Imaging in the Management of Ischemic Cardiomyopathy

Journal of the American College of Cardiology © 2012 by the American College of Cardiology Foundation Published by Elsevier Inc.

Vol. 59, No. 4, 2012 ISSN 0735-1097/$36.00 doi:10.1016/j.jacc.2011.08.076

STATE-OF-THE-ART PAPER

Imaging in the Management of Ischemic Cardiomyopathy Special Focus on Magnetic Resonance Andreas Schuster, MD,* Geraint Morton, MA, MBBS,* Amedeo Chiribiri, MD, PHD,* Divaka Perera, MD,* Jean-Louis Vanoverschelde, MD, PHD,† Eike Nagel, MD, PHD* London, United Kingdom; and Brussels, Belgium Heart failure of ischemic origin has become increasingly common over the last decade because of the improved survival of patients with acute myocardial infarction. Revascularization with coronary bypass grafting or percutaneous coronary intervention plays a pivotal role in patients with ischemic cardiomyopathy, although these interventions are often associated with relatively high peri-procedural risk. The pathophysiological substrate of ischemic cardiomyopathy is heterogeneous, varying from predominantly hibernating myocardium to irreversible scarring. There is evidence to suggest that patients with hibernating myocardium benefit most from revascularization, whereas medical therapy is associated with an adverse prognosis. Therefore, noninvasive testing is recommended by relevant guidelines to guide optimal management in these patients. However, the role of noninvasive testing has recently been challenged. There are various imaging modalities available that provide information on different aspects of the disease, and therefore, they differ significantly in sensitivity and specificity. In clinical practice, choosing among the different imaging modalities can be difficult. Cardiac magnetic resonance has evolved into a comprehensive modality that can accurately determine the amount of hibernating myocardium as well as the presence and degree of myocardial ischemia and the extent of the scar. This paper reviews the indications, accuracy, and clinical utility of the available imaging techniques, with a special focus on cardiac magnetic resonance in ischemic cardiomyopathy, and provides an outlook on how this field might evolve in the future. (J Am Coll Cardiol 2012;59:359–70) © 2012 by the American College of Cardiology Foundation

Heart failure and myocardial infarction secondary to coronary artery disease (CAD) constitute leading causes of death (1). Despite recent advances in therapy, ischemic cardiomyopathy (ICM) is associated with high mortality, and determining the best management is challenging. In patients with normal ejection fraction (EF), prognosis in CAD is associated with the ischemic burden and the amount of ischemia reduction achieved by therapy (2), as well as the presence or absence of hibernating myocardium (2,3). However, the former has not been specifically shown for patients with reduced EF. The definition of ICM is inconsistent. Some trials, including the STICH (Surgical Treatment for Ischemic

From the *Division of Imaging Sciences and Biomedical Engineering, King’s College London British Heart Foundation Centre of Excellence, National Institute of Health Research Biomedical Research Centre at Guy’s and St. Thomas’ NHS Foundation Trust, Wellcome Trust and Engineering and Physical Sciences Research Council Medical Engineering Centre, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom; and the †Division of Cardiology, Cliniques Universitaires St. Luc, Brussels, Belgium. This work was supported by the BHF (RE/08/003⫹FS/10/ 029/28253 to Drs. Schuster, Perera, and Nagel), the BRC (BRC-CTF 196 to Drs. Schuster, Perera, and Nagel), and a European Union grant (224495 to Drs. Morton and Nagel). Dr. Nagel has received significant grant support from Bayer Schering Pharma and Philips Healthcare. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received April 21, 2011; revised manuscript received July 18, 2011, accepted August 2, 2011.

Heart Failure) trial, defined it as a severe reduction of left ventricular (LV) function (⬍35%) (4,5), whereas others use an LV function ⬍50% in the presence of severe CAD (3,6). For this review, we use the latter definition. The pathophysiological substrate of ICM is heterogeneous, varying from predominantly hibernating myocardium to irreversible scarring. The concept of “hibernating myocardium” refers to myocardium that is supplied by a diseased coronary artery and is ischemic and dysfunctional but remains alive and thus has the potential to regain contractility after revascularization. There are different definitions of hibernating myocardium. The most accepted definition is an improvement in contractility after revascularization. Even though this definition is the most accurate, it is only after revascularization that the diagnosis can be made (i.e., it is a retrospective definition [7,8] and thus not useful for clinical decision making). Therefore, all diagnostic tests use surrogate definitions to assess the presence of hibernating myocardium. These definitions vary, and different imaging techniques provide information on different aspects of the pathophysiology such as metabolic imaging, scar imaging, or contractile reserve. Consequently, the results may depend on the chosen imaging test. Even though there is less evidence, the importance of an additional ischemic component to the presence of hibernat-

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DSE ⴝ dobutamine stress echocardiography

ing myocardium has been increasingly recognized (9). Because the relative importance of the ischemic component has not been fully established and different imaging strategies yield different results, it remains difficult to decide which test is clinically most suitable and which parameter most important in a given patient.

