Myocardial Viability: It is Still Alive Siok P. Lim, MBBS, BSc (Med), MRCP, FRCR,* Brian A. Mc Ardle, MB, BCh, MRCPI,* Rob S. Beanlands, MD, FRCPC, FACC,*,† and Renee C. Hessian, MD, MSc, FRCPC* Heart failure presents a significant problem in industrialized countries, with a high prevalence, morbidity, and mortality, where it is most frequently caused by coronary artery disease. Revascularization in patients with symptomatic heart failure has been associated with improved cardiovascular outcomes. Predictors of outcome benefit from revascularization include the presence and extent of hibernating myocardium, ischemia, scar, left ventricular ejection fraction, and renal function. Viability is useful in directing the management of patients with ischemic cardiomyopathy. It is especially useful in those with the highest risk where revascularization decisions are the most difficult. In the absence of definitive prospective randomized data on the benefit of routine viability testing in the management of ischemic cardiomyopathy, physicians will likely continue to use viability testing to assist them with their decision-making process. This review article focuses on the value of viability imaging and the modalities of its measurement, which include PET, SPECT, cardiac MRI, and dobutamine echocardiography. These imaging modalities should be seen as complementary rather than competing methods. In any given clinical setting, the indications, comorbidities, availability, local expertise, sensitivity, specificity, and limitations of each modality need to be considered. When advanced imaging (PET and cardiac MRI) are available, they are generally considered the preferred choice because of their overall higher accuracy. Finally, we explore the role of ischemia in patients with viability and the potential role of neurohormonal and viability imaging in deciding the need for implantable cardiac defibrillator as a primary prevention in patients with severe ischemic cardiomyopathy. Semin Nucl Med 44:358-374 C 2014 Elsevier Inc. All rights reserved.

Case

A

67-year-old man presented with new onset of cardiomyopathy with dyspnea. He had no history of coronary artery disease (CAD) or of angina. Cardiac risk factors include hypertension, smoking, and hypercholesterolemia. Findings

*Department of Medicine, National Cardiac PET Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada. †Department of Radiology, The Ottawa Hospital and the University of Ottawa, Ottawa, Ontario, Canada. This project was supported in part by IMAGE-Heart Failure, a Team Grant (Canadian Institute of Health Research team grant #CIF 99470). R.B. is a career investigator supported by the Heart and Stroke Foundation of Ontario and Tier 1 Chair in Cardiovascular Research supported by the University of Ottawa. R.B. is a consultant for Lantheus Medical Imaging and Jubilant DraxImage (JDI). R.B. has received grant funding from a government or industry research program (partners: GE Healthcare, Nordion, Lantheus Medical Imaging, and JDI). Address reprint requests to Renee Hessian, MD, FRCPC, University of Ottawa Heart Institute, 40 Ruskin St, Ottawa, Ontario, Canada K1Y 4W7. E-mail: [email protected]

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http://dx.doi.org/10.1053/j.semnuclmed.2014.07.003 0001-2998/& 2014 Elsevier Inc. All rights reserved.

on echocardiography showed severe reduction of left ventricular ejection fraction (LVEF) with an ejection fraction of 15%25%. Findings on coronary angiography showed significant lesions involving the left anterior descending artery (LAD) and right coronary artery (RCA). A PET viability study was performed, which demonstrated 8.6% perfusion-metabolism mismatch or viable myocardium in the middle to apical segments of the septal, inferoseptal, and inferolateral walls of the left ventricle (LV) and 9.2% scar in the apical segment of the inferior wall and apex, suggestive of involvement of both his LAD and RCA territories (Fig. 1). Will revascularization improve his LVEF? After a multidisciplinary discussion, the patient underwent percutaneous coronary intervention successful stent deployment in the LAD and the RCA. The patient was discharged on optimal medical therapy (OMT). At 3 months' follow-up, his echocardiogram showed a LVEF of 52.6%.

Introduction Heart failure (HF) is a common cause of morbidity and mortality in industrialized countries, and it is most frequently

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Figure 1 Rest 82Rb perfusion imaging (RstCTAC) and 18F-FDG imaging (FDGCTAC) (both with attenuation correction). (A) Short axis, (B) horizontal long axis, and (C) vertical long axis images show perfusion defects in the middle to apical segments of the septal, inferoseptal, inferior, and inferolateral walls of the left ventricle, including the apex, with preserved FDG uptake except in the apical segment of the inferior wall and apex. The polar maps demonstrated 8.6% perfusionmetabolism mismatch (indicating hibernating myocardium) in the middle to apical segments of the septal, inferoseptal, and inferolateral walls of the left ventricle (LV) and 9.2% scar in the apical segment of the inferior wall and apex. The patient underwent percutaneous coronary intervention with stents deployed successfully in the LAD and the RCA. A 3-month follow-up echocardiogram showed a LVEF of 52.6%. L, lateral; LCX, left circumflex artery; P, posterior; S, septum.

caused by CAD. Revascularization of significant CAD in patients with symptomatic HF has been associated with improved cardiac function and cardiovascular outcomes, in spite of the associated comorbidities often found in this patient population. Since 1985, with the publication of the Coronary Artery Surgery Study trial, there has been proof of improved outcome with coronary artery bypass grafting (CABG) in patients with triple vessel disease and impaired LV function.1 Surgical advances have allowed patients with more severe LV dysfunction and more significant comorbidities to undergo successful revascularization in spite of their increase in procedural risk. This has led to a greater understanding of which patients benefit the most from surgical treatment and how to predict a positive outcome

based on noninvasive testing. Although recently the Surgical Treatment for Ischemic Heart Failure (STICH) trial left questions about the utility of viability imaging, perhaps because of the patient selection, most centers continue to perform a steady volume of viability studies, reflecting that this is still a relevant question for physicians. Some of the predictors of outcome benefit from revascularization in these patients include (1) extent of ischemia, (2) extent of viable myocardial tissue (especially hibernating tissue) and therefore scar, (3) LVEF, and (4) renal function.2-5 In this review article, we explore the concept of hibernating myocardium and its effect on the outcome of revascularization and the influence of PET in decision making.

