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

Abstract

Total body irradiation causes acute and delayed toxicity to hematopoietic, pulmonary, cardiac, gastrointestinal, renal and other organ systems. Angiotensin converting enzyme (ACE) 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 being before lethal radiation pneumonitis (50 days) and the second after recovery from pneumonitis but before lethal radiation nephropathy (100 days) and to determine the actions of the ACE inhibitor lisinopril. Four groups of female WAG/RijCmcr rats at 11-12 weeks of age were studied: nonirradiated, nonirradiated+lisinopril, 13 Gy partial body irradiation sparing one hind leg (leg-out PBI), 13 Gy leg-out PBI+lisinopril. Lisinopril was started 7 days after radiation. Echocardiograms were obtained at 50 and 100 days and cardiac histology was assessed after 100 days. Irradiation without lisinopril demonstrated echocardiographic transient pulmonary hypertension by 50 days, which was largely resolved by 100 days in survivors. Irradiated rats given lisinopril showed no increase in pulmonary artery pressures at 50 days, but exhibited left ventricular remodeling. By 100 days these rats showed some signs of pulmonary hypertension. Lisinopril alone had no impact of echocardiographic endpoints at either time point in nonirradiated rats. Mild increases in mast cells and fibrosis in the heart were observed after 100 days following 13 Gy leg-out PBI. These data demonstrate irradiation-induced pulmonary hypertension which was reversed in survivors of

Mapping genetic modifiers of radiation-induced cardiotoxicity to rat chromosome 3

“…For instance, the adult female rats were smaller than agematched adult male rats, with corresponding smaller total lung volumes, and thus a higher percentage of the total lung volume would likely receive radiation using the image-guided radiation setup (Fig. 1), which could contribute to enhanced cardiac changes (25). In any case, both male and female SS rats had worse radiation-induced cardiotoxicity compared with their age-matched SS-3 BN consomic rat counterparts.…”

Advances in Preclinical Research Models of Radiation-Induced Cardiac Toxicity

“…The tolerance dose for loss of lung function was dependent upon the concomitant irradiation of the heart [101][102][103]. Conversely, manifestations of RIHD were more severe when both heart and lungs were exposed [66], and echocardiography after whole thorax or leg-out partial body irradiation revealed changes, including evidence of right-sided heart dysfunction, during periods when radiation pneumonitis was occurring [104,105]. Human studies have also suggested that both heart and lung doses can influence the development of cardiac and/or lung toxicities [14,[106][107][108].…”

Three-dimensional vascular and metabolic imaging using inverted autofluorescence

“…This sophisticated rat model is the first in rodents to express the acute and delayed syndromes of radiation exposure in the same animals. 28 – 30 In brief, rats were placed in Plexiglas jig. One hind leg was carefully externalized and shielded with a lead block.…”