RESEARCH
Radiation exposure and circulatory disease risk: Hiroshima
and Nagasaki atomic bomb survivor data, 1950-2003
Yukiko Shimizu, visiting research associate,1 Kazunori Kodama, chief scientist,2 Nobuo Nishi, assistantdepartment chief ,1 Fumiyoshi Kasagi, assistant department chief,1 Akihiko Suyama, department chief,3 Midori
Soda, assistant department chief,3 Eric J Grant, associate senior scientist,1 Hiromi Sugiyama, researchscientist,1 Ritsu Sakata, research scientist,1 Hiroko Moriwaki, research assistant,1 Mikiko Hayashi, research
assistant,1 Manami Konda, research assistant,1 Roy E Shore, vice chairman and chief of research2
1
Department of Epidemiology,
Radiation Effects Research
Foundation, 5-2 Hijiyama Park,
Minami-ku, Hiroshima 732-0815,
Japan
2
Radiation Effects Research
Foundation, Hiroshima
3
Department of Epidemiology,
Radiation Effects Research
Foundation, Nagasaki 850-0013,
Japan
Correspondence to: Y Shimizu
shimizu@rerf.or.jp

Cite this as: BMJ 2010;340:b5349
doi:10.1136/bmj.b5349

ABSTRACT
Objective To investigate the degree to which ionisingradiation confers risk of mortality from heart disease andstroke.
Design Prospective cohort study with more than 50 years
of follow-up.
Setting Atomic bomb survivors in Hiroshima andNagasaki, Japan.
Participants 86 611 Life Span Study cohort members withindividually estimated radiation doses from 0 to >3 Gy(86% received <0.2 Gy).
Main outcome measures Mortality from stroke or heartdisease as the underlying cause of death and doseresponse relations with atomic bomb radiation.
Results About 9600 participants died of stroke and 8400
died of heart disease between 1950 and 2003. For stroke,
the estimated excess relative risk per gray was 9% (95%
confidence interval 1% to 17%, P=0.02) on the basis of alinear dose-response model, but an indication of possible
upward curvature suggested relatively little risk at low
doses. For heart disease, the estimated excess relativerisk per gray was 14% (6% to 23%, P<0.001); a linear
model provided the best fit, suggesting excess risk evenat lower doses. However, the dose-response effect over
the restricted dose range of 0 to 0.5 Gy was not
significant. Prospective data on smoking, alcohol intake,education, occupation, obesity, and diabetes had almost
no impact on the radiation risk estimates for either strokeor heart disease, and misdiagnosis of cancers as
circulatory diseases could not account for the
associations seen.
Conclusion Doses above 0.5 Gy are associated with anelevated risk of both stroke and heart disease, but thedegree of risk at lower doses is unclear. Stroke and heartdisease together account for about one third as many
radiation associated excess deaths as do cancers among
atomic bomb survivors.
INTRODUCTION
The effects of radiation on incidence of or mortality
from circulatory disease have large implications for

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public health, especially if effects occur at doses
under 1 Gy. Given that the frequency of multiple computed tomography scans of the head or chest and ofinterventional radiographic procedures is increasing
rapidly, information on whether these may confer
risk for subsequent stroke or heart disease is essential.
Several studies, including randomised controlled
trials, have found that high doses of radiation to theheart from radiotherapy for Hodgkin’s disease orbreast cancer cause an excess of deaths from heart disease in later years,1-4 and other studies have suggested
that radiotherapy for Hodgkin’s disease, childhood
leukaemia or brain tumours, and head and neck cancer
increases the risk of stroke.5-8 Several authors have suggested that lower doses from occupational, medical,
and environmental exposures may be associated withexcess mortality from circulatory disease,9-14 althoughother studies have not found such low dose effects,15-19
and information on doses and potential confounding
lifestyle factors is limited in many of the studies oflow doses. We examined the dose-response information on the risk of heart disease and stroke in the largeLife Span Study cohort of atomic bomb survivors in
Hiroshima and Nagasaki who have been followed up
for 53 years, from 1950 to 2003.
METHODS
Study population
The Life Span Study cohort, defined on the basis of theJapanese national census in 1950 and special surveys
between 1950 and 1953, consists of 86 611 atomic
bomb survivors with estimated radiation doses. It
includes a large proportion of the survivors who were
within 2.5 km of the hypocentres at the time of thebombings and still resided in Hiroshima or Nagasaki
in 1950, plus a random age and sex matched sample ofpeople 2.5 to 10 km from the hypocentre who sustained small to negligible radiation doses.20 This
study population was of all ages and both sexes at thetime of the bombings.
Individual doses have been carefully estimatedusing the recent improved DS02 dosimetry system,
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RESEARCH

