Investigating The Associations Of Habitual Sleep Duration And Its Trajectories With Risk Of Incident Stroke And Its Mechanism

Objective: Stroke is the leading cause of global disability and death.The primary prevention is to explore the risk factors and early targeted interventions are crucial for reducing serious global disease burden caused by stroke.The American Heart Association has added sleep as one of the “eight principles of life” for promoting cardiovascular health.Previous studies have explored the relationship of sleep duration and stroke,but the results were inconsistent and the pathogenesis was still unclear.In addition,sleep duration was evaluated from a single time-point but not repeated measurement,and few studies have distinguished stroke subtypes.Therefore,based on two prospective cohorts from different countries,this study firstly intends to explore the association of sleep duration and dayime napping with incident stroke and its subtypes,then investigate the ralated factors of sleep duration trajectory and its subsequent risk of stroke,and finally confirme whether vascular risk factors and the function of glymphatic system play a mediating role between sleep duration and stroke.Methods: The participants of this study were recruited from the UK Biobank(UKB)and China Health and Retirement Longitudinal Study(CHARLS).The information of demographic characteristics,lifestyle behaviours,disease history,physical examination and blood test was collected.Self-reported sleep duration and daytime napping were obtained from the questionnaire.The outcome of interest was stroke and its subtype,collected from verbal interview and UK linked hospital-based clinical diagnosis in UKB and defined by self-reported physician diagnoses in CHARLS.In the first part,the baseline survey included 502 402 individuals in UKB and 17 708 individuals in CHARLS,and the final follow-up conducted until September,2022 and December,2018 respectivley.After excluding participants without information of sleep and stroke,those were lost to follow-up and those with stroke at baseline,489 354 participants from UKB and 14 057 individuals from CHARLS were included.We calculated the hazard ratio(HR)and 95% confidence interval(CI)of total sleep duration,nighttime sleep duration,the duration and frequency of daytime napping with stroke and its subtypes by Cox proportional risk model.Moreover,subgroup analysis,combined effect analysis and sensitivity analysis were conducted.The second part of this study included 9883 individuals with information of sleep and stroke at four waves.We explored influencing factors of the change of nighttime sleep duration through the latent class growth model.In addition,the trajectories of sleep duration was described via groupbased trajectory model,and its subsequent risk of stroke was evaluated by Cox proportional risk model.In the third part,489 354 individuals in UKB were included to explore the mediating role of vascular risk factors in abnormal sleep duration and stroke incidence using mediation effect model.In addition,among 4368 participants who completed diffusion tensor image(DTI)at two waves,we generated an ALPS index by diffusion tensor image analysis along the perivascular space(DTI-ALPS)method to explore whether the association between abnormal sleep duration and stroke was mediated via glymphatic system.Results: The first part of this study showed that a U-shaped relationship was observed between total sleep duration and incident stroke,ischemic stroke and intracranial hemorrhage in British,but a linear relationship was observed between total sleep duration and stroke among Chinese.Compared to those with total sleep duration of 7~<9 hours,the risk of incident stroke,ischemic stroke and intracranial hemorrhage increased by 7%(HR,1.07;95% CI,1.01-1.14),7%(HR,1.07;95% CI,1.00-1.14)and 25%(HR,1.25;95% CI,1.09-1.44)in participants with short sleep duration(<7 hours)and 17%(HR,1.17;95% CI,1.08-1.26),20%(HR,1.20;95% CI,1.10-1.30)and 24%(HR,1.24;95% CI,1.02-1.50)in those with long sleep duration(≥9 hours)in British.But in Chinese,a significant association was only observed between short sleep duration and stroke risk(HR,1.22;95% CI,1.01-1.47).Compared with those taking no naps,individuals who took occasional and regular naps had an increased risk of total stroke and ischemic stroke in UKB,but there was no significant associations between napping with stroke in CHARLS.The second part of the study found that sleep duration tended to decline with time by approximately 5.1 min/day and females,those aged 45~60 years,and those with poor health at baseline were prone to a larger decrease rate of sleep duration among middle-aged and old Chinese adults.In addition,compared to individauls with normal stable sleep trajectory,the risk of incident stroke increased 2.38 times(HR,2.38;95% CI,1.25-4.55),and 1.32 times(HR,1.32;95% CI,1.02-1.70)in those with increasing sleep trajectory and short stable sleep trajectory, respectively.The third part of the study confirmed that the association of abnormal sleep duration and stroke could be partly mediated by hypertension,diastolic blood pressure,diabetes,fasting blood glucose,glycosylated hemoglobin and high-density lipoprotein,and the proportion of mediation was 