Purpose of Review
In this review, we summarize recent epidemiological data (2014–2019) that examine the association of sleep variability with blood pressure (BP), discuss potential underlying ...mechanisms, and highlight future research directions.
Recent Findings
Higher standard deviations of sleep duration and sleep-onset timing were not related to BP. However, a higher Sleep Regularity Index score was associated with lower odds of hypertension. Studies on social jetlag, a prevalent form of sleep variability, reported null associations. In contrast, lower interdaily stability in circadian rest-activity rhythms, a measure of invariability in sleep-wake cycles between days and synchronization to light and dark cycles, was associated with higher BP and greater hypertension odds, particularly among non-shift workers.
Summary
Sleep variability is consistently associated with risk factors for hypertension. Evidence on sleep variability and BP is limited and varies depending on the measure used to characterize day-to-day variability in sleep. Studies that identify and utilize a standard definition of sleep variability, incorporate a 24-h ambulatory BP monitoring, and ensure coinciding timing of sleep and BP measurements are necessary to disentangle these relationships.
Purpose of Review
Night-to-night variability in sleep patterns leads to circadian disruption and, consequently, could increase cardiometabolic risk. The purpose of this review is to summarize ...findings from studies published between 2015 and 2020 examining various measures of night-to-night variability in sleep in relation to metabolic syndrome (MetS), type 2 diabetes (T2D), and their risk factors. We illustrate a potential causal pathway between irregular sleep patterns and T2D, highlighting knowledge gaps along the way.
Recent Findings
Across different measures of sleep variability, irregular sleep patterns were associated with poorer cardiometabolic outcomes. Higher standard deviations (SD) across nights of sleep duration and onset or midpoint of sleep were associated with increased odds of having MetS and clusters of metabolic abnormalities as well as greater adiposity and poorer glycemic control. Conversely, greater regularity of rest-activity patterns related to lower risk for T2D. Social jetlag was associated with glycemic dysregulation, adiposity, T2D, and MetS. These associations are often observed in both metabolically healthy and unhealthy individuals; both higher SD of sleep duration and social jetlag relate to poorer glucose regulation in individuals with diabetes.
Summary
There is consistent evidence of associations of sleep variability with increased risk for adiposity, glucose dysregulation, T2D, and MetS. Although experimental evidence is needed to determine causation, there is support to recommend stabilizing sleep patterns for cardiometabolic risk prevention.
CONTEXT Systemic hypertension is prevalent among patients with obstructive sleep apnea (OSA). Short-term studies indicate that continuous positive airway pressure (CPAP) therapy reduces blood ...pressure in patients with hypertension and OSA. OBJECTIVE To determine whether CPAP therapy is associated with a lower risk of incident hypertension. DESIGN, SETTING, AND PARTICIPANTS A prospective cohort study of 1889 participants without hypertension who were referred to a sleep center in Zaragoza, Spain, for nocturnal polysomnography between January 1, 1994, and December 31, 2000. Incident hypertension was documented at annual follow-up visits up to January 1, 2011. Multivariable models adjusted for confounding factors, including change in body mass index from baseline to censored time, were used to calculate hazard ratios (HRs) of incident hypertension in participants without OSA (controls), with untreated OSA, and in those treated with CPAP therapy according to national guidelines. MAIN OUTCOME MEASURE Incidence of new-onset hypertension. RESULTS During 21 003 person-years of follow-up (median, 12.2 years), 705 cases (37.3%) of incident hypertension were observed. The crude incidence of hypertension per 100 person-years was 2.19 (95% CI, 1.71-2.67) in controls, 3.34 (95% CI, 2.85-3.82) in patients with OSA ineligible for CPAP therapy, 5.84 (95% CI, 4.82-6.86) in patients with OSA who declined CPAP therapy, 5.12 (95% CI, 3.76-6.47) in patients with OSA nonadherent to CPAP therapy, and 3.06 (95% CI, 2.70-3.41) in patients with OSA and treated with CPAP therapy. Compared with controls, the adjusted HRs for incident hypertension were greater among patients with OSA ineligible for CPAP therapy (1.33; 95% CI, 1.01-1.75), among those who declined CPAP therapy (1.96; 95% CI, 1.44-2.66), and among those nonadherent to CPAP therapy (1.78; 95% CI, 1.23-2.58), whereas the HR was lower in patients with OSA who were treated with CPAP therapy (0.71; 95% CI, 0.53-0.94). CONCLUSION Compared with participants without OSA, the presence of OSA was associated with increased adjusted risk of incident hypertension; however, treatment with CPAP therapy was associated with a lower risk of hypertension.