DSMR ⴝ dobutamine stress magnetic resonance

Hibernating Myocardium

Abbreviations and Acronyms CABG ⴝ coronary artery bypass grafting CAD ⴝ coronary artery disease CMR ⴝ cardiac magnetic resonance CT ⴝ computer tomography

EF ⴝ ejection fraction

The observation of dysfunctional myocardium regaining function after coronary artery bypass grafting ICM ⴝ ischemic (CABG) (10) led to the introduccardiomyopathy tion of “hibernation” (11) and was LGE ⴝ late gadolinium related to reduced coronary blood enhancement flow (12). LV ⴝ left ventricular Hibernating myocardium reMCE ⴝ myocardial contrast fers to a progressive and dynamic echocardiography condition of chronic abnormally PET ⴝ positron emission contracting myocardium, with tomography function that improves after reSPECT ⴝ single-photon vascularization. The exact pathoemission computed tomography physiology is still controversial. Dysfunction initially is probably caused by reduced flow reserve leading to ischemic episodes during stress (13). Myocardial ischemia rapidly impairs contractile function, which may persist for several hours after reperfusion (myocardial stunning), and its repetitive occurrence might lead to chronic dysfunction even when perfusion at rest is still normal (14). This is referred to as “perfusion-contraction mismatch.” Over time, perfusion at rest will decrease, leading to a restitution of perfusion-contraction matching (15). In parallel with this, increased fibrosis and myocyte alterations (degeneration and apoptosis) occur, reducing the likelihood of complete functional recovery after revascularization (Fig. 1). Patients with hibernating myocardium (by any diagnostic test) have been shown to have a significant survival advantage following revascularization compared with those receiving medical therapy alone. Allman et al. (3) presented a meta-analysis pooling the data of 3,088 patients from 24 studies between 1992 and 1999. Hibernating myocardium was determined using single-photon emission computed tomography (SPECT), positron emission tomography (PET), or dobutamine stress echocardiography (DSE) with a 2-year follow-up. A strong association was found between hibernating myocardium identified with noninvasive testing and improved survival after revascularization. Revascularization was associated with a nearly 80% reduction in mortality in patients with hibernating myocardium (16% with medical therapy vs. 3.2% with revascularization). Conversely, in the FFR ⴝ fractional flow reserve

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absence of hibernating myocardium, there was no difference in mortality with revascularization (7.7%) versus medical therapy (6.2%). Camici et al. (16) more recently pooled the data from 14 nonrandomized studies, published between 1998 and 2006, that reported long-term Kaplan-Meier survival curves. They also found a survival benefit associated with revascularization compared with medical treatment in patients with hibernating myocardium but no benefit in those without. Interestingly, and in apparent contradiction to Allman et al. (3), the annual mortality rate in patients treated medically appeared to be independent of the presence of hibernating myocardium. Whether this contradiction might be explained by optimized patient care due to improved medical therapy including implantable cardioverter defibrillators or a higher revascularization rate in patients with significant amounts of hibernating myocardium remains speculative. The main disadvantage of both studies is their retrospective nature and the lack of randomization. The long-awaited STICH trial is a prospective, randomized, multicenter outcome study comparing 1,212 patients with ICM (EF ⬍35%) assigned to intensive medical therapy with patients assigned to intensive medical therapy and CABG (4). There was no significant difference with respect to the primary endpoint of death from any cause (4). A prospective substudy in 601 patients investigated whether assessment of hibernating myocardium (with SPECT and/or DSE) can identify patients who would benefit most from revascularization (5). A total of 298 patients were assigned to intensive medical therapy and CABG, and 303 were assigned to receive intensive medical therapy alone. Thirty-seven percent of patients with hibernating myocardium and 51% of patients without hibernating myocardium died during followup. After adjustment for differences in baseline variables and risk factors, there was no significant association of hibernating myocardium with mortality. Furthermore, patients with hibernating myocardium who were assigned to CABG plus medical therapy did not have improved survival compared with those assigned to medical therapy alone. Unfortunately, several limitations of this trial must be considered. 1) Assessment of hibernating myocardium was performed only in those STICH patients when investigators had the test available and actively referred the patient. It is unclear whether this referral was random or related to clinical factors. 2) There was an imbalance between patient groups because 81% of all patients had significant hibernating myocardium (leaving 19% without hibernating myocardium). 3) To be classified as a patient having significant hibernating myocardium, 65% of the myocardium had to be hibernating with SPECT (ⱖ11 segments) or 31% of the myocardium had to be hibernating with DSE (ⱖ5 segments). In addition, hibernating territories were not related to the coronary anatomy. Both factors may compound interpretation of these findings. 4) Hibernating myocardium was assessed with SPECT or DSE, neither of which is considered to be the gold standard tool for this investigation. In contrast, the retrospective analyses that demonstrated improved survival

