Review Article

Myocardial Viability and Microvascular Obstruction Role of Cardiac Magnetic Resonance Imaging Jorge Romero, MD,*† Florentino Lupercio, MD,*† Linda B. Haramati, MD, MS,*† Mario J. Garcia, MD,*†‡ and Richard J. Lucariello, MD*†

Abstract: Established coronary artery disease has a prevalence of 7% in adult Americans, accounting for 16 million people. As morbidity and mortality rates have risen, research efforts to identify the pathophysiologic mechanisms of systolic dysfunction have risen in parallel. The current goal is to develop new therapeutic strategies with the potential to reverse ­systolic dysfunction in patients with established coronary artery disease. Cardiac magnetic resonance imaging has gained a key role in cardio­vascular medicine. We will comment on the potential pivotal role of cardiac magnetic resonance imaging for the assessment of myocardial viability, including hibernating and stunned myocardium and microvascular obstruction. Key Words: myocardial viability, microvascular obstruction, cardiac magnetic resonance imaging, hibernating myocardium, stunned myocardium (Cardiology in Review 2014;22: 246–252)

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stablished coronary artery disease (CAD) has a prevalence of 7% in adult Americans, accounting for 16 million people. Cardiovascular preventive and therapeutic options have changed the clinical course of CAD from an acute and frequently fatal disease to a more chronic condition with an increasing prevalence of heart failure with impaired left ventricle (LV) systolic function.1 As morbidity and mortality rates have risen, research efforts to identify pathophysiologic mechanisms of systolic dysfunction have risen in parallel. The current goal is to develop new therapeutic strategies with the potential for reversing systolic dysfunction in patients with established CAD.2,3 The management of chronic CAD has changed with percutaneous and surgical coronary interventions offered to patients who would have previously been considered poor candidates for revascularization due to poor systolic function and high periprocedural risks. Improved surgical techniques and diagnostic tools that allow the differentiation of viable and nonviable myocardium allow for better selection of patients who are most likely to benefit. This has led to superior outcomes in LV function and subsequent heart failure morbidity.4,5 Cardiac magnetic resonance (CMR) is currently considered a reference standard in calculating myocardial mass and volumes from 3-dimensional data, increasingly relied on when accurate and reproducible data are crucial.6,7 In this review, we will comment on the potential pivotal role of CMR on the assessment of myocardial viability, including hibernating and stunned myocardium and microvascular obstruction (MVO). From the *Departments of Internal Medicine; †Division of Cardiology; and ‡Department of Radiology, Montefiore-Einstein Center for Heart and Vascular Care, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY. Disclosure: The authors have no conflicts of interest to report. Correspondence: Jorge Romero, MD, Montefiore-Einstein Center for Heart and Vascular Care, Albert Einstein College of Medicine, 111 East 210th Street, Silver Zone, Bronx, NY 10467-2400. E-mail: [email protected]. Copyright © 2014 Lippincott Williams & Wilkins ISSN: 1061-5377/14/2205-0246 DOI: 10.1097/CRD.0000000000000024

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MYOCARDIAL VIABILITY: MYOCARDIAL STUNNING VERSUS HIBERNATING MYOCARDIUM Prolonged ischemia triggers a cascade of events that lead to myocardial injury and terminate in cell death. However, it has long been recognized that revasculaization of dysfunctional but viable myocardium improves regional and global LV function.8–14 This dynamic state of the myocardium is represented by 2 distinct entities: myocardial stunning and hibernation. Myocardial stunning, originally described by Heyndrickx et al,15 is a reversible contractile dysfunction that occurs in the presence of restored coronary blood supply, after a brief period of reduced coronary blood. This contractile dysfunction can persist for several hours, days, weeks, or even months. A consensus time frame has yet to be defined. It is a potentially reversible injury that can lead to hemodynamic instability requiring aggressive management with inotropic agents, circulatory support devices (ie, intra-aortic balloon pump, impella device), and temporary ventricular assist devices.16 In clinical practice, various causes of myocardial stunning have been described, including CAD, global ischemia during coronary artery bypass grafting (CABG), and plaque disruption with distal embolization during percutaneous coronary intervention (PCI).17 In contrast, hibernating myocardium is a chronic phenomenon that has been defined as a state of persistently impaired myocardial function at rest leading to LV dysfunction attributable to chronically reduced coronary blood flow that can be partially or completely restored to normal either by improving blood flow or by reducing oxygen demand. This myocardium has potentially reversible contractile dysfunction and represents viable myocardium.3,18 There is compelling evidence that myocardial stunning and hibernation are not completely separate phenomena. A number of studies provide support for the hypothesis that hibernation may result from repetitive stunning, secondary to repeated episodes of ischemia or from chronic stunning. Thus, myocardial dysfunction in CAD may be a combination of both entities.19–21 A substantial amount of hibernating myocardium may be found in 50–80% of patients with ischemic cardiomyopathy.22,23 Understanding that hibernating myocardium is a potentially reversible phenomenon that requires the restoration of a normal blood supply for an improvement in contractile function is crucial. Therefore, accurately identifying the amount of hibernating myocardium in patients with ischemic cardiomyopathy might significantly increase the number of candidates who would benefit from myocardial revascularization.23

