Objective 
Vasomotor symptoms (VMS) are prevalent symptoms that can have a negative impact on quality of life. VMS have also been linked to cardiovascular disease risk, yet the mechanisms underlying these associations have not been elucidated. Some initial works link VMS to adverse adipokine profiles or cytokines produced by adipose tissue. However, results are not entirely consistent and are based entirely on self-report VMS, which is influenced by a range of memory and reporting biases. The aim of this work was to test whether physiologically assessed VMS are associated with lower adiponectin, the most abundant adipokine in the body, controlling for confounding factors. We also consider whether adiponectin explains previously documented relationships between VMS and carotid atherosclerosis.
Methods 
A total of 300 peri- and postmenopausal nonsmoking women aged 40 to 60 years enrolled in the MsHeart study comprised the analytic sample. Women were free of hormone therapy or other medications impacting VMS, insulin-dependent diabetes, and cardiovascular disease. Participants underwent ambulatory physiologic VMS monitoring, physical measures, a carotid ultrasound, and fasting phlebotomy.
Results 
More frequent physiologically assessed VMS were associated with lower adiponectin (B [SE] = −0.081 [0.028], P = 0.004; or 0.081 lower μg/mL in adiponectin for each additional VMS over 24 hours), controlling for age, race/ethnicity, education, insulin resistance, and waist circumference. Associations were not explained by endogenous estradiol. Adiponectin did not explain associations between VMS and carotid atherosclerosis.
Conclusions 
Physiologic VMS were associated with lower adiponectin after considering potential confounders. The role of adipokines in VMS and in links between VMS and health warrants further attention.

Objective
To test whether more physiologically assessed hot flashes were associated with more connectivity in the default mode network (DMN), the network of brain regions active during rest. We particularly focus on DMN networks supporting the hippocampus as this region is rich in estrogen (E) receptors (ER) and has previously been linked to hot flashes.
Design
Women underwent 24 hours of physiologic and diary hot flash monitoring, functional magnetic resonance imaging (MRI), 72 hours of sleep actigraphy monitoring, a blood draw, questionnaires, and physical measures.
Setting
University medical center.
Patient(s)
Twenty midlife women aged 40–60 years who had their uterus and both ovaries and were not taking hormone therapy (HT).
Intervention(s)
None.
Main Outcome Measure(s)
The DMN functional connectivity.
Result(s)
Controlling for age, race, and education, more physiologically-monitored hot flashes were associated with greater DMN connectivity (beta, B [SE] = 0.004 [0.002]), particularly hippocampal DMN connectivity (B [SE] = 0.005 [0.002]). Findings were most pronounced for sleep physiologic hot flashes (with hippocampal DMN, B [SE] = 0.02 [0.007]). Associations also persisted controlling for sleep, depressive symptoms, and serum E2 concentrations.
Conclusion(s)
More physiologically-monitored hot flashes were associated with more DMN connectivity, particularly networks supporting the hippocampus. Findings were most pronounced for sleep hot flashes. Findings underscore the importance of continued investigation of the central nervous system in efforts to understand this classic menopausal phenomenon.

Objective
Most midlife women report vasomotor symptoms, yet their physiology remains poorly understood. This study tested whether acute decreases in cardiac vagal control would occur with vasomotor symptoms in a large sample of women monitored during wake and sleep.

Methods
215 nonsmoking women ages 40–60 with evidence of vasomotor symptoms were included. Women were free of a history of clinical cardiovascular disease or arrhythmia; or use of insulin, beta blockers, calcium channel blockers, or medications impacting vasomotor symptoms. Women underwent 24 hours of ambulatory monitoring for physiological (sternal skin conductance) and self-report (electronic diary) measurement of vasomotor symptoms; heart rate variability (electrocardiogram); and respiratory rate. Changes in cardiac vagal control as assessed by respiratory sinus arrhythmia during vasomotor symptoms relative to periods preceding and following vasomotor symptoms were tested in linear mixed models.

