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Cardiac Remodeling and Reversible Pulmonary Hypertension During Pneumonitis in Rats after 13-Gy Partial-Body Irradiation with Minimal Bone Marrow Sparing

Effect of Lisinopril

Jacobs, Elizabeth R.1,2,3,4; Narayanan, Jayashree5; Fish, Brian L.5; Gao, Feng5; Harmann, Leanne M.3,6; Bergom, Carmen5; Gasperetti, Tracy5; Strande, Jennifer L.3,6; Medhora, Meetha1,2,3,4,5

doi: 10.1097/HP.0000000000000919
MURINE MODELS OF MULTIPLE-ORGAN INJURY: NOTES
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Total-body irradiation causes acute and delayed toxicity to hematopoietic, pulmonary, cardiac, gastrointestinal, renal, and other organ systems. Angiotensin-converting enzyme inhibitors mitigate many of the delayed injuries to these systems. The purpose of this study was to define echocardiographic features in rats at two times after irradiation, the first before lethal radiation pneumonitis (50 d) and the second after recovery from pneumonitis but before lethal radiation nephropathy (100 d), and to determine the actions of the angiotensin-converting enzyme inhibitor lisinopril. Four groups of female WAG/RijCmcr rats at 11–12 wk of age were studied: nonirradiated, nonirradiated plus lisinopril, 13-Gy partial-body irradiation sparing one hind leg (leg-out partial-body irradiation), and 13-Gy leg-out partial-body irradiation plus lisinopril. Lisinopril was started 7 d after radiation. Echocardiograms were obtained at 50 and 100 d, and cardiac histology was assessed after 100 d. Irradiation without lisinopril demonstrated echocardiographic transient pulmonary hypertension by 50 d which was largely resolved by 100 d in survivors. Irradiated rats given lisinopril showed no increase in pulmonary artery pressures at 50 d but exhibited left ventricular remodeling. By 100 d these rats showed some signs of pulmonary hypertension. Lisinopril alone had no impact on echocardiographic end points at either time point in nonirradiated rats. Mild increases in mast cells and fibrosis in the heart were observed after 100 d following 13-Gy leg-out partial-body irradiation. These data demonstrate irradiation-induced pulmonary hypertension which was reversed in survivors of pneumonitis. Lisinopril modified cardiovascular remodeling to enhance survival in this model from 41% to 86% (p = 0.0013).

1Department of Pulmonary Medicine, Medical College of Wisconsin, Milwaukee, WI;

2Department of Physiology, Medical College of Wisconsin Milwaukee, WI;

3Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI;

4Research Service, Department of Veterans Affairs, Zablocki VAMC, Milwaukee, WI;

5Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI;

6Cardiology Department, Medical College of Wisconsin, Milwaukee, WI.

The authors declare no conflicts of interest.

For correspondence contact Meetha Medhora, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, or email at medhoram@mcw.edu.

(Manuscript accepted 9 May 2018)

© 2019 by the Health Physics Society