Although the mortality associated with ischemic heart disease has significantly declined due to therapeutic improvements and prevention campaigns reducing the incidence of myocardial infarction (MI), ischemic heart disease remains the principal cause of heart failure and death in adults in developed countries, and its prevalence will continue to increase as the population ages and life expectancy increases.1–3 Ischemic heart failure (IHF) poses an enormous medical and financial burden on our society, and the prognosis of these patients is significantly worse than patients with nonischemic heart failure.4 The onset of heart failure in coronary artery disease (CAD) patients may be abrupt (eg, after acute MI) or may be insidious (due to chronic or repeated ischemia). Those patients have single or multivessel CAD and typically present with dilated ventricles showing focal or more generalized ventricular dysfunction.5 The histologic substrate of a dysfunctional myocardium, however, can consist of nonviable (ie, necrotic or scarred) and/or viable (ie, stunned, ischemic, hibernating) myocardium. On the basis of observational and retrospective studies, showing beneficial effects of coronary artery revascularization on a viable myocardium leading to (i) improved regional and global ventricular function, (ii) reversal of the adverse remodeling process, (iii) improved exercise capacity, and (iv) decreased symptoms of heart failure, myocardial viability assessment has become an important tool in therapy planning of patients with IHF.6–8 Myocardial viability can be assessed by analyzing/evaluating myocardial wall thickness, myocardial contractile reserve, myocyte cellular integrity, myocardial metabolism, and myocardial extracellular distribution volume. Although these “viability” parameters can be evaluated by a myriad of noninvasive imaging modalities such as dobutamine stress echocardiography (DSE), nuclear imaging (single photon emission computed tomography [SPECT] and positron emission tomography [PET]), cardiovascular computed tomography (CCT), and cardiovascular magnetic resonance imaging (CMR), it should be emphasized that none of them are perfect to predict or rule out functional recovery after revascularization. Moreover, the recent publication of the first prospective randomized trials of myocardial viability assessment has questioned the value of preprocedural viability imaging. In the multicenter Surgical Treatment for Ischemic Heart Failure (STICH) trial, in which viability of nearly half of the enrolled patients (601 of 1212 patients) was determined by means of DSE and/or SPECT, assessment of myocardial viability did not identify patients with a differential survival benefit from coronary artery bypass graft (CABG), as compared with medical therapy alone.9 In line with the study of Bonow and colleagues were the results of the PET And Recovery following Revascularization (PARR-2) trial reporting no benefit of assessing viability in guiding patient management.10 Both studies, however, were prone to significant methodologic limitations, urging for a reflection and open debate about the role of revascularization and viability testing in ischemic cardiomyopathy patients.11–14
PATHOPHYSIOLOGY OF HIBERNATING MYOCARDIUM
The coronary arteries are particularly vulnerable to the systemic disorder of atherosclerosis. Although the clinical presentation is most dramatic in the presence of coronary plaque rupture/thrombosis with sudden impairment or abolishment of coronary flow causing an acute coronary syndrome, many atherosclerotic plaques will slowly and progressively impinge on the coronary artery lumen (chronic stable plaque) and alter myocardial perfusion. Both events lead to ischemia, dysfunction, and/or ultimately to necrosis of the myocardium. When disturbances in myocardial demand/supply persist over a longer period (ie, weeks, months, or years), myocytes become dysfunctional by downregulating their energy consumption through a lower level of aerobic and/or anaerobic metabolism.15 This spontaneous “salvage” reaction is histologically characterized by loss of contractile proteins without altering cell volume and by intracytoplasmatic deposition of glycogen-rich material (Figs. 1, 2).5 The severity of this cellular dedifferentiation is dependent on the duration and intensity of chronic ischemia. If perfusion to these dysfunctional areas is restored before irreversible ultrastructural changes (ie, apoptosis or necrosis) occur, these segments may functionally improve and recover to normal, although this process is typically slow, taking up to >1 year in severe forms (Fig. 1).16,17
