Abstract
Although the link between high doses of ionizing radiation and damage to the heart and coronary arteries has been well established for some time, the association between lower-dose exposures and late occurring cardiovascular disease has only recently begun to emerge, and is still controversial. In this paper, we extend an earlier systematic review by Little et al. on the epidemiological evidence for associations between low and moderate doses of ionizing radiation exposure and late occurring blood circulatory system disease. Excess relative risks per unit dose in epidemiological studies vary over at least two orders of magnitude, possibly a result of confounding and effect modification by well-known (but unobserved) risk factors, and there is statistically significant (p < 0.00001) heterogeneity between the risks. This heterogeneity is reduced, but remains significant, if adjustments are made for the effects of fractionated delivery or if there is stratification by endpoint (cardiovascular disease vs. stroke, morbidity vs. mortality). One possible biological mechanism is damage to endothelial cells and subsequent induction of an inflammatory response, although it seems unlikely that this would extend to low-dose and low-dose-rate exposure. A recent paper of Little et al. proposed an arguably more plausible mechanism for fractionated low-dose effects, based on monocyte cell killing in the intima. Although the predictions of the model are consistent with the epidemiological data, the experimental predictions made have yet to be tested. Further epidemiological and biological evidence will allow a firmer conclusion to be drawn.
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Adams MJ, Hardenbergh PH, Constine LS, Lipshultz SE (2003) Radiation-associated cardiovascular disease. Critical Rev Oncol Hematol 45:55–75
Ashmore JP, Krewski D, Zielinski JM, Jiang H, Semenciw R, Band PR (1998) First analysis of mortality and occupational radiation exposure based on the National Dose Registry of Canada. Am J Epidemiol 148:564–574
Atkinson WD, Law DV, Bromley KJ, Inskip HM (2004) Mortality of employees of the United Kingdom Atomic Energy Authority, 1946–97. Occup Environ Med 61:577–585
Azizova TV, Muirhead CR (2009) Epidemiological evidence for circulatory diseases—occupational exposure. EU Scientific Seminar 2008. “Emerging evidence for radiation induced circulatory diseases”. Proceedings of a scientific seminar held in Luxembourg on 25 November 2008. Radiation Protection 158:33–46 (downloadable from http://ec.europa.eu/energy/nuclear/radiation_protection/doc/publication/158.pdf)
Benditt EP, Benditt JM (1973) Evidence for a monoclonal origin of human atherosclerotic plaques. Proc Natl Acad Sci USA 70:1753–1756
Bobik A, Agrotis A, Kanellakis P, Dilley R, Krushinsky A, Smirnov V, Tararak E, Condron M, Kostolias G (1999) Distinct patterns of transforming growth factor-β isoform and receptor expression in human atherosclerotic lesions. Colocalization implicates TGF-β in fibrofatty lesion development. Circulation 99:2883–2891
Braganza DM, Bennett MR (2001) New insights into atherosclerotic plaque rupture. Postgrad Med J 77:94–98
Burns DM (2003) Epidemiology of smoking-induced cardiovascular disease. Prog Cardiovasc Disease 46:11–29
Carr ZA, Land CE, Kleinerman RA, Weinstock RW, Stovall M, Griem ML, Mabuchi K (2005) Coronary heart disease after radiotherapy for peptic ulcer disease. Int J Radiat Oncol Biol Phys 61:842–850
Chung I-M, Schwartz SM, Murry CE (1998) Clonal architecture of normal and atherosclerotic aorta. Implications for atherogenesis and vascular development. Am J Pathol 152:913–923
Clark KJ, Cary NR, Grace AA, Metcalfe JC (2001) Microsatellite mutation of type II transforming growth factor-β receptor is rare in atherosclerotic plaques. Arterioscler Thromb Vasc Biol 21:555–559
Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans E, Godwin J, Gray R, Hicks C, James S, MacKinnon E, McGale P, McHugh T, Peto R, Taylor C, Wang Y, Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (2005) Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 366:2087–2106
Clarke MC, Littlewood TD, Figg N, Maguire JJ, Davenport AP, Goddard M, Bennett MR (2008) Chronic apoptosis of vascular smooth muscle cells accelerates atherosclerosis and promotes calcification and medial degeneration. Circ Res 102:1529–1538
Danesh J, Whincup P, Lewington S, Walker M, Lennon L, Thomson A, Wong Y-K, Zhou X, Ward M (2002) Chlamydia pneumoniae IgA titres and coronary heart disease. Prospective study and meta-analysis. Eur Heart J 23:371–375
Darby SC, Doll R, Gill SK, Smith PG (1987) Long term mortality after a single treatment course with X-rays in patients treated for ankylosing spondylitis. Br J Cancer 55:179–190
Darby S, McGale P, Taylor CW, Peto R (2005) Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300 000 women in US SEER cancer registries. Lancet Oncol 6:557–565
Davis FG, Boice JD Jr, Hrubec Z, Monson RR (1989) Cancer mortality in a radiation—exposed cohort of Massachusetts tuberculosis patients. Cancer Res 49:6130–6136
dos Santos Silva I, Malveiro F, Jones ME, Swerdlow AJ (2003) Mortality after radiological investigation with radioactive Thorotrast: a follow-up study of up to fifty years in Portugal. Radiat Res 159:521–534
Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352:1685–1695
Howe GR, Zablotska LB, Fix JJ, Egel J, Buchanan J (2004) Analysis of the mortality experience amongst U.S. nuclear power industry workers after chronic low-dose exposure to ionizing radiation. Radiat Res 162:517–526
Ivanov VK, Maksioutov MA, Chekin SY, Petrov AV, Biryukov AP, Kruglova ZG, Matyash VA, Tsyb AF, Manton KG, Kravchenko JS (2006) The risk of radiation-induced cerebrovascular disease in Chernobyl emergency workers. Health Phys 90:199–207
Johnson P, Atkinson WD, Nicholls JL (1999) Updated analysis of mortality in workers at UK atomic weapons establishments. In: Proceedings of the SRP Sixth International Symposium: Achievements & challenges: advancing radiation protection into the 21st century
Kreuzer M, Kreisheimer M, Kandel M, Schnelzer M, Tschense A, Grosche B (2006) Mortality from cardiovascular diseases in the German uranium miners cohort study, 1946–1998. Radiat Environ Biophys 45:159–166
Kreuzer M, Grosche B, Schnelzer M, Tschense A, Dufey F, Walsh L (2009) Radon and risk of death from cancer and cardiovascular diseases in the German uranium miners cohort study—follow-up 1946–2003. Radiat Environ Biophys: doi:10.1007/s00411-009-0249-5
Lauk S, Rüth S, Trott K-R (1987) The effects of dose-fractionation on radiation-induced heart disease in rats. Radiother Oncol 8:363–367
Little MP, Tawn EJ, Tzoulaki I, Wakeford R, Hildebrandt G, Paris F, Tapio S, Elliott P (2008) A systematic review of epidemiological associations between low and moderate doses of ionizing radiation and late cardiovascular effects, and their possible mechanisms. Radiat Res 169:99–109
Little MP, Tawn EJ, Tzoulaki I, Wakeford R, Hildebrandt G, Tapio S, Elliott P (2009a) Comments. The non-cancer mortality experience of male workers at British Nuclear Fuels plc, 1946–2005 (letter to the editor). Int J Epidemiol 38:1159–1164
Little MP, Gola A, Tzoulaki I (2009b) A model of cardiovascular disease giving a plausible mechanism for the effect of fractionated low-dose ionizing radiation exposure. PLoS Comput Biol 5(10):e1000539. doi:10.1371/journal.pcbi.1000539
Matthews C, Gorenne I, Scott S, Figg N, Kirkpatrick P, Ritchie A, Goddard M, Bennett M (2006) Vascular smooth muscle cells undergo telomere-based senescence in human atherosclerosis. Effects of telomerase and oxidative stress. Circ Res 99:156–164