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Metabolism and Definition of Viable Myocardium (Hibernation) In surgical trials, it has been observed that regions of impaired wall motion, even if severe, can sometimes partially or completely improve after revascularization. This improvement occurs in spite of the fact that these regions have features suggestive of a scar at angiography.1 Rahimtoola first described this improvement of regional LV function after a systematic review of the literature of CABG trials. These areas had significant dysfunction but there was no diagnosis of previous myocardial infarction (MI) either historically or with electrocardiography (ECG) evidence of Q waves. He described this as a pathophysiological concept of “myocardial hibernation” and defined it as “a state of persistent regional contractile dysfunction, in patients with CAD that is reversible with revascularization.”1

Stunning The description of myocardial stunning was given decades after Tennant and Wiggers demonstrated that the onset of ischemia quickly impairs the contractile function of the myocardium in their 1935 publication. The reduction in blood flow initially causes contractile dysfunction that persists after the blood flow is restored or as referred to as “hit, run and stun.”6 The recovery of contractile function is related to the duration, severity, and size of the ischemic insult and may take days to weeks for its function to improve.7 It is unclear which molecular events are responsible for stunning and what molecular changes are responsible for continued dysfunction once blood flow is restored.8,9 The changes in the myocardium in the case of stunning are largely metabolic and not structural, as electron microscopy of these cells show normal or mildly degenerated cells. Camici and Dutka10 capture the concept well in the term “functional hibernation.” Some investigators feel that repeated stunning causes changes in myocardial structure that can become more severe and more permanent.11

Hibernation It was initially thought to be a state where there is downregulation of the myocytes and the extracellular matrix to adapt to the reduction in blood flow. However, in some circumstances, reductions in blood flow follow and do not precede myocyte dysfunction.11,12 Hibernating myocytes exhibit no histologic evidence of scar or acute ischemic damage and most have fairly severe cellular defects. There are microscopic abnormalities of both the contractile apparatus and the interstitial environment. There is a significant loss of sarcomeres, which can be virtually absent, and of myofibrils. The spaces previously occupied by myofilaments become filled with glycogen. This is demonstrated during periodic acid-Schiff staining13 (Fig. 2). It is not clear what the role of the uptake of glucose is by these cells. Under baseline conditions, normal myocytes do not show glycogen uptake. These cells

transition from a functional state that is “rich in contractile material” to a state of survival characterized by contractile material deficiency and a “glycogen-rich” state.14 Fibrotic remodeling eventually occurs in the interstitium, perhaps associated with an increased inflammatory response. The extent of fibrosis is thought to be an important predictor of reversibility of hibernation.15 The number of functional myocytes, the number of cells with large glycogen stores, and the absence of fibrosis in myocardial tissue samples all have thresholds that predict for regional functional improvement after revascularization.16

How They Differ? A complex relationship is thought to exist between hibernating, stunned, and normal myocardium. Histologic studies of myocardial biopsies in areas thought to be hibernating show that areas of stunned myocardium coexist with areas of hibernation and that the cellular changes are less severe than those seen with hibernation.13,17,18 Hibernating myocardium shows severe cellular defects in most cells. There is myofibrillar loss even at the cell periphery, absent contractile material; and large areas of mitochondria. The nuclei become abnormal and the sarcoplasmic reticulum becomes absent; more end-stage features such as fat droplets and degenerative vacuoles are common.17,18 The distinction becomes blurred between stunning and hibernation, as some authors believe that hibernation can be produced by repeated episodes of stunning.11,12 The fundamental difference between these entities was thought to be that stunned myocardium has an intact resting blood supply and that it is significantly reduced in hibernating myocardium. Initially, myocardial cells were thought to reduce their function to match the available coronary flow, thus protecting the myocardium from death. This became known as the “smart heart theory.”19 This theory fits all the observations that were available about hibernation at the time. There is now significant controversy regarding this distinction, as repeated episodes of stunning are now believed to be one of the mechanisms, leading to a hibernating myocardium associated with a secondary reduction in flow.10,20 Some authors believe that resting flow to the hibernating myocardium is normal or mildly reduced and that the coronary flow reserve (CFR) of the hibernating myocardium is severely reduced.10,21,22 Others still maintain that a chronic reduction of flow is responsible for hibernation.12,23 Review of PET and myocardial blood flow (MBF) data has been at the center of this controversy. PET studies have been pivotal in demonstrating that MBF was not always severely reduced in hibernating areas. In fact, it was almost normal in a study.24 This finding was corroborated in the same study by demonstrating normal oxygen consumption with 11C acetate in normal and biopsyconfirmed mildly and severely hibernating myocardium. The stress-induced MBF increased less in the hibernating segments that in the normal segments, suggesting that abnormal CFR and repeated episodes of ischemia may account for hibernation in humans.

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Figure 2 (A) Normal cardiomyocytes with almost no glycogen staining (PAS staining in red) shown in light micrograph. (B) Normal cardiomyocytes in a transmission electron micrograph. (C) Representative light micrograph of human hibernating myocardium. Cardiomyocytes are depleted of contractile material and filled with glycogen (PAS-positive staining). (D) Representative transmission electron micrograph of a hibernating cardiac myocyte. Absence of sarcomeres in myolytic cytoplasm that is filled with glycogen (Magnification: A and C,
320; B,
7100; and D,
7500). PAS, periodic acid-Schiff. (Reprinted with permission from Wolters Kluwer Health and Vanoverschelde et al.17)

A review of this topic discussed the results of PET studies and the relation of MBF and the recovery of function at followup. The authors conclude that available studies demonstrate a reduction in flow in areas of hibernating myocardium.23 However, an alternate opinion on the same data exits.21 After a detailed technical discussion describing issues with PET use to determine MBF in this population, they concluded that (1) the resting MBF in areas of hibernating myocardium is not different from that of healthy controls; (2) in a minority of

hibernating areas of myocardium, there may be a 20% reduction of blood flow when compared with remote areas; and (3) a severely impaired CFR is present in areas of hibernating myocardium. This remains an interesting debate as it speaks directly on how revascularization improves viable myocardial segments. The ability of both stunned and hibernating myocardium to respond to inotropic stress can be preserved, which is useful in some methods of evaluating viability.25 There are differences

362 between the responses to inotropes on how they affect the cells' energy stores.25 Factors such as the degree of contractile apparatus disruption,10 degree of scar formation within the region,10 vessel patency, subendocardial flow reserve, variability in stress protocols, or a change in the functional response11 may all affect the response to ionotropes.