Cardiac Magnetic Resonance in the Evaluation of Myocardial Viability In general, noninvasive imaging techniques used to establish the presence of viable myocardium are based on demonstrating contractile reserve, sufficient perfusion for the delivery of substrates, removal of metabolic byproducts, intact cell membranes, and preserved metabolism.24 In the past, various imaging techniques have been studied including dobutamine stress echocardiography (DSE), positron emission tomography with fluorine-18 deoxyglucose (PET-FDG), single photon emission computed tomography (SPECT) with thallium-201

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stress-redistribution-reinjection, thallium-201 late redistribution, and technetium-99m sestamibi.25 Recently, CMR has become an increasingly accepted clinical tool, particularly due to its lack of radiation exposure, high spatial as well as temporal resolution, 3-D imaging and contrast resolution that enables tissue characterization.26 A basic resting CMR imaging protocol for the evaluation of myocardial viability includes scout images, steady-state free precession (SSFP) cine images in long- and short-axis planes to assess ventricular function and regional wall motion. Late gadolinium enhancement (LGE) images in long- and short-axis planes are then obtained (ie, dynamic first-pass perfusion imaging is performed in the short axis. The inversion time that best demonstrates myocardial nulling is chosen 8–10 minutes after contrast administration. Ten to 20 minutes after contrast administration, LGE imaging is performed using a 2- or 3-D inversion recovery fast gradient echo sequence in both short and long axis). LGE images are reviewed in conjunction with the cine images. Myocardium that demonstrate wall motion abnormalities but not LGE are considered viable. The transmural extent of LGE also has prognostic implications with myocardial segments that demonstrate LGE with 2 mm), but not scarred myocardium. This is due to the fact that only viable myocytes are capable of responding to an inotropic stimulus. It is recommended that patients be monitored for ischemic symptoms or electrocardiographic changes, arrhythmias, severe changes in blood pressure, and new wall motion abnormalities. The main contraindications to dobutamine stress CMR are severe systemic hypertension, unstable angina, severe aortic stenosis, and a history of complex cardiac arrhythmias.24

Accuracy of Cardiac Magnetic Resonance in the Identification of Hibernating Myocardium The accuracy of CMR in the detection of viable myocardium and comparisons with previous trials using DSE and SPECT have been made.29–32 In the setting of chronic LV dysfunction, we recently published a meta-analysis describing the accuracy of different MR sequences to identify hibernating myocardium.33 Our meta-analysis indicates that LGE provides the highest sensitivity and the highest negative predictive value (NPV) for improved segmental LV contractile function after revascularization. On the contrary, dobutamine stress CMR offered the highest specificity and positive predictive value (PPV). These differences in diagnostic accuracy might be primarily due to the fact that LGE-CMR is essentially an anatomic test and that dobutamine stress CMR provides a physiologic assessment. Therefore, if a myocardial segment contracts with dobutamine, it will most likely be viable after coronary revascularization, making this modality a more specific test. We further compared these values with those reported for 4 different imaging modalities scrutinized in the meta-analyses published by Bax et al34 and Schinkel et al,35 including DSE, www.cardiologyinreview.com | 247

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FIGURE 1.  Ischemic and nonischemic patterns of hyperenhancement on late gadolinium enhancement-cardiac magnetic resonance. Due to the nature of its blood supply, the subendocardium is the portion of the myocardium that is most sensitive to ischemic insults. Thus, the most common reason for delayed contrast enhancement in this region is a nontransmural infarction. If the enhancement involves >50% of the myocardial thickness, the infarction is considered transmural. Transmurality is inversely proportional to viability and prognosis. Abnormal enhancement caused by ischemic heart disease should be limited to a vascular territory and is usually accompanied by regional wall motion abnormalities. Reprinted with permission from Rajiah et al.27

