doi:10.1111/imj.14002

Choice reaction time and grip strength as predictors ofcardiovascular mortality in middle-aged and elderly Japanese:from the Radiation Effects Research Foundation Adult Healthstudy
Masaki Shimizu,1† Munechika Misumi,2 Michiko Yamada
Yasuki Kihara3,1 Waka Ohishi,1 Hideya Yamamoto3 andDepartments of 1Clinical Studies, and 2Statistics (Hiroshima), Radiation Effects Research Foundation, and 3Department of Cardiovascular Medicine,
Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan

Key words
reaction time, grip strength, heart disease,stroke, mortality.
Correspondence
Masaki Shimizu, Department of Clinical Studies,
Radiation Effects Research Foundation, 5-2
Hijiyama Park, Minamiku Hiroshima 732-0815,
Japan.
Email: sm537f-1@ac.auone-net.jp
Received 9 January 2018; accepted
11 June 2018.

Abstract
Background: Cognitive function and physical function are important predictors ofmortality.
Aim: To investigate whether or not reaction time (RT) as a cognitive function and grip
strength (GS) as a physical function were associated, alone or in combination, withmortality from heart disease or stroke.
Methods: The subjects included 4901 Adult Health Study participants in Hiroshima
who had undergone RT and GS measurements, were 35–74 years old at baseline(1970–1972) and were followed until the end of 2007.
Results: After adjustment for other potential risk factors, RT was positively and GS was
negatively associated with mortality from both heart disease and stroke. These associations were persistent in the model when adjusting simultaneously for RT, GS and otherfactors, but hazard ratios were attenuated. When we evaluated the associations by baseline age and gender, we found the greater hazard ratios for RT in the younger cohort,
but no clear modiﬁcation by age for GS. The interaction between RT and GS was statistically signiﬁcant (P = 0.012) for stroke mortality. In the stratiﬁed analyses divided using
the age-speciﬁc median value of RT or GS, the estimated hazard ratio of stroke mortality for RT was signiﬁcant in participants with weak or strong GS but greater in the former, and for GS, it was only signiﬁcant in participants with slow RT.
Conclusion: RT and GS, alone and in combination, predicted heart disease and strokemortalities. Interventions for both cognitive function and physical function may be beneﬁcial for the prevention of cardiovascular disease mortality.

Introduction
Cognitive function and physical function are important
predictors of mortality. Reaction time (RT) is a measure†Present address: Working Hours and Welfare Division,
Employee Welfare Bureau, National Personnel Authority.
Funding: The Radiation Effects Research Foundation (RERF),
Hiroshima and Nagasaki, Japan, is a public interest foundation
funded by the Japanese Ministry of Health, Labour and Welfare(MHLW) and the US Department of Energy (DOE). Thispublication was supported by RERF Research Protocol RP-A6-12
and, in part, by a Grant-in-Aid from the MHLW, Health and Labor
Sciences Research Grants, Japan (H26-Junkankitou [Seisaku]Ippann-001 and H29-Junkankitou-Ippan-003). The views of theauthors do not necessarily reﬂect those of the two governments.
Conﬂict of interest: None.

of processing speed,1 and processing speed reﬂects cognitive function.2 Using the Radiation Effects Research
Foundation (RERF) Adult Health Study (AHS), which
covered a wide age range of men and women over a
period of 30 years, our previous study showed RT to be astrong and consistent predictor of mortality.3 Somecohort studies found RT, including the digit symbol substitution test, to be related to cardiovascular disease(CVD) mortality4,5 and CVD incidence.6
A meta-analysis by Cooper et al. found that grip
strength (GS), which is a measure of physical function, isassociated with all-cause mortality in younger, as well as
older, community-dwelling populations.7 The prospective Urban–Rural Epidemiology study, a large, longitudinal population study, showed that GS was inversely
associated with all-cause mortality, cardiovascularInternal Medicine Journal 48 (2018) 1331–1336
1331© 2018 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of PhysiciansThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium,provided the original work is properly cited, the use is non-commercial and no modiﬁcations or adaptations are made.