primarily on the basis of people’s location and shielding at the time of the atomic bomb.21 22 We estimatedrisks by using weighted colon doses in gray (Gy) for all
analyses. We used weighted doses, the sum of the γdose plus 10 times the smaller neutron dose, to allow
for the greater biological effectiveness of neutrons.
The follow-up of vital status took place from 1 October 1950 to the end of 2003 and was based on thenationwide obligatory family registration system(koseki) that documents mortality and is virtually
100% complete. Causes of death came from the official
vital statistics death schedules based on the death certificates. Underlying and contributing causes of death
were classified according to the ICD-7 (internationalclassification of diseases, 7th revision) (for deaths in
1950-68), ICD-8 (in 1969-78), ICD-9 (in 1979-97),
and ICD-10 (in 1998-2003). However, for the purposesof these analyses we converted them to ICD-9 codes
390-459 for all circulatory disease, 430-438 for stroke,and 393-429 (excluding 401, 403, and 405) for heartdisease. We used only underlying causes of death in
the primary analyses but examined underlying plus
contributing causes in a subsidiary analysis.
Collection of covariate data and data from autopsy andtumour registry
A mail survey was sent to a defined sub-cohort of51 965 Life Span Study cohort members in 1978. Information was obtained from 36 468 (response rate of70%) on sociodemographic (education, type of occupation), lifestyle (smoking, alcohol intake), and healthvariables (obesity, diabetes mellitus), which enabled
the evaluation of possible confounding by these variables. Between 1950 and 1985 autopsy data were alsoavailable on more than 1900 deaths that had an underlying cause of circulatory disease on the death certificate, which permitted evaluation of diagnostic
accuracy. To identify pre-existing cases of cancer, weused the Hiroshima and Nagasaki tumour registries(available since 1958) and tissue registries (since 1974).
Statistical analysis
We based the analyses on a detailed summary table ofthe number of deaths and person years stratified bydose, city, sex, and five year intervals of age at exposure, attained age, and follow-up period. We divided
participants into categories according to the weighted
colon dose (in Gy=γ dose plus 10 times neutron dose):0-, 0.005-, 0.02-, 0.04-, 0.06-, 0.08-, 0.1-, 0.125-, 0.15-,
0.175-, 0.2-, 0.25-, 0.3-, 0.5-, 0.75-, 1-, 1.25-, 1.5-, 1.75-,
2-, 2.5-, and ≥3. As described elsewhere, we truncatedthe colon doses to correspond to the 4 Gy shieldedkerma level,20 but this affected only 317 participants.
We used Poisson regression methods for groupedsurvival data to describe the dependence of risk onradiation dose and to evaluate the variation of thedose-response effects with respect to city, sex, age at
exposure, time since exposure, and attained age,23
essentially identical to the methods used previously
to examine mortality from cancer in this cohort.20 We
page 2 of 8