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Figure 1

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Development of Ischemic Cardiomyopathy as a Time-Dependent Phenomenon

At a pathophysiological level, there are 3 different phenomena contributing: 1) initially repetitive episodes of stunning result in a mismatch between oxygen delivery and contractile function; 2) over time, there will eventually be a decrease in resting perfusion (oxygen delivery), restoring the perfusion/contraction balance and leading to the state of hibernating myocardium; and 3) there is further disease progression with fibrosis and myocyte alterations marking the end stage of the disease. The likelihood of functional recovery following revascularization diminishes as the disease progresses, with a high likelihood of recovery early (first to early second stages) and little to no recovery later (late second to third stage).

after revascularization also included PET (3) and cardiac magnetic resonance (CMR) (16). 5) Patients in the medical therapy arm of the trial had a significantly higher rate of aspirin and statin use at baseline compared with patients who underwent CABG, which may have improved survival in the medical therapy group. Current guidelines recommend noninvasive testing before revascularization (17). This may be subject to change based on the STICH trial. However, there is still a need for well-defined prospective outcome studies using state-ofthe-art noninvasive testing to plan revascularization in patients with ICM. Ischemia The role of inducible ischemia in ICM is less well established than the role of hibernating myocardium. In patients with stable, symptomatic CAD and preserved EF, revascularization only confers a prognostic benefit (reduced rate of death, nonfatal myocardial infarction, and repeat revascularization) if patients have significant myocardial ischemia (as assessed by fractional flow reserve [FFR]), whereas revascularization of stenoses not limiting flow has a negative effect on prognosis. The role of “medical therapy only,” however, was not clarified in this study (18). Vasodilator stress CMR correlates well with FFR (19) and can be

used as a noninvasive alternative to FFR in similar patients to identify individuals at high risk for cardiac death, nonfatal myocardial infarction, or congestive heart failure (20). It is unknown whether this holds true in patients with ICM with or without hibernating myocardium. Rizzello et al. (9) examined 128 consecutive patients with DSE before revascularization and showed that the presence of ischemia did not add significantly to predicting outcome, whereas the extent of hibernating myocardium was a strong predictor of long-term prognosis. In contrast, Pasquet et al. (21) reported that ischemia as determined by 201thallium-SPECT was an important predictor of outcome in patients with chronic left ventricular dysfunction. They prospectively assessed hibernating myocardium and ischemia in 137 consecutive patients who underwent 201thallium-SPECT and DSE with a follow-up of 3 years and reconfirmed the prognostic value of revascularization in patients with hibernating myocardium. In addition, they found improved survival in patients with ischemic myocardium (as determined by 201thallium-SPECT) who underwent revascularization independent of the presence of hibernating myocardium (21). Interestingly and in line with Rizzello et al. (9), they did not show a relationship between ischemia assessed by high-dose DSE and prognosis. It is unclear whether this difference can be explained by the different pathophysiolo-

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Surrogate of Measures Hibernating Table 1 Measures Surrogate of Myocardium Hibernating Myocardium Metabolism

Perfusion

Nonviability Scar

Contractile Reserve

CMR

Modalities and Targets

⫺

⫹

⫹

⫹

CT

⫺

⫹

⫹

⫺

Echocardiography

⫺

⫹

(⫹)

⫹

PET

⫹

⫹

⫺

⫺

⫹

⫹

⫺

(⫹)

Assessment of functional integrity of myocardial cells

Detection of blood flow toward the myocardium

Exact localization and size of necrosis/fibrosis

Assessment of contractile function

SPECT

CMR ⫽ cardiac magnetic resonance; CT ⫽ computed tomography; PET ⫽ positron emission tomography; SPECT ⫽ single-photon emission computed tomography; (⫹) ⫽ technique potentially useful to make this assessment.

gies tested (i.e., DSE reflects oxygenation on a cellular level, whereas 201thallium-SPECT reflects cellular integrity combined with flow) or possible technical limitations of DSE, which might suffer from poor acoustic windows and difficult endocardial border delineation, especially in patients with ICM. The findings also need to be interpreted in the context of the relatively small study population and the unblinded, nonrandomized study design. It remains unclear to date whether ischemia is an important parameter in patients with ICM. Given the controversial results of the STICH trial and the lack of data on ischemia testing in ICM, there is a clear need for prospective outcome studies investigating the relative importance of both ischemia and hibernating myocardium, preferably in a multicenter setting.