Shimizu et al.

mortality, myocardial infarction incidence and stroke
incidence.8 Our previous study found that GS was significantly associated with heart disease and strokemortality,9 in accordance with the Hisayama Study inJapan.10
Although the relationship between cognitive function
and physical function suggests both separate and sharedprocesses of ageing,11,12 only a few studies have reported
the simultaneous potential of cognitive and physicalfunction on mortality.13,14 Here, we investigated the
independent and combined effects of RT and GS as predictors of heart disease mortality and stroke mortality todetermine whether cognitive function and physical function are modiﬁable predictors of CVD mortality.

Methods
General procedure
The AHS, a population-based longitudinal clinical studyof atomic bomb survivors and unexposed controls of
approximately a similar number, has conducted biennial
health examinations and mortality surveys continuously
since 1958.15 The subjects of the present study were4901 AHS participants living in Hiroshima, who underwent RT and handgrip measurements and were 35–74
years old between July 1970 and June 1972. The AHS
biennial clinical examination included medical history(diabetes mellitus (DM)), physical examination (bloodpressure and body mass index (BMI) calculated as bodyweight (kg)/height2 (m)), measurements (serum cholesterol) and questionnaire (smoking habit and alcohol
intake). The RERF institutional review boards approved
this study, and all participants provided informed consent and conﬁrmed their anonymity.

Measurement of reaction time and handgrip
RT was deﬁned as the length of time for extinction of
10 lights mounted on a rectangular board.3 The test was
repeated after practice, and that time was used for analysis. Handgrip strength was measured twice for each handwith participants in a standing position. The maximum
GS among all measurements was used in the analysis.9

Mortality follow up
Mortality was followed for all study participants from thebaseline measurements in 1970–1972 to the end of
2007. We identiﬁed 3338 deaths not due to externalcauses. The primary cause of death was assessed fromdeath certiﬁcates and classiﬁed according to the International Classiﬁcation of Diseases (ICD) (ICD, 8–10th1332

revision, WHO, Geneva). We analysed deaths caused byheart disease (390–429 in ICD 8 and 9, I01-I51 in ICD10) and stroke (430–438 in ICD 8 and 9, I60–I69 in
ICD 10).

Statistical analysis
We used multivariate Cox proportional hazards models
to investigate the association of RT and GS with mortality. We treated age as the timescale in the Cox regression
models, instead of follow-up time.16 We also handledadjustments for age effects non-parametrically based on
this approach. First, we evaluated the association
between the mortality of each disease and either RT or
GS, adjusting for gender and other potential confounding factors (systolic blood pressure (SBP), BMI, DM,smoking and drinking habits, total cholesterol and radiation dose). We then investigated the associations by
including both RT and GS with the same multivariate
adjustments. Considering the wide age range, we conducted the Cox regression analysis by age categories of
35–54, 55–64 and over 65 years at the time of measurement for each gender. In addition, we tested two-way
interaction effects of RT and GS. If a signiﬁcant interaction was shown, we examined the association between
RT and mortality after stratifying for GS and the association between GS and mortality after stratifying for
RS. To prevent contamination caused by latent diseases,
we excluded participants who died within 2 years of thebaseline examination or were diseased at baseline. All
statistical tests were two-sided and conducted using the
R survival package R 3.0.1 (http://www.cran.r-project.
org/).

