“Shades of Gray” in Cardiac Magnetic Resonance Images of Infarcted Myocardium
Can They Tell Us What We’d Like Them to?
Identifying individuals at risk of sudden death continues to be a challenging problem. Subgroups classified as high risk on the basis of prior myocardial infarction, low ejection fraction, and arrhythmia-related parameters are recognized to include only a small proportion of the sudden cardiac deaths occurring annually.1 Nevertheless, as the indications for implantable cardioverter-defibrillators expand to intermediate-risk groups, issues related to cost and the potential morbidity of implantable cardioverter-defibrillator implantation take on greater significance.
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The possibility that high-resolution cardiac magnetic resonance imaging (CMR) of acute and chronic infarctions with the use of delayed gadolinium enhancement2 can improve risk stratification is now being evaluated by several groups. Bello et al3 have reported that measurements of infarct mass and surface area predict inducible monomorphic ventricular tachycardia more reliably than ejection fraction does in coronary patients referred for electrophysiological study. Because of the known limitation in positive predictive accuracy of electrophysiological testing,4 a need remains for studies of more definitive outcomes. Although CMR measurements of infarct size have also been used to forecast the extent of functional recovery after acute infarction and myocardial revascularization, studies of their predictive value for mortality are just beginning to become available.
The study of Yan et al5 in this issue provides an initial look at the mortality question. It proposes a new approach for identifying a “potentially arrhythmic heterogeneous zone of viable and nonviable peri-infarct myocardium.” The authors hypothesize that the size of this zone can provide prognostic value for mortality incremental to that offered by ejection fraction and left ventricular (LV) end-systolic volume. Their study group consisted of patients with a history of coronary artery disease referred for CMR examination and found to have areas of myocardial delayed gadolinium enhancement. With the use of specialized image analysis software, the areas of delayed enhancement were subdivided into “core” and “peri-infarct” zones on the basis of differences in signal intensity (core zone = signal ≥3 SD above that in remote noninfarcted myocardium, and peri-infarct zone = signal 2 to 3 SD above that in remote myocardium).
When peri-infarct zones (MDEperiphery) defined in this manner were expressed as percentages of total infarct size, patients with percentages above the median proved to be at higher risk of death than those with values below the median. Even after adjusting for age and LV ejection fraction, %MDEperiphery remained independently associated with all-cause and cardiovascular mortality (median follow-up, 2.4 years). The study concludes that infarct characteristics quantified by delayed contrast-enhanced imaging “may prove to be a unique and valuable noninvasive predictor of post–myocardial infarction mortality.”
The approach for identifying a “peri-infarct” zone consisting of an admixture of viable and nonviable myocardium is a clever attempt to capitalize on partial volume effects, which are ordinarily considered an artifact of images with lower-than-ideal resolution. In both situations, different signal intensities within a single voxel are averaged; the important question is what the component signals represent:
Admixture of viable and nonviable myocardium clearly does alter signal intensity. Even when areas of delayed gadolinium enhancement correspond exactly with areas of triphenyltetrazolium chloride (TTC) negativity in ultra–high-resolution ex vivo images (0.5×0.5×0.5 mm), partial volume effects produce intermediate signal intensities along the periphery of the hyperenhanced area when images are summated into a clinically typical 8-mm slice.6
Because voxels overlap the LV cavity and extramyocardial tissue at the endocardial and epicardial myocardial borders, the manually drawn endocardial and epicardial borders of even interpolated images must exclude the innermost and outermost edges of myocardium. The degree to which this is necessary increases with slice thickness as the ventricle tapers from base to apex.
From a technical viewpoint, the importance of careful T1 nulling of remote noninfarcted myocardium is now well recognized.7 The optimal cutoff values for normal, peri-infarct, and core zones of myocardium are unknown and may in fact vary, depending on the quality of the study. When areas of microvascular obstruction are evident, it seems reasonable to incorporate them into the “core” infarct zone (as done in the present study). It is uncertain whether differences in contrast wash-in and wash-out patterns in core and peri-infarct areas that have been demonstrated in the first few hours after an acute infarction8 can be a confounding factor at later stages of acute infarction or in chronic infarction.
Intermediate-intensity hyperenhancement can be seen in a number of clinical entities other than coronary disease–induced myocardial infarction—for example, nonischemic cardiomyopathy, myocarditis, and hypertrophic cardiomyopathy. Differing patterns of hyperenhancement help to identify the noncoronary origins of disease.
