EXPEDITED PUBLICATION: EDITORIAL COMMENT
Fighting the "Fire" of Myocardial Reperfusion InjuryHow to Define Success?*
Katherine C. Wu, MD, FACC*
Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland
* Reprint requests and correspondence: Dr. Katherine C. Wu, Division of Cardiology, Johns Hopkins Hospital, 600 N. Wolfe Street, Carnegie 568, Baltimore, Maryland 21287 (Email: kwu{at}jhmi.edu).
Key Words: myocardial reperfusion injury • cardiac magnetic resonance imaging • microvascular obstruction
It is axiomatic that after an acute myocardial infarction, the greatest impact in limiting infarct size and improving patient prognosis occurs with prompt reperfusion by mechanical or pharmacologic thrombolysis. However, as Jennings et al. (1) originally observed, reperfusion itself potentially exacerbates myocardial damage above that produced by the initial ischemic insult in 2 irreversible ways: lethal reperfusion injury and vascular reperfusion injury or no-reflow (1–3). Lethal reperfusion injury arises when sudden restoration of coronary flow causes necrosis of myocytes that, while injured by the antecedent ischemia, were potentially salvageable at the time of reperfusion. Postulated mechanisms include the interactive effects of abrupt bio- chemical and metabolic alterations provoked by reperfusion, specifically, inflammation, calcium overload, oxidative stress, the rapid restoration of normal pH, and mitochondrial re-energization. The second form of reperfusion injury is that of no-reflow or microvascular obstruction (MVO). This describes the further disruption upon reperfusion of the microvascular architecture, already subjected to ischemia-induced endothelial injury. With reintroduction of epicardial flow, there is additional endothelial disruption and capillary plugging by inflammatory cells and microthrombi due to activation of inflammatory pathways, reactive oxygen species, and the complement system. That limits adequate tissue perfusion distally.
In animal models, lethal reperfusion injury accounts for up to 50% of the final infarct size (3,4). One report involving serial cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement (LGE) suggests ongoing myocardial injury up to 48 h post-reperfusion with increases in total infarct size and MVO (5). Multiple agents have successfully limited infarct size when delivered just before or at the time of reperfusion (3,4). Despite promising experimental data, confirmation of therapeutic efficacy of a reperfusion adjunct in human clinical trials continues to be elusive, as demonstrated by the results of the phase II trial, the F.I.R.E. (Efficacy of FX06 in the Prevention of Myocardial Reperfusion Injury) study, using FX-06, reported in this issue of the Journal (6). FX06 is an anti-inflammatory fibrin derivative that competes with fibrin fragments for binding with the vascular endothelial molecule VE-cadherin, deterring transmigration of leukocytes across the endothelial cell monolayer from the bloodstream into the infarcted tissue. It could thus theoretically reduce both lethal reperfusion injury and no-reflow/MVO. In this multicenter trial involving 26 European sites, 234 patients (of 252 screened) with first ST-segment elevation myocardial infarction (STEMI) were randomly assigned to either placebo or FX-06 given in 2 intravenous boluses at the time of percutaneous coronary intervention (PCI). The pre-specified primary end point of total infarct size, as measured by CMR-LGE, was not different between the 2 groups. However, the authors report a significant reduction in the secondary end point of the "necrotic core zone" as well as encouraging results with regard to the safety and tolerability of FX-06.
Is the F.I.R.E. study just another disappointing example in a long list of failed adjunctive therapies for reperfused MI, or can we learn from its design? A notable strength is the use of CMR-LGE, which accurately indexes the region of irreversible myocardial injury. In fact, it is the first published multicenter trial of a therapeutic reperfusion agent that implements CMR-LGE to quantify the primary end point. While the nuclear technique of single-photon emission computed tomography (SPECT) is an established method for infarct quantification, the higher spatial resolution of CMR-LGE allows increased sensitivity for infarct detection, particularly of subendocardial infarcts (7). Infarct size by CMR-LGE also has higher reproducibility than SPECT, allowing a potential sample size reduction to 42% of that required for SPECT (8). This is advantageous, even when considering the relatively high dropout rates in the F.I.R.E. study: 87% of those eligible completed CMR-LGE at 5 days post-MI whereas only 74% underwent follow-up CMR at 4 months. These are likely realistic rates and are certainly comparable to those expected for nuclear imaging. They do, however, have to be factored into sample size calculations or else one risks loss of statistical power to detect group differences, particularly at later time points, as was observed with the F.I.R.E. study.
While it is encouraging that a CMR-LGE study was successfully executed in a multitude of centers with varying CMR expertise, using scanners from all major vendors, it is critical that emphasis be placed on methodology to ensure uniformity, accuracy, and reproducibility of image acquisition and interpretation. It is particularly critical to provide specific details on how total infarct size, MVO, and necrotic core regions were defined. Prior studies in which the necrotic core zone was differentiated from the infarct periphery used the semiautomatic criterion of full-width one-half maximum with high reproducibility (9,10). If subjective planimetry of the regions of interest is proposed instead, as was presumably done in the F.I.R.E trial, it is insufficient to only report the variability in the identification of myocardial CMR-LGE areas (i.e., presence or absence). Rather, in-depth reproducibility of the actual infarct size quantification results (including MVO and necrotic core regions) are required. Additionally, the use of the nonstandard, relatively high 0.25 mmol/kg gadolinium dosing for LGE (11) has disadvantages, the risks of nephrogenic sclerosing fibrosis notwithstanding. The brighter blood pool may cause underdetection of subendocardial infarcts. Higher gadolinium dosing may also lead to underestimation of MVO, particularly as MVO was measured relatively late after contrast administration, allowing ample time for contrast diffusion into the true no-reflow region.