used Epicure software for parameter estimation andtests,24 and we based significance tests and 95% confidence intervals on likelihood profiles.
The primary models used here are excess relativerisk (ERR) models of the form λ0 (c,s,a,b) [1+ERR (d,e,s,a)], where λ0 () is the baseline, or background death
rate (that is, the rate for people with zero dose), which
depended on city (c), sex (s), attained age (a), and birthyear (b). The function ERR (d,e,s,a) describes the relative change in rates associated with dose (d), allowing
for the effects of sex, age at exposure (e), and attained
age. We examined effect modifiers by using models
corresponding to those in Preston et al.20 25 We examined both dose and dose squared terms to evaluate thedegree of linearity or curvature in the dose-response
forms. We also tested a linear threshold model. We
used differences in maximum likelihood to compare
nested models or the Akaike information criterion for
non-nested models.26 We evaluated a linear thresholdmodel repeatedly for a wide range of possible values ofa threshold dose (d0), modelling the risk function ERR
on doses d as β(d−d0) for d>d0 or d=0 for d≤d0. We
empirically determined the values yielding the maximum likelihood and 95% confidence bounds.
We examined the impact of the possible confounding factors of smoking (never, past, present <20/day,present ≥20/day), alcohol intake (regular, seldom/
never), education (primary or less, secondary, college/university), occupation for household (professional/technical, clerical/sales, farmer/craftsman,transportation/service), obesity (body mass index<20, 20-24, ≥25), and diabetes (yes, no) on the estimates of radiation risk, including codes for missing
information, for the Life Span Study participants
included in the 1978 mail survey. We included Coxtype regression models fitted to the individual data,
where radiation dose was modelled as a linear excess
relative risk, and indicator variables for the potential
confounders jointly in the models as conventional
exponential relative risk terms by using the Peanuts
program in Epicure.24
RESULTS

During follow-up, 19 054 deaths from circulatory disease occurred among the 86 611 Life Span Study members with DS02 dose available. Table 1 shows thenumbers of participants and deaths from circulatory
disease by age, sex, and radiation dose. The cohort
covers a wide range of doses but is weighted towards
low doses, which indicates that it has considerable capability to examine risks at low doses and to examine theshape of the dose-response curve. The deaths included
9622 from stroke, 8463 from heart disease, and 969
from other circulatory diseases. The excess relativerisk per Gy for all circulatory disease based on the linear model over the full dose range was 11% (95% confidence interval 5% to 17%, P<0.001). This represents
about 210 excess cases of death from circulatory disease associated with the exposure to radiation.
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RESEARCH

Table 1 | Number of participants and deaths from circulatory disease
No of deaths
Characteristics

No of people(n=86 611)

Circulatory disease(n=19 054)

Stroke(n=9 622)

Heart disease(n=8 463)

Other circulatory
disease (n=969)

Sex:
Male

35 687

7 607

3 958

3 261

388

Female50 92411 447

5 664

5 202

581

0-9

17 833

428

176

238

14

10-19

17 563

951

404

508

39

20-29

10 891

1 551

652

831

68

30-49

25 774

9 712

4 735

4 575

402

≥50

14 550

6 412

3 655

2 311

446

<5

38 509

8 440

4 247

3 723

470

5-

23 427

5 089

2 637

2 205

247

50-

12 508

2 838

1 405

1 305

128

200-

6 356

1 485

735

680

70

500-

3 424

745

363

342

40

1000-

1 763

341

176

158

7

≥2000

624

116

59

50

7

Age at atomic bomb exposure (years):

Weighted colon radiation dose (mGy):

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Heart disease

The excess relative risk per Gy for all heart disease
based on the linear model in the full dose range was
14% (6% to 23%, p<0.001) (table 2). Figure 2 shows
the results for the linear and linear-quadratic models.
The test for non-linearity based on a comparison of
linear and linear-quadratic dose-response models was
not statistically significant (P>0.5). A pure linear model
fitted the data nominally better than did a pure dosesquared model (difference in Akaike information criterion statistics of 2.47). The excess relative risks per
Gy for heart disease over restricted dose ranges weresimilar to that for the full dose range. Specifically, theexcess relative risk per Gy based on the linear modelfor the dose ranges under 2, 1, and 0.5 Gy were 14%(4% to 25%), 18% (3% to 33%), and 20% (−5% to 45%).
In figure 2, the slope over the lower part of the dose
range was almost identical to the one for the entire dose
Excess relative risk

