Noninvasive Evaluation of No-Reflow Phenomenon

Circulation: Cardiovascular Imaging EDITORIAL Noninvasive Evaluation of No-Reflow Phenomenon Potential Role of Molecular Imaging See Article by Ozawa et al Albert J. Sinusas, MD REPERFUSION INJURY POST-MYOCARDIAL INFARCTION Downloaded from http://ahajournals.org by on July 7, 2020 The primary treatment for acute myocardial infarction (MI) involves early revascularization, and millions of individuals each year presenting with acute MI are successfully treated with early and effective interventional reperfusion strategies. However, despite this initial strategy to reduce the ischemic injury post-MI, these patients are at significant risk for additional acute reperfusion injury and subsequent adverse left ventricular remodeling and heart failure.1 In this context, a period of ischemia that is followed by reperfusion initiates a cascade of biological events within the injured myocardium, leading to reperfusion injury. This reperfusion injury can be associated with the no-reflow phenomenon, which refers to the failure to restore perfusion to the microvasculature supplying the parenchyma of an organ after restoration of patency of the artery.2,3 In the heart, no reflow occurs on reperfusion after 30 to 90 minutes of coronary occlusion and progresses for about 2 hours after the restoration of epicardial flow. This phenomenon has been attributed to microvascular injury and microvascular plugging resulting in microvascular obstruction (MVO) after restoration of epicardial flow with a percutaneous coronary intervention (PCI) generally in the setting of acute MI. The presence of MVO is associated with late post-MI remodeling, heart failure, and higher mortality.4–7 DETECTION OF NO REFLOW In patients after ischemia/reperfusion (I/R), no reflow can be identified immediately after a PCI angiographically by slow coronary filling (low The Thrombolysis in Myocardial Infarction score, high frame count) and low myocardial blush grade,8 or by demonstration of retrograde systolic flow and rapid deceleration of diastolic flow velocity with an intracoronary Doppler wire. Nuclear approaches have also been applied9 but may be less reliable in this setting because of lower resolution and partial-volume effects related to regional wall motion abnormalities post-MI. No reflow can be most effectively detected noninvasively with myocardial contrast echocardiography,4 or by late gadolinium-enhanced cardiac magnetic resonance imaging.6,7 The magnetic resonance-defined no-reflow area that has been termed MVO is characterized by a hypoenhanced area within the hyperenhanced infarct region.6,10 This magnetic resonance signature has become the preferred index for determination of MVO. The magnetic resonance-defined area of no reflow has been found to be associated with intramyocardial hemorrhage (IMH) in addition to complete MVO.11 IMH occurs after severe microvascular injury because of loss of endothelial cell integrity and increases in vascular permeability and is accompanied by edema Circ Cardiovasc Imaging. 2018;11:e008576. DOI: 10.1161/CIRCIMAGING.118.008576 The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. Key Words: Editorials ◼ heart ◼ humans ◼ molecular imaging ◼ myocardial infarction © 2018 American Heart Association, Inc. https://www.ahajournals.org/journal/ circimaging November 2018 1 Sinusas; No Reflow: Molecular Imaging and vascular compression.11 The presence of IMH postI/R has significant clinical implication and relevance to the study by Ozawa et al12 in the current issue, which relied solely on hypoperfusion on myocardial contrast echocardiography to demonstrate no reflow. IMPORTANT ROLE OF INFLAMMATION AND PLATELET ACTIVATION POST-I/R Several studies have demonstrated that neutrophils exacerbate myocardial I/R injury.13,14 Neutrophils contribute to myocardial I/R via several mechanisms, including microvascular plugging, release of vasoconstrictors, production of reactive oxygen species, release of proteolytic enzymes, including matrix metalloproteinases, and platelet-activating factors. Neutrophils can cross the inflamed endothelium via an interaction between endothelium-bound VWF (von Willebrand factor) and platelets mediated via platelet GP (glycoprotein) Ibα.15 ADAMTS-13 AND VWF: DYNAMIC DUO Downloaded from http://ahajournals.org by on July 7, 2020 A recent review by South and Lane16 highlights the important interactive role of VWF and a disintegrin and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS-13). VWF is an adhesive GP that is essential for hemostasis that acts as a carrier for factor VIII and the capturing platelets at sites of vascular injury. ADAMTS-13 is a metalloproteinase that regulates the size and function of VWF. Severe deficiencies in ADAMTS-13, either congenital or acquired, result in excesses of VWF and result in thrombocytopenic purpura. Moderate decreases in ADAMTS-13 activity can predispose to cardiovascular disease and increase the risk for MI in humans.17 Prior preclinical studies have demonstrated that ADAMTS-13 deficiency can lead to increased injury in murine models of myocardial I/R using the C57BL6/J strain of mice.18,19 In the study by Gandhi et al19 that used a murine model of 30 minutes of ischemia and 24 hours of reperfusion, ADAMTS-13 deficiency was associated with larger infarcts and increased neutrophil infiltration and myocyte apoptosis compared with wild-type controls. In contrast, VWF knockout mice demonstrated small infarcts and reduced neutrophil infiltration using the same model. These investigators also observed that myocardial I/R injury in the double knockout mice was similar to VWF−/− mice, suggesting that the exacerbation of I/R injury in the setting of ADAMTS-13 deficiency is VWF dependent. De Meyer et al18 previously demonstrated using a similar closed-chest murine model of I/R that ADAMTS-13–deficient mice develop larger infarcts and