Results
Table 1 shows the characteristics of the study participants. After the exclusion of participants who diedwithin 2 years of the baseline examination or were diseased at baseline (80 cases of heart disease and 85 ofstroke), 4821 participants remained in the analysis ofheart disease and 4816 in the analysis of stroke. By theend of 2007, 616 participants had died of heart disease
and 512 of stroke. At baseline, Spearman’s correlation
coefﬁcient between RT and GS was −0.33.
Table 2 shows the hazard ratio (HR) per unit increment for mortality due to each disease associated with
RT and GS in the gender-adjusted model, the multivariate (gender and other factors)-adjusted (a) model andthe multivariate (gender, other factors and RT or GS)adjusted (b) model. In all models, RT was positively andsigniﬁcantly associated with mortality from heart disease
and stroke, and GS was negatively and signiﬁcantly

Internal Medicine Journal 48 (2018) 1331–1336© 2018 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians

Reaction time and grip predict CVD death

Table 1 Baseline characteristics of the study participants
Variable

Total

Men

Women

Number of participants
Age at baseline (years)

4901
54.4
(10.9)
127.4(23.6)
192.2(36.3)
22.3
(3.5)
32.7
34.3
8.7

1689
55.5
(11.1)
131.0(23.6)
183.7(34.3)
21.6
(3.1)
68.4
70.0
14.3

3212
53.8
(10.7)
125.5(23.3)
200.4(36.2)
22.6
(3.6)
13.9
15.7
5.7

7.53
(1.69)
7.2
6.5, 8.2
4.5, 27.2

7.48(1.69)
7.1
6.4, 8.2
4.5, 27.2

7.56(1.70)
7.2
6.5, 8.1
4.6, 27.0

35.1(11.0)
33
27, 42
7, 73
47.2

46.4
(9.0)
46
41, 5214, 73
48.8

29.2
(6.3)
30
25, 34
7, 50
46.3

0.43
(0.58)

0.47(0.62)

0.41(0.55)

Systolic blood pressure (mmHg)
Total cholesterol (mg/dL)
Body mass index (kg/m2)
Current smokers (%)
Current alcohol drinkers (%)
Diabetes mellitus (%)
Reaction time (s)MeanMedianFirst, third quartile
Minimum, maximum
Grip strength (kg)MeanMedianFirst, third quartile
Minimum, maximum
Unexposed subjects (dose<0.001 Gy) (%)
Dose (Gy) among exposed
subjects

Continuous variables are shown as means (SD). SD, standard deviation.

associated with mortality from heart disease and stroke,
although the HR were slightly attenuated in the lattermodel. Additional calculations per 1 SD of deteriorationin RT and/or GS showed that the range of the HR ofmortality for heart disease or stroke for a 1 SD increaseof RT alone or a 1 SD decrease in GS alone is 1.17–1.31,
and the range of the HR of mortality for 1 SD of simultaneous change in both variables is 1.27–1.43. (Table 3)
Signiﬁcant predictive values were detected for factors

other than RT and GS in the (b) model. An SBP increaseof 10 mmHg was associated with heart disease mortality(HR = 1.10, 95% conﬁdence interval (CI) = 1.07–1.14)
and stroke mortality (HR = 1.16, 95% CI = 1.12–1.20),
DM with heart disease mortality (HR = 1.80, 95% CI =1.41–2.30) and stroke mortality (HR = 1.43, 95% CI =1.08–1.90), current smoking with heart disease mortality(HR = 1.62, 95% CI = 1.30–2.02) and a 10 mg/dL
increase of total cholesterol with stroke mortality (HR =0.95, 95% CI = 0.92–0.98). Radiation dose was not associated with either mortality. When we evaluated theassociation of RT or GS with mortality in the stratiﬁed
model by gender and baseline age categories (35–54,
55–64 and over 65 years old), we found an associationof RT with CVD mortality in more than half the age andgender categories with greater HR in younger birthcohorts and an association of GS with CVD mortality infewer age and gender categories (Table 4).
In the model including the interaction between RT
and GS, the interaction showed a signiﬁcant effect on
only stroke mortality (P = 0.012), showing a better ﬁtthan the model that included only main effects. In thestratiﬁed analyses divided by the median value of RT or
GS of each gender and age category, RT was signiﬁcantly
associated with stroke mortality for participants withweak GS (HR = 1.17, 95% CI = 1.11–1.25) and for participants with strong GS (HR = 1.09, 95% CI =1.03–1.15), and GS was signiﬁcantly associated withstoke mortality for participants with slow RT (HR = 0.98,
95% CI = 0.96–0.99) but not for subject with fast RT(HR = 1.00, 95% CI = 0.98–1.03) (Fig. 1).