FIGURE 2.  Algorithm for the evaluation of myocardial viability with cardiac magnetic resonance. In a patient with LV dysfunction and regional wall motion abnormalities, LGE-CMR should be the initial test, given its high NPV. If no hyperenhancement is seen and there is evidence of coronary artery disease, revascularization is indicated. If hyperenhancement is >50% of the region affected, the infarct is considered transmural and nonviable. Medical therapy should be started. If hyperenhancement is 50% transmularity were considered nonviable due to the high specificity and NPV of this technique. In patients with segments showing 50% was used to determine whether a segment was viable or not. On DS-CMR testing, viability was defined as a 2-mm increase in LV systolic wall thickening during a variable infusion rate of 5–10 mg/kg/min. DS-CMR indicates dobutamine stress cardiac magnetic resonance; LGE-CMR = late gadolinium enhancement-cardiac magnetic resonance; NPV, negative predictive value; PPV, positive predictive value.

greater functional recovery after CABG. Similarly, Nagel and Schuster’s algorithm based on our results suggests that complete absence of LGE provides also acceptable specificity and PPV. This combined approach has yet to be validated in a large-scale randomized trial.37

Accuracy of Cardiac Magnetic Resonance in the Identification of Stunned Myocardium In the setting of myocardial stunning, the accuracy of CMR imaging has been previously assessed. The CMR sequences in detecting stunned myocardium are similar to those used for the detection and evaluation of hibernating myocardium. In a recent meta-analysis, we showed that LGE-CMR provides the highest sensitivity and NPV for detecting stunned myocardium, while dobutamine stress CMR provides the highest specificity and PPV.38 Comparing our results with individual studies using different imaging modalities, CMR's superiority was evident. The diagnostic value of CMR in the detection of myocardial stunning and hibernation is displayed in Table 1. Although the overall trend of accuracy is similar, differences in performance of CMR in detecting hibernating myocardium compared to stunning are evident. These differences in performance may be due to the differences in timing of follow-up CMR imaging, given the lack of a standard temporal definition of myocardial stunning. In addition, there is an expected decrease in scar volume over time after acute myocardial infarction, which may further add to the difficulty in predicting viability.

Viability Testing and Treatment of Coronary Artery Disease Associated Left Ventricular Dysfunction: Clinical Outcome Prediction LV systolic dysfunction in patients with CAD has consistently been shown to be an important independent predictor of death.39–41 The role of revascularization with CABG or PCI in the treatment of patients with CAD and heart failure has not been clearly established. Previous observational studies have suggested the potential long-term survival benefit of CABG versus medical therapy alone.42 Recently, these findings were evaluated in the Surgical Treatment for Ischemic Heart Failure (STICH) trial, a prospective, multicenter, nonblinded randomized trial in which a major hypothesis was that CABG plus intensive medical therapy based on current guidelines, compared with medical therapy alone, would reduce mortality. However, the study failed to show a significant difference between the 2 groups with respect to the primary endpoint of death from any cause. Nonetheless, results slightly in favor of CABG were seen with respect to the rate of death from cardiovascular causes and in the rate of hospitalization for cardiovascular causes in the intention-to-treat analysis.43 In the absence of direct evidence that CABG provided a survival benefit in patients with CAD and LV dysfunction, attention has been placed on the detection of viable myocardium. The selection © 2014 Lippincott Williams & Wilkins

