conclusions drawn with the previous studies noted above.4,9 Finally, as other modalities such as CMR and CCTA become capable of flow quantification, absolute flow allows for standardization across modalities.

detection and treatment of ischemia, Tc-99 SPECT MPI and invasive angiography, are fraught with limitations. With the development of flow derived techniques, FFR and absolute flow with PET, the definition of ischemia has become better defined, highly reproducible and can be standardized. Non-invasive PET offers the benefit of attenuation free relative images, measurements of basal and hyperemic flow, in addition to CFR throughout the entire myocardium. Although there are no standardized reporting guidelines for absolute flow with PET, there are published frameworks that define flow capacities and how they relate to underlying perfusion. Given the results of anatomic based revascularization,41,112,137 the limited results of MPI associated revascularization4,9 and the benefits of invasive flow guided revascularization,7,8 future studies are warranted to determine if a non-invasive “flow capacity” guided strategy for revascularization with PET (or other modalities capable of flow) will be a clinically useful, superior and cost effective strategy. After all, one cannot fix a problem until one can define what the problem really is.

Conclusions Case Study 1 Defining “ischemia” is challenging and not as straightforward as once believed. In this era of multi-modality imaging, there are various definitions used based on whether anatomic, metabolic, or physiologic methods are employed. The variation amongst modalities essentially arises from the fact that each modality assesses a surrogate of ischemia and does not truly quantify oxygenation on the tissue level. Furthermore, the most common methods for

A 65-year-old man presented with worsening shortness of breath over a period of several months. He had a history of CABG 15 years prior to presentation, with anatomy as follows: LIMA to LAD, SVG to OM2, and SVG to PDA. He underwent cardiac PET stress scanning with quantification of absolute myocardial blood flow.

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Fig 5 – Adapted with permission from the Journal of the American College of Cardiology: Cardiology Imaging.134 Fig 2. Representative examples of varying stages of flow capacity Each subfigure contains relative stress uptake images (rows 1, 3, 5, 7) appearing above integrated flow maps (rows 2, 4, 6, 8). Relative rest uptake images are not shown but were clinically normal and/or minimally abnormal (where noted) and do not change the clinical analysis. Subfigures A1 and A2: A1, Elderly man with normal relative images with minimally reduced flow capacity (whole heart average stress flow 1.71 cc/min/gm, CFR 2.87). A2, Middle aged man with previous mechanical revascularization with a stress induced septal and anterior relative defect; however, flow capacity is adequate (average septal CFR 2.99). Lateral and inferior quadrant CFR is 3.71 which accounts for the relative septal and anterior defect. In the current framework, this example illustrates reversibility without ischemia. Subfigures B1 and B2: B1, Elderly man with dense coronary calcifications and mild heterogeneity on relative stress images. Whole heart resting flows averaged .62 cc/min/gm, stress flows 2.55 cc/min/gm with CFR of 4.11. Despite elevated Ca score, flow capacity is normal. B2, Healthy 27 y/o volunteer with mild heterogeneity on relative stress images and normal flow capacity. Heterogeneous uptake thought to be secondary to nicotine. Subfigures C1 and C2: C1, Middle aged man with severe angina with a large stress induced anterior and septal relative defect. Resting images did indicate decreased uptake in the anterior wall consistent with non-transmural scar. Minimal stress flow and CFR were < .9 cc/min/gm and <1 respectively indicating severely reduced flow capacity and myocardial steal. These findings were confirmed on angiography. C2, Middle aged man with severe ischemia and hypotension during vasodilator stress testing. Stress induced relative defects in the inferolateral and anterior walls were present (resting relative images with a small relative basal inferolateral defect). Flow capacity is uniformly and severely diminished consistent with and confirmed on angiography — triple vessel with left main disease. Note the “normal” relative uptake in the basilar septum and distal lateral walls despite severely reduced flow capacity. In the current framework, these regions illustrate normal relative perfusion with severe ischemia. Subfigures D1 and D2: D1, Elderly woman with a large lateral wall stress induced relative defect; however, flow capacity is only mildly reduced and non-ischemic in the current framework. Note the normal flow capacity in the first septal territory compared with the mildly reduced flow capacity and a small region of moderately reduced flow capacity (green on flow maps) in the left circumflex territory. The regional difference in flow capacity is termed relative CFR and is the non-invasive correlate to invasively derived FFR. In the current framework, this example illustrates reversibility with little or minimal ischemia. D2, Middle aged man with multiple large stress induced relative defects comprising ~50% of the LV myocardium. Flow maps demonstrate mildly reduced flow capacity for the majority of the myocardium with only several scattered small regions of moderately reduced flow capacity or definite ischemia. In the current framework, this example illustrates reversibility with little or minimal ischemia.

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Case Study Fig 1 Relative images

The relative perfusion images seen in Case Study Fig 1 demonstrate a mild anterior and anterolateral wall stress-induced defect (yellow, anterior/lateral quadrants at stress). The summed difference score is 12, which portends high risk for major adverse cardiac events. Case Study Fig 2

In Case Study Fig 2, absolute myocardial flow (top images) and integrated flow maps134 (bottom images) demonstrate that the mild stress induced defect seen in Fig 1 has only mildly reduced flow capacity in the myocardial region commonly supplied by diagonal branches and the proximal circumflex artery. In this region, MBF reaches levels at which some patients might experience angina (i.e., 1.19 g/cc/min).131 Note that the regions with the highest MBF are located in the OM2, PDA, and septal territories, consistent with the existence of patent bypass grafts to these regions. The patient was subsequently referred for angiography, at which time high-grade lesions were noted in the SVG-PDA and SVG-OM2. FFR was not performed. Based on the angiographic appearance, these lesions were treated with drug-eluting stents, with residual 0% stenosis after PCI. Also noted on angiography was a high-grade ostial lesion in the circumflex artery, which was not intervened upon. At follow-up three months later, the patient reported no improvement in his angina. He was referred for another cardiac PET.

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Case Study Fig 3 Relative images

On relative perfusion imaging, Case Study Fig 3, the anterior and anterolateral stress-induced defect has resolved, and the summed stress score has improved. Based solely on these relative images, one might conclude that intervention was successful and that percutaneous treatment of the vessels supplying the PDA and OM2 territories somehow contributed to the resolution of the geographically remote anterior defect. However, review of absolute myocardial quantitative data presents a different picture. See Case Study Fig 4. In the OM2 and PDA territories, absolute myocardial flow has actually worsened following intervention. Whole-heart MBF decreased from 1.82 cc/min/gm to 1.53 cc/min/gm, and minimum flow decreased from 1.19 cc/min/gm to 0.97 cc/min/gm. Absolute flow at hyperemia throughout the majority of myocardium is uniformly decreased, which results in perceived “improvement” of relative images (Case Study Fig 3) and thus, the normal summed stress score. Hence, globally poor myocardial perfusion can result in a falsely negative test when only relative images are utilized, but the addition of PET-derived absolute myocardial flow data reveals the truly poor perfusion. Case Study Fig 4

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Statement of conflict of interest Dr. Jahangir has no personal disclosures. Dr. Bober is associated with Bracco as a Consultant and Astellas as Speakers’ Bureau.

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