Discussion
Our results showing the association between CVD mortality and RT or GS suggest that RT and GS are associatedwith vascular ageing. RT, a measure of processing
speed,1 may reﬂect vascular function in the whole body

Table 2 Hazard ratio (HR) for death per one unit increment of reaction time and grip strength
Gender-adjusted model

Reaction time (1 s)Heart disease
StrokeGrip strength (1 kg)
Heart disease
StrokeMultivariate-adjusted model

HR (95% CI)

Model A, HR (95% CI)

Model B, HR (95% CI)

1.13 (1.10–1.17)**
1.16 (1.12–1.19)**

1.10 (1.06–1.14)**
1.12 (1.09–1.16)**1.08 (1.04–1.13)**
1.11 (1.07–1.15)**

0.97 (0.96–0.98)**
0.97 (0.96–0.98)**

0.97 (0.96–0.98)**
0.97 (0.96–0.99)**

0.98 (0.97–0.99)*
0.98 (0.97–0.99)**P < 0.01. **P < 0.001. In all models, adjustment for the effect of age was handled non-parametrically using age as the timescale of the Cox regression. We used a gender-adjusted model with gender as a covariate. Multivariate model A was adjusted for gender, systolic blood pressure, diabetes
mellitus, smoking habit, alcohol consumption, radiation dose and total cholesterol. Model B was adjusted for factors in model A and reaction time or
grip strength. CI, conﬁdence interval.

Internal Medicine Journal 48 (2018) 1331–1336© 2018 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians1333

Shimizu et al.

Table 3 Hazard ratio (HR) for death per 1 SD deterioration in reaction time and grip strength
Gender-adjusted model

Reaction time (1 SD)
Heart disease
StrokeGrip strength (1 SD)
Men
Heart disease
StrokeWomen
Heart disease
StrokeMultivariate-adjusted model

HR (95% CI)

Model A, HR (95% CI)

Model B, HR (95% CI)

1.23 (1.17–1.30)***1.29 (1.22–1.36)***

1.17 (1.10–1.24)***1.21 (1.15–1.29)***1.14 (1.07–1.22)***
1.19 (1.12–1.27)***1.32 (1.13–1.53)***
1.23 (1.06–1.43)***1.31 (1.12–1.53)***
1.19 (1.02–1.40)**

1.25 (1.07–1.47) ***1.15 (0.99–1.34)*

1.32 (1.13–1.53)***1.31 (1.16–1.48)***1.17 (1.05–1.30)***1.25 (1.11–1.41)***

1.11 (1.00–1.24)*
1.14 (1.01–1.29)***P < 0.05. **P < 0.01. ***P < 0.001. The HR for death per 1 SD decrease in grip strength was analysed by gender due to differences in grip strength
between the genders. In all models, adjustment for effect of age was handled non-parametrically by using age as the timescale of the Cox regression.
The multivariate model A was adjusted for gender, systolic blood pressure, diabetes mellitus, smoking habit, alcohol consumption, radiation dose andtotal cholesterol. Model B was adjusted for factors in model A and reaction time or grip strength. CI, conﬁdence interval; SD, standard deviation.
Table 4 Multivariate-adjusted hazard ratio (HR) for reaction time (1 s) and grip strength (1 kg) by gender and baseline age
GenderMen

Age (years)

35–54
55–64
65–74

Women

35–54
55–64
65–74

Reaction time (1 s)

Grip strength (1 kg)

Heart diseasen (subjects)
HR (95% CI)

Stroken (subjects)
HR (95% CI)Heartn (subjects)
HR (95% CI)

Stroken (subjects)
HR (95% CI)

