Radionuclide Imaging of Viable Myocardium: Is it Underutilized?
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- Mylonas, I. & Beanlands, R.S.B. Curr Cardiovasc Imaging Rep (2011) 4: 251. doi:10.1007/s12410-011-9074-8
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Coronary artery disease is the major cause of heart failure in North America. Viability assessment is important as it aims to identify patients who stand to benefit from coronary revascularization. Radionuclide modalities currently used in the assessment of viability include 201Tl SPECT, 99mTc-based SPECT imaging, and 18F-fluorodexoyglucose (18F-FDG)-PET imaging. Different advances have been made in the last year to improve the sensitivity and specificity of these modalities. In addition, the optimum amount of viable (yet dysfunctional) myocardium is important to identify in patients, as a risk–benefit ratio must be considered. Patients with predominantly viable/hibernating myocardium can benefit from revascularization from a mortality and morbidity standpoint. However, in patients with minimal viability (predominantly scarred myocardium), revascularization risk may certainly be too high to justify revascularization without expected benefit. Understanding different radionuclide modalities and new developments in the assessment of viability in ischemic heart failure patients is the focus of this discussion.
Coronary artery disease (CAD) is a major cause of heart failure due to depressed left ventricular (LV) function. As such, myocardial viability is an important question one must answer in predicting outcomes and assessing treatment options. Although results of recent randomized trials such as STICH  are still pending, best evidence supports improved clinical outcomes after revascularization in patients with impaired LV function and evidence of myocardial viability [2••, 3–5]. On the other hand, patients without evidence of viable myocardium may not gain the same benefit with revascularization. Thus the clinician must carefully select the patients that will benefit from coronary revascularization as patients with impaired LV function have increased procedurally related morbidity and mortality [1, 6].
There are currently many methods used to estimate myocardial viability, of which radionuclide methods are the most sensitive. Among these, SPECT methods are widely available and include thallium-201 single photon emission tomography (201Tl SPECT) and the use of technetium-99 (99mTc)–based SPECT imaging. Fluorine-18-fluorodeoxy-glucose (18F-FDG) positron emission tomography (PET) imaging has also been used where PET is available. The aim of this discussion will be to review the radionuclide imaging modalities used in the assessment of viability and highlight new findings and developments in this field.
It is important to describe the term “viability” in the capacity and spectrum of heart failure and coronary artery disease. Viability can broadly be described as “living myocardium.” However, in imaging when we are discussing viable myocardium, we are most interested in whether dysfunctional myocardium is alive (and potentially recoverable) or dead (necrotic or scar and not recoverable). Dysfunctional but viable myocardium usually refers to regions that may be either “stunned” or “hibernating.”
Stunning refers to a state of LV dysfunction that persists following an episode of ischemia after restoration of normal coronary blood flow. This may last minutes to hours following an episode of transient ischemia as may occur during exercise, or days to weeks following reperfusion of a transiently occluded coronary artery [7, 8]. The time of recovery depends on the duration, severity, and size of the ischemic insult.
Hibernation refers to metabolic downregulation of myocardium in response to a reduced state of myocardial perfusion . Physiologically there is a decreased coronary flow reserve, with severe cases exhibiting a reduction of resting flow [10, 11]. There is evidence to suggest that hibernation is the result of repetitive stunning; that is repeated ischemic insults that occur while the myocardium is still stunned. Thus, it is part of the continuum from ischemia to cell death . In patients with heart failure and chronic LV dysfunction, improvements in ejection fraction (EF), end-diastolic and end-systolic volumes, and restoration of LV geometry are possible through coronary revascularization . Most importantly, however, revascularization of hibernating myocardium may result in improved prognosis [2••, 3]. It is for these reasons that viable myocardium must be closely investigated through viability testing.
201Tl SPECT imaging is the oldest and most common method of assessing myocardial ischemia. It is also well established as a means of measuring myocardial viability. Traditional viability assessment using 201Tl may be accomplished by various protocols which universally utilize the favorable kinetics of thallium-201. The initial myocardial uptake early after intravenous injection of thallium is proportional to regional blood flow. However, redistribution of 201Tl is related to the rate of 201Tl “washout” from the myocardium, dependant on the concentration gradient between myocytes and the thallium concentrations in the blood and the integrity of the membrane-based Na+/K+ ATPase pump [7, 14–17]. As a potassium analogue 201Tl uptake, retention, and washout are partly dependent on this pump and therefore the integrity of the cell membrane. Loss of membrane integrity is indicative of cell death. Therefore, in regions of reduced initial uptake (indicating reduced flow), 201Tl washout is slower in regions that are viable because the myocardium is able retain the tracer and take up circulating 201Tl via the intact membrane transport. The corollary is that when there is necrosis or scar, there is no mechanism to retain or take up 201Tl and hence washout is more rapid. On imaging, the former is seen as redistribution indicating viability; while in the latter, a persistent fixed defect indicates a region with loss of viability.
