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Background— Intramyocardial hemorrhage frequently accompanies large reperfused myocardial infarctions. However, its influence on the makeup and the ensuing effect on the infarcted tissue during the chronic phase remain unexplored. Methods and Results— Patients (n=15; 3 women), recruited after successful percutaneous coronary intervention for first segment–elevation myocardial infarction, underwent cardiovascular magnetic resonance imaging on day 3 and month 6 after percutaneous coronary intervention. Patients with hemorrhagic (Hemo+) infarctions, as determined by T2* cardiovascular magnetic resonance on day 3 (n=11), showed persistent T2* losses colocalized with scar tissue on the follow-up scans, suggesting chronic iron deposition. T2* values of Hemo+ territories were significantly higher than nonhemorrhagic (Hemo−) and remote territories ( P P =0.51). Canines (n=20) subjected to ischemia-reperfusion injury (n=14) underwent cardiovascular magnetic resonance on days 3 and 56 after ischemia-reperfusion injury. Similarly, sham-operated animals (Shams; n=3) were imaged using cardiovascular magnetic resonance at similar time points. Subsequently, hearts were explanted and imaged ex vivo, and samples of Hemo+, Hemo−, remote, and Sham myocardium were isolated and stained. The extent of iron deposition ([Fe]) within each sample was measured using mass spectrometry. Hemo+ infarcts showed significant T2* losses compared with the other (control) groups ( P P R 2 =0.7 and P Conclusions— Hemorrhagic myocardial infarction can lead to iron depositions within the infarct zones, which can be a source of prolonged inflammatory burden in the chronic phase of myocardial infarction.

Background— Emerging evidence indicates that persistent microvascular obstruction (PMO) is more predictive of major adverse cardiovascular events than myocardial infarct (MI) size. But it remains unclear how PMO, a phenomenon limited to the acute/subacute period of MI, drives adverse remodeling in chronic MI setting. We hypothesized that PMO resolves into chronic iron crystals within MI territories, which in turn are proinflammatory and favor adverse remodeling post-MI. Methods and Results— Canines (n=40) were studied with cardiac magnetic resonance imaging to characterize the spatiotemporal relationships among PMO, iron deposition, infarct resorption, and left ventricular remodeling between day 7 (acute) and week 8 (chronic) post-MI. Histology was used to assess iron deposition and to examine relationships between iron content with macrophage infiltration, proinflammatory cytokine synthesis, and matrix metalloproteinase activation. Atomic resolution transmission electron microscopy was used to determine iron crystallinity, and energy-dispersive X-ray spectroscopy was used to identify the chemical composition of the iron composite. PMO with or without reperfusion hemorrhage led to chronic iron deposition, and the extent of this deposition was strongly related to PMO volume ( r >0.8). Iron deposits were found within macrophages as aggregates of nanocrystals (≈2.5 nm diameter) in the ferric state. Extent of iron deposits was strongly correlated with proinflammatory burden, collagen-degrading enzyme activity, infarct resorption, and adverse structural remodeling ( r >0.5). Conclusions— Crystallized iron deposition from PMO is directly related to proinflammatory burden, infarct resorption, and adverse left ventricular remodeling in the chronic phase of MI in canines. Therapeutic strategies to combat adverse remodeling could potentially benefit from taking into account the chronic iron-driven inflammatory process.

Introduction Hemorrhage can complicate reperfusion injury in myocardial infarction, but no in vivo imaging method exists. We hypothesized that a T2*-weighted cardiovascular magnetic resonance imaging (CMR) sequence accurately detects myocardial hemorrhage in vivo. Methods Reperfused myocardial infarcts were generated in 14 dogs by ligation of the LAD for 3– 6 hours. At day 3, a CMR study was performed using established sequences for quantification of function, microvascular obstruction and myocardial infarction in short axis slices covering the entire myocardium. For hemorrhage, a T2*-weighted multi-echo gradient-echo sequence was applied (TE=35msec, TR=1 RR, FOV 380x280mm, matrix 256 x 192). A segmental analysis was performed using 6 segments per slice: T2*-segments were considered hemorrhagic when signal intensity was >2 standard deviations below the mean of remote myocardium. The contrast-to-noise ratio of hemorrhagic segments over normal segments was assessed. Post-mortem TTC staining was performed with infarcted and hemorrhagic areas analyzed with the same segmental approach. In vivo/ ex vivo correlation statistics were performed. Results In 14 dogs, 378 segments were assessed. Of the T2* CMR segments, 10.2% were excluded due to artifacts; 27 segments yielded a signal drop consistent with hemorrhage (see figure ). The correlation with ex vivo TTC staining was R=0.79 and contrast-to-noise ratio was 9.2±3.4. Sensitivity to detect a hemorrhagic segment was 77%, specificity 99%. Conclusion T2*-weighted CMR accurately detects reperfusion hemorrhage in vivo. The method may be applied in patients to study hemorrhage as a complication of reperfusion injury.