title: Role of Interleukin-1 in Radiation-Induced Cardiomyopathy.
abstract: Thoracic X-ray therapy (XRT), used in cancer treatment, is associated with increased risk of heart failure. XRT-mediated injury to the heart induces an inflammatory response leading to cardiomyopathy. The aim of this study was to determine the role of interleukin (IL)-1 in response to XRT injury to the heart and on the cardiomyopathy development in the mouse. Female mice with genetic deletion of the IL-1 receptor type I (IL-1R1 knockout mice [IL-1R1 KO]) and treatment with recombinant human IL-1 receptor antagonist anakinra, 10 mg/kg twice daily for 7 d, were used as independent approaches to determine the role of IL-1. Wild-type (wt) or IL-1R1 KO mice were treated with a single session of XRT (20 or 14 gray [Gy]). Echocardiography (before and after isoproterenol challenge) and left ventricular (LV) catheterization were performed to evaluate changes in LV dimensions and function. Masson's trichrome was used to assess myocardial fibrosis and pericardial thickening. After 20 Gy, the contractile reserve was impaired in wt mice at d 3, and the LV ejection fraction (EF) was reduced after 4 months when compared with sham-XRT. IL-1R1 KO mice had preserved contractile reserve at 3 d and 4 months and LVEF at 4 months after XRT. Anakinra treatment for 1 d before and 7 d after XRT prevented the impairment in contractile reserve. A significant increase in LV end-diastolic pressure, associated with increased myocardial interstitial fibrosis and pericardial thickening, was observed in wt mice, as well as in IL-1R1 KO-or anakinra-treated mice. In conclusion, induction of IL-1 by XRT mediates the development of some, such as the contractile impairment, but not all aspects of the XRT-induced cardiomyopathy, such as myocardial fibrosis or pericardial thickening.
authors.affiliation: Virginia Commonwealth University (VCU) Pauley Heart Center, Richmond, Virginia, United States of America.|VCU Victoria Johnson Center, Richmond, Virginia, United States of America.|School of Pharmacy, VCU, Richmond, Virginia, United States of America.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Mezzaroma
authors.affiliation: Radiation Oncology, Massey Cancer Center, VCU, Richmond, Virginia, United States of America.
authors.forename: Ross B
authors.initials: RB
authors.lastname: Mikkelsen
authors.affiliation: Virginia Commonwealth University (VCU) Pauley Heart Center, Richmond, Virginia, United States of America.|VCU Victoria Johnson Center, Richmond, Virginia, United States of America.
authors.forename: Stefano
authors.initials: S
authors.lastname: Toldo
authors.affiliation: Virginia Commonwealth University (VCU) Pauley Heart Center, Richmond, Virginia, United States of America.|VCU Victoria Johnson Center, Richmond, Virginia, United States of America.
authors.forename: Adolfo G
authors.initials: AG
authors.lastname: Mauro
authors.affiliation: Pharmacology and Toxicology, Massey Cancer Center, VCU, Richmond, Virginia, United States of America.
authors.forename: Khushboo
authors.initials: K
authors.lastname: Sharma
authors.affiliation: Virginia Commonwealth University (VCU) Pauley Heart Center, Richmond, Virginia, United States of America.|VCU Victoria Johnson Center, Richmond, Virginia, United States of America.
authors.forename: Carlo
authors.initials: C
authors.lastname: Marchetti
authors.affiliation: Radiation Oncology, Massey Cancer Center, VCU, Richmond, Virginia, United States of America.
authors.forename: Asim
authors.initials: A
authors.lastname: Alam
authors.affiliation: Virginia Commonwealth University (VCU) Pauley Heart Center, Richmond, Virginia, United States of America.|VCU Victoria Johnson Center, Richmond, Virginia, United States of America.|School of Pharmacy, VCU, Richmond, Virginia, United States of America.
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Van Tassell
authors.affiliation: Pharmacology and Toxicology, Massey Cancer Center, VCU, Richmond, Virginia, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Gewirtz
authors.affiliation: Virginia Commonwealth University (VCU) Pauley Heart Center, Richmond, Virginia, United States of America.|VCU Victoria Johnson Center, Richmond, Virginia, United States of America.
authors.forename: Antonio
authors.initials: A
authors.lastname: Abbate
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005355:Fibrosis; D006439:Hemodynamics; D007375:Interleukin-1 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011833:Radiation Injuries, Experimental; D053573:Receptors, Interleukin-1 Type I / Q000172:deficiency; D015398:Signal Transduction; D018487:Ventricular Dysfunction, Left
chemical_list: D007375:Interleukin-1; D053573:Receptors, Interleukin-1 Type I
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