Recent efforts have been focused on improving the ability of 201Tl SPECT imaging to detect viable myocardium. Adjuvant glucose administration has been proposed. A number of studies using either glucose or glucose-insulin-potassium (GIK) infusion have been published showing that 201Tl uptake is enhanced, thus improving detection of viable segments [23–25]. Since 201Tl and potassium possess similar kinetics, glucose administration will increase endogenous insulin release, thus ultimately acting to increase uptake of 201Tl in myocardial cells. Hasbek et al.  recently demonstrated the benefit of oral glucose administration with 201Tl. Using nondiabetic patients, they performed rest-redistribution-24 h late SPECT. When a perfusion defect was observed, 1 mCi of 201Tl was given 30 min after a 75-g oral glucose load upon completion of the 24-hour late SPECT. Repeat imaging was then performed. Glucose plus 201Tl images yielded the lowest number of perfusion defects, and showed the highest segmental perfusion improvement. The authors also found that ECG-gated in the EF calculations after oral glucose administration were significantly higher compared to EF calculations prior to glucose, attributed to both enhanced 201Tl uptake and improvement in wall detection in segments with perfusion defects . In summary, 201Tl uptake can be enhanced by oral glucose administration and the detection of viable myocardium may be improved through a simple oral glucose administration protocol that is applicable to routine daily clinical practice.
Heiba et al.  recently published a study using a protocol combining rest-redistribution with 201Tl and low-dose dobutamine contractility assessment. Data for perfusion were obtained first by a single rest injection of 201Tl with gated SPECT image acquisition. Then 4-hour delayed gated SPECT images were acquired during dobutamine infusion. Segments were analyzed for rest-redistribution 201Tl perfusion (normal, reversible, and fixed decreased perfusion) and wall motion and/or wall-thickening difference (normal, fixed dysfunctional, improved dysfunctional contractility) with low-dose dobutamine. Furthermore, segments with a fixed decrease in 201Tl uptake were subclassified into mild, moderate, and severe fixed segments. In this study, over half of the dysfunctional segments with either a mild to moderate fixed decrease in thallium uptake showed evidence of improved wall motion or wall thickening. Only 30% of the segments with a severe fixed defect on redistribution showed improvement. Using this protocol the authors could obtain complementary data regarding myocardial viability. Using not only perfusion-redistribution data, contractile reserve and regional contractility could simultaneously be assessed adding to the functional characterization of viable myocardium. Perceived nonviable myocardium on 201Tl imaging may actually have viable tissue identified with low-dose dobutamine potentially improving the prediction of patient outcomes and impacting management decisions. Another attractive feature is the routine ease of administration of low-dose dobutamine in the clinical setting. There is no additional 201Tl injection or extra imaging time, making this protocol particularly attractive.
Thallium imaging remains the most utilized method for assessing myocardial viability. Important strides in research have been made to improve its specificity as highlighted above. However, other radionuclide modalities as well have also made important advances in the assessment of myocardial viability.
99mTc-based radiopharmaceuticals currently available and used in daily clinical practice include sestamibi and tetrofosmin. To briefly review, they are lipid-soluble compounds that cross membranes through passive diffusion driven by the transmembrane electrochemical gradient ultimately being retained within the mitochondria of the myocyte . In comparison to 201Tl, 99mTc-based radiopharmaceuticals have a higher energy spectrum (140 vs 80 keV) and shorter half-life (enabling a higher dose) which can serve to improve image quality; but have a worse relationship to flow and minimal redistributing properties. However, mitochondrial uptake of these compounds requires an intact mitochondrial membrane and oxidative metabolism, thus the basis for sensitive viability detection [27–29]. A complete review of the properties and pharmacokinetics of 99mTc-based radiopharmaceuticals is available in any major textbook .