of patients for revascularization based on the presence of significant viable myocardium, and thus, potential reversibility of LV dysfunction, has a rational basis. Studies have documented that these selected patients have an improvement in LV regional and global function, benefits in quality of life, and diminished heart failure symptoms.5,44,45 There is a body of evidence suggesting that there is a mortality benefit to selecting patients for revascularization based on viability status. A meta-analysis published in 2002 in which 24 observational studies with over 3000 patients were pooled, suggested an annual mortality of 16% in medically treated patients with viable myocardium versus only 3.2% in revascularized patients. In patients without viable myocardium, no significant difference was detected between the treatment groups. The imaging studies used to evaluate viability status were SPECT, low-dose DSE (or high dose with atropine augmentation), and PET-FDG.46 A subanalysis of the STICH trial addressed the question of whether or not myocardial viability had an effect on patient outcome. The original design of the STICH trial required patients to undergo viability testing with SPECT. However, as enrollment was hindered due to this requirement, viability testing became optional and could be evaluated with SPECT or DSE. As a result, the analyses were conducted on an “as available” basis. On univariate analysis, there was a significant association between myocardial viability and overall rate of death with a reported hazard ratio of 0.64 (95% CI 0.48–0.46; P = 0.003) in patients with viable myocardium; however, this association lost significance on multivariable analysis.47 Limitations in the study make it difficult to interpret this lack of significance. First, viability testing was not performed on a randomly selected subgroup of patients, but rather was obtained according to test availability and provider judgment. The analyses only included 601 of the 1212 patients in the hypothesis 1 component of the trial. Moreover, within this limited group, the sample size of patients with nonviable myocardium was relatively small, making it difficult to identify significant differences in outcomes. Second, revascularization was not guided by the presence of viable myocardium. Furthermore, as previously mentioned, SPECT and DSE have a significantly lower specificity and sensitivity than CMR. Many of these limitations were further analyzed recently in a publication questioning the current relevance of viability testing.48 Thus, ambiguity strongly calls for further well-designed prospective trials of viability testing using more accurate imaging modalities such as CMR and using the algorithm integrating LGE and dobutamine stress techniques in patients with moderate-tosevere ischemic LV systolic dysfunction being evaluated for revascularization either with PCI or CABG. In the setting of myocardial stunning, the potential therapeutic interventions that can be considered are less clear. It is logical to believe that in the absence of significant myocardial stunning, that the www.cardiologyinreview.com | 249

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LV ejection fraction will remain low over time. Therefore, advanced therapies such as implantable cardioverter-defibrillators (ICD) could be considered earlier when the incidence of sudden cardiac death is the highest.49 Currently, the consensus opinion is to wait 3 months for evaluation of necessity of ICD.50 More studies are necessary to justify earlier ICD placement based on CMR findings. Furthermore, in the advent of significant myocardial stunning, aggressive invasive and/ or novel treatment strategies maybe indicated. However, evidence in this regard is limited. The reader is referred to a recent review by Siribaddana,51 discussing the treatment options in the CABG patient with cardiac dysfunction.

MICROVASCULAR OBSTRUCTION AND INTRAMYOCARDIAL HEMORRHAGE The “no-reflow phenomenon” was initially described in the 1970s by Kloner et al52 in a canine model of ischemia reperfusion which showed the lack of dye penetration to subendocardial tissue after prolonged occlusion of epicardial vessels; the failure of reflow was associated with extensive capillary damage and myocardial cell swelling. In humans, the physiopathological process of spontaneous coronary plaque rupture or the mechanically induced coronary plaque rupture by PCI might lead to embolization of atherosclerotic and thrombotic materials with subsequent distal vessel inflammatory response that leads to clinical no-reflow. This no-reflow is depicted in CMR as hypoenhanced areas within the core of the infarct zone following gadolinium administration and it is termed “microvascular obstruction.”53,54 This hypoxic-reperfusion injury is also known to facilitate disruption of the endothelial barrier and microvasculature, which precipitates red blood cell extravasation upon reflow, causing intramyocardial hemorrhage (IMH). This is most likely visible on T2-weighted images as hypoenhanced regions which may be surrounded by hyperenhanced areas representing myocardial edema (Figs. 3A, B, 4).55,56 MVO has been found to correlate with and predict clinical outcomes and adverse LV remodeling, initially reported by Wu et al57 in late 1990s. A higher incidence of major adverse cardiac events (MACE) was found in patients with MVO seen 1 to 2 minutes

