A Model of Cardiovascular Disease Giving a Plausible Mechanism for the Effect of Fractionated Low-Dose Ionizing Radiation Exposure

Atherosclerosis is the main cause of coronary heart disease and stroke, the two major causes of death in developed society. There is emerging evidence of excess risk of cardiovascular disease at low radiation doses in various occupationally exposed groups receiving small daily radiation doses. Assuming that they are causal, the mechanisms for effects of chronic fractionated radiation exposures on cardiovascular disease are unclear. We outline a spatial reaction-diffusion model for atherosclerosis and perform stability analysis, based wherever possible on human data. We show that a predicted consequence of multiple small radiation doses is to cause mean chemo-attractant (MCP-1) concentration to increase linearly with cumulative dose. The main driver for the increase in MCP-1 is monocyte death, and consequent reduction in MCP-1 degradation. The radiation-induced risks predicted by the model are quantitatively consistent with those observed in a number of occupationally-exposed groups. The changes in equilibrium MCP-1 concentrations with low density lipoprotein cholesterol concentration are also consistent with experimental and epidemiologic data. This proposed mechanism would be experimentally testable. If true, it also has substantive implications for radiological protection, which at present does not take cardiovascular disease into account. The Japanese A-bomb survivor data implies that cardiovascular disease and cancer mortality contribute similarly to radiogenic risk. The major uncertainty in assessing the low-dose risk of cardiovascular disease is the shape of the dose response relationship, which is unclear in the Japanese data. The analysis of the present paper suggests that linear extrapolation would be appropriate for this endpoint.

[1]  R. B. Richardson.  Age-dependent changes in oxygen tension, radiation dose and sensitivity within normal and diseased coronary arteries–Part C: Oxygen effect and its implications on high- and low-LET dose , 2008, International journal of radiation biology.

[2]  F. Stewart,et al.  Ionizing radiation accelerates the development of atherosclerotic lesions in ApoE-/- mice and predisposes to an inflammatory plaque phenotype prone to hemorrhage. , 2006, The American journal of pathology.

[3]  K. Manton,et al.  THE RISK OF RADIATION-INDUCED CEREBROVASCULAR DISEASE IN CHERNOBYL EMERGENCY WORKERS , 2006, Health physics.

[4]  M. Little.  Threshold and other departures from linear-quadratic curvature in the non-cancer mortality dose-response curve in the Japanese atomic bomb survivors , 2004, Radiation and environmental biophysics.

[5]  T. Seyama,et al.  Flow cytometry measurements of subsets of T, B and NK cells in peripheral blood lymphocytes of atomic bomb survivors. , 1998, Radiation research.

[6]  E. Benditt,et al.  Evidence for a monoclonal origin of human atherosclerotic plaques. , 1973, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Keith Binks,et al.  The non-cancer mortality experience of male workers at British Nuclear Fuels plc, 1946–2005 , 2008, International journal of epidemiology.

[8]  F. Stewart,et al.  Single-dose and fractionated irradiation promote initiation and progression of atherosclerosis and induce an inflammatory plaque phenotype in ApoE(-/-) mice. , 2008, International journal of radiation oncology, biology, physics.

[9]  岩崎 民子.  SOURCES AND EFFECTS OF IONIZING RADIATION : United Nations Scientific Committee on the Effects of Atomic Radiation UNSCEAR 2000 Report to the General Assembly, with Scientific Annexes , 2002 .

[10]  M. Bennett,et al.  New insights into atherosclerotic plaque rupture , 2001, Postgraduate medical journal.

[11]  K. Williams,et al.  Atherosclerosis--an inflammatory disease. , 1999, The New England journal of medicine.

[12]  J R Walton,et al.  A mathematical model of atherogenesis as an inflammatory response. , 2005, Mathematical medicine and biology : a journal of the IMA.