McCaffrey TA, Du BH, Consigli S, Szabo P, Bray PJ, Hartner L, Weksler BB, Sanborn TA, Bergman G, Bush HL (1997) Genomic instability in the type II TGF-β1 receptor gene in atherosclerotic and restenotic vascular cells. J Clin Invest 100:2182–2188
McCullagh P, Nelder JA (1989) Generalized linear models, 2nd edn. Chapman & Hall, London
McGale P, Darby SC (2005) Low doses of ionizing radiation and circulatory diseases: a systematic review of the published epidemiological evidence. Radiat Res 163:247–257,711
McGeoghegan D, Binks K, Gillies M, Jones S, Whaley S (2008) The non-cancer mortality experience of male workers at British Nuclear Fuels plc, 1946–2005. Int J Epidemiol 37:506–518
Morgan WF (2003) Non-targeted and delayed effects of exposure to ionizing radiation: II. Radiation-induced genomic instability and bystander effects in vivo, clastogenic factors and transgenerational effects. Radiat Res 159:581–596
Muirhead CR, O’Hagan JA, Haylock RGE, Phillipson MA, Willcock T, Berridge GLC, Zhang W (2009) Mortality and cancer incidence following occupational radiation exposure: third analysis of the National Registry for Radiation Workers. Br J Cancer 100:206–212
Pai JK, Pischon T, Ma J, Manson JE, Hankinson SE, Joshipura K, Curhan GC, Rifai N, Cannuscio CC, Rimm EB (2004) Inflammatory markers and the risk of coronary heart disease in men and women. N Engl J Med 351:2599–2610
Preston DL, Shimizu Y, Pierce DA, Suyama A, Mabuchi K (2003) Studies of mortality of atomic bomb survivors. Report 13: solid cancer and noncancer disease mortality: 1950-1997. Radiat Res 160:381–407
Richardson RB (2008a) Age-dependent changes in oxygen tension, radiation dose and sensitivity within normal and diseased coronary arteries—Part A: Dose from radon and thoron. Int J Radiat Biol 84:838–848
Richardson RB (2008b) Age-dependent changes in oxygen tension, radiation dose and sensitivity within normal and diseased coronary arteries—Part B: Modeling oxygen diffusion into vessel walls. Int J Radiat Biol 84:849–857
Richardson RB (2008c) 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. Int J Radiat Biol 84:858–865
Richardson DB, Wing S (1999) Radiation and mortality of workers at Oak Ridge National Laboratory: positive associations for doses received at older ages. Environ Health Perspect 107:649–656
Ridker PM (1998) Inflammation, infection, and cardiovascular risk. How good is the clinical evidence? Circulation 97:1671–1674
Ridker PM, Rifai N, Stampfer MJ, Hennekens CH (2000a) Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 101:1767–1772
Ridker PM, Hennekens CH, Buring JE, Rifai N (2000b) C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 342:836–843
Schultz-Hector S, Trott K-R (2007) Radiation-induced cardiovascular diseases: is the epidemiologic evidence compatible with the radiobiologic data? Int J Radiat Oncol Biol Phys 67:10–18
Schultz-Hector S, Sund M, Thames HD (1992) Fractionation response and repair kinetics of radiation-induced heart failure in the rat. Radiother Oncol 23:33–40
Schwartz SM, Murry CE (1998) Proliferation and the monoclonal origins of atherosclerotic lesions. Annu Rev Med 49:437–460
Stamler J, Neaton JD, Garside DB, Daviglus ML (2005) Current status: six established major risk factors—and low risk. In: Marmot M, Elliott P (eds) Coronary heart disease epidemiology: from aetiology to public health, 3rd edn. Oxford University Press, Oxford, pp 32–70
Talbott EO, Youk AO, McHugh-Pemu KP, Zborowski JV (2003) Long-term follow-up of the residents of the Three Mile Island accident area: 1979–1998. Environ Health Perspect 111:341–348
Travis LB, Land CE, Andersson M, Nyberg U, Goldman MB, Knudson Gaul L, Berger E, Storm HH, Hall P, Auvinen A, Janower ML, Holm L-E, Monson RR, Schottenfeld D, Boice JD Jr (2001) Mortality after cerebral angiography with or without radioactive Thorotrast: an international cohort of 3,143 two-year survivors. Radiat Res 156:136–150