This type of ischemia associated with a chronic and reversible left ventricular (LV) dysfunction has been termed hibernating myocardium18 and is used to describe a viable myocardium in a state of persistent but potentially reversible dysfunction secondary to a chronic coronary artery stenosis. Hibernating myocardium should be considered as an adaptive mechanism to preserve structural integrity of the myocardium and to prevent myocyte death. There is still controversy regarding whether or not the resting myocardial blood flow is impaired in hibernated segments. Initially it was believed that chronic myocardial hypoperfusion (chronic ischemia) was responsible for these structural and functional myocardial alterations, but PET studies have shown that the resting myocardial blood flow to these segments is preserved. Instead, the PET studies assumed a mechanism of repeated episodes of demand/exercise-induced ischemia with consequent myocardial stunning (Fig. 1).5 Incomplete functional recovery of stunning segments between consecutive ischemia episodes may lead to permanently depressed myocardial function. Recently, quantitative CMR perfusion has challenged the PET findings by showing impaired resting myocardial blood flow in hibernating myocardium, which normalizes after revascularization.19
In the setting of a patient with CAD, dysfunctional myocardium covers a wide spectrum of histologic substrates. In the individual patient and even within a coronary perfusion territory, different histologic substrates may coexist.20 Dysfunctional myocardium may be viable (ie, ischemic, stunned, hibernating) or nonviable (ie, necrotic or scarred) (Fig. 3), and differentiation and characterization of these substrates is of utmost importance to determine preoperatively the potential benefit of revascularization procedures (ie, CABG or percutaneous coronary intervention) (Fig. 4).21
THE QUEST FOR THE IDEAL IMAGING TECHNIQUE TO DEPICT HIBERNATING MYOCARDIUM
Dysfunctional myocardium recovering after successful coronary revascularization is deemed to reflect hibernating myocardium, although reversed cellular differentiation has never been documented but only assumed.5 Hibernating myocardium is thus a post hoc observation and as such not useful to select those patients who might benefit from revascularization. Over the years, the quest to prospectively evaluate myocardial viability has resulted in many approaches using different viewpoints to assess a highly complex issue as viability. As shown in Table 1, the ideal imaging approach has not been established yet, and none of them can be considered really superior to the others.
A first approach is the use of a cutoff in end-diastolic wall thickness (EDWT) to determine whether a segment is viable or not. The rationale is that if a previous MI has occurred, subsequent scar formation will cause a wall thinning, whereas a preserved wall thickness is considered to reflect a viable myocardium (Fig. 1). Most studies use a cutoff of ≥5.5 to 6 mm.22 Both echocardiography and CMR can be used for this purpose, but the latter is advantageous for accurate measurements throughout the entire LV. Despite high sensitivity to predict functional recovery on a segmental basis (94%, range 87 to 100), specificity is low (48%, range 33 to 63),7 and comparable values are reported for CMR-based wall thickness measurements.23 Many segments with preserved wall thickness fail to functionally recover after revascularization, whereas thinned segments usually but not always reflect a scarred myocardium. Shah et al24 recently showed limited scar burden in thinned wall segments in nearly 20% of patients. Contractility of these thinned segments improved and wall thinning resolved after revascularization. Thus, using a single cutoff value in wall thickness to discriminate between viable and nonviable myocardium is difficult and prone to several critical reflections. It ignores the significant variation in wall thickness throughout the LV, as well as sex-related differences, and does not take into account the presence of preexisting or concomitant hypertrophy due to, for example, arterial hypertension.25,26 Most studies measured the total wall thickness, that is, a combination of compacta and trabeculations, whereas in particular the contribution of trabeculations to the total wall thickness is highly variable throughout the LV.26 Moreover, the initial studies evaluating EDWT by CMR were obtained by the currently “obsolete” spoiled gradient-recalled echo sequences (eg, Turbo FLASH or Turbo field-echo), which are known to overestimate myocardial wall thickness when compared with the currently used steady-state free precession CMR sequences.27 This urges for a reappraisal of LV wall thickness as a discriminator for myocardial viability. A recent study by Symons et al28 assessed the compacted myocardium with steady-state free precession cine CMR in an elderly group (58±11 y) of healthy volunteers (n=40) and reported a mean value of 6.2±1 mm. Similar observations were found in the remote (noninfarcted) myocardium at 1-year follow-up in patients with a history of ST-segment elevation MI (6.6±1 mm, age 57±11 y, n=58).29
