Cardiac Magnetic Resonance for Early Detection of Radiation Therapy-Induced Cardiotoxicity in a Small Animal Model

Figures

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  Figure 1. Mast Cell Infiltration in the Myocardium After Localized Cardiac RT Adult female rats were administered 24 Gy of localized cardiac radiation therapy (RT) or sham treatment, and at 10 weeks post-treatment, their hearts were harvested. Mast cells were stained using toluidine blue and quantified. The figure shows a significant increase in mast cell infiltration after RT, n = 4/condition. Values are mean ± SEM. SS = salt-sensitive.

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  Figure 2. SS Rats and Myocardial Vacuolization and Necrosis SS rats demonstrate myocardial vacuolization and necrosis, with a marginally significant decrease of microvascular density, 10 weeks after 24-Gy localized cardiac RT. Adult female rats were administered 24 Gy of localized cardiac RT or sham treatment, and at 10 weeks post-treatment, their hearts were harvested. Hematoxylin and eosin–stained sections demonstrated healthy left ventricular (LV) myocardial tissue in sham-treated hearts (A and B), whereas RT-treated hearts had notable necrosis and vacuolization (C and D), which was increased in the LV lateral wall (D) when compared with the interventricular septum (C). (E to G) Fixed heart sections were stained for cardiomyocytes (caveolin-3) and blood vessels (Sh2b3). The number of blood vessels per cardiomyocyte was calculated, with representative images from sham-treated (E) and RT-treated (F) hearts. This demonstrated a marginally significant decrease of capillary density after RT (G). n = 3/condition. Values are mean ± SEM. Abbreviations as in Figure 1.

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  Figure 3. SS Rats and Increase in Fibrosis SS rats demonstrate no appreciable increase in fibrosis 10 weeks after 24-Gy localized cardiac RT. Ten weeks after 24 Gy of localized cardiac RT or sham treatment, Masson’s trichrome staining was performed, and the interstitial and perivascular fibrosis was quantified. There was a nonsignificant increase in interstitial (A to C) and perivascular (D to F) fibrosis in the RT-treated hearts. n = 4 to 5/condition. Values are mean ± SEM; p = 0.476. Abbreviations as in Figure 1.

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  Figure 4. Cine Images of RT and Sham-Treated Rats Cine images of radiation therapy (RT) and sham-treated (Sham T.) rats demonstrate ventricular remodeling and hypertrophy post-RT. Short-axis (SAX) and long-axis (LAX) cine cardiac magnetic resonance images showing end-diastolic (ED) and end-systolic (ES) slices in both sham-treated and RT-treated rats at 8 weeks post-treatment. The images show preserved global cardiac function post-RT, along with hypertrophy (solid arrow) and cardiac remodeling (dotted arrow) compared with sham-treated rats.

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  Figure 5. Strain Curves in Sham-Treated and RT Rats Strain curves in sham-treated and radiation therapy (RT) rats demonstrate reduced strain and altered patterns post-RT. Representative circumferential, radial, and longitudinal strain curves across different myocardial segments in the left ventricle throughout the cardiac cycle in sham-treated, 8-week, and 10-week post-RT rats. Color code is shown in the upper left corner of the left panels for mid-ventricular short-axis segments (1, anterior; 2, anteroseptal; 3, inferoseptal; 4, inferior; 5, inferolateral; 6, anterolateral) and 4-chamber long-axis segments (1, basal-lateral; 2, mid-lateral; 3, apical-lateral; 4, apical-septal; 5, mid-septal; 6, basal-septal). The strain curves show strain values throughout the whole cardiac cycle (20 heart phases), starting with time frame #1 immediately after the electrocardiogram R-wave, through end-systole at time frame #9 or #10 until end-diastole at time frame #20. Overall, peak strain worsens post-RT. Furthermore, the curves show lack of synchrony for contraction of different segments at 10 weeks post-RT.

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  Figure 6. Strain Measurements in RT and Sham-Treated Rats Strain measurements in radiation therapy (RT) and sham-treated rats reveal early worsening in strain, especially in the circumferential direction, post-RT. Compared with sham, circumferential strain changes occurred at the basal, mid-ventricular, and apical levels (p < 0.05 for all), especially at the lateral regions, which suggests that circumferential strain is a sensitive marker of RT-induced cardiotoxicity.

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  Central Illustration. Strain Measurements in Radiation Therapy and Sham Rats Strain measurements in radiation therapy (RT) and sham rats reveal early worsening in strain, especially in the circumferential direction, post-RT. Compared with sham treatment, circumferential strain changes occurred at the basal, mid-ventricular, and apical levels (p < 0.05 for all), especially at the lateral regions, which suggests that circumferential strain a sensitive marker of RT-induced cardiotoxicity.

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  Figure 7. Segmental Strain Distribution in RT and Sham-Treated Rats Segmental strain distribution in radiation therapy (RT) and sham-treated rats demonstrates reduced strain post-RT. Average segmental strain (A, circumferential; B, radial; C, longitudinal) in sham-treated, 8-week, and 10-week post-RT rats. The left-ventricular 17-segment model is used for presenting strain at the basal, mid-ventricular, and apical levels. Blue and yellow represent better and worse strain, respectively, in the circumferential and longitudinal directions, whereas the color interpretation is the opposite for radial strain (blue and yellow represent worse and better strain, respectively). Overall, strain values are reduced post-RT, which occurs differently in different myocardial segments and strain dimensions. Greater changes in strain are seen in the lateral wall (solid arrows) versus the septum for circumferential strain. Longitudinal strain showed apical and basal strain reduction at 8 weeks and 10 weeks post-RT, respectively (dashed arrows).

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  Figure 8. Segmental Tissue Displacement in RT and Sham-Treated Rats Segmental tissue displacement in RT and sham-treated rats demonstrate maintained tissue motion post-RT. Segmental distribution of average myocardial tissue displacement (A, rotation angle; B, SAX motion, mm; C, LAX motion, mm) in the left ventricle in sham-treated, 8-week, and 10-week post-RT rats. The left-ventricular 17-segment model is used for presenting values at basal, mid-ventricular, and apical levels. Note different tissue displacement values post-RT compared with the sham-treated rats, which differ based on location of the myocardial segment and type of displacement. Abbreviations as in Figure 4.

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  Figure 9. T1 and T2 Maps of RT and Sham-Treated Rats (A to C) Apparent T1 and (D to F) T2 maps of a mid-ventricular slice from (A and D) sham-treated, (B and D) 8-week post-radiation therapy (RT), and (C and F) 10-week post-RT rats (T1 and T2 measurements in milliseconds). Note the slight difference in values (color) between sham and RT rats.