Chronobiology International, 2015; 32(3): 310–317 ! Informa Healthcare USA, Inc. ISSN: 0742-0528 print / 1525-6073 online DOI: 10.3109/07420528.2014.974809

ORIGINAL ARTICLE

Light exposure at night is associated with subclinical carotid atherosclerosis in the general elderly population: The HEIJO-KYO cohort Kenji Obayashi, Keigo Saeki, and Norio Kurumatani Department of Community Health and Epidemiology, Nara Medical University School of Medicine, Nara, Japan

Epidemiological and cellular biological studies indicate the influence of impaired circadian biological rhythmicity on atherosclerosis. Increased exposure to light at night (LAN) is common in modern life, and LAN exposure is the most important environmental cue for circadian misalignment. However, the association between LAN exposure and atherosclerosis has never been explored in humans. In this cross-sectional study, we measured nighttime light intensity in the bedroom along with the intima-media thickness (IMT) of the common carotid artery using ultrasonography in 700 elderly individuals (mean age 71.6 years). Averages of mean and maximal carotid IMT were 0.88 ± 0.15 mm and 1.09 ± 0.32 mm, respectively. Median intensity of LAN exposure was 0.74 lux (interquartile range, 0.08–3.34). Both mean and maximal carotid IMT significantly increased across quartiles of increasing LAN intensity (p for trend ¼ 0.002 and 50.001, respectively). After adjustment for confounding factors, including age, gender, body mass index, current smoking status, hypertension, diabetes, dyslipidemia, sleep medication, estimated glomerular filtration rate, nocturia, bedtime, duration in bed (scotoperiod), day length (photoperiod), urinary 6-sulfatoxymelatonin excretion and daytime and nighttime physical activity, multivariate linear regression models revealed significant associations of LAN exposure with carotid IMT measurements [mean: , 0.032 (fourth versus first quartiles); 95% confidence intervals (CI), 0.002–0.061; p ¼ 0.037; maximal: , 0.100 (fourth versus first quartiles); 95% CI, 0.034–0.165; p ¼ 0.003]. In conclusion, these results suggested that LAN exposure in home settings is significantly associated with subclinical carotid atherosclerosis in the general elderly population. Keywords: Carotid intima media thickness, circadian rhythm, elderly, epidemiology, light at night

INTRODUCTION

including obesity, dyslipidemia and diabetes; and cardiovascular diseases (Karlsson et al., 2001; Pan et al., 2011; Vyas et al., 2012; Yamasaki et al., 1998). Recent advances in the knowledge of the association between disrupted SCN function and cardiovascular systems reveal a cellular biological basis, where mutations of the circadian clock gene alter vascular endothelial function by the dysregulation of superoxide and nitric oxide (NO) synthesis (Anea et al., 2009, 2012; Viswambharan et al., 2007). Thus, several lines of evidence indicate the influence of impaired circadian biological rhythmicity on atherosclerosis. In modern society, a global increase of exposure to light at night (LAN) is observed not only among nightshift workers but also among the general population because of the increased use of artificial lighting (Navara & Nelson, 2007). The direct input of non-visual light information into the SCN through the photosensitive

Conventional clinical risk factors for cardiovascular diseases cannot predict all cardiovascular events, and previous studies have suggested an incremental benefit of subclinical atherosclerosis testing in the prediction of cardiovascular events (Khot et al., 2003; Law et al., 2004; Simon et al., 2007). Carotid artery intima-media thickness (IMT) is a widely accepted marker of subclinical atherosclerosis burden, and measurements of IMT of the common carotid artery (CCA) using ultrasonography can strongly predict cardiovascular events even after adjustment for conventional risk factors (O’Leary et al., 1999). Circadian biological rhythmicity is regulated by the suprachiasmatic nucleus (SCN) of the master biological clock. Epidemiological studies have suggested that shift work, a disruptive exposure on SCN function, is associated with hypertension; metabolic abnormalities

Submitted March 3, 2014, Returned for revision August 30, 2014, Accepted October 6, 2014

Correspondence: Kenji Obayashi, MD, PhD, Department of Community Health and Epidemiology, Nara Medical University School of Medicine, 840 Shijocho, Kashiharashi, Nara 634-8521, Japan. Tel: +81-744-22-3051. Fax: +81-744-25-7657. E-mail: [email protected]