Time Frame of Improvement Few clinical studies have investigated the time course of improvement after revascularization, and those that have looked at this demonstrate a variable improvement, likely related to the extent of the underlying structural abnormalities and completeness of revascularization. Both viable and stunned areas of myocardium improve in parallel.17,18 The more advanced stages of cellular degeneration determine the time frame of improvement, as the time to recovery after revascularization depends on the time required to synthesize new contractile material.26 The period can be as long as 6 months or longer with more severe structural abnormalities.13,17,18 A clinical study observed the time frame of improvement of stunned and hibernating myocardium. Cells demonstrating little structural abnormalities can improve within 10 days after revascularization.19 After revascularization, 61% of stunned segments improved by 3 months when compared with 30% of hibernating segments. There was further improvement of hibernating segments, but at the end of 14 months of follow-up, 30% of the stunned segments and 8% of the hibernating segments did not improve.27

Myocardial Remodeling Scar is noncontractile and occurs regionally in the distribution of coronary blood flow. It occurs with severe permanent reduction in flow as with a MI or as the hibernation progresses with the cells that are unable to continue their adaptive processes. After the acute loss of myocardium during an infarct, there is an increase in loading conditions that induces remodeling involving the infarcted border zone and even the remote noninfarcted myocardium. The early phase of remodeling involves expansion of the infarct zone and possible aneurysm formation. Late remodeling involves the LV globally and is associated with ventricular dilatation, distortion, and hypertrophy. With continued increase in wall stress in this remodeled region, there is progressive dilatation, recruitment of border zone myocardium into the scar, and deterioration in contractile function, even in nonischemic areas. In a study of 79 patients undergoing CABG, a poorer prognosis occurred in patients with larger LV sizes and was worse within this group if there was no viability. Those with viability and small LV sizes (o130 mL) had the best prognosis at 3 years after CABG.28 It is now believed that there is a spectrum of myocardial viability, which includes stunning, hibernation, and remodeling (Fig. 1). Each of these features interacts to determine prognosis with and without revascularization in these

S.P. Lim et al. patients.22 Understanding the pathology of each of these areas is important to understand how each technique that examines viability determines prognosis.

Imaging Techniques Employed for Viability (Hibernation) Assessment Viability testing is used in the assessment of areas of dysfunctional myocardium in patients with ischemic cardiomyopathy to determine the degree of viability, nonviability, and scar. Although viability testing is widely used to identify regions of myocardium that may benefit from revascularization, there are distinct advantages and disadvantages to each modality. Nuclear imaging–based modalities and echocardiographic or cardiac MRI (CMR)–based modalities are most commonly used. It is hoped that viability-directed revascularization would predict improvement of LV function, as it is the most powerful predictor of cardiovascular outcome. It is also hoped that viability-directed revascularization would improve cardiovascular outcomes, reduce HF symptoms, reduce admissions to hospital, and improve quality of life. There is little head-to-head comparison of viability tests. We are left with largely older and smaller studies. Attempts at randomized trials, as explained later, did not lead to the desired results, leaving more questions than answers on how best to use viability testing in these patients. At this point, we do have ongoing studies that may help clarify how best to investigate and treat these patients. Unfortunately, equipoise needs to exist around the enrollment of patients into future studies, which may be difficult for clinicians given the existing body of literature around the use of and general acceptance of viability testing. In considering revascularization, the amount of viable myocardium required to achieve an improvement of LV function after coronary revascularization is highly relevant. Consensus is that the changes in LVEF after revascularization are positively correlated with the number of hibernating segments.22 The presence of viability on PET has been shown to predict functional recovery after revascularization even when contractile reserve is exhausted on functional testing.29 Revascularization in patients with significant viability has been shown to improve outcomes, LV function, and functional class.30 This can be shown as late as 4 years after surgery.31 Confusingly, improvement in outcomes are not necessarily linked to improvements in LV function.32 In patients treated medically, mortality rates increase significantly with the degree of viable myocardium, with the worse outcomes in those with 420% viability, even with medical therapy.33 This is further supported by the work of Ling et al, who showed that as the amount of viable myocardium increases above the threshold of 10%, the likelihood of benefit for revascularization increases. In addition, the outcome with this level of viability when the patient is managed medically is poorer and increases linearly with increasing hibernation.5

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Studies demonstrating a positive effect of viability testing on outcome are nonrandomized, of small size, and frequently older.34 In spite of this, viability testing has been incorporated into the management of patients with ischemic cardiomyopathy. In combination with this, both techniques for viability testing and revascularization techniques have improved, suggesting an even greater potential for outcome improvement. Multiple noninvasive modalities are readily available and able to determine the extent of hibernating myocardium and scar and, thus, prognosis with revascularization.

Rationale for PET Viability Imaging

Positron Emission Tomography

PET Viability Imaging Protocol

Technical Aspects of PET Imaging PET defines metabolic cell integrity and is the most sensitive modality for detecting hibernating myocardium.35 For several years now, there have been advances in PET camera technology that have improved image quality. PET systems manufactured in combination with a CT scanner of variable specification (16, 64, and 128 slice) provide robust attenuation correction, which is particularly useful in imaging obese patients and female patients. In addition, 3dimensional PET systems, in which the lead septae that divided the rings of detector crystals in older 2-dimensional systems have been removed, have increased count statistics, allowing for reductions in radiation dose per scan. Time of flight capability in PET technology enables more accurate localization of the annihilation reaction along the line of detection, hence improving the spatial resolution of FDGPET imaging.36,37

Radionuclides for PET Imaging PET radionuclides for cardiac imaging are categorized into those that image either perfusion or metabolism. The commonly used PET perfusion radionuclides are rubidium-82 (82Rb) and N13-ammonia (13NH3) in North America and 15Owater in Europe. 82Rb is a potassium analogue, which is actively transported into myocytes through the cellular Na-K pump. 13NH3 diffuses freely across cell membranes and is incorporated into glutamine in the myocardium by the enzyme glutamine synthetase. Both these tracers rely on intact cellular function for their uptake and distribution, and their uptake is directly related to MBF. 15O-water is freely diffusible with a linear extraction-flow relationship, making it an ideal tracer for flow quantification. The main PET metabolic tracer used is 18F-FDG. FDG is a glucose analogue and is therefore a surrogate marker for glucose use. It is transported into the cell by the same sarcolemmal carrier as that of glucose and is phosphorylated to FDG-6-phosphate by the enzyme hexokinase. There is no phosphatase that can facilitate the dephosphorylation of FDG6-phosphate, resulting in intracellular accumulation of FDG-6phosphate. FDG uptake is hence proportional to the overall rate of transsarcolemmal transport and hexokinase phosphorylation of circulating glucose.38

The heart is an opportunistic organ, in that it uses the most readily available energy source, which is free fatty acids (FFAs), in normal circumstances. However, oxidation of FFAs is a process that is highly oxygen dependant, and in the setting of ischemia, and especially in the case of hibernation, anaerobic glycolysis becomes the main source of energy production. As FDG uptake is a marker of glucose use, its uptake is normal or increased in areas with viable and hibernating myocardium. Perfusion imaging is performed to distinguish hibernating and stunned myocardium from scar or remodeled myocardium.

