Association of Sleep Duration and Quality with Activation of Two Neuroendocrine Systems: Hypothalamic-Pituitary-Adrenal Axis and Sympathetic Nervous System. The Multi-Ethnic Study of Atherosclerosis (MESA)

Many studies have shown that short sleep duration and/or poor sleep quality is associated with increasing rates of cardiovascular (CVD) mortality and morbidity. One hypothesized explanation for this association has been that sleep loss is a type of chronic stress that induces dysregulation of biological systems that ultimately increase the risk of CVD. One biological system that has been thought to link sleep loss and CVD is the hypothalamus-pituitary-adrenal (HPA) axis. A number of studies using small or convenience samples have addressed the effects of sleep deprivation on cortisol. Only a few studies have examined the association of habitual short sleep duration and/or poor sleep quality with changes in the diurnal cortisol in population based-samples; those studies vary in their methodology and in findings. Another biological system that has been thought to link sleep loss and CVD is the autonomic nervous system (ANS), through overactivation of the sympathetic nervous system (SNS) and/or probably a withdrawal of the parasympathetic nervous system. Experimental studies have shown an association between the sleep stages and markers of the sympathetic system. However, very few studies of habitual sleep duration/sleep quality and ANS markers have been conducted. Even fewer studies have examined the association of habitual sleep duration and/or sleep quality and ANS responses to a stress challenge in a population-based sample. The findings again have been inconsistent probably due to the use of different methodology and different samples. This dissertation used measures of salivary diurnal cortisol as well as cortisol responses to a stress challenge protocol to assess the relationship of habitual sleep duration and/or sleep quality with diurnal cortisol profile in natural conditions and in response to a stress challenge protocol in a laboratory setting. Diurnal cortisol was assessed from up to 16 samples of salivary cortisol for two days. Cortisol responses to a stress challenge were assessed from four salivary samples taken during the stress challenge that was performed in a different day than the diurnal cortisol collection. To examine the relationship of habitual sleep duration and/or sleep quality and markers of the ANS, this dissertation used continuous cardiovascular measures (heart rate and heart rate variability) and four salivary amylase samples obtained during the stress challenge. The stress challenge included mental stress and orthostatic stress. Sleep duration and sleep efficiency (an objective measure of sleep quality) were assessed from 7-day actigraphy and sleep diaries. Insomnia symptoms (a subjective measure of sleep quality) were also assessed using a questionnaire that included the Women’s Health Initiative Insomnia rating scale (WHIIRS). We used mixed models so as to account for the repeated measures of diurnal salivary cortisol levels as well as the responses (reactivity and recovery) to the stress challenge tests. Chapter 1 presents an introduction to this dissertation discussing the relationship between short sleep duration and/or poor sleep quality and CVD morbidity and mortality. Chapter 2 presents a systematic literature review of studies of the association between habitual sleep duration and/or sleep efficiency and markers of neuro-endocrine systems: HPA and ANS. These are plausible mechanisms that link short and/or poor sleep to CVD morbidity and mortality. Chapter 3 presents our analyses of the relationship between short sleep duration and/or poor sleep quality and features of the diurnal cortisol. We hypothesized that those participants whose slept < 6 hours per night or whose sleep efficiency was < 85% would have higher cortisol levels on awakening, flatter cortisol awakening responses (CAR), and higher evening cortisol levels than participants who slept longer or slept better. We found that short sleepers had higher evening cortisol than the longer sleepers and that this association persisted after the adjustment for several known confounders. In chapter 4, we examined how the same groups of participants responded in terms of hormones (cortisol and amylase) and cardiovascular indices (heart rate (HR) and HR variability (HRV)) to a stress challenge test. We hypothesized that those participants who slept for a shorter time or whose sleep was of poorer quality would have more exaggerated responses to and less recovery from a stress challenge test than participants who slept longer or slept better. We found that participants with insomnia had exaggerated high frequency-HRV (HF-HRV) orthostatic reactivity. In an extended analysis, we found that participants who slept less than 7 hours/night had exaggerated heart rate reactivity to a mental stress test compared to participants who slept 7 or more hours/night, but this association was attenuated after adjustment for naps. Paradoxically, we also found that participants who slept less than 7 hours had higher HF-HRV recovery from mental stress compared to longer sleepers (≥7 hours). Short sleep duration or low sleep efficiency was not associated with cortisol or amylase responses to the stress challenge protocol. These findings suggest that sustained high evening cortisol levels and cardiovascular responses to a stress challenge may be among the mechanisms linking short/poor sleep and CV disease