Stroke
The excess relative risk per Gy for stroke based on thelinear model over the full dose range was 9% (1% to17%, P=0.02) (table 2). Figure 1 shows estimates ofthe shape of the dose-response curve for all stroke,
including the fitted linear and linear-quadratic models.
The test for non-linearity based on a comparison of
linear and linear-quadratic dose-response models was
not statistically significant (P=0.17), but the pure quadratic model, which suggests relatively little risk at lower
doses, nominally provided a slightly better fit (difference in Akaike information criterion statistics of 1.87)
than did the linear model. This was confirmed by analyses of lower dose ranges which showed excess relative risk per Gy of 3% (−10% to 16%) for 0-1 Gy and−7% (−28% to 16%) for 0-0.5 Gy. Figure 1 also shows
no apparent risk for the lower part of the dose range; anon-negligible threshold may exist below which noexcess occurs. The best estimate of a threshold dose
was 0.5 Gy with an upper 95% confidence limit ofabout 2 Gy. However, the lower 95% confidence
limit was not greater than 0, so no threshold dose
may exist.
An analysis of effect modification of the risk of stroke
by sex, attained age, and age at exposure showed astatistically significant difference for attained age(P=0.04): the radiation excess relative risk per Gy forstroke was higher before age 60 than after, especiallyamong men (web table A). We also found a non-significant indication (P=0.23) that the risk of stroke associated with radiation may be highest after exposure atyoung ages: the excess relative risk per Gy were 36%,9%, 15%, and 5% for ages <10, 10-19, 20-39, and ≥40.
An evaluation of subtypes of stroke was not very meaningful because, before the 1990s, differential diagnosis
was often not done, resulting in many cases being classified as stroke, not otherwise specified.

0.5
0.4
0.3

Linear-quadratic
Linear

0.2
0.1
0
-0.1
-0.2
0

0.5

1.0

1.5

2.0

2.5

3.0

Weighted colon dose (Gy)Fig 1 | Radiation dose-response relation (excess relative risk
per Gy) for death from stroke, showing linear and linearquadratic functions. Shaded area is 95% confidence region
for fitted linear line. Vertical lines are 95% confidence
intervals for specific dose category risks. Point estimates ofrisk for each dose category are indicated by circles
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Table 2 | Summary excess relative risks (ERR)* per Gy and excess additive risks per 104 person year Gy† (EAR/104 PY-Gy) fortypes of circulatory disease mortality
Indicated as underlying cause of death

Underlying or contributing cause of death

Circulatory
diseaseDeathsP value% ERR/Gy (95% CI)

EAR/104 PY-Gy (95% CI)†

Deaths% ERR/Gy (95% CI)

Total

19 054<0.001

11 (5 to 17)

5.5 (2.7 to 8.4)

25 11315 (10 to 20)

Stroke

9 622

0.02

9 (1 to 17)

2.3 (0.4 to 4.4)

12 13912 (5 to 19)

Heart disease

8 463<0.00114 (6 to 23)

3.2 (1.3 to 5.2)

14 01818 (11 to 25)

Other

969

>0.5

2 (−18 to 29)

0.1 (−0.4 to 0.7)

5 846

58 (45 to 72)*Estimates based on linear model, adjusted for city, sex, age at exposure, and attained age.
†Average EARs calculated directly from fitted ERR models.