A second approach relies on demonstrating the myocyte membrane integrity and is used by both nuclear imaging and contrast-enhanced CMR techniques. Both thallium-201 and technetium-99m sestamibi/tetrofosmin SPECT techniques compare the uptake of radiotracers in the dysfunctional myocardium relative to the remote (normal) myocardium.30 A tracer activity >50% of the maximum tracer uptake is used as the threshold for viable tissue (Fig. 1).5 Although generally accepted and widely used, the downside is the low spatial resolution (ie, 7 mm) limiting its ability to depict subendocardial infarcts (Table 1). A study by Wagner et al31 reported that subendocardial infarcts were missed in up to 13% of patients by thallium-201 SPECT when compared with CMR and histology. Furthermore, to avoid false-positive readings and to improve test specificity, use of attenuation correction methods and gated analysis of wall motion is recommended. Moreover, the radiation exposure of SPECT examinations ranges between 8 and 20 mSv, depending on the protocol used. Whereas the high sensitivities to predict segmental functional recovery after revascularization of thallium-201 SPECT and technetium-99m sestamibi SPECT are quite similar (ie, 87%, range 76 to 96 vs. 83%, range 72 to 96), the specificity of technetium-99m sestamibi SPECT (65%, range 53 to 88) is better than that of thallium-201 SPECT (54%, 25 to 65).8 In addition to SPECT imaging, T1-weighted CMR with late or delayed imaging after administration of gadolinium chelates, that is, late–gadolinium-enhancement (LGE)-CMR, has become an interesting alternative to depict myocardial damage in ischemic and nonischemic diseases. Image contrast relies on the differences in wash-in/wash-out characteristics and distribution volume between normal and pathologic myocardium after intravenous injection of gadolinium-chelated paramagnetic contrast agents. By suppressing the signal of the normal myocardium, the differential contrast with the pathologic myocardium can be significantly enhanced.32 The high spatial and contrast resolution allows myocardial damage as small as 1 g to be depicted, and the location and pattern of enhancement can differentiate between an ischemic and nonischemic origin.33 It is assumed that in patients with acute MI, the infarct enhancement is in part caused by intracellular diffusion of gadolinium molecules through the damaged membrane of the necrotic myocytes. In contrast, enhancement in a scarred myocardium (see below) relies on increase in extracellular volume. Acute infarctions can be differentiated from chronic ones using T2-weighted CMR.34 The presence of myocardial edema makes acute infarcts bright on T2-weighted imaging; the signal is normal or reduced in chronic infarcts.35
A third approach is imaging of myocardial metabolism. The latter is typically assessed by quantitative PET using radiolabeled metabolic tracers (fatty acid or glucose analogs) in combination with a perfusion tracer.30 Magnetic resonance (MR)-spectroscopy and quantitative perfusion imaging have become an interesting alternative to study myocardial viability allowing to explore new pathways, such as the intracellular measurement of pH using hyperpolarized carbon dioxide and bicarbonate.19,36 In the clinical setting, nitrogen-13 ammonia (13NH3)/fluorine-18-fluorodeoxyglucose (18F-FDG) PET is a well-validated, highly sensitive, and widely accepted “tracer combination” to study myocardial viability. 13NH3 is used to quantify myocardial blood flow, whereas 18F-FDG depicts myocardial metabolism (Fig. 5). Comparing results of perfusion and metabolism will yield 1 of 4 common patterns. A PET-viable pattern can consist of either hypoperfusion with relatively preserved FDG uptake (PET mismatch, hallmark of a hibernating myocardium) or normal flow and metabolism (normal tissue). A combined reduction of both perfusion and metabolism (PET match) is indicative of necrosis/scar (transmural or nontransmural). Finally, the reverse mismatch pattern denotes relatively reduced metabolism with preserved perfusion and can be observed, for example, in nonischemic cardiomyopathy and left bundle branch block (Fig. 2; Table 2). Patients with CAD-viable and PET-viable segments are known to improve function after revascularization, whereas a PET match pattern (concordance of decreased flow and metabolism) predicts the absence of contractile recovery after CABG. This technique yields excellent sensitivity (92%, range 86 to 100) and moderate specificity (63%, range 58 to 87).8 An alternative to assess viability and perfusion is carbon-11-acetate, which provides both quantitative myocardial perfusion and total myocardial oxygen consumption information, but it is used primarily in research settings.37 The main strengths of PET compared with SPECT are its superior spatial resolution, lower radiation burden, and absolute quantification of myocardial blood flow. Drawbacks are availability and short half-life of current available PET perfusion tracers, cost, and the lower spatial resolution compared with CMR (Table 1).
A next approach is the assessment of contractile reserve. It has already been shown 4 decades ago that inotropic stimulation with epinephrine caused transient improvement in regional and global LV dysfunction in patients with CAD, reflecting myocardial viability.38 Resting contractile function, in contrast, cannot be used to rule out myocardial scarring. Using LGE-CMR it was shown in patients with chronic MI that the transmural extent of infarction needs to approach 50% before contractile dysfunction can be systematically identified.39 Currently, DSE and, increasingly, dobutamine stress CMR are used to assess contractile reserve. If patients are closely monitored and resuscitation equipment and trained personnel are available, dobutamine stress CMR (including high-dose dobutamine±atropine) can be safely performed in an MR environment.40 Dysfunctional myocardium that contracts (or improves contraction) is deemed viable if stimulated appropriately (Fig. 3). Nonviable myocardium, in contrast, shows no functional improvement or even a worsening in wall motion. Low doses of dobutamine (ie, 5 to 10 μg/kg body weight) suffice because the contractile reserve in a dysfunctional but viable myocardium is limited, and myocardial wall motion worsens at higher doses of dobutamine (ie, 20 μg/kg body weight), the so-called “biphasic effect” of a viable myocardium.41 Of course, the worsening in myocardial contractility may be caused by the presence of ischemia in the dysfunctional myocardium as well. Whereas sensitivities for both imaging modalities are similar, that is, 80% (range, 57 to 96) for DSE versus 81% (range, 61 to 89) for dobutamine stress CMR, the latter shows a better specificity (91%, range 82 to 100 vs. 78%, range 44 to 85) for DSE.8,23 CMR has the advantage over echocardiography of not being limited by the adequacy of the acoustic window (up to 15% of patients are not evaluable when using transthoracic ultrasound, compared with 97% and 98% successful studies by transesophageal ultrasound and CMR, respectively).42,43 Ultrasound-based and CMR-based techniques quantifying myocardial strain and strain rate such as strain-rate imaging, speckle tracking, myocardial tagging, and strain-encoded imaging may further improve accuracy to discriminate between viable and nonviable myocardium but are currently not integrated into routine clinical practice.44–46
A last approach is based on the principle of increased interstitial space (or extracellular volume) in a scarred myocardium. As mentioned above, the LGE-CMR technique is a well-validated, highly accurate, and reproducible technique for sizing healed infarcts and is therefore routinely used to depict infarct-related myocardial scarring.31,39,47 Moreover, the technique is helpful to differentiate dilated cardiomyopathy from LV dysfunction related to CAD,48 and it has prognostic significance.49 Delayed myocardial enhancement in dysfunctional segments in patients with CAD is associated with nonviability obtained by SPECT imaging, PET, and DSE, whereas absence of LGE correlates with measures of viability, regardless of resting contractile function.50,51 In a landmark paper by Kim et al,21 the likelihood of improvement in contractility after revascularization was predicted by the transmural extent of enhancement. In dysfunctional segments without LGE, 78% of segments improved contractility after revascularization, compared with 2% of segments with a scar involving >75% of wall thickness (Figs. 6–8). Although the LGE-CMR technique yields an excellent sensitivity (95%, range 90 to 99), specificity is rather low (51%, range 25 to 94).23 LGE-CMR is superior to nuclear imaging (SPECT/PET) for the identification of segments that are unlikely to recover function at follow-up,52 whereas in heart failure patients treated with β-blockers, it predicts the response in LV function and ventricular remodeling.53
The accuracy of viability imaging can be improved by combining approaches. In particular, the likelihood of functional recovery is uncertain in patients showing dysfunctional myocardium with preserved EDWT and in those presenting with intermediate grades of scar transmurality (ie, 25% to 75%). Additional low-dose dobutamine stress imaging may provide valuable information with regard to viability in these dysfunctional segments.54–56 Kühl et al57 assessed the thickness of the nonenhanced rim of myocardial segments showing LGE. A cutoff value of 3 mm was superior to a cutoff value of 5.4 mm for EDWT to assess viability. As PET and CMR assess dysfunctional myocardium from a different perspective—that is, metabolic versus scar imaging±contractile reserve, respectively—they can be considered complementary. As such, the emergence of hybrid PET-MR scanners raises new expectations with regard to improved viability detection—for example, to study myocardial metabolism in the nonenhanced rim on LGE-CMR.58 Although initial results are promising, several hurdles need to be overcome to integrate this novel hybrid technique into clinical routine59,60 (Table 1).
If deemed necessary, viability imaging can be combined with stress imaging to exclude concomitant myocardial ischemia. For these combined purposes, stress-rest SPECT/PET imaging, high-dose DSE (±atropine), high-dose dobutamine CMR (±atropine), and/or stress perfusion CMR can be performed.61,62
Finally, with the advent of multidetector CT technology more than a decade ago, reliable cardiac imaging became a reality. Although the focus has mainly been on coronary imaging, this technique has the intrinsic potential to offer a comprehensive approach in evaluating a heart failure patient merging coronary artery imaging, myocardial perfusion, and myocardial viability imaging into a single examination.63–65 However, it should be emphasized that many patients with IHF have advanced CAD with high coronary calcium values hampering an accurate evaluation of coronary artery lumen. Radiation doses for a CT-based myocardial perfusion/viability study remain high (≈15 mSv),65 and in patients with comorbidities such as renal failure, administration of iodinated contrast agents may be contraindicated. Nevertheless, a greater role for CCT in viability imaging might be expected in the coming years.
HOW MUCH VIABLE TISSUE IS NEEDED TO IMPROVE FUNCTION AND OVERALL SURVIVAL?
From a clinical perspective, recovery of global ventricular function and ultimately improved patient survival are more important than regional improvement (Fig. 8).7 Revascularization of the myocardium deemed viable is only indicated if LV ejection fraction is assumed to increase significantly (ie, ≥5%) after revascularization, thereby improving patient survival, stressing the importance to define an optimal cutoff of viability extent. This can be achieved by expressing viable myocardium as a percentage of LV mass or by the number of viable segments, as determined using the standardized myocardial segmentation approach as proposed by the American Heart Association.66 There is substantial evidence that patients with significant myocardial viability treated medically had a significantly worse prognosis compared with patients treated with revascularization.67,68 Importantly, those without proof of viability had intermediate rates of mortality regardless of treatment option.68 The minimal extent of myocardial viability to predict improvement of survival varies among techniques. PET requires the least amount of viable myocardium (25.8%) in comparison with DSE (35.9%) and SPECT (38.7%).69 On CMR, a patient is typically considered to have a viable myocardium when ≥4 dysfunctional segments are considered viable, showing an LGE transmurality ≤50% or improved contractility during low-dose dobutamine stress.68
WHY MYOCARDIAL VIABILITY TECHNIQUES MAY FAIL TO PREDICT PATIENT OUTCOME?
Since the initial observations of improved contractility in severely dysfunctional myocardium after CABG 4 decades ago, it has become clear that predicting outcome in patients with IHF is difficult, multifactorially determined, and definitely not driven by the presence and extent of myocardial viability alone (Table 3). It is a misunderstanding to consider viability as binomially distributed (ie, viable vs. nonviable); rather than this dichotomy, many shades of gray are present that influence outcome. As preservation of myocyte fraction is an important determinant of functional recovery after revascularization, it is obvious that a higher myocyte fraction is required to maintain contractile reserve than to achieve significant tracer uptake. This may explain, for example, the higher sensitivity of SPECT imaging compared with DSE in the identification of myocardial hibernation.70 Moreover, both myocardial viability and adverse ventricular remodeling (ie, increase in end-systolic volume) provide independent, incremental prognostic value, and thus viability should not be assessed in isolation.71 Although, as discussed above, increasing extent of viability generally implies increased potential for recovery, this coincides with an increased risk for major adverse events.14 Moreover, progression of LV remodeling adversely affects outcome, and once the LV has become too dilated, the ability for functional improvement is lost, and revascularization will not improve patient outcome despite the presence of viable myocardium. In addition, ancillary morbidities related to severe LV dilatation such as mitral regurgitation and thrombus formation also negatively influence patient outcome. Several other issues come into play when considering functional recovery after revascularization. Time between viability assessment and intervention is important with improved survival if an early intervention is performed.72 Moreover, the time frame of recovery is highly variable within patients; in some of them it may take longer than 1 year depending on the severity of myocardial hibernation.16,17 In these patients, it may be difficult to differentiate between an unsuccessful revascularization procedure, evolving CAD, or a false-positive myocardial viability test. Moreover, an increasing number of patients are elderly patients with comorbidities such as renal failure or diabetes mellitus that may substantially contribute to mortality in the follow-up period. Conversely, lack of functional recovery not necessarily implies lack of improved patient outcome, suggesting that revascularization may have a beneficial impact on other factors such as protection against future infarction and death possibly by improving myocardial electrical stability.73 Another potentially confounding issue, not yet highlighted, is the periprocedural necrosis after percutaneous coronary intervention or CABG evidenced by elevation of cardiac enzymes, altered myocardial perfusion, and new myocardial enhancement on LGE-CMR, which is associated with increased long-term mortality.74,75 These and other confounding factors explain to a large extent the controversies on predicting patient outcome in literature, and hopefully may help better design future viability studies (Table 3).12,76
WHAT CAN NONINVASIVE IMAGING ADD BESIDES MYOCARDIAL VIABILITY ASSESSMENT IN PATIENTS WITH IHF?
Although current standard care of treatment in IHF patients is largely focused on improving heart failure symptoms and minimizing the risk for premature death using optimal medical treatment with/without coronary revascularization, an increasing number of patients receives cardiac resynchronization therapy and/or an implantable cardioverter-defibrillator (Fig. 9).77 Although beyond the scope of this paper, noninvasive imaging may provide valuable information with regard to the presence and severity of ventricular dyssynchrony, to visualize coronary venous anatomy, and to determine the presence, location, and extent of myocardial scarring (using LGE-CMR or PET). This information is helpful to select the optimal access (eg, intravascular vs. pericardial), to locate the cardiac resynchronization therapy leads, and to estimate the risk for future adverse cardiac events. Information with regard to LV geometry may be of interest in patients scheduled for surgical ventricular reconstruction. Although the STICH trial did not show an added benefit of this procedure to bypass surgery, the trial’s inclusion criteria did not contain shape or viability parameters.78 CMR may contribute to a better patient selection, providing information on 2-dimensional or 3-dimensional LV geometry (eg, sphericity index, apical conicity index), scar tissue assessment and the consequences on regional and global function, and evaluate the reshaping and functional recovery after surgery.79 In patients with chronic total occlusions, CCT provides important preprocedural data regarding the occlusion length, degree of calcification, vessel tortuosity, and bridging collaterals, whereas LGE-CMR may show evidence of chronic MI in territories subtended by the occluded coronary artery.80,81
CURRENT RECOMMENDATIONS FOR VIABILITY IMAGING
In the appropriate clinical setting, viability imaging has been recommended for patients with CAD and severe LV dysfunction by both the American College of Cardiology/American Heart Association (ie, class IIa recommendation) and by the European Society of Cardiology and European Association for Cardio-Thoracic Surgery.14 Although these recommendations date from before publication of the STICH trial results, a recent conjoint appropriate use document (2013 ACCF/ACR/ASE/ASNC/SCCT/SCMR) has recommended CMR and PET for investigating viability in patients with severe LV dysfunction, while at the same time indicating the possibility for the use of stress imaging with SPECT and echocardiography.4,14
Detection of potentially reversible contractile dysfunction in patients with ischemic heart disease has become a valuable clinical strategy for determining the need for revascularization. Further combined-modality research is needed, however, for better comprehension, patient stratification, and treatment guidance.
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