The most commonly used technique for PET viability imaging is to perform rest perfusion imaging and to compare this with FDG imaging. However, FDG uptake into myocardium is dependent on insulin-sensitive glucose transporters that must be stimulated to provide diagnostic images. Glucose and FDG uptake is favored by the myocardium over FFAs by either using an oral glucose load inducing an endogenous glucose response or the administration of insulin together with glucose (euglycemic intravenous insulin clamp) before FDG injection.39-41 Many patients with CAD have diabetes or are insulin resistant, which may result in poor FDG uptake and poor image quality.42 A hyperinsulinemic euglycemic clamp protocol has been designed to overcome this problem. This protocol is based on simultaneous infusion of insulin and glucose acting on the tissue as a metabolic challenge and stimulating maximal FDG uptake.43 This can be challenging to implement, but once a routine is established, sites that apply this approach are generally satisfied with it in terms of patient preparation, comfort, and image quality. The alternative is reduced oral loading plus supplemental insulin as per the American Society of Nuclear Cardiology guidelines.44 Initially, a low-dose CT attenuation correction scan is obtained, followed by rest perfusion imaging, where a PET flow radionuclide is injected and images are obtained 2-5 minutes later. Metabolic imaging is then undertaken with the administration of 5-10 mCi of FDG, and tomographic images are usually obtained 30-50 minutes after the injection. Most centers perform list-mode acquisitions with simultaneous acquisition of static and ECG-gated images.44

Image Interpretation There are 4 patterns of images. The regions with relatively preserved or increased FDG uptake and reduced myocardial perfusion (metabolic-perfusion mismatch) are hibernating. Regions that have normal perfusion and metabolic activity are also viable but may be normal, stunned, or remodeled. Normal myocardium shows normal motion and thickening on ECG-gated images. However, stunned myocardium cannot be distinguished from remodeled myocardium based on rest images, as both demonstrate normal resting perfusion and FDG uptake, with abnormal wall motion. This is a relevant distinction, as although both these scenarios represent viable myocardium, remodeled myocardium may not regain

364 function with revascularization as does stunning. Therefore, the addition of stress perfusion imaging is useful to identify reversible ischemia that indicates repetitively stunned myocardium. A myocardial scar is metabolically inert and shows reduction in both FDG uptake and myocardial perfusion (perfusionmetabolism match). The extent of scar on PET has been shown to be an independent predictor of improvement of LV function after revascularization in a cohort of patients with severe LV dysfunction. Across tertiles of scar scores (small [0%-16%], moderate [16%-27.5%], and large [27.5%-45%]), the improvement in LV ejection fraction after revascularization was 9%, 3.7%, and 1.3%, respectively.45 A reverse mismatch pattern, where the myocardial perfusion is normal but the FDG uptake is low, may be observed in a few settings, including following revascularization early after MI, left bundle branch block, nonischemic cardiomyopathy, and diabetes. As perfusion is preserved, these regions are interpreted as being viable, although the prognostic significance of reverse mismatch remains unclear. However, there is some recent evidence suggesting that reverse mismatch may be a predictor of response to cardiac resynchronization therapy.46

Role of PET Viability Imaging to Guide Patient Management FDG-PET is currently considered the most sensitive means of detecting viable myocardium.2,33-35,47-49 For prediction of recovery of regional function after revascularization, a pooled analysis of 24 studies (756 patients) reports a weighted mean sensitivity and specificity of 92% and 63% and a positive predictive value and negative predictive value of 74% and 87%, respectively35 (Fig. 3). There are several observational studies that show increased risk for adverse events in patients with significant hibernating myocardium, who do not undergo timely revascularization, on FDG-PET images.33-35,50-53

Figure 3 Comparing sensitivities and specificities of the different techniques with 95% CIs for the prediction of recovery of regional function after revascularization. FDG-PET had the highest sensitivity and dobutamine echocardiography had the highest specificity than other methods (*P o 0.05). (Reprinted from Schinkel et al.35)

S.P. Lim et al. The usefulness of a PET-guided strategy for revascularization in patients with ischemic cardiomyopathy has been prospectively evaluated in a randomized controlled study, the PET and Recovery Following Revascularization 2 (PARR-2) study.54 PARR-2 was a multicenter study and included 430 patients with an LVEF r 35%, which was presumed to be because of suspected CAD, who were being considered for revascularization. Patients were randomized to undergo FDG-PET or to standard care to define the degree of scar and viability. Following the PET scan, a recommendation was rendered as part of the study regarding the potential benefit of revascularization to the treating physician (ie, revascularization or medical therapy), and patients were followed up for adverse events. The primary outcome was a composite of cardiac death, MI, or cardiac hospitalization at 1 year. At follow-up, the primary intention-to-treat analysis showed a hazard ratio of 0.78 (P ¼ 0.15) for the primary outcome of hospital admission for congestive HF, MI, or cardiac death in the PET group. The end point was achieved in 30% of the PETarm patients and 36% of those in the OMT arm. However, the revascularization recommendation, based on the PET results, was not adhered to in a significant number of patients. A post hoc analysis, including only PET patients who adhered to the imaging recommendations, showed that a significant reduction in adverse outcomes was observed in the PET arm.54 A further substudy of the PARR-2 data included only patients who were enrolled at a site with availability of an FDG tracer, significant cardiac PET experience, and a multidisciplinary approach to decision making. This substudy demonstrated significantly improved outcomes in the PET arm, which served to emphasize the importance of experience, the need to incorporate all available clinical information into PET interpretation, and for this to be conveyed clearly to the treating physician.55 There is an important relationship between viability defined by PET and revascularization, such that as the extent of hibernation increases, the likelihood of benefit from revascularization also increases.2 Inaba et al56 performed a meta-analysis that showed that FDG-PET had the lowest amount of viability needed to predict survival benefit. Another substudy of PARR2 trial performed by D'Egidio et al demonstrated that in patients who underwent revascularization with metabolicperfusion mismatch score of Z7% in PET imaging, there is a reduction in occurrence of adverse events. Di Carli et al50 and Lee et al53 used 5% and 7.6%, respectively, as the cutoff to define significant hibernation (Fig. 4). In addition to reducing adverse clinical events, a PET-guided strategy has been shown to improve HF symptoms and quality of life and has been found to be cost effective. A small study correlated the magnitude of improvement in functional class after revascularization to the preoperative extent of myocardial viability as assessed by FDG-PET.57 Subsequently, a small study demonstrated that patients with viable myocardium had an improvement in functional class, with no change in those without viability. Viability, as assessed by PET rather than by dobutamine echocardiography, was superior in this prediction.58

Myocardial viability

Figure 4 PET adherence group vs standard care arm in determining the clinical effect of 18F-FDG-PET viability studies in the PARR-2 trial. In the post hoc analysis, the ADHERE group that included only PET patients who adhered to the imaging recommendations showed a significant reduction in adverse outcomes when compared with the standard group. The hazard ratio for the ADHERE group was 0.62 (*95% CI: 0.42-0.93, P ¼ 0.019). (Reprinted with permission Elsevier and Beanlands et al.54)