Several other advantages of CMR could be exploited in future studies. Myocardial edema is a hallmark of even transient periods of ischemia that impair the sodium-potassium-adenosine triphosphatase pump function, allowing intracellular sodium accumulation. The T2-weighted CMR sequences are ultrasensitive to water-bound protons and can distinguish acute from chronic MI (12). Recently, the T2-weighted technique has demonstrated high accuracy in measuring the area at risk in reperfused infarcts (13,14) and has been applied to patients (14). This technique allows the direct quantification of myocardial salvage, which is a better indicator of therapeutic efficacy in MI trials, given the strong influences of collateral flow and area of risk on final infarct size. Furthermore, serial imaging to assess changes in T2 region, MVO, necrotic core, and total infarct size could be quite powerful to better understand the pathophysiology and document the extent and time course of human reperfusion injury. Serial imaging expands the potential appeal of CMR-LGE as a clinical trial tool since both reversible and irreversible injury can be potentially quantified in a single examination post-revascularization and tracked serially over time.
In summary, to determine the efficacy of adjunctive reperfusion therapy in humans, judicious selection and definition of end points are paramount. For phase II clinical trials, it is most logical to select the efficacy end point of infarct size, and CMR-LGE is particularly effective for substantiating the existence and quantifying the extent of reperfusion injury and verifying persistent therapeutic benefits. While it is important pathophysiologically to document acute decreases in infarct size and MVO, an agent should demonstrate sustained, long-term infarct size reduction to be a plausible therapeutic candidate. With an increased incorporation of CMR to measure end points in clinical infarct trials, one may be better able to gauge the success of cardioprotective strategies in patients.
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Footnotes
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Dr. Wu is supported by the Donald W. Reynolds Cardiovascular Research Center at Johns Hopkins University; and has received research grant support from GE Healthcare Technologies.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Jennings RB, Sommers HM, Smyth GA, et al. Myocardial necrosis induced by temporary occlusion of a coronary artery in the dog Arch Pathol 1960;70:68-78.[Web of Science][Medline]2. Braunwald E, Kloner RA. Myocardial reperfusion: a double-edged sword? J Clin Invest 1985;76:1713-1719.[Web of Science][Medline] 3. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury N Engl J Med 2007;357:1121-1135.[CrossRef][Web of Science][Medline] 4. Dirksen MT, Laarman GJ, Simoons ML, Duncker DJ. Reperfusion injury in humans: a review of clinical trials on reperfusion injury inhibitory strategies Cardiovasc Res 2007;74:343-355.[Abstract/Free Full Text] 5. Rochitte CE, Lima JA, Bluemke DA, et al. Magnitude and time course of microvascular obstruction and tissue injury after acute myocardial infarction Circulation 1998;98:1006-1014.[Abstract/Free Full Text] 6. Atar D, Petzelbauer P, Schwitter J, et al. Effect of intravenous FX06 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction: results of the F.I.R.E. (Efficacy of FX06 in the Prevention of Myocardial Reperfusion Injury) trial J Am Coll Cardiol 2009;53:720-729.[Abstract/Free Full Text] 7. Wagner A, Mahrholdt H, Holly TA, et al. Contrast-enhanced MRI and routine single photon emission computed tomography (SPECT) perfusion imaging for detection of subendocardial myocardial infarcts: an imaging study Lancet 2003;361:374-379.[CrossRef][Web of Science][Medline] 8. Mahrholdt H, Wagner A, Holly TA, et al. Reproducibility of chronic infarct size measurement by contrast-enhanced magnetic resonance imaging Circulation 2002;106:2322-2327.[Abstract/Free Full Text] 9. Amado LC, Gerber BL, Gupta SN, et al. Accurate and objective infarct sizing by contrast-enhanced magnetic resonance imaging in a canine myocardial infarction model J Am Coll Cardiol 2004;44:2383-2389.[Abstract/Free Full Text] 10. Schmidt A, Azevedo CF, Cheng A, et al. Infarct tissue heterogeneity by magnetic resonance imaging identifies enhanced cardiac arrhythmia susceptibility in patients with left ventricular dysfunction Circulation 2007;115:2006-2014.[Abstract/Free Full Text] 11. Kramer C, Barkhausen J, Flamm S, et al. Standardized cardiovascular magnetic resonance imaging (CMR) protocols, Society for Cardiovascular Magnetic Resonance: Board of Trustees Task Force on Standardized Protocols J Cardiovasc Magn Reson 2008;10:35.[Medline] 12. Abdel-Aty H, Zagrosek A, Schulz-Menger J, et al. Delayed enhancement and T2-weighted cardiovascular magnetic resonance imaging differentiate acute from chronic myocardial infarction Circulation 2004;109:2411-2416.[Abstract/Free Full Text] 13. Aletras AH, Tilak GS, Natanzon A, et al. Retrospective determination of the area at risk for reperfused acute myocardial infarction with T2-weighted cardiac magnetic resonance imaging: histopathological and displacement encoding with stimulated echoes (dense) functional validations Circulation 2006;113:1865-1870.[Abstract/Free Full Text] 14. Friedrich MG, Abdel-Aty H, Taylor A, et al. The salvaged area at risk in reperfused acute myocardial infarction as visualized by cardiovascular magnetic resonance J Am Coll Cardiol 2008;51:1581-1587.[Abstract/Free Full Text]
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