OBJECTIVE:Patients with psoriasis have impaired vascular health and increased cardiovascular disease (CVD). Platelets are key players in the pathogenesis of vascular dysfunction in cardiovascular ...disease and represent therapeutic targets in cardiovascular prevention. The object of this study was to define the platelet phenotype and effector cell properties on vascular health in psoriasis and evaluate whether aspirin modulates the platelet-induced phenotype.
APPROACH AND RESULTS:Platelets from psoriasis patients (n=45) exhibited increased platelet activation (relative to age- and gender-matched controls, n=18), which correlated with psoriasis skin severity. Isolated platelets from psoriasis patients demonstrated a 2- to 3-fold (P<0.01) increased adhesion to human aortic endothelial cells and induced proinflammatory transcriptional changes, including upregulation of IL 8 (interleukin 8), IL1β, and Cox (cyclooxygenase)-2 Platelet RNA sequencing revealed an interferon signature and elevated expression of COX-1, which correlated with psoriasis disease severity (r=0.83, P=0.01). In a randomized trial of patients with psoriasis, 2 weeks of 81 mg low-dose aspirin, a COX-1 inhibitor, reduced serum thromboxane (Tx) B2 and reduced brachial vein endothelial proinflammatory transcript expression >70% compared with the no-treatment group (P<0.01). Improvement in brachial vein endothelial cell inflammation significantly correlated with change in serum TxB2 (r=0.48, P=0.02).
CONCLUSIONS:In patients with psoriasis, platelets are activated and induce endothelial cell inflammation. Low-dose aspirin improved endothelial cell health in psoriasis via platelet COX-1 inhibition. These data demonstrate a previously unappreciated role of platelets in psoriasis and endothelial cell inflammation and suggests that aspirin may be effective in improving vascular health in patients with psoriasis.
REGISTRATION:URLhttp://www.clinicaltrials.gov. Unique identifierNCT03228017.
Variability in daily sleep patterns is an emerging factor linked to metabolic syndrome. However, whether reducing bedtime variability improves markers of disease risk has not been tested. Here, we ...assessed whether body composition and inflammation were impacted by changes in bedtime variability over a 6-week period, during which, women were instructed to maintain healthy, habitual sleep (HS) patterns (one arm of a randomized trial). Data were available for 37 women (age 34.9 ± 12.4 years, BMI 24.7 ± 2.9 kg/m
, sleep duration 7.58 ± 0.49 h/night). Body composition and leukocyte platelet aggregates (LPA) were measured at baseline and endpoint using magnetic resonance imaging and flow cytometry, respectively. Sleep data were collected daily using wrist actigraphy. Change in bedtime variability was calculated as the difference in the standard deviation (SD) of bedtimes measured during the 2-week screening period and the 6-week intervention period. Results showed that women who reduced their bedtime variability (n = 29) during the intervention had reductions in total (P < 0.001) and subcutaneous adipose tissue (P < 0.001) relative to women who increased/maintained (n = 8) bedtime variability. Similar effects were observed for LPA levels between women who reduced vs increased/maintained bedtime variability (P = 0.011). Thus, reducing bedtime variability, without changing sleep duration, could improve cardiometabolic health by reducing adiposity and inflammation.