Results
Significant decreases in respiratory sinus arrhythmia were observed during physiologically-measured vasomotor symptoms relative to periods preceding (b(SE)=.13(.004), p<.0001) and following the VMS (b(SE)=.13(.004), p<.0001), adjusted for age, race, body mass index, sleep/wake. Decreases were observed for women not aware of their vasomotor symptoms, and persisted controlling for respiration rate. Interactions indicated that respiratory sinus arrhythmia decreases were most pronounced during sleep and for younger women. Conclusions Physiologically-measured vasomotor symptoms were accompanied by an inhibition of cardiac vagal control in a large sample of women. Changes were observed irrespective of whether the vasomotor symptoms were reported, were most pronounced during sleep, and were greatest among younger women. These findings contribute to the understanding of vasomotor symptom physiology.

Objective
A childhood history of abuse or neglect may be associated with elevated adult cardiovascular disease (CVD) risk. No studies have examined associations between child abuse/neglect and subclinical CVD using a validated measure of abuse and neglect. We hypothesized that midlife women with a childhood abuse or neglect history would have increased subclinical CVD beyond standard CVD risk factors. We tested moderation of associations by sleep, hot flashes, and race/ethnicity.

Methods
295 midlife women completed the Child Trauma Questionnaire, physiologic hot flash and actigraphic sleep monitoring, blood draw, and carotid ultrasound (intima media thickness, IMT; plaque). Relations between abuse/neglect and outcomes were tested in linear regression models adjusting for demographic, psychosocial, and CVD risk factors. Interactions with sleep, hot flashes, and race/ethnicity were tested.

Results
45% of women reported a history of child abuse or neglect. Women with any child abuse or neglect had higher IMT [b(SE)=.039(.011), p<.01] and carotid plaque [OR(95%CI= 1.95 (1.15–3.33), p<.05] than non-abused/neglected women. Further, physical abuse, emotional abuse, or emotional neglect were associated with higher subclinical CVD. Sexual abuse was associated with higher IMT among nonwhite women. Interactions with sleep time and sleep hot flashes (p values <.05) indicated that higher subclinical CVD with an abuse/neglect history was observed primarily among women sleeping <6 hours/night or with sleep hot flashes. Conclusions A history of child abuse or neglect is associated with higher subclinical CVD in women, particularly when paired with short sleep or hot flashes. Findings underscore the importance of childhood adversity in midlife women’s CVD risk.

Midlife, which encompasses the menopause transition in women, can be a time of disrupted sleep and accelerated atherosclerosis accumulation. Short or poor sleep quality has been associated with cardiovascular disease (CVD) risk; few studies have investigated relations among midlife women. We tested whether shorter actigraphy sleep time or poorer subjective sleep quality was associated with carotid atherosclerosis among midlife women.Two hundred fifty-six peri- and postmenopausal women aged 40–60 years completed 3 days of wrist actigraphy, hot flash monitoring, questionnaires (Pittsburgh Sleep Quality Index [PSQI], Berlin), a blood draw, and carotid ultrasound [intima media thickness (IMT), plaque]. Associations of objective (actigraphy) and subjective (PSQI) sleep with IMT/plaque were tested in regression models (covariates: age, race, education, body mass index, blood pressure, lipids, insulin resistance, medications, snoring, depressive symptoms, sleep hot flashes, and estradiol).Shorter objective sleep time was associated with higher odds of carotid plaque (for each hour shorter sleep, plaque score ≥ 2, odds ratio (OR) [95% confidence interval, CI] = 1.58 [1.11–2.27], p = .01; plaque score = 1, OR [95% CI] = 0.95 [0.68–1.32], p = .75, vs. no plaque, multivariable). Poorer subjective sleep quality was associated with higher mean IMT [β, b (standard error, SE) = 0.004 (0.002), p = .03], maximal IMT [b (SE) = 0.009 (0.003), p = .005], and plaque [plaque score ≥ 2, OR (95% CI) = 1.23 (1.09–1.40), p = .001; score = 1, OR (95% CI) = 1.06 (0.93–1.21), p = .37, vs. no plaque] in multivariable models. Findings persisted additionally adjusting for sleep hot flashes and estradiol.Shorter actigraphy-assessed sleep time and poorer subjective sleep quality were associated with increased carotid atherosclerosis among midlife women. Associations persisted adjusting for CVD risk factors, hot flashes, and estradiol.