In prior studies, extent of myocardial scar has been consistently overestimated using 99mTc compared to 201Tl [31–33]. A recent study by Crean et al.  comparing 18F-FDG, cardiac magnetic resonance imaging (CMR), and 99mTc-sestamibi (MIBI) found that a significantly higher number of segments were identified as scar by MIBI than by either 18F-FDG or CMR. The greatest discrepancy between MIBI and 18F-FDG and MRI was in detection of scar of the inferior and lateral wall. By the same token, nitrate (sublingual or intravenous) administration prior to MIBI imaging has been proposed to increase ability to detect myocardial viability while performing perfusion imaging. The exact mechanism is not well understood; however, it is theorized that nitrates improve myocardial blood flow to hypoperfused myocardial segments by dilating stenotic epicardial arteries. This may enable increased blood flow through collateral vessels to ischemic segments .
Outcome data of eight reviewed 99mTc-based SPECT studies for viability
Follow-up (mean, months)
Viability and outcome
Risk ratio (95% CI)
Basu et al.
Cardiac death, nonfatal MI, unstable angina, CHF
Reversible perfusion defects
Sciagra et al.
Cardiac death, nonfatal MI
Number of viable non-revascularized asynergic segments
Senior et al.
Revascularization and >4 viable segments
Kostkiewicz et al.
Cardiac death, nonfatal MI, repeat revascularization
Number of viable non-revascularized segments
He et al.
Cardiac death, nonfatal MI
Number of viable segments
Bosevski et al.
Acampa et al.
Cardiac death, nonfatal MI, late revascularization
Extent of viability
Sorrentino et al.
Cardiac death, nonfatal MI, late revascularization
Evangelista et al.
Cardiac death, nonfatal MI, late revascularization
Administration of nitrates is easy, affordable, and effective in SPECT-assisted imaging for myocardial viability. Although scar-based quantitative and qualitative assessment may differ, patient outcomes and management decisions may not significantly be altered.
Cardiac PET utilizing 18F-FDG is considered the most sensitive modality for detecting hibernating viable myocardium. The premise behind 18F-FDG viability imaging relies on basic cardiac physiology during ischemia/injury. Under aerobic conditions and the fasting state, the preferential energy substrate of the heart is fatty acids. However, under conditions of ischemia or injury when oxidative metabolism is compromised, free fatty acid utilization is impaired, while glucose utilization is increased. Increased cardiac glucose utilization is also seen following an oral carbohydrate load. 18F-FDG is a glucose analog, which is transported into cells though glucose membrane transporters GLUT1 and GLUT4, and subsequently phosphorylated by hexokinase to 18F-FDG-6-phosphate. FDG does not undergo any further metabolism (unlike glucose) and essentially is trapped within the cell as 18F-FDG-6-phosphate. Trapped 18F-FDG accumulates and becomes an index of cellular glucose utilization and hence ongoing cellular metabolism .
There are two key patterns of clinical significance identifying either scar or hibernating, viable myocardium. A match pattern is an equivalent reduction in perfusion and FDG uptake (reduced or absent glucose metabolism), thus signifying myocardial scar. Conversely, a mismatch pattern is a visible reduction in perfusion with preserved uptake of FDG, signifying glucose metabolism and thus viability. There is another pattern of preserved perfusion, yet reduced glucose metabolism on PET viability imaging described as “reverse mismatch” and likely represents viable myocardium. This pattern may be seen in left bundle branch block, nonischemic cardiomyopathy, or diabetes; and may be relevant in patients being considered for resynchronization therapy [44, 45].
Currently, 18F-FDG PET is considered the most sensitive means of assessing viable myocardium and hence predicting LV functional recovery post–coronary revascularization [2••, 4, 5, 46••, 47–54]. Prior observational outcome studies have suggested that 18F-FDG PET can help identify patients at high risk for cardiac events . The PET and Recovery Following Revascularization (PARR 2) randomized controlled trial of 430 patients investigated patients with an EF < 35% and suspected or confirmed CAD, who were considered for revascularization, transplant, or heart failure work-up. A standardized clinical report was produced by the interpreting physician detailing the amount of scar, viable myocardium, and degree of mismatch. The results along with the perceived likelihood of recovery were conveyed to the treating physician and a decision was made on an individual basis. PET-assisted decision-making compared to standard care showed a trend but did not reach statistical significance with respect to the primary composite end point (cardiac death, myocardial infarction, or recurrent hospital admission for cardiac causes). However, a post hoc analysis of the data was performed investigating adherence to PET recommendations. When management adhered to the imaging recommendations, a significant reduction in adverse outcomes was observed in the PET arm .