As the authors carefully point out, the present findings have important limitations. The patient group is relatively small (n=144), and the primary reasons for CMR study were variable: assessment of myocardial viability and infarct size (39% of patients), myocardial ischemia (40%), and assessment of microvascular dysfunction after reperfusion in acute infarction (16%). In addition, a 20% mortality rate over a median follow-up period of 2.4 years seems unusually high for infarctions averaging 17% of LV mass and having LV ejection fractions averaging 44%. Kaplan-Meier analysis (Figure 2 in Yan et al5) indicates that 62% of deaths (18/29) occurred within 1 year after CMR was performed. It is important to note that these observations may reflect selection and/or referral bias. Additionally, information about the circumstances of death is available in only 69% (19/29) of fatal cases. Although all deaths for which information was available could be classified as cardiovascular, it is also unknown how many may have been precipitated by arrhythmia rather than advanced congestive failure or recurrent ischemia/infarction.
The fact that patients with values of %MDEperiphery above the median proved to be at increased risk of death despite having significantly smaller infarcts than those below the median is in some respects puzzling. The suggestion that relative increases in peri-infarct zone can identify “morphologically complex infarcts (which) may portend a worse outcome” is provocative. However, the strengths and limitations of %MDEperiphery as a prognostic factor for mortality merit further exploration. The delayed enhancement criterion used to define MDEperiphery in the present study is admittedly arbitrary. Additional indexes of tissue heterogeneity must be investigated, and others have already been proposed.9,10 The ratio of surface area to volume of an infarct may be an additional consideration—that is, should this ratio vary inversely with infarct size, smaller infarcts might be expected to have larger values of %MDEperiphery on the basis of geometry alone. In the present study, %MDEperiphery and total infarct size did show a negative correlation for the entire patient group (r=−0.50, P<0.0001).
Finally, it is surprising that infarct size was not associated with mortality in this study. As the authors suggest, this may relate to the variable chronicity of myocardial infarction and/or inadequate study power caused by the relatively small sample size. It should be noted that greater absolute values of MDEperiphery did show a significant association (P=0.035) with a higher risk of death, albeit less strongly so than %MDEperiphery. This seems compatible with the substantial evidence indicating that infarct size and mortality are usually related11,12 and the likelihood that absolute values of MDEperiphery vary directly with infarct size.
As the authors caution, the report of Yan et al5 should be regarded as a pilot study of a potentially novel approach for improving our ability to identify patients with coronary disease who are at increased risk of unexpected death. It nonetheless represents a valuable initial application of emerging, widely applicable CMR technology to assess postinfarction mortality directly rather than through surrogate parameters. Studies of larger, less heterogeneous patient groups, with more complete mortality information and less opportunity for selection and referral bias, should allow the present findings to be placed in proper clinical context. These studies can also evaluate a variety of criteria for determining whether infarct tissue heterogeneity characterized by delayed contrast enhancement can indeed provide new prognostic information.
Sources of Funding
Dr Klocke is a co-investigator on 2 NIH grants dealing with CMR: RO1 HL057484 (Detection of Coronary Stenoses Using T2 MRI) and RO1 HL070859 (MRI-Guided Angioplasty of Coronary Stenosis). Dr Wu is the principle investigator on several grants: an AHA Greater Midwest Affiliate research grant, “Detection of Microvascular Obstruction in Acute Myocardial Infarction by Contrast-Enhanced MRI”; a Women’s Board of Northwestern Memorial Hospital research grant, “Rapid Evaluation of Myocardial Function Using 3D Tomographic Imaging”; a Northwestern Memorial Hospital research grant, “Diagnostic MRI Evaluation in Suspected Congestive Heart Failure”; and a GlaxoSmithKline Research and Education Foundation for Cardiovascular Disease research grant, “Intracoronary Adenosine to Prevent Microvascular Obstruction as Determined by Cardiac Magnetic Resonance Imaging in Patients With Acute ST-Segment Myocardial Infarction.” Dr Wu is also a co-investigator on NIH RO1 HL079148, “Self-Gated Cardiac MRI.” Dr Lee is the principle investigator on an AHA Fellow-to-Faculty Transition Award, “Quantification of Myocardial Blood Flow by Cardiac Magnetic Resonance Imaging.”
Dr Wu has served as a consultant for Mallinckrodt Imaging (performed blinded reading of CMR images in a study of myocardial infarct detection). The other authors report no disclosures.
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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