Indirect evidence implicates endothelial dysfunction in the pathogenesis of vascular diseases associated with obstructive sleep apnea (OSA). We investigated directly whether dysfunction and ...inflammation occur in vivo in the vascular endothelium of patients with OSA. The effects of continuous positive airway pressure (CPAP) therapy on endothelial function and repair capacity were assessed.
Thirty-two patients with newly diagnosed OSA and 15 control subjects were studied. Proteins that regulate basal endothelial nitric oxide (NO) production (endothelial NO synthase eNOS and phosphorylated eNOS) and inflammation (cyclooxygenase-2 and inducible NOS) and markers of oxidative stress (nitrotyrosine) were quantified by immunofluorescence in freshly harvested venous endothelial cells before and after 4 weeks of CPAP therapy. Vascular reactivity was measured by flow-mediated dilation. Circulating endothelial progenitor cell levels were quantified to assess endothelial repair capacity. Baseline endothelial expression of eNOS and phosphorylated eNOS was reduced by 59% and 94%, respectively, in patients with OSA compared with control subjects. Expression of both nitrotyrosine and cyclooxygenase-2 was 5-fold greater in patients with OSA than in control subjects, whereas inducible NOS expression was 56% greater. Expression of eNOS and phosphorylated eNOS significantly increased, whereas expression of nitrotyrosine, cyclooxygenase-2, and inducible NOS significantly decreased in patients who adhered to CPAP > or = 4 hours daily. Baseline flow-mediated dilation and endothelial progenitor cell levels were lower in patients than in control subjects, and both significantly increased in patients who adhered to CPAP > or = 4 hours daily.
OSA directly affects the vascular endothelium by promoting inflammation and oxidative stress while decreasing NO availability and repair capacity. Effective CPAP therapy is associated with the reversal of these alterations.
Sleep restriction is associated with increased cardiovascular risk, which is more pronounced in female than male persons. We reported recently first causal evidence that mild, prolonged sleep ...restriction mimicking "real-life" conditions impairs endothelial function, a key step in the development and progression of cardiovascular disease, in healthy female persons. However, the underlying mechanisms are unclear. In model organisms, sleep restriction increases oxidative stress and upregulates antioxidant response via induction of the antioxidant regulator nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Here, we assessed directly endothelial cell oxidative stress and antioxidant responses in healthy female persons (n = 35) after 6 weeks of mild sleep restriction (1.5 h less than habitual sleep) using randomized crossover design. Sleep restriction markedly increased endothelial oxidative stress without upregulating antioxidant response. Using RNA-seq and a predicted protein-protein interaction database, we identified reduced expression of endothelial Defective in Cullin Neddylation-1 Domain Containing 3 (DCUN1D3), a protein that licenses Nrf2 antioxidant responses, as a mediator of impaired endothelial antioxidant response in sleep restriction. Thus, sleep restriction impairs clearance of endothelial oxidative stress that over time increases cardiovascular risk.Trial Registration: NCT02835261 .
Unrecognized obstructive sleep apnea (OSA) is highly prevalent in obesity. Both obesity and OSA are associated with vascular endothelial inflammation and increased risk for cardiovascular diseases. ...We investigated directly whether the endothelial alterations that are attributed commonly to obesity are in fact related to OSA.