Clinically, a single test that provides assessment of the presence and extent of hibernating myocardium and the presence and severity of ischemia seems most appropriate to guide therapy. The current evidence is, however, not adequate to direct clinicians toward either an ideal diagnostic test or toward understanding the relative importance of ischemia versus hibernating myocardium in patients with ICM (22). LV Function Impaired LV function is associated with adverse prognosis (23). The potential survival benefit in patients with hibernating myocardium who undergo revascularization may well be mostly explained by improved global LV function after restoration of blood flow. Bax et al. (24) pooled data from

Characteristics of Hibernating Table 2 Characteristics of Myocardium Hibernating Myocardium Imaging Technique Echocardiography

SPECT

Imaging Target

Definition of Hibernating Myocardium

Contractile reserve (dobutamine stress echocardiography)

Improvement in contraction (visual or quantitative analysis using strain rate [69])

Perfusion (MCE)

Homogenous contrast enhancement during rest steady-state perfusion (35)

Scarring (MCE)

Contrast agent uptake visualized with 3-dimensional echocardiography (36)

Contractile reserve (dobutamine-gated SPECT)

Improvement in contraction (70)

Perfusion intact cell membrane (201thallium-SPECT)

Tracer uptake ⬎50%

Perfusion intact cell membrane/intact mitochondria (99mtechnetium-tetrofosmin/MIBI SPECT)

Tracer uptake ⬎65%

Free fatty acid metabolism (123I-BMIPP SPECT)

PET

Glucose metabolism (18FDG-SPECT)

Preserved glucose metabolism

Perfusion (13NH3-labeled ammonia, 15O2-labeled water, and 82Rb-labeled PET) (71)

Irreversible injury: flow metabolism match; ischemic but viable: flow metabolism mismatch

Glucose metabolism (FDG-PET) CMR

Perfusion (perfusion CMR)

Irreversible injury: defect with stress and at rest; Myocardium at risk*: inducible defect with stress and not at rest

Oxygenation (high-dose DSMR)

New wall motion abnormalities with stress reflect cellular hypoxia

Contractile reserve (low-dose DSMR)

Improvement in function

Scarring (LGE-CMR)

Gadolinium uptake visualized in LGE images

Oxygenation (blood oxygen level–dependent CMR)

Irreversible injury: defect with stress and at rest; Myocardium at risk*: inducible defect with stress and not at rest

CT

Perfusion

Irreversible injury: defect with stress and at rest; Myocardium at risk*: inducible defect with stress and not at rest

Scarring (DE-CT)

Iodine contrast agent uptake visualized in late enhancement images

Integrated PET-CT and SPECT-CT

Combined DE-CT and perfusion PET (13NH3 and 15O2 PET)

Anatomy of coronary arteries, ischemia, and hibernating myocardium

*Myocardium at risk for significant ischemia. BMIPP ⫽ ␤-methyl-p-iodophenyl-pentadecanoic acid; DE ⫽ delayed enhancement; DSMR ⫽ dobutamine stress magnetic resonance; FDG ⫽ fluorodeoxyglucose; LGE ⫽ late gadolinium enhancement; MCE ⫽ myocardial contrast echocardiography; MIBI ⫽ methoxyisobutylisonitrile; other abbreviations as in Table 1.

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Pathophysiological Targets of Different Imaging Methods

Thallium–single-photon emission computed tomography (SPECT) depends on intact cellular membranes and energy-dependent uptake via the Na⫹K⫹-antiporter. Technetiumlabeled tracers tetrofosmin (TF) and methoxyisobutylisonitrile (MIBI) are lipophilic cations that can be imaged with SPECT after passively crossing the mitochondrial membranes (driven by the transmembrane electrochemical gradient), where they are retained. Dobutamine targets ␤1 and ␤2 adrenoreceptors (␤-AR), leading to increased intracellular Ca2⫹ and positive inotropy. Responses to dobutamine stress are mainly imaged with dobutamine stress echocardiography and dobutamine stress magnetic resonance. 18-fluorodeoxyglucose (18FDG) targets glucose metabolism and is mainly imaged with positron emission tomography (PET) after uptake via the glucose transporter uniporter. FDG is intracellularly phosphorylated by hexokinase to FDG-6-phosphate, which is not further used in glycolysis or glycogen synthesis. 82-Rubidium (82Rb)-PET depends on intact cellular membranes and energy-dependent uptake via the Na⫹-K⫹-antiporter similarly to 201thallium. 13NH3-PET depends on passive diffusion or on the active Na⫹-K⫹-antiporter mechanism. H215O diffuses freely through the membrane and reaches equilibrium between extravascular and intravascular compartments. Gadolinium is an extracellular contrast agent that passively diffuses into the extracellular space. When the extracellular space is significantly increased (e.g., after cell membrane rupture in acute myocardial infarction or in collagenous subendocardial scar as shown in this case), gadolinium accumulates and is retained due to altered wash in/wash out kinetics and can then be imaged with late gadolinium enhancement– cardiac magnetic resonance imaging. 201

Figure 3

Diagnostic Accuracy of Different Techniques to Assess Hibernating Myocardium

Although an increase in global ejection fraction (EF) after revascularization is associated with improved prognosis in patients with ICM, most studies have evaluated the impact of revascularization on improvement of regional function of hibernating myocardium rather than global improvement of function. The black line represents late gadolinium enhancement– cardiac magnetic resonance (LGE-CMR) as a reference standard for nonviability. The individual percentage terms refer to the extent of transmurality of scar. Although techniques addressing hibernating myocardium by looking at cellular integrity lie on or close to the LGE accuracy line (16,74), techniques looking at contractile reserve reach a higher accuracy (16,48), which can be even further increased by applying quantitative wall motion analysis techniques such as strain (51,75). DSE ⫽ dobutamine stress echocardiography; DSMR ⫽ dobutamine stress magnetic resonance; other abbreviations as in Figures 1 and 2.