Research suggests that sleep disturbances are associated with elevated levels of inflammation. Some evidence indicates that women may be particularly vulnerable; increased levels of inflammatory biomarkers with sleep disturbances are primarily observed among women. Midlife, which encompasses the menopause transition, is typically reported as a time of poor sleep. We tested whether poorer objectively measured sleep characteristics were related to a poorer inflammatory profile in midlife women.Two hundred ninety-five peri- and postmenopausal women aged 40–60 completed 3 days of wrist actigraphy, physiologic hot flash monitoring, questionnaires (e.g. Berlin sleep apnea risk questionnaire], and a blood draw for the assessment of inflammatory markers, including C-reactive protein (CRP), interleukin-6 (IL-6), and von Willebrand factor (VWF) antigen. Associations of objective (actigraphy) sleep with inflammatory markers were tested in regression models. Sleep efficiency was inverse log transformed. Covariates included age, race/ethnicity, education, body mass index, sleep apnea risk, homeostatic model assessment (a measure of insulin resistance), systolic blood pressure, low-density lipoprotein cholesterol, and physical activity.In separate models controlling for age, race/ethnicity, and education, lower sleep efficiency was associated with higher IL-6 [b(SE) = .02 (.10), p = .003] and VWF [b(SE) = .02 (.08), p = .002]. More minutes awake after sleep onset was associated with higher VWF [b(SE) = .12 (.06), p = .01]. Findings persisted in multivariable models.Lower sleep efficiency and more minutes awake after sleep onset were independently associated with higher circulating levels of VWF. Lower sleep efficiency was associated with higher circulating levels of IL-6. These findings suggest that sleep disturbances are associated with greater circulating inflammation in midlife women.

Objective
Hot flashes are experienced by most midlife women. Emerging data indicate that they may be associated with endothelial dysfunction. No studies have tested whether hot flashes are associated with endothelial function using physiologic measures of hot flashes. We tested whether physiologically-assessed hot flashes were associated with poorer endothelial function. We also considered whether age modified associations.

Methods
272 nonsmoking women reporting either daily hot flashes or no hot flashes, aged 40-60, and free of clinical cardiovascular disease underwent ambulatory physiologic hot flash and diary hot flash monitoring; a blood draw; and ultrasound measurement of brachial artery flow mediated dilation to assess endothelial function. Associations between hot flashes and flow mediated dilation were tested in linear regression models controlling for lumen diameter, demographics, cardiovascular disease risk factors, and estradiol.

Results
In multivariable models incorporating cardiovascular disease risk factors, significant interactions by age (p<.05) indicated that among the younger tertile of women in the sample (ages 40-53), the presence of hot flashes [beta(standard error)=-2.07 (.79), p=.01], and more frequent physiologic hot flashes were associated with lower flow mediated dilation [for each hot flash: beta(standard error)=-.10(.05), p=.03, multivariable]. Associations were not accounted for by estradiol. Associations were not observed among the older women (ages 54-60) or for prospective-reported hot flash frequency, severity, or bother. Among the younger women, hot flashes explained more variance in flow mediated dilation than standard cardiovascular disease risk factors or estradiol. Conclusions Among younger midlife women, frequent hot flashes were associated with poorer endothelial function and may provide information about women's vascular status beyond cardiovascular disease risk factors and estradiol.

Objective:
Childhood maltreatment is related to adverse health outcomes. However, the relation of childhood maltreatment to the menopause transition, a universal transition for women often accompanied by troubling symptoms such as vasomotor symptoms, is relatively underexplored. This study tested whether childhood abuse and neglect are associated with menopausal vasomotor symptoms, utilizing both physiologic and prospective self-report measures of vasomotor symptoms.