2.24%,2.25%,5.41%,3.15%,5.76% and 0.57%,respectively.In addition,the function of glymphatic system was associated with stroke,but didn’t mediate the relationship between abnormal sleep duration and stroke.Conclusion: Short or long sleep duration and frequent naps were the important risk factors for incident stroke.Additionally,it is significant to pay attention to sleep duration trajectory for prevention of stroke.However,traditional vascular risk factors and the function of glymphatic system could only partially explain the relationship between abnormal sleep duration and stroke incidence,thus the mechanism needs further research.Part Ⅰ: Associations of Sleep Duration and Daytime napping with Incident Stroke and its Subtype: Two Prospective Cohort StudiesObjective: Previous researches showed that sleep duration and daytime napping were related to the onset of stroke,but the conclusions were inconsistent.What’s more,few studies focused on stroke subtypes.Based on UKB and CHARLS,our study aimes to explore the risk of total sleep duration,nighttime sleep duration,the duration and frequency of daytime napping on incident stroke and its subtypes.Methods: At the baseline survey of UKB with 502 402 individuals from 2006 to 2010 and CHARLS with 17 708 individuals in 2011,a total of 489 354 and 14 057 individuals were included in the longitudinal analysis after excluding individuals without information of sleep duration,napping and stroke,those who were lost to follow-up,or those with stroke at baseline.The participants were followed up to September,2022 and December,2018,respectively.The baseline total sleep duration is divided into < 7 hours/day,7-< 9 hours/day,and ≥ 9 hours/day.The nighttime sleep duration is divided into < 6 hours/night,6-8 hours/night,and > 8 hours/night.The duration of nap is divided into no naps,1-60 minutes/day,and > 60 minutes/day.The frequency of nap is divided into never/rarely,sometimes and usually.The outcome of interest was the incidence of stroke and its subtype,while deaths caused by other disease except stroke were considered as competitive risk events.The associations of total sleep duration,nighttime sleep duration,duration and frequency of daytime napping with stroke and its subtypes were explored by Cox proportional hazard regression models.In addition,we investigated the combined effects of sleep duration,duration and frequency of daytime napping,insomnia,snoring and chronotype on stroke.Furthermore,we conducted subgroup analysis and sensitivity analysis.Results: After an average follow-up of 12.9 years,a total of 10 279 stroke events occurred in the British population,a U-shaped relationship was observed between total sleep duration and incident stroke,ischemic stroke and intracranial hemorrhage.After an average followup of 6.3 years,a total of 744 participants have experienced stroke,and a linear relationship was observed between total sleep duration and stroke among Chinese.Taking the normal total sleep duration(7~<9 hours)as reference,the risk of incident total stroke,ischemic stroke and intracranial hemorrhage increased by 7%(HR,1.07;95% CI,1.01-1.14),7%(HR,1.07;95% CI,1.00-1.14)and 25%(HR,1.25;95% CI,1.09-1.44)respectively in individuals with short sleep duration(<7 hours)and 17%(HR,1.17;95% CI,1.08-1.26),20%(HR,1.20;95% CI,1.10-1.30)and 24%(HR,1.24;95% CI,1.02-1.50)in individuals with long sleep duration(≥9 hours)in the British population.In Chinese,a higher stroke risk was observed in those with short sleep duration(HR,1.22;95% CI,1.01–1.47),but not long sleep duration.In the British population,those who took regular naps had a 19%(HR,1.19;95%CI,1.09-1.30)and 18%(HR,1.18;95%CI,1.06-1.30)increased risk of stroke and ischemic stroke compared to those who had no naps.In addition,when combined long sleep duration with regular naps,no insomnia,no snoring and early morning chronotype,the risk ratio and 95%CI was 1.40(1.19-1.65),1.18(1.02-1.36),1.21(1.09-1.33)and 1.23(1.11-1.36)respectively.Although there was no significant association between nighttime sleep duration and daytime napping with incident stroke among Chinese,a stroke risk ratio was 1.33(1.01-1.74)times when combined short sleep duration with no naps.Conclusions: Short or prolonged sleep duration and taking naps frequently were important risk factors for total stroke.And individuals with long sleep duration and regular naps,as well as those with short sleep duration and no naps hade the highest risk of stroke.This study confirmed the importance of maintaining appropriate sleep duration and naps for stroke prevention.Part Ⅱ: Association between sleep duration trajectories and related factors with subsequent risk for incident strokeObjective: A single time-point measure of sleep duration has been extensively studied as an important risk factor for stroke,but few studies have focused on the impact of sleep duration trajectory on stroke.This study aims to model the trajectory of sleep duration among middle-aged and older Chinese adults along with associated factors as predictors for the subsequent development of incident stroke.Methods: The subjects of this study were participants who completed the baseline survey in 2011 and the three follow-up surveys in 2013,2015,and 2018 from CHARLS.A total of 9883 subjects aged at least 45 