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Magnetic susceptibility of hemorrhagic myocardial infarction: correlation with tissue iron and comparison with relaxation time MRI
Brianna F. Moon1, Srikant Kamesh Iyer PhD2, Michael P. Solomon1, Anya T. Hall1, Rishabh Kumar3, Elizabeth M. Higbee-Dempsey4, Andrew Tsourkas PhD1, Akito Imai MD5, Keitaro Okamoto MD5, Yoshiaki Saito MD5, Jerry Zsido II5, Joseph H. Gorman III MD5, Robert C. Gorman MD5, Giovanni Ferrari PhD6, and Walter R.T. Witschey PhD2

1Bioengineering, University of Pennsylvania, Philadelphia, PA, United States, 2Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States, 3Biophysics, University of Pennsylvania, Philadelphia, PA, United States, 4Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, United States, 5Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States, 6Surgery, Columbia University, New York City, NY, United States

Synopsis

Hemorrhagic myocardial infarction (MI) is a frequent complication of primary percutaneous coronary intervention and independently associated with impaired LV remodeling, function, and arrhythmias. We demonstrate that cardiac quantitative susceptibility mapping (QSM) shows increased susceptibility in infarcts compared to remote myocardium and correlates with iron content and infarct pathophysiology. QSM is a more specific marker of hemorrhagic MI than relaxation time MRI, susceptibility-weighted imaging, and late gadolinium enhanced (LGE) MRI.

Purpose:

Hemorrhagic myocardial infarction (MI) has been reported in 41%1 and 54%2 of ST-elevated MI patients after primary percutaneous coronary intervention. These patients are at high risk for adverse left ventricle (LV) remodeling, impaired LV function and increased risk of fatal arrhythmias1–3. Relaxation time MRI such as T2*-maps are sensitive to hemorrhagic infarct iron content, but are also affected by myocardial edema and fibrosis4. Quantitative Susceptibility Mapping (QSM), which uses the MR signal phase to quantify tissue magnetic susceptibility, may be a more specific and sensitive marker of hemorrhagic MI. The objective of this study was to develop and validate cardiac QSM in a large animal model of myocardial infarction, investigate the association of magnetic susceptibility with iron content and infarct pathophysiology, and compare QSM to relaxation time mapping, susceptibility-weighted imaging (SWI), and late-gadolinium enhanced (LGE) MRI.

Methods:

MI was induced by circumflex coronary artery surgical ligation and released after 90 minutes of ischemia (N=3), or permanent ligation (N=2) in male Yorkshire swine. LGE MRI was performed 7 days post-MI using 3D phase-sensitive inversion recovery segmented gradient echo at 3T (Trio, Siemens Healthcare). Afterwards, the animal was sacrificed, the heart was bathed in non-1H magnetic susceptibility-matched fluid (Fomblin), and multi-echo gradient-echo images of whole heart specimens were obtained at 0.2 mm3 isotropic resolution. Additional scan parameters were TR/TEfirst/TElast=42/3.3/38.5 ms, ΔTE=3.2 ms, FA=16 degrees, FOV=17.9×10 cm2, BW=610 Hz/pixel. T2*-maps and SWI images were obtained from T2*-weighted images using standard techniques5,6. As shown in Figure 1, QSM images were reconstructed using the morphology-enabled dipole inversion7,8. Three regions of interest (ROIs) were obtained by T2*-weighted thresholding active contour segmentation (ITK-SNAP, University of Pennsylvania)9 including remote myocardium (“isointense”), peripheral-infarct (“hyperintense”), and core-infarct (“hypointense”). Validation of iron content and fibrosis includes histopathological staining (Prussian Blue, Trichrome) of infarct tissue (2mm slice thickness) and iron concentration was quantified in adjacent slices by inductively coupled plasma atomic emission spectrometry (ICP-AES)10. Statistics included one-way analysis of variance pairwise comparisons between ROIs and student’s t-test comparison between tissue region iron concentrations (results are reported as mean±SD, significance if p<0.05).

Results:

Figure 2 displays results obtained from a reperfused 90 min MI animal. Circumflex artery first branch ligation induced a posterolateral infarct with 20% area-at-risk (Figure 2A). 7 days post-MI, there was a non-transmural infarct and hypointense “core”, a phenotype of microvascular obstruction (Figure 2B). Increased magnetic susceptibility was found in the infarct region (Δχ=0.08±0.09 ppm) compared to remote myocardium (Δχ=0.01±0.01 ppm) (Figure 2C-E). This was associated with elevated iron concentration (infarct samples n=5, [Fe]=0.19±0.03 mg/g vs. remote myocardium samples n=13, [Fe]=0.04±0.003 mg/g) (p<0.001) (Figure 2H). Histology showed extensive extracellular matrix deposition peripheral to non-viable cardiomyocytes (Figure 2F) and substantial iron deposition (Figure 2G).