[13]  M. Gordon.  Letter: A comparison of the radiosensitivity and o.e.r. of human and mouse marrow progenitor cells cultured in agar in diffusion chambers. , 1975, International journal of radiation biology and related studies in physics, chemistry, and medicine.

[14]  Sarah C. Darby,et al.  Low Doses of Ionizing Radiation and Circulatory Diseases: A Systematic Review of the Published Epidemiological Evidence , 2005, Radiation research.

[15]  P. Hall,et al.  Mortality after Cerebral Angiography with or without Radioactive Thorotrast: An International Cohort of 3,143 Two-Year Survivors , 2001, Radiation research.

[16]  A. Swerdlow,et al.  Mortality after Radiological Investigation with Radioactive Thorotrast: A Follow-up Study of up to Fifty Years in Portugal , 2003, Radiation research.

[17]  P. Deschavanne,et al.  A review of human cell radiosensitivity in vitro. , 1996, International journal of radiation oncology, biology, physics.

[18]  G. G. Eigenwillig.  Comment on “Mortality from cardiovascular diseases in the German uranium miners cohort study, 1946–1998” by Kreuzer M, Kreisheimer M, Kandel M, Schnelzer M, Tschense A, Grosche B (2006) Radiat Environ Biophys 45:159–166 , 2007, Radiation and environmental biophysics.

[19]  L. Segel,et al.  Traveling bands of chemotactic bacteria: a theoretical analysis. , 1971, Journal of theoretical biology.

[20]  G. Howe,et al.  Analysis of the Mortality Experience amongst U.S. Nuclear Power Industry Workers after Chronic Low-Dose Exposure to Ionizing Radiation , 2004, Radiation research.

[21]  Aldons J. Lusis,et al.  Atherosclerosis : Vascular biology , 2000 .

[22]  R. Sievert,et al.  Book Reviews : Recommendations of the International Commission on Radiological Protection (as amended 1959 and revised 1962). I.C.R.P. Publication 6. 70 pp. PERGAMON PRESS. Oxford, London and New York, 1964. £1 5s. 0d. [TB/54] , 1964 .

[23]  Y. Yazaki,et al.  An in vitro coculture model of transmigrant monocytes and foam cell formation. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[24]  R. Wakeford,et al.  Review and meta-analysis of epidemiological associations between low/moderate doses of ionizing radiation and circulatory disease risks, and their possible mechanisms , 2010, Radiation and environmental biophysics.

[25]  P. Kirkpatrick,et al.  Vascular Smooth Muscle Cells Undergo Telomere-Based Senescence in Human Atherosclerosis: Effects of Telomerase and Oxidative Stress , 2006, Circulation research.

[26]  A. J. Valente,et al.  Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[27]  K. Kodama,et al.  Radiation dose-dependent increases in inflammatory response markers in A-bomb survivors , 2003, International journal of radiation biology.

[28]  R K Sachs,et al.  The linear-quadratic model and most other common radiobiological models result in similar predictions of time-dose relationships. , 1998, Radiation research.

[29]  K. Trott,et al.  The effects of dose-fractionation on radiation-induced heart disease in rats. , 1987, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[30]  M. Kreuzer,et al.  Mortality from cardiovascular diseases in the German uranium miners cohort study, 1946–1998 , 2006, Radiation and Environmental Biophysics.

[31]  S. Schwartz,et al.  Clonal architecture of normal and atherosclerotic aorta: implications for atherogenesis and vascular development. , 1998, The American journal of pathology.

[32]  R. B. Richardson.  Age-dependent changes in oxygen tension, radiation dose and sensitivity within normal and diseased coronary arteries–Part B: Modeling oxygen diffusion into vessel walls , 2008, International journal of radiation biology.

[33]  Steven E Lipshultz,et al.  Radiation-associated cardiovascular disease. , 2003, Critical reviews in oncology/hematology.