Trott K-R, Kamprad F (1999) Radiobiological mechanisms of anti-inflammatory radiotherapy. Radiother Oncol 51:197–203
Tüchsen F, Hannerz H, Burr H (2006) A 12 year prospective study of circulatory disease among Danish shift workers. Occup Environ Med 63:451–455
Tzoulaki I, Murray GD, Lee AJ, Rumley A, Lowe GD, Fowkes FG (2005) C-reactive protein, interleukin-6, and soluble adhesion molecules as predictors of progressive peripheral atherosclerosis in the general population. Edinburgh Artery Study. Circulation 112:976–983
United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) (2000) Sources and effects of ionizing radiation. UNSCEAR 2000 report to the general assembly, with scientific annexes. Volume II: Effects. United Nations, New York
Vasan RS (2006) Biomarkers of cardiovascular disease. Molecular basis and practical considerations. Circulation 113:2335–2362
Villeneuve PJ, Lane RSD, Morrison HI (2007) Coronary heart disease mortality and radon exposure in the Newfoundland fluorspar miners’ cohort, 1950–2001. Radiat Environ Biophys 46:291–296
Vrijheid M, Cardis E, Ashmore P, Auvinen A, Bae J-M, Engels H, Gilbert E, Gulis G, Habib RR, Howe G, Kurtinaitis J, Malker H, Muirhead CR, Richardson DB, Rodriguez-Artalejo F, Rogel A, Schubauer-Berigan M, Tardy H, Telle-Lamberton M, Usel M, Veress K (2007) Mortality from diseases other than cancer following low doses of ionizing radiation: results from the 15-Country Study of nuclear industry workers. Int J Epidemiol 36:1126–1135
Wakeford R, Little MP (2009) Epidemiological evidence for circulatory diseases—non-occupational exposure. EU Scientific Seminar 2008. “Emerging evidence for radiation induced circulatory diseases”. Proceedings of a scientific seminar held in Luxembourg on 25 November 2008. Radiation Protection 158:21–31 (downloadable from http://ec.europa.eu/energy/nuclear/radiation_protection/doc/publication/158.pdf)
Whincup P, Danesh J, Walker M, Lennon L, Thomson A, Appleby P, Hawkey C, Atherton J (2000) Prospective study of potentially virulent strains of Helicobacter pylori and coronary heart disease in middle-aged men. Circulation 101:1647–1652
Wilson PWF, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB (1998) Prediction of coronary heart disease using risk factor categories. Circulation 97:1837–1847
Wong FL, Yamada M, Sasaki H, Kodama K, Akiba S, Shimaoka K, Hosoda Y (1993) Noncancer disease incidence in the atomic bomb survivors: 1958–1986. Radiat Res 135:418–430
Yamada M, Wong FL, Fujiwara S, Akahoshi M, Suzuki G (2004) Noncancer disease incidence in atomic bomb survivors, 1958–1998. Radiat Res 161:622–632
Acknowledgments
The authors are grateful for the detailed and helpful comments of the editor and two referees. This work was funded partially by the European Commission under contracts FI6R-CT-2003-508842 (RISC-RAD) and FP6-036465 (NOTE). The Mayak worker analysis by Drs. Azizova and Muirhead was conducted with support from the European Commission’s Euratom Nuclear Fission and Radiation Protection Programme as part of the SOUL project; more details of this analysis can be found in separate papers by the study investigators.
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This paper is based on a presentation given at the International Conference on Late Health Effects of Ionizing Radiation, 4–6 May 2009, Georgetown University, Washington DC, USA.
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Little, M.P., Tawn, E.J., Tzoulaki, I. et al. Review and meta-analysis of epidemiological associations between low/moderate doses of ionizing radiation and circulatory disease risks, and their possible mechanisms. Radiat Environ Biophys 49, 139–153 (2010). https://doi.org/10.1007/s00411-009-0250-z
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DOI: https://doi.org/10.1007/s00411-009-0250-z