that administration of recombinant human ADAMTS-13 to wild-type mice was cardioprotective and that the benefit was associated with a reduction in the infiltration of neutrophils and a reduction in platelet recruitment. Similar findings were observed by Ozawa et al12 using the same mouse strain and similar I/R protocol. This study used both myocardial contrast echocardiography perfusion imaging and molecular imaging to evaluate the role of microvascular endothelial-associated VWF and platelet adhesion in the no-reflow phenomenon. They observed increased mortality in ADAMTS-13–deficient mice and reduced mortality in wild-type mice after delivery of recombinant ADAMTS-13. Molecular imaging demonstrated increased signal for platelets and VWF in the postischemic risk area, and this was abolished by delivery of recombinant ADAMTS-13 early post-reperfusion. Findings in these C57BL6/J mice might not be directly translatable to humans, since these mice express a truncated and less-active variant of ADAMTS-13. In addition, activation of VWF is shear mediated and arterial and venous flow rates are different in mice and humans, and these differences could influence VWF function.16,19 There is also the theoretical concern for clinical translation that administration of recombinant ADAMTS-13 could induce a bleeding diathesis. More importantly, these observations in mice have not been confirmed by studies in a more clinically relevant porcine model and a pilot clinical study. Eerenberg et al20 administered recombinant ADAMTS-13 to pigs immediately after I/R of the left circumflex coronary artery and demonstrated no reduction in infarct size or IMH as assessed with cardiac magnetic resonance imaging, or formation of microthrombi or microvessels histologically as determined by CD (cluster of differentiation) 31 staining compared with pigs given a vehicle control injection after reperfusion. These pigs received unfractionated heparin, acetylsalicylic acid, and clopidogrel. Therefore, in the presence of dual anti platelet therapy and heparin, which represents the standard of care, the administration of recombinant ADAMTS-13 did not reduce infarct size after I/R. These same investigators also evaluated 49 patients post-PCI who had cardiac magnetic resonance imaging 4 to 6 days post-PCI and demonstrated an early increase in VWF activity and antigen and reductions of blood ADAMTS-13 activity 4 and 7 days post-PCI in only the subset of patients with cardiac magnetic resonance evidence of IMH.20 However, VWF or ADAMTS-13 activity was not related to infarct size. These data significantly challenge the role of the balance of VWF and ADAMTS-13 as the cause of the no-reflow phenomenon. It should be noted that these patients received antiplatelet therapy, including administration of acetylsalicylic acid, prasugrel, and bivalrudin. Regardless, VWF and ADAMTS-13 may represent a surrogate marker of IMH and predict an increased risk of late post-MI complications. MOLECULAR TARGETED IMAGING The important contribution of the study by Ozawa et al12 is the confirmation of a previously identified mecha- Circ Cardiovasc Imaging. 2018;11:e008576. DOI: 10.1161/CIRCIMAGING.118.008576 November 2018 2 Sinusas; No Reflow: Molecular Imaging nism of the no-reflow phenomenon with noninvasive molecular imaging. These investigators applied biotinylated lipid-shelled decafluorobutane microbubbles that were conjugated with ligands to target both VWF and platelets. In wild-type mice treated early post-I/R with recombinant ADAMTS-13, there was no increase in either the VWF or platelet signal within the postreperfusion ischemic risk area. The risk area signal was also less than that observed in both the untreated wildtype mice and the ADAMTS-13 knockout mice. Some regional differences were observed in the signal from the injured region compared with the salvaged postischemic region. These regional differences were not corrected for potential regional differences in flow and potential differences in microbubble delivery. However, their molecular imaging findings were confirmed by fluorescent immunohistochemistry for the presence of platelet adhesion within the risk area. CONCLUSIONS Downloaded from http://ahajournals.org by on July 7, 2020 Although the current study by Ozawa et al12 does not provide any new mechanistic insight into reperfusion injury and the no-reflow phenomenon, their study does provide an important illustration of how targeted molecular imaging can noninvasively assess mechanisms of injury and theoretically be used to guide and evaluate therapeutic interventions. Unfortunately, the observed benefit of delivery of recombinant ADAMTS-13 postreperfusion in these murine models has not been confirmed by large animal studies or an early clinical observational trial. It would be important to apply this novel ultrasound-based targeted molecular and physiological imaging approach in these other more clinically relevant settings. The ultrasound imaging technology is uniquely suited for addressing this problem and could be potentially performed at the bedside. Reperfusion injury post-PCI in the setting of acute MI remains a major clinical problem, and application of this novel imaging technology could help solve this challenging problem. ARTICLE INFORMATION Correspondence Albert J. Sinusas, MD, FAHA, Section of Cardiovascular Medicine, Department of Medicine, Yale Translational Research Imaging Center, PO Box 208017, Dana 3, New Haven, CT 06520-8017. Email [email protected] Affiliations Section of Cardiovascular Medicine, Department of Medicine, Yale Translational Research Imaging Center, Yale University School of Medicine, New Haven, CT. Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT. Disclosures None. REFERENCES 1. Bhatt AS, Ambrosy AP, Velazquez EJ. Adverse remodeling and reverse remodeling after myocardial infarction. 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