Optimal cutoff values for the presence of viability leading to improved survival with revascularization over medical therapy
Imaging techniques (number of studies)
Mean viable myocardium (SD),%
Optimal threshold for viability,%
PET overall (n = 7)
PET with FDG/NH3 (n = 3)
PET with FDG/99mTc (n = 3)
Stress echo overall (n = 8)
Stress echo with LDDE (n = 4)
Stress echo with HDDE (n = 2)
SPECT overall (n = 6)
SPECT with 201T1 (n = 5)
With more data and ongoing investigation, 18F-FDG PET imaging will likely continue to be a key modality into the investigation of myocardial viability. Image quality and confidence in interpretation is high with PET imaging, and this can be attributed to many factors, such as camera technology, attenuation correction techniques, and the pathophysiology of hibernation and its effect on FDG/glucose metabolism among others. However, a very important question is how PET data, imaging, and interpretation can impact clinical outcomes in comparison to SPECT imaging. Outcome comparison studies are limited to date but a multicenter randomized trial is now underway (IMAGE-HF), which will evaluate and compare heart failure patients using 18F-FDG PET, SPECT, and CMR, and how relevant clinical decisions and outcomes are impacted  by the different approaches.
Comparison to Other Viability Modalities
Other modalities commonly used to assess myocardial viability include low-dose dobutamine stress echocardiography (LD-DSE) and cardiac MRI. The basic premise behind LD-DSE is that it induces contractility as an expression of the contractile reserve of dysfunctional yet viable myocardium, displaying a biphasic response. At low-dose dobutamine (5 mg/kg), there is recruitment of contractile reserve with improvement in wall motion and thickening. However, at higher doses of dobutamine, wall motion becomes impaired due to stress-induced subendocardial ischemia . If, however, a territory is nonviable and consists mostly of scar, there will be relatively little to no improvement in wall motion with dobutamine. In a meta-analysis that included 1421 patients from 41 studies who underwent LD-DSE, and also compared 201Tl SPECT, 18F-FDG PET, 99mTc-based SPECT, and CMR, specificity was highest for LD-DSE but LD-DSE had reduced sensitivity compared to radionuclide methods [46••]. Observational outcome studies and a systematic review that included 1645 patients from 10 studies have demonstrated that LD-DSE also identified patients with viable myocardium who had a high risk for cardiac events if they did not undergo revascularization, although the increment of this risk did not appear to be as great as it was with 18F-FDG PET [46••]. In the work by Inaba et al. [56••], 35.9% (CI = 31.6–40.3) of the LV had to be viable using LD-DSE to predict a survival benefit with revascularization in comparison to standard medical therapy (Table 2).
There are two common methods to assess viability via CMR: dobutamine stress CMR, which uses the same principles as dobutamine echocardiography, and delayed enhancement CMR (DE-CMR), which takes advantage of the kinetic properties of contrast to identify regions of scar. Pooled data report the sensitivity and specificity of dobutamine stress CMR in the detection of viable myocardium to be 91% and 94%, respectively, and DE-CMR a sensitivity of 81% and specificity of 83% . DE-CMR has been used to predict functional LV recovery after acute myocardial infarction , predict functional LV response to myocardial revascularization in patients with chronic ischemic heart disease [63, 64], and predict response to medical therapy in patients with LV dysfunction . In a comparison of 18F-FDG SPECT, 99mTc-SPECT, and DE-CMR, there was a close correlation between 18F-FDG and DE-CMR techniques, although 99mTc- SPECT overestimated the amount of scar . In another similar study investigating myocardial viability in 60 patients with severe ischemic LV dysfunction, correlation was good between 18F-FDG SPECT and DE-CMR; however, this was limited to segments with either transmural scar or no scar tissue at all . In segments with nontransmural or subendocardial scar agreement was lacking. In a meta-analysis that included 421 patients from 13 studies who underwent cMRI, and compared 201Tl SPECT, 18F-FDG PET, 99mTc-based SPECT, and LD-DSE, prediction of functional recovery after revascularization appeared comparable to Tc-99 m–based SPECT but was not as sensitive as 18F-FDG PET nor as specific as LD-DSE [46••]. While outcome studies have been done with CMR, they are limited in number and do not focus on patients with the most severe LV dysfunction where viability is most relevant. In the study by Inaba et al. [56••] 25.8 (CI = 16.6–35.5) of the LV had to be viable using PET to predict a survival benefit with revascularization in comparison to standard medical therapy (Table 2).