Association of Sleep Duration and Quality With Alterations in the Hypothalamic-Pituitary Adrenocortical Axis: The Multi-Ethnic Study of Atherosclerosis (MESA)

Context: Short sleep duration and poor sleep quality are associated with cardiovascular outcomes. One mechanism proposed to explain this association is altered diurnal cortisol secretion. Objective: The objective of the study was to examine the associations of sleep duration and sleep quality with diurnal salivary cortisol levels. Design: This was a cross-sectional analysis using data from examination 5 (2010–2012) of the Multi-Ethnic Study of Atherosclerosis. Actigraphy-based measures of sleep duration and efficiency were collected over 7 days, and salivary cortisol samples were collected over 2 days from participants aged 54–93 years (n = 600 with analyzable data). Results: Shorter average sleep duration (<6 h/night) was associated with less pronounced late decline in cortisol [2.2% difference in slope; 95% confidence interval (CI) 0.8–3.7; P ≤ .01] and less pronounced wake-to-bed slope (2.2% difference; 95% CI 1.0–3.4; P ≤ .001) compared with longer sleep duration (≥6 h/night). Lower sleep efficiency (<85%) was associated with less pronounced early decline in cortisol (29.0% difference in slope; 95% CI 4.1–59.7; P < .05) compared with higher sleep efficiency (≥85%). Subjects reporting insomnia had a flatter cortisol awakening response (−16.1% difference in slope; 95% CI −34.6 to −0.1; P < .05) compared with those not reporting insomnia. Conclusions: Shorter sleep duration, lower sleep efficiency, and insomnia are associated with alterations in diurnal cortisol levels consistent with changes in hypothalamic-pituitary-adrenal regulation

Association of subclinical atherosclerosis with echocardiographic indices of cardiac remodeling: The Framingham Study

BACKGROUND: It is well established that coronary artery disease progresses along with myocardial disease. However, data on the association between coronary artery calcium (CAC) and echocardiographic variables are lacking. METHODS AND RESULTS: Among 2,650 Framingham Study participants (mean age 51 yrs, 48% women; 40% with CAC \u3e 0), we related CT-based CAC score to left ventricular (LV) mass index (LVMi), LV ejection fraction (LVEF), E/e\u27, global longitudinal strain (GLS), left atrial emptying fraction (LAEF), and aortic root diameter (AoR), using multivariable-adjusted generalized linear models. CAC score (independent variable) was used as log-transformed continuous [ln(CAC+1)] and as a categorical (0, 1-100, and \u3e /=101) variable. Adjusting for standard risk factors, higher CAC score was associated with higher LVMi and AoR (betaLVMI per 1-SD increase 0.012, betaAoR 0.008; P \u3c 0.05, for both). Participants with 1 \u3c /=CAC \u3c /=100 and those with CAC \u3e /=101 had higher AoR (betaAoR 0.013 and 0.020, respectively, P = 0.01) than those with CAC = 0. CAC score was not significantly associated with LVEF, E/e\u27, GLS or LAEF. Age modified the association of CAC score with AoR; higher CAC scores were associated with larger AoR more strongly in older ( \u3e 58 years; betaAoR0.0042;P \u3c 0.007) than in younger ( \u3c /=58 years) participants (betaAoR0.0027;P \u3c 0.03). CONCLUSIONS: We observed that subclinical atherosclerosis was associated with ventricular and aortic remodeling. The prognostic significance of these associations warrants evaluation in additional mechanistic studies

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men