title: Mechanisms and dose-response relationships for radiation-induced cardiovascular disease.
abstract: Epidemiological studies have shown a clear association between therapeutic doses of thoracic irradiation and increased risk of cardiovascular disease in long-term cancer survivors. Survivors of Hodgkin's lymphoma and childhood cancers, for example, show 2- to >7-fold increases in risk of cardiac death after total tumour doses of 30-40 Gy, given in 2-Gy fractions. The risk of cardiac mortality increases linearly with dose, although there are large uncertainties for mean cardiac doses <5 Gy. Experimental studies show that doses of ≥ 2 Gy induce the expression of inflammatory and thrombotic molecules in endothelial cells. In the heart, this causes progressive loss of capillaries and eventually leads to reduced perfusion, myocardial cell death, and fibrosis. In large arteries, doses of ≥ 8 Gy, combined with elevated cholesterol, initiates atherosclerosis and predisposes to the formation of inflammatory, unstable lesions, which are prone to rupture and may cause a fatal heart attack or stroke. In contrast, doses <1 Gy inhibit inflammatory cell adhesion to endothelial cells and inhibit the development of atherosclerosis in mice. It seems likely that mechanisms other than accelerated atherosclerosis are responsible for cardiovascular effects after low total-body exposures of radiation (e.g. impaired T-cell immunity or persistent increase in systemic cytokines).
authors.affiliation: Experimental Therapy, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. f.stewart@nki.nl
authors.forename: F A
authors.initials: FA
authors.lastname: Stewart
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000453:epidemiology / Q000209:etiology*; D001943:Breast Neoplasms / Q000532:radiotherapy; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000209:etiology* / Q000401:mortality; D004307:Dose-Response Relationship, Radiation; D042783:Endothelial Cells / Q000528:radiation effects; D005260:Female; D006321:Heart / Q000528:radiation effects*; D006689:Hodgkin Disease / Q000532:radiotherapy; D006801:Humans; D008297:Male; D051379:Mice; D009206:Myocardium / Q000473:pathology*; D009369:Neoplasms / Q000532:radiotherapy; D011878:Radiotherapy / Q000009:adverse effects*; D051381:Rats; D012306:Risk