title: Local heart irradiation of ApoE(-/-) mice induces microvascular and endocardial damage and accelerates coronary atherosclerosis.
abstract: OBJECTIVE
  Radiotherapy of thoracic and chest-wall tumors increases the long-term risk of radiation-induced heart disease, like a myocardial infarct. Cancer patients commonly have additional risk factors for cardiovascular disease, such as hypercholesterolemia. The goal of this study is to define the interaction of irradiation with such cardiovascular risk factors in radiation-induced damage to the heart and coronary arteries.
  
  
  METHODS
  Hypercholesterolemic and atherosclerosis-prone ApoE(-/-) mice received local heart irradiation with a single dose of 0, 2, 8 or 16 Gy. Histopathological changes, microvascular damage and functional alterations were assessed after 20 and 40 weeks.
  
  
  RESULTS
  Inflammatory cells were significantly increased in the left ventricular myocardium at 20 and 40 weeks after 8 and 16 Gy. Microvascular density decreased at both follow-up time-points after 8 and 16 Gy. Remaining vessels had decreased alkaline phosphatase activity (2-16 Gy) and increased von Willebrand Factor expression (16 Gy), indicative of endothelial cell damage. The endocardium was extensively damaged after 16 Gy, with foam cell accumulations at 20 weeks, and fibrosis and protein leakage at 40 weeks. Despite an accelerated coronary atherosclerotic lesion development at 20 weeks after 16 Gy, gated SPECT and ultrasound measurements showed only minor changes in functional cardiac parameters at 20 weeks.
  
  
  CONCLUSIONS
  The combination of hypercholesterolemia and local cardiac irradiation induced an inflammatory response, microvascular and endocardial damage, and accelerated the development of coronary atherosclerosis. Despite these pronounced effects, cardiac function of ApoE(-/-) mice was maintained.
authors.affiliation: Department of Pathology, Cardiovascular Research Institute Maastricht, The Netherlands.
authors.forename: Karen
authors.initials: K
authors.lastname: Gabriels
authors.forename: Saske
authors.initials: S
authors.lastname: Hoving
authors.forename: Ingar
authors.initials: I
authors.lastname: Seemann
authors.forename: Nils L
authors.initials: NL
authors.lastname: Visser
authors.forename: Marion J
authors.initials: MJ
authors.lastname: Gijbels
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Pol
authors.forename: Mat J
authors.initials: MJ
authors.lastname: Daemen
authors.forename: Fiona A
authors.initials: FA
authors.lastname: Stewart
authors.forename: Sylvia
authors.initials: S
authors.lastname: Heeneman
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D003324:Coronary Artery Disease / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004307:Dose-Response Relationship, Radiation; D004699:Endocardium / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D006321:Heart / Q000528:radiation effects*; D051379:Mice; D018345:Mice, Knockout; D011829:Radiation Dosage; D011833:Radiation Injuries, Experimental; D013997:Time Factors
chemical_list: D001057:Apolipoproteins E