Figure 3A,B displays T2*-maps, SWI and QSM images at the same imaging location of posterolateral non-transmural 90 min and transmural permanent MI. Both infarcts had LGE hypointense cores. T2*-weighted, T2*-maps and SWI show hypointense regions for 90 min MI. QSM showed increased susceptibility in both infarcts (90 min and permanent MI) and substantial increase in hypointense region of 90 min MI. In reperfused infarcts (90 min MI), T2*-weighted and T2*-maps were spatially heterogenous, having both hypointense (T2*=11.0 ms) and hyperintense (T2*=65.7 ms) regions. The low T2* regions correspond to an elevated susceptibility and iron content. Magnetic susceptibility, but not T2*, was significantly different between ROIs of 90 min and permanent MIs (p<0.001) (Figure 3C,D). There was an increasing amount of iron concentration found in the infarct of 90 min and permanent animals compared to remote myocardium (Figure 3E).

Discussion and Conclusion:

The key finding of the present study was the increased infarct magnetic susceptibility after myocardial infarction compared to remote myocardium, and its correlation with tissue iron content at 7 days post-MI. All animals had LGE hypointense cores, indicating large severe infarcts with microvascular obstruction. T2*-weighted and T2*-maps of reperfused infarcts had hypointense regions attributed to hemorrhagic MI. Hypointense regions were not observed in permanently infarcted animals, despite increased iron content and magnetic susceptibility, suggesting that T2* is affected by other factors besides iron such as fibrosis and edema. This is consistent with the histological findings that showed substantial extracellular matrix deposition. Additionally, T2* may not directly reflect iron content due to the nonlocal effects of iron on T2* signal and dependence on imaging parameters such as voxel size. In summary, these findings show QSM is a more sensitive and specific marker of hemorrhagic MI. In a clinical environment, QSM could be used to determine targeted periprocedural therapy, risk stratification for aggressive pharmacologic treatment and monitoring of post-MI patients.

Acknowledgements

We gratefully acknowledge support from R00-HL108157, NRSA in interdisciplinary Cardiovascular Biology NIH T32-HL007954, and HHMI-NIBIB Interfaces Program NIH T32-EB009384.

References

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Figures

Figure 1: QSM image processing pipeline of 90 min reperfusion model. A,D) Complex multi-echo GRE images are acquired. B) Initial field map was obtained by voxel-based linear regression of A) phase images obtained at multiple echo times. C) Graph-cuts based phase unwrapping method called SPURS was used with the IDEAL fat/water separation algorithm iteratively to remove fat chemical shift. D) Magnitude images were used to create E) cardiac mask in application to F) projection onto dipole field (PDF) background field removal algorithm11. G) QSM generated by morphology enabled dipole inversion (MEDI)7,8.

Figure 2: Reperfused 90min MI magnetic susceptibility is associated with high iron content. A) Coronary artery map ligation sites (X) at circumflex artery first obtuse marginal branch (OM1), 20% infarct area (red dashes). B) In vivo LGE with hyperintense infarct and hypointense core. Elevated susceptibility in C) QSM, D) histogram and E) mean measurement of infarct region (“IR”) compared to myocardium (“Myo”) correspond to H) increased IR iron concentration. F) Trichrome histology shows non-transmural infarct, extensive peripheral fibrosis and non-viable core cardiomyocytes. G) Prussian-Blue histology shows iron accumulation at periphery. Arrows: myocardium (blue), infarct region (red), microvascular obstruction “core” (white).

Figure 3: QSM comparison with LGE, T2*-weighted, T2*-maps, and SWI after 90 min reperfusion and permanent ischemia. A) 90 min and B) permanent infarcts had hypointense LGE regions (white arrow). T2*-weighted (T2*w), susceptibility-weighted images (SWI) and T2*-maps show distinct hypointense regions in 90 min but not in permanent infarcts. QSM showed elevated susceptibility in both infarcts. C) Susceptibility, but not D) T2*, were substantially different in myocardium and infarct regions in 90 min and permanent infarcts (p<0.001). E) Elevated iron concentration in permanent and 90 min infarcts compared to myocardium. T2*-weighted Mag contrast ROIs were created from whole heart specimens.

Proc. Intl. Soc. Mag. Reson. Med. 26 (2018)
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