Confounding factors and misdiagnosis
We examined the impact of the possible confounding
factors on the radiation risk estimates among the51 965 Life Span Study participants included in the1978 mail survey. Table 3 shows the excess relative
risks unadjusted and adjusted for six potential confounding factors. Note that the excess relative risks intable 3 differ slightly from those in table 2, because theestimates in table 3 are based on only the subcohort of
the Life Span Study, whereas those in table 2 are basedon the full cohort (86 611 participants). Althoughsmoking, alcohol intake, education, type of occupation, obesity (body mass index), and diabetes wererisk factors for heart disease and stroke in their own
right (for example, the relative risks for heart disease
were 1.4 for smoking, 1.6 for diabetes, 1.1 for bodymass index 25 or over, and 0.75 for university education), they showed virtually no confounding with doseof radiation. That is, adjustment for the six variables
simultaneously produced inconsequential changes inthe excess relative risk per Gy: only 0.1% for heart disease and −0.9% for stroke (table 3). Analyses limited torespondents similarly showed little impact of the confounder variables (data not shown). These results suggest that in the Life Span Study, the associations of doseof radiation with mortality from stroke and heart disease is unlikely to be an artefact of confounding bymajor lifestyle, sociodemographic, or disease risk
factors.
page 4 of 8

We also examined the diagnostic accuracy of deathcertificates by comparing them with autopsy reports
among the 1963 cases with death certificate designatedcirculatory disease for whom autopsies were available
from our autopsy programme between 1950 and
1985.27 For the broad categories of stroke and heartdisease, the accuracy of the diagnoses on the death certificates was fairly good. For death certificates withstroke as the underlying cause of death, 86% of autopsies listed stroke as a cause; 92% of death certificateswith heart disease as the underlying cause had heartdisease listed as a cause on the autopsy report. Moreover, the accuracy of diagnoses on death certificateshas probably improved since 1985. However, the corresponding accuracy was rather poor for the differential diagnosis of specific subcategories of stroke orheart disease (for example, 65% for cerebral infarction,
39% for cerebral haemorrhage, 69% for ischaemic
heart disease, 22% for hypertensive heart disease, and
64% for rheumatic heart disease); web table B shows
risk estimates for separate subcategories.
Deaths from circulatory disease based on death certificates may include misdiagnosed deaths from cancer
or cases arising from cardiotoxicity due to chemotherapy or radiotherapy for cancer. To remove the effectsof misdiagnosis of cases of cancer, we estimated risks
after excluding people who had previous diagnoses ofcancer, on the basis of our tumour registry data. These
excess relative risks were reduced by about 30% compared with estimates based on the full cohort, but still
Excess relative risk

range. The best estimate of a threshold dose was 0 Gy,
with an upper 95% confidence limit of about 0.5 Gy.
We found no significant modification of effect by sex,
age at exposure, or age at risk (web table A).
Analyses of different subtypes of heart disease
revealed some diversity in dose-response effects (webtable B) but involve a variety of uncertainties, thearticulation of which is beyond the scope of this report.
The risk of ischaemic heart disease increased only inthe higher dose categories, and the linear increase was
not significant. We found stronger associations
between radiation and other heart diseases, such as
hypertensive heart disease and heart failure. However,unlike the relatively high accuracy in diagnosing thegeneral category of heart disease, substantial misclassification of subtypes of heart disease occurs (see below),which limits the meaning that can be attached to theanalyses of subtypes.

0.6
0.5
0.4

Linear-quadratic
Linear

0.3
0.2
0.1
0
-0.1
0

0.5

1.0

1.5

2.0

2.5

3.0

Weighted colon dose (Gy)Fig 2 | Radiation dose-response relation (excess relative risk)for death from heart disease, showing linear and linearquadratic functions. Shaded area is 95% confidence region
for fitted linear line. Vertical lines are 95% confidence
intervals for specific dose category risks. Point estimates ofrisk for each dose category are indicated by circles
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Table 3 | Effects of potential confounding factors on radiation risk estimates for types ofcirculatory disease mortality
No of deaths% ERR/Gy unadjusted
for confounders*% ERR/Gy adjusted
for all confounders*†

Total

7907

10.0

9.6

Stroke

3366

8.1

7.2

Heart disease

4204

12.2

12.3

Other

337

2.4

0.9

Circulatory disease

ERR=excess relative risks.
*All analyses adjusted for city, sex, age at exposure, and attained age.
†Additionally adjusted for smoking, alcohol intake, education, type of household occupation, obesity (bodymass index), and diabetes mellitus (on basis of about 52 000 participants).