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Positron Tomography Table 3Emission Positron Emission Tomography Target Perfusion

Hibernating myocardium

Tracer Perfusion tracer (15O2, 13NH3, 82Rb)

Metabolism tracer FDG (used in combination with perfusion tracer 13NH3)

Kinetics

Protocols

Detection of blood flow through competent vessels

1. Rest perfusion: first bolus injection

Metabolism: FDG is intracellularly phosphorylated by hexokinase to FDG-6-phosphate, which is not further used in glycolysis or glycogen synthesis

1. Rest perfusion

2. Stress perfusion: acquisition 5 half-times after rest scan after second injection during vasodilator stress

2. Metabolic imaging

Abbreviation as in Table 2.

105 studies that used SPECT, PET, or DSE to predict regional or global recovery. An improvement in global EF was detected in 28 studies. In the presence of hibernating myocardium, LVEF improved (from 37% to 45%), whereas in the absence of hibernating myocardium, EF remained unchanged (36%). Patients with an improvement in LVEF after revascularization have an improved prognosis (25). When considering revascularization, it is important to note that even if regional wall motion remains unchanged, global function may improve (26). Noninvasive Functional Assessment There are several imaging modalities assessing 3 main surrogate parameters of hibernating myocardium (Tables 1 and 2,

Fig. 2) (27): 1) myocardial metabolism with functional integrity of cells and mitochondria; 2) nonviable tissue by determining the localization and extent of necrosis or fibrosis; and 3) contractile reserve during inotropic stimulation. Different imaging modalities measure different aspects of physiology and pathophysiology, resulting in different accuracies (Fig. 3). PET and SPECT. PET imaging is well validated, and metabolism-perfusion mismatch has high negative and positive predictive values (Table 3) (28). With PET, myocardial perfusion and metabolism can be fully quantified, a potential advantage compared with SPECT or DSE. Furthermore, PET is associated with outcome: A post hoc analysis, PARR-2 (PET and Recovery Following Revascularization-2),

Single-Photon Emission Computed Table 4 Single-Photon EmissionTomography Computed Tomography Kinetics

Protocols

201

Tracer

Similar to potassium (monovalent cation)

1. Initial tracer uptake dependent on regional perfusion 2. Sustained uptake (usually imaged 3–4 h after injection) dependent on cell membrane integrity, which reflects hibernating myocardium (72)

1. Stress: reversible defect from peak stress to delayed “redistribution” (3–4 h or 24 h after injection) is marker of reversible ischemia in hibernating myocardium 2. Rest: reversible defect at redistribution indicates hibernating myocardium with resting hypoperfusion; fixed defects reflect scar tissue 3. Reinjection: in case of limited initial uptake during stress in severe CAD, a “fixed” defect might be present in hibernating myocardium because 201 Tl is normally cleared from blood pool rapidly; second “reinjection” of small dose of 201Tl at rest is necessary to proof hibernating myocardium after the redistribution images

99

Lipophilic cations

Similar flow kinetics but emission of higher energy and shorter half-life compared with 201Tl (better detection and less radiation)

Retention in mitochondria with minimal redistribution requires separate injection at rest and stress; information about perfusion and hibernating myocardium; dysfunctional segments with tracer uptake ⬎65% are considered hibernating

123

Radioiodine-labeled fatty acid tracer

Metabolic imprint related to persistent decrease in ␤-oxidation with increased shunt retention of BMIPP in triglyceride pool

Assessment of hibernating myocardium and “ischemic memory”; after ischemic episode, fatty acid metabolism may be suppressed for prolonged time, and BMIPP imaging can demonstrate regional metabolic defect even if perfusion has returned to normal

18

Glucose analogue positron emitter

Metabolic imaging of glycolysis

Hibernating myocardium shows preserved or even relatively higher glucose metabolism compared with flow; principle referred to as metabolismperfusion mismatch

Thallium

Technetium metastable tetrofosmin and MIBI

I-BMIPP

FDG*

Biological Properties

*With the introduction of 511 keV collimators, 18FDG is being increasingly used for SPECT imaging. Clinical data have shown excellent agreement between SPECT and PET for FDG imaging (73); however, FDG is originally a PET tracer. CAD ⫽ coronary artery disease; other abbreviations as in Tables 1 and 2.