Although each modality attempts to assess myocardial viability in a different manner (ie, radiotracer uptake reflecting cell integrity, contractile reserve, delayed gadolinium enhancement), these modalities strive to provide the same basic information: is the tissue viable or not? They should not be viewed as competing modalities. Instead, these modalities should be viewed as complementary methods evaluating different aspects of the same problem. A clinician now has a wide variety of modalities to choose from, selecting the most appropriate for the patient and taking into account desire for sensitivity or specificity, comorbidities, indications, contraindications, availability, and local expertise . Studies such as IMAGE HF will help to ascertain which methods are most suitable for which types of patient .
Current American College of Cardiology (ACC) published guidelines on heart failure (ACC-focused update 2009 of 2005 guidelines) assign a IIa recommendation to viability assessment in patients with heart failure, known CAD, and the absence of angina. Additionally, they suggest that further studies are needed to determine the usefulness of routine myocardial viability assessment in patients with ischemic-LV dysfunction in the absence of angina . However, the Canadian Cardiovascular Society (CCS guidelines 2006) states as a class I indication that patients with large areas of viability should be evaluated for revascularization . The joint appropriateness criteria published by the ACCF/ASNC/ACR/ASE/SCCT/SCMR/SNM in 2009 assign an appropriate use score of 9 (highest indication) for assessment of myocardial viability in ischemic cardiomyopathy patients with reduced LV function . The CCS/CAR/CANM/CNCS/CanSCMR joint position statement on advanced noninvasive imaging strongly supports (class I recommendation) the use of cardiac PET and CMR in the evaluation and prognostication of patients with ischemic cardiomyopathy and LV dysfunction .
Radionuclide myocardial viability imaging has continually grown together with the concept of hibernation and stunning. As we learn more about the pathophysiologic mechanisms behind myocardial viability, research is being directed into understanding the clinical ramifications of the data, interpretations, and clinical recommendations that these modalities provide. As discussed above, there is credible evidence that in patients with moderate to severe LV dysfunction, myocardial viability is best treated with revascularization for survival benefit. Also, given recent studies [2••, 56••], we are learning more about the optimal amount of viable myocardium in order to yield a positive outcome benefit. However, many more issues remain unanswered that impact patient outcomes. Issues such as quality of life, arrhythmic benefit, CCS and NYHA class of symptoms, and health care costs are also important but remain under-investigated. Many physicians may avoid radionuclide viability imaging based on preconceptions that either no benefit can be obtained in LV dysfunction, or that benefit is achieved with revascularization regardless of the presence of viability. However, as previously shown, there is a considerable increase in risk of stroke and death in patients with severe LV dysfunction undergoing revascularization (post–coronary artery bypass surgery outcome in 30 days: stroke ~3%, death ~5%) .
The decision to proceed with revascularization should be a carefully educated clinical decision that takes into account evidence, advantages, disadvantages, and risk. Radionuclide imaging can help detect, quantify, and risk stratify patients who will likely benefit from revascularization. In other patients, radionuclide imaging can help prevent unnecessary intervention risk that can lead to poor clinical outcomes.
Although methods such as CMR have become popular despite the lack of outcome studies, the strength of the data and the large number of prior outcome studies suggest that radionuclide methods should be used more widely when there is a question regarding viability. Given the benefits of radionuclide imaging methods for myocardial viability (in particular their sensitivity), the range of modality options, and their widespread availability, they should be applied more routinely in patients with ischemic cardiomyopathy where revascularization is an option.
Dr. Beanlands is a Career Investigator supported by the Heart and Stroke Foundation of Ontario (HSFO). Dr. Mylonas is a Clinical/Research Fellow supported by the Vered-Beanlands Cardiology Endowed Research Fellowship, the Division of Cardiology, University of Ottawa Heart Institute, and the Molecular Function and Imaging (MFI) Program (HSFO program grant # PRG6242). The project was supported in part by the MFI HSFO program grant and IMAGE Heart Failure Team (Canadian Institutes for Health Research).
I. Mylonas: none; R.S.B. Beanlands: consultant for DraxImage and Lantheus Medical Imaging and has received grant funding from a government/industry program (partners: GE Healthcare and MDSNordion).
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