showed a tendency to significant dose-response effects.
Excluding previous cases of cancer changed the excess
relative risk per Gy from 10.8% to 7.3% (dose-response
P=0.008) for all circulatory disease, from 8.8% to 6.2%
(P=0.11) for stroke, and from 14.0% to 9.5% (P=0.03)
for heart disease.
Although we used the designated underlying causeof death in the mortality analyses, selecting a single
cause of death is difficult when several correlated diseases or conditions contributed to death. Therefore, we
examined the risks on the basis of both underlying andcontributing causes of death (table 2). The radiation
dose-response effects were nominally higher thanthose based on underlying cause of death alone (12%v 9% excess relative risk per Gy for stroke, and 18% v
14% for heart disease), which lends additional support
to the hypothesis of radiation risk.
DISCUSSION

This study found dose-response evidence for risk ofheart disease and stroke among atomic bomb survivors
over the radiation dose range 0-4 Gy (mostly 0-2 Gy)
based on well characterised individual doses andessentially complete ascertainment of mortality overthe period of five to 58 years after exposure to radiation. This report updates earlier brief reports of a dose
related excess of circulatory disease among atomic
bomb survivors.20 28 29 These results, based on about
25% more deaths than the previous paper, are substantially stronger, and we now provide more elaborationof the associations.
As shown in table 1, at the youngest ages of exposure(more recent birth cohorts) the deaths from heart disease outnumber those from stroke, whereas the opposite is true of the earlier birth cohorts; this reflects thegeneral secular trends in the Japanese population. The
table also shows that the cohort covers a wide range ofdoses but is weighted toward low doses, indicating thatit has substantial capability to examine risks at low
doses and to examine the shape of the dose-response
curve. Because several plausible disease mechanisms
centre around systemic effects after whole body irradiation, we used colon doses as an approximation towhole body doses for all analyses, although analyses
using brain dose for stroke and lung dose for heart disease produced very similar results (data not shown).
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Summary of features and coherence of radiation risk data
Although the data were statistically consistent withlinearity over the full dose range in this study, considerable uncertainty exists about the shape of the doseresponse curve in the low dose range. The extent ofcurvature seemed to be larger for stroke than forheart disease; a pure dose-squared model fitted thestroke data slightly better than did a pure linear
model, whereas the linear model provided a better fit
for heart disease. However, the dose-response effectwas not statistically significant for either end point
when we limited the calculation to the dose range 00.5 Gy, implying that evidence is limited on the risk
below about 0.5 Gy. For stroke, the estimated threshold dose was 0.5 Gy, with an upper 95% confidence
limit of about 2 Gy. For heart disease, the estimatedthreshold dose was 0 Gy, with an upper 95% confidence limit of about 0.5 Gy.
Additional analyses supported the association ofradiation with stroke and heart disease. Adjustmentof the data for other potential risk factors for circulatory disease—obesity, diabetes, smoking, alcohol consumption, education, and occupation—had almost no
impact on the associations with radiation, whereas ananalysis for possible misdiagnosis of cancer as circulatory disease showed a small diminution of radiation
risk. Because the underlying cause of death is often
uncertain, we also did analyses of stroke and heart disease indicated as either an underlying or contributing
cause; these showed nominally stronger associations
with radiation than did the analyses of underlying
cause alone.
The findings of the epidemiological study of circulatory disease among atomic bomb survivors are confirmed and extended by our Adult Health Study,
which consists of biennial clinical and laboratory examinations since 1958 of about 15% of the Life Span Study
cohort members. The Adult Health Study has founddose related increases in the incidence of stroke andmyocardial infarction and in the incidence or prevalence of hypertension, elevated serum cholesterol concentrations, and aortic arch calcification.30-35 Lateradiation effects have also been found for potential
biomarker precursors of circulatory disease, including
biomarkers for inflammation,36-38 deficient immunological responses,39 and alterations in immune cell
repertoire.40 41 The findings present a reasonably coherent picture of preclinical and clinical risk of circulatory
disease associated with exposure to radiation. However, this needs to be complemented by a risk assessment of low doses based on mechanistic and animalmodels.
Strengths and limitations of study
This study has several strengths, including a large
population not pre-selected for existing disease or
occupational fitness, a wide but relatively low dose
range (0->3 Gy) and well characterised doses, a
53 year follow-up with virtually complete mortality
ascertainment, and corroborative evidence frompage 5 of 8