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LAN and subclinical carotid atherosclerosis retinal ganglion cells is associated with a wide range of neurobiological effects. Under controlled laboratory conditions, LAN suppresses melatonin secretion, delays the internal biological rhythm and reduces sleepiness (Cajochen et al., 2000, 2005 Czeisler et al., 1986; Lockley et al., 2006). Therefore, LAN exposure causes disrupted SCN function and impaired circadian biological rhythmicity, possibly leading to progression in atherosclerosis. However, the association between LAN exposure and atherosclerosis has never been explored in humans. To determine the association of LAN exposure with atherosclerosis, we conducted a cross-sectional study comprising 700 community-based elderly individuals. In this study, nighttime light intensity in the bedroom was measured at 1-min intervals using light meters as an index of LAN exposure.

MATERIALS AND METHODS Participants Between September 2010 and March 2013, we recruited community-dwelling elderly individuals aged  60 years with the cooperation of local residents’ associations and elderly residents’ clubs, and a total of 880 elderly subjects were voluntarily enrolled in a study titled ‘‘Housing Environments and Health Investigation among Japanese Older People in Nara, Kansai Region: a prospective community-based cohort (HEIJO-KYO) study’’. Of these subjects, 700 participants completed measurements of LAN exposure and carotid IMT. Our study protocol was previously reported (Obayashi et al., 2012). All participants provided written informed consent, and the study protocol was performed in accordance with the ethics committee of Nara Medical University and the ethical standards of the Journal (Portaluppi et al., 2010). Measurements of carotid IMT To measure carotid IMT, ultrasonography of CCA was performed using a 7.5-MHz linear array transducer (Aplio MX/Viamo, Toshiba Medical Systems Corporation, Tokyo, Japan) by two trained sonographers who had no medical information about the participants. We obtained optimal longitudinal images of the distal CCA (0–10 mm proximal to the bulb widening or if widening was not determinable, 18–8 mm proximal to the tip of the flow divider). CCA–IMT was measured, not including focal plaques at the proximal edge, mid-point and distal edge of the distal CCA in the far wall in both the right and left side. Mean carotid IMT was the average of these six values of CCA–IMT. Maximal carotid IMT was the highest value of these six values of CCA– IMT. These measurement methods followed those of the previous population-based study (Heeringa et al., 2007). Intersonographer reproducibility was evaluated by the intraclass correlation coefficient (ICC) of the mean carotid IMT in the initial consecutive 107 participants. !

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The ICC of the mean carotid IMT was 0.86 [95% confidence intervals (CI), 0.81–0.91]. Carotid atherosclerosis was defined as maximal carotid IMT 1.2 mm, because cardiovascular events increase above this cut-off value in elderly people (O’Leary et al., 1999).

Measurement of LAN exposure LAN intensity was measured at 1-min intervals over two consecutive nights using a light meter (LX-28SD; Sato Shouji Inc., Kanagawa, Japan) with the sensor 60 cm above the floor near the head of the bed and facing the ceiling. The sensor of this light meter has a similar spectral sensitivity to human eye. We used the average light intensity between bedtime and rising time for a parameter of LAN exposure. The night-to-night reproducibility of average LAN intensity was moderately high (the Spearman rank correlation coefficient, 0.66– 0.70) (Obayashi et al., 2012). We divided the participants into quartile groups according to the intensity of LAN exposure. Other measurements Body mass index (BMI) was objectively measured with calculation as weight (kg) per height (m)2. The current smoking status and medical information, including previous diagnosis of cancer and cardiovascular disease and medication use, were evaluated by administering a questionnaire to the participants. Hypertension was defined based on self-reported medical history and current antihypertensive therapy, including calcium channel blocker, angiotensin converting enzyme inhibitor, angiotensin receptor blocker, diuretics, alpha blocker and beta blocker. Diabetes mellitus was defined on the basis of the following assessments: self-reported medical history, current antidiabetic therapy, fasting plasma glucose levels 7.0 mmol/L and glycated hemoglobin levels 6.5% of the National Glycohemoglobin Standardization Program value. Dyslipidemia was defined by self-reported medical history, current lipidlowering medications or triglyceride (TG) levels 150 mg/dL, low-density-lipoprotein cholesterol levels 140 mg/dL and/or high-density-lipoprotein cholesterol (HDL-C) levels 540 mg/dL. The estimated glomerular filtration rate (eGFR) was calculated using the formula of the Japanese Society of Nephrology-Chronic Kidney Disease Practice Guide. Participants were instructed to maintain a standardized sleep and urination diary by logging their bedtime, rising time and nocturnal void frequency. Data regarding the day length from sunrise to sunset in Nara (latitude 34 N) on the measurement days were obtained from the webpage of the National Astronomical Observatory of Japan. Endogenous melatonin levels were measured using data on urinary 6-sulfatoxymelatonin excretion (UME), and details were reported in our previous papers (Obayashi et al., 2012). Daytime and nighttime physical activity were the average of all valid physical activity counts from rising time to bedtime and from bedtime to

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rising time, respectively, which were evaluated at 1-min intervals using an actigraph (Actiwatch 2; Respironics Inc., Murrysville, PA) worn on the non-dominant wrist.

Statistical analyses Association trends of quartiles of LAN exposure with means, proportions and medians of variables were evaluated using linear and logistic regression models and the Jonckheere–Terpstra test (Bewick et al., 2004) for trends, respectively. Univariate linear regression models included the mean and maximal carotid IMT as dependent variables and LAN exposure, age, gender, BMI, current smoking status, hypertension, diabetes, dyslipidemia, sleep medication, eGFR, bedtime, duration in bed (scotoperiod), day length (photoperiod), UME and daytime and nighttime physical activity as independent variables. These independent variables were mutually adjusted in multivariate linear and logistic regression models, where there were no serious multicollinearity (all variance inflation factors 510). Statistical analyses were performed using the SPSS version 19.0 for Windows (IBM SPSS Inc., Chicago, IL). A two-sided p value of 50.05 was considered significant. RESULTS The mean age of the 700 participants was 71.6 ± 6.8 years, and 357 individuals (51.0%) were female. Averages

of mean and maximal carotid IMT were 0.88 ± 0.15 mm and 1.09 ± 0.32 mm, respectively. Median intensity of LAN exposure was 0.74 lux (interquartile range, 0.08–3.34). Mean age, dyslipidemia prevalence, sleep medication use, mean duration in bed and median nighttime physical activity significantly increased, and mean daytime physical activity significantly decreased across quartiles of increasing LAN intensity (Table 1). Nocturia (2 times/night) did not significantly increase across quartiles of increasing LAN intensity (Ptrend ¼ 0.88). With a quartile increase in LAN exposure, mean carotid IMT significantly increased (Q1, 0.85 ± 0.12 mm; Q2, 0.87 ± 0.15 mm; Q3, 0.89 ± 0.13 mm; Q4, 0.90 ± 0.17 mm; Ptrend ¼ 0.002). Furthermore, maximal carotid IMT significantly increased with a quartile increase in LAN exposure (Q1, 1.03 ± 0.23 mm; Q2, 1.07 ± 0.29 mm; Q3, 1.12 ± 0.32 mm; Q4, 1.16 ± 0.41 mm; Ptrend 50.001). Regarding the mean carotid IMT (Table 2), univariate linear regression models revealed significant associations of LAN exposure with mean carotid IMT [ , 0.034 (third versus first quartiles); 95% CI, 0.003–0.064; p ¼ 0.031; , 0.046 (fourth versus first quartiles); 95% CI, 0.016–0.077; p ¼ 0.003]. In addition, univariate linear regression models revealed significant associations between mean carotid IMT and age, gender, BMI, diabetes, dyslipidemia, bedtime, duration in bed and

TABLE 1. Basic and clinical parameters stratified by quartiles of LAN intensity. Quartiles of LAN intensity, median, [range, lux] Variables No. of participants Basic parameters Age, mean, years Gender, number, male BMI (25 kg/m2), number Current smoker, number Clinical parameters Hypertension, number Diabetes, number Dyslipidemia, number Sleep mediation, number eGFR, mean, mL/min/1.73 m2 Circadian rhythm parameters Bedtime, mean, clock time Duration in bed (scotoperiod), mean, min Day length (photoperiod), median, min UME, median, mg Daytime physical activity, mean, counts/min Nighttime physical activity, median, counts/min

Q1 0 [50.1]

Q2 0.3 [0.1–0.7]

Q3 1.6 [0.7–3.3]

Q4 9.3 [3.3]

175

175

175

175

Ptrend

70.4 80 44 10

(6.6) (45.7) (25.1) (5.7)

71.5 82 40 9

(6.7) (46.9) (22.9) (5.1)

72.7 88 37 5

(6.7) (50.3) (21.1) (2.9)

71.8 93 51 19

(6.9) (53.1) (29.1) (10.9)

0.016 0.13 0.48 0.75

74 18 104 11 73.6

(42.3) (10.3) (59.4) (6.3) (15.5)

75 18 105 15 71.9

(42.9) (10.3) (60.0) (8.6) (15.3)

75 28 107 20 72.3

(42.9) (16.0) (61.1) (11.4) (13.9)

76 21 123 21 70.1

(43.4) (12.0) (70.3) (12.1) (14.9)

0.84 0.33 0.040 0.044 0.10 0.17 50.001

22:28 (1:03) 480.5 (69.7)

22:53 (1:03) 484.4 (67.2)

22:36 (1:03) 501.4 (74.7)

22:20 (1:13) 513.1 (73.5)

646.0 (606.0–687.0)

650.0 (605.0–687.0)

666.0 (617.0–717.0)

649.0 (607.0–688.0)

0.24

6.9 (4.2–10.6) 312.2 (106.6)

6.6 (4.0–9.9) 301.0 (103.9)

6.2 (3.8–9.2) 305.0 (111.9)

7.3 (4.6–11.5) 285.9 (95.7)

0.51 0.035

20.3 (15.5–28.9)

21.8 (14.9–30.6)

23.7 (16.6–33.0)

26.9 (18.5–39.9)

50.001

Data are expressed as means (SD), median (interquartile range) or number (%). LAN, light at night; BMI, body mass index; eGFR, estimated glomerular filtration rate; and UME, urinary 6-sulfatoxymelatonin excretion. Chronobiology International

LAN and subclinical carotid atherosclerosis

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TABLE 2. Univariate and multivariate linear regression analysis for the asociation between variables and mean carotid IMT. Variables LAN exposure Q2 versus Q1 Q3 versus Q1 Q4 versus Q1 Basic parameters Age (per five years) Gender (male versus female) BMI (25 versus 525 kg/m2) Current smoker (yes versus no) Clinical parameters Hypertension (yes versus no) Diabetes (yes versus no) Dyslipidemia (yes versus no) Sleep medication (yes versus no) eGFR (per 10 mL/min/1.73 m2) Circadian rhythm parameters Bedtime (per hour delay) Duration in bed (scotoperiod; per hour) Day length (photoperiod; per quartile increment) UME (per log mg) Daytime physical activity (per 100 counts/min) Nighttime physical activity (per log counts/min)

95% CI



p

Adjusted a

95% CI

p

2

0.019 0.034 0.046

0.011 to 0.050 0.003 to 0.064 0.016 to 0.077

0.033 0.047 0.035 0.011

0.025 0.025 0.010 0.039

to to to to

0.041 0.068 0.061 0.062

0.018 0.036 0.024 0.014 0.007

0.004 0.003 0.002 0.023 0.014

to to to to to

0.040 0.069 0.047 0.051 0.0001

0.020 0.021 0.006 0.013 0.019 0.008

0.030 0.013 0.016 0.029 0.029 0.009

to to to to to to

0.011 0.030 0.004 0.003 0.008 0.024

0.21 0.031 0.003

0.014 0.020 0.032

(R ¼ 0.160) 0.015 to 0.043 0.009 to 0.049 0.002 to 0.061

50.001 50.001 0.006 0.66

0.034 0.041 0.045 0.019

0.025 0.018 0.020 0.031

to to to to

0.043 0.064 0.070 0.070

50.001 50.001 50.001 0.46

0.10 0.035 0.035 0.45 0.055

0.017 0.016 0.024 0.002 0.001

0.039 0.016 0.002 0.033 0.006

to to to to to

0.005 0.048 0.046 0.037 0.009

0.12 0.32 0.031 0.91 0.68

50.001 50.001 0.23 0.12 50.001 0.37

0.006 0.003 0.007 0.007 0.003 0.011

0.018 0.008 0.016 0.022 0.008 0.028

to to to to to to

0.006 0.014 0.002 0.009 0.014 0.006

0.31 0.59 0.15 0.42 0.58 0.20

0.36 0.18 0.037

IMT, intima media thickness; CI, confidence interval; BMI, body mass index; eGFR, estimated glomerular filtration rate; and UME, urinary 6-sulfatoxymelatonin excretion. a Adjusted for all covariates shown.

TABLE 3. Univariate and multivariate linear regression analysis for the association between variables and maximal carotid IMT. Variables LAN exposure Q2 versus Q1 Q3 versus Q1 Q4 versus Q1 Basic parameters Age (per 5 years) Gender (male versus female) BMI (25 versus 525 kg/m2) Current smoker (yes versus no) Clinical parameters Hypertension (yes versus no) Diabetes (yes versus no) Dyslipidemia (yes versus no) Sleep medication (yes versus no) eGFR (per 10 mL/min/1.73 m2) Circadian rhythm parameters Bedtime (per hour delay) Duration in bed (scotoperiod; per hour) Day length (photoperiod; per quartile increment) UME (per log mg) Daytime physical activity (per 100 counts/min) Nighttime physical activity (per log counts/min)

95% CI



p

Adjusted a

95% CI

p

2

0.045 0.095 0.130

0.022 to 0.111 0.028 to 0.162 0.063 to 0.197

0.19 0.006 50.001

0.035 0.067 0.100

(R ¼ 0.144) 0.029 to 0.099 0.0001 to 0.132 0.034 to 0.165

0.054 0.138 0.030 0.165

0.037 0.091 0.026 0.055

to to to to

0.071 0.185 0.085 0.276

50.001 50.001 0.29 0.003

0.049 0.120 0.032 0.146

0.029 0.069 0.023 0.037

0.069 0.170 0.088 0.255

50.001 50.001 0.25 0.009

0.068 0.120 0.040 0.053 0.015

0.020 0.047 0.009 0.028 0.030

to to to to to

0.116 0.192 0.089 0.134 0.001

0.005 0.001 0.11 0.20 0.07

0.014 0.078 0.041 0.029 0.002

0.035 to 0.063 0.007–0.149 0.008 to 0.089 0.049 to 0.107 0.013 to 0.018

0.57 0.031 0.10 0.47 0.77

0.045 0.050 0.003 0.017 0.030 0.029

0.066 0.031 0.024 0.053 0.051 0.007

to to to to to to

0.024 0.069 0.019 0.019 0.008 0.065

50.001 50.001 0.81 0.35 0.008 0.11

0.010 0.013 0.007 0.010 0.016 0.017

0.036 0.011 0.028 0.045 0.009 0.055

0.46 0.29 0.48 0.58 0.21 0.37

to to to to

to to to to to to

0.016 0.038 0.013 0.025 0.041 0.021

0.29 0.045 0.003

IMT, intima media thickness; CI, confidence interval; BMI, body mass index; eGFR, estimated glomerular filtration rate; UME, urinary 6-sulfatoxymelatonin excretion. a Adjusted for all covariates shown.

daytime physical activity. In the multivariate linear regression model that was simultaneously adjusted for covariates, higher intensity of LAN exposure was significantly associated with increased mean carotid IMT [ , 0.032 (fourth versus first quartiles); 95% CI, 0.002– 0.061; p ¼ 0.037]. These data indicate that the adjusted !

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mean of mean carotid IMT increased by 0.032 mm (95% CI, 0.002–0.061) in the fourth quartile compared with the first quartile of LAN intensity. This association between LAN exposure and mean carotid IMT was still significant after additional adjustment for nocturia and self-reported previous diagnosis of cancer and

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cardiovascular diseases such as stroke and ischemic heart disease [ , 0.031 (fourth versus first quartiles); 95% CI, 0.001–0.061; p ¼ 0.043]. Regarding the maximal carotid IMT (Table 3), univariate linear regression models revealed significant associations of LAN exposure with maximal carotid IMT [ , 0.095 (third versus first quartiles); 95% CI, 0.028– 0.162; p ¼ 0.006; , 0.139 (fourth versus first quartiles); 95% CI, 0.063–0.197; p50.001]. In addition, univariate linear regression models revealed significant associations between maximal carotid IMT and age, gender, current smoker, hypertension, diabetes, bedtime, duration in bed and daytime physical activity. In the multivariate linear regression model that was simultaneously adjusted for covariates, higher intensity of LAN exposure was significantly associated with increased maximal carotid IMT [ , 0.100 (fourth versus first quartiles); 95% CI, 0.034–0.165; p ¼ 0.003]. These data indicate that the adjusted mean of maximal carotid IMT increased by 0.100 mm (95% CI, 0.034–0.165) in the fourth quartile compared with the first quartile of LAN intensity. This association between LAN exposure and maximal carotid IMT was still significant after additional adjustment for nocturia and self-reported previous diagnosis of cancer and cardiovascular diseases [ , 0.092 (fourth versus first quartiles); 95% CI, 0.026– 0.158; p ¼ 0.006]. In addition, when carotid atherosclerosis was defined as maximal carotid IMT  1.2 mm (Table 4), univariate logistic regression models revealed a significant association of LAN exposure with carotid atherosclerosis [odds ratio (OR), 1.901 (third versus first quartiles); 95% CI,

1.162–3.109; p ¼ 0.011; OR, 2.109 (fourth versus first quartiles); 95% CI, 1.294–3.437; p ¼ 0.003]. In the multivariate logistic regression model that was simultaneously adjusted for the covariates, higher intensity of LAN exposure was significantly associated with increased prevalence of carotid atherosclerosis [adjusted OR, 1.861 (fourth versus first quartiles); 95% CI, 1.101–3.145; p ¼ 0.020]. Furthermore, we have conducted additional analyses with regard to LAN exposure in the actual sleep period defined by actigraphy. In the analyses, levels of LAN exposure were divided into three tertile groups, because 240 participants who were not exposed to LAN. Consistently, in the multivariate linear regression model adjusted for the covariates mentioned above, higher intensity of LAN exposure was significantly associated with increased maximal carotid IMT [ , 0.083 (third versus first tertiles); 95% CI, 0.026–0.140; p ¼ 0.004].

DISCUSSION This study is, to the best of our knowledge, the first human evidence examining the association between subclinical atherosclerosis and LAN exposure, which is the most important environmental cue for circadian misalignment (Brzezinski, 1997). These findings support the results of previous epidemiological studies showing the influence of shift work on atherosclerosis. Shift work is known to be a disruptive exposure on SCN function and a cause of circadian misalignment. Previous epidemiological studies have revealed that engaging in shift work is a risk factor for development of hypertension

TABLE 4. Univariate and multivariate logistic regression analysis for the association between variables and carotid atherosclerosis. Variables LAN exposure Q2 versus Q1 Q3 versus Q1 Q4 versus Q1 Basic parameters Age (per five years) Gender (male versus female) BMI (25 versus 525 kg/m2) Current smoker (yes versus no) Clinical parameters Hypertension (yes versus no) Diabetes (yes versus no) Dyslipidemia (yes versus no) Sleep medication (yes versus no) eGFR (per 10 mL/min/1.73 m2) Circadian rhythm parameters Bedtime (per hour delay) Duration in bed (scotoperiod; per h) Day length (photoperiod; per quartile increment) UME (per log mg) Daytime physical activity (per 100 counts/min) Nighttime physical activity (per log counts/min)

OR

95% CI

p

Adjusted ORa

95% CI

p

2

1.479 1.901 2.109

0.894–2.447 1.162–3.109 1.294–3.437

0.13 0.011 0.003

1.442 1.658 1.861

(Nagelkerke R ¼ 0.131) 0.849–2.449 0.980–2.805 1.101–3.145

1.416 1.939 1.052 2.148

1.249–1.605 1.384–2.717 0.718–1.542 1.068–4.318

50.001 50.001 0.79 0.032

1.356 1.772 1.164 2.124

1.161–1.582 1.196–2.626 0.758–1.786 0.981–4.597

50.001 0.004 0.49 0.06

1.409 1.592 1.108 1.517 0.946

1.010–1.965 0.988–2.564 0.785–1.563 0.893–2.576 0.848–1.055

0.043 0.06 0.56 0.12 0.32

1.048 1.290 1.147 1.398 1.056

0.719–1.527 0.769–2.163 0.784–1.678 0.794–2.462 0.935–1.192

0.81 0.34 0.48 0.25 0.38

0.736 1.357 1.007 0.832 0.818 1.171

0.633–0.855 1.186–1.554 0.869–1.168 0.650–1.064 0.694–0.962 0.920–1.492

50.001 50.001 0.92 0.14 0.016 0.20

0.876 1.074 0.991 0.872 1.023 0.908

0.712–1.077 0.888–1.298 0.846–1.162 0.665–1.145 0.841–1.245 0.672–1.227

0.21 0.46 0.92 0.33 0.82 0.53

0.18 0.06 0.020

OR, odds ratio; CI, confidence interval; BMI, body mass index; eGFR, estimated glomerular filtration rate; and UME, urinary 6-sulfatoxymelatonin excretion. a Adjusted for all covariates shown. Chronobiology International

LAN and subclinical carotid atherosclerosis and metabolic abnormalities, including obesity, high TG levels, low HDL-C levels and diabetes (Karlsson et al., 2001; Pan et al., 2011; Yamasaki et al., 1998). Similar to our findings, engaging in shift work was associated with increased mean and maximal carotid IMT (Haupt et al., 2008; Puttonen et al., 2009). In addition, a recent large scale meta-analysis has concluded that shift work is a risk factor of myocardial infarction and ischemic stroke (Vyas et al., 2012). LAN intensity nocturnally averaged in the bedroom (Q4: median, 9.3 lux) was significantly lower than that experienced by night-shift workers (Dumont et al., 2001). Although, indeed, the effect of low intensity of LAN on health is currently under investigation, recent experimental studies showed that low intensity exposure of LAN (e.g. 5 lux) promotes obesity, metabolic abnormalities, depression and cognitive impairment in mice (Bedrosian et al., 2011; Fonken et al., 2010, 2012). Furthermore, averaged LAN intensity in the present study can include LAN with high intensity but short duration. A previous study has suggested that LAN exposure with high intensity but short duration may effect on human circadian physiology (Chang et al., 2012). Thus, we also provided additional evidence that lower levels of LAN exposure compared with that related to night-shift work is significantly associated with atherosclerosis. Several potential mechanisms about negative effects of LAN exposure on the vasculature can be based on previous studies regarding the potential associations of LAN with altered clock gene expression, endothelial dysfunction, increased sympathetic nerve activation, impaired sleep quality, metabolic abnormalities and melatonin suppression. Previous genetic studies have demonstrated that LAN exposure with 20 lux altered clock gene expression in mice and that mice with Bmal1-knockout, Clock mutation and/or Period-2 mutation exhibited endothelial dysfunction with increased superoxide and decreased NO synthesis (Anea et al., 2009, 2012; Shuboni & Yan, 2010; Viswambharan et al., 2007). In addition, it was demonstrated that LAN with 100 lux increased nighttime heart rate in humans, suggesting that LAN exposure may increase sympathetic nerve activity (Scheer et al., 1999). LAN exposure may also disturb sleep through circadian misalignment, where the effective threshold may exist at approximately 10 lux (Cajochen et al., 2000). Inadequate sleep is associated with decreased leptin levels and increased ghrelin levels, resulting in metabolic abnormalities (Gangwisch, 2009; Scheer et al., 2009; Spiegel et al., 2004). Furthermore, LAN exposure, even at 3 lux, suppresses melatonin secretion, a highly effective antioxidant, in controlled settings but not in home settings, possibly because of altered light sensitivity by prior light condition (Brzezinski, 1997; Davis et al., 2001; He´bert et al., 2002; Obayashi et al., 2012; Zeitzer et al., 2000). In our previous studies, LAN exposure is significantly associated with increased nighttime blood pressure, impaired sleep quality and obesity and dyslipidemia !