In another substudy of PARR-2, FDG-PET–directed management improved quality of life, at least in the short term, with adherence to recommendations.59 An economic model was developed to compare the costeffectiveness of the following 3 management strategies: CABG, FDG-PET–guided imaging strategy, and medical therapy. It demonstrated that the FDG-PET–guided strategy was cost effective and that the prevalence of hibernation and the survival rate of patients who did not undergo revascularization, in spite of the PET results, were most likely to influence costeffectiveness.60 Single-Photon Emission Computed Tomography The radionuclides used in SPECT perfusion or viability imaging are thallium-201 (201Tl) and technetium-99m (99mTc). 201Tl-SPECT imaging was an early method in assessing myocardial viability and is still in use today. 201Tl is a potassium analogue that is actively taken up via the sarcolemmal Na-K adenosine triphosphatase pump. The initial uptake and washout of 201Tl in viable myocardium is directly proportional to blood flow. Almost 85% of 201Tl is absorbed by cardiac myocytes during its first pass. Washout of the 201Tl from the cells then occurs, which allows a second phase of uptake and reflects intact sarcolemmal function and thus cell integrity. Subsequently reuptake of 201Tl occurs after washout begins and reflects intact sarcolemmal and thus cell integrity. The process is slow, occurring between 4 and 24 hours after injection. A stress-redistribution protocol is used in many centers. Reinjection can be followed by reimaging at 3-4 hours or again at 24 hours, which improves uptake in areas of hibernation.61,62 A mismatch defect in the case of 201Tl also indicates the presence of hibernating myocardium. However, a matched defect has, unlike PET, 3 possible explanations: markedly reduced regional perfusion, impaired cellular membrane

365 integrity, or scar. Hence, a matched defect may reflect severe hypoperfusion and not necessarily a scar tissue.63 This is a distinct disadvantage when compared with PET. The sensitivity and the specificity of 201Tl-SPECT is similar to those of PET. However, in a large systematic review and meta-analysis, FDG-PET was found to be the most sensitive method35 (whereas dobutamine echocardiography was the most specific). 201Tl-SPECT's detection of viable myocardium can be further improved with the use of adjuvant glucose administration and combining rest-redistribution 201Tl and low-dose dobutamine contractility assessment.64-68 99m Tc SPECT is also used in the assessment of myocardial viability. 99mTc enters cells passively because of its lipophilic properties. Once it enters the cell, it binds to the mitochondria as a free cationic complex. The mitochondrial uptake of 99mTc requires oxidative metabolism and an intact mitochondrial membrane, thus serving as a marker of cell integrity and of myocardial viability.62 It has been thought that 99mTc SPECT tends to underestimate viability.26 However, a recent review has identified 8 studies that compared the performance of SPECT and PET for the assessment of viability. In this study, the sensitivity ranged from 59%-95% and the specificity from 79%-100%, with PET being considered the gold standard.69 However, there were significant differences between the studies, making the interpretation of the results difficult, such as variation in stress protocols, type of radiotracers used, and definitions of viability. 99m Tc SPECT has a less linear relation to flow and minimal redistributing properties compared with that of 201 Tl.70,71 There is a significantly greater extent of area identified as scar by 99mTc SPECT imaging when compared with FDG and CMR, with the greatest discrepancy being in the inferior and lateral LV walls.70 Nitroglycerin administration has been recommended to improve 99mTc uptake in the hibernating myocardium.72-74 Cardiac MRI CMR is becoming a powerful tool in the assessment of myocardial viability, and both delayed gadoliniumenhancement CMR and dobutamine stress CMR are used. CMR offers superior spatial and contrast resolution. Global and regional cardiac wall motion can be assessed using cine CMR imaging. In addition to its ability to determine myocardial viability, CMR can also evaluate the extent of proximal coronary artery atherosclerotic lesions, and ejection fraction.

Delayed Gadolinium Enhancement After injection, gadolinium leaks into the interstitial space of scar, which appears enhanced on a CMR image. The transmural extent of hyperenhancement on delayed gadolinium images determines the viability of each myocardial segment. Myocardium that does not enhance is considered viable.75 Owing to its superior spatial, contrast resolution and large intensity between hyperenhanced and unenhanced areas, CMR can define transmural variations in viability, which is not possible in nuclear imaging and echocardiography.76

366 Kim et al,76 in a landmark study, showed that the likelihood of improvement in regional contractility after revascularization decreased progressively as the extent of transmural viability increased. In this study, 90% of the regions with hyperenhancement of 51%-75% of tissue before revascularization did not improve after revascularization. Thus, this cutoff value is used for the extent of hyperenhancement to predict functional myocardial improvement. In a study, the prediction of regional and global functional improvement after revascularization seen on contrastenhanced CMR image is comparable with that seen on FDGPET images. In nonviable areas, CMR was superior in direct comparison with PET in predicting the lack of functional recovery.77 However, this study included only a very small number of patients with hibernating myocardium, which may have underestimated the value of FDG-PET imaging. It is noteworthy that the systematic review by Schinkel et al included FDG-PET and delayed enhancement-CMR, and as noted, FDG-PET was the most sensitive of all methods for predicting wall motion recovery. CMR's performance was intermediate among tests.35 A key physiological distinction is that CMR defines scar or viability.78 It also does not define hibernation per se, unless perfusion is also evaluated. However, perfusion defects with FDG uptake define hibernating myocardium, which is distinct from other forms of viable tissue (stunned or remodeled). This may explain the greater sensitivity of PET for viability reported previously.35 Conversely, a more recent meta-analysis by Romero et al reports high sensitivity and low specificity values in the range of FDG-PET imaging. End-diastolic wall thickness may also be useful with high sensitivity but has a very low specificity.79 Outcome studies for delayed enhancement CMR have been limited in comparison with the wealth of data for PET, but studies are emerging that indicate similar findings to the FDGPET literature that patients with viable myocardium who have undergone medical therapy or incomplete revascularization have worse outcomes than those with viability who are revascularized.80

Dobutamine Stress CMR Recently, dobutamine CMR combines low-dose dobutamine stress with the CMR technique, which offers evaluation of both scar and contractile reserve. This technique is particularly useful in cases with intermediate extent of transmural enhancement (25%-75%) seen on CMR images, where low-dose dobutamine is required to optimally define the likelihood of functional recovery after revascularization.81,82 The metaanalysis by Romero et al79 indicated a high specificity but lower sensitivity for dobutamine CMR, similar to the high specificity and low sensitivity of dobutamine echocardiography demonstrated by Schinkel et al.35 Myocardial tagging is another new technique used to enhance efficacy of dobutamine CMR, which allows better assessment for the changes in the midwall and subepicardial circumferential shortening in the prediction of cardiac functional improvement after revascularization.83

