Influence of Myocardial Hemorrhage on Staging of Reperfused Myocardial Infarctions With T2 Cardiac Magnetic Resonance Imaging: Insights Into the Dependence on Infarction Type With Ex Vivo Validation

Abstract

Objectives: This study sought to determine whether T2 cardiac magnetic resonance (CMR) can stage both hemorrhagic and nonhemorrhagic myocardial infarctions (MIs).

Background: CMR-based staging of MI with or without contrast agents relies on the resolution of T2 elevations in the chronic phase, but whether this approach can be used to stage both hemorrhagic and nonhemorrhagic MIs is unclear.

Methods: Hemorrhagic (n = 15) and nonhemorrhagic (n = 9) MIs were created in dogs. Multiparametric noncontrast mapping (T1, T2, and T2*) and late gadolinium enhancement (LGE) were performed at 1.5- and 3.0-T at 5 days (acute) and 8 weeks (chronic) post-MI. CMR relaxation values and LGE intensities of hemorrhagic, peri-hemorrhagic, nonhemorrhagic, and remote territories were measured. Histopathology was performed to elucidate CMR findings.

Results: T2 of nonhemorrhagic MIs was significantly elevated in the acute phase relative to remote territories (1.5-T: 39.8 ± 12.8%; 3.0-T: 27.9 ± 16.5%; p < 0.0001 for both) but resolved to remote values by week 8 (1.5-T: -0.0 ± 3.2%; p = 0.678; 3.0-T: -0.5 ± 5.9%; p = 0.601). In hemorrhagic MI, T2 of hemorrhage core was significantly elevated in the acute phase (1.5-T: 17.7 ± 10.0%; 3.0-T: 8.6 ± 8.2%; p < 0.0001 for both) but decreased below remote values by week 8 (1.5-T: -8.2 ± 3.9%; 3.0-T: -5.6 ± 6.0%; p < 0.0001 for both). In contrast, T2 of the periphery of hemorrhage within the MI zone was significantly elevated in the acute phase relative to remote territories (1.5-T: 35.0 ± 16.1%; 3.0-T: 24.2 ± 10.4%; p < 0.0001 for both) and remained elevated at 8 weeks post-MI (1.5-T: 8.6 ± 5.1%; 3.0-T: 6.0 ± 3.3%; p < 0.0001 for both). The observed elevation of T2 in the peri-hemorrhagic zone of MIs and the absence of T2 elevation in nonhemorrhagic MIs were consistent with ongoing or absence of histological evidence of inflammation, respectively.

Conclusions: Hemorrhagic MIs are associated with persisting myocardial inflammation and edema, which can confound staging of hemorrhagic MIs when T2 elevations alone are used to discriminate between acute and chronic MI. Moreover, given the poor prognosis in patients with hemorrhagic MI, CMR evidence for myocardial hemorrhage with persistent edema may evolve as a risk marker in patients after acute MI.

Keywords: acute myocardial infarction; cardiac magnetic resonance; hemorrhage; inflammation; iron; preclinical study.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

FIGURE 1. Time Line for Canine Studies

After a 3-h no-flow ischemia and then reperfusion, 24 animals were randomized for imaging at 1.5- and 3.0-T, on day 5 and week 8 post-MI. After the week 8 CMR study, animals were sacrificed and their hearts harvested for histology and immunohistochemistry. CMR = cardiac magnetic resonance; MI = myocardial infarction.

FIGURE 2. LGE and Noncontrast-Enhanced Relaxation Maps of Canine Hearts in the Acute and Chronic Phases of Reperfused MI at 1.5-T

(A, B) Representative LGE images and native T2*, T2, and T1 maps acquired 5 days (acute) and 8 weeks (chronic) after reperfusion in a dog with hemorrhagic MI. (C,D) Representative LGE images and native T2*, T2, and T1 maps acquired 5 days (acute) and 8 weeks (chronic) after reperfusion in a dog without hemorrhagic MI. LGE = late gadolinium enhancement; MI = myocardial infarction.

FIGURE 3. LGE and Noncontrast-Enhanced Relaxation Maps of Canine Hearts in the Acute and Chronic Phases of Reperfused MI at 3.0-T

(A, B) Representative LGE images and native T2*, T2, and T1 maps acquired 5 days (acute) and 8 weeks (chronic) after reperfusion in a dog with hemorrhagic MI. (C, D) Representative LGE images and native T2*, T2, and T1 maps acquired 5 days (acute) and 8 weeks (chronic) after reperfusion in a dog without hemorrhagic MI. LGE = late gadolinium enhancement; MI = myocardial infarction.

FIGURE 4. Noncontrast-Enhanced T2 of Infarct and Remote Territories and Corresponding Δ T2 (%) in the Acute and Chronic Phases of MI at 1.5- and 3.0-T

At both field strengths, T2 and ΔT2(%) of all MI territories (Hemo+, Peri-Hemo+, and Hemo−) were significantly higher in the acute phase than in the chronic phase. In the chronic phase, at both 1.5- and 3.0-T, ΔT2(%) was negative in the Hemo+ territory, positive in the Peri-Hemo+ territory, and not different from zero in the Hemo− territory. ΔT2(%) of Hemo+ and of Peri-Hemo+ MI territories were different between 1.5- and 3.0-T but not Hemo− territory. The magnitude of ΔT2(%) of Hemo+ and Peri-Hemo+ territories was field dependent but not of Hemo− territories. Hemo+ = hemorrhagic MI territories; Peri-Hemo+ = peri-hemorrhagic MI territories; Hemo− = nonhemorrhagic MI territories. *p < 0.05. MI = myocardial infarction.

FIGURE 5. Histopathologic Findings From Myocardial Tissue Section of Hemorrhagic and Nonhemorrhagic Chronic MIs

Representative ex vivo images (T2*-weighted and corresponding TTC stained sections) from dogs with hemorrhagic and nonhemorrhagic MIs. Remote myocardial sections from a dog with a history of hemorrhagic MI are shown for reference. TTC images were used to localize the infarct zone, and ex vivo T2*-weighted images were used to identify whether the infarcted zones were of hemorrhagic origin (based on hypointensities within infarcted myocardium). Histopathology (H&E for tissue damage, EMT for fibrosis, and Perl for iron, at 4× and 40×) and immunohistochemistry (MAC387) analyses were performed from corresponding segments collected from the infarct core and remote sections. H&E = hematoxylin and eosin; EMT = elastin masson trichrome; MI = myocardial infarction; TTC = triphenyltetrazolium chloride.