54 (750)
1.23 (1.00–1.51)
66 (485)
1.13 (0.97–1.31)
72 (411)
1.10 (1.03–1.18)**103 (1740)
1.22 (1.08–1.39)***163 (771)
1.08 (0.96–1.22)
158 (664)
1.10 (1.02–1.19)*

50 (750)
1.24 (1.01–1.52)*
65 (485)
1.19 (1.06–1.34)**
76 (410)1.05 (0.96–1.14)
67 (1740)
1.28 (1.11–1.47)***120 (771)
1.19 (1.08–1.31)***134 (660)
1.12 (1.03–1.21)**54 (750)
0.97 (0.93–1.00)
66 (485)
0.98 (0.95–1.02)
72 (411)0.94 (0.91–0.98)***103 (1740)
0.95 (0.92–0.99)*
163 (771)
0.99 (0.97–1.02)
158 (664)
0.97 (0.94–1.01)

50 (750)
0.98 (0.95–1.02)
65 (485)
0.98 (0.94–1.01)
76 (410)0.99 (0.96–1.02)
67 (1740)
1.00 (0.96–1.05)
120 (771)
0.99 (0.96–1.02)
134 (660)
0.96 (0.93–1.00)**P < 0.05. **P < 0.01. ***P < 0.001. In all models, adjustment for the effect of age was handled non-parametrically by using age as the timescale of
the Cox regression. The multivariate model was adjusted for systolic blood pressure, diabetes mellitus, smoking habit, alcohol consumption, radiationdose, total cholesterol and reaction time/grip strength. CI, conﬁdence interval.

Figure 1 Hazard ratio (HR) for
stroke mortality per unit increase
in reaction time (RT) or grip
strength (GS). The left graphshowed HR for Stroke Mortality
per unit increase in RT among participants with strong and weak
GS. The right graph showed HR
for Stroke Mortality per unit
increase in GS among participants
with fast and slow RT.

1334

Internal Medicine Journal 48 (2018) 1331–1336© 2018 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians

Reaction time and grip predict CVD deathas well as in the brain as white matter brain changes
reﬂecting vascular brain function are associated withchanges in processing speed,17 and such morphologicalchanges in brain are thought to reﬂect aortic atherosclerosis and microvascular disease in the whole body.18
Regarding the effect of GS, the role of skeletal muscle asa secretory organ might be involved. Inﬂammatory processes or secreted myokines associated with a lack of
exercise may favour the development of CVD,19 linking
CVD mortality with GS. Another possible mechanism isthrough a genetic factor, such as Apolipoprotein E(APOE) genotype, that is related not only to CVD but
also to RT or GS.20
Although studies investigating an association of RT or
GS with CVD mortality across different age and gendergroups are limited, the Health and Lifestyle Survey
showed the effect of different ages on associations
between RT and all CVD and stroke mortalities,5 and the
Cooperative Health Research in the Region of AugsburgAge study showed the effect of different genders on association between GS and CVD mortality.21 In our study,
RT was signiﬁcantly associated with heart disease andstroke mortalities in those aged 35–74 years at baseline,with greater HR in the younger birth cohort, and noclear gender difference was shown in the association
between GS and CVD mortality.
Two studies have investigated the effects of the combination of cognitive and physical functions on mortality. Rosano and colleagues reported that a low digit
symbol substitution test score and slow gait were independent risk factors for mortality,13 and Sanders andcolleagues reported that slow processing speed and slow
gait independently predicted mortality.14 In our study,
RT and GS were independently associated with bothstroke mortality and heart disease mortality. Although
the interaction between gait speed and neither the digit
symbol substitution test13 nor processing speed14 weresigniﬁcantly associated with mortality, we found theinteraction between RT and GS to be signiﬁcantly associated with stroke mortality (P = 0.012), suggesting thatan intervention for cognitive function may be more
effective for participants with less physical function,
and an intervention for physical function may be more

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Internal Medicine Journal 48 (2018) 1331–1336© 2018 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians