Sleep, circadian rhythm characteristics, and melatonin levels in later life adults with and without coronary artery disease
2022; American Academy of Sleep Medicine; Volume: 19; Issue: 2 Linguagem: Inglês
10.5664/jcsm.10308
ISSN1550-9397
AutoresChooza Moon, Christopher J. Benson, Alaa Albashayreh, Yelena Perkhounkova, Helen J. Burgess,
Tópico(s)Psychological and Temporal Perspectives Research
ResumoFree AccessScientific InvestigationsSleep, circadian rhythm characteristics, and melatonin levels in later life adults with and without coronary artery disease Chooza Moon, PhD, RN, Christopher J. Benson, MD, Alaa Albashayreh, PhD, RN, Yelena Perkhounkova, PhD, Helen J. Burgess, PhD Chooza Moon, PhD, RN Address correspondence to: Chooza Moon, PhD, RN, University of Iowa College of Nursing, 50 Newton Rd, Iowa City, IA 52242, United States; Email: E-mail Address: [email protected] University of Iowa College of Nursing, Iowa City, Iowa , Christopher J. Benson, MD University of Iowa Carver College of Medicine, Department of Internal Medicine, Iowa City, Iowa , Alaa Albashayreh, PhD, RN University of Iowa College of Nursing, Iowa City, Iowa , Yelena Perkhounkova, PhD University of Iowa College of Nursing, Iowa City, Iowa , Helen J. Burgess, PhD University of Michigan, Sleep and Circadian Research Laboratory, Department of Psychiatry, Ann Arbor, Michigan Published Online:February 1, 2023https://doi.org/10.5664/jcsm.10308SectionsAbstractEpubPDF ShareShare onFacebookTwitterLinkedInRedditEmail ToolsAdd to favoritesDownload CitationsTrack Citations AboutABSTRACTStudy Objectives:The purpose of this study was to conduct a comprehensive assessment of sleep and circadian rhythms in individuals with and without coronary artery disease (CAD).Methods:This was a cross-sectional study. Participants were 32 individuals, mean age = 70.9, female 46.9%, 19 with CAD, and 13 without CAD. We assessed sleep quality and 24-hour rest-activity rhythms for 14 days using wrist actigraphy and self-report measures, and circadian rhythm using dim light melatonin onset.Results:Melatonin levels prior to habitual bedtime were significantly lower in individuals with CAD than in those without CAD (median area under the curve = 12.88 vs 26.33 pg/ml × h, P = .049). The median circadian timing measured by dim light melatonin onset was the same for the 2 groups with 20:26 [hours:minutes] for individuals with CAD and 19:53 for the control group (P = .64, r = .14). Compared to the control group, the CAD group had significantly lower amplitude (P = .03, r =–.48), and lower overall rhythmicity (pseudo-F-statistic P = .004, r = –.65) in their 24-hour rest-activity rhythms.Conclusions:This is one of the first studies to comprehensively assess both sleep and circadian rhythm in individuals with CAD. Compared to non-CAD controls, individuals with CAD had lower levels of melatonin prior to habitual bedtime and a lower 24-hour rest-activity rhythm amplitude and overall rhythmicity. Future studies using larger sample sizes should further investigate the possibility of suppressed circadian rhythmicity in individuals with CAD.Citation:Moon C, Benson CJ, Albashayreh A, Perkhounkova Y, Burgess HJ. Sleep, circadian rhythm characteristics, and melatonin levels in later life adults with and without coronary artery disease. J Clin Sleep Med. 2023;19(2):283–292.BRIEF SUMMARYCurrent Knowledge/Study Rationale: Few studies have examined sleep and circadian rhythm characteristics in individuals with coronary artery disease.Study Impact: In this cross-sectional study, we studied the sleep and circadian rhythm characteristics of individuals with coronary artery disease compared to a control group without CAD. Compared to controls, individuals with coronary artery disease had lower levels of melatonin prior to habitual bedtime and a lower 24-hour rest-activity rhythm amplitude and overall rhythmicity. Future studies using larger sample sizes should further investigate the possibility of suppressed circadian rhythmicity in individuals with coronary artery disease.INTRODUCTIONCoronary artery disease (CAD) (ie, myocardial infarction [MI] or angina) is one of the most prevalent forms of heart disease in older adults and is a significant health burden affecting approximately 6.3% of adults in the United States.1 Sleep problems are a common health challenge among individuals with CAD, with up to 55% of such individuals complaining of sleep problems.2 Individuals with CAD have poorer sleep quality, shorter sleep time, later sleep timing, and a higher frequency of insomnia.3–5Epidemiological evidence suggests that shorter sleep duration increases the risk of developing CAD, hypertension, pulmonary embolism, cardiovascular mortality, and all-cause mortality.6,7 In CAD, in particular, shorter sleep duration or disturbed sleep has been found to be related to health outcomes that include higher levels of inflammatory biomarkers,8 MI events,9,10 cerebrovascular incidents,11 and increased mortality rates.12 In addition to the shorter sleep duration, later sleep timing in CAD is associated with MI events.10,13Sleep disruption is often due, in part, to aging, sleep disorders, cardiovascular conditions, or psychological problems.14,15 Individuals with CAD commonly have sleep apnea,16 depression or anxiety,17 and comorbid cardiovascular conditions including hypertension, diabetes, arrhythmia, or peripheral artery disease.18,19 Disruptions to the internal biological clock, as reflected in disrupted circadian rhythms, could also contribute to shorter sleep duration, altered sleep timing, and poorer sleep quality in CAD.20Circadian timing and regularity can be assessed in several ways. For example, proxy makers of circadian timing can be derived from questionnaires that ask for preferred timing of daily activities,21 or from wrist actigraphy data, which are curve-fit to derive estimates of circadian timing, amplitude, and overall rhythmicity.22,23 Circadian timing can also be directly assessed with the gold standard circadian phase marker, dim light melatonin onset (DLMO).24,25Research suggests that circadian rhythm disruption is associated with the development of CAD and cardiometabolic outcomes.26–28 For example, shift work is associated with CAD or cardiometabolic outcomes.29 The risk for adverse cardiovascular events, such as MI, stroke, and ventricular arrhythmias tends to peak in the morning.30 However, only a handful of studies have assessed circadian rhythms in individuals with CAD.31 Several studies have reported that individuals with CAD have lower levels of melatonin levels compared to controls without CAD, as assessed with urine, plasma, or saliva sampling.32–36 However, few studies have assessed DLMO in CAD to examine circadian timing and presleep melatonin levels. Furthermore, no studies have examined rest-activity rhythms in people with CAD vs controls to examine rest-activity amplitude and overall rhythmicity.The aim of this study was to compare sleep characteristics, rest-activity rhythm characteristics, and the DLMO between individuals with and without a history of CAD. Based on the literature, we hypothesized that individuals with a history of CAD would have shorter total sleep time, higher sleep fragmentation, and lower circadian amplitude (ie, lower melatonin levels before habitual bedtime and lower rest-activity amplitude and overall rhythmicity).METHODSParticipants and study proceduresThis cross-sectional study examined 19 individuals with a history of CAD and 13 volunteers without CAD recruited from the University of Iowa Hospitals and Clinics. The study was approved by the University of Iowa Institutional Review Board, and participants gave written informed consent in accordance with the Declaration of Helsinki. The participants were older adults who could speak, read, and write in English. Exclusion criteria included shift workers, people who crossed time zones in the previous 2 weeks, color blind individuals, and individuals with chronic insomnia disorder, neurological disorders (eg, dementia, Alzheimer disease, stroke, traumatic brain injury), cardiovascular conditions other than CAD (eg, heart failure, valve disease, arrhythmia, uncontrolled hypertension), untreated major psychiatric disorders, history of alcohol or substance abuse, or other health conditions that may affect sleep and health (eg, severe kidney failure, chronic liver failure, uncontrolled cancer, ongoing chemotherapy). The CAD group participants had a history of CAD based on a cardiac angiogram. The control group participants had no history of CAD.We sent out invitation letters to eligible individuals identified through medical record reviews at the University of Iowa Hospitals and Clinics through the TriNetX database ( https://icts.uiowa.edu/investigators/biomedical-informatics-core/trinetx). Individuals who showed interest in the study were rescreened. We first collected data from individuals with CAD. Next, we then identified potential participants who met the study criteria for the control group, again through TriNetX, and invited them to participate. We then included individuals matched by sex and age with the CAD group. The participants completed a screening interview, questionnaires, and color-deficiency test using the Ishihara color vision test37 at the initial visit. Participants were asked to follow a 2-week actigraphy protocol and keep a daily sleep diary, followed by a 1-night sleep-disordered breathing assessment and a single home DLMO session.MeasuresCoronary artery disease diagnosisWe conducted a medical chart review to confirm CAD from angiography results including information on coronary artery lesions, type(s) of stent(s), or type of CAD (eg, ST-segment elevation MI, non-ST segment elevation MI, or angina).Clinical informationWe gathered information about participants' previous medical and medication histories from reviews of medical charts and confirmed the information during the interviews, when we also measured body weight and height to calculate the body mass index (BMI). In addition, we asked questions about caffeine intake (caffeinated drinks per day) and alcohol intake (alcoholic beverages per week), and continuous positive airway pressure use. To assess depression symptoms, we used the Center for Epidemiologic Studies Depression Scale,38 which is a 20-item questionnaire that asks individuals to rate how often during the past week they experienced symptoms associated with depression. Scores for each item range from 0 to 3. Total scores range from 0 to 60, with higher sores indicating greater depressive symptoms. The State and Trait Anxiety Inventory Scale (STAI)39 was used to assess anxiety symptoms. STAI includes 20 items to assess trait anxiety (form Y1) and 20 for state anxiety (form Y2). Total scores range from 20 to 80. Higher scores indicate higher levels of anxiety. The internal consistency of STAI was 0.85.39Sleep characteristicsObjective sleep measures.Participants were asked to wear a wrist actigraphy monitor (Actiwatch Spectrum Plus; Respironics, Bend, OR) for 14 days on their nondominant wrist. Participants received instructions to press the event marker on the monitor before and after sleep each night. We analyzed the data using the Actiware 5.70.1 program (Respironics). The event markers, light data, and activity levels guided us in setting the nightly rest intervals for analysis.40 Objective sleep characteristics (ie, total sleep time, total time in bed, sleep latency, wake after sleep onset, and sleep efficiency) were estimated and verified with the sleep time and wake time in participants' sleep diaries. Sleep efficiency was defined as the proportion of total sleep time to time in bed, expressed as a percentage. Midpoint of sleep was identified after reviewing the habitual wake-up time and sleep time. The sleep characteristics were extracted for each study night and averaged over the 14-day period.Sleep-disordered breathing.We used Watch-PAT 200 (Itamar Medical, Caesarea, Israel)41 to measure the apnea-hypopnea index and respiratory distress index. Watch-PAT is a 4-channel sleep monitoring device that measures peripheral arterial tone (PAT), pulse oximetry, heart rate, and actigraphy. Respiratory events were considered when 1 of the following 3 criteria were present: (1) a reduction in PAT amplitude with an acceleration of the pulse rate or an increase in wrist activity, (2) a reduction in PAT amplitude with ≥ 3% oxyhemoglobin desaturation, and/or (3) ≥ 4% oxyhemoglobin desaturation only. In previous studies, the device has shown good sensitivity (%) and specificity (%) in diagnosing sleep-disordered breathing compared to polysomnography in individuals with CAD.41Self-reported sleep measures.We used the following 3 questionnaires to evaluate self-reported sleep and daytime symptoms. The Pittsburgh Sleep Quality Index was used to measure sleep quality.42 The Epworth Sleepiness Scale was used to measure excessive daytime sleepiness.43 The Insomnia Severity Index was used to measure insomnia symptom severity.44Circadian rhythm characteristicsCircadian timing and melatonin levels.DLMO is a reliable marker of the circadian clock. We utilized a home DLMO kit from Burgess et al (2016).45 All participants were asked to be awake and seated in a dim light environment (< 50 lux) for 6.5 hours before bedtime at home and collect a saliva sample on a cotton swab every 30 minutes during the 6 hours. Participants were not permitted to consume any alcohol or caffeine at least 24 hours before the DLMO session. Participants were also instructed to not take nonsteroidal anti-inflammatory drugs except for an aspirin in a CAD medication regimen. To ensure compliance, participants wore an actigraph on their wrist with a photosensor (Actiwatch Spectrum) to measure light exposure and were instructed to not cover the actigraph. The cotton swabs were placed in plastic vials with MEMS Track Caps (MWV Healthcare, Richmond, VA) which registered each time the participants opened the bottles for saliva collection.We removed data for 1 participant because this participant took melatonin the night before saliva collection. We removed data from 7 other participants due to a brighter light environment (> 50 lux) measured by the photosensor that affected the 2 points used to calculate the DLMO. No DLMOs were lost due to sample timing errors. The saliva samples were stored in the participant's home freezer overnight and transferred the next day to our research lab, where the samples were stored in a –80°F freezer. The samples were sent to Solidphase Inc. (Portland, ME) for radioimmunoassay (Buhlmann RIA). To assess each participant's melatonin profile, a threshold was calculated as twice the mean of the first 3 low daytime melatonin values. This threshold was used since it calculates DLMO more closely to the initial melatonin rise.46,47 Each participant's DLMO was the point in time (as determined by linear interpolation) when the melatonin concentration exceeded and remained above the threshold for at least 2 hours. The area under the curve (pg/ml × h) was calculated to estimate the melatonin levels over the 6 hours prior to the average bedtime using the trapezoidal method.48,4924-hour rest-activity patterns.The circadian rest-activity measures were calculated using the epoch-by-epoch data from the Actiwatch Spectrum Plus. We used an extended cosine model to calculate the pseudo-F-statistics, amplitude, acrophase, mesor, and slope. An extended cosine model uses nonlinear least squares to calculate the circadian activity parameters. The following rest-activity rhythm parameters were calculated: (1) amplitude (the peak to nadir difference in activity measured in arbitrary units of activity [counts/min], which is an indicator of the strength of the rhythm); (2) acrophase (the time of day of peak activity measured by the peak of the fitted curve) (3) mesor (the midline estimated statistic of rhythm, which is the mean level of activity); and (4) pseudo-F-statistics for goodness of extended cosine fit (a measure of overall rhythmicity). Higher amplitude values indicate greater strength of the rhythms. Higher acrophase values indicate delayed peak timing of the activity. Higher mesor values indicate greater average activity, and higher pseudo-F-statistics indicate more robust rhythms.50Chronotypes.The Morningness-Eveningness Questionnaire was used to determine chronotype.21Statistical analysisStatistical analysis was performed with SAS software (SAS Institute, Cary, NC), using statistical significance alpha = .05 for hypothesis testing. Study variables were summarized using medians and interquartile ranges for continuous variables and frequencies and percentages for categorical variables. Distributions of continuous sleep measures were examined by creating separate boxplots for CAD and control groups. Based on the assessment of the distributions, we chose the Wilcoxon rank-sum test to compare the groups on continuous variables and Fisher's exact test to compare the groups on categorical variables. Effect sizes (r) for the Wilcoxon rank-sum test were defined as rank-biserial correlation coefficients and calculated as the test statistic (W) divided by the total rank sum (S).RESULTSSample characteristicsA total of 32 older adults participated in the study with a mean age of 70.9 years (standard deviation [SD] = 7.4). Nearly half of the participants (46.9%) were women. The mean score on the Center for Epidemiologic Studies Depression Scale (CESD) was 7.14 (SD = 6.5), and mean STAI score was 46.8 (SD = 2.4). Descriptive statistics for the sample are reported in Table 1, by group. The most frequent CAD type was stable angina (47.4%). Individuals with CAD had comorbidities and were on cardiac medications more frequently compared to individuals in the control group. CESD scores were higher in the CAD group compared to the control group (P = .01). Table 2 and Table 3 show the descriptive statistics for sleep measures and circadian rhythm characteristics, by group. Figure 1 and Figure 2 display box plots for selected variables. Figure 3 displays the saliva melatonin levels.Table 1 Demographic and clinical characteristics, by study group (n = 32).Variable [Range]CAD (n = 19)Control (n = 13)PAge (years) [58–88]71 (65, 80)67 (66, 74).43Sex (female)8 (42.1%)7 (53.9%).72BMI (kg/m2) [20.4–44.3]29.6 (24.4, 36.2)28.1 (25.8, 29.8).24CESD score [0–25]9 (5, 12)4 (1, 4).01STAI score [40–55]48 (45, 50)46 (45, 48).41CAD type< .001 Stable angina9 (47.4%)0 (0%) Unstable angina2 (10.5%)0 (0%) STEMI2 (10.5%)0 (0%) Non-STEMI6 (31.6%)0 (0%)Comorbidities Diabetes8 (42.1%)2 (15.4%).14 Hypertension17 (89.5%)3 (23.1%)< .001 Hyperlipidemia15 (79%)2 (15.4%)< .001 COPD6 (31.6%)1 (7.7%).20 Chronic kidney disease3 (15.8%)0 (0%).25Medication Aspirin19 (100%)3 (23.1%)< .001 Clopidogrel6 (31.6%)0 (0%).06 Nitrate13 (68.4%)0 (0%)< .001 Beta blockers14 (73.7%)0 (0%)< .001 Angiotensin converting enzyme inhibitors6 (31.6%)2 (15.4%).42 Loop diuretics0 (0%)0 (0%) Thiazide diuretics6 (31.6%)0 (0%).06 Potassium sparing diuretics0 (0%)0 (0%)Caffeine and alcohol intake Caffeine intake (caffeinated drinks/d) [0–6]1.0 (0.0, 3.0)3.0 (2.0, 5.0).047 Alcohol intake (alcoholic beverages/wk) [0–22]0 (0.0, 7.0)4.0 (0, 7.0).53Values are median (interquartile range) or n (%). P-values from the Wilcoxon rank-sum test to compare the groups on continuous variables and Fisher's exact test to compare the groups on categorical variables. BMI = body mass index, CAD = coronary artery disease, CESD = Center for Epidemiologic Studies Depression scale, COPD = chronic obstructive pulmonary disorder, Non-STEMI = non-ST segment elevation myocardial infarction, STAI = State and Trait Anxiety Scale, STEMI = ST segment elevation myocardial infarction.Table 2 Descriptive statistics for sleep measures, by group (n = 32).Variable [Range]CAD (n = 19)Control (n = 13)PrObjective sleep Habitual bedtime (h:min) [18:46–00:40]22:10 (21:17, 23:13)21:53 (21:40, 22:25).940.02 Final Wake time (h:min) [4:20–7:55]6:41 (6:21, 7:13)7:00 (6:19, 7:22).48–0.15 Midpoint of sleep (h:min) [11:41–4:00]2:27 (1:37, 3:01)2:31 (2:10, 2:51).98–0.01 Time in bed (min) [389.0–718.0]487.0 (452.0, 581.0)529.0 (487.0, 548.0).31–0.21 Total sleep time (min) [308.4–548.3]407.6 (350.4, 472.5)434.0 (407.1, 447.4).26–0.25 Sleep latency (min) [5.9–89.0]25.5 (15.7, 37.9)23.5 (17.9, 54.4).82–0.04 Sleep efficiency (%) [63.6–93.1]82.1 (77.5, 87.3)83.9 (81.6, 88.6).38–0.19 Wake after sleep onset (min) [13.4–106.5]40.9 (26.2, 59.1)33.0 (27.3, 38.3).230.26 Number of awakenings [6.9–44.5]31.8 (23.3, 36.8)26.6 (23.8, 37.5).880.04Sleep-disordered breathing Apnea-hypopnea index [1.0–78.0]14.6 (5.5, 21.3)16.3 (10.7, 23.8).47–0.16 Respiratory distress index [5.7–87.0]19.2 (15.2, 25.3)25.2 (18.5, 33.0).28–0.23 Oxygen desaturation index [0.4–39.0]4.9 (2.1, 9.2)5.3 (1.5, 6.7)1.000.00CPAP use9 (47.4%)2 (15.4%).13Self-reported sleep Insomnia Severity Index total [0–25]10.0 (4.0, 15.0)10.0 (4.0, 11.0).280.23 Insomnia category.47 No insomnia12 (63.2%)6 (46.2%) Subthreshold insomnia7 (36.8%)7 (53.9%) Moderate insomnia0 (0%)0 (0%) Severe insomnia0 (0%)0 (0%) Pittsburgh Sleep Quality Index [1–15]8.0 (4.0, 9.0)6.0 (4.0, 8.0).430.17 Poor sleep (score > 5)13 (68.4%)7 (53.9%).47 Epworth Sleepiness Scale total [0–16]8.0 (3.5, 12.0)5.0 (4.0, 7.0).370.19 Excessive daytime sleepiness (score > 10)5 (26.3%)1 (7.7%).47Values are median (interquartile range) or n (%). P-values from the Wilcoxon rank-sum test to compare the groups on continuous variables and Fisher's exact test to compare the groups on categorical variables. r = Rank-biserial correlation to indicate effect sizes for differences between groups. CAD = coronary artery disease, CPAP = continuous positive airway pressure.Table 3 Circadian rhythm characteristics, by group (n = 32).Variable [Range]CAD (n = 19)Control (n = 13)PrMidpoint of sleep time (h:min) [23:19–03:59]2:27 (1:32, 3:01)2:31 (2:10, 2:51).92–0.01DLMO (n = 24)a DLMO time (h:min) [17:30–21:42] (n = 20)b20:26 (19:12, 21:51)19:53 (19:17, 20:59).640.14 AUC of melatonin (pg/ml × h) [6.0–72.7]12.88 (7.90, 26.15)26.33 (15.20, 58.28).049–0.4824-hour rest-activity patterns Amplitude [0.61–1.78]1.32 (0.96, 1.52)1.56 (1.47, 1.68).03–0.48 Acrophase (h:min) [11:40–15:45]14:30 (13:30, 15:05)14:17 (14:03, 14:38).540.13 Mesor [0.60–1.25]0.83 (0.70, 0.89)0.85 (0.78, 0.91).41–0.18 Pseudo-F-statistic [934.02–10609.60]3300.0 (2077.8, 4529.3)5808.7 (4754.1, 7561.9).004–0.65Chronotypes Morningness-eveningness total [42.0–74.0]62.0 (57.0, 68.0)66.0 (59.0, 70.0).44–0.17 Types of morningness-eveningness.34 Definite evening0 (0%)0 (0%) Moderate evening0 (0%)0 (0%) Intermediate7 (36.8%)3 (25.0%) Moderate morning9 (47.4%)4 (33.3%) Definite morning3 (15.8%)5 (41.7%)Values are median (interquartile range) or n (%). P-values from the Wilcoxon rank-sum test to compare the groups on continuous variables and Fisher's exact test to compare the groups on categorical variables. bFor dim light melatonin onset (DMLO) time, n = 8 for the CAD group and n = 12 for control. r = Rank-biserial correlation to indicate effect sizes for differences between groups. aDLMO data were excluded for 7 participants due to a brighter light environment (> 50 lux) and for 1 participant who was taking melatonin regularly, resulting in n = 12 for CAD group and n = 12 for control group. CAD = coronary artery disease, DLMO = dim light melatonin onset.Figure 1: Key objective sleep characteristics, by CAD status.CAD group n = 19, control group n = 13. Objective sleep characteristics did not demonstrate statistically significant differences. CAD = coronary artery disease.Download FigureFigure 2: Key circadian rhythm and 24-hour rest activity pattern characteristics, by CAD status.*P-value < .05. For dim light melatonin onset (DMLO), n = 8 for the CAD group and n = 12 for control group. For area under the curve (AUC) for melatonin, n = 12 for the CAD group and n = 12 for control group, and for other variables n = 19 for the CAD group and n = 13 for control group. CAD group had median DLMO time of 20:26 (hours:minutes) and control group had 19:53. The median mesor and acrophase were similar between the CAD and healthy control groups. The amplitude and pseudo-F-statistics were higher in the control group. CAD = coronary artery disease.Download FigureFigure 3: Comparison of dim light melatonin levels by hours prior to the average bedtime.CAD group n = 12, control group n = 12. CAD group had lower overall salivary melatonin levels compared to the control group. CAD = coronary artery disease.Download FigureSleep characteristicsTable 2 shows descriptive statistics for objective and self-reported sleep measures. Although in our sample individuals with CAD had on average shorter total sleep time, lower sleep efficiency, and longer wake after sleep onset, the differences between the CAD group and control group on these measures were not statistically significant (r = –.25, –.19, .26, respectively, P > .05). There were no significant differences between the groups with respect to the apnea-hypopnea index, respiratory distress index, oxygen desaturation index, or the frequency of using continuous positive airway pressure therapy. Sleep quality and daytime sleepiness were worse in participants with CAD (r = .17, .19, respectively); however, the differences were not statistically significant (P > .05). Figure 1 shows the box plots for total sleep time, wake after sleep onset, sleep latency, and sleep efficiency.Circadian rhythm characteristicsTable 3 shows the descriptive statistics for circadian rhythm characteristics. For DLMO, although all 32 participants completed the DLMO sessions, data were excluded for 6 participants from the CAD group and 1 participant from the control group because of light exposure that was greater than 50 lux. We also excluded 1 participant from the CAD group who regularly took melatonin. Therefore, the sample for analysis of DLMO included 12 in the CAD group and 12 in the control group. Moreover, we could not determine the DLMO time for 4 participants in the CAD group due to disorganized melatonin levels throughout the sessions, which resulted in a final sample of 8 participants in the CAD group and 12 participants in the control group with DLMO time. The median circadian timing measured by DLMO was similar for the 2 groups with median = 20:26 [hours:minutes] for individuals with CAD and 19:53 control group (P = .64, r = .14). The melatonin level over 6 hours prior to the average bedtime measured by the area under the curve was significantly lower in the CAD group (median = 12.88 pg/ml × h [n = 12]) than in the control group (median = 26.33 pg/ml × h [n = 12], P = .049, r = –.48). The 2 upper box plots in Figure 2 depict the distributions of DLMO and the area under the curve. Melatonin levels over 6 hours prior to the average bedtime for the CAD and control groups are shown in Figure 3.With respect to 24-hour rest-activity patterns, CAD participants had a significantly lower amplitude (P = .03, r = –.48), and lower overall rhythmicity (pseudo-F-statistic P = .004, r = –.65), compared to controls. Figure 2 shows box plots for amplitude, acrophase, mesor, and pseudo-F-statistic. No statistically significant differences between the groups were found with respect to chronotypes (ie, morningness-eveningness).DISCUSSIONThis is the first study to comprehensively assess sleep and circadian rhythm characteristics in a CAD sample vs an age-matched non-CAD sample. The findings suggest that while some aspects of sleep and circadian characteristics did not significantly differ between the groups, participants with CAD had reduced circadian rhythm amplitude, as demonstrated by a weaker 24-hour rest-activity rhythm and lower melatonin levels prior to habitual bedtime. CAD was not associated with differences in sleep characteristics (eg, self-report sleep quality, total sleep time), daytime sleepiness timing or rhythmicity, or with other study variables.We found that the CAD group had lower circadian amplitude based on the melatonin levels prior to habitual bedtime and 24-hour rest-activity rhythm pattern amplitude. Our findings indicate timing of circadian rhythm, measured by DLMO, was similar in both groups at around 8 pm. Similarly, the midpoint of sleep and acrophase did not differ by CAD status. However, we found lower melatonin levels in individuals with CAD vs controls in the 6 hours prior to habitual sleep time as shown in Figure 3. Thus, while sleep and circadian timing did not differ between the 2 groups, the amplitude of the rest-activity rhythm and melatonin levels prior to habitual bedtime were reduced.With respect to the 24-hour rest-activity patterns, we found that individuals with CAD had reduced amplitude and overall rhythmicity (pseudo-F-statistics). These findings are consistent with previous studies indicating lower serum or urine melatonin levels in individuals with CAD compared to those without CAD.32,34,35 Similar to our findings, the longitudinal results from the Osteoporotic Fractures in Men study indicated that reduced 24-hour rest-activity pattern amplitude is associated with CAD events, such as MI or death related to coronary heart disease.51 These results may provide insights in the relationships between CAD and reduced circadian rhythm characteristics.Unlike prior studies, our findings indicate that the differences in sleep characteristics (eg, total sleep time, sleep efficiency, and self-reported sleep quality) did not reach statistical significance. However, the results demonstrated that on average individuals with CAD had shorter total sleep time (CAD group = 6.8 hours vs control group = 7.2 hours), longer wake after sleep onset (CAD group = 40.9 minutes vs control group = 33.0 minutes), and reduced sleep efficiency (CAD group = 82.1% vs control group = 83.9%) than those without CAD. In contrast to our findings, Johansson et al (2013) reported that women with CAD had shorter sleep duration (CAD group = 5.2 hours vs control group = 6.3 hours), lower sleep efficiency (CAD group = 64% vs control group 72%), and higher sleep fragmentation index (CAD group = 43.5 vs control group = 36.3).52 In a systematic review by Madsen et al (2019),5 sleep c
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