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more detailed clinical and biomarker studies of risk ofcirculatory disease on a random subsample of thecohort.30-41 In addition, we believe medical surveillance bias to be minimal, as all of the cohort is eligible
for free, special medical care, and many people havelittle idea of the doses they received, so that the level ofradiation related medical concern is not highly correlated with the actual dose received. In addition, theanalyses of radiation dose with stroke and heart diseasemortality showed that the association is reasonably
robust with respect to confounding by lifestyle, sociodemographic, or other health factors or misdiagnosis.
The study also has several limitations and uncertainties. Ascertainment of circulatory disease from deathcertificates is of limited diagnostic accuracy and represents only a fraction of cases of incident disease. Analyses for confounders, although very important, areincomplete, lacking information on, for example,
blood lipids, physical activity, and nutrition. Someselection effects due to dose related early mortality
from the bombs may have occurred, although theimpact of these is likely to be small.42 Other limitations
include unclear dose-response effects below about 0.5
Gy, inadequate information about possible biologicalmechanisms, and uncertainty about the generalisability of these results to Western populations because ofdifferences in genetic factors, dietary and lifestyle risk
factors, and baseline levels of risk for stroke and heartdisease.43
Comparison with other studies
Although epidemiological and experimental data arelimited, several studies suggest the possibility of effectsof radiation on circulatory disease. Among medically
exposed cohorts, excess heart disease mortality has
been shown among patients who received radiotherapy for Hodgkin’s lymphoma or breast
cancer.1-4 44 At somewhat lower doses, an increase incoronary heart disease was seen among patients who
received radiotherapy for peptic ulcer.9 An association
was also seen among patients with scoliosis who
received multiple fluoroscopic examinations,45 but
not among patients with tuberculosis who received
multiple fluoroscopic examinations of the chest,16 noramong patients who received radiographic treatment
for benign gynaecological disease.46 47
Studies of cohorts with occupational or environmental exposure to radiation have not provided clear evidence for or against a radiation associated increase inmortality from circulatory disease. In a long term follow-up of early US radiologists, circulatory diseasemortality was higher than for a comparison group ofother medical specialists,48 but a similar increase was
not seen among early UK radiologists.17 Increased
mortality from circulatory disease was found among
US radiological technologists who worked before
1950, when radiation exposures tended to be higher,
but individual people’s doses were not documented.10
Significant associations with radiation for both strokeand heart disease were reported for emergency
page 6 of 8