S.P. Lim et al. There are several limitations of CMR. This technique is costly and requires considerable expertise. Traditionally, there is a need for breath-holding sequences during acquisition, and an irregular heart rhythm results in suboptimal images. Some of these limitations have been reduced by techniques such as heart rate variability correction algorithm and non–breath-hold sequences.84,85 CMR has low temporal resolution especially when compared with echocardiography, but real-time cine imaging has improved this.86 CMR contraindications exist with ferromagnetic objects (eg, pacemakers, implantable cardioverter-defibrillators, and cerebral aneurysm clips) and severe claustrophobia. Gadolinium is contraindicated in patients with glomerular filtration rates o30 mL/min or patients undergoing dialysis, because of the small but important risk of nephrogenic systemic fibrosis.87 Dobutamine Echocardiography The basis for the use of dobutamine echocardiography is the improvement in wall motion and thickening or “contractile reserve” observed on echocardiography in response to dobutamine. Afridi et al88 found that a biphasic response is the best type of wall motion response in predicting recovery of myocardial function with dobutamine echocardiography. In a biphasic response, improvement in contractile performance is seen at lower doses (2.5 mg/kg/min), and deterioration of contractile function is seen when the metabolic demand is overwhelmed at higher doses (up to 40 mg/kg/min). In viable myocardium, an area with reduced wall thickening or motion at rest demonstrates improvement in contractile function when given low-dose dobutamine infusion. At a higher dose of dobutamine, ischemia ensues, resulting in renewed worsening of wall motion.88 Echocardiography is a widely available technique and does not involve ionizing radiation. It may be more specific for the prediction of recovery of regional function after revascularization when compared with other noninvasive imaging modalities, including PET.35 Thus, it is still used in many centers that do not have access to PET or CMR imaging to assess myocardial viability. However, there are certain limitations to this technique. It is largely operator dependent, and assessment can be limited in patients with obesity because of poor acoustic windows. The diagnostic accuracy of dobutamine echocardiography is also reduced with increasing severity of regional and global LV dysfunction. We have learned much about the pathophysiology of viability from dobutamine echocardiography. In transmural biopsies of hibernating myocardium with 417% fibrosis, there is failure of contractile reserve when challenged with lowdose dobutamine.89 This is consistent with clinical data showing that the accuracy of dobutamine echocardiography in predicting improvement of regional wall motion was poor in areas of severe reduction of wall motion.90 In this head-to-head comparison of PET vs dobutamine echocardiography with the gold standard being the improvement of dysfunctional segments by multi-gated acquisition scan, the more severe areas of

Myocardial viability function showed positive findings for FDG uptake but not for dobutamine infusion. PET performed much better, with a negative predictive value of 80% in akinetic segments. It is assumed that the more dyskinetic segments in this study had more fibrosis and loss of contractile apparatus. Which Technique to Use for Myocardial Hibernation Assessment? The amount of viable myocardium that predicts survival benefit with revascularization varies by imaging modality.56 In a meta-analysis of FDG-PET using amount of mismatch, stress echocardiography using contractile reserve, and SPECT (201Tl or 99mTc), the threshold was 25.8% (95% CI: 16.6%35.0%), 35.9% (95% CI: 31.6%-40.3%), and 38.7% (95% CI: 27.7%-49.7%), respectively.56 Each diagnostic modality assesses myocardial viability at a different point along the course of cell death, so the prediction for myocardial global and regional recovery needs to take this into account. Other factors such as the overall LV function and the degree of scar and patient comorbidities also need to be factored into the decision. In addition, the sensitivity and specificity of the test is important but are in part based on the patient population in which it was studied. Investigation of the current literature allows us to understand the performance characteristics of each test, but it must be interpreted carefully. There are unfortunately no head-to-head clinical trial data suggesting the optimum testing modality for determining the degree of hibernating myocardium. In the systematic review by Schinkel et al,35 a review of the noninvasive modalities of viability testing was undertaken. This is a highly cited work in the viability literature as it describes the pooled estimate for the sensitivity for prediction of improvement of regional and global LV function based on the available viability tests. It suggests that PET is the most sensitive viability test for prediction of outcome and that dobutamine echocardiography is the most specific. Guidelines exist for the pooling of diagnostic review studies. Included studies need to be looked at closely to determine their similarities and their potential for significant bias. Summary end points can be presented only once this examination is undertaken. There are many groups, including QUADAS and Cochrane,91,92 that suggest a detailed examination of studies and their potential biases be undertaken to be able to understand whether the patients in each study are similar enough to pool and obtain a summary point. Given that PET testing is generally accepted to have the highest sensitivity of the imaging modalities of the review mentioned earlier, the studies that have provided the summary point have been carefully reviewed.24,77,93-95 The largest included study is a systematic review published in 2001 containing 20 studies and 1532 patients. It contains the largest number of patients and has the narrowest CIs. The authors discuss limitations of their review, which includes the use different protocols and criteria for viability, the lack of use of a euglycemic clamp, and the use of 13N, 82Rb, and SPECT tracers for perfusion imaging.93 The age of this publication would need to be discussed before inclusion, as advances in medical,

367 surgical, and diagnostic testing as well as the author's concerns should cause hesitation in including the results of this review into a later one. Of the remaining 4 studies, none has the primary purpose to evaluate PET perfusion to improvement in LV function regionally or globally. The primary purpose in 1 study24 was to compare hibernation regions with their MBF,24 2 compared PET94,95 as 1 of 2 tests, and 1 compared PET-SPECT with LV function77 using CMR. CMR was the study used as the gold standard in 3 studies,77,94,95 and in 1 study, the gold standard was echocardiography and LV function by angiogram.24 The interpretation of the entry PET was not blinded or the information was missing in all cases. The included studies were not structured in a way that follow-up would be complete,24,77,94 and the unit of analysis was dysfunctional myocardial segments of revascularized vessels,95 severe myocardial dysfunction,24,77 or regions of infarction.94 The ejection fractions at study entry were 33%-42% and there were 21%-34% patients with diabetes24,77,95 and no reports on the number of patients with angina. A study included only postinfarction patients with open infarct-related arteries.94 The follow-up studies were completed at 4-6 months after revascularization in all cases. A study chose to report data at the cutoff FDG threshold at 470% as it gave the best prediction of recovery and the best sensitivity and specificity.24 The examination of these studies illustrates many of the issues with the nonrandomized literature on viability testing in PET and, by extension, on the remaining noninvasive modalities. The summary end point, as presented, combines the significant heterogeneity of the patient population, unit of analysis, and testing thresholds, which leads to difficult interpretation when choosing a viability test. The primary decision needs to be made on what the gold standard is for PET viability and other viability testing. Regional improvement of abnormal regions may not be the best gold standard for analysis of patient outcomes. It is more likely to be useful when the patient is used as the unit of analysis. In addition, the technique of the test or the threshold should be predetermined. It is only with rigorous techniques that we can understand the testing that we have and understand which test is best used in which patient. When the patient's late outcomes are used as the unit of analysis, in a subsequent meta-analysis a strong signal comes from the nonrandomized literature again, suggesting that the use of such testing reduces adverse outcomes. A review of patient outcomes after revascularization reveals that no matter which test is used, there is a reduction in late clinical events. The benefit was directly related to the magnitude of viable myocardium that was noted on testing. This study did not show any difference between methods of testing and demonstrated no difference in outcome if no viability was demonstrated.34 This brings up the discussion of not only what test is best to use but also which patient should undergo viability testing. It is important to understand the patient's risk of revascularization around testing. The test one orders depends in part on availability of the test as well as local expertise. A general approach to viability testing is noted in the flow diagram

S.P. Lim et al.