after gadolinium administration than those without it (45% versus 9%; P = 0.016) and in a positive correlation with LV remodeling (P < 0.05).57 Several subsequent studies have shown similar outcomes inclusively after adjusting for other predictors such as infarct size, intracardiac hemorrhage, and LV ejection fraction.58–60 Only a few studies report that MVO is dependent of infarct size.61,62 With most of the evidence favoring MVO as an important magnetic resonance outcome predictor, the lack of standardized CMR protocols and timing of imaging postmyocardial infarction has contributed to the persistent heterogeneous outcome results.63 Recognition and quantification of MVO has been assessed by multiple techniques that differ on the delay between gadolinium administration and image acquisition, as first pass perfusion early and LGE sequences.64,65 As the presence and extent of MVO decreases between early and late imaging, Mather et al64 showed a higher sensitivity for MVO with first pass perfusion versus early or LGE (incidence of 22% by perfusion vs 14% by LGE). Nonetheless, the LGE sequence demonstrated the most consistent quantification of MVO. The presence and extent of MVO in LGE were identified by de Waha et al60 as the strongest predictors for MACE in a multivariable Cox regression analysis (hazard ratio 4.23, 95% CI 1.73–10.34, P = 0.002). When LV remodeling was assessed, Nijveldt et al65 reported that MVO on LGE was the strongest predictor for increase in LV systolic and diastolic volumes. Likewise, intermediate and LGE had the best correlation with further LV ejection fraction.65 Given the evidence of MVO portending a poor prognosis, efforts have been made to develop interventions targeting MVO after PCI with the aim of preventing or limiting it.54 Vasodilators have demonstrated benefit in treating MVO. Recently, Doolub and Dall’armellina66 found significant evidence that selective high-dose intracoronary administration of adenosine distal to the occlusion site of the culprit lesion in ST-elevation myocardial infarct patients results in a decrease in incidence and size of MVO. Likewise, IIb/IIIa inhibitors have been reported to reduce MVO and MACE incidence and improve LV function by CMR.67 Mechanical interventions have been assessed as well. Although thrombectomy significantly reduced MACE and the incidence of MVO, conflicting results have been reported for “conditioning” therapies.68–71

FIGURE 3.  A and B, Sixty-two-year-old man underwent magnetic resonance imaging 3 days after percutaneous coronary intervention for acute inferior myocardial infarction. Short-axis T2-weighted image demonstrates dark signal surrounded by higher signal consistent with myocardial hemorrhage and microvascular obstruction (MVO) with associated edema. Late gadolinium enhancement (LGE) short-axis image at the same level shows transmural high signal LGE of the inferior wall with several foci of low signal at the core of the infarct, in the mid-myocardium, typical for MVO. 250  |  www.cardiologyinreview.com

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FIGURE 4.  Sixty-nine-year-old women who underwent magnetic resonance imaging after an acute lateral wall myocardial infarction. Late gadolinium enhancement (LGE) image in the axial plane demonstrates a focal area of transmural high signal LGE in the mid lateral. There is a central focus of low signal at the core of the infarct, in the mid-myocardium, typical for microvascular obstruction. Note increased wall thickness at the site of the infarct which can be due to edema and hemorrhage. Both MVO and IMH are currently considered manifestations of the same physiopathological process; both can appear in T2 MR images as hypoenhanced rings within the infarct zone and are difficult to distinguish given their anatomic correlation.72,73 In addition, the role of “reperfusion induced hemorrhage” has gained attention. Robbers et al72 recently depicted the close correlation between MVO and IMH in animal models. On microscopic histological assessment, they found red blood cell extravasation and the absence of microthrombi normally seen in humans with acute myocardial infarction. This suggests that the term MVO for the abscess of gadolinium enhancement might not be completely appropriate.72 Furthermore, several studies have shown intramyocardial hemorrhage to be an independent predictor of MACE and to provide additional prognostic value beyond MVO alone74–76 (Figs. 3A, B, 4).

CONCLUSIONS Myocardial viability and MVO continue to be studied as prognostic indicators in CAD and LV dysfunction and the role of CMR is evolving and under ongoing investigation. Given the versatility and accuracy of CMR in comparison to other imaging modalities, it is probable that it will become the reference standard for viability imaging. The data presented here suggest that a combined assessment with LGE and dobutamine stress CMR may provide the highest diagnostic value in guiding treatment decisions and predicting functional recovery. Currently, preliminary evidence supports the prognostic value of identifying MVO and IMH in acute myocardial infarction. Further study of the value of CMR for patients with CAD is needed with well-designed randomized, long-term, large-scale clinical trials that measure hard outcomes. REFERENCES 1. Wilkins JT, Ning H, Berry J, et al. Lifetime risk and years lived free of total cardiovascular disease. JAMA. 2012;308:1795–1801. 2. Rahimtoola SH. Coronary bypass surgery for chronic angina—1981. A perspective. Circulation. 1982;65:225–241.

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Myocardial viability and microvascular obstruction: role of cardiac magnetic resonance imaging.

Established coronary artery disease has a prevalence of 7% in adult Americans, accounting for 16 million people. As morbidity and mortality rates have...
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