Methods:
295 nonsmoking perimenopausal and postmenopausal women aged 40 to 60 years with and without vasomotor symptoms completed psychosocial measures including the Child Trauma Questionnaire, ambulatory physiologic (sternal skin conductance) and self-report measurement of vasomotor symptoms during wake and sleep, and actigraphy measurement of sleep. Relationships between childhood abuse/neglect and vasomotor symptoms during wake and sleep were tested in linear regression models controlling for demographics, body mass index, and menopause stage.

Results:
44% of the sample reported abuse or neglect during childhood. Among women reporting vasomotor symptoms, childhood sexual or physical abuse was associated with more frequent physiologically-recorded vasomotor symptoms during sleep (sexual abuse: b(SE)=1.45(0.52), p=0.006; physical abuse: b(SE)=0.97(0.47), p=0.03) in multivariable models. Among these women, women with a physical or sexual abuse history had approximately 1.5-two fold the number of sleep vasomotor symptoms than women without this history.

Conclusions:
Childhood abuse is associated with more frequent physiologically-detected vasomotor symptoms during sleep.

Traumatic experiences are common and linked to cardiovascular disease (CVD) risk, yet the mechanisms underlying these relationships is less well understood. Few studies have examined trauma exposure and its relation to autonomic influence over cardiac function, a potential pathway linking trauma exposure to CVD risk. Investigating autonomic influence over cardiac function during both wake and sleep is critical, given particular links of sleep autonomic function to cardiovascular health. Among midlife women, we tested whether trauma exposure would be related to lower high frequency heart rate variability (HF-HRV), an index of vagal influence over cardiac function, during wake and sleep. Three hundred and one nonsmoking midlife women completed physical measures, a 24-hr electrocardiogram, actigraphy sleep measurement, and questionnaires about trauma (Brief Trauma Questionnaire), childhood abuse (Child Trauma Questionnaire [CTQ]), mood, demographics, and medical/psychiatric history. Relations between trauma and HF-HRV were assessed in linear mixed effects models adjusting for covariates (age, race, education, body mass index, blood pressure, psychiatric history, medication use, sleep, mood, childhood abuse history). Results indicated that most women had experienced trauma. Any trauma exposure as well as a greater number of traumatic experiences were associated with lower HF-HRV during wake and particularly during sleep. Relations were not accounted for by covariates. Among midlife women, trauma exposure was related to lower HF-HRV during wake and sleep. Trauma may have an important impact on vagal influence over the heart, particularly during sleep. Decreased vagal influence over cardiac function may be a key mechanism by which trauma is associated with CVD risk.

Sleep disturbance is common among midlife women. Poor self-reported sleep characteristics have been linked to cerebrovascular disease and dementia risk. However, little work has considered the relation of objectively assessed sleep characteristics and white matter hyperintensities (WMHs), a marker of small vessel disease in the brain. Among 122 midlife women, we tested whether women with short or disrupted sleep would have greater WMH, adjusting for cardiovascular disease (CVD) risk factors, estradiol, and physiologically assessed sleep hot flashes.We recruited 122 women (mean age = 58 years) without a history of stroke or dementia who underwent 72 h of actigraphy to quantify sleep, 24 h of physiologic monitoring to quantify hot flashes; magnetic resonance imaging to assess WMH; phlebotomy, questionnaires, and physical measures (blood pressure, height, and weight). Associations between actigraphy-assessed sleep (wake after sleep onset and total sleep time) and WMH were tested in linear regression models. Covariates included demographics, CVD risk factors (blood pressure, lipids, and diabetes), estradiol, mood, and sleep hot flashes.Greater actigraphy-assessed waking after sleep onset was associated with more WMH [B(SE) = .008 (.002), p = 0.002], adjusting for demographics, CVD risk factors, and sleep hot flashes. Findings persisted adjusting for estradiol and mood. Neither total sleep time nor subjective sleep quality was related to WMH.Greater actigraphy-assessed waking after sleep onset but not subjective sleep was related to greater brain WMH among midlife women. Poor sleep may be associated with brain small vessel disease at midlife, which can increase the risk for brain disorders.