[34]  H. Thames,et al.  Fractionation response and repair kinetics of radiation-induced heart failure in the rat. , 1992, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[35]  Jack Valentin,et al.  The 2007 Recommendations of the International Commission on Radiological Protection. ICRP publication 103. , 2007, Annals of the ICRP.

[36]  Schwartz Sm,et al.  Proliferation and the Monoclonal Origins of Atherosclerotic Lesions , 1998 .

[37]  G. Gulis,et al.  Mortality from diseases other than cancer following low doses of ionizing radiation: results from the 15-Country Study of nuclear industry workers. , 2007, International journal of epidemiology.

[38]  M. Goddard,et al.  Differential Gene Expression in Vascular Smooth Muscle Cells in Primary Atherosclerosis and In Stent Stenosis in Humans , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[39]  M W Charles.  Studies of mortality of atomic bomb survivors. Report 13: Solid cancer and noncancer disease mortality: 1950-1997. , 2003, Journal of radiological protection : official journal of the Society for Radiological Protection.

[40]  D. Richardson,et al.  Radiation and mortality of workers at Oak Ridge National Laboratory: positive associations for doses received at older ages. , 1999, Environmental health perspectives.

[41]  Femoral artery diameter and arteriogenic cytokines in healthy women. , 2009, Vascular pharmacology.

[42]  R Wakeford,et al.  A Systematic Review of Epidemiological Associations between Low and Moderate Doses of Ionizing Radiation and Late Cardiovascular Effects, and Their Possible Mechanisms , 2008, Radiation research.

[43]  K. Kodama,et al.  Effects of radiation on the longitudinal trends of total serum cholesterol levels in the atomic bomb survivors. , 1999, Radiation research.

[44]  B. Okopień,et al.  Effects of atorvastatin, simvastatin, and fenofibrate therapy on monocyte chemoattractant protein-1 secretion in patients with hyperlipidemia , 2003, European Journal of Clinical Pharmacology.

[45]  Charles Mw,et al.  Studies of mortality of atomic bomb survivors. Report 13: Solid cancer and noncancer disease mortality: 1950-1997. , 2003 .

[46]  K. Trott,et al.  Radiation-induced cardiovascular diseases: is the epidemiologic evidence compatible with the radiobiologic data? , 2007, International journal of radiation oncology, biology, physics.

[47]  C R Muirhead,et al.  Mortality and cancer incidence following occupational radiation exposure: third analysis of the National Registry for Radiation Workers , 2009, British Journal of Cancer.

[48]  Alan D. Lopez,et al.  Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study , 1997, The Lancet.

[49]  K. Preissner,et al.  Enzymatically modified, nonoxidized LDL induces selective adhesion and transmigration of monocytes and T-lymphocytes through human endothelial cell monolayers. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[50]  R. B. Richardson.  Age-dependent changes in oxygen tension, radiation dose and sensitivity within normal and diseased coronary arteries–Part A: Dose from radon and thoron , 2008, International journal of radiation biology.

[51]  S. Schwartz,et al.  Proliferation and the monoclonal origins of atherosclerotic lesions. , 1998, Annual review of medicine.

[52]  M. Akahoshi,et al.  Noncancer Disease Incidence in Atomic Bomb Survivors, 1958–1998 , 2004, Radiation research.

[53]  J A Sherratt,et al.  Lipoprotein oxidation and its significance for atherosclerosis: A mathematical approach , 2002, Bulletin of mathematical biology.

[54]  L. Segel,et al.  Model for chemotaxis. , 1971, Journal of theoretical biology.

[55]  K. Nakachi,et al.  Long-term effects of radiation dose on inflammatory markers in atomic bomb survivors. , 2005, The American journal of medicine.

[56]  J. VandeBerg,et al.  Arterial endothelial dysfunction in baboons fed a high-cholesterol, high-fat diet. , 2005, The American journal of clinical nutrition.

[57]  R. Ross,et al.  Cell biology of atherosclerosis. , 1995, Annual review of physiology.