368 (Fig. 5).96 Some general principles for whom to refer and whom not to refer for viability imaging are noted in Tables 1 and 2.97-99 Randomized Controlled Trial Evidence in Viability Testing The role of viability testing has been defined primarily by a multitude of observational studies as described earlier. Overall, 2 randomized trials have been performed. Siebelink et al100 performed a small randomized controlled trial (RCT) of 103 patients that compared NH3/FDG-PET with MIBI-SPECT. PET was slightly better than SPECT but did not have statistically significant results. This study was too small to draw conclusions and had variable definitions of viability based on perfusion tracer uptake in the SPECT arm but did not consider the perfusion data in the PET arm. It also included many patients without severe LV dysfunction and had delays in revascularization, all of which could influence the outcome.100 PARR-2 is discussed earlier, essentially in 430 randomized patients; FDG-PET–directed treatment showed a trend for outcome benefit. Subsets of patients with high risk (where the severity of CAD was not known) had significant mortality benefit. When adherence to PET imaging recommendations was considered, significant outcome benefits could be achieved. In a subset of patients in a center with direct access to FDG, experience with cardiac PET, and a multidisciplinary team approach did better when FDG-PET was used to inform care.2,55

Table 1 Who Do I Send for FDG Viability Imaging? Known or strongly suspected IHD 4NHYA II Moderate to severe LV dysfunction (EF r 40%) Moderate to large persistent perfusion defects—no significant ischemia The presence of significant comorbidities or poor distal targets Equivocal viability results on another test EF, ejection fraction; IHD, ischemic heart disease; NHYA, New York Heart Association. (Adapted with permission from Mc Ardle and Beanlands96 and Beanlands et al.116)

More recently, the benefit of imaging to define the extent of viability has been called into question following the publication of the STICH viability substudy. The main STICH study was the first prospective, international multicenter controlled trial testing the hypothesis that CABG improved survival when compared with aggressive medical therapy. It randomized 1212 patients who were amenable to CABG with ischemic LV dysfunction to either CABG or OMT vs OMT. Although the primary intention-to-treat analysis failed to show an overall benefit of CABG over medical therapy, the as-treated analysis did show a mortality reduction in patients who underwent CABG.21,101,102 This trial generated significant controversy, which still exists in the literature. There was strong criticism of the trial's methodology. Most patients had angina, not dyspnea, as a

Figure 5 Flow diagram with a suggested algorithm for viability testing. CRT, cardiac resynchronization therapy; EF, ejection fraction; ICD, implantable cardiac defibrillator; NYHA, New York Heart Association; PCI, percutaneous coronary intervention. †The required indications for 18F-FDG-PET imaging in Ontario. **In young patients, consider nonionizing imaging techniques. (Adapted with permission from McArdle et al.96)

Myocardial viability

369

Table 2 Who Does Not Need Viability Imaging? Predominantly angina CCS Z II Normal or mild LV dysfunction Critical left mainstem coronary disease Good targets Documented moderate or severe ischemia Minimal or no comorbidities CCS, Canadian Cardiovascular Society. (Adapted with permission from Mc Ardle and Beanlands96

predominant symptom and most patients were New York Heart Association Class I-II. There was a poor recruitment rate with only 2 patients per site per year. Significant crossover rates occurred between the study groups (17% of the medical therapy group underwent CABG and 9% patients who were assigned to CABG never underwent surgery), which may have reduced the benefits of the CABG arm in the primary intention-to-treat analysis. Patients with left mainstem disease were excluded, which is a group in which revascularization would have shown a survival benefit. In the OMT group, 6% of them had percutaneous coronary intervention but it was not counted as revascularization. In spite of the limitations of this trial, STICH was a well-run trial. Patients assigned to CABG underwent surgery at a median interval of only 10 days after randomization. OMT was ensured by oversight committees, and participating surgeons were required to demonstrate surgical expertise, having o5% operative mortality. Given the size of this study, only o1% patients were lost to followup.30 Although the original design of the STICH study specified that all patients were to undergo viability testing before randomization, the protocol was changed because of slow recruitment. Therefore, only a proportion of patients underwent viability testing, and this was performed at the discretion of the treating physician. For the substudy, viability was assessed using either SPECT or dobutamine echocardiography and patients were classified as either having significant viability or not, and not by the amount of viability. The thresholds used were controversial and different between both the diagnostic tests. In total, 601 patients underwent viability testing, of whom 81% had significant viability and a small number, 19%, had no viability at all.103 The results showed that patients

with viability had a lower mortality rate on univariate analysis (hazard ratio ¼ 0.64, P ¼ 0.003), but this was no longer significant when adjusted for other baseline clinical variables. The authors found no relationship between viability status and either randomized treatment group or treatment received. However, there are several limitations to this study as well. Firstly, the decision to perform viability testing was not part of randomization and was made by the treating physician and therefore there may be a degree of selection bias. In addition, the patients in the STICH trial had already been defined as suitable candidates for CABG before enrollment, contrary to PARR-2, where the decision regarding treatment had not yet been made. Therefore, the patient population has a low prevalence of multivessel disease, previous CABG surgery, and other comorbidities, such as renal dysfunction, when compared with other studies such as PARR-2.104 In clinical practice, patients eligible for STICH do not need viability testing as they are already good surgical candidates (Table 3). Finally, the imaging modalities used in the study, SPECT and dobutamine echocardiography, are less sensitive for hibernating myocardium than FDG-PET or CMR are. As described earlier, the outcome benefit from revascularization is driven more by the presence of hibernation than simply viability as a whole and this should be borne in mind when interpreting these results. Ongoing Trials STICH-Extended Study. This is a follow-up of STICH patients currently being performed to assess if longer followup can confirm or refute the nonsignificant trend seen in the original study. IMAGE-HF (Imaging Modalities to Assist With Guiding Therapy and the Evaluation of Patients With HF) Study. Of the 3 IMAGE-HF RCTs, 1 is enrolling patients who are being assessed for either ischemia or hibernation or both. This is a collaborative Canadian-Finnish–funded study (soon to include sites in the United States and South America) including patients with LV dysfunction and CAD, who are assessed by PET/CT or CMR and compared with SPECT imaging to determine myocardial ischemia vs hibernation. The