workers at Chernobyl,12 although the study may have
limitations related to sample selection and to variations
in circulatory disease risk factors and medical surveillance. Among workers for British Nuclear Fuels, a significant dose-response association was found for
ischaemic heart disease but not cerebrovasculardisease.13 No association was found between radiationdose and circulatory diseases among German uranium
miners.19 Preliminary results for the Mayak nuclear
workers show a statistically significant dose-response
association for ischaemic heart disease and stroke.49
A new update of the UK national registry for radiation
workers shows a marginally positive association ofdose of radiation with heart disease, but further analyses suggest that the finding might be due to variations
in smoking habits.14 An analysis of combined cohortsof 275 000 nuclear workers from 15 countries who
were exposed to low, well documented doses of external radiation did not show a significant association
between dose of radiation and either stroke or heartdisease.15
With the exception of the study of US radiological
technologists, the studies were not able to adjust forpotential lifestyle factors or other confounding factors,
and some of the studies had no or only crude estimatesof individual doses. Most of the studies of low doses
had limited statistical power and some potential for
bias; consequently, the potential for both false positiveand false negative results may be high. The United
Nations Scientific Committee on the Effects of Atomic
Bomb Radiation (UNSCEAR) concluded that little
evidence, other than the atomic bomb studies, exists
to support an association between circulatory disease
and radiation in the dose range less than 1-2 Gy.50 A
recent review article reached a similar conclusion,51
although additional suggestively positive data haveappeared since these reviews were written.13 14 49
Mechanisms of circulatory disease
Knowledge of the mechanisms by which radiation
doses of 2 Gy or less may cause circulatory disease islimited. Evidence suggests that pro-inflammatory
responses to radiation, cellular loss or functionalchanges in the endothelium, or microvascular damage
may be early events in the cascade of pathogenic
changes that lead to radiation related heartdisease.52-55 These may augment other risk factors,
such as hypertension, high serum cholesterol, smoking, diabetes, and infection, to promote heartdisease.56 Associations between dose of radiation andlong term levels of inflammatory markers have been
documented among atomic bomb survivors,36-38 possibly because of damage to the immune system.39 Radiation associated microvascular damage to the renalparenchyma and vascular endothelial cells may promote hypertension and ischaemia.50 57
Conclusions and implications
The effect of radiation on risk of circulatory disease ispotentially a very important public health concern.
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WHAT IS ALREADY KNOWN ON THIS TOPICHigh doses of radiation to the heart or head and neck from radiotherapy cause a subsequent
excess of deaths from heart disease or stroke

4

Whether radiation exposures at dose levels under 1 Gy also increase the risk of heart diseaseor stroke is not known

5

WHAT THIS STUDY ADDS

6

Radiation may increase the rates of stroke and heart disease at moderate dose levels (mainly
0.5-2 Gy), although the results below 0.5 Gy were not statistically significant

7

The association was reasonably robust with respect to confounding by lifestyle,sociodemographic, or other health factors or misdiagnosis
8

Given the widespread use of multiple computed tomography scans,58 59 and other relatively high dose diagnostic medical procedures, as well as radiotherapy that
exposes the heart, the implications are substantial insofar as effects occur at doses under 1 Gy. The potential
magnitude of the risk is shown by the fact that in theLife Span Study cohort, who received whole body irradiation, the radiation related excess of deaths from circulatory diseases (about 210) is about a third as large as
the total excess number of deaths from cancer (about
625).
This study provides the strongest evidence available
to date that radiation may increase the rates of strokeand heart disease at moderate dose levels (mainly 0.5-2Gy), but robust confirmatory evidence from other studies is needed. Although our results below 0.5 Gy are
not statistically significant, the additional cases occurring with further follow-up time should provide more
precise estimates of the risk at low doses.
We thank the members of Radiation Effects Research Foundation Master
File section for their diligent efforts to provide accurate data on mortality
in the Life Span Study and Hiroshima and Nagasaki tumour and tissue
registries for their approval for the use of the data. We also thankYoshisuke Nonaka for statistical advice.
Contributors: YS, RES, KK, NN, FK, EJG, HS, RS, AS, and MS contributed tothe study concept and design and to writing the paper. NN, HS, and MS
advised on the tumour registry data. HM, MH, and MK contributed to datapreparation for statistical analyses. All authors participated in interpreting
the results. YS is the guarantor.
Funding: The Radiation Effects Research Foundation (RERF), Hiroshima
and Nagasaki, Japan is a private, non-profit foundation funded by theJapanese Ministry of Health, Labour and Welfare (MHLW) and the US
Department of Energy (DOE), the latter in part through the National
Academy of Sciences. This publication was supported by RERF research
protocol 1-75. The views expressed in this paper are those of the authors
alone.
Competing interests: None declared.
Ethical approval: The research was conducted under the formal approvalof RERF’s Human Investigation Committee.
Data sharing: Detailed tabulation of data used for the analysis and thestatistical code are available from the corresponding author.
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Accepted: 8 September 2009

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