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Echocardiography Table 5 Echocardiography Modality

Target

Technique

Protocols

MCE

Perfusion, hibernating myocardium (microcellular integrity), and scar

Destruction (by a high mechanical index ultrasound beam) and restoration velocity of a continuously infused microbubble contrast agent

1. Stress: replenishment of ultrasound beam after microbubble destruction takes approximately 1 s 2. Rest: replenishment of ultrasound beam after microbubble destruction takes approximately 5 s 3. Scar imaging: increased subendocardial or transmural brightness

Scar imaging (MCE)

Scar

Contrast agent accumulation visualized with 3-dimensional echocardiography (36)

Absence of scar in areas where there is hypokinesia at rest diagnostic of hibernating myocardium

DSE

Biphasic response: contractile reserve and ischemia

Acquisition of functional images at rest and various stress levels

1. Contractile reserve: low dosages of dobutamine (5 to 10 ␮g·kg⫺1·min⫺1) 2. ischemia: ⱕ40 ␮g·kg⫺1·min⫺1 plus atropine to meet target heart rate

DSE ⫽ dobutamine stress echocardiography; MCE ⫽ myocardial contrast echocardiography; other abbreviation as in Tables 1 and 2.

showed that revascularization improved outcome in patients with ICM and a myocardial perfusion-metabolism mismatch of ⬎7% and did not in those with ⬍7% (29). SPECT has been a cornerstone of noninvasive imaging for many years. Myocardial perfusion and hibernating myocardium can be assessed from tracer uptake and redistribution specifically targeting cell membrane integrity and mitochondrial function (Table 4, Fig. 2). Other tracers targeting ␤-oxidation and assessment of function with low-dose dobutamine are available, but their clinical utility has not been sufficiently established (Table 4) (30). The main disadvantages of PET and SPECT remain their radiation exposure and relatively low spatial resolution. Echocardiography. Echocardiography is widely available, fast, relatively cheap, and therefore frequently used first line. Although improved function with low-dose dobutamine indicates hibernating myocardium (31,32), the occurrence of new wall motion abnormalities at higher stress levels or a biphasic response are considered diagnostic of inducible myocardial ischemia. Myocardial contrast echocardiography (MCE) further improves the accuracy to detect regional wall motion abnormalities (33). MCE has also been proposed for the detection of inducible myocardial ischemia during vasodilator stress and might evolve as an alternative to DSE for the assessment of ischemia (Table 5) (34,35). Quantification of myocardial blood flow using MCE is accurate for the

prediction of hibernating myocardium and seems to be superior to DSE and 201thallium-SPECT (32). Echocardiography has also been used for the detection and quantification of myocardial infarct scars, and good agreement with late gadolinium enhancement (LGE) CMR has been demonstrated (36). However, these recent advances need to be confirmed in larger studies. Clinically, routine echocardiography frequently suffers from poor acoustic windows and inadequate endocardial border definition. Computed tomography. Even though computed tomography (CT) can be used to assess LV function (37), perfusion (38), and scar (Table 2) (39), its main clinical application is imaging of the coronary arteries. Especially in patients with chronic CAD, CT may be limited by high calcium burden. Dedicated cardiac PET-CT and SPECT-CT systems may allow for the assessment of coronary artery anatomy and the presence and extent of ischemia and hibernating myocardium at the same time. Again, this approach might be hampered by high doses of ionizing radiation, particularly if coronary anatomy, function, hibernating myocardium, and perfusion are studied (40). Cardiac magnetic resonance. CMR is a comprehensive, accurate, and increasingly available method to assess patients with ICM and to guide therapy (41). CMR is the reference standard for the assessment of ventricular volume and function and the visualization of scar. It is

Cardiovascular Magnetic Resonance Table 6 Cardiovascular Magnetic Resonance Target

Method

Protocols

Interpretation

Oxygenation

DSMR (dobutamine ⫹ atropine)

Increasing dosages (ⱕ40 ␮g·kg⫺1·min⫺1 ⫹ atropine) to achieve target heart rate ([220 ⫺ age] ⫻ 0.85)

Ischemia can be diagnosed in presence of new wall motion abnormalities on cine CMR

Perfusion

Vasodilator (adenosine, dipyridamole)

Gadolinium first-pass perfusion

Induced underperfusion (“perfusion defect”) with stress that is reversible at rest is diagnostic of inducible ischemia

Hibernating myocardium

DSMR (dobutamine)

Low dosages (ⱕ10 ␮g·kg⫺1·min⫺1)

Increased contractility at low-dose stress in areas where there is hypokinesia at rest is diagnostic of hibernating myocardium

Hibernating myocardium

Scar (LGE)

Nonviability, extent of fibrosis/necrosis

Absence of scar in areas where there is hypokinesia at rest is diagnostic of hibernating myocardium

Abbreviations as in Tables 1 and 2.