years and with information of sleep duration at four waves were included.The characteristics of sleep duration change were explored by the latent class growth model,and the effects of time-invariant and time-varying covariates on sleep duration trajectory were discussed.In addition,further excluding individuals with stroke at baseline,a total of 9222 individuals were finally included in the analysis.The data of nighttime sleep duration tracked from the first three years from 2011 to 2015 was used to depict sleep duration trajectories by group-based trajectory modeling.Then the onset of stroke was defined by self-reported physician diagnoses from 2015 to 2018 and the association of different sleep duration trajectories with incident stroke was examined by Cox proportional hazards regression model.Results: Among middle-aged and elderly people in China,sleep duration tended to yearly decline by 5.1 min/day,with more pronounced decline in females,those aged 45-60 years and those with depression and poor health conditions.We identified four sleep duration trajectories,named normal-stable trajectory,short-stable trajectory,increasing and decreasing trajectory.After an average of 3.0 years follow-up and adjusting for potential confounds,the risk of incident stroke increased by 1.38 times(HR,2.38;95% CI,1.25-4.55)in individuals with increasing trajectory and 32%(HR,1.32;95% CI,1.02-1.70)in those with short-stable trajectory compared to those with normal-stable trajectory.But there was no significant association between decreasing trajectory of sleep duration and stroke.Conclusions: Sleep duration was affected by age,mental and physical health.Both increasing trajectory and short-stable trajectory were associated with higher risk of incident stroke.This systematic investigation of dynamic sleep duration trajectory provided novel insights for predicting and preventing stroke based on changing sleep patterns among middle-aged and older Chinese adults.Part ⅡI: Exploration of mediating factors between abnormal sleep duration and strokeObjective: Previous studies have confirmed that abnormal sleep duration could increase the risk of stroke,but little attention was attached to its mechanism.This study aims to inveatigate whether associations between abnormal sleep duration and stroke was mediated via vascular risk factors and the function of glymphatic system among adults in UK Biobank.Methods: In the baseline survey of 502 402 participants in UKB,a total of 489 354 individuals were included in the mediation analysis of vascular risk factors,after excluding individuals without information of sleep duration and stroke,or who reported a previous diagnosis of stroke at baseline.While 4368 participants with data of diffusion tensor imaging at the second and third follow-up were included to explore the mediating role of glymphatic system function.<7 hours or ≥9 hours of sleep duration was defined as abnormal sleep duration.Vascular risk factors included binary variables(obesity,hypertension,diabetes and hyperlipidemia)and continuous variables(body mass index,systolic blood pressure,diastolic blood pressure,fasting blood glucose,glycosylated hemoglobin,highdensity lipoprotein,low-density lipoprotein,total cholesterol and triglycerides).The function of the brain glymphatic system was evaluated by ALPS index based on a noninvasive diffusion tensor image analysis along the perivascular space method.First,we assessed the associations of abnormal sleep duration,vascular risk factors or ALPS index,and stroke incidence by multivariate logistic regression and linear regression models.Then we explored whether or the extent to which the association between abnormal sleep duration and stroke was mediated by vascular risk factors and the function of glymphatic system.Results: The findings showed that hypertension,diabetes,diastolic blood pressure,fasting blood glucose,glycosylated hemoglobin and high-density lipoprotein played a partly mediating role in the relationship between abnormal sleep duration and stroke.A significant indirect association mediated via hypertension and diastolic pressure was observed,and the proportion of mediation was 2.24% and 2.25%,respectively.Additionally,diabetes,fasting blood glucose and glycosylated hemoglobin accounted for 5.41%,3.15% and 5.76% of the association between abnormal sleep duration and stroke,respectively.High-density lipoprotein only partially mediated 0.57% association of abnormal sleep duration with stroke.In addition,abnormal sleep duration was not associated with baseline ALPS index,but significant association was observed between baseline ALS index and stroke(ALPS_b1000: β=-2.006,P<0.05;ALPS_b2000: β=-2.580,P<0.05).Therefore,the function of glymphatic system didn’t play a mediating role in the relationship between abnormal sleep duration and stroke.Conclusions: The relationship between abnormal sleep duration and stroke was partially mediated by vascular risk factors,but not the function fo glymphatic system.This study provided a new idea for further mechanism research.The relationship between sleep duration and the function of brain lymphatic system,as well as the role of the function of brain lymphatic system in the occurrence and development of stroke,requires further research to explore.