Seventy-one subjects with a body mass index ranging from normal to obese underwent attended polysomnography. To assess vascular inflammation and oxidative stress directly, we quantified the expression of nuclear factor-kappaB and nitrotyrosine by immunofluorescence in freshly harvested venous endothelial cells. To evaluate basal endothelial nitric oxide (NO) production and activity, we quantified the expression of endothelial NO synthase (eNOS) and phosphorylated eNOS. Vascular reactivity was measured by brachial artery flow-mediated dilation. Expression of eNOS and phosphorylated eNOS and flow-mediated dilation were significantly lower, whereas expression of nitrotyrosine was significantly greater in OSA patients (n=38) than in OSA-free subjects (n=33) regardless of central adiposity. Expression of nuclear factor-kappaB was greater in obese OSA patients than in obese OSA-free subjects (P=0.004). Protein expression and flow-mediated dilation were not significantly affected by increasing body mass index or central obesity in OSA patients and in OSA-free subjects. After 4 weeks of continuous positive airway pressure therapy, flow-mediated dilation and expression of eNOS and phosphorylated eNOS significantly increased whereas expression of nitrotyrosine and nuclear factor-kappaB significantly decreased in OSA patients who adhered to continuous positive airway pressure >/=4 hours daily.
Untreated OSA rather than obesity is a major determinant of vascular endothelial dysfunction, inflammation, and elevated oxidative stress in obese patients.
Diagnostic and Therapeutic Challenges in Patients With Coexistent Chronic Obstructive Pulmonary Disease and Chronic Heart Failure Thierry H. Le Jemtel, Margherita Padeletti, Sanja Jelic Chronic ...obstructive pulmonary disease (COPD) may delay the diagnosis of chronic heart failure (CHF), and promote nonadherence to therapeutic guidelines, especially beta-blockade. Skeletal muscle alterations are strikingly similar in both conditions. Improvement of pulmonary or cardiac function does not translate into improved functional capacity unless skeletal muscle alterations concomitantly regress. Beta-blockade is safe in stable COPD. Beta -blockade should be attempted in all CHF patients with coexistent CHF and COPD.
Insufficient sleep increases blood pressure. However, the effects of milder, highly prevalent but frequently neglected sleep disturbances, including poor sleep quality and insomnia, on vascular ...health in women are unclear. We investigated whether poor sleep patterns are associated with blood pressure and endothelial inflammation in a diverse sample of women.
Women who participated in the ongoing American Heart Association Go Red for Women Strategically Focused Research Network were studied (n=323, 57% minority, mean age=39±17 years, range=20-79 years). Sleep duration, sleep quality, and time to sleep onset were assessed using the Pittsburgh Sleep Quality Index (score ≥5=poor sleep quality). Risk for obstructive sleep apnea was evaluated using the Berlin questionnaire, and insomnia was assessed using the Insomnia Severity Index. In a subset of women who participated in the basic study (n=26), sleep duration was assessed objectively using actigraphy, and endothelial inflammation was assessed directly in harvested endothelial cells by measuring nuclear translocation of nuclear factor kappa B. Vascular reactivity was measured by brachial artery flow-mediated dilation (n=26). Systolic and diastolic blood pressure were measured by trained personnel (n=323). Multivariable linear regressions were used to evaluate associations between sleep patterns and blood pressure, nuclear factor kappa B, and flow-mediated dilation. Mean sleep duration was 6.8±1.3 hours/night in the population study and 7.5±1.1 hour/night in the basic study. In the population study sample, 50% had poor sleep quality versus 23% in the basic study, and 37% had some level of insomnia versus 15% in the basic study. Systolic blood pressure was associated directly with poor sleep quality, and diastolic blood pressure was of borderline significance with obstructive sleep apnea risk after adjusting for confounders (
=0.04 and
=0.08, respectively). Poor sleep quality was associated with endothelial nuclear factor kappa B activation (β=30.6;
=0.03). Insomnia and longer sleep onset latency were also associated with endothelial nuclear factor kappa B activation (β=27.6;
=0.002 and β=8.26;
=0.02, respectively). No evidence was found for an association between sleep and flow-mediated dilation.
These findings provide direct evidence that common but frequently neglected sleep disturbances such as poor sleep quality and insomnia are associated with increased blood pressure and vascular inflammation even in the absence of inadequate sleep duration in women.
URL: https://www.clinicaltrials.gov. Unique identifier: NCT02835261.
PDF