Table 3 STICH Viability Study Compared With PARR-2 Data STICH

PARR-2

Patient population

Accepted for revascularization 75% Multivessel disease 25% Single vessel disease 7.5% Renal disease 3% Before CABG

Decisions about revascularization uncertain 90% Multivessel disease among patients observed with angiography 34% Renal disease 19% Before CABG

Viability testing

SPECT or dobutamine echo 81% Viable

FDG-PET vs standard care 22% Viable by mismatch cutoff

Assessed ischemia or hibernation

Dobutamine echo: yes—hibernation SPECT: no—relative uptake

FDG-PET: yes—hibernation

Ischemia was not assessed in the original STICH viability substudy,103 but was studied separately in an ischemia substudy.114 Reprinted with permission from Mielniczuk et al.104

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370 outcomes include composite clinical end points (cardiac death, MI, cardiac arrest, and hospitalization), quality of life, cost, resource utilization, and safety.105 Viability imaging is of greatest value in patients in whom the risks of surgery are higher (ie, patients with poor target vessels, previous surgery, and multiple comorbidities) because it is in these patients where the potential benefits of revascularization may also be the highest. In these complex patients, the current evidence would suggest that the use of a more advanced imaging modality such as PET or CMR, where available, may yield better results. However, these hypotheses required further validation and are the focus of the ongoing mulitcenter, multiarm trials, for example, IMAGE HF study.105 Cardiac 18F-FDG-PET Viability Registry (CADRE). The aim of this study was to evaluate the use of FDG-PET viability imaging in the decision-making process for patients with reduced LV function who may be candidates for revascularization and to study the downstream effect of the clinical management decisions.106

New Concepts in Viability Imaging to Direct Device Therapy Cardiac sympathetic neuronal dysfunction has been shown to be abnormal in viable myocardium.107 The Prediction of Arrhythmic Events With PET trial has shown that the extent of denervation determined by 11C hydroxyephedrine PET is an independent predictor of cardiac arrest in patients with CAD and HF.108 These interesting findings suggest that the neurohormonal and viability-hibernation imaging may play complimentary roles in defining patients at risk needing an intervention. There is some recent evidence suggesting that reverse mismatch seen in perfusion or FDG-PET with the extent of lateral scar and viability can be used to predict outcome response in patients undergoing cardiac resynchronization therapy.46,109-111

Role of Ischemia in Managing Patients With Viability Furthermore, for consideration is the role between reversible ischemia, hibernation, and outcome benefit from revascularization. There are data on patients without LV dysfunction that support revascularization instead of medical therapy. Patients with significant ischemia (410%) and without extensive scar on SPECT stress perfusion imaging realized a survival benefit from early revascularization,4 and the nuclear substudy of the Clinical Outcomes Using Revascularization and Aggressive Drug Evaluation trial demonstrated that patients with at least moderate ischemia who had a significant reduction in ischemic burden on repeat testing had better clinical outcomes.112 The Bypass Angioplasty Revascularization Investigation 2 Diabetes, a randomized trial using SPECT, showed that LV function, reduction of ischemia by revascularization, and extent of scar at 1 year are important predictors of patient outcome.113

More recently, an observational prospective study, using stress-rest 82Rb and FDG-PET, showed a relationship between 410% LV hibernating myocardium and revascularization, which conferred survival benefit.5 There are few data suggesting that there is a clear mortality benefit in patients with normal or mildly reduced LV function. A STICH substudy of 399 patients evaluated the prognostic value of inducible ischemia. The decision to perform ischemia testing was made by the treating physician and there was heterogeneity in the imaging modality used: exercise or pharmacologic stress SPECT or dobutamine echocardiography. The results showed no effect of ischemia in either arm on mortality or treatment allocation.114 By contrast, an observational study5 evaluated the effect of both ischemia and hibernation and survival benefit from revascularization as defined on stress-rest 82Rb and rest FDG-PET imaging in 648 patients. They demonstrated that patients who had significant hibernation had better survival if they underwent early revascularization. There was no such finding with ischemia alone. The role of ischemia to predict outcome and to guide subsequent therapy in patients with severe LV dysfunction may not be as clearly defined. Patients with severe LV dysfunction and significant scar and viability are at one end of the coronary disease spectrum, whereas patients with angina, significant coronary disease, and normal LV function are at the other end. In the middle are the patients having some degree of LV dysfunction, a mixture of hibernating myocardium, and evidence of ischemia or symptoms of angina or both. The latter group is known to derive benefit from revascularization since the time of the Coronary Artery Surgery Study trials, allowing an easier revascularization decision. The benefit of revascularization in these patients is thought to result from improved perfusion of myocardial territories at risk, preventing future plaque rupture, cell death, and subsequent adverse events.104,115 One author reviewing the discordant literature on the role of ischemia in the prognosis of patients with ischemic cardiomyopathy feels that the more extensive the CAD and the more potential areas for viable myocardium, the more important viability testing becomes, and in the patients who have less severe coronary disease, the more important is ischemia testing.30 When a patient has LV dysfunction, no angina, and HF symptoms and requires workup, functional testing to assess for ischemia should be considered. It is when such testing shows large areas of possible scar (persistent perfusion defects at stress and rest), without moderate ischemia, that viability should be considered.97

Conclusions In deciding on the best treatment strategy for patients with ischemic cardiomyopathy, the benefits and risks of revascularization must be carefully evaluated. Viability, and subsequently hibernation, is only one of the predictors of outcome benefit from revascularization in these patients. Other predictors include extent of ischemia, scar, LVEF, and renal

Myocardial viability function. There are other issues that may affect patient outcomes, such as health care costs, quality of life, and arrhythmia benefits. In the absence of definitive prospective randomized data on the benefit viability testing in guiding the management of patients with ischemic cardiomyopathy, it is likely that physicians would continue to use viability testing in assisting them with their decision-making process. Imaging modalities available for viability testing should be seen as complementary rather than competing methods. Indications, comorbidities, availability, local expertise, sensitivity or specificity, and limitations of each modality should be taken into account in determining which modality is the best test to choose in a given clinical setting. In view of the lack of direct comparative evidence, where advanced modalities are available (PET and MRI), they are generally regarded as the preferred choice because of their overall higher accuracy. The patients who benefit most from viability imaging are likely those with highest risks where decisions are most difficult (patients with known or strongly suspected CAD, moderate to severe LV dysfunction, moderate to large persistent perfusion defects with no significant ischemia, and significant comorbidities). Focus needs to be placed on value-based imaging with careful selection of patients, standardization of our techniques or protocols, and continuation to strive for highquality research studies.

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