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(Obayashi et al., 2013, 2014a,b). Furthermore, impaired melatonin secretion may be associated with arterial stiffness (Obayashi et al., 2014c); however, in this study, the association between UME and carotid IMT did not reach a statistical significance. Moreover, there were no significant linear association trend between LAN exposure and obesity (BMI 25 kg/m2), although, obesity was more prevalent in the higher LAN (3 lux) than lower LAN (53 lux) groups in a multivariate model, which was consistent with our previous finding (data not shown) (Obayashi et al., 2013). Whereas, this study suggests the association between LAN exposure and subclinical carotid atherosclerosis is independent of sleep medication, nighttime physical activity, BMI, diabetes, dyslipidemia, day length (photoperiod) and UME. This indicated that the possible mechanisms underlying association of LAN with atherosclerosis could not be explained only by some parameters of sleep quality, metabolic abnormalities, light sensitivity and melatonin secretion. The clinical implications of an increase in carotid IMT associated with LAN exposure for cardiovascular events could be interpreted from data in a populationbased prospective study (O’Leary et al., 1999). Among elderly individuals, a 0.100-mm increase (95% CI, 0.034– 0.165) in maximal carotid IMT associated with LAN exposure (fourth versus first quartiles) is predicted to increase myocardial infarction by 12.0% (95% CI, 4.1–19.8) and ischemic stroke by 14.0% (95% CI, 4.8–23.1). In addition, such low levels of LAN intensity in the highest quartile are considered to be a common exposure in modern society, and population attributable risks of cardiovascular diseases would be high. The clinical implications described above may be underestimated because covariates in the final multivariate models could be intermediators underlying the association between LAN exposure and subclinical carotid atherosclerosis, such as BMI, hypertension, diabetes, dyslipidemia and UME. Further epidemiological research with a longitudinal design is required to better understand the association between LAN exposure and atherosclerosis in humans. The advantages of this study include a large sample of home measurements of LAN intensity in the general elderly population. There are several limitations in this study. First, this study was conducted with a crosssectional design; therefore, causality of the findings cannot be ascertained. Second limitation is non-random sampling method. Participants in this study were recruited through local resident associations and elderly resident clubs; and 180 participants of the total sample were excluded because of incompletion of measurements of LAN exposure or carotid IMT. These procedures may possibly lead to selection bias. However, some basic data, such as BMI and eGFR, were concordant with those of the Japanese National Data (The National Health and Nutrition Survey Japan, 2010), and these basic data did not significantly differ between the

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excluded 180 participants and the 700 current participants. Therefore, the generalizability of our findings may be acceptable. Finally, bedroom light meters used in this study were not ambulatory devices, and LAN intensity may be underestimated because of additional unrecorded light exposure occurred during nocturia. This may explain non-significant association between LAN exposure and nocturia in this study. Further investigation using ambulatory light meters is required. In conclusion, this study demonstrated the significant association of LAN exposure with subclinical atherosclerosis in carotid IMT in the general elderly population. Intensity of LAN exposure is considered to be a common exposure in modern society, and the LAN intensity at risk observed in this study was low. Therefore, population attributable risks of LAN exposure in home settings for cardiovascular diseases may be high.

ACKNOWLEDGEMENTS We would like to thank Sachiko Uemura and Naomi Takenaka for their valuable support during the data collection.

DECLARATION OF INTEREST All authors report no conflicts of interest. This work was supported by Grants from the Department of Indoor Environmental Medicine, Nara Medical University; Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology; Mitsui Sumitomo Insurance Welfare Foundation; Meiji Yasuda Life Foundation of Health and Welfare; Osaka Gas Group Welfare Foundation; Japan Diabetes Foundation; Daiwa Securities Health Foundation; and the Japan Science and Technology Agency.

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Light exposure at night is associated with subclinical carotid atherosclerosis in the general elderly population: the HEIJO-KYO cohort.

Epidemiological and cellular biological studies indicate the influence of impaired circadian biological rhythmicity on atherosclerosis. Increased expo...
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