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Figure 4

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CMR Scanning Following a Standardized Protocol Recommended by the SCMR

The figure shows the different protocols (43) we currently use to assess patients with ICM. Protocol 1 is a basic protocol for ejection fraction (EF) and scar. Protocol 2 is our standard protocol if the clinical question is mainly hibernating myocardium. If ischemia is also of clinical relevance, we add adenosine stress perfusion (protocol 4) or high-dose dobutamine (protocol 3). Although a high-dose dobutamine protocol is slightly quicker, the feasibility of adenosine perfusion in patients with low EF is somewhat higher because of fewer complications. It is important to note that there is currently no evidence showing the efficacy of adenosine perfusion imaging or high-dose dobutamine stress in patients with low EF. DSMR ⫽ dobutamine stress magnetic resonance; HD ⫽ high dose; LAX ⫽ long axis; LD ⫽ low dose; SAX ⫽ short axis; SCMR ⫽ Society for Cardiovascular Magnetic Resonance; SSFP ⫽ steady-state free precession; other abbreviations as in Figure 1.

highly accurate to assess contractile reserve and ischemia in a single examination without exposure to ionizing radiation. Furthermore, recent registry data showed that CMR provides an unsuspected new diagnosis in every fifth referral (42). The main limitations at this time are the exclusion of patients with pacemakers or cardiac resynchronization therapy devices and the potential reduction of image quality in patients with significant arrhythmia or severe shortness of breath.

CMR of Hibernating Myocardium Prediction of functional recovery. A basic CMR protocol includes the assessment of LV volumes and global and regional function (43) based on contiguous short-axis cine images (44). Different protocols focused on the clinical question are shown in Figure 4. LGE imaging visualizes irreversible damage (myocardial scar or fibrosis) due to an accumulation of contrast agent in areas with increased extracellular space (Fig. 2) (45). In LGE images, viable

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Figure 5

Images of a 51-Year-Old Male Patient With RCA-CTO

CMR showed reduced left ventricular (LV) systolic function (LVEF 45%) at rest with akinesia of the inferolateral wall at basal level. There was nontransmural scarring (25% to 50%) in the region of the wall motion abnormality. There was extensive inducible ischemia in the inferior and inferolateral walls with adenosine stress, which was not present at rest. The wall motion abnormality in the inferolateral wall at basal level was completely reversible with normal wall thickening during LD-DSMR (arrowheads). RCA-CTO ⫽ right coronary artery chronic total occlusion; other abbreviations as in Figures 3 and 4.

myocardium appears dark, whereas necrotic or fibrotic myocardial tissue appears bright. Myocardium with wall motion abnormalities at rest but remaining viable tissue is then regarded as hibernating. LGE has unprecedented spatial resolution (46) and can determine the transmural extent of scar and the remaining viable rim, which is not possible with other imaging modalities. The likelihood of functional recovery can be predicted based on scar transmurality (45): in the absence of scar, the likelihood of functional recovery is 78%; if the scar has more than 75% transmural extent, the likelihood of recovery is ⬍2%. However, the value of LGE to predict functional recovery in intermediate scars (ranging from 1% to 75% transmurality) is limited, with a likelihood of approximately 40% (45). In these patients, additional low-

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dose dobutamine stimulation can be performed in the same examination. Forty-two percent of segments with an intermediate scar show contractile reserve during lowdose dobutamine stimulation (47), and the combination of contractile reserve and scar quantification leads to optimal results (48). The specificity of low-dose dobutamine stress magnetic resonance (DSMR) to detect hibernating myocardium is superior to that of radionuclide methods (49), and endocardial and epicardial border definition are superior compared with those of echocardiography (50). Potentially sensitivity could be improved further by the use of myocardial tagging (Fig. 3) (51); however, this potential improvement needs to be confirmed in a controlled, prospective investigation. A more recent approach to hibernating myocardium is the assessment of the thickness and function of the remaining nonenhanced viable rim, which can potentially be combined with the previously mentioned parameters (52,53). Assessment of prognosis. Prognosis is progressively worse with increasing amounts of scar (54). Some evidence has suggested that scar detected by CMR is a stronger predictor of adverse clinical outcome than LVEF and volumes (55). In patients with fewer than 6 scarred segments, the presence of scar on LGE images was more accurate for predicting events than hibernating myocardium assessed by low-dose DSMR. Conversely, in patients with myocardial scar involving more than 6 segments, hibernating myocardium assessed by low-dose DSMR was a better predictor of events than scar tissue with LGE (56). Dall’Armellina et al. (57) investigated the relative merit of high-dose DSMR in 200 patients with EF ⬍55%. Although DSMR was an independent predictor of outcome with EF of 40% to 55%, it had no additional value in the presence of EF⬍40% (57). From a clinical perspective, a CMR examination including scar imaging and dobutamine contractile reserve may well emerge as the gold standard, with the particular advantage of targeting more than one surrogate parameter of hibernating myocardium. Its accuracy compared with that of other available techniques to predict functional recovery is shown in Figure 3. In general, methods looking at functional response to stress seem to be more predictive for functional recovery after revascularization than methods looking at nonviability (scar) or at cellular integrity. CMR of Ischemia Wall motion imaging during high-dose (ⱕ40 ␮g·kg⫺1·min⫺1 ⫹ atropine) DSMR as well as perfusion imaging during vasodilator stress are highly accurate for assessing ischemia (Table 6) and are appropriate tests for certain groups with stable angina (8,17,58,59). They are particularly helpful in combination with LGE to determine whether there are areas with ischemia extending beyond irreversibly scarred myocardium (60). DSMR mirrors DSE protocols and analyses (50). In combination with scar imaging, this technique delivers

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Figure 6

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Images of a 60-Year-Old Male Patient With RCA-CTO and Severe Proximal LAD Disease

CMR showed reduced LV systolic function (LVEF 25%) with severe wall motion abnormalities at rest predominantly in the anterior wall and the septum. The inferior wall showed moderate hypokinesia. There was nontransmural scarring (25% to 50%) in the anterior wall, septum (1% to 25%), and inferior wall (1% to 25%; arrowheads). All dysfunctional segments increased wall thickening with low-dose DSMR and showed diffuse inducible ischemia with adenosine (arrowheads). ED ⫽ end-diastolic; ES ⫽ end-systolic; LAD ⫽ left anterior descending coronary artery; other abbreviations as in Figures 3, 4, and 5.

accurate information on ischemia and hibernating myocardium. Quantitative assessment of strain at peak stress is mildly more accurate for ischemia detection than visual analysis alone (61). This may be of specific importance in patients with ICM because LV remodeling results in complex wall motion abnormalities at rest. High-dose dobutamine stress is not recommended in patients with EF ⬍25% due to increased incidence of complications (62). In addition to being more accurate, quantitative analysis of regional strain or the rapid untwisting of the heart in isovolumic relaxation might allow for the detection of ischemia below peak stress (63), potentially reducing the need for high-dose dobutamine stress (64). Advanced first-pass perfusion CMR imaging during adenosine-induced coronary vasodilation has unprecedented spatial resolution (ⱕ2 ⫻ 2 mm or better) and may detect ischemia in thinned and remodeled segments. Examples are shown in Figures 5 and 6. However, so far, there are no specific data on the accuracy of CMR perfusion imaging in patients with heart failure and low EF. Recent published reports have been based on patient populations with near normal EF (20,65) or did not look at subgroups of patients with different levels of LV function (66). These data may be important because the relatively slow transport of the contrast agent might obscure inducible ischemia. Future developments involve dobutamine stress perfusion imaging (67) and measurements of blood oxygenation levels (68) as an alternative to adenosine first-pass perfusion imaging. An additional advantage of imaging ischemia at the same time as hibernating myocardium is the potential detection of inducible ischemia in a coronary artery territory other than the territory under investigation for hibernating myocardium.

Conclusions Heart failure secondary to chronic CAD is a major problem in clinical cardiology. In patients with inducible ischemia and hibernating myocardium, revascularization is likely to result in improvement of regional and global LV function, heart failure symptoms, and long-term prognosis. Guidelines recommend revascularization in patients with hibernating myocardium based on previous evidence suggesting that patients with hibernating myocardium who were treated medically have an adverse prognosis. However, the STICH trial has challenged this view, particularly when DSE or SPECT is used to define hibernating myocardium. Noninvasive assessment of hibernating myocardium in patients with ICM can guide treatment; however, in light of this study, we may need to reconsider the optimal approach. Various tests are available for identifying hibernating myocardium: SPECT imaging is sensitive for detecting cellular integrity and is widely available. DSE is also widely available; however, the sensitivity of this technique is inferior, and the prognostic relevance of both SPECT and DSE have been called into question by the STICH data. In patients with severely depressed EF, PET imaging may be useful for assessment of hibernating myocardium because this technique has high sensitivity and superior resolution to SPECT. Contrast-enhanced CMR in combination with low-dose dobutamine stimulation seems to be the most accurate technique, with a growing body of evidence to support it. At this time, we tend to restrict the use of CMR to more complex patients. Future research will help us to better define the relative contribution of ischemia to outcome in patients with hibernating myocardium and the relative value of the different diagnostic techniques, particularly PET and CMR.

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Reprint requests and correspondence: Dr. Andreas Schuster, King’s College London, Division of Imaging Sciences and Biomedical Engineering, St. Thomas’ Hospital, London, United Kingdom. E-mail: [email protected]. REFERENCES

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Key Words: cardiovascular magnetic resonance imaging y hibernating myocardium y ischemia y ischemic cardiomyopathy y noninvasive imaging.